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Aug 19, 2015 – BMS–919373, from $BMS for atrial fibrillation #ACSBoston MEDI 1st disclosures @bmsnews pic.twitter.com/y3D4Yv2U7M.

BMS 919373

CAS 1272353-82-8

C₂₅ H₂₀ N₆ O₂ S, 468.53

3-Pyridinesulfonamide, 5-[5-phenyl-4-[(2-pyridinylmethyl)amino]-2-quinazolinyl]-

5-[5-phenyl-4-[[(pyridin-2-yl)methyl]amino]quinazolin-2-yl]pyridine-3-sulfonamide

Phase IIParoxysmal atrial fibrillation
Phase IAcute coronary syndromes; Atrial fibrillation
- 01 Oct 2014Phase-I clinical trials in Atrial fibrillation in Canada (PO) (NCT02153437)
- 01 Jul 2014Phase-II clinical trials in Paroxysmal atrial fibrillation in Canada (PO) (NCT02156076)
- 01 Jul 2014Phase-II clinical trials in Paroxysmal atrial fibrillation in USA (PO)
- https://clinicaltrials.gov/ct2/show/NCT02153437
- https://clinicaltrials.gov/ct2/show/NCT02156076
CAS HCL SALT 1272356-77-0

Company	Bristol-Myers Squibb Co.
Description	IKur antagonist
Molecular Target	Potassium channel Kv1.5 (KCNA5)
Mechanism of Action	Potassium channel Kv1.5 (KCNA5) inhibitor
Therapeutic Modality	Small molecule

Latest Stage of Development	Phase I
Standard Indication	Fibrillation
Indication Details	Treat atrial fibrillation

Synthesis

PATENT

WO 2011028741

http://www.google.co.in/patents/WO2011028741A1?cl=en

EXAMPLE 7

5-(5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)pyridine-3-sulfonamide

Step 1. Preparatio -Bromopyridine-3 -sulfonamide

See also U.S. Publication Nos. 2006/217387 and 2006/375834, and J. Org. Chem., 54:389 (1989). A mixture of pyridine-3 -sulfonic acid (10.3 g, 64.8 mmol), phosphorous pentachloride (20.82 g, 100 mmol) and phosphorous oxychloride (10 mL, 109 mmol) was heated to reflux where it stirred for 4h. At the conclusion of this period, the reaction mixture was allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was evaporated to dryness under reduced pressure to yield a residue. The residue was treated with bromine (6.00 mL, 1 16 mmol) and then heated to reflux where it stirred for 14h. After this time, the reaction mixture was cooled to 0 °C and then a saturated solution of NH₄OH in ¾0 (40 mL) was slowly added. The resulting mixture was allowed to warm to room temperature where it stirred for 30 min. The reaction mixture was then filtered and the filter cake was washed with hexane to afford 5 -bromopyridine-3 -sulfonamide (6.0 g) as an off- white solid. The product was used without further purification. LCMS Method Q: retention time 0.75 min; [M+l] = 237.0.

Step 2. Preparation of pyridine-3-sulfonamide-5-ylboronic acid pinacol ester

See also WO2008/150827 Al and WO2008/144463. A mixture of 5- bromopyridine-3 -sulfonamide (1.5 g, 6.33 mmol), bis(pinacolato)diboron (2.41 g, 9.5 mmol) and potassium acetate (1.86 g, 19.0 mmol) in 1,4-dioxane (15 mL) was degassed with nitrogen for 15 min then (l, l’-bis(diphenylphosphino)- ferrocene)palladium (II) chloride dichloromethane complex (232 mg, 0.317 mmol) was added and the resulting mixture was degassed again with nitrogen for 10 min. At the conclusion of this period, the reaction mixture was heated in a microwave at 120 °C for 45 min. After this time, the reaction mixture was filtered through CELITE® and the filtrate was concentrated under reduced pressure to provide pyridine-3- sulfonamide-5-ylboronic acid pinacol ester (740 mg) as a brown solid. The product was used without further purification. ^XH NMR (400 MHz, DMSO-d₆) δ (ppm): 8.83 (s, 1H), 8.80 (s, 1H), 8.26 (s, 1H), 7.56-7.74 (bs, 2H), 1.17 (s, 12H).

Step 3. Example 7

To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4- amine (150 mg, 0.43 mmol) in 1,4-dioxane (6 mL) and ¾0 (1 mL) under nitrogen was added pyridine-3-sulfonamide-5-ylboronic acid pinacol ester (185 mg, 0.65 mmol), and potassium carbonate (119 mg, 0.86 mmol). Upon completion of addition, the mixture was degassed with nitrogen for 15 minutes and then (1, 1′- bis(diphenylphosphino)ferrocene)palladium (II) chloride dichloromethane complex (31 mg, 0.043 mmol) was added. The resulting mixture was again degassed with nitrogen for 10 min. After this time, the mixture was heated to 90 °C where it stirred for 16h. At the conclusion of this period, the reaction mixture was allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was quenched by the addition of water and then transferred to a separation funnel. The aqueous layer was extracted with ethyl acetate. The combined organic portions were washed with water and saturated NaCl, dried over Na₂S0₄, filtered and concentrated under reduced pressure. The resulting concentrate was purified by preparative TLC using 5% methanol in dichloromethane to afford Example 7 (50 mg) as a brown solid. ‘H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.81 (s, 1H), 9.17 (s, 1H), 9.09 (s, 1H), 8.24 (d, J= 4.4 Hz, 1H), 7.94 (d, J=7.2 Hz, 1H), 7.86 (t, J= 7.6 Hz, 1Η),7.75-7.72 (t, J= 7.6 Hz, 3H), 7.59-7.51 (m, 5H), 7.34 (d, J=7.2 Hz, 2H), 7.24 (t, J=6.4 Hz, 1H), 6.98 (t, J= 3.2 Hz, 1H), 4.77 (d, J= 4.0 Hz, 2H). LCMS Method Q: retention time 1.39 min; [M+l] = 469.0. HPLC Method B: purity 98.1%, retention time = 8.74 min. [00120] Alternatively, Example 7 can be synthesized as follows:

Step 1. Preparation of 5-Bromo-pyridine-3-sulfonyl chloride

PC1₅ (2.95 Kg, 14.16 moles) and POCl₃ (2.45 Kg, 15.98 moles) were added into pyridine-3 -sulfonic acid (1.5 Kg, 9.42 mol) in 10 L RB flask equipped with mechanical stirrer under inert atmosphere. The reaction mass was heated to 120- 125°C where it stirred for 18 h. After this time, the reaction progress was monitored by HPLC, which indicated the reaction was complete. Excess POCI3 was removed under vacuum to give a residue. The residue was cooled to ambient temperature and bromine (1.2 Kg, 7.5 moles) was added. Upon completion of addition, the resulting mixture was heated to 120-125°C where it stirred for 5 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated the reaction was complete. The reaction mixture was cooled to ambient temperature and then poured into ice-water (10 L), and the resulting mixture was extracted with DCM (10.5 Lx2). The DCM extracts were combined and the solvent was removed under vacuum to yield crude product (1.8 Kg, 74.4% yield).

Step 2. Preparation of 5-bromo-N-tert-butylpyridine-3 -sulfonamide

Crude 5 -bromopyridine-3-sulfonyl chloride from step 1 above was dissolved in THF (14 L, 8 vol) and then transferred to a 20 L RB flask equipped with mechanical stirrer under inert atmosphere. The solution was cooled to 0-5°C and tert- butyl amine (1.95 Kg, 26.66 moles) was added at 0-5°C. Upon completion of addition, the reaction mixture was warmed to ambient temperature where it stirred for 2 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated that the reaction was complete. The solvent was evaporated under vacuum to give a thick residue. The residue was dissolved in ethyl acetate (18 L, 12 vol). The organic layer was separated, washed with water (9 L, 5 vol) and then concentrated under vacuum to yield a residue. Hexanes (9 L, 5 vol) were added to the residue and the product precipitated out and was collected by filtration to yield a free flowing yellow solid (1.5 Kg, 54.28% overall yield). ¾ NMR (DMSO-D6, 400 MHz, δ ppm); 8.99 (d, J = 2Hz, 1H), 8.81 (d, J= 2 Hz, 1H), 8.29 (t, J= 2Hz, 1H). [M⁺+l] = 293. Step 3. Preparation of 5-bromo-N-tert-butylpyridine-3 -sulfonamide

5 -Bromo-N-tert-butylpyridine-3 -sulfonamide (1.5 Kg, 5.11 moles) was dissolved in dimethylformamide (7.5 L, 5 vol) and the solution was added to a 20 L glass-lined reactor equipped with mechanical stirrer. The solution was degassed with nitrogen for 30 min. After this time, potassium ferrocyanide trihydrate (867 g, 2.05 moles), sodium carbonate (1.08 Kg, 10.189 moles), copper (I) iodide (73.2 g, 0.374 moles) and dichloro-bis (triphenylphosphine) palladium (II) (71.6 g, 0.102 moles) were added. Upon completion of addition, the reaction mixture was heated to 120- 125°C where it stirred for 4 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated the reaction was complete. The reaction mixture was cooled to ambient temperature and then filtered through a celite bed. Water (18 L, 12 vol) was added into the filtrate and the resulting mixture was extracted with ethyl acetate (7.5L*2). The organic layers were combined, washed with water and then concentrated to yield a thick residue. Hexanes (7.5 L, 5 vol) were added to the residue. The product precipitated out and was collected by filtration to yield a free flowing yellow solid (1.0 Kg, 82.8% yield, 89% purity by HPLC). ¾ NMR (DMSO-D6, 400 MHz, δ ppm); 9.21 – 9.24 (d,d J= 7.2Hz, 3.2Hz, 2H), 8.70-8.71(m,lH), 7.98 (s, lH). [M⁺+l] = 239.2.

Step 4. Preparation of 3-aminobiphenyl-2-carbonitrile

2-Amino-6-bromo-benzonitrile (1.0 Kg, 5.07 moles) and toluene (10 L, 10 vol) were added to a 20 L glass-lined reactor equipped with mechanical stirrer under inert atmosphere. Potassium acetate (996 g, 10.16 moles) and phenylboronic acid (866, 7.10 moles) were added into the solution and the solution was degassed with nitrogen for 30 min. After this time, dichloro-bis (triphenylphosphine) palladium (II) (17.8 g, 0.025 moles) was added to the reaction mixture at ambient temperature. The mixture was heated to 110°C, where it stirred for 17 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated the reaction was completed. The reaction mixture was filtered through a celite bed. The filtrate was transferred back to the reactor and concentrated hydrochloric acid (-35%, 2 L, 2 vol) was charged to the reactor at ambient temperature. The HCl salt of the title compound precipitated out from the reaction and was collected by filtration. The HCl salt was transferred into the 20 L reactor and then made basic with 10% NaOH solution (pH 8-9). The resulting product was extracted with ethyl acetate (10 L, 10 vol). The ethyl acetate layer was washed with water (5 L, 5 vol) and then the solvent was evaporated under vacuum to give a residue. Hexanes (5 L, 5 vol) were added to the residue at 35-40°C, and the resulting slurry was cooled to ambient temperature. Once at the prescribed temperature, the product was collected by filtration to provide a pale yellow solid (802 g, 81.4%, 99% by HPLC). ^XH NMR (DMSO-D6, 400 MHz, δ ppm); 7.43-7.52 (m, 5H), 7.33-7.37 (m, 1H), 6.83 (d, J=8Hz, 1H), 6.62 (d, J=8Hz, 1H), 6.1 (s, 2H). ES-MS: [M⁺+l] = 194.23.

Step 5. Preparation of 5-(4-amino-5-phenylquinazolin-2-yl)-N-tert-butylpyridine-3-

3-Aminobiphenyl-2-carbonitrile (1028 g, 5.30 moles), 5-bromo-N-tert- butylpyridine-3 -sulfonamide (1440 g, 5.55 moles) and 1,4-dioxane (10 L, 10 vol) were added to a 20 L glass-lined reactor equipped with mechanical stirrer. Sodium tert-butoxide (1.275 Kg 12.870 moles) was added to the solution portion-wise at 20- 30°C. Upon completion of addition, the reaction mixture was heated to reflux where it stirred for 2 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated the reaction was complete. The reaction mixture was cooled to 30-35°C and then poured into water (40 L, 40 vol). The resulting mixture was extracted with DCM (20 L*2). The DCM layers were combined, washed with water (10 L, 10 vol) and then dried over sodium sulfate. The solvent was evaporated under vacuum to give a residue. Isopropyl alcohol (1.2 L, 1.2 vol) was added to the residue at 40°C. The resulting precipitate slurry was cooled to 10-15°C and then stirred for 2 h. After this time, the precipitate was collected by filtration and dried at 50°C for 16 h to yield the product (1.9 Kg, 82.9% yield, 99% purity by HPLC). Ή NMR (DMSO-D6, 400 MHz, δ ppm); 9.72 (s, 1H), 9.11 (s, 2H), 7.83-7.94 (m, 4H), 7.49-7.60 (m, 5H), 7.31 (d,d /=6.8Hz,1.2Hz, 1H). ES-MS: [M⁺+l] = 433.53.

Step 6. Preparation of N-tert-butyl-5-(5-phenyl-4-(pyridin-2-ylmethylamino) quinazolin-2-yl) pyridine-3 -sulfonamide

2-(Chloromethyl) pyridine hydrochloride (564 g, 3.44 moles) and dimethyl acetamide (7L, 7 vol) were added to a 20 L RB flask- 1 equipped with mechanical stirrer under inert atmosphere. The resulting solution was cooled to 0- 5°C and triethylamine (346.3, 3.44 moles) was added at 0-5°C. 5-(4-Amino-5- phenylquinazolin-2-yl)-N-tert-butylpyridine-3-sulfonamide (1.0 Kg. 2.306 moles) and dimethylacetamide (4 L, 4 vol) were added to a separate 20 L RB flask-2 equipped with mechanical stirrer under inert atmosphere. This solution was cooled to 0-5°C and sodium tert-butoxide (884 g, 9.24 moles) was added at 0-5°C. The resulting solution was stirred to affect dissolution and then transferred to the RB flask- 1 at 0- 5°C. Upon completion of addition, the reaction mixture was stirred at 0-5°C for 2 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated that the reaction was complete. The reaction mass was poured into water (60 L, 60 vol) with stirring. The crude product was collected by filtration and dried at 60°C for 12 h. After this time, the dried material was dissolved in THF (20 L, 20 vol). Upon dissolution, 6M HC1 in isopropyl alcohol (1 L, 1 vol) was added at 20-25°C. The crude HCL salt of the product was obtained a pale-yellow free flow solid (920 g, 71% yield, 93% purity by HPLC). The crude HC1 salt (1.345 Kg, 2.56moles), methanol (6.7 L, 5 vol) and dichloromethane (13.5 L, 10 vol) were added to a 20 L glass-lined reactor equipped with mechanical stirrer. The slurry was stirred for 20-30 min at 30°C. After this time, the solvent was distilled to 4 vol with respect to input under vacuum. The resulting slurry was cooled to 20-25°C, where stirred for 2 h. At the conclusion of this period, the slurry was filtered and dried at 50°C for 6 h to yield the product (1.1 Kg, 82% yield, 98% purity by HPLC). ^XH NMR (DMSO- D6, 400 MHz, δ ppm); 9.72 (s, 1H), 9.10-9.14 (m, 2H), 8.39 (s, 1H), 7.92-8.03 (m, 4H), 7.56-7.58 (m, 5H), 7.43-7.49 (m, 3H), 7.1 (bs, 1H), 4.88 (s, 2H), 1.17 (2, 9H).

Step 7. Example 7

N-tert-butyl-5-(5-phenyl-4-(pyridin-2-ylmethylamino) quinazolin-2-yl) pyridine-3 -sulfonamide (1.0 Kg, 1.9 moles) and concentrated hydrochloric acid (7 L, 7 vol) were added to a 20 L glass-lined reactor equipped with mechanical stirrer. The reaction mixture was heated to 90-100°C where it stirred for 1 h. At the conclusion of this period, the reaction progress was monitored by HPLC, which indicated the reaction was complete. The reaction mixture was cooled to 5-10°C and the pH was adjusted to 1.7 to 2.0 using 12% aqueous sodium hydroxide solution. Once at the prescribed pH, the crude HC1 salt of the product was collected by filtration. The HC1 salt filter cake and ethanol (5 L, 5 vol) were added to 10 L glass-lined reactor equipped with a mechanical stirrer. The resulting mixture was made basic to pH 7-8 at 20-25°C using triethyl amine (2.25 Kg, 22.23 moles). Once at the prescribed pH, the basic mixture was stirred for 2 h. After this time, the free base of product was filtered and washed with water (10 L, 10 vol) followed by ethanol (2L, 2 vol). The resulting product was dried at 50-55°C for 8 h to yield Example 7 (644 g, 72% yield, 99.9% purity by HPLC).

^XH NMR (DMSO-D6, 400 MHz, δ ppm); 9.81 (d, J=2.0Hz, 1H), 9.18 (t, J=2Hz, 1H), 9.1 1 (d, J=2Hz, 1H), 8.23 (d, J=4.4Hz, 1H), 7.92-7.94 (m, 1H), 7.83-7.87 (m, 1H), 7.78 (s, 2H), 7.70-7.72 (m, 1H), 7.50-7.59 (m, 5H), 7.31-7.34 (m, 2H), 7.22-7.25 (m, 1H), 6.95 (t, J=4Hz, 1H), 4.76 (d, J=4Hz, 2H). ES-MS: [M⁺+l] = 469.

/////////atrial fibrillation, Potassium channel Kv1.5 (KCNA5) inhibitor, IKur antagonist, Bristol-Myers Squibb Co., BMS 919373, BMS-919373, PHASE 2

NS(=O)(=O)c1cc(cnc1)c4nc2cccc(c2c(NCc3ccccn3)n4)c5ccccc5

DS-1040, Activated thrombin activatable fibrinolysis (TAFIa) inhibitor

April 1, 2016 10:23 am / Leave a comment

DS-1040

Daiichi Sankyo Co Ltd

Ischemic stroke

(2S)-5-amino-2-[[1-(4-methylcyclohexyl)imidazol-4-yl]methyl]pentanoic acid

1H-Imidazole-4-propanoic acid, α-(3-aminopropyl)-1-(trans-4-methylcyclohexyl)-, (αS)-

(2S)-5-amino-2-{[1-(trans-4-methylcyclohexyl)-1H-imidazol-4-yl]methyl}pentanoic acid

free form cas 1335138-62-9

1:1 TOSYLATE 1335138-89-0

1335138-90-3 1:1:1 TOSYLATE HYDRATE

phase 2, Ischemic stroke

Molecular Formula:	C₁₆H₂₇N₃O₂
Molecular Weight:	293.40448 g/mol

TAFIa inhibitors, useful for treating myocardial infarction, angina, pulmonary hypertension and deep vein thrombosis.

In March 2016, DS-1040 was reported to be in phase 2 C clinical development, and the study was expected to complete in June 2017.

https://clinicaltrials.gov/ct2/show/NCT02560688

01 Feb 2016Daiichi Sankyo initiates a phase I trial in Healthy volunteers in United Kingdom (NCT02647307)
09 Jan 2016Daiichi Sankyo plans a phase I trial in Healthy volunteers in United Kingdom (NCT02647307)
29 Sep 2015Daiichi Sankyo plans a drug-interaction phase I trial in Healthy volunteers in United Kingdom (IV) (NCT02560688)

SYNTHESIS

COMPLETE SYNTHESIS

Patent

WO201111506

PATENT

WO2013039202

PATENT

WO 2016043254

PATENT

WO2016043253

COMPLETE SYN……….

WO2016043253

The optical purity of the obtained compound was measured by the following HPLC analysis conditions.
(2S) -5 – [(tert- butoxycarbonyl) amino] -2 – {[1- (trans -4- methylcyclohexyl)-lH-imidazol-4-yl] methyl} valeric acid (S)-2-amino 1-propanol salt (A1 step, A2 step, A3 step), (2S) -5 – [ (tert- butoxycarbonyl) amino] -2 – {[1- (trans -4- methylcyclohexyl)-lH-imidazole 4-yl] methyl} optical purity measurement conditions valerate (A4 step):
column: CHIRAL AGP 4.6mmI. D. × 250mm (5μm),
mobile phase: methanol / 10mM phosphate buffer solution (pH7.0) = 95/5,
temperature: 40 ℃,
flow rate: 0.5mL / min,
detection method: UV at 220nm,
retention time: R body: 5.9 minutes, S body: 7.3 minutes.

(2S)-5-amino-2 – Optical purity measurement conditions {[1- (trans-4- methylcyclohexyl)-lH-imidazol-4-yl] methyl} valerate p- toluenesulfonate (A5 Step) :
column: CHIRLCEL OZ-H 4.6mmI. D. × 250mm (5μm),
mobile phase: hexane / ethanol / methanol / isopropanol / trifluoroacetic acid / triethylamine = 860/100/20/2/2
temperature: 30 ℃
flow rate: 1.0mL / min
detection method: UV at 220nm
retention time: R body: 16.1 minutes, S body: 13.0 minutes 　(example 　1) (1-1) 5 – [(Tert- butoxycarbonyl) amino] -2-methoxy-carbonyl) valeric acid morpholine salt

[Of 11]

　In methanol (400mL) solution of di -tert- butyl (100.0g) and 3-chloro-propylamine hydrochloride (71.5g), was added dropwise triethylamine (51.0g) at 0 ℃, at the same temperature It was stirred for 16 hours. To the reaction solution was added toluene (400 mL) and water (400 mL), then were separated, and the organic layer was washed with water. Toluene 400mL was added to the organic layer, was concentrated under reduced pressure to 300 mL, N, N-dimethylacetamide (210 mL) was added and concentrated in vacuo to 300 mL. Potassium carbonate solution (126.66g), tetrabutylammonium bromide (44.32g), was added dimethyl malonate (90.82g) and N, N-dimethylacetamide (100 mL), stirred for 20 hours at 55 ° C. did. Toluene (400 mL) and water (700 mL) was added to the reaction mixture, after separation, The organic layer was washed with water, with 1M aqueous sodium hydroxide and water, and concentrated under reduced pressure to 150 mL. This solution methanol (1870mL) and 1M sodium hydroxide solution (430.8mL) in addition to, and the mixture was stirred for 27.5 hours at 0 ℃. Concentrated hydrochloric acid to the reaction solution (2.5 mL) was added, the pH was adjusted to 7-9, and concentrated in vacuo to 375 mL. After addition of ethyl acetate (500mL) to the reaction solution, concentrated hydrochloric acid (35.1mL) was added, the pH was adjusted to 2.2-2.5, and the layers were separated. The aqueous layer was extracted with ethyl acetate (500 mL), after mixing the organic layer under reduced pressure, and prepared by dehydration condensation of ethyl acetate (250 mL) solution. The resulting solution of ethyl acetate (500 mL) and morpholine (37.5 g) was added to and stirred overnight. The precipitated crystals were filtered, washed with ethyl acetate, and dried under reduced pressure, to give the title compound (136.1g, 81.9% yield).

¹ H-NMR _{(DMSO-d- . 6} ) [delta]: 6.79 (1H, t, J = 5.5 Hz), 3.61 (4H, t, J = 4.9 Hz), 3.58 The (3H, s) , 3.14 (1H, t, J = 7.8Hz), 2.90-2.80 (6H, m), 1.74-1.59 (2H, m), 1.37 (9H, s) , 1.34-1.25 (2H, m).

(1-2) [1- (trans-4- methylcyclohexyl) -1H- imidazole-4-yl] methanol

[Of 12]

　N, and stirred for 4 h methanol (56 mL) solution at 5 ~ 10 ℃ of N- dimethylformamide dimethyl acetal (77.4 g) and ethyl isocyanoacetate (70.0g).The reaction solution was cooled to 0 ℃, water (5.3mL) and trans-4- methylcyclohexyl amine (105.1g) was added, and the mixture was stirred for 24 hours at 60 ~ 65 ℃. The reaction was cooled to room temperature, toluene (420 mL), supplemented with 10% brine (280 mL) and concentrated hydrochloric acid (68 mL), After separation, the organic layer was washed with 10% brine (140 mL). Organic layer to 10% sodium chloride solution (280mL) and concentrated hydrochloric acid were added for liquid separation after (78.4g), was added to separate liquid further 10% saline solution into the organic layer (210mL) and concentrated hydrochloric acid (31.3g). After dissolving sodium chloride (70.0 g) in aqueous layer, adding toluene (420 mL) and 50% aqueous sodium hydroxide (85 mL), after separation, toluene (350 mL) the organic layer was added, under reduced pressure, dehydration concentrated was prepared in toluene (420 mL) solution was. The solution was cooled to 0 ℃, dropped the hydrogenated bis (2-methoxyethoxy) aluminum sodium (70% toluene solution) (207.4g), and the mixture was stirred at room temperature for 1 hour. The reaction was cooled to 0 ° C., was added dropwise 12.5% aqueous sodium hydroxide solution (700 mL), stirred for 1 hour at room temperature. After the solution was separated and the organic layer was washed successively with 12.5% aqueous solution of sodium hydroxide (700mL) and 20% sodium chloride solution (140mL), toluene in the organic layer (140mL), 1- butanol (14mL), water ( 280mL) and was added to aliquots of concentrated hydrochloric acid (48mL). It was further added to liquid separation with water (140 mL) and concentrated hydrochloric acid (2 mL) to the organic layer. Met The aqueous layer was stirred in for 1 hour activated carbon (10.5 g), activated charcoal was filtered off, the activated carbon was washed with water (210 mL). Matches the filtrate and washings, sodium chloride (140 g), toluene was added (980 mL) and 50% aqueous sodium hydroxide (42 mL), After separation, under reduced pressure and the organic layer was dried concentrated toluene (210 mL) It was prepared in solution. The solution was stirred 30 minutes at 50-55 ° C., cooled to room temperature, it was added dropwise heptane (560 mL), and stirred at the same temperature for 3 hours. The precipitated crystals were filtered to give after washing with toluene / heptane (1/4) mixture solution, the title compound was dried under reduced pressure (77.2 g, 64.2% yield).

　¹ H-NMR (CDCl ₃ ) [delta]: 7.49 (1H, s), 6.91 (1H, s), 4.58 (2H, s), 3.83 (1H, tt, J = 12.0 , 3.9Hz), 2.10-2.07 (2H, m), 1.87-1.84 (2H, m), 1.70-1.61 (2H, m), 1.48-1 .42 (1H, m), 1.15-1.06 (2H, m), 0.95 (3H, d, J = 6.5Hz).

(1-3) (2E) -5 – [(tert- butoxycarbonyl) amino] -2 – {[1-trans-4- methylcyclohexyl]-lH-imidazol-4-yl} methylidene} methyl valerate

[Of 13]

　(1-2) The compound obtained in (50.0 g) in toluene (350 mL) and acetic acid (150 mL) was dissolved in a mixed solution, 2,2,6,6-tetramethylpiperidine -N- oxyl at 30 ° C. It was added (966mg) and ortho-periodic acid (16.9g), and the mixture was stirred for 1 hour at 30-35 ℃. The reaction mixture was added 10% aqueous sodium bisulfite solution (150 mL), after stirring for 30 minutes at room temperature, toluene was added (400 mL), and concentrated in vacuo to 300 mL. The solution further by the addition of toluene (400 mL), after concentration under reduced pressure again to 300 mL, was added toluene (500 mL), water (200 mL) and 50% aqueous sodium hydroxide (118 mL). Were separated, the organic layer was washed with 20% brine (150 mL), addition of toluene (200 mL), under reduced pressure and dehydrated concentrated prepared in toluene (400 mL) solution. The compound obtained in the solution (1-1) (116.5g), N, N- dimethylformamide (175 mL) and acetic acid (4.2 mL) was added, under reduced pressure, and dried for 8 hours under reflux. The reaction was cooled to room temperature, adding toluene (400 mL), washed once with 3 times with 5% aqueous sodium bicarbonate solution (400 mL) and 10% brine (250 mL), under reduced pressure and the organic layer was dried concentrated toluene It was prepared (900 mL) solution. This solution was added activated charcoal (15 g) at 35 ~ 40 ° C., after stirring for 30 minutes at the same temperature, filtered and the activated carbon was washed with toluene. Meet the filtrate and washings, after which was concentrated under reduced pressure until 250mL, it was added dropwise heptane (500mL) at room temperature. After stirring for 1.5 hours at the same temperature, then cooled to 0 ℃, and the mixture was stirred for 1 hour. The precipitated crystals were filtered to give after washing with toluene / heptane (1/2) mixture solution, the title compound was dried under reduced pressure (85.0 g, 81.5% yield).

　¹ H-NMR (CDCl ₃ ) [delta]: 7.59 (1H, s), 7.47 (1H, s), 7.15 (1H, s), 7.08 (1H, brs), 3.92- 3.87 (1H, m), 3.78 (3H, s), 3.16-3.12 (2H, m), 2.96 (2H, t, J = 7.5Hz), 2.14- 2.11 (2H, m), 1.90-1.87 (2H, m), 1.77-1.65 (5H, m), 1.47 (9H, s), 1.17-1. 10 (2H, m), 0.96 (3H, d, J = 6.5Hz).

　(1-4) (2S) -5 – [(tert- butoxycarbonyl) amino] -2 – {[1- (trans-4- methylcyclohexyl)-lH-imidazol-4-yl] methyl} valerate (S ) -2-amino-1-propanol salt (A1 process, A2 process, A3 process)

[Of 14]

　The compound obtained in (1-3) (40.0g), (R) -2,2′- bis (di-3,5-xylyl) -1,1′-binaphthyl (507.4Mg) and dichloro (p- cymene) ruthenium (II) (dimer) and (211.4mg), were dissolved in degassed 2,2,2 trifluoroethanol (400 mL), hydrogen under pressure (400-450kPa) , and the mixture was stirred for 24 hours at 60 ℃. The reaction was cooled to room temperature, after nitrogen substitution, and then concentrated under reduced pressure to 60 mL.Tetrahydrofuran (200 mL) was added, was concentrated under reduced pressure to 120 mL, of tetrahydrofuran was added (200 mL).

　To the resulting solution was added water (160mL), cooled to 0 ℃, was added a 50% aqueous solution of sodium hydroxide (24.0mL). After stirring the reaction mixture at room temperature for 26 hours, and the addition of 50% sodium hydroxide solution (8.00mL), and the mixture was stirred for a further 4 hours. The reaction mixture under ice-cooling was added dropwise concentrated hydrochloric acid (28 mL), activated carbon was added (2.0 g) was stirred at room temperature for 10 minutes. The active carbon was filtered off, washed with tetrahydrofuran / water (2/1) mixed solvent (180 mL), sodium chloride (40 g) was separated by adding and re-extract the aqueous layer with tetrahydrofuran (400 mL). The organic layer was matched, and concentrated in vacuo to 200 mL. After addition of toluene (400 mL) to this solution, under reduced pressure and dehydrated concentrated prepared in toluene (200 mL) solution.

　After adding tetrahydrofuran (400 mL) to the resulting solution was added (S) -2- amino-1-propanol (8.2 g) at room temperature and stirred for 3 hours. The solution was cooled to 0 ℃, and was filtered after stirring for 1.5 hours, it was precipitated crystals. The crystals were washed with tetrahydrofuran and dried under reduced pressure to give the title compound (45.4g, 98.2% yield, optical purity: ee 97.5%) was obtained.

　¹ H-NMR _(CD 3 OD) [delta]: 7.57 (1H, s), 6.94 (1H, s), 3.98-3.85 (1H, yd), 3.69-3.64 ( 1H, m), 3.47-3.42 (1H , m), 3.29-3.23 (1H, m), 3.01 (2H, t, J = 6.5Hz), 2.84 ( 1H, dd, J = 14.6,8.4Hz) , 2.55 (1H, dd, J = 14.6,6.2Hz), 2.52-2.45 (1H, m), 2.03 (2H, d, J = 12.7Hz ), 1.83 (2H, d, J = 13.3Hz), 1.71 (2H, q, J = 12.5Hz), 1.60-1.44 ( 5H, m), 1.41 (9H , s), 1.23-1.20 (3H, m), 1.18-1.09 (2H, m), 0.94 (3H, d, J = 6.8Hz).

　(1-5) (2S) -5 – [(tert- butoxycarbonyl) amino] -2 – {[1- (trans-4- methylcyclohexyl)-lH-imidazol-4-yl] methyl} valerate (A4 process)

[Of 15]

　(1-4) The compound obtained in (40.0 g) in tetrahydrofuran (400 mL) and dissolved in a mixed solvent of water (160 mL), concentrated hydrochloric acid (7.3 mL) and added separation of sodium chloride (40 g) and washed 3 times with the organic layer 20% (w / w) brine (160 mL). The organic layer under reduced pressure, dehydrated concentrated prepared in toluene (320 mL) solution was dissolved after addition of tetrahydrofuran (80 mL) was warmed precipitated 83 ° C. crystal. After stirring overnight and cooled to room temperature, and stirred for a further 3 hours at 0 ℃, and filtered the precipitated crystals. After washing the crystals with toluene / tetrahydrofuran (4/1) mixed solution, and dried under reduced pressure to give the title compound (30.9g, 92.1% yield, optical purity: 97.4% ee) was obtained.

　¹ H-NMR (CDCl ₃ ) [delta]: 7.59 (1H, s), 6.73 (1H, s), 4.67 (1H, brs), 3.85-3.80 (1H, yd), 3.12-3.08 (2H, m), 2.88 (1H, dd, J = 15.2,8.8Hz), 2.79 (1H, dd, J = 15.2,3.6Hz) , 2.70-2.64 (1H, m), 2.13-2.06 (2H, m), 1.90-1.82 (2H, m), 1.79-1.52 (5H, m), 1.49-1.44 (2H, m ), 1.43 (9H, s), 1.15-1.05 (2H, m), 0.95 (3H, d, J = 6. 5Hz).

　(1-6) (2S) -5- amino -2 – {[1- (trans-4- methylcyclohexyl)-lH-imidazol-4-yl] methyl} valerate p- toluenesulfonate (A5 Step)

[Of 16]

　In tetrahydrofuran (100 mL), was dissolved the compound obtained in (1-5) (25.0 g) and p- toluenesulfonic acid monohydrate (13.3 g), activated charcoal (1 to this solution. 25 g) was added and stirred for 1 hour at 20 ~ 30 ℃. The charcoal was filtered and washed with tetrahydrofuran (50 mL).It matches the filtrate and washings, p- toluenesulfonic acid monohydrate (13.3 g) and water (7.5 mL) and the mixture was heated under reflux for 6 hours. The reaction was cooled to room temperature, it was added triethylamine (7.7 g), at room temperature and stirred overnight. To the reaction solution was added dropwise tetrahydrofuran (350 mL), after stirring for 3 hours at room temperature and filtered the precipitated crystal. After washing with tetrahydrofuran / water (50/1) mixed solution, and dried under reduced pressure to give the title compound (27.7g, 93.5% yield, optical purity: 98.4% ee) was obtained.

　¹ H-NMR _(CD 3 OD) [delta]: 8.18 (1H, s), 7.70 (2H, d-, J = 8.1 Hz), 7.22 (2H, d-, J = 7.5 Hz), 7.16 (1H, s), 4.06 (1H, tt, J = 12.0,3.9Hz), 2.94-2.86 (3H, m), 2.69 (1H, dd, J = 14.6,5.8Hz), 2.62-2.59 (1H, m), 2.36 (3H, s), 2.08-2.05 (2H, m), 1.86-1 .83 (2H, m), 1.76-1.46 (7H, m), 1.18-1.11 (2H, m), 0.94 (3H, d, J = 6.5Hz).

　(Example
2) (2-1) (2S) -5 – [(tert-butoxycarbonyl) amino] -2 – {[1- (trans -4- methylcyclohexyl)-lH-imidazol-4-yl] methyl } methyl valerate

[Of 17]

　It was asymmetrically reduced using a number of catalysts. The reaction conversion and the optical purity of the obtained title compound was determined by the following HPLC analysis conditions.

　Reaction conversion rate measurement:
Column: Waters XBridge C18 4.6mmI. D. × 150mm (3.5μm),
mobile phase: (A) 10mM aqueous ammonium acetate solution, (B)
acetonitrile, Gradient conditions: B: conc. ; 20% (0-5 minutes), 20-90% (5-20 minutes), 90% (20-24 minutes),
temperature: 40 ℃,
flow rate: 1.0mL / min,
detection method: UV at 215nm
retention time: raw material: 21.1 minutes, the product: 19.1 minutes,
(peak area of peak area + product of raw materials) peak area / of the reaction conversion rate = product.

　Optical purity measurement conditions:
column: CHIRALPAK IA 4.6mmI. D. × 250mm (5μm),
mobile phase: ethanol / hexane = 20/80
Temperature: 35 ℃,
flow rate: 1.0mL / min,
detection method: UV at 210nm,
retention time: R body: 6.8 minutes, S body: 7.8 minutes.

PATENT

Daiichi Sankyo Company,Limited, 第一三共株式会社

WO2011115064…..

http://www.google.co.in/patents/WO2011115064A1?cl=en

[Reference Example 1] 5 – [(tert- butoxycarbonyl) amino] -2- (diethoxyphosphoryl) valeric acid tert- butyl

Diethylphosphonoacetate tert- butyl (20.0g) was dissolved in tetrahydrofuran (500mL), sodium hydride (63%, 3.32g) was added at 0 ℃, 15 min at 0 ℃, and stirred for 1 hour at room temperature . (3-bromopropyl) tetrahydrofuran carbamic acid tert- butyl (20.0g) (20mL) was slowly at room temperature, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to give the solvent was distilled off under reduced pressure the crude product. This silica gel column chromatography and purified (eluent hexane / ethyl acetate = 1/1-ethyl acetate) to give the title compound (26.6g).
¹ H-NMR (CDCl ₃₎ ^δ: 1.31-1.36 (6H, m), 1.44 (9H, m), 1.48 (9H, m), 1.51-1.59 (2H, m), 1.78-2.00 (2H, m) , 2.83 (1H, ddd, J = 22.9, 10.7, 4.4 Hz), 3.06-3.18 (2H, m), 4.10-4.18 (4H, m), 4.58 (1H, br).

[Reference Example 2] 5 – [(tert- butoxycarbonyl) amino] -2- (1H- imidazol-4-ylmethyl) valeric acid tert- butyl

In acetonitrile (100mL) solution of the compound obtained in Reference Example 1 (8.35g), at room temperature 1,8-diazabicyclo [5.4.0] undec-7-ene (4.58mL) and lithium chloride (1 .30g) and we were added. The suspension was added with 1-trityl–1H- imidazole-4-carbaldehyde (6.90g) was stirred at room temperature overnight, under vacuum, and the solvent was evaporated. After the solution separated by adding ethyl acetate and 10% citric acid aqueous solution, an organic layer, saturated brine, and then washed with a saturated aqueous sodium bicarbonate solution and brine. Dried over anhydrous sodium sulfate, (2E) -5 – [(tert- butoxycarbonyl) amino] -2 – [(1-trityl–1H- imidazol-4-yl) methylene] valeric acid tert- butyl and (2Z) -5 – obtain [(1-trityl–1H- imidazol-4-yl) methylene] valeric acid tert- butyl mixture (11.3g) – [(tert- butoxycarbonyl) amino] -2. The mixture was suspended in methanol (500mL), 10% palladium-carbon catalyst (water content, 4g) was added and stirred for 3 days at room temperature under hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Silica gel chromatography gave (eluting solvent: methylene chloride / methanol = 9/1) the title compound (5.60g).
¹ H-NMR (CDCl ₃₎ ^δ: 1.41 (9H, s), 1.44 (9H, s), 1.48-1.57 (3H, m), 1.57-1.66 (1H, m), 2.58-2.68 (1H, m) , 2.73 (1H, dd, J = 14.7, 5.3 Hz), 2.89 (1H, dd, J = 14.7, 8.4 Hz), 3.02-3.19 (2H, m), 4.67 (1H, br s), 6.79 (1H, s), 7.54 (1H, s).

[Reference Example 3] 5 – [(tert- butoxycarbonyl) amino] -2- (methoxycarbonyl) valeric acid

Sodium methoxide in dimethyl malonate (102mL) – methanol (28%, 90.4mL) was added at room temperature and stirred at 60 ℃ 30 minutes. After cooling the white suspension solution to room temperature, (3-bromopropyl) was added carbamic acid tert- butyl (106g) in one portion and stirred at room temperature for 12 hours. Water was added to the reaction solution and the organics extracted with diethyl ether. The organic layer was successively washed with 1 N sodium hydroxide aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered and the solvent was distilled off under reduced pressure {3 – [(tert- butoxycarbonyl) amino] propyl} malonic I got acid dimethyl of crude product. The resulting ester (94g) was dissolved in methanol (100mL), water lithium hydroxide monohydrate (13.6g) (300mL) – was added to methanol (300mL) solution at 0 ℃, 15 h stirring at room temperature It was. The methanol was distilled off under reduced pressure and the organics were extracted with ethyl acetate. 2N hydrochloric acid (160mL) was added to the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to give the solvent was distilled off under reduced pressure the crude product. This silica gel column chromatography: – is purified (eluent methylene chloride methylene chloride / methanol = 10/1) to give the title compound (69.1g).
¹ H-NMR (CDCl ₃₎ ^δ: 1.44 (9H, m), 1.50-1.60 (2H, m), 1.86-2.01 (2H, m), 3.07-3.20 (2H, m), 3.43 (1H, m) , 3.77 (3H, s), 4.64 (1H, br).

[Reference Example 4] 1- (trans-4- methylcyclohexyl) -1H- imidazole-4-carbaldehyde [Step 1] 1- (trans-4- methylcyclohexyl) -1H- imidazole-4-carboxylic acid ethyl

Was dissolved in 3- (dimethylamino) -2-isocyanoethyl ethyl acrylic acid (Liebigs Annalen der Chemie, 1979 years 1444 pages) (1.52g) and the trans-4- methyl cyclohexylamine (3.07g), 70 ℃ in it was stirred for 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, the organic matter was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered to give the solvent was distilled off under reduced pressure the crude product. This silica gel column chromatography and purified (eluent hexane / ethyl acetate = 2 / 1-1 / 2) to give the title compound (1.90g).
¹ H-NMR (CDCl ₃₎ ^δ: 0.96 (3H, d, J = 6.6 Hz), 1.13 (2H, m), 1.39 (3H, d, J = 7.0 Hz), 1.47 (1H, m), 1.68 ( 2H, m), 1.88 (2H, m), 2.12 (2H, m), 3.91 (1H, tt, J = 12.1, 3.9 Hz), 4.36 (2H, q, J = 7.0 Hz), 7.54 (1H, s ), 7.66 (1H, s).

[Step 2] [1- (trans-4- methylcyclohexyl) -1H- imidazole-4-yl] methanol

Lithium aluminum hydride (92%, 0.31g) it was suspended in tetrahydrofuran (6mL). The compound obtained in Step 1 of this reference example (1.50g) was dissolved in tetrahydrofuran (6mL), it was slowly added dropwise to the suspension at 0 ℃.0 After stirring for 30 min at ℃, the reaction solution was diluted with diethyl ether, it was added a saturated aqueous solution of sodium sulfate. After stirring for 1 hour at room temperature, the resulting inorganic salt was removed by filtration through Celite. The filtrate to give the crude product was concentrated under reduced pressure. Mixed solvent of this from hexane and ethyl acetate: water (5 1), to give the title compound (1.09g).
¹ H-NMR (CDCl ₃₎ ^δ: 0.95 (3H, d, J = 6.6 Hz), 1.04-1.17 (2H, m), 1.44 (1H, m), 1.59-1.73 (2H, m), 1.81-1.89 (2H, m), 2.04-2.13 (2H, m), 2.78 (1H, br), 3.84 (1H, tt, J = 12.1, 3.9 Hz), 4.59 (2H, s), 6.91 (1H, s), 7.49 (1H, s).

[Step 3] 1- (trans-4- methylcyclohexyl) -1H- imidazole-4-carbaldehyde

The compound obtained in Step 2 of this reference example (1.04g) was dissolved in toluene (10mL). Aqueous solution of sodium hydrogen carbonate (1.35g) (5mL), iodine (2.72g) and 2,2,6,6-tetramethyl-1-sequential piperidinyloxy (84mg) was added and stirred for 2 hours at room temperature It was. The reaction solution was added saturated aqueous sodium thiosulfate solution and the organics were extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered to give the solvent was distilled off under reduced pressure the crude product. This silica gel column chromatography and purified (eluent hexane / ethyl acetate = 1 / 1-1 / 2) to give the title compound (0.900g).
¹ H-NMR (CDCl ₃₎ ^δ: 0.97 (3H, d, J = 6.8 Hz), 1.09-1.19 (2H, m), 1.48 (1H, m), 1.65-1.75 (2H, m), 1.87-1.93 (2H, m), 2.11-2.18 (2H, m), 3.95 (1H, tt, J = 12.2, 3.9 Hz), 7.62 (1H, s), 7.68 (1H, s), 9.87 (1H, s).

[Example 15] (2R) -5- amino -2 – {[1- (trans-4- methylcyclohexyl) -1H- imidazole-4-yl] methyl} valeric acid and (2S) -5- amino-2 – {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} valeric acid [Step 1] 5 – [(tert- butoxycarbonyl) amino] -2 – {[1- (trans 4-methylcyclohexyl) -1H- imidazole-4-yl] methyl} methyl valerate

The compound obtained in Reference Example 4 (300mg) and the compound obtained in Reference Example 3 (860mg) was suspended in cyclohexane (10mL). Piperidine (0.154mL) and cyclohexane propionic acid (0.116mL) and (10mL) solution was added, and the mixture was heated under reflux for 48 hours. After cooling, aqueous potassium carbonate solution was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained crude product was dissolved in ethanol (12mL), 10% palladium-carbon catalyst (water, 250mg) was added and atmospheric pressure hydrogen atmosphere at room temperature for 4 hours and stirred at 60 ℃ 2.5 hours. After Celite filtration, to give the crude product and the filtrate was concentrated under reduced pressure. This silica gel column chromatography and purified (eluent hexane / ethyl acetate = 2 / 1-1 / 3) to give the title compound (562mg).
¹ H-NMR (CDCl ₃₎ ^δ: 0.94 (3H, d, J = 6.6 Hz), 1.02-1.15 (2H, m), 1.34-1.69 (7H, m), 1.43 (9H, s), 1.80-1.87 (2H, m), 1.99-2.09 (2H, m), 2.69 (1H, dd, J = 13.7, 6.3 Hz), 2.79 (1H, m), 2.88 (1H, dd, J = 13.7, 7.4 Hz), 3.03-3.13 (2H, m), 3.63 (3H, s), 3.79 (1H, tt, J = 12.1, 3.9 Hz), 4.76 (1H, br), 6.67 (1H, s), 7.47 (1H, s) .

[Step 2] (2R) -5 – [(tert- butoxycarbonyl) amino] -2 – {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} methyl valerate and ( 2S) -5 – [(tert- butoxycarbonyl) amino] -2 – {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} methyl valerate

The compound obtained in Step 1 of this Example (40mg) was dissolved in hexane (1.5mL) and ethanol (0.5mL), using CHIRALPAK IA semi-preparative column (2.0cm × 25.0cm) It was optically resolved by high performance liquid chromatography. Flow rate: 15mL / min, elution solvent: hexane / ethanol = 75/25, detection wavelength: 220nm.

The solvent of the divided solution was evaporated under reduced pressure to give both enantiomers each (15mg). Both enantiomers were confirmed to be optically pure by analytical HPLC. Column: CHIRALPAK IA (0.46cm × 25.0cm), flow rate: 1mL / min, elution solvent: hexane / ethanol = 80/20 <v / v>, detection wavelength: 220nm, retention time: (2R) -5- [(tert- butoxycarbonyl) amino] -2 – {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} methyl valerate (7.2 min), (2S) -5 – [(tert- butoxycarbonyl) amino] -2 – {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} methyl valerate (11.2 min).

[Step 3] (2R) -5- amino -2 – {[1- (trans-4- methylcyclohexyl) -1H- imidazole-4-yl] methyl} valerate

Obtained in Step 2 of this Example (2R) -5 – [(tert- butoxycarbonyl) amino] -2 – {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl } the methyl valerate (15.0mg) was added to 5 N hydrochloric acid (2mL), and the mixture was heated under reflux for 4 hours. After cooling, the solvent it was evaporated under reduced pressure. The resulting crude hydrochloride salt was dissolved in methanol, was added DOWEX50WX8-200. After the resin was washed with water and eluted with 4% aqueous ammonia. The eluate was concentrated, the crude product was washed with acetone to give the title compound (2.2mg).

[Step 4] (2S) -5- amino -2 – {[1- (trans-4- methylcyclohexyl) -1H- imidazole-4-yl] methyl} valerate

Obtained in Step 2 of this Example (2S) -5 – [(tert- butoxycarbonyl) amino] -2 – {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl } the methyl valerate (15.0mg) was added to 5 N hydrochloric acid (2mL), and the mixture was heated under reflux for 4 hours. After cooling, the solvent it was evaporated under reduced pressure. The resulting crude hydrochloride salt was dissolved in methanol, was added DOWEX50WX8-200 (200mg). After the resin was washed with water, ammonia water (4%, 80mL) and eluted with. The eluate was concentrated, the crude product was washed with acetone to give the title compound (1.8mg).

[Example 16] 5-amino -2 – {[1- (trans-4- methylcyclohexyl) -1H- imidazole-4-yl] methyl} valeric acid benzyl hydrochloride [Step 1] 5 – [(tert- butoxycarbonyl) amino] -2 – {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} valerate

The compound obtained in step 1 of Example 15 (7.00g) was dissolved in a mixed solvent consisting of tetrahydrofuran (70mL) and water (14mL), lithium hydroxide monohydrate and (1.26g) at room temperature The mixture was stirred overnight.The reaction solution 2 N hydrochloric acid (8.6mL) was added to neutralize, followed by distilling off the solvent under reduced pressure. The resulting residue was dried with anhydrous sodium sulfate added methylene chloride was to give the crude product was distilled off the solvent under reduced pressure the title compound. This it was used in the next reaction.
MS (ESI) m / z 394 [M ⁺ H] +.

[Example 40] (2S) -5- Amino -2 – {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} valerate · p- toluenesulfonate, anhydrous

The compound obtained in Step 4 of Example 15 (2.04g) was suspended stirring in tetrahydrofuran (15mL), p- toluenesulfonate monohydrate (1.32g) was added, at room temperature for 1 day the mixture was stirred. The precipitated crystals were collected by vacuum filtration to obtain dried in one day like the title compound (3.01g).
¹ H-NMR (CD ₃ OD) ^δ: 0.95 (3H, d, J = 6.5 Hz), 1.11-1.21 (2H, m), 1.43-1.79 (7H, m), 1.83-1.89 (2H, m), 2.05-2.10 (2H, m), 2.37 (3H, s), 2.57-2.64 (1H, m), 2.70 (1H, dd, J = 14.5, 5.5 Hz), 2.85-2.95 (3H, m), 4.07 ( 1H, tt, J = 11.7, 3.9 Hz), 7.18 (1H, s), 7.23 (2H, d, J = 7.8 Hz), 7.70 (2H, d, J = 8.2 Hz), 8.22 (1H, s).
Elemental _{analysis: C 16} H ₂₇ N _{3 O 2} · C 7 H ₈ O ₃ S,
Theoretical value: C; 59.33, H; 7.58, N; 9.02, O; 17.18, S; 6.89,
Measured value: C; 59.09, H; 7.53, N; 8.92, O; 17.22, S; 6.78.
———————————-.

[Example 41] (2S) -5- Amino -2 – {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} valerate · p- toluenesulfonate & 1 Water hydrate

The obtained compound (101.6mg) in 6% water-containing tetrahydrofuran (600μL) was added in Example 40, was dissolved by heating at 60 ℃. Was allowed to stand at room temperature for 1 day, it was collected by filtration and the precipitated crystals were obtained by dried for one day wind the title compound (79.3mg).
Elemental _{analysis: C 16 H 27} N ₃ O ₂ · C 7 H 8 O ₃ S · _{1H 2} O,
Theoretical value: C; 57.12, H; 7.71, N; 8.69, O; 19.85, S; 6.63,
Measured value: C; 56.90, H; 7.69, N; 8.67, O; 19.81, S; 6.42.

References

Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of DS-1040b in Subjects With Acute Ischemic Stroke (NCT02586233

Phase I Study to Evaluate the Safety and Tolerability of DS-1040b Intravenous Infusion With Clopidogrel in Healthy Subjects (NCT02560688)

Study of the Effects of Ethnicity on the Pharmacokinetics, Pharmacodynamics and Safety of DS-1040b (NCT02647307)

Edo, N.; Noguchi, K.; Ito, Y.; Morishima, Y.; Yamaguchi, K.
Hemorrhagic risk assessment of DS-1040 in a cerebral ischemia/reperfusion model of rats with hypertension and hyperglycemia
41st Int Stroke Conf (February 17-19, Los Angeles) 2016, Abst TP283

Noguchi, K.; Edo, N.; Ito, Y.; Morishima, Y.; Yamaguchi, K.
Improvement of cerebral blood flow with DS-1040 in a rat thromboembolic stroke model
41st Int Stroke Conf (February 17-19, Los Angeles) 2016, Abst TP271

Lapchak, P.A.; Boitano, P.D.; Noguchi, K.
DS-1040 an inhibitor of the activated thrombin activatable fibrinolysis inhibitor improves behavior in embolized rabbits
41st Int Stroke Conf (February 17-19, Los Angeles) 2016, Abst WP282

A first-in-human, single ascending dose study of DS-1040, an inhibitor of the activated form of thrombinactivatable fibrinolysis inhibitor (TAFIa), in healthy subjects
25th Congr Int Soc Thromb Haemost (ISTH) (June 20-25, Toronto) 2015, Abst PO621-MON

Dow, J.; Puri, A.; McPhillips, P.; Orihashi, Y.; Dishy, V.; Zhou, J.
A drug-drug interaction study of DS-1040 and aspirin in healthy subjects
25th Congr Int Soc Thromb Haemost (ISTH) (June 20-25, Toronto) 2015, Abst PO603-TUE

Noguchi, K.; Edo, N.; Ito, Y.; Yamaguchi, K.
Effect of DS-1040 on endogenous fibrinolysis and impact on bleeding time in rats
25th Congr Int Soc Thromb Haemost (ISTH) (June 20-25, Toronto) 2015, Abst AS145

Noguchi, K.; Edo, N.; Ito, Y.; Maejima, T.; Yamaguchi, K.
DS-1040: A novel selective inhibitor of activated form of thrombin-activatable fibrinolysis inhibitor
25th Congr Int Soc Thromb Haemost (ISTH) (June 20-25, Toronto) 2015, Abst PO203-MON

DS1040b/Aspirin Drug/Drug Interaction Study (NCT02071004)
ClinicalTrials.gov Web Site 2014, February 26

Patent ID	Date	Patent Title
US2014178349	2014-06-26	Cycloalkyl-Substituted Imidazole Derivative
US8609710	2013-12-17	Cycloalkyl-substituted imidazole derivative

//////DS-1040, DS 1040, phase 2, Daiichi Sankyo Co Ltd, Ischemic stroke

O=C(O)[C@@H](CCCN)Cc1cn(cn1)[C@@H]2CC[C@@H](C)CC2

O=S(=O)(O)c1ccc(C)cc1.O=C(O)[C@@H](CCCN)Cc1cn(cn1)[C@@H]2CC[C@@H](C)CC2

AZD 7594

March 30, 2016 3:11 am / Leave a comment

Picture credit….Bethany Halford

AZD 7594

$AZN‘s asthma candidate

AZ13189620; AZD-7594

Bayer Pharma Aktiengesellschaft, Astrazeneca Ab

Molecular Formula:	C₃₂H₃₂F₂N₄O₆
Molecular Weight:	606.616486 g/mol

3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]indazol-1-yl]-N-(oxolan-3-yl)benzamide

Benzamide, 3-[5-[(1R,2S)-2-[(2,2-difluoro-1-oxopropyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propoxy]-1H-indazol-1-yl]-N-[(3R)-tetrahydro-3-furanyl]-

Cas 1196509-60-0

AZD-7594 is in phase II clinical trials by AstraZeneca for the treatment of mild to moderate asthma.

It is also in phase I clinical trials for the treatment of chronic obstructive pulmonary disorder (COPD).

https://clinicaltrials.gov/ct2/show/NCT02479412

Company	AstraZeneca plc
Description	Inhaled selective glucocorticoid receptor (GCCR) modulator
Molecular Target	Glucocorticoid receptor (GCCR)

Phase II Asthma
Phase I Chronic obstructive pulmonary disease

01 Feb 2016 AstraZeneca completes a phase II trial in Asthma in Bulgaria and Germany (Inhalation) (NCT02479412)
09 Jan 2016 AstraZeneca plans to initiate a phase I trial in Healthy volunteers in USA (IV and PO) (NCT02648438)
01 Jan 2016 Phase-I clinical trials in Chronic obstructive pulmonary disease (In volunteers) in USA (PO, IV, Inhalation) (NCT02648438)

PATENT

http://www.google.com/patents/WO2009142569A1

PATENT

US20100804345

UNWANTED ISOMER

WANTED COMPD

PATENT

WO 2009142571

Example 6

WANTED ISOMER

3-(5- { TC 1 R,2SV2-r(2,2-difluoropropanoyl)aminol- 1 -(2,3-dihydro-l ,4-benzodioxin-6-5 yDpropylioxy) – 1 H-indazol- 1 -ylVN-[(3R)-tetrahydrofuran-3-vnbenzamide. APCI-MS: m/z 607 [MH⁺] ¹H NMR ^OO MHz, DMSOd₆) δ 8.71 (IH, d), 8.65 (IH, d), 8.24 (IH, s), 8.18 (IH, s), 7.90 – 7.84 (2H, m), 7.77 (IH, d), 7.65 (IH, t), 7.21 (IH, dd), 7.13 (IH, d), 6.89 – 6.78 (3H, m), 5.17 (IH, d), 4.48 (IH, m), 4.23 – 4.10 (5H, m), 3.89 – 3.82 (2H, m), 3.72 (IH, td), 3.61 (IH, dd), 2.16 (IH, m), 1.94 (IH, m), 1.55 (3H, t), 1.29 (3H, d). LC (method A) rt = 12.03 min LC (method B) rt = 11.13 min Chiral SFC (method B) rt = 4.71 min M.p. = 177 °C

UNWANTED

o 3-(5- { IY 1 R,2S V2-r(2,2-difluoropropanoyl^‘)amino^‘|- 1 -(2,3-dihydro- 1 ,4-benzodioxin-6- yl)propyl]oxy } – 1 H-indazol- 1 -yP-N-IO S)-tetrahydrofuran-3 -yl^“|benzamide

APCI-MS: m/z 607 [MH⁺]

¹H NMR (400 MHz, DMSO-J₆) δ 8.71 (IH, d), 8.65 (IH, d), 8.24 (IH, s), 8.18 (IH, s),

7.90 – 7.84 (2H, m), 7.77 (IH, d), 7.65 (IH, t), 7.21 (IH, dd), 7.13 (IH, d), 6.89 – 6.78 (3H,s m), 5.17 (IH, d), 4.48 (IH, m), 4.24 – 4.11 (5H, m), 3.90 – 3.81 (2H, m), 3.72 (IH, td), 3.61

(IH, dd), 2.16 (IH, m), 1.94 (IH, m), 1.55 (3H, t), 1.29 (3H, d).

LC (Method A) rt = 12.02 min

LC (Method B) rt = 11.12 min

Chiral SFC (method B) rt = 5.10 min o M.p. = 175 ⁰C

PATENT

WO 2011061527

http://www.google.com/patents/WO2011061527A1?cl=en

Intermediate 12

( 1 R,2S)-2-amino- 1 -(2,3 -dihydrobenzo b [ 1 ,41dioxin-6-yl)propan- 1 -ol hydrochloride. (12)

5-6 N HC1 in 2-propanol (8 mL, 40-48 mmol) was added to tert-butyl (lR,2S)-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxypropan-2-ylcarbamate (I2a) (3.1 g, 10.02 mmol) in ethyl acetate (40 mL) at 40°C and stirred for 3 hours. The reaction mixture was allowed to reach r.t. and was concentrated by evaporation. Ether was added and the salt was filtered off and washed with ether. The salt was found to be hygroscopic. Yield 2.10 g (85%)

APCI-MS: m/z 210 [MH⁺-HC1]

1H-NMR (300 MHz, DMSO-^): δ 8.01 (brs, 3H), 6.87-6.76 (m, 3H), 5.93 (brd, 1H), 4.79 (brt, 1H), 4.22 (s, 4H), 3.32 (brm, 1H), 0.94 (d, 3H).

tert-butyl (1R,2S)- 1 -(2,3-dihvdrobenzorbl Γ 1 ,41dioxin-6-yl)- 1 -hvdroxypropan-2-ylcarbamate.

The diastereoselective catalytic Meerwein-Ponndorf-Verley reduction was made by the method described by Jingjun Yin et. al. J. Org. Chem. 2006, 71, 840-843.

(S)-tert-butyl 1 -(2,3-dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)- 1 -oxopropan-2-ylcarbamate (I2b) (3.76 g, 12.23 mmol), aluminium isopropoxide (0.5 g, 2.45 mmol) and 2-propanol (12 mL, 157.75 mmol) in toluene (22 mL) were stirred at 50°C under argon for 16 hours. The reaction mixture was poured into 1M HC1 (150 mL) and the mixture was extracted with ethyl acetate (250 mL). The organic phase was washed with water (2×50 mL) and brine (100 mL), dried over Na₂SC”4, filtered and concentrated. The crude product was purified by flash- chromatography on silica using ethyl acetate/hexane (1/2) as eluent. Fractions containing product were combined. Solvent was removed by evaporation to give the desired product as a colourless solid. Yield 3.19 g (84%) APCI-MS: m/z 236, 210, 192 [MH -tBu-18, MH -BOC, MH -BOC- 18]

1H NMR (300 MHz, DMSO-^): δ 6.80-6.70 (m, 3H), 6.51 (d, IH), 5.17 (d, IH), 4.36 (t, IH),

4.19 (s, 4H), 3.49 (m, IH), 1.31 (s, 9H), 0.93 (d, 3H).

(S)-tert-butyl 1 -(2,3-dihydrobenzo[bl [ 1 ,41dioxin-6-yD- 1 -oxopropan-2-ylcarbamate. (I2b)

A suspension of (S)-tert-butyl l-(methoxy(methyl)amino)-l-oxopropan-2-ylcarbamate (3 g, 12.92 mmol) in THF (30 mL) was placed under a protective atmosphere of argon and cooled down to -15 to -20°C. Isopropylmagnesium chloride, 2M in THF (6.5 mL, 13.00 mmol), was added keeping the temperature below -10°C. The temperature was allowed to reach 0°C. A freshly prepared solution of (2,3-dihydrobenzo[b][l,4]dioxin-6-yl)magnesium bromide, 0.7M in THF (20 mL, 14.00 mmol) was added. The temperature was allowed to reach r.t. overnight. The reaction mixture was poured into ice cooled IN HC1 (300 mL). TBME (300 mL) was added and the mixture was transferred to a separation funnel. The water phase was back extracted with TBME (200 mL). The ether phases were washed with water, brine and dried (Na₂S0₄). The crude product was purified by flash chromatography using TBME /Heptane 1/2 as eluent. Fractions containing the product were combined and solvents were removed by evaporation to give the subtitle compound as a slightly yellow sticky oil/gum. Yield 3.76g

(95%)

APCI-MS: m/z 208 [MH⁺ – BOC]

1H NMR (300 MHz, DMSO-^): δ 7.50 (dd, IH), 7.46 (d, IH), 7.24 (d, IH), 6.97 (d, IH), 4.97 (m, IH), 4.30 (m, 4H), 1.36 (s, 9H), 1.19 (d, 3H).

Intermediate 13

(lR,2S)-2-amino-l-(4H-benzo[dl[l,31dioxin-7- l)propan-l-ol hydrochloride (13)

Tert-butyl ( 1 R,2S)- 1 -(4H-benzo[d] [ 1 ,3]dioxin-7-yl)- 1 -hydroxypropan-2-ylcarbamate (I3b) (403 mg, 1.30 mmol) was dissolved in ethyl acetate (5 mL) and 5-6 N HC1 solution in 2- propanol (1.5 mL, 7.5-9 mmol) was added. The mixture was stirred at 50 °C for 1.5 hours. The solvents was removed by evaporation. The residual sticky gum was treated with ethyl acetate and evaporated again to give a solid material that was suspended in acetonitrile and stirred for a few minutes. The solid colourless salt was collected by filtration and was found to be somewhat hygroscopic. The salt was quickly transferred to a dessicator and dried under reduced pressure. Yield 293 mg (92%)

APCI-MS: m/z 210 [MH⁺ -HC1]

1H NMR (300 MHz, DMSO-^) δ 8.07 (3H, s), 7.05 (IH, d), 6.92 (IH, dd), 6.85 (IH, d), 6.03 (IH, d), 5.25 (2H, s), 4.87 (3H, m), 3.42 – 3.29 (IH, m), 0.94 (3H, d).

(4S.5R -5-(4H-benzordiri.31dioxin-7-vn- -methyloxazolidin-2-one (I3a

A mixture of (lR,2S)-2-amino-l-(4H-benzo[d][l,3]dioxin-7-yl)propan-l-ol hydrochloride (I3b) (120 mg, 0.49 mmol), DIEA (0.100 mL, 0.59 mmol) and CDI (90 mg, 0.56 mmol) in THF (2 mL) was stirred at r.t. for 2 hours. The reaction mixture was concentrated by evaporation and the residual material was partitioned between ethyl acetate and water. The organic phase was washed with 10% NaHS0₄, dried over MgS0₄, filtered and evaporated. The crude product was analysed by LC/MS and was considered pure enough for further analysis by NMR. Yield 66 mg (57%)

The relative cis conformation of the product was confirmed by comparing the observed 1H- NMR with the literature values reported for similar cyclised norephedrine (Org. Lett. 2005 (07), 13, 2755-2758 and Terahedron Assym. 1993, (4), 12, 2513-2516). In a 2D NOESY experiment a strong NOE cross-peak was observed for the doublet at 5.64 with the multiplet at 4.19 ppm. This also confirmed the relative czs-conformation.

APCI-MS: m/z 236 [MH⁺]

1H NMR (400 MHz, CDC1₃) δ 6.99 (d, J= 8.0 Hz, IH), 6.88 (dd, J= 8.0, 1.4 Hz, IH), 6.83 (s, IH), 5.81 (brs,lH), 5.64 (d, J= 8.0 Hz, IH), 5.26 (s, 2H), 4.91 (s, 2H), 4.19 (m, IH), 0.85 (d, J = 6.4 Hz, 3H). Tert-butyl ( 1 R,2S)- 1 -(4H-benzord1 Γ 1 ,31dioxin-7-yl)- 1 -hvdroxypropan-2-ylcarbamate (I3b)

A mixture (S)-tert-butyl l-(4H-benzo[d][l,3]dioxin-7-yl)-l-oxopropan-2-ylcarbamate (I3c) (680 mg, 2.21 mmol), triisopropoxyaluminum (140 mg, 0.69 mmol) and propan-2-ol (3 mL, 38.9 mmol) in toluene (3 mL) was stirred at 65 °C for 15 hours. The reaction mixture was allowed to cool down, poured into 1M HC1 (50 mL) and extracted with ethyl acetate (2×50 mL). The organic phase was washed with water, brine, dried over MgS0₄, filtered and solvents were removed by evaporation to afford a colourless solid. The crude product was purified by flash chromatography, (solvent A = Heptane, solvent B = EtOAc + 10% MeOH. A gradient of 10%B to 50%B in A was used). The obtained product was crystallised from DCM / heptane to afford the subtitle compound as colourless needles. Yield 414 mg (60%)

APCI-MS: m/z 210 [MH⁺ -BOC]

1H NMR (400 MHz, DMSO- ¾ δ 6.97 (1H, d), 6.88 (1H, d), 6.77 (1H, s), 6.56 (1H, d), 5.27 (1H, d), 5.22 (2H, s), 4.83 (2H, s), 4.44 (1H, t), 3.53 (1H, m), 1.32 (9H, s), 0.93 (3H, d). (S)-Tert-butyl 1 -(4H-benzord1 Γ 1 ,31dioxin-7-vD- 1 -oxopropan-2-ylcarbamate (I3c)

7-Bromo-4H-benzo[d][l,3]dioxine (1 g, 4.65 mmol) was dissolved in THF (5 mL) and added to magnesium (0.113 g, 4.65 mmol) under a protective atmosphere of argon. One small iodine crystal was added. The coloured solution was heated with an heat gun in short periods to initiate the Grignard formation. When the iodine colour vanished the reaction was allowed to proceed at r.t. for 1.5 hours.

In a separate reaction tube (S)-tert-butyl l-(methoxy(methyl)amino)-l-oxopropan-2- ylcarbamate (1 g, 4.31 mmol) was suspended in THF (5 mL) and cooled in an ice/acetone bath to below -5 °C. Isopropylmagnesium chloride, 2M solution in THF (2.5 mL, 5.00 mmol) was slowly added to form a solution. To this solution was added the above freshly prepared Grignard reagent. The mixture was allowed to reach r.t. and stirred for 4 hours. The reaction mixture was slowly poured into ice-cold 150 mL 1M HC1. Ethyl acetate (150 mL) was added and the mixture was stirred for a few minutes and transferred to a separation funnel. The organic phase was washed with water and brine, dried over MgS04, filtered and concentrated. The obtained crude product was further purified by flash chromatography using a prepacked 70g silica column with a gradient of 10% TBME to 40% TBME in heptane as eluent. The subtitle compound was obtained as a colourless solid. Yield 790 mg (59%>)

APCI-MS: m/z 208 [MH⁺ -BOC]

1H NMR (400 MHz, DMSO-^) δ 7.53 (IH, dd), 7.39 (IH, s), 7.30 (IH, d), 7.22 (IH, d), 5.30 (2H, s), 4.98 (IH, m), 4.95 (2H, s), 1.35 (9H, s), 1.20 (3H, d).

Preparation 4

3-(5-([(lR,2S)-2-[(2,2-difluoropropanoyl)aminol-l-(2,3-dihydro-l,4-benzodioxin-6- yl)propyl]oxy| – 1 H-indazol- 1 -yl)-N-[(3R)-tetrahydrofuran-3-yllbenzamide

TEA (2.0 g, 20.65 mmol) was added to a mixture of 3-(5-((lR,2S)-2-(2,2- difluoropropanamido)- 1 -(2,3-dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)propoxy)-l H-indazol-1 – yl)benzoic acid (14) (3.6 g, 6.70 mmol), (R)-tetrahydrofuran-3 -amine hydrochloride (0.99 g, 8.0 mmol) and HBTU (2.65 g, 6.99 mmol) in DCM (15 mL). The reaction was stirred at r.t. for 3h, then quenched by addition of a mixture of water and ethyl acetate. The mixture was shaken and the organic layer was collected. The water phase was extracted twice with ethyl acetate. The combined organic layers were washed with a small portion of water and dried over magnesium sulphate. The product was purified by flash chromatography (silica, eluent: a gradient of ethyl acetate in heptane). The residue was crystallized by dissolving in refluxing acetonitrile (50 mL) and then allowing to cool to r.t. over night. The solid was collected by filtration, washed with a small volume of acetonitrile and dried at 40°C in vaccum to give the title compound (2.5 g, 61%).

APCI-MS: m/z 607 [MH⁺]

1H NMR (400 MHz, DMSO-d₆) δ 8.71 (IH, d), 8.65 (IH, d), 8.24 (IH, s), 8.18 (IH, s), 7.90 – 7.84 (2H, m), 7.77 (IH, d), 7.65 (IH, t), 7.21 (IH, dd), 7.13 (IH, d), 6.89 – 6.78 (3H, m), 5.17 (IH, d), 4.48 (IH, m), 4.23 – 4.10 (5H, m), 3.89 – 3.82 (2H, m), 3.72 (IH, td), 3.61 (IH, dd), 2.16 (IH, m), 1.94 (IH, m), 1.55 (3H, t), 1.29 (3H, d).

LC (method A) rt = 12.03 min

LC (method B) rt = 11.13 min

Chiral SFC (method B) rt = 4.71 min

M.p. = 177 °C

Patent ID	Date	Patent Title
US2015080434	2015-03-19	PHENYL AND BENZODIOXINYL SUBSTITUTED INDAZOLES DERIVATIVES
US8916600	2014-12-23	Phenyl and benzodioxinyl substituted indazoles derivatives
US8211930	2012-07-03	Phenyl and Benzodioxinyl Substituted Indazoles Derivatives

REFERENCES

https://www.astrazeneca.com/content/dam/az/press-releases/2014/Q2/Pipeline-table.pdf

////////AZD 7594, AZ13189620, AZD-7594 , phase 2, astrazeneca, 1196509-60-0

c21cc(ccc1n(nc2)c3cc(ccc3)C(=O)NC4COCC4)O[C@H](c5cc6c(cc5)OCCO6)[C@@H](NC(=O)C(F)(F)C)C

CC(C(C1=CC2=C(C=C1)OCCO2)OC3=CC4=C(C=C3)N(N=C4)C5=CC=CC(=C5)C(=O)NC6CCOC6)NC(=O)C(C)(F)F

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

amcrasto@gmail.com

P.S

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India.

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SUVN-502, From Suven Life Sciences Ltd

March 1, 2016 9:17 am / 1 Comment on SUVN-502, From Suven Life Sciences Ltd

STR1

SUVN-502

CAS OF MONOHYDRATE MESYLATE 1791396-45-6

CAS MESYLATE 1791396-46-7

1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate

l-{(2-BROMOPHE YL) SULFONYLJ-5-METHOXY-3- [(4-METHYL-l-PIPERAZINYL) METHYLJ-1H-INDOLE DIMESYLATE MONOHYDRATE

l-[(2- bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indoIe dimesylate monohydrate

MF OF DIMESYLATE – C₂₁ H₂₄ Br N₃ O₃ S . 2 C H₄ O₃ S

Serotonin 6 receptor antagonists

STR1

……………..BASE form of SUVN-502

1 -[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l -piperazinyl)methyl]-lH-indole

CAS OF BASE 701205-60-9, 478.40, C₂₁ H₂₄ Br N₃ O₃ S

1H-Indole, 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-, methanesulfonate (1:2)

5-HT 6 receptor antagonist

SUVN-502 (in phase II)

https://www.clinicaltrials.gov/ct2/show/NCT02580305

Suven Life Sciences Ltd

IN 2013CH05537

Used as 5-HT 6 receptor antagonist for treating Alzheimer’s disease, attention deficit hyperactivity disorder, Parkinson’s disease and schizophrenia.

SUVN-502

SUVN-502 is a pure 5-HT₆ receptor antagonist with >1200-fold selectivity over 5-HT_2A receptor with a superior profile that differentiates from competitor 5-HT₆ antagonists. SUVN-502 has an excellent human pharmacokinetics for once a day treatment.

The Phase 2A trial is designed to evaluate the safety, tolerability, pharmacokinetics and efficacy of SUVN-502 for the treatment of moderate Alzheimer’s Disease (AD).This trial is expected to enrol 537 patients and the primary objective of the study is to evaluate the efficacy of a serotonin receptor subtype 6 (5-HT₆) antagonist, SUVN-502, at daily doses of 50 mg or 100 mg compared to placebo, as adjunct treatment in subjects with moderate Alzheimer’s disease (Mini-Mental State Examination [MMSE] score of 12 to 20) currently treated with the acetylcholinesterase inhibitor, Donepezil Hydrochloride (HCl) and the N-methyl-D-aspartic acid (NMDA) antagonist, MemantineHCl. Efficacy will be assessed by the 11-item Alzheimer’s Disease Assessment Scale for Cognitive Behaviour (ADAScog-11) after 26 weeks of treatment. The trial is likely to complete by end of second quarter 2017, subject to the achievement of estimated 12 months’ enrolment goal in USA.

Secondary objectives of this POC study are to further evaluate the efficacy of these treatments usingClinical Dementia Rating (CDR) Scale, Sum of Boxes (CDR-SB), MMSE, Alzheimer’s Disease Co-operative Study Activity of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI) 12 item and Cornell Scale for Depression and Dementia (C-SDD).

This study is being coordinated by Dr. Jeffrey Cummings, MD, Director, Cleveland Clinic Lou RuvoCenter for Brain Health, Las Vegas, NV, USA.

Prior to the initiation of Phase 2A study, SUVN-502 has successfully undergone two phase 1 studies in Switzerland and USA on 122 healthy young and elderly male populations with no major adverse events and no serious adverse events.

5-HT₆ receptor is one of the potential therapeutic target for the development of cognitive enhancers for the treatment of Alzheimer’s disease (AD) and schizophrenia. 5-HT₆ receptor is localized exclusively in central nervous system, in areas important for learning and memory. In recent years several studies (Brain Research, 1997, 746, 207-219; Journal of

Neuroscience, 1998, 18(15), 5901-5907; International Review of Neurobiology Volume 96, 201 1 , 27-47 & Annual Reviews in Pharmacology and Toxicology, 2000, 40, 319-334a) have reported that 5-HT₆ receptor antagonists show beneficial effect on cognition in animal models.

PATENT

WO2015083179

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015083179

l-[(2- bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indoIe dimesylate monohydrate of formula (I) of the present invention is illustrated by the Sc eme-1 as given below:

Mannich Adduct

Scheme-1

Example 1: Preparation of l-[(2-bromophenyI)suIfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyI)methyl]-lH-indole dimesylate monohydrate

Step (i) & (u): Preparation of 5-methoxy-3-[(4-methyl-l-piperazinyI)methyl]-lH-indole

Step (i):

1-Methylpiperazine (15 Kg, 0.15 Kg Mole) was charged into a reactor. The mass was cooled to 5 °C – 10 °C. Demineralised water (12 Kg) was added to the above mass slowly, maintaining the mass temperature 10 °C – 20 °C, over a period of 30 minutes. Then added acetic acid (6.16 Kg, 0.103 Kg Mole) to the above mass in 30 minutes, maintaining the mass temperature at 10 °C – 20 °C. The mass was further stirred for another 15 – 20 minutes at 10 °C – 20 °C and aqueous formaldehyde solution (15.67 Kg, 30 % w/v, 0.1567 Kg Mole) was added in 60 minutes maintaining the mass temperature at 15 °C – 20 °C. The resultant thick, red colored reaction mass was stirred for another 2 hours at 20 °C – 30 °C to obtain the mannich adduct.

Step (ii):

Simultaneously in a separate reactor 125 Kg of methanol was charged at 25 °C – 35 °C. 5-methoxyindole (20 Kg, 0.1359 Kg Mole) was added and the mass was stirred to obtain a clear solution. The mass was cooled to 8 °C – 10 °C in 1.5 hours by circulating brine in the reactor jacket. The Mannich adduct, prepared as above, was charged into the reactor containing cooled methanolic solution of 5-methoxyindole from an addition tank over a period of 50 – 60 minutes, while maintaining the temperature of the reaction mass at 8 °C – 16 °C. After completion of addition, the mass temperature was allowed to rise to 20 °C – 35 °C. Then the reaction mass was further stirred for 3 hours at 20 °C – 35 °C. After completion of the reaction (thin layer chromtography), the reaction mass was discharged into clean and dry containers.

Another reactor was charged with 400 L of demineralised water followed by the addition of 20 Kg of lye solution at 20 °C – 35 °C. The content was cooled to 10 °C – 15 °C under stirring. The above reaction mass in the containers was added to the reactor, maintaining the mass temperature at 10 °C – 15 °C in 30 – 40 minutes. The final pH of the solution was adjusted to 9 – 12, if necessary by adding some more lye solution. Then the product was extracted with ethyl acetate (1 x 260 L & 4 x 160 L) maintaining the mass temperature at 10 °C – 15 °C during the entire operations. The pH of aqueous layer was adjusted to 9 – 12 before each extraction.

The combined organic layer was washed with (2 x 170 Kg) of brine solution (the brine solution was prepared by adding 95 Kg of vacuum salt to 245 Kg of demineralised water) at 20 °C – 35 °C. The total organic extracts, obtained after the brine washing, were dried over 35 Kg of anhydrous sodium sulfate under stirring for 30 minutes at 20 °C – 35 °C.

The organic layer was filtered and charged into another clean reactor. The solvent was removed totally under 500 – 600 mm of Hg vacuum, at 20 °C – 45 °C.

The residual mass, thus obtained, was cooled to room temperature and charged 60 L toluene and stirred the contents at 20 °C – 45 °C for 15 minutes. The solvent was distilled off under reduced pressure (500 – 700 mm of Hg vacuum) at 45 °C – 65 °C. The operation was repeated again by the addition of 60 L toluene and stirring the contents at 20 °C – 45 °C for 15 min. The solvent was distilled off under reduced pressure (500 – 700 mm of Hg vacuum) at 45 °C – 65 °C again to ensure total removal of ethylacetate to avoid losses during recrystallization step. The residual technical product, 5-methoxy-3-[(4-methyl-l- piperazinyl)methyl]-lH-indole, thus obtained, was recrystallized twice, as per the details given below, to obtain the product of desired purity.

Step (Hi): Crystallization of 5-methoxy-3-[(4-methyI-l-piperazinyl)methyl]-lH-indoIe

Charged 61 Kg of toluene into the above reactor which contains the technical product, 5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole. The contents were heated to 85 °C – 95 °C and maintained for an hour at 85 °C – 95 °C. The clear solution, thus obtained, was allowed to cool to 30 °C – 40 °C by circulating room temperature water in the reactor jacket. The mass was further cooled to 10 °C – 15 °C and maintained for 3 hours at the same temperature. The crystalline solid mass was filtered through nutsche and the solid on the nutsche was washed with 18 L of chilled (10 °C – 15 °C) toluene and sucked well. The material was further washed with 20 L of n-hexane and sucked dry to obtain 22.7 Kg of crystalline material.

Step (iv): Recrystallization of 5-methoxy-3-[(4-methyI-l-piperazinyI)methyl]-lH-indole

Charged 40 Kg of toluene into a reactor followed by the addition of the 5-methoxy- 3-[(4-methyl-l-piperazinyl)methyl]-l H-indole (22.7 Kg) obtained in the first crystallization step under stirring. The contents were heated to 95 °C – 105 °C and maintained for 2 hours to obtain a clear solution. The mass was allowed to cool to 35 °C -40 °C by circulating room temperature water in the jacket. It was further cooled to 10 °C -15 °C and maintained for 3 hours at 10 °C – 15 °C. The crystalline solid mass was filtered through nutsche and the solid on the nutsche was washed with 8 L of chilled (10 °C – 15 °C) toluene and sucked well. The material was further washed with 15 L of n-hexane and sucked dry. The material was further dried in tray driers at 20 °C – 25 °C to obtain the title product, as off white crystalline powder.

Weight of the crystallized material: 19.95 Kg;

Yield (based on 5-methoxyindole charged): 56.6 %;

HPLC purity: 99.74 %;

Total impurities: 0.26 %;

Assay: 100.6 %;

Moisture content: 0.24 %;

Melting range (°C): 139 – 140.6;

IR spectra (cm^“1): 3125, 2951, 1875, 1622, 1585, 1492, 1351, 1288, 1215, 1059, 930, 654; Ή – NMR (CDCI3, δ ppm): 2.30 (3H, s), 2.5 (8H, bs), 3.71 (2H, s), 3.86 (3H, s), 6.83 -6.86 (1H, dd, J = 8.81, 2.7 Hz), 7.01 (1H, d, J = 2.06 Hz), 7.18 – 7.20 (2H, m), 8.91 (1H, s); ¹³C – NMR (CDCI3, δ ppm): 45.89, 52.79, 53.39, 55.1 1, 55.83, 101.3, 1 1 1.39, 11 1.75, 1 11.81, 124.88, 128.45, 131.48, 153.77;

Mass [M+H]⁺: 260.3.

Step (v): Preparation of l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyl)methyI]-lH-indoIe

Tetrahydrofuran (85.78 Kg) was charged into a reactor at 20 °C – 35 °C. Then charged the crystallized 5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole (21.5 Kg, 0.0829 Kg Mole) into the reactor at 20 – 35 °C and stirred the mass well. The mass was cooled to 10 °C – 20 °C with chilled water in the jacket. Charged powdered potassium hydroxide (16.1 1 Kg) to the above suspension at 10 °C – 20 °C in 10 minutes under stirring. Slight exotherm was observed. Mass temperature rose from 15.1 °C to 16.3 °C. The mass was further stirred for 60 minutes at 10 °C – 20 °C. A solution of 2-bromobenzenesulfonyl chloride (27.71 Kg, 0.1084 Kg Mole) in 41.72 Kg tetrahydrofuran was added through addition tank at a constant rate in 60 minutes at 10 °C – 30 °C. The reaction was exothermic and the mass temperature went up from 16 °C to 30 °C. Then removed the chilled water from the jacket and stirred the mass for 3 hours at 25 °C – 35 °C. As the reaction was progressing the mass thickened due to formation of potassium chloride. The progress of the reaction was monitored by thin layer chromatography (Eiuent system: Chloroform and Methanol in 8:2 ratio and the product is relatively non-polar). Since thin layer chromatography shows the presence of starting material (5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole), another lot of 2-bromo benzenesulfonyl chloride (4.5 Kg, 0.0176 Kg Mole) dissolved in 13.71 Kg tetrahydrofuran was added to the reaction mass at 30 °C in 25 minutes. No exotherm observed. The reaction mass was further stirred for 60 minutes at 30 °C – 35 °C. Since the starting material was absent as per thin layer chromatography, it was taken for further workup.

In the mean while charged 360 L demineralised water into another reactor and cooled the contents to 10 °C – 15 °C. The above reaction mass was quenched into chilled water in 60 minutes (mass temperature was 12.1 °C). The pH of the reaction mass was adjusted to ~ 9.5 with an aqueous solution of potassium hydroxide. The product was extracted with (4 x 155 L) ethyl acetate maintaining the mass temperature at 10 °C – 15 °C. The pH of aqueous layer was adjusted to ~ 9.5 before each extraction. The combined organic layer was taken for extraction of the product into aqueous acetic acid. _…. j

Acetic acid (8.69 Kg, 0.1448 Kg mole) was dissolved in 137 L of demineralised water and cooled the mass to 10 °C – 15 °C. Charged the above organic extracts into it and stirred for 30 minutes at 10 °C – 15 °C. The mass was allowed to settle for 20 minutes and separated the bottom aqueous acetic acid extract containing the product into a fresh clean reactor.

Further, the extraction and separation process with fresh aqueous acetic acid solution was repeated thrice using 3 x 145 Kg of aqueous acetic acid solution (prepared by dissolving 25.74 Kg, 0.429 Kg Mole of acetic acid in 412 L of demineralised water) following the similar procedure mentioned above, maintaining mass temperature at 10 °C -15 °C. The combined aqueous acetic acid extracts (containing the product) were taken into the reactor. It was washed with 44 L of ethyl acetate by stirring the mass at 10 °C – 15 °C for 15 minutes, followed by 15 minutes settling. The aqueous product layer was separated. The pH of the aqueous solution was found to be 4.5. The mass was cooled to 10 °C – 15 °C and the pH of the solution was adjusted to ~ 9.5 with chilled caustic lye solution (31 Kg). The product was extracted with (4 x 155 L) of ethyl acetate, maintaining the mass temperature at 10 °C – 15 °C. The pH of aqueous layer was adjusted to ~ 9.5 before each extraction.

The organic layer was washed with (2 x 1 12 Kg) brine solution (prepared from 51.6 Kg vacuum salt and 175 L water) at 10 °C – 15 °C. The organic layer was dried over 32 Kg of anhydrous sodium sulfate at 20 °C – 35 °C and filtered into another clean reactor.

Solvent was removed under 500 – 600 mm Hg by circulating 50 °C – 55 °C water in the jacket of the reactor.

To the residual mass in the reactor after solvent removal, charged 36 L of methanol followed by 72 L of isopropanol. The reaction mass was heated to reflux temperature (65 °C – 75 °C). At mass temperature ~ 70 °C a clear solution was obtained. The mass was allowed to cool to 35 – 45 °C with room temperature water circulation in the reactor jacket. Further, it was cooled to 15 °C – 20 °C by circulating brine in the jacket and maintained under stirring for 2 hours at 15 °C – 20 °C. The solids were filtered through nutsche and sucked well under vacuum. The cake was washed with 36 L of isopropanol (15 °C – 20 °C) and sucked well. The wet solid material (37.76 Kg) was taken in tray drier and air dried at 25 °C – 35 °C for 60 minutes. Further, it was dried at 40 °C – 45 °C for 6 hours to obtain 32.64 Kg of the title product.

Overall Yield: 82.3 % (based on Mannich base charged);

HPLC purity: 99.36 %;

Single major impurity: 0.29 %;

Total impurities: 0.64 %;

Assay: 100.5 %;

Loss on drying at 105 °C: 0.21 %;

Melting range (°C): 128.1 – 129.2;

IR spectra (cm^‘1): 2931, 2786, 1607, 1474, 1369, 1222, 1 178, 1032, 737, 597;

Ή – NMR (CDC1₃, δ ppm): 2.29 (3H, s), 2.32 – 2.50 (8H, bs), 3.62 (2H, s), 3.83 (3H, s),

6.83 – 6.86 (1H, dd, J = 8.98, 2.46 Hz), 7.19 – 7.20 (1H, d, J = 2.42 Hz), 7.36 – 7.40 (1 H, dt,

J.= 7.68, 1.56 Hz), 7.45 – 7.47 (1H, t, J = 7.50 Hz), 7.53 – 7.55 (1H, d, J = 9.00, Hz), 7.64 – 7.66 (2H, m), 8.03 – 8.05 (1H, dd, J = 7.89, 1.54 Hz);

¹³C – NMR (CDCI3, δ ppm): 45.94, 53.07, 53.33, 55.17, 55.60, 103.28, 1 13.20, 1 13.69,

117.83, 120.42, 127.05, 127.69, 129.57, 131.16, 131.57, 134.48, 135.90, 138.09, 156.12;

Mass [M+Hf: 478.1, 480.1.

Step (vi): Preparation of l-[(2-bromophenyl)sulfonyI]-5-methoxy-3-[(4-methyI-l-piperazinyl)methyI]-lH-indoIe dimesylate

Charged 182.5 Kg of absolute ethanol into a reactor at 20 °C – 35 °C. Then charged l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole -(obtained in the above step, 32.02 Kg, 0.067 Kg Mole) under stirring in a single lot at 20 °C – 35 °C (mass temperature), added methanesulfonic acid (13.9 Kg, 0.1446 Kg Mole) slowly to the above reaction mass from a holding tank in 60 minutes, maintaining mass temperature at 20 °C – 35 °C. No clear solution was obtained at any stage. The mass became thick, but stirrable. The reaction mass was stirred for 24 hours maintaining mass temperature between 25 °C – 30 °C. The mass was filtered through nutsche under nitrogen atmosphere and it was sucked well. The cake, thus obtained, was washed thoroughly with 48 L of ethyl alcohol (slurry wash), sucked well and the cake was again washed with 18 L of ethyl alcohol (spray wash) followed by washing with n-hexane (27 L). It was sucked dry to obtain 70.23 Kg wet cake. The wet cake was taken in a tray drier and dried at 20 °C – 35 °C for 10 hours to obtain 49.43 Kg product (LOD: ~ 9.57 %).

Weight of product on dry basis: 44.65 Kg

Yield of salt: Quantitative (based on l -[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methy 1- 1 -piperaziny l)methy 1]- 1 H- indo le charged) ;

HPLC purity: 99.69 %;

Total impurities: 0.31 %;

Salt content: 27.39 %.

Step (vii): Preparation of l-[(2-bromop enyl)sulfonyI]-5-methoxyr3-[(4-methyI-l-piperazinyl)methyl]-lH-indole dimesylate monohydrate

Charged 415 Kg of aqueous ethanol (95 % ethanol & 5 % water) into a reactor, followed by the addition of l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole dimesylate (44.65 Kg, 0.0666 Kg Mole, obtained from the above step) at 20 °C – 35 °C. In the meanwhile carbon slurry was prepared separately by adding 6.7 Kg of carbon powder into 18 Kg of aqueous ethanol (95 % ethanol & 5 % water). Then the carbon slurry was transferred to the reactor and the reaction mass was heated at 75 °C – 80 °C by circulating 80 °C – 90 °C hot water in the reactor jacket for 45 minutes. The mass was filtered hot into another clean reactor, washed the carbon bed with 54.25 Kg of aqueous ethanol (95% ethanol & 5% water) at 75 °C – 80 °C. The contents of the reactor were heated at reflux temperature (76 ^PC – 78 °C) for 30 minutes to obtain a clear solution. The mass was allowed to cool on its own to 45 °C in 10 hours by applying compressed air in the reactor jacket. It was further cooled to 10 °C – 15 °C with chilled water circulated in the jacket and maintained under stirring for 3 hours. Filtered the crystalline material through a centrifuge and the material on the centrifuge was washed with 18.6 Kg of aqueous ethanol (95 % ethanol & 5 % water) (10 °C – 15 °C) and spin dried. The whole material was air dried in a tray drier for 14 hours at 20 °C – 35 °C. The material was milled, sieved and collected in poly bag to obtain 37.7 Kg of the title product. The uniform material was sampled for analysis.

Weight of dry product: 37.7 Kg;

Yield of salt: 82.2 %;

HPLC purity: 99.7 %;

Single impurity: 0.3 %;

Assay: 99.9 %;

Moisture content: 2.61 %;

Salt content (Dimesylate) 27.56 %;

Melting range (°C): 218.0 – 220.0;

IR spectra (cm^“1): 3148, 3012, 161 1, 1590, 1471, 1446, 1439, 1382, 1220, 1 194, 1 180, 1045, 775, 596;

Ή – NMR (D20, δ ppm): 2.65 (6H, s), 2.89 (3H, s), 3.52 (8H, bs), 3.70 (3H, s), 4.46 (2H, s), 6.75 – 6.78 (1H, dd, J = 9.07, 2.02 Hz), 7.10 – 7.1 1 (1H, d, J = 1.9 Hz), 7.32 – 7.38 (2H, m), 7.44 – 7.47 (1H, t, J = 7.6 Hz), 7.54 – 7.56 (1H, dd, J = 7.79 Hz), 8.04 (1H, s), 8.14 -8.16 (lH, d, J = 7.94 Hz);

^, C – NMR (δ ppm): 38.42, 42.79, 48.19, 50.35, 55.80, 102.57, 108.20, 113.72, 114.07, 1 19.62, 128.25, 128.56, 130.17, 131.80, 132.15, 135.28, 135.95, 156.21 ;

Mass [M+H]⁺: 478, 480.

PATENT………on metabolite and not the drug

caution……….drug has a methyl

WO-2016027276

Suven Life Sciences Ltd is developing l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl- l -piperazinyl)methyl]-lH-indole dimesylate monohydrate, which is a selective 5-HT₆ receptor antagonists intended for the symptomatic treatment of AD and other disorders of memory and cognition like attention deficient hyperactivity, parkinson’s and schizophrenia. 1 -[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l -piperazinyl)methyl]-lH-indole, and its pharmaceutically acceptable salts were disclosed by Ramakrishna et al. in WO 2004/048330. l -[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l-piperazinyl)methyl]-lH-indole dimesylate;monohydrate has already completed Phase 1 clinical trials. Based on phase I clinical trials results, we confirmed l -[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l -piperazinyl)methyl]-lH-indole of formula (I) as an active metabolite of l -[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl- 1 -piperazinyl)methyl]- 1 H-indoIe dimesylate monohydrate in human volunteers.

The development and understanding of the metabolism of l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-l -piperazinyl)methyl]-lH-indole dimesylate monohydrate is desirable for progression of science and necessary step in the commercialization of this compound. Therefore, there is a need to understand regarding metabolism and metabolites of l-t(2-bromophenyl)sulfonyI]-5-methoxy-3-[(4-methyl-l -piperazinyl)methyl]-lH-indole dimesylate monohydrate.

In order to improve pharmaceutical properties and efficacy of active metabolite, we performed salt selection program for l -[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[( l -piperazinyl)methyl]-lH-indole. Based on the results obtained, dimesylate dihydrate salt of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-piperazinyl)methyl]-lH-indole of formula (Π) is selected for further development along with the compound of formula (I).

l -[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[( l -piperazinyl)methyl]-lH-indole. NOTE THE DRUG IS WITH A METHYL

SCHEME 1

SCHEME2

Example 1: Preparation of l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-piperazinyl)methyl]-lH-indo

Step (i) & (ii): Preparation of 3-[(l-t-Butyloxycarbonyl piperazin-4-yl)methyI]-5-methoxy-lH-indole

Step (i):

Demineralized water (DM water) (660 mL) and N-Boc piperazine ( 150.0 grams, 0.8034 moles) were charged into a 2 Litres three necked round bottomed flask provided with a mechanical stirrer and a thermometer pocket. The mass was stirred for 10 minutes at 25 °C, to obtain a clear solution. Then acetic acid (32.5 mL, 0.5416 moles) was added to the above mass while maintaining the mass temperature at ~ 25 °C in 10 minutes. After completion of addition, the clear solution was stirred at 25 °C for 30 minutes.

To the above stirred mass at 25 °C, aqueous formaldehyde solution (81 mL, 30 % w/v, 0.81 moles) was added slowly through an addition funnel over a period of 30 minutes maintaining the mass temperature below 25 °C. During the addition, white slurry mass was formed. The resultant white slurry mass was stirred for another 1 hour at 25 – 30 °C. Methanol (MeOH) (300 mL) was added to the above mass to obtain a clear solution. The solution was further stirred for 30 minutes at 25 °C to obtain Mannich adduct.

Step (ii):

5-Methoxyindole (106.4 grams, 0.7238 moles) and methanol (550 mL) were charged into a 4 necked round bottom flask. The mass was stirred for 10 minutes at 25 °C to obtain a clear solution and then cooled the mass to 18 – 20 °C. The mannich adduct (prepared in above step) was added to the flask through an addition funnel maintaining mass temperature below 20 °C, over a period of 1 hour. The mass was further stirred for a period of 1 hour at 25 – 30 °C, while monitoring the progress of the reaction by thin layer chromatography (TLC).

After completion of the reaction (1 hour), DM water (2.2 Litres) and ethyl acetate (1

Litre) were added to the reaction mass and pH adjusted to 10.5 (on pH paper) with lye solution (80 mL) maintaining the mass temperature at 20 – 24 °C. The organic (product) layer was separated and the aqueous layer was further extracted with ethyl acetate (2 x 500 mL). The combined organic layer was washed with saturated brine solution (300 mL) and dried over anhydrous sodium sulfate. The organic layer was filtered free of sodium sulfate and concentrated under reduced pressure. n-Hexane (300 mL) was added to the residual mass and further concentrated under vacuum for removal of traces of ethyl acetate to obtain 272.2 grams of technical product.

Purity: 96.16 %;

Ή – NMR (CDC1₃, δ ppm): 1.45 (9H, s), 2.44 (4H, bm), 3.41 – 3.43 (4H, bm), 3.69 (2H, s), 3.87 (3H, s), 6.85 – 6.88 (1H, dd, J = 8.75, 2.23 Hz), 7.10 ( 1 H, d, J = 0.96 Hz), 7.19 (1 H, d, J = 2.24 Hz), 7.24 – 7.26 (1H, d), 8.04 (1H, bs);

Mass [M+H]⁺: 346.2.

Step (iii): Purification of 3-[(l-t-Butyloxycarbonyl piperazin-4-yl)methyI]-5-methoxy-lH-indole

n-Hexane (1.25 Litres) was taken in 2 Litres four necked round bottom flask equipped with thermometer pocket and mechanical stirrer and charged the above obtained technical compound (270.9 grams). The mass was stirred for 1 hour at 25 °C. The product was filtered through Buckner funnel under vacuum. The compound was washed with n-hexane (2 x 125 mL), sucked well and air dried at 25 °C for 20 hours to obtain 240.0 grams of above title compound. Yield: 96 %;

Purity: 97.09 %;

Ή – NMR (CDCI3, δ ppm): 1.45 (9H, s), 2.45 (4H, s), 3.43 (4H, s), 3.69 (2H, s), 3.86 (3H, s), 6.85 – 6.88 (1H, dd, J = 8.7, 2.2 Hz), 7.08 – 7.09 (1H, d, J = 1 .57 Hz), 7.19 ( 1 H, d, J = 2.2 Hz), 7.23 – 7.25 (l H, d, J = 8.77 Hz), 8.25 (lH, bs); –

Mass [M+H]⁺: 346.2.

Step (iv): Preparation of l-[(2-BromophenyI)sulfonyl]-5-methoxy-3-[(l-t-butyloxycarbonyl piperazin-4-yl)methyI]-lH-indole

Tetrahydrofuran (THF) (4.6 Litres) was charged into a reactor at 25 °C, followed by the addition of powdered potassium hydroxide (860.6 grams, 85 %, 13.06 moles) at 25 °C under stirring. THF (3 Litres) was charged into a 5 Litres, three necked round bottom flask, provided with a mechanical stirrer and thermometer pocket. 3-[(l -t-Butyloxycarbonyl piperazin-4-yl) methyl]-5-methoxy-lH-indole (obtained in above step) (1287.7 grams, 3.7324 moles) was charged into the flask at 25 °C and stirred the mass well for complete dissolution. Then the clear 3-[(l-t-Butyloxycarbonyl piperazin-4-yl) methyl]-5-methoxy-l H-indole solution, prepared as above, was slowly transferred to the reactor containing potassium hydroxide under stirring, maintaining the mass temperature below 25 °C. After completion of the addition, the reaction mass was stirred at 25 °C for 2 hours. A solution of 2-bromophenylsulfonyl chloride (1293.04 grams, 5.062 moles) dissolved in THF (2.0 Litres) was added to the reaction mass through an addition funnel at a constant rate in 30 minutes, maintaining the mass temperature at 20 – 32 °C. The reaction was exothermic in nature. The mass was further stirred for 1 hour at 25 – 30 °C.

As the reaction was progressing the mass thickened due to formation of potassium chloride. The progress of the reaction was monitored by TLC (Eluent system: Ethyl acetate) and the product is relatively non-polar. The starting material was absent as per TLC. A second lot of 2-bromophenylsuIfonyl chloride (52.5 grams, dissolved in 100 mL of THF) was added to the reaction mass at 28 °C and further stirred the mass at 28 °C for another hour to ensure completion of the reaction, The reaction mass was unloaded into neat carboys.

Ice-water (40 Litres) was charged into a clean reactor and the reaction mass unloaded in the carboys was quenched into the reactor under stirring and the pH of the resulting solution was found to be 1 1.5 (pH paper). The product was extracted with (15 Litres + 7.5 Litres + 7.5 Litres) ethyl acetate. The combined organic layer was washed with saturated brine solution (2 x 5 L) and dried over anhydrous sodium sulfate. Total volume of the organic layer was 30 Litres. A small portion of the organic layer was concentrated in laboratory and the solid obtained was analyzed to check the quality of the technical product.

Purity: 91.46 %;

Ή – NMR (CDC1₃, 5 ppm): 1.45 (9H, s), 2.42 – 2.43 (4H, bs), 3.42 (4H, bs), 3.62 (2H, s), 3.81 (3H, s), 6.83 – 6.86 (1H, m), 7.18 – 7.19 (1H, m), 7.38 – 7.45 (2H, m), 7.52 – 7.55 (1H, m), 7.64

– 7.66 (2H, m), 8.06 – 8.08 (1H, d, J = 7.76 Hz);

Mass [M+Hf : 564.3, 566.4.

The organic layer.was taken for further workup and the technical product was purified without isolation.

Step (v): Purification of l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-t-butyloxycarbonyl piperazin-4-yI)methyI]-lH-indole

The above organic layer was filtered (30 Litres) and charged into a reactor. Solvent was distilled off under vacuum at 40 – 45 °C to obtain solids. Isopropanol (14 Litres) and methanol (7 Litres) were charged into the reactor containing the solid product. The reaction mass was heated to reflux temperature (70.5 °C) under stirring and further stirred the mass at reflux for two hours to ensure formation of clear solution.

Reaction mass was then slowly cooled to room temperature (30 minutes) with room temperature water circulation in the jacket. It was further cooled to 18 °C and stirred for 1 hour. The product was centrifuged and the cake on the centrifuge was washed with isopropanol / methanol mixture (1.6 Litres + 0.8 Litres). It was sucked well and air dried at 40 – 45 °C for 4 hours in tray driers.

Weight of compound: 1554.8 grams, Cream colored crystalline powder, Yield: 77.7 %

Purity: 99.42 %;

Ή – NMR (CDCI₃, δ ppm): 1.45 (9H, s), 2.42 (4H, bs), 3.42 (4H, bs), 3.63 (2H, s), 3.82 (3H, s), 6.83 – 6.86 (lH, dd, J = 8.34, 2.09 Hz), 7.19 (1 H, d, J = 2.0 Hz), 7.36 – 7.40 (1 H, t, J = 7.14 Hz), 7.43 – 7.47 (1H, t, J = 7.56 Hz), 7.52 – 7.55 (1 H, d, J = 8.95 Hz), 7.64 – 7.66 (2H, m), 8.06

– 8.08 ( 1H, d, J = 7.87 Hz); Mass: [M+H]⁺: 564.3, 566.3.

Step (vi): Preparation of l-((2-bromophenyl)snlfonyI]-5-methoxy-3-[(l-piperazinyl)methyl]-lH-indole dihydrochloride

l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-t-butyloxycarbonyl-l -piperazinyl)methyl]-lH-indole (20.2 grams, 0.03578 M, obtained in the above step) was suspended in 250 mL of absoliite ethanol at 25 °C and then added 20 mL of 30 % (w/w) aqueous hydrochloric acid drop wise under stirring over a period of 30 minutes, whereby a clear solution was obtained. The reaction was exothermic and temperature went upto 38 °C. The mass was further heated at reflux for 4 hours. During this period solids separated. The mass was stirred for another 2 hours at reflux. The progress of the reaction was monitored by thin layer chromtography. After completion of the reaction, the mass was cooled to 25 °C and filtered the solids under suction. The solid on the filter was washed with 30 mL of absolute ethanol and the mass was dried under rotavacuum at 40 – 45 °C for 1 hour to obtain l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[( 1 -piperazinyl)methyl]- 1 H-indole dihydrochloride (19.28 grams).

Purity: 99.8 %,

Mass: [M+H]⁺: 464.2, 466.2.

Step (vii): Preparation of l-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(l-piperazinyl)methyl]-lH-indole

The above obtained compound (19.09 grams) was suspended in demineralised water (300 mL) and cooled to 15 – 20 °C. The mass was basified to pH 10.5 to 1 1.0 by adding 40 % (w/w) lye solution, maintaining mass temperature below 20 °C under nitrogen atmosphere. The product was extracted with (2 x 150 mL) ethylacetate. The combined organic layer was washed with (100 mL) saturated brine solution, dried over anhydrous sodium sulfate and

solvent removed under rotavacuum at 40 – 45 °C to obtain the title compound (15.91 grams).

Yield: 96. 4 %

Purity: 99.89 %,

DSC (5 °C / minutes): 99.6 °C;

TGA (5 °C / minutes): 0.76 %;

Ή – NMR (CDCI₃, δ ppm): 1.85 (1H, s), 2.44 (4H, bs), 2.86 – 2.88 (4H, t), 3.59 (2H, s), 3.76 (3H, s), 6.82 – 6.84 (lH, dd, J = 9.0, 2.45 Hz), 7.20 – 7.21 (1H, d, J = 2.28 Hz), 7.33 – 7.37 (1H, dt, J = 7.48 Hz), 7.41 – 7.44 (1 H, t), 7.52 – 7.54 (1H, d, J = 7.65 Hz), 7.62 – 7.64 (2H, m), 8.01 – 8.03 (1H, dd, J = 7.98, 1.15 Hz);

Mass: [M+H]⁺: 464.2, 466.2.

Example 2: Preparation of l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-piperazinyl)methyl]-lH-in

Step (i) & (ii): Preparation of 3-[(l-t-Butyloxycarbonyl piperazin-4-yl)methyl]-5-methoxy-lH-indoIe

Step (i):

Step (ii):

5-Methoxy indole (106.4 grams, 0.7238 moles) and methanol (550 mL) were charged into a 4 necked round bottom flask. The mass was stirred for 10 minutes at 25 °C to obtain a clear solution and then cooled the mass to 18 – 20 °C. The mannich adduct (prepared in above step) was added to the flask through an addition funnel maintaining mass temperature below 20 °C, over a period of 1 hour. The mass was further stirred for a period of 1 hour at 25 – 30 °C, while monitoring the progress of the reaction by thin layer chromatography (TLC).

After completion of the reaction (1 hour), DM water (2.2 Litres) and ethyl acetate (1 Litre) were added to the reaction mass and pH adjusted to 10.5 (on pH paper) with lye solution (80 mL) maintaining the mass temperature at 20 – 24 °C. The organic (product) layer was separated and the aqueous layer was further extracted with ethyl acetate (2 x 500 mL). The combined organic layer was washed with saturated brine solution (300 mL) and dried over anhydrous sodium sulfate. The organic layer was filtered free of sodium sulfate and concentrated under reduced pressure. n-Hexane (300 mL) was added to the residual mass and further concentrated under vacuum for removal of traces of ethyl acetate to obtain 272.2 grams of technical product.

Purity: 96.16 %;

Ή – NMR (CDC1₃, δ ppm): 1.45 (9H, s), 2.44 (4H, bm), 3.41 – 3.43 (4H, bm), 3.69 (2H, s), 3.87 (3H, s), 6.85 – 6.88 (1H, dd, J = 8.75, 2.23 Hz), 7.10 (1Ή, d, J = 0.96 Hz), 7.19 (1H, d, J = 2.24 Hz), 7.24 – 7.26 (1 H, d), 8.04 (1H, bs);

Mass [M+H]⁺: 346.2.

Step (iii): Purification of 3-[(l-t-ButyloxycarbonyI piperazin-4-yl)methyl]-5-methoxy-lH-indole

Purity: 97.09 %;

Ή – N R (CDC1₃, δ ppm): 1.45 (9H, s), 2.45 (4H, s), 3.43 (4H, s), 3.69 (2H, s), 3.86 (3H, s), 6.85 – 6.88 (lH,jdd, J = 8.7, 2.2 Hz), 7.08 – 7.09 (1 H, d, J = 1.57 Hz), 7.19 ( 1H, d, J = 2.2 Hz),

7.23 – 7.25 (1H, d, J = 8.77 Hz), 8.25 (1H, bs);

Mass [M+H]⁺: 346.2.

Step (iv): Preparation of l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-t-butyloxycarbonyl pipera

the addition, the reaction mass was stirred at 25 °C for 2 hours. A solution of 2- bromophenylsulfonyl chloride (1293.04 grams, 5.062 moles) dissolved in THF (2.0 Litres) was added to the reaction mass through an addition funnel at a constant rate in 30 minutes, maintaining the mass temperature at 20 – 32 °C. The reaction was exothermic in nature. The mass was further stirred for 1 hour at 25 – 30 °C.

As the reaction was progressing the mass thickened due to formation of potassium chloride. The progress of the reaction was monitored by TLC (Eluent system: Ethyl acetate) and the product is relatively non-polar, The starting material was absent as per TLC. A second lot of 2-bromophenylsulfony] chloride (52.5 grams, dissolved in 100 mL of THF) was added to the reaction mass at 28 °C and further stirred the mass at 28 °C for another hour to ensure completion of the reaction. The reaction mass was unloaded into neat carboys.

Ice-water (40 Litres) was charged into a clean reactor and the reaction mass unloaded in the carboys was quenched into the reactor under stirring and the pH of the resulting solution was 11.5 (pH paper). The product was extracted with (15 Litres + 7.5 Litres + 7.5 Litres) ethyl acetate. The combined organic layer was washed with saturated brine solution (2 x 5 L) and dried over anhydrous sodium sulfate. Total volume of the organic layer was 30 Litres. A small portion of the organic layer was concentrated in laboratory and the solid obtained was analyzed to check the quality of the technical product.

Purity: 91.46 %;

Ή – NMR (CDC , δ ppm): 1.45 (9H, s), 2.42 – 2.43 (4H, bs), 3.42 (4H, bs), 3.62 (2H, s), 3.81 (3H, s), 6.83 – 6.86 (1 H, m), 7.18 – 7.19 (1H, m), 7.38 – 7.45 (2H, m), 7.52 – 7.55 (1 H, m), 7.64 – 7.66 (2H, m), 8.06 – 8.08 (1 H, d, J = 7.76 Hz);

, Mass [M+H : 564.3, 566.4.

The organic layer was taken for further workup and the technical product was purified without isolation.

Step (v): Purification of l-[(2-BromophenyI)suIfonyl]-5-methoxy-3-[(l-t- butyloxycarbonyl piperazin-4-yl)methyl]-lH-indole

The above organic layer was filtered (30 Litres) and charged into a reactor. Solvent was distilled off under vacuum at 40 – 45 °C to obtain solids. Isopropanol (14 Litres) and

methanol (7 Litres) were charged into the reactor containing the solid product. The reaction mass was heated to reflux temperature (70.5 °C) under stirring and further stirred the mass at reflux for two hours to ensure formation of clear solution.

Reaction mass was then slowly cooled to room temperature (30 minutes) with room temperature water circulation in the jacket. It was further cooled to 18 °C and stirred for 1 hour. The product was centrifuged and the cake on the centrifuge was washed with isopropanol / methanol mixture (1 .6 Litres + 0.8 Litres). It was sucked well and air dried at 40

– 45 °C for 4 hours in tray driers.

Weight of compound: 1554.8 grams, Gream colored crystalline powder, Yield: 77.7 %

Purity: 99.42 %;

Ή – NMR (CDQlj, δ ppm): 1.45 (9H, s), 2.42 (4H, bs), 3.42 (4H, bs), 3.63 (2H, s), 3.82 (3H, s), 6.83 – 6.86 (1H, dd, J =.8.34^* 2.09 Hz), 7.19 (1H, d, J = 2.0 Hz), 7.36 – 7.40 (1H, t, J = 7.14 Hz), 7.43 – 7.47 (1H, t, J = 7÷56 Hz), 7.52 – 7.55 (lH, d, J = 8.95 Hz), 7.64 – 7.66 (2H, m), 8.06

– 8.08 (1 H, d, J = 7.87 Hz); Mass: [M+H]⁺: 564.3, 566.3.

Step (vi): Preparation of l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l-piperazinyl)methyl)-l

l-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(l -t-butyIoxycarbonyl piperazin-4-yl)methyl]-lH-indole (obtained in the above step, 1540 grams, 2.73 mole) was dissolved in acetone (30.8 Litres) and charged into a glass lined reactor. The temperature of the reaction mass was raised to reflux temperature (56 °C). Methanesulfonic acid (920 grams, 9.57 moles) diluted with acetone (6 Litres) was added to the above mass at reflux temperature, slowly over a period of 30 minutes, through an addition funnel. During addition vigorous reflux was observed. The reaction mass was a clear solution before and after the addition of methanesulfonic acid solution. After stirring for ~ 90 minutes at reflux, thick mass of solids separated out. The progress of the reaction was monitored by TLC. The reaction was completed in 4 hours. Then the mass was cooled to 25 °C and further stirred for two hours at 25 °C. The product was filtered through nutsche filter under vacuum. The product on the nutsche filter was washed with acetone (8 Litres). The material was unloaded into trays and air dried at 30-35 °C for 4 hours in a tray drier. Weight of the product: 1.61 Kg (off white with pinkish tinge).

Yield: 90 %;

Salt content (dimesylate): 32.1 % w/w;

Purity: 99.97 %;

Ή – NMR (D₂0, 5 ppm): 2.64 (6H, s), 3.48 (4H, bs), 3.53 (4H, bs), 3.70 (3H, s), 4.50 (2H, s), 6.75 – 6.78 (1H, dd, J = 8.97, 1.92 Hz), 7.11 (1H, d, J = 1.78 Hz), 7.32 – 7.34 ( 1H, t, J = 9.28 Hz), 7.34 – 7.38 (lH, t, J = 7.63 Hz), 7.44 – 7.48 ( 1H, d, 3 = 7.76 Hz), 7.54 – 7.56 (2H, d, J = 7.85 Hz), 8.06 (1H, s), 8.15 – 8.17 (2H, d, J = 7.87 Hz);

Mass: [M+H]⁺: 464.2, 466.2.

Step (vii): Preparation of l-{(2-Bromophenyl)suIfonyl]-5-methoxy-3-[(l-piperazinyl)methyl]-l

Acetone (24.15 L) was taken in a Glass Lined Reactor at 25-30 °C, followed by l-[(2-Bromo phenyl)sulfonyl]-5-methoxy-3-[(l-piperazinyl)methyl]-lH-indole dimesylate (obtained in the above step) (1.61 Kg) and the resulting mass was stirred To obtain slurry. DM water (4.0 L) was added to the reactor and then the mass temperature was raised to reflux temperature (56.0-57.5 °C). A clear solution was obtained at reflux. It was maintained for 15 minutes. The mass was cooled to 45-50 °C and added activated carbon (161 grams) to the mass and stirred the mass for 45 minutes at reflux temperature: It was filtered hot into another reactor, which was maintained at 50 °C. The clear filtrate was allowed to cool on its own, under nitrogen

blanket. Solids separated when the mass temperature was ~ 44 °C. The mass was allowed to cool to room temperature (30-35 °C) and then it was further cooled at 10-12 °C for 2 hours. The product was centrifuged, washed with acetone (5 L) and sucked well. The wet product (weight: 1.5 Kg) was spread into trays and dried in a tray drier at 40-45 °C for 7.5 hours, till organic volatile impurities are below the allowable limits. Weight of the dry product obtained: 1.3 Kg. Yield: – 76.5 %

Purity: 99.98 %;

Melting range (°C): 203.8 – 205.3;

Salt content (Dimesylate): 28.26 %;

Moisture Content: 5.2 %;

TGA: 4.9 %; ,

Ή – NMR (D₂0, δ ppm): 2.65 (6H, s), 3.48 (8H, bm), 3.71 (3H, s), 4.48 (2H, s), 6.77 – 6.80 (1H, dd, J = 9.18, 2.24 Hz), 7.12 – 7.13 (1 H, d, J = 2.12 Hz), 7.35 – 7.37 (1H, d, J = 9.06 Hz), 7.37 – 7.41 (1 H, t, J = 7.98 Hz), 7.46 – 7.50 (1 H, t, J = 7.66 Hz), 7.57 – 7.58 (1 H, d, J = 7.86 Hz), 8.06 ( 1H, s), 8.17 – 8.20 (1H, dd, J = 7.95, 0.87 Hz),

Mass [M+H]⁺: 464.2, 466.1 ;

PATENT

WO 2004/048330

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2004048330

REFERENCES

http://www.avarx.com/search/showOpportunityDetails?asset_id=2424
Phase II
Alzheimer’s disease; Schizophrenia
Phase I
Attention-deficit hyperactivity disorder; Cognition disorders; Parkinson’s disease

05 Jan 2016
Suven Life Sciences has patent protection for chemical entities targeting serotonin receptors for the treatment of neurodegenerative disorders in Canada, Africa and South Korea
11 Dec 2015
Suven Life Sciences receives patent allowance for chemical entities targeting serotonin receptors in Eurasia, Europe, Israel and Macau
01 Oct 2015
Phase-II clinical trials in Schizophrenia in USA (PO)

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Brc1ccccc1S(=O)(=O)n4cc(CN2CCN(C)CC2)c3cc(ccc34)OC

Saperconazole

February 20, 2016 8:45 am / Leave a comment

Saperconazole

CAS 110588-57-3

4-[4-[4-[4-[[2-(2,4-Difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one

(±)-1-sec-butyl-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-D2-1,2,4-triazolin-5-one

2-butan-2-yl-4-[4-[4-[4-[[(2R,4S)-2-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one

R-66905

MF: C35H38F2N8O4

MW: 672.72

Percent Composition: C 62.49%, H 5.69%, F 5.65%, N 16.66%, O 9.51%

Properties: Crystals from acetonitrile, mp 189.5°. Poorly sol in water.

Melting point: mp 189.5°

Therap-Cat: Antifungal.

Janssen Pharmacuetica N.V.

PHASE 2

Systemic fungal diseases (systemic mycoses) are typically chronic conditions that develop very slowly. These diseases are often induced by opportunistic causative fungi that are not normally pathogenic and commonly live in the patient’s body or are commonly found in the environment. While systemic fungal diseases used to be relatively rare in temperate countries, there has been an increasing incidence of numerous life-threatening systemic fungal infections that now represent a major threat to susceptible patients. Susceptible patients include immunocompromised patients, particularly those already hospitalized, and patients compromised by HIV infection, ionizing irradiation, corticosteroids, immunosuppressives, invasive surgical techniques, prolonged exposure to antimicrobial agents, and the like, or by diseases or conditions such as cancer, leukemia, emphysema, bronchiectasis, diabetes mellitus, burns, and the like. The symptoms manifested by these fungal diseases are generally not intense, and may include chills, fever, weight loss, anorexia, malaise, and depression.
The most common systemic fungal infections in humans are blastomycosis, candidosis, aspergillosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, and cryptococcosis.
Fungal diseases are often confined to typical anatomic sites, and many involve a primary focus in the lung, with more characteristic manifestations of specific fungal infections appearing once the infection spreads from a primary site. For example, blastomycosis primarily involves the lungs, and occasionally spreads to the skin. Similarly, the primary form of coccidioidomycosis occurs as an acute, benign, self-limiting respiratory disease, which can then progress to a chronic, often-fatal infection of the skin, lymph glands, liver, and spleen. Other infectious diseases such as paracoccidioidomycosis and candidiasis present in different manners, and depending on the etiology, may exhibit several forms involving internal organs, the lymph nodes, skin, and mucous membranes. Diagnosis of specific fungal diseases can be made by isolation of the causative fungus from various specimens, such as sputum, urine, blood, or the bone marrow, or with certain fungus types, through evidence of tissue invasion.
Many patients suffering from severe systemic fungal infections are hardly, or not at all, able to receive medication via oral administration, as such patients are often in a coma or suffering from severe gastroparesis. As a result, the use of insoluble or sparingly soluble antifungals such as itraconazole free base, which are difficult to administer intravenously to treat such patients, is significantly impeded.
Local or superficial fungal infections are caused by dermatophytes or fungi that involve the outer layers of the skin, nails, or hair. Such infections may present as a mild inflammation, and can cause alternating remissions and eruptions of a gradually extending, scaling, raised lesion. Yeast infections, such as candidiasis and oral candidiasis (thrush), are usually localized to the skin and mucous membranes, with the symptoms varying depending on the site of infection. In many instances, such infections appear as erythematous, often itchy, exudative patches in the groin, axillas, umbilicus, between toes, and on finger-webs. Oral thrush involves an inflamed tongue or buccal mucosa, typically accompanied by white patches of exudate. Chronic mucocutaneous candidiasis is manifested in the form of red, pustular, crusted, thickened lesions on the forehead or nose.Itraconazole or (±)-£is-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(lH-l-2,4-triazol-l- ylmethyl)- 1 ,3-dioxolan-4-yl]methoxy]phenyl]- 1 -ρiperazinyl]phenyl]-2,4-dihydro-2-( 1 – methyl-propyl)-3H-l,2,4-triazol-3-one, is a broadspectrum antifungal compound developed for oral, parenteral and topical use and is disclosed in US-4,267,179.

Its difluoro analog, saperconazole or (±)-_πs-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2- ( 1H- 1 ,2,4-triazol- 1-yl-methyl)- 1 ,3-dioxolan-4-yl]methoxy]phenyl] – 1 -piperazinyl]- phenyl]-2,4-dihydro-2-(l-methylpropyl)-3H-l,2,4-triazol-3-one, has improved activity against Aspergillus spp. and is disclosed in US-4,916,134. Both compounds exist as a mixture of four stereoisomers.

The development of effϊcaceous pharmaceutical compositions of itraconazole and saperconazole is hampered considerably by the fact that said compounds are only very sparingly soluble in water. The solubility of both compounds can be increased by complexation with cyclodextrins or derivatives thereof as described in WO 85/02767 and US-4,764,604.

Unexpectedly, it has now been found that each of the individual stereoisomers of itraconazole and saperconazole have greater water solubility than the diastereomeric mixtures of said compounds, in particular when complexed with cyclodextrin or its derivatives. As a result, pharmaceutical compositions having good bioavailability, yet comprising less cyclodextrin as a complexing agent, can be prepared. The present invention is concemced with the stereoisomeric forms of itraconazole (X = CI) and saperconazole (X = F), which may be represented by the formula

cis-©,and the pharmaceutically acceptable acid addition salt forms thereof. The three asterisks indicate the three chiral centers, and ‘cis’ means that the (lH-l,2,4-triazol-l-ylmethyl) moiety and the substituted phenoxy moiety are located at the same side of the plane defined by the 1,3-dioxolane ring.

The four possible stereoisomeric cis forms can be described using various rules of nomenclature. The following tables show the correlation among the C. A. stereochemical descriptor, the absolute configuration at each of the chiral centers and the specific optical

20 rotation [α]_jj in 1% methanol (itraconazole; table I) (saperconazole; table H).

Table I

itraconazole

Table π

saperconazole

Synthesis

US 4916134

http://www.google.co.in/patents/US4916134

PATENT

WO 2005118577

Itraconazole is a broad-spectrum antifungal agent developed for oral, parenteral and topical use, and is disclosed in U.S. Patent No. 4,267,179. Itraconazole is a synthetic triazole derivative that disrupts the synthesis of ergosterol, the primary sterol of fungal cell membranes. This disruption appears to result in increased permeability and leakage of intracellular content, and at high concentration, cellular internal organelles involute, peroxisomes increase, and necrosis occurs.
As set forth in the USP Dictionary of Drug Names and USAN, itraconazole is defined as 4-[4-[4-[4- [[2-(2,4-dichlorophenyl)-2-(lH-l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl] methoxy]phenyl]-l-piperazinyl]phenyl]- 2,4-dihydro-2-(l-methylpropyl)-3H-l,2,4-triazol-3-one, or alternatively, as (±)-l-5ec-butyl-4-[/7-[4-[/7-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(lH-l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl]methoxy]phenyl]-l-piperazinyl]phenyl]-Δ²-l,2,4-triazolin-5-one. There are three asymmetric carbons in itraconazole: one in the sec-butyl side chain on the triazolone and two in the dioxolane ring. As a result, eight possible stereoisomers of itraconazole exist: (R,R,R), (S,S,S), (R,R,S), (S,S,R), (R,S,S), (R,S,R), (S,R,S), and (S,R,R).
(±)Cz^‘s-Itraconazole comprises a mixture of only those isomers that describe a “cis” relationship in the dioxolane ring, i.e., the (1Η-1, 2, 4-triazol-l-ylmethyl) moiety and the substituted phenoxy moiety are located on the same side of a plane defined by the 1, 3-dioxolane ring. By convention, the first represented chiral center is at the C-2 position of the dioxolane ring, the second is at the C-4 position of the dioxolane ring, and the third is in the sec-butyl group. Hence, (±)c.s-itraconazole is a mixture of (R,S,S), (R,S,R), (S,R,S) and (S,R,R) isomers.
The four possible stereoisomeric cis forms of itraconazole, and
diastereomeric pairs thereof, are described in more detail in U.S. Patent Nos. 5,474,997 and 5,998,413. In general, the individual stereoisomeric forms of c s-itraconazole have antifungal properties, and contribute to the overall activity of (±)cw-itraconazole.
(±)Ciy-Itraconazole free base is only very sparingly soluble in water, and thus it is extremely difficult to prepare effective pharmaceutical compositions containing the same. A number of means have been used to increase the solubility of itraconazole free base, including complexing or co-formulation with cyclodextrins or derivatives thereof, as described in U.S. Patent No. 4,764,604, U.S. Patent No.5,998,413, and U.S. Patent No. 5,707,975, and coating beads with a film comprising a hydrophilic polymer and itraconazole, as described in U.S. Patent No. 5,633,015.
[0014] Another approach to increase solubility of itraconazole focuses on preparation of the stereoisomers of c s-itraconazole, and in particular (2R, 4S) itraconazole, which may comprise a mixture of two diastereomers ((R,S,S) and
(R,S,R)), as described in U.S. Patent Nos. 5,414,997 and 5,998,413.

Commercially available itraconazole (SPORANOX^® brand (±)cis-itraconazole, Janssen Pharmaceutica Products, L.P., Titusville, NJ, U.S.A.) is a free base and a racemic mixture of the cis isomer in the dioxolane ring and is represented by structural formula (I):

(i)

SPORANOX has been approved for use as an antifungal agent for treating immunocompromised and non-immunocompromised patients having: blastomycosis (pulmonary and extrapulmonary); histoplasmosis, including chronic cavitary pulmonary disease and disseminated non-meningeal histoplasmosis; and aspergillosis. In addition, in non-immunocompromised patients, it has been approved for treatment of onychomycosis. See generally, Physician ‘s Desk Reference, 56^th ed. (2002). The compound has also been investigated for use in coccidioidomycosis, cryptococcosis, dermatophyte, and candidiasis infections.
Adverse effects associated with the administration of (±)cts-itraconazole free base include nausea, vomiting, anorexia, headache, dizziness, hepatotoxicity, and inhibition of drug metabolism in the liver, leading to numerous, clinically significant, adverse drug interactions. See, Physician ‘s Desk Reference, 56^th ed. (2002); Honig et al., J. Clin. Pharmacol. 33:1201-1206 (1993) (terfenadine interaction); Gascon and Dayer, Eur. J. Clin. Pharmacol., 41_:573-578 (1991) (midazolam interaction); and Neuvonen et al, Clin. Pharmacol. Therap., 60:54-61 (1996) (lovastatin interaction). Reactions associated with hypersensitivity, such as urticaria and serum liver enzymes elevation, are also associated with the administration of the drug. A more serious, though less common, adverse effect is hepatotoxicity. See, e.g., Lavrijsen et al., Lancet, 340:251-252 (1992).
In addition, as discussed herein, c/s-itraconazole free base is only very sparingly soluble in water. Thus, due to its relative non-polarity and insolubility, itraconazole free base suffers from two other drawbacks: it cannot be readily formulated in parenteral solution, and it does not effectively penetrate the blood-brain barrier. The latter problem is exacerbated by drug interactions, such as one observed between itraconazole free base and valproate, as described in Villa et al. , Rev. Inst. Med. Trop., Sao Paulo, pp. 231-234 (Jul-Aug 2000), which is incorporated by reference herein in its entirety. In another case of CNS fungal infection, extremely high doses of itraconazole free base were used to treat residual aspergillus infection, as reported by Imai et al., Intern. Med, 38(10):829-832 (1999), which is incorporated by reference herein in its entirety. As a result, numerous therapeutic indications that require rapid achievement of effective blood levels or access to the CNS are difficult to treat or beyond treatment with itraconazole free base.
Furthermore, the emergence of antifungal resistance (e.g., in Aspergillus fumigatus isolates as described by Dannaoui et al., J. Antimicrob. Chemother., 47:333-340 (2001), which is incorporated by reference herein in its entirety) presents an added challenge to the efficacy of itraconazole free base. For those strains of fungi that show resistance, high and relatively constant levels of itraconazole free base must be produced in the target organs of infected patients.
Over the years, a number of formulation routes have been used in order to enhance the adsorption and bioavailability of itraconazole. For example, the currently marketed SPORANOX^® solid dosage capsule form of itraconazole free base utilizes sugar-based beads coated with a hydrophilic polymer and an amorphous film of itraconazole. See Physicians Desk Reference, 56^th ed., pp.1800- 1804 (2002); and U.S. Patent No. 5,633,015. This dosage form requires up to two capsules three times daily depending on the condition being treated.
Even with the various formulation routes, the dosage amounts and dose frequency for itraconazole can be burdensome to patients. In addition, administration of existing dosage forms of itraconazole have shown significant variability in bioavailability and adsorption, which likely results from food effects. See, Physician ‘s

Desk Reference, 56^th ed., pp. 1800-1804 (2002). Thus, it would be desirable to increase bioavailability and adsorption and decrease the per-dose pill count and decrease dosing frequency (e.g., twice a day to once a day) associated with administration of itraconazole in order to provide an improvement over current therapy, particularly with regard to patient compliance, convenience, ease of ingestion, especially with regard to immunocompromized polypharmacy patients (e.g., AIDS or cancer patients).

Posaconazole and Saperconazole Chemistry and Uses
Other related conazoles have also been discovered and used as antifungals. Two of these conazoles that are closely structurally related to itraconazole are posaconazole and saperconazole. Posaconazole (CAS Registry Number: 171228-49-2; CAS Name: 2,5-Anhydro-l ,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[l -[(1 S,2S)- 1 -ethyl-2-hydroxypropyl]- 1 ,5-dihydro-5-oxo-4H- 1 ,2,4-triazol-4-yl]phenyl]- 1 -piperazinyl]phenoxy]methyl]- 1 -( 1 H- 1 ,2,4-triazol- 1 -yl)-D-t/Veo-pentitol; Additional Name: (3R-c s)-4-[4-[4-[4-[5-(2,4-difluorophenyl)-5-(l,2,4-triazol-l-ylmethyl)tetrahydrofuran-3-ylmethoxy]phenyl]piperazin- 1 -yl]phenyl]-2-[l (S)-ethyl-2(S)-hydroxypropyl]-3,4-dihydro-2H-l,2,4-triazol-3-one) is represented by structural formula (II):

(II)

Saperconazole (CAS Registry Number: 110588-57-3; CAS Name: 4-[4-[4-[4-[[2-(2,4-Difluorophenyl)-2-(lH-l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl]methoxy]phenyl]- 1 -piperazinyl]phenyl]-2,4-dihydro-2-(l -methylpropyl)-3H- 1 ,2,4-triazol-3-one; Additional Name: (±)-l-sec-butyl-4-[ -[4-| -[[(2R* 4S*)-2-(2,4- difluorophenyl)-2-( 1 H- 1 ,2,4-triazol- 1 -ylmethyl)- 1 ,3 -dioxolan-4-yl]methoxy]phenyl]- 1 -piperazinyl]phenyl]-Δ2-l,2,4-triazolin-5-one) is represented by structural formula (III):

(III)

Consequently, there is a need for soluble forms of conazoles including cis itraconazole, posaconazole and saperconazole that can be readily formulated for use in various modes of administration, including parenteral and oral administration.

PATENT

EP 0283992

A. Preparation of intermediates: Example 1a) utilizing water separator, by 200 parts of glycerin, 90 parts of 1- (2,4-difluorophenyl) -2- (1H-1,2,4- three mixture of 1-yl) ethanone, 600 parts of methanesulfonic acid, 190 parts of benzene was stirred first at reflux for 3 hours, then stirred at room temperature overnight. The reaction mixture was added dropwise a solution of sodium bicarbonate. The product was extracted with chloroform, the extract was washed with water, dried, filtered and evaporated. With 4-methyl-2-pentanone and the residue triturated product was filtered off and dried, yielding 80 parts (67.2%) (cis + trans) -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolane-4-methanol (intermediate 1).

b) by 69 parts of 3,5-dinitrobenzoyl chloride, 80 parts of (cis + trans) -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolane-4-methanol, 400 parts of pyridine and 520 parts of dichloromethane was stirred at room temperature for 3 hours. The reaction mixture was evaporated, and the residue was dissolved in water. The product was extracted with chloroform. The extract was dried, filtered and evaporated. The residue was subjected to silica gel column chromatography, eluting with chloroform / methanol (99:1v / v). Pure fractions were collected, the eluent was evaporated, to give 90 parts (70.4%) of cis -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1 ylmethyl) -1,3-dioxolane-4-methanol 3,5-dinitrobenzoate (residue) (intermediate 2).

c) by 90 parts of (cis) -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxo- dioxolan-4-methanol 3,5-dinitrobenzoate, 16 parts of 50% sodium hydroxide solution, 800 parts of 1,4-dioxane, 400 parts of water and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and the product was extracted with dichloromethane, extracts washed with water, dried, filtered and evaporated. With 4-methyl-2-pentanone and the residue triturated product was filtered off and dried, yielding 30 parts (56.0%) of cis -2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1,3-dioxolane-4-methanol (residue) (intermediate 3).

d) by 11.4 parts of methanesulfonyl chloride, 25 parts of cis -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1, mixture of 1,3-dioxolane-4-methanol, 300 parts of pyridine, 390 parts of dichloromethane was stirred at room temperature for 3 hours. The reaction mixture was evaporated, and the residue was dissolved in chloroform. The organic phase was dried, filtered and evaporated. The residue was triturated with dipropyl ether. The product was filtered off and dried, yielding 29.4 parts (93.2%) of cis -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) – 1,3-dioxolane-4-methanol methanesulfonate (residue) of intermediate 4).

In a similar manner there were also prepared: cis-2- (2,4-difluorophenyl) -2- (1H- imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol mesylate ethanedioate (1/1) (interm. 5).

Example 2a) over 2 hours, dissolved in 100 parts of pyridine 121.2 parts of 2-naphthalenesulfonyl chloride was added dropwise to a stirred, was dissolved in 1300 parts of dichloromethane, and 122.0 parts of (cis + trans ) -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolane-4-methanol and 1.0 parts of N, N- dimethyl-4-pyridin-amine solution. Upon completion, stirring was continued at room temperature overnight. The reaction mixture was washed twice with water, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with chloroform. Pure fractions were collected, the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 102.3 parts (51.0%) of cis – [[2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-yl-methyl ) -1,3-dioxolan-4-yl] methyl] -2-naphthalene sulfonate; mp139.5 ℃ (intermediate 6).

Example 3a) at 70 ℃, under nitrogen atmosphere, by 9.0 parts of 4- [4- (4-nitrophenyl) -1-piperazinyl] phenol, 13.6 parts of cis-2- [2,4- difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolane-4-methanol methanesulfonate ester, 6.0 parts of potassium hydroxide and 90 parts of a mixture of DMF was stirred overnight. After cooling, the reaction mixture was diluted with water. The precipitated product was filtered off and purified by silica gel column chromatography, the chloroform / ethyl acetate / hexane / methanol (500:300:200:0.5v / v / v / v) mixture as eluent. Pure fractions were collected, the eluent was evaporated. The residue was crystallized 4-methyl-2-pentanone. The product was filtered off and dried, yielding 6.69 parts (38.5%) of cis -1- [4 – [[2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol – 1- ylmethyl) -1,3-dioxolan-4-yl] methoxy) phenyl] -4- (4-nitrophenyl) piperazine; mp169.8 ℃ (Intermediate 7) .

b) at atmospheric pressure, 50 ℃, with 2 parts of 5% palladium – on-charcoal catalyst by 38.3 parts of cis -1- [4 – [[2- (2,4-difluorophenyl) -2- (1H -1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -4- (4-nitrophenyl) piperazine, 2 parts of a solution of thiophene (4% solution in methanol) and 600 parts of 2-methoxy-ethanol mixture. After absorption of the calculated amount of hydrogen finished, hot filtered to remove the catalyst, and the filtrate was saturated with water. After cooling, the precipitated product was filtered off, washed with water and 2-propanol and crystallized from 1,4-dioxane. The product was filtered off and dried, yielding 22.7 parts (62.6%) of cis-4- [4- [4 – [[2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] aniline; mp193.0 ℃ (interm. 8).

Example 4a) by 10 parts of 2,4-dihydro-4- [4- [4- [4-methoxyphenyl) -1-piperazinyl] phenyl] -3H-1,2,4- triazol-3-one (U.S. Patent No. 4,267,179 in the implementation of the method in Example ⅩⅦ obtained), 1.5 parts of sodium hydride (50% dispersion), 300 parts of the mixture consisting of dimethyl sulfoxide, at 60 ℃ under a nitrogen atmosphere begging, stirring, until no bubble up. Was then added 5.24 parts of 2-bromopropane, and at 60 ℃, stirring was continued for 1 hour. Further added 1.5 parts of sodium hydride (50% dispersion) and stirring was continued until no more bubble up. Then 5.24 parts of 2-bromopropane was added, and the whole was stirred for 1 hour at 60 ℃. The reaction mixture was cooled, poured into water and the product was extracted with chloroform. The extract was washed with water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography, eluting with chloroform / methanol (99:1v / v). Pure fractions were collected, the eluent was evaporated, the residue was crystallized in 1-butanol, yielding 5.2 parts (47% (2,4-dihydro-4- [4- [4- (4-methoxyphenyl ) -1-piperazinyl] phenyl] -2- (1-methylethyl) -3H-1,2,4- triazol-3-one; mp209.5 ℃ (intermediate 9).

b) by 4.7 parts of 2,4-dihydro-4- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -2- (1-methylethyl) -3H-1,2,4- triazol-3-one, a mixture of 75 parts of 48% aqueous hydrobromic acid was stirred at reflux for 3 hours. The reaction mixture was evaporated, and the residue was dissolved in a mixture of methanol and water. With sodium bicarbonate solution, and the whole was, and the product was extracted with chloroform. The extract was dried, filtered and evaporated. The residue was triturated with 2-propanol, yielding 3.9 parts (86%) of 2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -2 – (1-methylethyl) -3H-1,2,4- triazol-3-one, mp208.4 ℃ (intermediate 10).

PATENT

EP 0228125

Literature References:

Orally active, fluorinated triazole antifungal. Prepn: J. Heeres et al., EP 283992; eidem, US 4916134 (1988, 1990 both to Janssen).

In vitro antifungal activity: F. C. Odds, J. Antimicrob. Chemother. 24, 533 (1989);

D. W. Denning et al., Eur. J. Clin. Microbiol. Infect. Dis. 9, 693 (1990).

In vivo efficacy vs Aspergillus species: J. Van Cutsem et al., Antimicrob. Agents Chemother. 33, 2063 (1989).

ChemMedChem (2010), 5(5), 757-69

Jingxi Huagong Zhongjianti (2009), 39(5), 8-12, 22

EP0006711A1 *	13 Jun 1979	9 Jan 1980	Janssen Pharmaceutica N.V.	Heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)-methyl-1H-imidazoles and 1H-1,2,4-triazoles, processes for preparing them and compositions containing them
EP0118138A1 *	24 Jan 1984	12 Sep 1984	Janssen Pharmaceutica N.V.	((4-(4-(4-Phenyl-1-piperazinyl)phenoxymethyl)-1,3-dioxolan-2-yl)methyl)-1H-imidazoles and 1H-1,2,4-triazoles
DE2804096A1 *	31 Jan 1978	3 Aug 1978	Janssen Pharmaceutica Nv	1-(1,3-dioxolan-2-ylmethyl)-1h-imidazole und -1h-1,2,4-triazole und deren salze, verfahren zu ihrer herstellung und ihre verwendung bei der bekaempfung pathogener pilze und bakterien

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///////Antifungal, Triazoles,

CCC(C)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OCC5COC(O5)(CN6C=NC=N6)C7=C(C=C(C=C7)F)F

Pfizer’s Fosdagrocorat, PF-04171327 for Rheumatoid Arthritis

February 15, 2016 6:53 am / Leave a comment

Fosdagrocorat, PF-04171327,

CAS 1044535-58-1

(2R,4aS,10aR)-4a-Benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-1,2,3,4,4a,9,10,10a-octahydrophenanthren-2-yl dihydrogen phosphate

2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-N-(2-methyl-3-pyridinyl)-4b-(phenylmethyl)-7-(phosphonooxy)-7-(trifluoromethyl)-, (4bS,7R,8aR)-

(2R,4aS,10aR)-4a-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-1,2,3,4,4a,9,10,10a-octahydrophenanthren-2-yl dihydrogen phosphate

MF C29H30F3N2O5P
Exact Mass: 574.1844

PF 04171327
PF-04171327
UNII-HPI19004QS
Selective Glucocorticoid Receptor Modulator

phase 2 .Rheumatoid Arthritis

Glucocorticoid receptor modulators

Pfizer

03 Sep 2015Phase II development of fosdagrocorat is ongoing
01 Jun 2014Pfizer completes a phase II trial in Rheumatoid arthritis in US, Bulgaria, Colombia, the Czech Republic, Germany, Hungary, India, South Korea, Malaysia, Mexico, Poland, Romania, Russia, Serbia, Slovakia, South Africa, Spain and the Ukraine (NCT01393639)
30 Sep 2011Phase-II clinical trials in Rheumatoid arthritis in Bulgaria, Colombia, Germany, India, Malaysia, Mexico, Poland, Romania and South Africa (PO)

Fosdagrocorat, also known as PF-04171327, a dissociated agonist of the glucocorticoid receptor (DAGR), a selective high-affinity partial agonist of the GR with potent anti-inflammatory activity at exposures that provide less undesirable effects on bone and glucose metabolism compared with prednisone (pred).

Glucocorticoid receptor modulators are glucocorticoid receptor ligands that are used to treat a variety of conditions because of their powerful anti-inflammatory, antiproliferative and immunomodulatory activity. J. Miner, et al., Expert Opin. Investig. Drugs (2005) 14(12):1527-1545.
Examples of glucocorticoid receptor modulators include dexamethasone, prednisone, prednisolone, RU-486, and as described in WO 2000/66522 and WO 2004/005229.
Treatment with glucocorticoid receptor modulators is often associated with side effects, such as bone loss and osteoporosis.
Identifying a glucocorticoid receptor modulator that is efficacious, potent, and has mitigated side-effects fulfills a medical need.

SYNTHESIS COMING…………

PATENT

WO 2008093227/US 20100286214

https://www.google.com/patents/WO2008093227A1?cl=en

SCHEME A

The 1 (/?)-Benzyl-5-bromo-9(S)-hydro-10(R)-hydroxy-10(R)-methyl-tricyclo[7.3.1.0²‘⁷]trideca-2,4,6-trien-13-one of Formula A-8 was prepared using the protocol described in Scheme A, which is generally disclosed in WO 00/66522. Ph depicts Phenyl. Bn depicts Benzyl. Compound A-1 can be purchased (for example, VOUS and Riverside; CAS No. 4133-35-1 ). Compound A-2 can be prepared as described in Org. Syn. 1971 , 51 , 109-112.

SCHEME B

The (4βS,7R,8αR)-4β-benzyl-7-hydroxy-Λ/-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-4b,5,6,7,8α,9,10-octahydrophenanthrene-2-carboxamide was prepared as described in Scheme B.

SCHEME C

The (2R,4αS, 10αR)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-1 ,2,3,4,4α,9,10,10α-octahydrophenanthren-2-yl dihydrogen phosphate of C-3 was prepared as described in Scheme C. Bn depicts benzyl.

SCHEME D

The (2R,4αS,10αR)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-1 ,2,3,4,4α,9,10,10α-octahydrophenanthren-2-yl dihydrogen phosphate of C-3 was prepared as described in Scheme D. Bn depicts benzyl. Ph depicts phenyl.

SCHEME E

The (2R,4αS, 10αR)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoy[)-2-(trifluoromethyl)-1 ,2,3,4,4α,9,10,10α-octahydrophenanthren-2-yl dihydrogen phosphate of C-3 was prepared as described in Scheme E. Bn depicts benzyl. Ph depicts phenyl.

Starting Material A-8 is 1(R)~Benzyl-5-bromo-9(S)-hydro-10(R)-hydroxy-10(R)-methyl-tricyclo[7.3.1.0²‘⁷]trideca-2,4,6-trien-13-one as depicted by the following formula:

Preparation 1 : (S)-4a-benzyl-7-bromo-2-ethoxy-3,4,4a,9-tetrahydrophenanthrene

Starting Material A-8 (450 g; 1.17 moles) was dissolved in ethanol (4.5 L) at ambient temperature. 21% sodium ethoxide in ethanol (44 mL; 0.12 moles) was added and the mixture was heated to reflux for three hours. Once the Starting Material A-8 was consumed, the reaction mixture was chilled to -25⁰C. Acetyl chloride (250 mL; 3.51 moles) was slowly added to the mixture while the temperature was maintained near -25°C. After the addition was complete, the mixture was warmed to O⁰C and held there until the intermediate enone was consumed. The mixture was slurry at this point. 21 % sodium ethoxide in ethanol (1.31 L; 3.51 moles) was added to the mixture while the temperature was maintained between -5°C and 5⁰C. If the mixture was not basic, more sodium ethoxide was added. The temperature of the mixture was increased to 25°C and then diluted with water (5.9 L). The mixture was filtered and the solid was washed with water (3 X). The title compound (440 g; 85 area %) was obtained as a beige solid. ¹H NMR (DMSO) δ ppm: 1.27 (t, 3H), 1.65 (dt, 1 H), 2.06 (d, 1 H), 2.21 (dd, 1 H)₁ 2.49 (m, 1 H), 2.65 (m, 2H), 2.89 (m, 2H), 3.85 (q, 2H), 5.45 (m, 2H), 6.44 (d, 2H), 6.98 (t, 2H), 7.06 (m, 2H), 7.25 (d, 1 H), 7.33 (dd, 1 H).

Preparation 2: (S)-4a-benzyl-7-bromo-2,2-(1,2-ethylenedioxy)-1,2,3,4,4a,9-hexahydrophenanthrene

The (S)-4α-benzyl-7-bromo-2-ethoxy-3,4,4α,9-tetrahydrophenanthrene (1270 g; 3.2 moles; 85 area %, which may be prepared as described in Preparation 1 ) was dissolved in toluene (6.45 L). The ethylene glycol (898 mL; 16.1 moles) and p-toluenesulfonic acid (6.1 g; 0.03 moles) were added and the reaction heated to reflux. Solvent (1 L) was distilled from the mixture and replaced with fresh toluene (1 L). This distillation process was repeated twice more. More p-toluenesulfonic acid (6.1 g) was added each time fresh toluene was added. During the reaction, two intermediates (detected by LC) were formed as the substrate was converted into product. The end point of the reaction was an equilibrium point between the two intermediates and the product. Once the endpoint was reached, the mixture was cooled to ambient temperature. The mixture was washed with 0.5 M NaOH (2 L). The phases separated quickly and both were dark with a small rag layer. The mixture was washed with water (2 L). The phases
separated very slowly. The mixture was dried by azeotropic distillation. Methanol (4 L) was added to the mixture and solvent (4 L) was distilled from the mixture. The methanol addition and solvent distillation were repeated twice more. Methanol was added to the mixture and precipitation occurred a few minutes later. More methanol (4 L) was added to the mixture and then brought to reflux. After 30 minutes, the mixture was cooled to 0⁰C. The mixture was filtered and the solid was washed with chilled methanol (2 X 2L). The solid was dried in a vacuum oven at 65°C. The title compound (882 g; 98 area %) was obtained as a beige solid. ¹H NMR (DMSO) δ ppm: 1.71 (m, 2H), 2.06 (m, 2H), 2.31 (dd, 1 H), 2.39 (m, 1 H), 2.68 (d, 1 H), 2.77 (m, 1 H), 2.86 (dd, 1 H), 3.36 (d, 1 H), 3.86 (m, 4H), 5.45 (m, 1 H), 6.50 (m, 2H), 7.00 (m, 4H), 7.37 (dd, 1 H), 7.44 (d, 1 H).

Preparation 3: (S)-methyl 4β-benzyl-7,7-(1,2-ethylenedioxy)-4β,5,6,7,8,10-hexahydrophenanthrene-2-carboxylate

The (S)-4α-benzyl-7-bromo-2,2-(1 ,2-ethylenedioxy)-1 ,2,3,4,4α,9-hexahydrophenanthrene (719 g; 1.75 moles, which may be prepared as described in Preparation 2) was dissolved in tetrahydrofuran (7.19 L) and chilled to -7O⁰C. The 1.6 M n-butyl lithium in hexane (2270 mL; 2.27 moles) was added at a rate such that the temperature was maintained below -6O⁰C. The mixture held an additional 15 minutes after the addition. Carbon dioxide (108 g; 2.45 moles) was added while the temperature was maintained below -60°C. The mixture held an additional 15 minutes after the addition. The mixture was warmed to ambient temperature. Solvent (7 L) was distilled from the mixture at atmospheric pressure. DMF (7 L) was added to the mixture. The mixture was cooled to ambient temperature. Methyl iodide (152 mL; 2.45 moles) was added and the mixture was held until the reaction was completed (~1 hour). The mixture was heated to 7O⁰C and solvent was distilled by gradually reducing the pressure to 70 mmHg. Once distillation had ceased, the mixture was cooled to room
temperature. Water (6.5 L) was slowly added to the mixture to precipitate the product. The mixture was filtered and the solid washed with water (3 X). The solid was dried on the filter. The crude product (736 g; 74 area %) was obtained as a beige solid. The product was purified by chromatography. 463 g of product was recovered from the chromatography. This material was separated from n-heptane (6130 mL). 394 g of the title compound was recovered. Another 70 g of title compound was recovered from the mother liquor by chromatography. ¹H NMR (DMSO) δ ppm: 1.74 (m, 2H), 2.10 (m, 2H)₁ 2.33 (dd, 1 H), 2.45 (m, 1 H), 2.72 (d, 1 H), 2.79 (m, 1 H), 2.94 (dd, 1 H), 3.40 (d, 1 H), 3.87 (m, 7H), 5.49 (m, 1 H), 6.47 (m, 2H), 6.93 (m, 2H), 7.01 (m, 1 H), 7.42 (d, 1 H), 7.64 (d, 1 H), 7.79 (dd, 1 H).

Preparation 4: (4βS,8α/?)-methyl 4β-benzyl-7,7-(1,2-ethylenedioxy)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate

The (S)-methyl 4β-benzyl-7,7-(1 ,2-ethylenedioxy)-4β,5,6,7,8,10-hexahydrophenanthrene-2-carboxylate (201 g; 0.515 moles, which may be prepared as described in Preparation 3) and 50 ml of ethylene glycol was dissolved in toluene (2.0 L) in an autoclave. To this was added 10 grams of a 5% Pd/C (dry catalyst). The autoclave was then sealed and purged with nitrogen (three cycles) followed by hydrogen (three cycles). The reaction was run for 18 hours with a pressure of 80 psig and temperature of 50 ⁰C. HPLC analysis for completion and selectivity (typical selectivity’s are: 95 to 5, Trans to Cis). The suspension was filtered through Celite® to remove the catalyst and the toluene solution is concentrated at 50 ⁰C, under vacuum, to
approximately 200 ml. While still at 50 ⁰C, 1 L of 1-butanol was added and the solution heated to 60 ⁰C, until clear. Upon cooling, the resulting solid title compound was isolated by vacuum filtration (196 grams; 97%; Trans to Cis 95.75 to 4.24). ¹H NMR (300 MHz, CDCI₃) δ ppm: 7.79 (bs, 1 H₁ Ar-H), 7.47 (d, J= 9 Hz, 1 H, Ar-H), 7.13-7.05 (cm, 3H, Ar-H), 6.56-6.53 (cm, 2H, Ar-H), 6.43 (d, J= 9 Hz, 1 H, Ar-H), 4.04-3.93 (cm, 4H, 2-CH₂), 3.89 (s, 3H, CH₃),3.08-3.03 (cm, 3H, CH₂, CH-H), 2.63 (d, J= 15 Hz, CH-H), 2.22-1.72 (cm, 8H, 4-CH₂), 1.57 (cm, 1 H, CH-H).; ¹³CNMR (CDCI₃, δ): 167.7, 149.2, 137.7, 136.4, 131.1 , 130.5, 127.8, 127.7, 127.4, 126.3, 125.5, 108.9, 64.6, 64.5, 52.1 , 40.5, 39.8, 38.3, 35.8, 31.6, 30.3, 27.9, 24.6.

Preparation 5: (4βS,8α/?)-methyl 4β-benzyl-7-oxo-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate

ThΘ (4βS,8αR)-mΘthyl 4β-benzyl-7,7-(1 ,2-ethylenΘdioxy)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate (150 g, 382 mmol, which may be prepared as described in Preparation 4) was dissolved in dichloromethane (630 ml). Water (270 ml) was added with stirring followed by trifluoroacetic acid (73 ml. 1150 mmol) via drop funnel over 30 minutes, maintaining the internal temperature below 3O⁰C. After the addition was complete, the reaction was heated at 4O⁰C for 2 hours. In process check indicated incomplete reaction with around 9% (area percent) starting material. The layers were separated and fresh water (270 ml) and trifluoroacetic acid (31 ml) was added. The reaction mixture was heated at 4O⁰C for 1 hour. This process was continued until the starting material was consumed. The organic phase was washed with 5% aqueous sodium bicarbonate (300 ml), water (300 ml) and dried over MgSO₄ and concentrated to dryness to give 126.4 g of the title compound (representing a 95% yield). ¹H NMR (DMSO) δ ppm: 7.70 (s, 1 H), 7.37 (d, J=8.4 Hz, 1 H), 7.11 (m, 3H), 6.6 (d, J= 5.70 Hz, 2H), 6.45 (d, J=8.4 Hz, 1H), 3.80 (s, 3H), 3.80 (m, 2H), 3.04-1.48 (m, 11 H).

Preparation 6: (4βS,7f?,8α/?)-methyl 4β-benzyl-7-hydroxy-7-(trifluoromethyl)-4β,5_J6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate

The (4βS,8αf?)-methyl 4β-benzyl-7-oxo-4β,5,6,7,8_I8α,9,10-octahydrophenanthrene-2-carboxylate (118g, 0.339 mole, which may be prepared as described in Preparation 5) dissolved in dichloromethane was chilled to -5O⁰C. The solution became turbid. 1.0 M Tetrabutylammonium fluoride a solution in THF (3.4 ml, 0.003 mol) was added with no appreciable temperature change. Trifluorotrimethylsilane (79 ml, 0.51 mol) was added over 20 minutes with a color change to bright orange to light red in color. The reaction mixture was held at -50 ⁰C for about 2 hours and then allowed to warm to 0 ⁰C.
Tetrabutylammonium fluoride (340 ml, 0.34 moles) was added very slowly at 0 ⁰C, to the reaction mixture over 45 minutes. An exotherm was observed with gas evolution. The reaction mixture was stirred 10 minutes and HPLC analysis indicated complete desilylialation. Water (1 L) was added to the reaction mixture and with vigorous stirring and allowed to warm to room temperature. The organic layer was washed with water (1 L). The organic layer was concentrated and chromatographed to produce 72 g, 51 % of the title compound, with an additional 32 g of impure product. ¹H NMR (DMSO) δ ppm: 7.70 (s, 1 H), 7.37 (d, J=8.1 Hz, 1 H)₁ 7.09 (m, 3H), 6.5 (dd, J=1.2, 6.6 Hz, 2H), 6.38 (d, J=8.4 Hz, 1 H), 3.80 (s, 3H), 3.80 (m, 2H), 3.09-1.21 (m, 13H).

Preparation 7: (4βS,7/?,8α/?)-methyl 4β-benzyl-7-(bis(benzyloxy)phosphoryloxy)-7-(trifluoromethyl)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate

The (4βS,7R,8αf?)-methyl 4β-benzyl-7-hydroxy-7-(trifluoromethyl)-4β₎5,6,7₎8,8α,9,10-octahydrophenanthrene-2-carboxylate (5.0 g; 11.9 mmol, which may be prepared as in Preparation 6) and 5-methyltetrazole (3.6 g; 43.0 mmol) were mixed together in dichloromethane (50 mL) at ambient temperature. Dibenzylphosphoramidite (8.3 mL; 25.1 mmol) was added and the mixture was stirred until the reaction was completed (1 hour). The mixture was chilled to 0⁰C and 30% hydrogen peroxide (10 mL) was added. The reaction was stirred until the oxidation was completed (30 minutes). The aqueous phase was separated from the organic phase. The organic phase was washed with 10% sodium meta-bisulfite (50 ml_). The organic phase was dried with anhydrous magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography with 15% ethyl acetate in hexanes. The purified title compound (8.41 g; 94% yield) was obtained as a colorless oil that contained 6% ethyl acetate by weight. ¹H NMR (DMSO): δ 1.31 (t, 1 H), 1.63-1.92 (m, 3H), 2.05-2.35 (m, 3H), 2.63 (d, 1 H), 2.75-3.16 (m, 4H), 3.80 (s, 3H), 5.13 (m, 4H), 6.43 (d, 1 H), 6.49 (m, 2H), 7.04-7.17 (m, 3H), 7.33-7.42 (m, 12H), 7.71 (d, 1 H).

Preparation 8: dibenzyl (2f?,4αS,10αR)-4α-benzyl-7-((2-methylpyridin-3-o yl)carbamoyl)-2-(trifluoromethyl)-1 ,2,3,4,4α,9,10,10α-octahydrophenanthren-2-yI phosphate

The (4βS,7R,8αf?)-methyl 4β-benzyl-7-(bis(benzyloxy)phosphoryloxy)-7- (trifluoromethyl)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate (7.9 g; 11.6 5 mmol, which may be prepared as in Preparation 7) and 3-amino-2-picoline (1.3 g; 12.2 mmol) were mixed together in tetrahydrofuran (80 ml_) and chilled to 0°C. The 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (24 ml_; 24.4 mmol) was added while maintaining the temperature below 10⁰C. The mixture was stirred for 30 minutes. Water (50 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate. The organic extract was washed with water. The organic phase was dried with anhydrous magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography with 70% ethyl acetate in hexanes. The purified title compound (6.79 g; 68% yield) was obtained as a yellow gum that contained 6% ethyl acetate by weight. ¹H NMR (DMSO): δ 1.33 (t, 1 H), 1.66-1.93 (m, 3H), 2.08-2.34 (m, 3H), 2.41 (s, 3H), 2.68 (d, 1 H), 2.76-3.19 (m, 4H), 5.14 (m, 4H), 6.47 (d, 1 H), 6.56 (m, 2H), 7.07-7.19 (m, 3H), 7.20-7.53 (m, 12H), 7.71 (d, 1 H), 7.76 (s, 1 H), 8.32 (d, 1 H), 9.93 (s, 1 H).

Example 1 : (4βS,7/?,8αR)-4β-benzyl-7-hydroxy-W-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxamide

The (4βS,7ft,8αR)-methyl 4β-benzyl-7-hydroxy-7-(trifluoromethyl)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate (10 g; 23.9 mmol, which may be prepared as described in Preparation 6), and 3-amino-2-picoline (2.71 g; 25.1 mmol) were dissolved in toluene (200 ml_). The 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (74.1 mL; 74.1 mmol) was added at a rate such that the temperature was maintained below 35⁰C. There was a mild exotherm and a solid precipitated during the addition. The mixture was held an additional 30 minutes after the addition. Water (250 mL) was added to the mixture. There was a mild exotherm and the solid dissolved. Ethyl acetate (50 mL) was added to the mixture to ensure the product did not precipitate. Stirring was stopped to allow the phases to separate. The aqueous phase was removed. The organic phase was washed with water (250 mL). Solvent (230 mL) was distilled at atmospheric pressure from the organic phase. The mixture was cooled to ambient temperature. The mixture was filtered and the solid was washed with toluene (2 times) followed by heptane (2 times). The solid was dried in a vacuum oven at 70⁰C. The title compound of the present example (10 g) was obtained as a beige solid. ¹H NMR (DMSO) δ ppm: 1.32 (m, 1 H), 1.82 (m, 4H), 2.10 (m, 4H), 2.41 (s, 3H), 2.68 (d, 1 H), 3.08 (m, 3H), 6.00 (s, 1H), 6.43 (d, 1 H), 6.59 (m, 2H), 7.12 (m, 3H), 7.25 (dd, 1H), 7.44 (dd, 1H), 7.71 (dd, 1 H), 7.75 (d, 1 H), 8.31 (dd, 1 H), 9.91 (s, 1 H).

Example 2: (2f?,4αS,10αR)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-i ,2,3,4,4α,9,10,1 Oα-octahydrophenanthren-2-yl dihydrogen phosphate

The dibenzyl (2R,4αS, 10αR)-4α-bθnzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-1 ,2,3,4,4a,9,10,10a-octahydrophenanthren-2-yl phosphate (6 g; 7.9 mmol, which may be prepared as described in Preparation 8) was dissolved in methanol (120 ml_). 5% palladium on carbon (63% water) (1.3 g; 0.4 mmol) was added to the mixture. The mixture was treated with hydrogen (50 psi) at room temperature. The reaction stalled with 12% of the monobenzylic intermediate remaining. The mixture was filtered through a pad of Celite®. Fresh catalyst (1.3 g) was added to the solution and resubmitted to the hydrogenation conditions. Once the reaction was completed, the mixture was filtered through a pad of Celite®. The solution was concentrated to about 60 ml_ by distillation and not by using a rotary evaporator. During the distillation a white solid precipitated. The mixture was cooled to ambient temperature. The mixture was filtered and the solid washed with methanol. The solid was dried in a vacuum oven at 70⁰C. The compound of the present example (3.36 g; 75% yield) was obtained as a white solid and had an LC purity of 98 area %. ¹H NMR (DMSO): δ 1.33 (t, 1 H)₁ 1.69-1.98 (m, 3H), 2.07-2.29 (m, 3H)₁ 2.42 (s, 3H), 2.61-2.80 (m, 2H)₁ 2.93-3.19 (m, 3H)₁ 3.30 (d, 1 H), 6.50 (d, 1 H), 6.64 (m, 2H), 7.08-7.20 (m, 3H), 7.29 (dd, 1 H), 7.48 (dd, 1 H), 7.75 (dd, 2H), 8.33 (dd, 1 H), 9.96 (s, 1 H).

PATENT

WO 2008093236

http://www.google.co.in/patents/WO2008093236A1?cl=en

Example 1 : (4βS,7/?,8α/?)-4β-benzyl-7-hydroxy-N-(2-methylpyridin-3-yl)-7- (trifluoromethyl)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxamide

The (4βS,7R,8α/?)-methyl 4β-benzyl-7-hydroxy-7-(trifluoromethyl)-4β,5,6_J7,8,δα,9, 10- octahydrophenanthrene-2-carboxylate (10 g; 23.9 mmol, which may be prepared as described in Preparation 6), and 3-amino-2-picoline (2.71 g; 25.1 mmol) were dissolved in toluene (200 ml_). The 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (74.1 ml_; 74.1 mmol) was added at a rate such that the temperature was maintained below 35⁰C. There was a mild exotherm and a solid precipitated during the addition. The mixture was held an additional 30 minutes after the addition. Water (250 ml_) was added to the mixture. There was a mild exotherm and the solid dissolved. Ethyl acetate (50 ml_) was added to the mixture to ensure the product did not precipitate. Stirring was stopped to allow the phases to separate. The aqueous phase was removed. The organic phase was washed with water (250 ml_). Solvent (230 ml_) was distilled at atmospheric pressure from the organic phase. The mixture was cooled to ambient temperature. The mixture was filtered and the solid was washed with toluene (2 times) followed by heptane (2 times). The solid was dried in a vacuum oven at 70⁰C. The title compound of the present example (10 g) was obtained as a beige solid. ¹H NMR (DMSO) δ ppm: 1.32 (m, 1H), 1.82 (m, 4H), 2.10 (m, 4H), 2.41 (s, 3H), 2.68 (d, 1 H), 3.08 (m, 3H), 6.00 (s, 1 H), 6.43 (d, 1 H), 6.59 (m, 2H), 7.12 (m, 3H), 7.25 (dd, 1 H), 7.44 (dd, 1 H), 7.71 (dd, 1 H), 7.75 (d, 1 H), 8.31 (dd, 1 H), 9.91 (s, 1 H).

Example 2: (2f?,4αS,10α/?)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2- (trifluoromethyl)-1,2,3,4,4α,9,10,10α-octahydrophenanthren-2-yl dihydrogen phosphate

The dibenzyl (2R,4αS,10αR)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2- (trifluoromethyl)-1 ,2,3,4,4a,9,10,10a-octahydrophenanthren-2-yl phosphate (6 g; 7.9 mmol, which may be prepared as described in Preparation 8) was dissolved in methanol (120 ml_). 5% palladium on carbon (63% water) (1.3 g; 0.4 mmol) was added to the mixture. The mixture was treated with hydrogen (50 psi) at room temperature. The reaction stalled with 12% of the monobenzylic intermediate remaining. The mixture was filtered through a pad of Celite®. Fresh catalyst (1.3 g) was added to the solution and resubmitted to the hydrogenation conditions. Once the reaction was completed, the mixture was filtered through a pad of Celite®. The solution was concentrated to about 60 ml_ by distillation and not by using a rotary evaporator. During the distillation a white solid precipitated. The mixture was cooled to ambient temperature. The mixture was filtered and the solid washed with methanol. The solid was dried in a vacuum oven at 7O⁰C. The compound of the present example (3.36 g; 75% yield) was obtained as a white solid and had an LC purity of 98 area %. ¹H NMR (DMSO): δ 1 .33 (t, 1 H), 1 .69- 1.98 (m, 3H), 2.07-2.29 (m, 3H), 2.42 (s, 3H), 2.61 -2.80 (m, 2H), 2.93-3.19 (m, 3H), 3.30 (d, 1 H), 6.50 (d, 1 H), 6.64 (m, 2H), 7.08-7.20 (m, 3H), 7.29 (dd, 1 H), 7.48 (dd, 1 H), 7.75 (dd, 2H), 8.33 (dd, 1 H), 9.96 (s, 1 H).

REFERENCES

https://www.pfizer.com/sites/default/files/product-pipeline/July%2028%202015%20Pipeline%20Update.pdf

https://clinicaltrials.gov/ct2/show/NCT00938587

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Cc1c(cccn1)NC(=O)c2ccc3c(c2)CC[C@H]4[C@]3(CC[C@@](C4)(C(F)(F)F)OP(=O)(O)O)Cc5ccccc5

O=P(O)(O[C@@]1(C(F)(F)F)C[C@@]2([H])CCC3=C(C=CC(C(NC4=CC=CN=C4C)=O)=C3)[C@]2(CC5=CC=CC=C5)CC1)O

BMS 911543

January 22, 2016 4:59 am / Leave a comment

BMS 911543

N,N-dicyclopropyl-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide

cas 1271022-90-2
Chemical Formula: C23H28N8O
Exact Mass: 432.23861

UNII-7N03P021J8;

N,N-dicyclopropyl-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide

Bristol-Myers Squibb Company innovator

BMS-911543 is an orally available small molecule targeting a subset of Janus-associated kinase (JAK) with potential antineoplastic activity. JAK2 inhibitor BMS-911543 selectively inhibits JAK2, thereby preventing the JAK/STAT (signal transducer and activator of transcription) signaling cascade, including activation of STAT3. This may lead to an induction of tumor cell apoptosis and a decrease in cellular proliferation. JAK2, often upregulated or mutated in a variety of cancer cells, mediates STAT3 activation and plays a key role in tumor cell proliferation and survival.

The JAK2 selective compound BMS911543 (WO2011028864) is in phase II clinical trials for the treatment of m elofibrosis. BMS91 1543 is shown below.

PAPER

ACS Medicinal Chemistry Letters (2015), 6(8), 850-855

Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms

Bristol-Myers Squibb R&D, US Route 206 and Province Line Road, Princeton, New Jersey 08543-4000, United States

ACS Med. Chem. Lett., 2015, 6 (8), pp 850–855

DOI: 10.1021/acsmedchemlett.5b00226

Publication Date (Web): July 12, 2015

*Tel: +1-609-252-4320. E-mail: ashok.purandare@bms.com

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile

str1

MS (ESI) m/z 434.3 (M+H). 1H NMR (CDCl3) δ: 7.96 (s, 1H), 7.65 (s, 1H), 6.83 (s, 1H), 4.67 (q, J = 7.1 Hz, 2H), 4.01 (s, 3H), 3.82 (s, 3H), 2.77 – 2.84 (m, 2H), 2.43 (s, 3H), 1.48 (t, J = 7.2 Hz, 3H), 0.79 – 0.86 (m, 4H), 0.71 – 0.77 (m, 4H).

PAPER

Journal of Organic Chemistry (2015), 80(12), 6001-601

Click to access jo5b00572_si_001.pdf

Ni-Catalyzed C–H Functionalization in the Formation of a Complex Heterocycle: Synthesis of the Potent JAK2 Inhibitor BMS-911543

Monica A Fitzgerald, Omid Soltani, Carolyn Wei, Dimitri Skliar, Bin Zheng, Jun Li, Jacob Albrecht, Michael Schmidt, Michelle Mahoney, Richard J. Fox, Kristy Tran, Keming Zhu, and Martin D. Eastgate^*

Chemical Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, United States

J. Org. Chem., 2015, 80 (12), pp 6001–6011

DOI: 10.1021/acs.joc.5b00572

Publication Date (Web): April 7, 2015

*Email: martin.eastgate@bms.com.

BMS-911543 is a complex pyrrolopyridine investigated as a potential treatment for myeloproliferative disorders. The development of a short and efficient synthesis of this molecule is described. During the course of our studies, a Ni-mediated C–N bond formation was invented, which enabled the rapid construction of the highly substituted 2-aminopyridine core. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only eight steps starting from readily available materials.

N,N-Dicyclopropyl-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide, 1

Amide 1(198.3 g, 89% yield) as off-white plates (mp 271–274 °C), which contained 0.13 wt % water by Karl Fisher analysis:

¹H NMR (600 MHz, DMF-d₇) δ 8.15 (br s, 1H), 8.07 (s, 1H), 7.30 (s, 1H), 6.96 (s, 1H), 4.66 (q, J = 7.1 Hz, 2H), 4.11 (s, 3H), 3.72 (s, 3H), 2.35 (s, 3H), 3.01 (m, 2H), 1.43 (t, J = 7.1 Hz, 3H), 0.81–0.73 (m, 8H);

¹³C NMR (125 MHz, DMF-d₇) δ 167.6, 148.5, 145.4, 144.7, 141.7, 139.7, 134.9, 128.0, 125.4, 102.9, 99.5, 96.9, 39.4, 36.0, 33.1, 32.0, 16.5, 11.6, 9.6;

HRMS-ESI (m/z) calcd for C₂₃H₂₉N₈O [M + H]⁺ 433.2464, found 433.2457.

http://pubs.acs.org/doi/suppl/10.1021/acs.joc.5b00572/suppl_file/jo5b00572_si_001.pdf

PATENT

WO 2015031562

These Schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to manufacture compounds disclosed herein.

As shown below in Scheme 1, the general preparation of compound 7 is described. Trichloroacetyl pyrrole (Compound 1) is reacted with a halogenating agent to give the C4-bromo pyrrole (Compound 2). Alcoho lysis occurs in the presence of an alcohol and base to generate ester (Compound 3), which can be selectively nitrated through contact with an appropriate nitrating agent (defined as a species that generates N0₂ ), yielding C5-nitro pyrrole (Compound 4). Compound 4 can be isolated as its free form, or optionally as a salt with an appropriate base. Ethylation with an appropriate alkylating agent generates the N-ethyl pyrrole (Compound 5), which in the presence of an imidazole, base, palladium and an appropriate phosphine ligand, will undergo a coupling process to form Compound 6. Reduction of the nitro-group of Compound 6 in the presence of hydrogen, a metal catalyst and optionally a base will produce Compound 7.

Scheme 1

As shown below in Scheme 2, the preparation of Compound 13 is described. Trichloroacetyl pyrrole is treated with NBS in acetonitrile to produce Compound 8. Treatment with sodium ethoxide in EtOH yields the ethyl ester Compound 9. This may be treated with a range of nitrating systems, in this example, NaNC /SCVPy, to generate nitro-pyrrole Compound 10, which can be isolated directly or as a salt form with an appropriate base, preferably dibenzylamine. Ethylation with ethyl iodide generates Compound 11 which may be isolated, or optionally telescoped directly into the arylation with Compound 32. Arylation proceeds in the presence of palladium, Xantphos, potassium pivylate and Hunig’s base to generate Compound 12. Hydrogenation presence of Pt/C followed by cyclization with NaOEt yields Compound 13.

Scheme 2

Another process of the invention is disclosed in Scheme 3 shown below. Compound 14 is prepared from Compound 3 in the presence of an alkylating agent. Treatment with a suitable diboron reagent produces Compound 15, which can then be coupled with a suitably functionalized imidazole derivative to yield Compound 16. Amino lysis with a suitable nitrogen donor produces Compound 17, which can cyclize under appropriate conditions to produce Compound 7.

Scheme 3

Step 3 Step 4 Step 5

As shown below in Scheme 4, ethylation of Compound 9 with ethyl iodide produces Compound 18. This may be directly reacted with dipinacol-diboron in the presence of Pd(OAc)₂ and tricyclohexylphosphin hexafluorophosphate and

tetramethylammonium acetate to yield Compound 19. Subsequent coupling with 5-Br-imidazole derivative yields Compound 20. Treatment with hydroxylamine hydrochloride in the presence of triethylamine yields the Compound 21. Subsequent cyclization with Piv₂0 in the presence of PRICAT™ and hydrogen yields Compound 13.

Scheme 4

77% isolated over 2-steps%

Step 5 Pd(OAc)₂

PPh₃

78%

As shown below in Scheme 5, Compound 23 may be converted to Compound 26 by two pathways. In one option, Compound 23 can be treated with palladium, ligand and a mild base to prepare Compound 25. Reaction of Compound 25 with a metal hydroxide produces Compound 26.

Alternately, Compound 23 can be treated with palladium and ligand in the presence of a soluble hydroxide base, followed by treatment with the metal counter-ion to prepare Compound 26 directly. Once Compound 26 is formed, it can be coupled to Compound 27 to form compound I.

A solution of Compound 1 in acetonitrile (1238.0 kg, 264.9 kg after correction) was charged into a 5000 L glass-lined reactor at a temperature of 20-30 °C. The mixture was added with stirring over about 2 h and then cooled to 0 °C. NBS (221.8 kg) was charged into the mixture at intervals of 20-30 min at 0-20 °C. The mixture was cooled to 0-5 °C and reacted until the content of Compound 8was < 1.0%. Additional NBS (4.0 kg) was charged into the mixture at 0-20 °C. The mixture was reacted over 3 h until the content of Compound 8 was < 1.0%. Purified water (2650.0 kg) was added over about 1.5 – 2.5 h at 0-20 °C. The mixture was cooled to 0-5 °C and then stirred for about 1 h for crystallization. The mixture was filtered and the filter cake was rinsed with water.

Example 2

While maintaining the temperature at 20-30 °C, anhydrous ethanol (950.0 kg) was charged into a 3000 L glass-lined reactor followed by Compound 8 (342.7 kg). The mixture was cooled to 0-5 °C over about 2 h. Sodium alcoholate solution in ethanol (21%, 36.4 kg) was added dropwise over about 1-1.5 h at 0-5 °C. The reaction mixture was then heated to about 25-30 °C and tested until the content of Compounds 8/9 was < 1.0%. The reaction mixture was concentrated at a temperature < 50 °C until about 1.3-1.4 volume of Compound 8 was left. The concentrated mixture was cooled at 25-30 °C. The mixture was quenched into cooled water (3427.0 kg) over about 2 h. After addition, the mixture was stirred at 0-5 °C over about 2 h for crystallization. The mixture was filtered and the filter cake was rinsed. The solid was dried at 30-40 °C over 40-45 h to afford 234.3 kg of Compound 9 , 99.9% purity and 91.3% yield.

Example 3

9 10

A mixture of NaN0₃, NaHS0₄, and Na₂S0₄ in CH₃CN is wet-milled to constant particle size of -50 micron. To the slurry of inorganic salts is added S0₃ -pyridine and Compound 9. The reaction mixture is agitated at 25 °C until 90-95% conversion is achieved. The reaction is quenched with aqueous sodium hydroxide and the spent inorganic salts are removed by filtration. The filtrate is passed through a carbon pad and distilled under constant volume distillation and diluted with water to a target 15

volumes/kg of Compound 9 and a target ratio 1.0:2.0 vol/vol MeCN to water. The resulting solids are deliquored, washed, and dried to afford Compound 10.

Example 4

Toluene (10 L/Kg)

65 °C

Compound 10 (1.0 eq) and TBABr (1.0 eq) were added to a biphasic mixture of toluene (8 L/kg 10) and potassium carbonate (1.5 eq) in water (5 L/kg 10). The batch temperature was held at 25 °C. The resulting triphasic slurry was heated to 60-65 °C and diethylsulfate (1.5 eq, in a solution of toluene 2 L/kg 10) was slowly added over ~ 1 h. The reaction was aged until less than 1 RAP of Compound 10 (10:11) remained. The resulting homogeneous biphasic mixture was cooled to 20 °C and the lean aq. phase was removed. The rich organic phase was washed with water (2×7 L/kg 10) and concentrated to 6 mL/g 10. The concentrated stream was dried via azeotropic, constant volume distillation with toluene until the water content of the stream was <0.1 wt %. The resulting stream was telescoped into the subsequent direct arylation reaction.

Example 5

11 28 12

To the toluene stream of Compound 11, with potassium pivalate (1.5 equiv.) was charged, followed by DIPEA (3 eq.), Compound 28 (3 eq.) and Pd(Xantphos)Cl₂ (0.04 eq.). The vessel was evacuated to < 200 torr and backfilled with nitrogen (3 X) followed by heating to 95 °C until residual Compound 11 was less than 1 RAP (11: 12). The reaction mixture was cooled to 25 °C and diluted with ethyl acetate (15 mL/g vs input pyrrole) and aq. N-acetylcysteine (0.2 eq., 5 wt % solution, 1.8 mL/g vs. input pyrrole) and heated to 50 °C for 1 h. The biphasic mixture was cooled to 25 °C. The lower aqueous layer was removed. The ethyl acetate stream was washed with water (2×7 mL/g vs. input pyrrole). The rich organic phase was polish filtered followed by a vessel/polish filter rinse with ethyl acetate (2 mL/g vs. input pyrrole). The rich organic stream was concentrated to 4 mL/g vs. input pyrrole via vacuum distillation, while maintaining the batch temperature above 50 °C. If spontaneous nucleation did not occur, Compound 12 seeds (1 wt %) were charged, followed by aging for 30 min at temperature. MTBE (5 mL/g vs. 11) was charged to the slurry over 1 hour while maintaining the batch temperature above 40 °C, followed by aging at 40 °C for 1 h. The slurry was cooled to 0 °C over 6 h and aged at 0°C for 6 h. The slurry was filtered and washed with

EtO Ac : Toluene : MTBE (1.5: 1.0: 1.5, 2 mL/g vs. input 11 ). The wet cake was dried (50 °C, 100 torr) until LOD was < 1 wt %.

Example 6

Compound 12 (1 eq., limiting reagent (LR)) is dissolved in THF/NMP (20 Vol wrt LR, 9/1 ratio) and submitted to hydrogenation using 10 wt% (wrt LR) Pt/C (5 wt%) at 25 to 40° C for 5-10 h. The reaction containing the corresponding amine is filtered. The rich organic stream is concentrated to Compound 12 Vol (wrt LR) and subjected to 0.1 eq of 21 wt% NaOEt/EtOH for 5 h at 20-25 °C, upon which Compound 13 forms. The stream is cooled to 0-10 °C, and water (5L/Kg, wrt to LR) is added and then filtered to isolate Compound 13. The product is dried at 50 °C under vacuum.

Example 7

in toluene solution

Compound 18 was prepared by treating the pyrrole with ethyl iodide and pulverized potassium carbonate in DMF at 25-30°C under inert atmosphere. After the reaction was completed, the batch mass was cooled to 15°C to 20°C and quenched by slow addition of water then MTBE. The MTBE layer was separated and washed with water. The MTBE layer was distilled to 4 Vol and solvent swapped with toluene. The toluene stream was then taken into the next step.

Example 8

18 19

Tetra-methyl ammonium acetate in toluene slurry was heated to 75-80°C to get a clear solution. The mass was cooled to below 30°C and pyrrole in toluene and bis (pinacolato) diborane were added. The reactor was inerted by nitrogen purging then the reaction was heated to 75-80°C. A freshly prepared catalyst/ligand complex (0.0 leq of palladium acetate, 0.025eq of tricyclohexyl phosphino hexafluoroborate and 0.2eq of tetra methyl ammonium acetate in toluene) was charged under nitrogen atmosphere at RT and stirred for 2h. The mass was then stirred at 75-80°C under nitrogen atmosphere. After the reaction was completed, the mixture was cooled below 30°C and quenched with aq. sodium bisulphate solution. The organic layer was polish filtered through a Celite bed and the filtrate was washed with water. The solvent swapped to ethanol until the toluene content became less than 0.5 %. The solution was cooled to 0-5°C and water was added for crystallization. The product was then isolated by filtration.

Example 9

Compound 20 was prepared by treating Compound 19 with Compound 34 in the presence of palladium acetate, triphenyl phosphine and potassium carbonate in dimethyl acetamide with the water mixture as the solvent. Dimethyl acetamide, water, potassium carbonate and the two starting materials were charged into the reactor. The mixture was made inert with nitrogen for 30 min and then charged with freshly prepared catalyst mixture (palladium acetate, triphenyl phosphine and potassium carbonate in dimethyl acetamide). The temperature was raised to 78-83 °C then the mass was stirred at this temperature. After the reaction was completed, the reaction mass was cooled to ambient temperature and purified water was added slowly into the mass for product

crystallization. The mass was stirred for a period of 3 h and filtered. The wet cake was washed with purified water and dried in VTD at 50-55 °C under vacuum.

Example 10

Compound 21 was prepared by treating Compound 20 with hydroxylamine hydrochloride and triethyl amine using ethanol as the solvent. Compound 20 was added into ethanol (15 Vol) and the reaction mass was heated to 38-40 °C. Hydroxylamine hydrochloride was charged and stirred for 10 min, then triethyl amine was added slowly at 38-40 °C over a period of lh. The above mass was stirred at 38-40 °C until Compound 20 becomes less than 5.0%, typically in about 15 h. After the reaction was completed, the above reaction mass was cooled to ambient temperature (below 30 °C) and filtered. The wet cake was washed with purified water (4 Vol) and dried under vacuum in VTD at 55-60 °C.

Example 11

Initially Compound 21 was treated with pivalic anhydride using toluene and acetic acid mixture as solvent under inert atmosphere until Compound 21 becomes less than 3.0% with respect to Compound 21, typically in about 30 min. PRICAT Nickel was then added under nitrogen atmosphere. The reaction mass was inerted with nitrogen for three cycle times and then degassed with hydrogen gas for three cycle times. Following this, 3.0 kg/cm² hydrogen pressure was applied to the reaction mass which was stirred for about 12h. After the reaction was completed, the reaction mixture was filtered through a sparkler filter. The filtrate was distilled and the solvent exchanged with toluene until the ratio of acetic acid & toluene reaches 1 :20. At this time, n-Heptane was charged and cooled to 15°C. Then the product was filtered and the wet cake was dried in VTD at 50-55°C under vacuum.

Compound 30 was prepared by the coupling of Compound 22 with Compound 29, 3 -bromo- 1,5 -dimethyl- lH-pyrazole in the presence of

Tris(dibenzylideneacetone)dipalladium chloroform adduct, t-Brettphos and potassium phosphate in tert-amyl alcohol at 98-103 °C under inert atmosphere. After completion of the reaction (typical level of Int.9 -5% & typical reaction hrs 20 h), the mass was cooled to ambient temperature and t-amyl alcohol (4 Vol) and 20 Vol of water were charged into the reaction mass. The reaction mass was stirred for 15 min. and then phase split. The organic layer was diluted with 10 Vol of MTBE and product was extracted with 20 Vol of 1M methane sulphonic acid. The MSA stream was treated with 15 wt % charcoal to reduce the residual palladium numbers. The filtrate was cooled to below 20 °C and the pH was adjusted to 1.7-1.9 using IN NaOH for product crystallization and then iltered. The wet cake was washed with purified water (3 x 5 Vol), followed by methanol (5 Vol). The cake was vacuum dried for 3 h. then the wet cake and dimethyl sulfoxide (20 Vol) were charged into a reactor. The mass was heated to 120-125 °C to get clear solution then the mass was cooled to ambient temperature and stirred for 2 h, then filtered. The wet cake was washed with methanol (3x 4.0 Vol) and vacuum dried for 2 h. The wet cake was dried in VTD at below 55°C under vacuum.

Example 13

Compound 30 , ethanol (16.5 Vol), water and aq sodium hydroxide solution were charged into a reactor then the mass was heated to 70-75 °C and stirred until Compound 30 becomes less than 1.0%. After the reaction was completed, the mass was diluted with ethanol for complete product precipitation at 65-75 °C. Then the mass was cooled to 50 °C for a period of lh and stirred for lh at 50 °C. The mass was further cooled to 20 °C and stirred for lh at 20 °C and then filtered. The wet cake was washed with 5 Vol of 15% aqueous ethanolic solution followed by THF. The wet cake was dried under vacuum at 70-75 °C till LOD comes to less than 5.0 %, typically in about 40 h.

Example 14

In a vessel 36.5 mmol (-42.6 mL) of Compound 29 solution in 2-methyl-2-butanol was combined with 30.7g (65.1 mmol) tetrabutylammonium hydroxide (55 wt% in water), 8.01g (27.0 mmol) Compound 13 , and 10 mL 2-methyl-2-butanol. The mixture was heated at 70 °C until hydrolysis of Compound 13 was complete (full dissolution, <15 min). The solution was cooled to 60 °C and 1.12g (2.22 mmol) of tBuBippyPhos followed by 384 mg (1.028 mmol) allylpalladium chloride dimer (L:Pd = 1 :1) was added. The mixture was heated to 80 °C and was aged at this temperature for 20h before cooling to 22 °C.

Water was added and the mixture concentrated, a constant volume distillation was then performed to swap to ethanol (40-55 °C, 150 mbar). The resulting solution was passed through a 5 micron filter to remove any particulates. The solution was heated to 55 °C and 8.10 mL (40.52 mmol, 1.5 equiv) 5N NaOH (aq) was added dropwise over a 3 h period. Crystals of Compound 31 began to form, and after aging for an additional lh, the mixture was cooled to 20 °C over 3 h. After an additional 6h of aging, crystals were collected on a frit and the cake was washed with 40 mL of 90: 10 ethanol: water, followed by 48 mL acetone. After drying at 80 °C in a vacu-oven for 16 h, Compound 31 was collected as an off-white solid (8.89g, 85%).

Example 15

Compound 31 was added into dichloromethane (20 Vol) and cooled to 15-20 °C. The reaction mass was charged with DMC in DCM solution (1.4 eq of DMC in 5.0 Vol of DCM). The mixture was stirred until Compound 31 becomes less than 2.0% with respect to the corresponding acid chloride, typically in about lh. After completion of the reaction, Compound 27 (1.4 eq) and N,N-diisopropylethyleneamine (3.0 eq) were charged and the mixture was stirred. After completion of the reaction, the mass was quenched with 12 Vol of water then the layers were separated. The organic layer was washed with water and filtered through a celite bed. The filtrate was concentrated to ~6.0 vol and then the mass was cooled to 35 °C. To the resulting solution was added THF, followed by seeds of product, then stirred for 3 h. The solvent was swapped with THF until

dichloromethane becomes less than 2 wt% (wrt THF). The mass was cooled to -5 to 0 °C over a period of 2 h and stirred for 2 h. The reaction mass was then filtered under a nitrogen atmosphere. The material was slurried with pre-cooled THF (2*2 Vol) and filtered. The wet cake was dried in VTD at 60 °C under vacuum till LOD becomes < 1%, typically in about 20 h.

Example 16

DC , RT

To a slurry of Compound 31 (15.00 g, 40.0 mmol) in dichloromethane (300 ml) was added diphenylphosphinic chloride (12.29 g, 51.9 mmol). The mixture was stirred at room temperature for 2 h and Ν,Ν-diisopropylethylamine ( 16.53 g, 127.9 mmol) was then added and stirred for another 30 min. Compound 27 (6.94 g, 51.9 mmol) and 4-dimethylaminopyridine (0.49 g, 4.0 mmol) were subsequently added and stirred for 16 h until the reaction was completed. The reaction mixture was treated with N-acetyl-L-cysteine (3.26 g, 20.0 mmol) and citric acid (10.10 g, 48.0 mmol) in deionized water (180 ml) for 2 h. After phase split, the dichloromethane phase was washed once with 0.42 N NaOH solution (180 ml) and washed twice with deionized water (180 ml each). The final dichloromethane phase was concentrated (to 90 ml) and acetone (30 ml) was added. The solution was cooled to 35 °C and N-2 form seed of Compound 1 ( 150 mg ) was added and aged for 1 h. The resulting slurry was solvent-swapped to acetone (DCM < 10% v/v), and cooled to 0 °C. The solid was filtered and washed with cold acetone and dried to afford 14.69 g (85%) of Compound I (HPLC AP 99.8) as off-white crystals.

Patent

WO 2011028864

http://www.google.com/patents/WO2011028864A1?cl=en

Compounds of general formula I in which the R group is thiazole (as in Ial) and R¹ and R² groups are CF₃ or alkyl or cycloalkyl or combine to form a saturated carbocyclic or heterocyclic ring or where R2 group is COOR^b could be prepared using the general method depicted in Scheme 1. Dichloro intermediate II (prepared using procedure reported in WO200612237) could be combined with a 2,4-dimethoxybenzyl and the resulting secondary amine is capped with suitable protective group (Boc) (III). The second chlorine atom could be converted into the

corresponding amine (IV) through the benzophenone imine intermediate. The amino compound could be halogenated to intermediate V. V could be subjected to transition metal mediated indole ring formation and the resulting indole nitrogen is capped with ethyl iodide to afford VI. Ester hydrolysis followed by amide bond formation and cleavage of protective groups with acid treatment would yield amine VII. Amine VII could be converted into thiourea VIII by first coupling with benzoyl isothiocyanate followed treatment with aqueous base. Formation of thiazole could be achieved by condensation with an a-bromoketone derivative (R^HBrCOR²).

a) 2,4-dimethoxybenzylamine, heat; b) NaHMDS, Boc₂0; c) (Ph)₂=NH; d) HCl; e) NIS; f) Pd₂(dba)₃, ethyl pyruvate; g) Etl, Cs₂C0₃; h) NaOH (aq); i) dicyclopropylamine HCl, HATU, DIPEA; j) TFA; k) Benzoyl isothiocyanate;

1) NaOH (aq); m) I^CHBrCOR¹

Scheme 1

Compounds of general formula Ia2 in which the R¹ group is CONR^aR^a could be made using Scheme 2. Thiourea intermediate (VIII) could be combined with Et0₂CCHBrCOR¹ to afford the thiazole ester (IX). The ester could be hydrolyzed and the acid could be coupled with amine to afford thiazole amide derivative (la)

a) Et0₂CCHBrCOR¹; b) NaOH (aq); c) HNR^aR^a, HATU, DIPEA

Scheme 2

Similarly, compounds of general formula Ia3 in which the R¹ group is CONR^aR^a could be prepared using the general protocol depicted in Scheme 3.

a) R²CHBrCOC0₂Me; b) NaOH (aq); c) HNR^aR^a, HATU, DIPEA

Scheme 3

Compounds of general formula la in which R¹ is halogen (CI, Br or I) could be prepared by condensing an a,a’-dihaloketone as depicted in Scheme 4.

a) R²COCH(Hal)₂

Scheme 4

Alternatively, thiourea derivative VIII could be converted to room temperature into C-5 un-substituted thiazole XI and then directly halogenated using electrophilic halogen source or through metallation followed by quenching with an electrophilic halogenating agent (Scheme 5).

a) BrCH₂COR²; b) Selectfluor or NCS or NBS or NIS or tBuLi followed Selectfluor or NBS or NCS

Scheme 5

Compounds of general formula Ia5 in which R¹ is S0₂R^b could be synthesized using the general synthetic approach shown in Scheme 6

a) Br2-acetic acid; b) EtOH, heat

Scheme 6

Compounds with general formula la in which R¹ and R² combine to form an aromatic or heteroaromatic ring could be prepared using Scheme 7.

X = hal, -S0₂Me

a) Pd(0) catalyst, NaOtBu, phosphine ligand, heat

Scheme 7

Alternatively, these compounds could be made by first coupling aniline or heteroaniline (XVI) with the isothiocyanate (XV) followed by oxidative cyclization (Scheme 8).

a) 1, 1 ‘-Thiocarbonyldi-2( 1 H)-pyridone; b) NaH; c) NIS

Scheme 8

Compounds of general formula Ibl could be prepared using the general synthetic approach depicted in Scheme 9. Aniline VII could be combined with γ-dithiomethylketone compound XVII, (prepared using the procedure reported at room temperature in Synlett, p 2331 (2008)) under basic condition to afford XVIII.

Stepwise condensation of the Boc-protected hydrazine derivative would give the required pyrazole Ibl.

a) NaH, THF; b) R¹N(Boc)NH₂, AcOH, 35-40°C; c) HCO₂H or TFA, 60°C

Scheme 9

Compounds of general formula Ibl or Ifl and If could also be prepared by coupling C-4 halo derivative (XIX) with an appropriately substituted 2-aminopyrazole derivative (XX) using a transition metal catalyzed reaction (Scheme 10).

a) isoamyl nitrite, CH2I2 or isoamyl nitrite, CH₂Br₂; b) Pd2(dba)₃, Xanphos, Cs₂C0₃

Scheme 10

Compounds of general formula Ib2 in which R² group is CONR^aR^a could be synthesized using Scheme 11. Aniline VII could be combined with γ-dithiomethylketone derivative XXII, (prepared using the procedure from

Tetrahedron, p 2631 (2003)) to afford intermediate XXIII. Stepwise condensation of Boc-protected hydrazine derivative would give the required pyrazole aldehyde XXIV. Aldehyde could be oxidized using oxone or sodium hypochlorite to furnish carboxylic acid XXV. Coupling of acid XXV with amine would give pyrazole amide Ib2.

a) NaH, THF, heat; b) R¹N(Boc)NH2, AcOH; c) TFA; d) oxone or sodium hypochlorite; e) HNR^aR^a, HATU, DIPEA

Scheme 11

Compounds of general formula Icl could be prepared using the general protocol as shown in Scheme 12. Aniline VII could be coupled with chloroacetyl chloride and the resulting amide could be treated with thioamide (R²CS H₂) to furnish thiazole Icl .

a) chloroacetyl chloride, base; b) R²CSNH₂

Scheme 12

00120] Compounds of general formula ldl could be made as per Scheme 13. Previously described isothiocyanate derivative XV could be combined with amidine XXV under dehydrating reaction conditions to give 1,2,4-thiadiazole (ldl).

Scheme 13

Compounds of general formula lei could be prepared using a synthetic approach as shown in Scheme 14. Isothiocyanate XV could be combined with azide XXVI in the presence of phosphine to yield 1,3-oxazole Iel .

Scheme 14

Compounds of general formula lgl could be prepared using a synthetic approach as shown in Scheme 15. Amine VII could be combined with acyl isothiocyanate XXVII. The acylthioureaido could be condensed with hydrazine derivative to yield the 1,2,4-triazol derivative lgl.

igi

Scheme 15

without a methyl

Preparation of 7V,7V-dicyclopropyl-6-ethyl-l-methyl-4-(5-m ethyl- lH-pyrazol-3- ylamino)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide

[00437] Prepared using similar protocol as for example 72 from hydrazine.

[00438] MS (ESI) m/z 419.3 (M+H)

[00439] 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.70 (br s, 1 H), 7.91 (br s, 1 H), 6.87 (s, 1 H), 6.09 (br s, 1 H), 4.64 (q, 2 H, J= 7.03 Hz), 4.08 (s, 3 H), 2.74 -2.95 (m, 2 H), 2.41 (s, 3 H), 1.51 (t, 3 H, J= 7.15 Hz), 0.81 – 0.95 (m, 4 H), 0.70 -0.81 (m, 4 H)

with an ethyl

7V,iV-dicyclopropyl-6-ethyl-4-(l-ethyl-5-methyl-lH-pyrazol-3-ylamino)-l-methyl- 1,6-dihydroimidazo [4,5-d] pyrrolo [2,3-b] pyridine-7-carboxamide

74A Preparation of fe/t-butyl l,3-dioxoisoindolin-2-yl(ethyl)carbamate

Diisopropyl azodicarboxylate (2.92 mL, 15.00 mmol) was added in one portion to a solution of tert-butyl l,3-dioxoisoindolin-2-ylcarbamate (2.62 g, 10 mmol, prepared following the procedure described by Nicolas Brosse et al. in Eur. J. Org. Chem. 4757-4764, 2003), triphenylphosphine (3.93 g, 15.00 mmol) and ethanol (0.691 g, 15.00 mmol) in THF (20 mL) at 0 °C and the reaction solution was stirred at room temperature for lh (monitored by TLC until completion). Solvent was evaporated and the residue was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 5-35% ethyl acetate / hexanes) to provide tert-butyl l,3-dioxoisoindolin-2-yl(ethyl)carbamate (2.6 g, 90 % yield) as a white solid which was used as it in the next step

74B Preparation of fe/t-butyl l-ethylhydrazinecarboxylate

Boc

H₂N-N

Methylhydrazine (1.415 niL, 26.9 mmol) was added to a solution oi tert-butyl l,3-dioxoisoindolin-2-yl(ethyl)carbamate (example 74A, 5.2 g, 17.91 mmol) in THF (40 mL) at 0 °C and the reaction mixture was stirred at room temperature overnight. A white precipitate formed and was filtered off through a pad of Celite, The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and extracted with IN HC1 (3×30 ml), the acid layer was washed with ethyl acetate (50 ml) and basified to pH 10 by addition of 20% NaOH. The basic solution was then extracted with ethyl acetate (3×50 ml) and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl 1 -ethylhydrazinecarboxylate (2.5 g, 87 % yield) as colorless oil.

^XH NMR (400 MHz, CDC1₃) δ: 3.90 (br. s., 2H), 3.35 (q, J = 7.0 Hz, 2H), 1.42 (s, 9H), 1.07 (t, J = 7.0 Hz, 3H)

74 Preparation of N.N-dicyclopropyl-6-ethyl-4-(l-ethyl-5-methyl-lH-pyrazol-3-ylamino)-l-methyl-l ,6-dihydroimidazor4,5-d1pyrrolor2,3-b1pyridine-7-carboxamide

A mixture of (Z)-N,N-dicyclopropyl-6-ethyl- 1 -methyl-4-( 1 -(methylthio)-3-oxobut-l-enylamino)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 74B, 70 mg, 0.155 mmol) and tert-butyl 1-ethylhydrazinecarboxylate (49.6 mg, 0.309 mmol) in acetic acid (1 mL) wan stirred at 35 °C for 4 h (monitored by LC/MS until no starting material left). Formic acid (1 mL) was added and the reaction mixture stirred at 60 °C for 6 h. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 2-10% methanol / dichloromethane). The material was further purified by preparative HPLC to afford N,N-dicyclopropyl-6-ethyl-4-( 1 -ethyl-5-methyl- lH-pyrazol-3-ylamino)- 1 -methyl- 1 ,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (38 mg, 53.4 % yield) as an off-white solid.

MS (ESI) m/z 447.3 (Μ+Η).

^XH NMR (500 MHz, CDC1₃) δ: 8.08 (s, 1H), 7.61 (s, 1H), 6.93 (s, 1H),

6.84 (s, 1H), 4.66 (q, J = 7.1 Hz, 2H), 4.02 (q, J = 7.2 Hz, 2H), 3.98 (s, 3H), 2.79 – 2.85 (m, 2H), 2.34 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H), 1.41 (t, J = 7.2 Hz, 3H), 0.82 -0.87 (m, 4H), 0.72 – 0.78 (m, 4H).

Patent

JAK2 INHIBITORS AND THEIR USE FOR THE TREATMENT OF MYELOPROLIFERATIVE DISEASES AND CANCER [US8202881]2011-03-102012-06-19

JAK2 inhibitors and their use for the treatment of myeloproliferative diseases and cancer [US8673933]2012-04-302014-03-18

: Purandare AV, McDevitt TM, Wan H, You D, Penhallow B, Han X, Vuppugalla R, Zhang Y, Ruepp SU, Trainor GL, Lombardo L, Pedicord D, Gottardis MM, Ross-Macdonald P, de Silva H, Hosbach J, Emanuel SL, Blat Y, Fitzpatrick E, Taylor TL, McIntyre KW, Michaud E, Mulligan C, Lee FY, Woolfson A, Lasho TL, Pardanani A, Tefferi A, Lorenzi MV. Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2. Leukemia. 2012 Feb;26(2):280-8. doi: 10.1038/leu.2011.292. Epub 2011 Oct 21. PubMed PMID: 22015772.

Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2http://www.nature.com/leu/journal/vaop/ncurrent/full/leu2011292a.html

GRAPHS str1

Click to access jo5b00572_si_001.pdf

str1

//////BMS 911543, phase 2, bms,

AT 9283

January 19, 2016 4:12 am / 1 Comment on AT 9283

AT9283, AT 9283

N-cyclopropyl-N’-[3-[6-(4-morpholinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea

1-cyclopropyl-3-[(3Z)-3-[5-(morpholin-4-ylmethyl)benzimidazol-2-ylidene]-1,2-dihydropyrazol-4-yl]urea

896466-04-9
Molecular Weight	381.43
Molecular Formula	C19H23N7O2

CAS

896466-04-9, 896466-57-2 ((±)-Lactic acid), 896466-61-8 (HCl), 896466-55-0 (methanesulfonate) AT9283/AT-9283

MolFormulaC22H29N7O5

MolWeight471.5096

CAS 896466-76-5 L LACTATE

(2S)-2-Hydroxypropanoic acid compd. with N-cyclopropyl-N’-[3-[6-(4-morpholinylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea

Astex Therapeutics Ltd, INNOVATOR

AT-9283 is a potent AuroraA/AuroraB and multi-kinase inhibitor. AT-9283 has shown to inhibit growth and survival of multiple solid tumor cell lines and is efficacious in mouse xenograft models.

AT 9283 is a substance being studied in the treatment of some types of cancer. It is small molecule a multi-targeted c-ABL, JAK2, Aurora A and B inhibition with 4, 1.2, 1.1 ad approximate 3 nM for Bcr-Abl (T3151), Jak2 and Jak3 aurora A and B, respectively. It blocks enzymes (Aurora kinases) involved in cell division and may kill cancer cells

WO2006070195 to Astex Therapeuitcs discloses pyrazole compounds of the general structure shown below as kinase inhibitors.

The compound AT9283 is in phase II clinical trials for treating advanced or metastatic solid tumors or Non-Hodgkin’s Lymphoma. AT9283 is shown below.

a Reagents and conditions:

(a) SOCl2, THF, DMF; (b) morpholine, THF, Et3N; ………FORMATION OOF ACID CHLORIDE AND COUPLING WITH MORPHOLINE

(d) 10% Pd-C, H2, EtOH; TWO NITRO GPS TO TWO AMINO , REDN

(e) EDC, HOBt, DMF; (f) AcOH, reflux;COUPLING WITH 4-Nitro-lH-pyrazole-3-carboxylic acid

(g) 10%Pd-C, H2, DMF; NITRO GP TO AMINO

(h) standard amide and urea coupling methods

WO2006070195

https://www.google.co.in/patents/WO2006070195A1?cl=en

Stage 10: Synthesis of l-cvclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- beiizoimidazol-2-ylV 1 H-pyrazol-4-yli -urea.

To a mixture of 7-morpholin-4-ylmethyl-2,4-dihydro- 1 ,2,4,5a, 10- pentaaza- cyclopenta[a]fluoren-5-one (10.7 g, 32.9 mmol) in NMP (65 mL) was added cyclopropylamine (6.9 mL, 99 mmol). The mixture was heated at 100 ⁰C for 5 h. LC/MS analysis indicated -75% conversion to product, therefore a further portion of cyclopropylamine (2.3 mL, 33 mmol) was added, the mixture heated at 100 ⁰C for 4 h and then cooled to ambient. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 niL). The organic portion was washed with sat. aq. NH₄Cl (2 x 50 mL) and brine (50 rnL) and then the aqueous portions re-extracted with EtOAc (3 x 100 mL). The combined organic portions were dried over MgSO₄ and reduced in vacuo to give l-cycloρropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea as an orange glassy solid (9.10 g).

Stage 11: Synthesis of l-cvclopropyl-S-P-fS-morpholin^-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yll-urea, L-lactate salt

To a solution of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2- yl)-lH-pyrazol-4-yl]-urea (9.10 g, 24 mmol) in EtOAc-iPrOH (1 :1, 90 mL) was added L-lactic acid (2.25 g, 25 mmol). The mixture was stirred at ambient temperature for 24 h then reduced in vacuo. The residue was given consecutive slurries using toluene (100 mL) and Et₂O (100 mL) and the resultant solid collected and dried (8.04 g).

This solid was purified by recrystallisation from boiling iPrOH (200 mL) to give after drying l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)- lH-pyrazol-4-yl]-urea, L-lactate salt (5.7 g) as a beige solid.

EXAMPLE 66

Stage 1: Preparation of (3,4-dinitrophenyl)-morpholin-4-yl-methanone

3,4-Dinitrobenzoic acid (1.000Kg, 4.71mol, l.Owt), tetiuhydrofuran (10.00L₅ lO.Ovol), and dimethylformamide (0.010L, O.Olvol) were charged to a flask under nitrogen. Thionyl chloride (0.450L, 6.16mol, 0.45vol) was added at 20 to 3O⁰C and the reaction mixture was heated to 65 to 7O⁰C. Reaction completion was determined by ¹H NMR analysis (d₆-DMSO), typically in 3 hours. The reaction mixture was cooled to 0 to 5⁰C and triethylamine (1.25L, 8.97mol, 1.25vol) was added at 0 to 10⁰C. Morpholine (0.62L, 7.07mol, 0.62vol) was charged to the reaction mixture at 0 to 1O⁰C and the slurry was stirred for 30 minutes at 0 to 1O⁰C. Reaction completion was determined by H NMR analysis (d₆-DMSO). The reaction mixture was warmed to 15 to 2O⁰C and water (4.00L, 4.0vol) was added. This mixture was then charged to a 4OL flange flask containing water (21.0OL, 21.0vol) at 15 to 25⁰C to precipitate the product. The flask contents were cooled to and aged at 0 to 5⁰C for 1 hour and the solids were collected by filtration. The filter-cake was washed with water (4x 5.00L, 4x 5.0vol) and the pH of the final wash was found to be pH 7. The wet filter-cake was analysed by H NMR for the presence of triethylamine hydrochloride. The filter-cake was dried at 40 to 45⁰C under vacuum until the water content by KF <0.2%w/w, to yield (3,4-dinitrophenyl)-morpholin-4-yl-methanone (1.286Kg, 97.0%, KF 0.069%w/w) as a yellow solid.

Stage 2: Preparation of 4-(3,4-dinitro-benzyl)-morpholine

C₁₁H₁₁N₃O₆ C₁₁H₁₃N₃O₅

FW:281.22 FW:267.24

(3,4-DinitiOphenyl)-morpholin-4-yl-methanone (0.750Kg, 2.67mol, l.Owt) and tetrahydrofuran (7.50L, lO.Ovol) were charged to a flask under nitrogen and cooled to 0 to 5⁰C. Borontrifluoride etherate (0.713L, 5.63mol, 0.95vol) was added at 0 to 5⁰C and the suspension was stirred at this temperature for 15 to 30 minutes. Sodium borohydride (0.212Kg, 5.60mol, 0.282wt) was added in 6 equal portions over 90 to 120 minutes. (A delayed exotherm was noted 10 to 15 minutes after addition of the first portion. Once this had started and the reaction mixture had been re-cooled, further portions were added at 10 to 15 minute intervals, allowing the reaction to cool between additions). The reaction mixture was stirred at 0 to 5⁰C for 30 minutes. Reaction completion was determined by ¹H NMR analysis (d₆-DMSO). Methanol (6.30L, 8.4vol) was added drop wise at 0 to 1O⁰C to quench the reaction mixture (rapid gas evolution, some foaming). The quenched reaction mixture was stirred at 0 to 1O⁰C for 25 to 35 minutes then warmed to and stirred at 20 to 3O⁰C (exotherm, gas/ether evolution on dissolution of solid) until gas evolution had slowed. The mixture was heated to and stirred at 65 to 7O⁰C for 1 hour. The mixture was cooled to 30 to 4O⁰C and concentrated under vacuum at 40 to 45⁰C to give crude 4-(3,4-dinitro-benzyl)-morpholine (0.702Kg, 98.4%) as a yellow/orange solid.

4-(3,4-Dinitro-benzyl)-niorpholme (2.815kg, 10.53mol, l.Owt) and methanol (12.00L, 4.3vol) were charged to a flask under nitrogen and heated to 65 to 7O⁰C. The temperature was maintained until complete dissolution. The mixture was then cooled to and aged at 0 to 5⁰C for 1 hour. The solids were isolated by filtration. The filter-cake was washed with methanol (2x 1.50L, 2x 0.5vol) and dried under vacuum at 35 to 45°C to give 4-(3,4-dinitro-benzyl)-morpholine (2.353Kg, 83.5% based on input Stage 2, 82.5% overall yield based on total input Stage 1 material,) as a yellow solid.

Stage 3: Preparation of 4-morpholin-4-yl-methyl-benzene-L2-diamine

C₁₁H₁₃N₃O₅ C₁₁H₁₇N₃O

FW:267.24 FW:207.27

4-(3,4-Dinitro-benzyl)-morρholine (0.800Kg, 2.99mol, l.Owt), and ethanol (11.20L, 14.0vol) were charged to a suitable flask and stirred at 15 to 25⁰C and a vacuum / nitrogen purge cycle was performed three times. 10% Palladium on carbon (10%Pd/C, 50%wet paste, 0.040Kg, 0.05wt wet weight) was slurried in ethanol (0.80L, l.Ovol) and added to the reaction. The mixture was cooled to 10 to 2O⁰C and a vacuum / nitrogen purge cycle was performed three times. A vacuum / hydrogen purge cycle was performed three times and the reaction was stirred under a hydrogen atmosphere at 10 to 2O⁰C. Reaction completion was determined by ¹H NMR analysis (d₆-DMSO), typically 14 to 20 hours. A vacuum / nitrogen purge cycle was performed three times and the reaction mixture was filtered through glass microfibre paper under nitrogen. The filter-cake was washed with ethanol (3x 0.80L, 3x l.Ovol) and the combined filtrate and washes were concentrated to dryness under vacuum at 35 to 45⁰C to give 4-morpholin-4-yl-methyl-benzene-l,2- diamine (0.61 IKg 98.6%) as a brown solid.

Stage 4: Preparation of 4-nitiO-lH-pyrazole-3-carboxγlic acid methyl ester

C₄H₃N₃O₄ C₅H₅N₃O₄

FW: 157.09 FW: 171.11

4-Nitro-lH-pyrazole-3-carboxylic acid (1.00kg, 6.37mol, l.Owt) and methanol (8.00L, 8.0vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The suspension was cooled to 0 to 5°C under nitrogen and thionyl chloride (0.52L, 7.12mol, 0.52vol) was added at this temperature. The mixture was warmed to 15 to 25°C over 16 to 24 hours. Reaction completion was determined by ¹H NMR analysis (d₆-DMSO). The mixture was concentrated under vacuum at 35 to 45°C. Toluene (2.00L, 2.0vol) was charged to the residue and removed under vacuum at 35 to 45⁰C. The azeotrope was repeated twice using toluene (2.00L, 2.0vol) to give 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.071Kg, 98.3%) as an off white solid.

Stage 5: Preparation of 4-amino-lH-pyrazole-3-carboxylic acid methyl ester. O₂Me

C₅H ₅N₃O₄ C₅H₇N₃O₂ FW: 171.11 FW: 141.13

A suspension of 4-nitro-lH-pyrazole-3-carboxylic acid methyl ester (1.084Kg, 6.33mol, l.Owt) and ethanol (10.84L, lO.Ovol) was heated to and maintained at 30 to 35°C until complete dissolution occurred. 10% Palladium on carbon (10% Pd/C wet paste, 0.152Kg, 0.14wt) was charged to a separate flask under nitrogen and a vacuum / nitrogen purge cycle was performed three times. The solution of 4-nitro- lH-pyrazole-3-carboxylic acid methyl ester in ethanol was charged to the catalyst and a vacuum / nitrogen purge cycle was performed three times. A vacuum / hydrogen purge cycle was performed three times and the reaction was placed under an atmosphere of hydrogen. The reaction mixture was stirred at 28 to 30°C until deemed complete by ¹H NMR analysis (d₆-DMSO). The mixture was filtered under nitrogen and concentrated under vacuum at 35 to 45⁰C to give 4-amino-lH- pyrazole-3-carboxylic acid methyl ester (0.883Kg, 98.9%) as a purple solid.

Stage 6: Preparation of 4-fert-butoxycarbonylamino-lH-pyrazole-3-carboxylic acid

C₅H₇N₃O₂ C₉H₁₃N₃O₄

FW: 141.13 FW:227.22

4-Amino-lH-pyrazole-3-carboxylic acid methyl ester (1.024Kg, 7.16mol, l.Owt) and dioxane (10.24L, lO.Ovol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. 2M aq. Sodium hydroxide solution (4.36L, 8.72mol, 4.26vol) was charged at 15 to 25⁰C and the mixture was heated to 45 to 55⁰C. The temperature was maintained at 45 to 55⁰C until reaction completion, as determined by ¹H NMR analysis (d₆-DMSO). Di-te/Y-butyl dicarbonate (Boc anhydride, 1.667Kg, 7.64mol, 1.628wt) was added at 45 to 55°C and the mixture was stirred for 55 to 65 minutes. ¹H NMR IPC analysis (d₆-DMSO) indicated the presence of 9% unreacted intermediate. Additional di-fert-butyl dicarbonate (Boc anhydride, 0.141Kg, 0.64mol, 0.14wt) was added at 55°C and the mixture was stirred for 55 to 65 minutes. Reaction completion was determined by ¹H NMR analysis (d₆-DMSO). The dioxane was removed under vacuum at 35 to 45⁰C and water (17.60L, 20.0vol) was added to the residue. The pH was adjusted to pH 2 with 2M aq. hydrochloric acid (4.30L, 4.20vol) and the mixture was filtered. The filter-cake was slurried with water (10.00L₃ 9.7vol) for 20 to 30 minutes and the mixture was filtered. The filter-cake was washed with heptanes (4.10L, 4.0vol) and pulled dry on the pad for 16 to 20 hours. The solid was azeodried with toluene (5x 4.00L, 5x 4.6vol) then dried under vacuum at 35 to 45°C to give 4-tert- butoxycarbonylamino-lH-pyrazole-3-carboxylic acid (1.389Kg, 85.4%) as a purple solid.

Stage 7: Preparation of [3-(2-amino-4-moipholin-4-ylmetliyl-phenylcarbamoviy lH-pyrazol-4-yl]-carbamic acid tert-butyl ester

C₉H₁₃N₃O₄ C₁₁H₁₇N₃O C₂₀H₂₈N₆O₄

FW: 227.22 FW: 207.27 FW: 416.48

+ regioisomer

4-førf-Butoxycarbonylamino-lH-pyrazole-3-carboxylic acid (0.750Kg, 3.30 mol, l.Owt), 4-morpholin-4yl-methyl-benzene-l,2-diamine (0.752Kg, 3.63mol, l.Owt) and N,N’-dimethylformamide (11.25L, 15.0vol) were charged under nitrogen to a flange flask equipped with a mechanical stirrer and thermometer. 1- Hydroxybenzotriazole (HOBT, 0.540Kg, 3.96mol, 0.72wt) was added at 15 to 25⁰C. N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide (EDC, 0.759Kg, 3.96mol, 1.01 wt) was added at 15 to 25⁰C and the mixture was stirred at this temperature for 16 to 24 hours. Reaction completion was determined by ¹H NMR analysis. The reaction mixture was concentrated under vacuum at 35 to 45°C. The residue was partitioned between ethyl acetate (7.50L, lO.Ovol) and sat. aq. sodium hydrogen carbonate solution (8.03L, 10.7vol) and the layers were separated. The organic phase was washed with brine (3.75L, 5.0vol), dried over magnesium sulfate (1.00Kg, 1.33wt) and filtered. The filter-cake was washed with ethyl acetate (1.50L, 2.0vol). The combined filtrate and wash were concentrated under vacuum at 35 to 45⁰C to give [3-(2-amino-4-morpholin-4-ylmethyl-phenylcarbamoyl)-lH-pyrazol- 4-yl]-carbamic acid tert-butyl ester (1.217Kg, 88.6%) as a dark brown solid.

Stage 8 : Preparation of 3 -f 5-morpholin-4-ylmethyl- 1 H-benzoimidazol-2-ylV 1 H- pyrazol-4-ylamme

C₁₅H₁₉N₆O

FW: 298.35

As a mixture of two regioisomers

[3-(2-Amino-4-morpholin-4-ylmethyl-phenylcarbamoyl)-lH-pyrazol-4-yl]- carbamic acid tert-butyl ester (1.350Kg, 3.24 mol, l.Owt) and ethanol (6.75L, 5.0vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. Cone. aq. hydrochloric acid (1.10L, 13.2 mol, 0.80vol) was added at 15 to 3O⁰C under nitrogen and the contents were then heated to 70 to 😯⁰C and maintained at this temperature for 16 to 24 hours. A second portion of hydrochloric acid (0.1 IL, 1.32 mol, O.OSOvol) was added at 70 to 😯⁰C and the reaction was heated for a further 4 hours. Reaction completion was determined by HPLC analysis. The reaction mixture was cooled to 10 to 20⁰C and potassium carbonate (1.355Kg, 9.08mol, l.Owt) was charged portionwise at this temperature. The suspension was stirred until gas evolution ceased and was then filtered. The filter-cake was washed with ethanol (1.35L, l.Ovol) and the filtrates retained. The filter-cake was slurried with ethanol (4.00L, 3.0vol) at 15 to 25⁰C for 20 to 40 minutes and the mixture was filtered. The filter-cake was washed with ethanol (1.35L₃ 1.Ovol) and the total combined filtrates were concentrated under vacuum at 35 to 45⁰C. Ethanol (4.00L, 3. Ovol) was charged to the residue and removed under vacuum at 35 to 45⁰C. Tetrahydrofuran (5.90L, 4.4vol) was added to the residue and stirred for 10 to 20 minutes at 15 to 25°C. The resulting solution was filtered, the filter-cake was washed with tetrahydrofuran (1.35L, l.Ovol) and the combined filtrates were concentrated under vacuum at 35 to 45⁰C. Tetrahydrofuran (5.40L, 4. Ovol) was charged to the concentrate and removed under vacuum at 35 to 45⁰C. Tetrahydrofuran (5.40L, 4. Ovol) was charged to the concentrate and removed under vacuum at 35 to 45°C to give the desired product, 3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-ylamine (0.924Kg, 95.5%, 82.84% by HPLC area) as a purple foam.

Stage 9: Preparation of 7-morpholin-4-ylmethyl-2,4-dihydro- 1,2,4,5a ,10-pentaaza- cyclopentaFal fluoren-5 -one

C₁₅H₁₈N₆O C₁₆H₁₆N₆O₂ FW: 298.35 FW: 324.34

As a mixture of two regioisomers

3-(5-Morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-pyrazol-4-ylamine (0.993Kg, 3.33 mol, l.Owt) and tetrahydrofuran (14.0L, 15.0vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. The contents were stirred under nitrogen at 15 to 25°C and l,l ‘-carbonyldiimidazole (0.596Kg, 3.67 mol, O.όOwt) was added. The contents were then heated to 60 to 70⁰C and stirred at this temperature for 16 to 24 hours. Reaction completion was determined by TLC analysis. The mixture was cooled to 15 to 20⁰C and filtered. The filter-cake was washed with tetrahydrofuran (4.00L, 4. Ovol) and pulled dry for 15 to 30 minutes. The solid was dried under vacuum at 35 to 45⁰C to yield 7- morpholin-4-ylmethyl-2,4-dihydro- 1 ,2,4,5a, 10-pentaaza-cyclopenta[a]fluoren-5- one (0.810Kg, 75.0%th, 92.19% by HPLC area) as a purple solid. Stage 10: Preparation of l-cvclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-vD- 1 H-pyrazol-4-yll -urea

C₁₆H₁₆N₆O₂ C₁₉H₂₃N₇O₂

FW: 324.34 FW: 381.44

As a mixture of two regioisomers

7-Morpholin-4-ylmethyl-2₅4-dihydro-l,2,4,5a,10-pentaaza-cyclopenta[a]fluoren-5- one (0.797Kg, 2.46mol, l.Owt) and l-methyl-2-pyrrolidinone (2.40L, 3.0vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. Cyclopropylamine (0.279Kg, 4.88mol, 0.35 lwt) was added at 15 to 30°C under nitrogen. The contents were heated to 95 to 105°C and stirred at this temperature for 16 to 24 hours. Reaction completion was determined by ¹H NMR analysis. The reaction mixture was cooled to 10 to 20⁰C and ethyl acetate (8.00L, lO.Ovol) and sat. aq. sodium chloride (2.50L, 3.0vol) were charged, the mixture was stirred for 2 to 5 minutes and the layers separated. The organic phase was stirred with sat. aq. sodium chloride (5.00L, ό.Ovol) for 25 to 35 minutes, the mixture filtered and the filter-cake washed with ethyl acetate (0.40L, 0.5vol). The filter-cake was retained and the filtrates were transferred to a separating funnel and the layers separated. The procedure was repeated a further 3 times and the retained solids were combined with the organic phase and the mixture concentrated to dryness under vacuum at 35 to 45⁰C. The concentrate was dissolved in propan-2-ol (8.00L, lO.Ovol) at 45 to 55°C and activated carbon (0.080Kg₅ O.lwt) was charged. The mixture was stirred at 45 to 55⁰C for 30 to 40 minutes and then hot filtered at 45 to 55°C. The filter-cake was washed with propan-2-ol (0.40L, 0.5vol). Activated carbon (0.080L, O.lwt) was charged to the combined filtrates and wash and the mixture stirred at 45 to 55⁰C for 30 to 40 minutes. The mixture was hot filtered at 45 to 55⁰C and the filter-cake washed with propan-2-ol (0.40L, 0.5vol). The filtrates and wash were concentrated under vacuum at 35 to 45⁰C. Ethyl acetate (8.00, lO.Ovol) and water (2.20L, 3.0vol) were charged to the concentrate at 25 to 35⁰C and the mixture stirred for 1 to 2 minutes. The layers were separated and the organic phase was concentrated under vacuum at 35 to 45°C. Ethyl acetate (4.00L, 5.0vol) was charged to the residue and concentrated under vacuum at 35 to 45⁰C. Ethyl acetate (4.00L, 5.0vol) was charged to the residue and the mixture was stirred for 2 to 20 hours at 15 to 25⁰C. The mixture was cooled to and aged at 0 to 5°C for 90 to 120 minutes and then filtered. The filter-cake was washed with ethyl acetate (0.80L, l.Ovol) and pulled dry for 15 to 30 minutes. The solid was dried under vacuum at 35 to 45⁰C to yield l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea (0.533Kg, 56.8%, 93.20% by HPLC area) as a brown solid.

Several batches of Stage 9 product were processed in this way and the details of the quantities of starting material and product for each batch are set out in Table IA.

Table IA – Yields from urea formation step – Stage 10

Stage 11 : Preparation of l-cyclopiOpyl-3-r3-(5-moipholin-4-ylmethyl-lH- benzoimidazol-2-yl^s)-lH-pyrazol-4-yll-urea £-lactic acid salt L-Lactic acid

acid

C₁₉H₂₃N₇O₂ C₂₂H₂₉N₇O₅

FW: 381.44 FW: 471.52 l-Cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2-yl)-lH-ρyrazol- 4-yl]-urea (1.859Kg, 4.872mol, l.Owt), propan-2-ol (9.00L₅ 5.0vol) and ethyl acetate (8.0OL, 4.5vol) were charged to a flange flask equipped with a mechanical stirrer and thermometer. The contents were stirred under nitrogen and L-lactic acid (0.504Kg, 5.59mol, 0.269wt) was added at 15 to 25°C followed by a line rinse of ethyl acetate (0.90L, 0.5vol). The mixture was stirred at 15 to 25°C for 120 to 140 minutes. The solid was isolated by filtration, the filter-cake washed with ethyl acetate (2x 2.00L, 2x l.Ovol) and pulled dry for 20 to 40 minutes. The filter-cake was dissolved in ethanol (33.00L, 17.7vol) at 75 to 85⁰C, cooled to 65 to 70⁰C and the solution clarified through glass microfibre paper. The filtrates were cooled to and aged at 15 to 25⁰C for 2 to 3 hours. The crystallised solid was isolated by filtration, the filter-cake washed with ethanol (2x 1.00L, 2x 0.5vol) and pulled dry for at least 30 minutes. The solid was dried under vacuum at 35 to 45°C to yield 1- cyclopropyl-3 – [3-(5 -morpholin-4-ylmethyl- 1 H-benzoimidazol-2-yl)- 1 H-pyrazol-4- yl]-urea l-lactic acid salt (1.386Kg, 58.7%th, 99.47% by HPLC area,) as a dark pink uniform solid.

The infra-red spectrum of the lactate salt (KBr disc method) included characteristic peaks at 3229, 2972 and 1660 cm^“1.

Without wishing to be bound by any theory, it is believed that the infra red peaks can be assigned to structural components of the salt as follow:

Peak: Due to:

3229 cm^“1 N-H

2972 cm^“1 aliphatic C-H

1660 cm^“1 urea C=O EXAMPLE 67

Synthesis of Crystalline Free Base And Crystalline Salt Forms Of l-Cyclopropyl-3-

[3-(5-Morpholin-4-ylmethyl-lH-Benzoimidazol-2-vπ-lH-Pyrazol-4-yll-Urea

A. Preparation of l-Cvclopropyl-3-[3-f5-Moφholm-4-ylmethyl-lH- Benzoimidazol-2-yl)-lH-Pyrazol-4-yll-Urea free base

A sample of crude l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol- 2-yl)-lH-pyrazol-4-yl]-urea free base was prepared as outlined in Example 60 and initially purified by column chromatography on silica gel, eluting with EtOAc- MeOH (98:2 – 80:20). A sample of the free base obtained was then recrystallised from hot methanol to give crystalline material of l-cyclopropyl-3-[3-(5-morpholin- 4-ylmethyl- 1 H-benzoimidazol-2-yl)- 1 H-pyrazol-4-yl] -urea free base.

B. Preparation of l-Cyclopropyl-S-rS-fS-Morpholin^-ylmethyl-lH-Benzoimidazol- 2-yl)-lH-Pyrazol-4-yl]-Urea free base dihydrate

A sample of crude l-cyclopropyl-3-[3-(5-moφholm-4-ylmethyl-lH-benzoimidazol- 2-yl)-l H-pyrazol-4-yl] -urea free base was dissolved in THF and then concentrated in vacuo to a minimum volume (~4 volumes). To the solution was added water dropwise (2 – 4 volumes) until the solution became turbid. A small amount of THF was added to re-establish solution clarity and the mixture left to stand overnight to give a crystalline material which was air-dried to give l-cyclopropyl-3-[3-(5- morpholin-4-ylmethyl- 1 H-benzoimidazol-2-yl)- 1 H-pyrazol-4-yl] -urea free base dihydrate.

C. Preparation of l-Cyclopl^pyl-3-[3-(5-Morpholm-4-ylmethyl-lH-Benzoimidazol- 2-ylVlH-Pyrazol-4-yl]-Urea hydrochloride salt

A sample of crude l-cyclopropyl-3-[3-(5-moφholin-4-ylmethyl-lH-benzoimidazol- 2-yl)-l H-pyrazol-4-yl] -urea free base was dissolved in the minimum amount of MeOH and then diluted with EtOAc. To the solution at 0 °C was slowly added 1.1 equivalents of HCl (4M solution in dioxane). Following addition, solid precipitated from solution which was collected by filtration. To the solid was added MeOH and the mixture reduced in vacuo. To remove traces of residual MeOH the residue was evaporated from water and then dried at 60 ⁰C/ 0.1 mbar to give the hydrochloride salt.

D. Preparation of l-Cyclopropyl-3-[3-(^‘5-Morpholm-4-ylmethyl-lH- Benzoimidazol-2-yiyiH-Pyrazol-4-yl1-Urea ethanesulfonate salt

To a solution of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2- yl)-lH-pyrazol-4-yl]-urea free base in MeOH-EtOAc was added 1 equivalent of ethanesulfonic acid. The mixture was stirred at ambient temperature and then reduced in vacuo. The residue was taken up in MeOH and to the solution was added Et₂O. Mixture left to stand for 72 h and the solid formed collected by filtration and dried to give l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea ethanesulfonate salt.

E. Preparation of l-Cvclopropyl-3-[3-(^‘5-Morpholm-4-ylmethyl-lH-Benzoimidazol- 2-yl)-lH-Pyrazol-4-yl]-Urea methanesulfonate salt

To a solution of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2- yl)-lH-pyrazol-4-yl]-urea free base (394 mg) in MeOH-EtOAc was added 1 equivalent of methanesulfonic acid (67 μl). A solid was formed which was collected by filtration, washing with EtOAc. The solid was dissolved in the minimum amount of hot MeOH, allowed to cool and then triturated with Et₂O. The solid was left to stand for 72 h and then collected by filtration, washing with MeOH, to give l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol-2- yl)-lH-pyrazol-4-yl]-urea methanesulfonate salt.

EXAMPLE 68

Characterisation of l-Cvclopropyl-3-[3-(5-Morpholin-4-ylmethyl-lH-

Benzoimidazol-2-yl)-lH-Pyrazol-4-yll-Urea Free Base and Salts

Various forms of l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH-benzoimidazol- 2-yl)-lH-pyrazol-4-yl]-urea were characterised. The forms selected for characterisation were identified from studies which primarily investigated extent of polymorphism and salt stability. The salts selected for further characterisation were the L-lactate salt, Free base dihydrate, Esylate salt, Free base and Hydrochloride salt.

Paper

Fragment-Based Discovery of the Pyrazol-4-yl Urea (AT9283), a Multitargeted Kinase Inhibitor with Potent Aurora Kinase Activity^†

Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, U.K.

J. Med. Chem., 2009, 52 (2), pp 379–388

DOI: 10.1021/jm800984v

Publication Date (Web): December 30, 2008

†

Coordinates of the protein complexes with compounds 5, 7, 9, 10, and 16 have been deposited in the Protein Data Bank under accession codes 2w1d, 2w1f, 2w1c, 2w1e, 2w1g (Aurora A), 2w1h (CDK2), and 2w1i (JAK2).

, * To whom correspondence should be addressed. Phone: +44 (0)1223 226209. Fax: +44 (0)1223 226201. E-mail: s.howard@astex-therapeutics.com.

http://pubs.acs.org/doi/abs/10.1021/jm800984v

http://pubs.acs.org/doi/suppl/10.1021/jm800984v/suppl_file/jm800984v_si_001.pdf

Abstract

Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC₅₀ ≈ 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound16 (AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Abl (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials.

1-Cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]urea (16)

16 as a pale-yellow solid (8.19 g, 87%). ¹H NMR (400 MHz, Me-d₃-OD): 8.07 (s, 1H), 7.58 (s, 2H), 7.26 (d, J = 8 Hz, 1H), 3.74−3.69 (m, 4H), 3.67 (s, 2H), 2.74−2.69 (m, 1H), 2.55−2.50 (m, 4H), 1.02−0.93 (m, 2H), 0.72−0.65 (m, 2H). LC/MS: t_R = 1.08 min, m/z = 382 [M + H]⁺.

1-Cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]urea (16), Hydrochloride Salt

¹H NMR (400 MHz, DMSO-d₆): 13.26−13.07 (m, 2H), 11.05−10.80 (m, 1H), 9.64 (s, 1H), 8.08 (s, 1H), 7.98−7.19 (4H, m), 4.44 (s, 2H), 3.94 (d, J = 12.4 Hz, 2H), 3.77 (t, J = 12.3 Hz, 2H), 3.28−3.20 (m, 2H), 3.17−3.05 (m, 2H), 2.65−2.57 (m, 1H), 0.96−0.79 (m, 2H), 0.63−0.51 (m, 2H).

Reference:

[1] J Med. Chem. 2009, 52, 379-388………http://pubs.acs.org/doi/pdf/10.1021/jm800984v

[2] Cell Cycle 2009, 8, 1921-1929.

[US2014336073]

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C1CC1NC(=O)NC2=CNNC2=C3N=C4C=CC(=CC4=N3)CN5CCOCC5

VAL-083

January 15, 2016 3:46 am / Leave a comment

VAL-083

(1R,2S)-1-((R)-oxiran-2-yl)-2-((S)-oxiran-2-yl)ethane-1,2-diol

Galactitol, 1,2:5,6-dianhydro-

1,2:5,6-Dianhydrodulcitol
1,2:5,6-Dianhydrogalactitol
1,2:5,6-Diepoxydulcitol

Dianhydrodulcitol; Dianhydrogalactitol; VAL083; VAL 083, Dulcitol diepoxide, NSC 132313

CAS 23261-20-3

MF C6H10O4, MW 146.14

VAL-083 is a bi-functional alkylating agent; inhibit U251 and SF188 cell growth in monolayer better than TMZ and caused apoptosis

VAL-083 is a bi-functional alkylating agent, with potential antineoplastic activity. Upon administration, VAL-083 crosses the blood brain barrier (BBB) and appears to be selective for tumor cells. This agent alkylates and crosslinks DNA which ultimately leads to a reduction in cancer cell proliferation. In addition, VAL-083 does not show cross-resistance to other conventional chemotherapeutic agents and has a long half-life in the brain. Check for active clinical trials or closed clinical trials using this agent

Currently, VAL-083 is approved in China to treat chronic myelogenous leukemia and lung cancer, while the drug has also secured orphan drug designation in Europe and the US to treat malignant gliomas.

LAUNCHED CHINA FOR Cancer, lung

Del Mar Pharmaceuticals Inc……..Glioblastoma…………..PHASE2

DelMar and MD Anderson to accelerate development of anti-cancer drug VAL-083
DelMar Pharmaceuticals has collaborated with the University of Texas MD Anderson Cancer Center (MD Anderson) to speed up the clinical development of its VAL-083 anti-cancer drug.

VAL-083 is a BI-Functional alkylating agent; INHIBIT U251 and SF188 Cell Growth in monolayer Better than TMZ and Caused apoptosis. IC50 Value : 5 uM (INHIBIT U251, SF188, T98G Cell Growth in monolayer after 72h) [1]. in vitro :.. VAL-083 INHIBITED U251 and SF188 Cell Growth in monolayer and as neurospheres Better than TMZ and Caused apoptosis after 72 hr Formation Assay In the colony, VAL-083 (5 uM) SF188 Growth suppressed by about 95% are T98G cells classically TMZ-resistant and express MGMT, but VAL-083 inhibited their growth in monolayer after 72 hr in a dose-dependent manner (IC50, 5 uM). VAL-083 also inhibited the growth of CSCs (BT74, GBM4, and GBM8) . by 80-100% in neurosphere self-Renewal assays Conversely, there was minimal normal Effect on Human Neural stem cells [1]. in Vivo : Clinical Trial : Safety Study of VAL-083 in Patients With Recurrent Malignant glioma or Secondary Progressive Brain Tumor. Phase 1 / Phase 2

VAL-083 has demonstrated activity in cyclophosphamide, BCNU and phenylanine mustard resistant cell lines and no evidence of cross-resistance has been encountered in published clinical studies. Based on the presumed alkylating functionality of VAL-083, published literature suggests that DNA repair mechanisms associated with Temodar and nitrosourea resistance, such as 06-methylguanine methyltransferace (MGMT), may not confer resistance to VAL-083. VAL-083 readily crosses the blood brain barrier where it maintains a long half-life in comparison to the plasma. Published preclinical and clinical research demonstrates that VAL-083 is selective for brain tumor tissue. VAL-083 has been assessed in multiple studies as chemotherapy in the treatment of newly diagnosed and recurrent brain tumors. In published clinical studies, VAL-083 has previously been shown to have a statistically significant impact on median survival in high grade gliomas when combined with radiation vs. radiation alone. The main dose-limiting toxicity related to the administration of VAL-083 in previous clinical studies was myelosuppression

Glioblastoma is the most common form of primary brain cancer

DelMar Pharmaceuticals has collaborated with the University of Texas MD Anderson Cancer Center (MD Anderson) to speed up the clinical development of its VAL-083 anti-cancer drug.

VAL-083 is a small-molecule chemotherapeutic designed to treat glioblastoma multiforme (GBM), the most common and deadly cancer that starts within the brain.

Under the deal, MD Anderson will begin a new Phase II clinical trial with VAL-083 in patients with GBM at first recurrence / progression, prior to Avastin (bevacizumab) exposure.

During the trial, eligible patients will have recurrent GBM characterised by a high expression of MGMT, the DNA repair enzyme implicated in drug-resistance, and poor patient outcomes following current front-line chemotherapy.

” … Our research shows that VAL-083 may offer advantages over currently available chemotherapies in a number of tumour types.”

The company noted that MGMT promoter methylation status will be used as a validated biomarker for enrollment and tumours must exhibit an unmethylated MGMT promoter for patients to be eligible for the trial.

DelMar chairman and CEO Jeffrey Bacha said: “The progress we continue to make with our research shows that VAL-083 may offer advantages over currently available chemotherapies in a number of tumour types.

“This collaboration will allow us to leverage world-class clinical and research expertise and a large patient population from MD Anderson as we extend and accelerate our clinical focus to include GBM patients, following first recurrence of their disease.

“We believe that VAL-083’s unique cytotoxic mechanism offers promise for GBM patients across the continuum of care as a potential superior alternative to currently available cytotoxic chemotherapies, especially for patients whose tumours exhibit a high-expression of MGMT.”

The deal will see DelMar work with the scientists and clinicians at MD Anderson to accelerate its research in order to transform the treatment of patients whose cancers fail or are unlikely to respond to existing treatments.

In more than 40 clinical trials, VAL-083 showed clinical activity against several cancers including lung, brain, cervical, ovarian tumours and leukemia both as a single-agent and in combination with other treatments.

PATENT

WO 2012024368

https://www.google.com/patents/WO2012024368A3?cl=en

Dianhydrogalactitol (DAG or dianhydrodulcitol) can be synthesized from dulcitol which can be produced from natural sources (such as Maytenus confertiflora) or commercial sources.The structure of DAG is given below as Formula (I).

One method for the preparation of dulcitol from Maytenus confertiflora is as follows: (1) The Maytenus confertiflora plant is soaked in diluted ethanol (50-80%) for about 24 hours, and the soaking solution is collected. (2) The soaking step is repeated, and all soaking solutions are combined. (3) The solvent is removed by heating under reduced pressure. (4) The concentrated solution is allowed to settle overnight and the clear supernatant is collected. (5) Chloroform is used to extract the supernatant. The chloroform is then removed under heat and reduced pressure. (6) The residue is then dissolved in hot methanol and cooled to allow crystallization. (7) The collected crystals of dulcitol are filtered and dried under reduced pressure. The purified material is dulcitol, contained in the original Maytenus confertiflora plant at a concentration of about 0.1% (1/1000).

DAG can be prepared by two general synthetic routes as described below:

Route 1 :

Dulcitol DAG

Route 2. Dulcitol

In Route 1 , “Ts” represents the tosyl group, or p-toluenesulfonyl group. PATENT

However, the intermediate of Route 1, 1,6-ditosy)dulcitol, was prepared with low yield (~36%), and the synthesis of 1,6-ditosyldulcitol was poorly reproducible. Therefore, the second route process was developed, involving two major steps: (1) preparation of dibromodulcitol from dulcitol; and (2) preparation of dianhydrodulcitol from dibromodulcitol.

Dibromodulcitol is prepared from dulcitol as follows: (1) With an aqueous HBr solution of approximately 45% HBr concentration, increase the HBr concentration to about 70% by reacting phosphorus with bromine in concentrated HBr in an autoclave. Cool the solution to 0° C. The reaction is:

2P+3Br₂→2PBr₃+H₂0→HBr†+H₃P0₄. (2) Add the dulcitol to the concentrated HBr solution and reflux at 80° C to complete the reaction. (3) Cool the solution and pour the mixture onto ice water. Dibromodulcitol is purified through recrystallization.

The results for the preparation of dibromodulcitol (DBD) are shown in Table 1, below.

TABLE 1

For the preparation of DAG from DBD, DBD was poorly dissolved in methanol and ethanol at 40° C (different from what was described in United States PATENT

Patent No. 3,993,781 to Horvath nee Lengyel et al., incorporated herein by this reference). At refluxing, DBD was dissolved but TLC showed that new impurities formed that were difficult to remove from DBD.

The DBD was reacted with potassium carbonate to convert the DBD to dianhydrogalactitol.

The results are shown in Table 2, below.

TABLE 2

In the scale-up development, it was found the crude yield dropped significantly. It is unclear if DAG could be azeotropic with BuOH. It was confirmed that t-BuOH is essential to the reaction. Using MeOH as solvent would result in many impurities as shown spots on TLC. However, an improved purification method was developed by using a slurry with ethyl ether, which could provide DAG with good purity. This was developed after a number of failed attempts at recrystallization of DAG.

str1

Bromination of dulcitol with HBr at 80°C gives dibromodulcitol , which upon epoxidation in the presence of K2CO3 in t-BuOH or NaOH in H2O or in the presence of ion exchange resin Varion AD (OH) (4) affords the target dianhydrogalactitol .

PATENT

US 20140155638

str1

SCHEME 5

str1 str1 str1

PATENT

CN 103923039

http://www.google.com/patents/CN103923039A?cl=en

The resulting Dulcitol 9g and 18ml mass percent concentration of 65% hydrobromic acid at 78 ° C under reflux for 8 hours to give 1,6-dibromo dulcitol, and the product is poured into ice crystals washed anhydrous tert-butyl alcohol, and dried to give 1,6-dibromo dulcitol crystal, then 10.0gl, 6- dibromo dulcitol sample is dissolved in t-butanol, adding solid to liquid 2 % obtained through refining process 1,6_ dibromo dulcitol seed stirred and cooled to 0 ° C, allowed to stand for seven days to give 1,6_ dibromo dulcitol crystal, anhydrous t-butanol, dried to give 1,6-dibromo dulcitol. 5g of the resulting 1,6_ dibromo Euonymus dissolved in 50ml tert-butanol containing 5g of potassium carbonate, the elimination reaction, at 80 ° C under reflux time was 2 hours, the resulting product was dissolved in t-butanol, Join I% stock solution to the water quality of 1,2,4,5_ two Dulcitol including through a purification step to get less than 1% of 1,2,5,6_ two to water Dulcitol seeded stirring, cooling to 0 ° C, allowed to stand for I-day, two to go get 1,2,5,6_ water Dulcitol crystals washed anhydrous tert-butyl alcohol, and dried to give 1,2,5,6 two to crystalline water Dulcitol and lyophilized to give two to water Dulcitol lyophilized powder, containing I, 2,4,5- two to water Dulcitol less than 0.3%.

PATENT

WO 2005030121

PATENT

US 20140066642

DAG can be prepared by two general synthetic routes as described below:
In Route 1, “Ts” represents the tosyl group, or p-toluenesulfonyl group.
However, the intermediate of Route 1, 1,6-ditosyldulcitol, was prepared with low yield (˜36%), and the synthesis of 1,6-ditosyldulcitol was poorly reproducible. Therefore, the second route process was developed, involving two major steps: (1) preparation of dibromodulcitol from dulcitol; and (2) preparation of dianhydrodulcitol from dibromodulcitol.
Dibromodulcitol is prepared from dulcitol as follows: (1) With an aqueous HBr solution of approximately 45% HBr concentration, increase the HBr concentration to about 70% by reacting phosphorus with bromine in concentrated HBr in an autoclave. Cool the solution to 0° C. The reaction is: 2P+3Br₂→2PBr₃+H₂O→HBr↑+H₃PO₄. (2) Add the dulcitol to the concentrated HBr solution and reflux at 80° C. to complete the reaction. (3) Cool the solution and pour the mixture onto ice water. Dibromodulcitol is purified through recrystallization.

PATENT

US 20150329511

PAPER

Molecules 2015, 20(9), 17093-17108; doi:10.3390/molecules200917093

Article

Antibacterial and Anti-Quorum Sensing Molecular Composition Derived from Quercus cortex (Oak bark) Extract

Dmitry G. Deryabin * and Anna A. Tolmacheva

Microbiological Department, Orenburg State University, 13 Pobedy Avenue, Orenburg 460018, Russia

* Author to whom correspondence should be addressed.

1,2: 5,6-dianhydrogalactitol ** in table 1

Paper

Takano, Seiichi; Iwabuchi, Yoshiharu; Ogasawara, Kunio
Journal of the American Chemical Society, 1991 , vol. 113, 7 pg. 2786 – 2787

http://pubs.acs.org/doi/pdf/10.1021/ja00007a082

REFERENCES

Currently, VAL-083 is approved in China to treat chronic myelogenous leukemia and lung cancer, while the drug has also secured orphan drug designation in Europe and the US to treat malignant gliomas.

[1]. Fotovati A, Hu KJ, Wakimoto H, VAL-083, A NOVEL N7 ALKYLATING AGENT, SURPASSES TEMOZOLOMIDE ACTIVITY AND INHIBITS CANCER STEM CELLS, PROVIDING A NEW POTENTIAL TREATMENT OPTION FOR GLIOBLASTOMA MULTIFORME. Neuro-oncology, 2012, 14, AbsET-37, Suppl. 6

[2]. Fotovati A, Hu KJ, Wakimoto H, VAL-083, A NOVEL AGENT N7 alkylating, SURPASSES temozolomide Inhibits TREATMENT ACTIVITY AND STEM CELLS, PROVIDING A NEW TREATMENT OPTION FOR POTENTIAL glioblastoma multiforme. Neuro-oncology, 2012, 14, AbsET-37, Suppl. 6

1: Szende B, Jeney A, Institoris L. The diverse modification of N-butyl-N-(4-hydroxybutyl) nitrosamine induced carcinogenesis in urinary bladder by dibromodulcitol and dianhydrodulcitol. Acta Morphol Hung. 1992;40(1-4):187-93. PubMed PMID: 1365762.

2: Anderlik P, Szeri I, BÃ¡nos Z. Bacterial translocation in dianhydrodulcitol-treated mice. Acta Microbiol Hung. 1988;35(1):49-54. PubMed PMID: 3293340.

3: Huang ZG. [Clinical observation of 15 cases of chronic myelogenous leukemia treated with 1,2,5,6-dianhydrodulcitol]. Zhonghua Nei Ke Za Zhi. 1982 Jun;21(6):356-8. Chinese. PubMed PMID: 6957285.

4: Anderlik P, Szeri I, BÃ¡nos Z, Wessely M, Radnai B. Higher resistance of germfree mice to dianhydrodulcitol, a lymphotropic cytostatic agent. Acta Microbiol Acad Sci Hung. 1982;29(1):33-40. PubMed PMID: 6211912.

5: BÃ¡nos Z, Szeri I, Anderlik P. Effect of Bordetella pertussis vaccine on the course of lymphocytic choriomeningitis (LCM) virus infection in suckling mice pretreated with dianhydrodulcitol (DAD). Acta Microbiol Acad Sci Hung. 1979;26(2):121-5. PubMed PMID: 539467.

6: BÃ¡nos Z, Szeri I, Anderlik P. Dianhydrodulcitol treatment of lymphocytic choriomeningitis virus infection in suckling mice. Acta Microbiol Acad Sci Hung. 1979;26(1):29-34. PubMed PMID: 484266.

7: GerÃ¶-Ferencz E, TÃ³th K, Somfai-Relle S, GÃ¡l F. Effect of dianhydrodulcitol (DAD) on the primary immune response of normal and tumor bearing rats. Oncology. 1977;34(4):150-2. PubMed PMID: 335301.

8: Kopper L, Lapis K, InstitÃ³ris L. Incorporation of 3H-dibromodulcitol and 3H-dianhydrodulcitol into ascites tumor cells. Autoradiographic study. Neoplasma. 1976;23(1):47-52. PubMed PMID: 1272473.

9: BÃ¡nos S, Szeri I, Anderlik P. Combined phytohaemagglutinin and dianhydrodulcitol treatment of lymphocytic choriomeningitis virus infection in mice. Acta Microbiol Acad Sci Hung. 1975;22(3):237-40. PubMed PMID: 1155228.

Carbohydrate Research, 1982 , vol. 108, p. 173 – 180

Deryabin, Dmitry G.; Tolmacheva, Anna A.
Molecules, 2015 , vol. 20, 9 pg. 17093 – 17108

Gati; Somfai-Relle
Arzneimittel-Forschung/Drug Research, 1982 , vol. 32, 2 pg. 149 – 151

WO2013128285A2 *	Feb 26, 2013	Sep 6, 2013	Del Mar Pharmaceuticals	Improved analytical methods for analyzing and determining impurities in dianhydrogalactitol
WO2013128285A3 *	Feb 26, 2013	Dec 27, 2013	Del Mar Pharmaceuticals	Improved analytical methods for analyzing and determining impurities in dianhydrogalactitol
US9029164	Nov 18, 2013	May 12, 2015	Del Mar Pharmaceuticals	Analytical methods for analyzing and determining impurities in dianhydrogalactitol

US3470179 *	Jun 14, 1966	Sep 30, 1969	Sandoz Ag	4-substituted-3,4-dihydroquinazolines
US20020032230 *	May 21, 2001	Mar 14, 2002	Dr. Reddy’s Laboratories Ltd.	Novel compounds having antiinflamatory activity: process for their preparation and pharmaceutical compositions containing them
US20020037328 *	May 31, 2001	Mar 28, 2002	Brown Dennis M.	Hexitol compositions and uses thereof

CN101045542A *	Apr 6, 2007	Oct 3, 2007	中国科学院过程工程研究所	Method for preparing water softening aluminium stone of sodium aluminate solution carbonation resolving
CN101654270A *	Sep 10, 2009	Feb 24, 2010	沈阳工业大学	Method for eliminating periodic thinning of granularity of seed product
CN101775413A *	Mar 23, 2010	Jul 14, 2010	禹城绿健生物技术有限公司	Technique for producing xylitol and dulcitol simultaneously
CN103270035A *	Aug 17, 2011	Aug 28, 2013	德玛医药	Method of synthesis of substituted hexitols such as dianhydrogalactitol

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C1C(O1)C(C(C2CO2)O)O

O[C@H]([C@H]1OC1)[C@@H](O)[C@H]2CO2

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

GS 9883, Bictegravir an HIV-1 integrase inhibitor

December 28, 2015 10:11 am / 1 Comment on GS 9883, Bictegravir an HIV-1 integrase inhibitor

GS 9883, bictegravir

CAS 1611493-60-7

PHASE 3

HIV-1 integrase inhibitor

(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

2,5-Methanopyrido(1′,2′:4,5)pyrazino(2,1-b)(1,3)oxazepine-10-carboxamide, 2,3,4,5,7,9,13,13a-octahydro-8-hydroxy-7,9-dioxo-N-((2,4,6-trifluorophenyl)methyl)-, (2R,5S,13aR)-

(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

(2 ,5S,13aI )-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluoroheoctahydro-2,5-methanopyrido[ 1 ‘,2’:4,5]pyrazino[2, 1 -b][ 1 ,3]oxazepine- 10-carboxamide

MF C₂₁H₁₈F₃N₃O_5,

MW	449.37993 g/mol

UNII-8GB79LOJ07; 8GB79LOJ07

2D chemical structure of 1611493-60-7

BICTEGRAVIR

16 Nov 2015 Phase-III clinical trials in HIV-1 infections (Combination therapy, Treatment-naive) in USA (PO) (Gilead Pipeline, November 2015)
01 Jul 2015 Gilead Sciences completes a phase I trial in HIV-1 infections in USA and New Zealand (NCT02400307)
01 Apr 2015 Phase-I clinical trials in HIV-1 infections (In volunteers) in New Zealand (PO) (NCT02400307)

UPDATE Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide); Gilead; For the treatment of HIV-1 infection in adults, Approved February 2018

Human immunodeficiency virus infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, et al. N. Engl. J Med. (1998) 338:853-860; Richman, D. D. Nature (2001) 410:995-1001). Accordingly, there is a need for new agents that inhibit the replication of HIV and that minimize PXR activation when co-administered with other drugs.

Certain polycyclic carbamoylpyridone compounds have been found to have antiviral activity, as disclosed in PCT/US2013/076367. Accordingly, there is a need for synthetic routes for such compounds.

SYNTHESIS

WO 2014100323

PATENTS

WO2014100323

xample 42

Preparation of Compound 42

(2 ,5S,13aI )-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorohe

octahydro-2,5-methanopyrido[ 1 ‘,2’:4,5]pyrazino[2, 1 -b][ 1 ,3]oxazepine- 10-carboxamide

Step 1

l-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-l ,4-dihydropyridine-3-carboxylic acid (3.15 g, 10 mmol) in acetonitrile (36 mL) and acetic acid (4 mL) was treated with methanesuffhnic acid (0.195 mL, 3 mmol) and placed in a 75 deg C bath. The reaction mixture was stirred for 7 h, cooled and stored at -10 °C for 3 days and reheated to 75 °C for an additional 2 h. This material was cooled and carried on crude to the next step.

Step 2

Crude reaction mixture from step 1 (20 mL, 4.9 mmol) was transferred to a flask containing (lR,3S)-3-aminocyclopentanol (0.809 g, 8 mmol). The mixture was diluted with acetonitrile (16.8 mL), treated with potassium carbonate (0.553 g, 4 mmol) and heated to 85 °C. After 2 h, the reaction mixture was cooled to ambient temperature and stirred overnight. 0.2M HQ (50 mL) was added, and the clear yellow solution was extracted with dichloromethane (2×150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to 1.49 g of a light orange solid. Recrystallization from dichloimethane:hexanes afforded the desired intermediate 42 A: LC S-ESI (m/z): [M+H]+ calculated for Ci5Hi7N206: 321.1 1 ; found: 321.3.

Step 3

Intermediate 42-A (0.225 g, 0.702 mmol) and (2,4,6-trifluorophenyl)methanamine (0.125 g, 0.773 mmol) were suspended in acetonitrile (4 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.183 mmol, 1.05 mmol). To this suspension was added (dimethyiammo)- V,A/-dimethyi(3H-[l ,2,3]triazolo[4,5-&]pyridm~3-yiox.y)methammimum hexafluorophosphate (HATU, 0.294 g, 0.774 mmol). After 1.5 hours, the crude reaction mixture was taken on to the next step. LfJMS-ESlT (m/z): [M+H calculated for (\ ,l l.,, i \\:0< : 464.14; found: 464.2.

Step 4

To the crude reaction mixture of the previous step was added MgBr2

(0.258 g, 1.40 mmol). The reaction mixture was stirred at 50 °C for 10 minutes, acidified with 10% aqueous HC1, and extract twice with dichloromethane. The combined organic phases were dried over MgS04, filtered, concentrated, and purified by silica gel chromatography (EtOH/dichlormethane) followed by HPLC (ACN H2O with 0.1 % TFA modifier) to afford compound 42: 1H~ M (400 MHz, DMSO-</6) δ 12.43 (s, 1H), 10.34 (t, J = 5.7 Hz, IH), 8.42 (s, 1H), 7.19 (t, J = 8.7 Hz, 2H), 5.43 (dd, ./’ 9.5, 4.1 Hz, I H), 5.08 (s, i l l ). 4.66 (dd, ./ 12.9, 4.0 Hz, IH), 4.59 (s, 1 1 1 ). 4.56 4.45 (m, 2H), 4.01 (dd, J = 12.7, 9.7 Hz, IH), 1.93 (s, 4H), 1.83 (d, J —— 12.0 Hz, I H),

1.56 (dt, J = 12.0, 3.4 Hz, I H). LCMS-ESI+ (m/z): [M+H]+ calculated for { · Ί ί ] ΝΓ :Χ.¾ϋ : 450.13; found: 450.2.

PATENT

WO2015177537

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015177537&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

PATENT

WO2015196116

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015196116&redirectedID=true

PATENT

WO2015196137

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015196137&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

PATENT

http://www.google.com/patents/US20140221356

Example 42 Preparation of Compound 42 (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide

Step 1

1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (3.15 g, 10 mmol) in acetonitrile (36 mL) and acetic acid (4 mL) was treated with methanesulfonic acid (0.195 mL, 3 mmol) and placed in a 75 deg C. bath. The reaction mixture was stirred for 7 h, cooled and stored at −10° C. for 3 days and reheated to 75° C. for an additional 2 h. This material was cooled and carried on crude to the next step.

Step 2

Crude reaction mixture from step 1 (20 mL, 4.9 mmol) was transferred to a flask containing (1R,3S)-3-aminocyclopentanol (0.809 g, 8 mmol). The mixture was diluted with acetonitrile (16.8 mL), treated with potassium carbonate (0.553 g, 4 mmol) and heated to 85° C. After 2 h, the reaction mixture was cooled to ambient temperature and stirred overnight. 0.2M HCl (50 mL) was added, and the clear yellow solution was extracted with dichloromethane (2×150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to 1.49 g of a light orange solid. Recrystallization from dichlormethane:hexanes afforded the desired intermediate 42A: LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C15H₁₇N₂O₆: 321.11; found: 321.3.

Step 3

Intermediate 42-A (0.225 g, 0.702 mmol) and (2,4,6-trifluorophenyl)methanamine (0.125 g, 0.773 mmol) were suspended in acetonitrile (4 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.183 mmol, 1.05 mmol). To this suspension was added (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (HATU, 0.294 g, 0.774 mmol). After 1.5 hours, the crude reaction mixture was taken on to the next step. LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₂H₂₁F₃N₃O₅: 464.14; found: 464.2.

Step 4

To the crude reaction mixture of the previous step was added MgBr₂(0.258 g, 1.40 mmol). The reaction mixture was stirred at 50° C. for 10 minutes, acidified with 10% aqueous HCl, and extract twice with dichloromethane. The combined organic phases were dried over MgSO₄, filtered, concentrated, and purified by silica gel chromatography (EtOH/dichlormethane) followed by HPLC (ACN/H₂O with 0.1% TFA modifier) to afford compound 42: ¹H-NMR (400 MHz, DMSO-d₆) δ 12.43 (s, 1H), 10.34 (t, J=5.7 Hz, 1H), 8.42 (s, 1H), 7.19 (t, J=8.7 Hz, 2H), 5.43 (dd, J=9.5, 4.1 Hz, 1H), 5.08 (s, 1H), 4.66 (dd, J=12.9, 4.0 Hz, 1H), 4.59 (s, 1H), 4.56-4.45 (m, 2H), 4.01 (dd, J=12.7, 9.7 Hz, 1H), 1.93 (s, 4H), 1.83 (d, J=12.0 Hz, 1H), 1.56 (dt, J=12.0, 3.4 Hz, 1H). LCMS-ESI⁺ (m/z): [M+H]⁺ calculated for C₂₁H₁₉F₃N₃O₅: 450.13; found: 450.2.

PATENT

WO-2015195656

General Scheme I:

General Scheme II:

General Scheme II

General Scheme III:

General Scheme III

General Scheme IV:

G-1

General Scheme V:

EXAMPLES

In order for this invention to be more fully understood, the following examples are set forth. These examples are for the purpose of illustrating embodiments, and are not to be construed as limiting the scope of this disclosure in any way. The reactants used in the examples below may be obtained either as described herein, or if not described herein, are themselves either commercially available or may be prepared from commercially available materials by methods known in the art.

In one embodiment, a multi-step synthetic method for preparing a compound of Formula I is provided, as set forth below. In certain embodiments, each of the individual steps of the Schemes set forth below is provided. Examples and any combination of two or more successive steps of the below Examples are provided.

A. Acylation and amidation of Meldrum ‘s acid to form C-la:

[0520] In a reaction vessel, Meldrum’s acid (101 g, 1.0 equivalent) and 4-dimethylaminopyridine (1.8 g, 0.2 equivalents) were combined with acetonitrile (300 mL). The resulting solution was treated with methoxyacetic acid (6.2 mL, 1.2 equivalents). Triethylamine (19.4 mL, 2.0 equivalents) was added slowly to the resulting solution, followed by pivaloyl chloride (9.4 mL, 1.1 equivalents). The reaction was then heated to about 45 to about 50 °C and aged until consumption of Meldrum’s acid was deemed complete.

A separate reaction vessel was charged with acetonitrile (50 mL) and J-la (13.4 g, 1.2 equivalents). The resulting solution was treated with trifluoroacetic acid (8.0 mL, 1.5 equivalents), and then this acidic solution was added to the acylation reaction in progress at about 45 to about 50 °C.

The reaction was allowed to age for at least 18 hours at about 45 to about 50 °C, after which time the solvent was removed under reduced pressure. The crude residue was dissolved in ethyl acetate (150 mL), and the organic layer was washed with water. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution, and the combined bicarbonate washes were back extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude material was purified twice via silica gel chromatography to yield C-la.

^lH NMR (400 MHz, CDC1₃): δ 7.12 (br, 1H), 6.66 (app t, J= 8.1 Hz, 2H), 4.50 (app d, J= 5.7 Hz, 2H), 4.08 (s, 2H), 3.44 (s, 2H), 3.40 (s, 3H). ¹³C NMR (100 MHz, CDC1₃): δ 203.96, 164.90, 162.37 (ddd, J= 250.0, 15.7, 15.7 Hz), 161.71 (ddd, J = 250.3, 14.9, 10.9 Hz), 110.05 (ddd, J= 19.7, 19.7, 4.7 Hz), 100.42 (m), 77.58, 59.41, 45.71, 31.17 (t, J= 3.5 Hz). LCMS, Calculated: 275.23, Found: 275.97 (M).

I l l

B. Alkylation of C-la to form E-la:

A solution of C-la (248 mg, 1.0 equivalent) and 2-methyl tetrahydrofuran (1.3 niL) was treated with N,N-dimethylformamide dimethylacetal (0.1 mL, 1.1 equivalent) and stirred at room temperature overnight (~14 hours). The reaction was treated with aminoacetaldehyde dimethyl acetal (0.1 mL, 1.0 equivalents), and was allowed to age for about 2 hours, and then was quenched via the addition of 2 Ν HC1

(1.5 mL).

The reaction was diluted via the addition of ethyl acetate, and phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography to yield E-la.

¹H NMR (400 MHz, CDC1₃): δ 10.85 (s, 1H), 9.86 (s, 1H), 8.02 (d, J= 13.1 Hz, 1H), 6.65 (dd, J= 8.7, 7.7 Hz, 2H), 4.53 (d, J= 3.9 Hz, 2H), 4.40 (t, J= 5.1 Hz, 1H), 4.18 (s, 2H), 3.42 (s, 6H), 3.39 (m, 2H), 3.37 (s, 3H). ¹³C MR (100 MHz, CDC1₃): δ 193.30, 169.15, 162.10 (ddd, J= 248.9, 15.5, 15.5 Hz), 161.7 (ddd, J =

250.0, 14.9, 1 1.1 Hz), 161.66, 1 11.08 (ddd J= 19.9, 19.9, 4.7 Hz) 103.12, 100.29 (ddd, J= 28.1, 17.7, 2.3 Hz), 76.30, 58.83, 54.98, 53.53, 51.57, 29.89 (t, J= 3.3 Hz). LCMS, Calculated: 390.36, Found: 390.92 (M).

c. Cyclization of E-la to form F-la:

E-1a F-1a

] E-la (0.2 g, 1.0 equivalent), dimethyl oxalate (0.1 g, 2.5 equivalents) and methanol (1.5 mL) were combined and cooled to about 0 to about 5 °C. Sodium methoxide (0.2 mL, 30% solution in methanol, 1.75 equivalents) was introduced to the reaction slowly while keeping the internal temperature of the reaction below about 10 °C throughout the addition. After the addition was completed the reaction was heated to about 40 to about 50 °C for at least 18 hours.

After this time had elapsed, the reaction was diluted with 2 N HC1 (1.5 mL) and ethyl acetate (2 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and solvent was removed under reduced pressure. The resulting crude oil was purified via silica gel chromatography to afford F-la.

^lR NMR (400 MHz, CDC1₃): δ 10.28 (t, J= 5.5 Hz, 1H), 8.38 (s, 1H), 6.66 – 6.53 (m, 2H), 4.58 (d, J= 5.6 Hz, 2H), 4.43 (t, J= 4.7 Hz, 1H), 4.00 (d, J= 4.7 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.32 (s, 6H). ¹³C NMR (100 MHz, CDC1₃): δ 173.08, 163.81, 162.17, 162.14 (ddd, J= 249.2, 15.6, 15.6 Hz), 161.72 (ddd, J= 250.5, 15.0, 10.9 Hz), 149.37, 144.64, 134.98, 119.21, 1 10.53 (ddd, J= 19.8, 4.7, 4.7 Hz), 102.70, 100.22 (m), 60.68, 56.75, 55.61, 53.35, 30.64. LCMS, Calculated: 458.39, Found: 459.15 (M+H).

D. Alkylation and cyclization of C-la to form F-la:

1 . DMFDMA

C-1a NaOMe, MeOH, 40 °C F-1a

To a reaction vessel were added C-la (245 mg, 1.0 equivalent) and N,N-dimethylformamide dimethylacetal (0.5 mL, 4.3 equivalent). The reaction mixture was agitated for approximately 30 minutes. The reaction was then treated with 2-methyl tetrahydrofuran (2.0 mL) and aminoacetaldehyde dimethyl acetal (0.1 mL, 1.0 equivalent). The reaction was allowed to age for several hours and then solvent was removed under reduced pressure.

The resulting material was dissolved in methanol and dimethyl oxalate was added (0.3 g, 2.5 equivalents). The reaction mixture was cooled to about 0 to about 5 °C, and then sodium methoxide (0.4 mL, 30% solution in methanol, 1.75 equivalents) was introduced to the reaction slowly. After the addition was completed the reaction was heated to about 40 to about 50 °C.

After this time had elapsed, the reaction was cooled to room temperature and quenched via the addition of 2 Ν HC1 (1.5 mL). The reaction was then diluted with ethyl acetate, and the resulting phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography to yield F-la.

E. Condensation of F-la with N-la to form G-la:

K₂C0₃, MeCN, 75 °C

To a reaction vessel were added F-la (202 mg, 1.0 equivalent) and acetonitrile (1.4 mL). The resulting solution was treated with glacial acetic acid (0.2 mL, 6.0 equivalents) and methane sulfonic acid (0.01 mL, 0.3 equivalents). The reaction was then heated to about 70 to about 75 °C.

After 3 hours, a solid mixture of N-la (0.128g, 1.5 equivalents) and potassium carbonate (0.2 g, 2.7 equivalents) was introduced to the reaction at about 70 to about 75 °C. After the addition was completed, the reaction was allowed to progress for at least about 1 hour.

After this time had elapsed, water (1.4 mL) and dichloromethane (1.4 mL) were introduced to the reaction. The phases were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, then were filtered and concentrated under reduced pressure. The resulting crude material was purified via silica gel chromatography to obtain G-la.

^lR NMR (400 MHz, CDC1₃): δ 10.23 (t, J= 5.5 Hz, 1H), 8.39 (s, 1H), 6.60 (t, J= 8.1 Hz, 2H), 5.29 (dd, J= 9.5, 3.7 Hz, 2H), 4.57 (d, J= 5.4 Hz, 3H), 4.33 (dd, J = 12.8, 3.8 Hz, 1H), 4.02 – 3.87 (m, 1H), 3.94 (s, 3H), 2.06 – 1.88 (m, 4H), 1.78 (dd, J = 17.2, 7.5 Hz, 1H), 1.55 – 1.46 (m, 1H). ¹³C MR (100 MHz, CDC1₃): δ 174.53, 163.75, 162.33 (dd, J= 249.4, 15.7, 15.7 Hz), 161.86 (ddd, J= 250.4, 14.9, 10.9 Hz), 154.18, 154.15, 142.44, 129.75, 1 18.88, 1 10.58 (ddd, J= 19.8, 4.7, 4.7 Hz), 100.42 (m), 77.64, 74.40, 61.23, 54.79, 51.13, 38.31, 30.73, 29.55, 28.04. LCMS, Calculated: 463.14, Found: 464.15 (M+H).

Γ. Deprotection of G-la to form a compound of Formula la:

G-la (14 g) was suspended in acetonitrile (150 mL) and dichloromethane (150 mL). MgBr₂ (12 g) was added. The reaction was heated to 40 to 50 °C for approximately 10 min before being cooled to room temperature. The reaction was poured into 0.5M HC1 (140 mL) and the layers separated. The organic layer was washed with water (70 mL), and the organic layer was then concentrated. The crude product was purified by silica gel chromatography (100% dichloromethane up to 6% ethanol/dichloromethane) to afford la.

REFERENCES

Patent	Submitted	Granted
POLYCYCLIC-CARBAMOYLPYRIDONE COMPOUNDS AND THEIR PHARMACEUTICAL USE [US2014221356]	2013-12-19	2014-08-07

US9216996	Dec 19, 2013	Dec 22, 2015	Gilead Sciences, Inc.	Substituted 2,3,4,5,7,9,13,13a-octahydropyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepines and methods for treating viral infections

see…………..http://apisynthesisint.blogspot.in/2015/12/gs-9883-bictegravir-hiv-1-integrase.html

see full gravir series at…………..http://medcheminternational.blogspot.in/p/ravir-series.html

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C1CC2CC1N3C(O2)CN4C=C(C(=O)C(=C4C3=O)O)C(=O)NCC5=C(C=C(C=C5F)F)F

c1c(cc(c(c1F)CNC(=O)c2cn3c(c(c2=O)O)C(=O)N4[C@H]5CC[C@H](C5)O[C@@H]4C3)F)F

Image result for CONCERT PHARMACEUTICALS, INC.

BICTEGRAVIR, NEW PATENT, WO 2018005328, CONCERT PHARMA

WO2018005328) DEUTERATED BICTEGRAVIR

CONCERT PHARMACEUTICALS, INC.

TUNG, Roger, D.; (US)

How A Kidney Drug Almost Torpedoed Concert Pharma’s IPO

Concert CEO Roger Tung

Novel deuterated forms of bictegravir is claimed. Gilead Sciences is developing the integrase inhibitor bictegravir as an oral tablet for the treatment of HIV-1 infection.

This invention relates to deuterated forms of bictegravir, and pharmaceutically acceptable salts thereof. In one aspect, the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein each of Y¹, Y², Y³, Y^4a, Y^4b, Y^5a, Y^5b, Y⁶, Y^7a, Y^7b, Y⁸, Y⁹, Y^10a, Y^10b, Y^11a, and Y^11b is independently hydrogen or deuterium; provided that if each Y¹, Y², Y³, Y^4a, Y^4b, Y^5a, Y^5b, Y⁶, Y^7a, Y^7b, Y⁸, Y⁹, Y^10a, Y^10b, and Y¹¹ is hydrogen, then Y^11b is deuterium.

Image result for CONCERT PHARMACEUTICALS, INC.

Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment. A rapidly metabolized drug may also expose patients to undesirable toxic or reactive metabolites.

[3] Another ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites. As a result, some patients receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited such that patients receive a suboptimal amount of the active agent. In certain cases, modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound.

[4] In some select cases, a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection. The FDA recommends that these drugs be co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs. Similarly, the

CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect. Quinidine, however, has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and FDA label for quinidine at http://www.accessdata.fda.gov).

[5] In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance. The inhibition of a CYP enzyme’s activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. CYP inhibition can cause other drugs to accumulate in the body to toxic levels.

[6] A potentially attractive strategy for improving a drug’s metabolic properties is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug or to reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.

[7] Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, MI et al, J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res 1985, 14:1-40 (“Foster”); Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006, 9:101-09 (“Fisher”)). The results have been variable and unpredictable. For some compounds deuteration caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated increased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p.35 and Fisher at p.101).

[8] The effects of deuterium modification on a drug’s metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem.1991, 34, 2871-76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.

Exemplary Synthesis

[72] Deuterium-modified analogs of bictegravir can be synthesized by means known in the art of organic chemistry. For instance, using methods described in US Patent No.9,216,996 (Haolun J. et al., assigned to Gilead Sciences, Inc. and incorporated herein by reference), using deuterium-containing reagents provides the desired deuterated analogs.

[73] Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.

[74] A convenient method for synthesizing compounds of Formula I is depicted in the Schemes below.

[75] A generic scheme for the synthesis of compounds of Formula I is shown in Scheme 1 above. In a manner analogous to the procedure described in Wang, H. et al. Org. Lett.2015, 17, 564-567, aldol condensation of compound 1 with appropriately deuterated compound 2 affords enamine 3. Enamine 3 is then reacted with primary amine 4 to afford enamine 5, which then undergoes cyclization with dimethyl oxalate followed by ester hydrolysis to provide carboxylic acid 7.

[76] In a manner analogous to the procedure described in US 9,216,996, acetal deprotection of carboxylic acid 7 followed by cyclization with appropriately deuterated aminocyclopentanol 9 provides carboxylic acid intermediate 10. Amide coupling with appropriately deuterated benzylamine 11 followed by deprotection of the methyl ether ultimately affords a compound of Formula I in eight overall steps from compound 1.

[77] Use of appropriately deuterated reagents allows deuterium incorporation at the Y¹, Y², Y³, Y^4a, Y^4b, Y^5a, Y^5b, Y⁶, Y^7a, Y^7b, Y⁸, Y⁹, Y^10a, Y^10b, Y^11a, and Y^11bpositions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y¹, Y², Y³, Y^4a, Y^4b, Y^5a, Y^5b, Y⁶, Y^7a, Y^7b, Y⁸, Y⁹, Y^10a, Y^10b, Y^11a, and/or Y^11b.

[78] Appropriately deuterated intermediates 2a and 2b, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 2 below.

S h 2 S th i f C d 2 d 2b

[79] Synthesis of compound 2a (wherein Y³=H) by acetal formation of N,N-dimethylformamide (DMF) with dimethylsulfate has been described in Mesnard, D. et. al. J. Organomet. Chem.1989, 373, 1-10. Replacing DMF with N,N-dimethylformamide-d₁ (98-99 atom % D; commercially available from Cambridge Isotope Laboratories) in this reaction would thereby provide compound 2b (wherein Y³=D).

[80] Use of appropriately deuterated reagents allows deuterium incorporation at the Y³ position of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at Y³.

[81] Appropriately deuterated intermediates 4a-4d, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 3 below.

[82] As described in Malik, M. S. et. al. Org. Prep. Proc. Int.1991, 26, 764-766, acetaldehyde is converted to alkylhalide 14a via reaction with chlorine gas and subsequent acetal protection with CaCl₂ in methanol. As described in CN 103739506, reaction of 14a with aqueous ammonia and then sodium hydroxide provides primary amine 4a (wherein Y⁹=Y^10a=Y^10b=H). Replacing acetaldehyde with acetaldehyde-d₁, acetaldehyde-2,2,2-d₃, or acetaldehyde-d₄ (all commercially available from CDN Isotopes with 98-99 atom % D) in the sequence then provides access to compounds 4b (Y⁹=D, Y^10a=Y^10b=H), 4c (Y⁹=H,

Y^10a=Y^10b=D) and 4d (Y⁹=Y^10a=Y^10b=D) respectively (Schemes 3b-d).

[83] Use of appropriately deuterated reagents allows deuterium incorporation at the Y⁹, Y^10a, and Y^10b positions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y⁹, Y^10a, and/or Y^10b.

[84] Appropriately deuterated intermediates 9a-9d, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents as exemplified in Scheme 4 below.

[85] Following the procedures described by Gurjar, M. et. al. Heterocycles, 2009, 77, 909-925, meso-diacetate 16a is prepared in 2 steps from cyclopentadiene. Desymmetrization of 16a is then achieved enzymatically by treatment with Lipase as described in Specklin, S. et. al. Tet. Lett.201455, 6987-6991, providing 17a which is subsequently converted to aminocyclopentanol 9a (wherein Y^4a=Y^4b=Y^5a=Y^5b=Y⁶=Y^7a=Y^7b=Y⁸=H) via a 3 step sequence as reported in WO 2015195656.

[86] As depicted in Scheme 4b, aminocyclopentanol 9b (Y^4a=Y^4b=Y^5a=Y^5b=Y⁶=Y^7a=Y^7b= Y⁸=D) is obtained through an analogous synthetic sequence using cyclopentadiene-d₆ and performing the penultimate hydrogenation with D₂ in place of H₂. Cyclopentadiene-d₆ is prepared according to the procedure described in Cangoenuel, A. et. al. Inorg. Chem.2013, 52, 11859-11866.

[87] Alternatively, as shown in Scheme 4c, the meso-diol obtained in Scheme 4a is oxidized to the diketone following the procedure reported by Rasmusson, G.H. et. al. Org. Syn.1962, 42, 36-38. Subsequent mono-reduction with sodium borodeuteride and CeCl₃ then affords the D₁-alcohol in analogy to the method described in WO 2001044254 for the all-protio analog using sodium borohydride. Reduction of the remaining ketone using similar conditions provides the meso-D₂-diol in analogy to the method reported in Specklin, S. et. al. Tet. Lett.2014, 55, 6987-6991 for the all protio analog using sodium borohydride. The meso-D₂-diol is then converted to 9c (Y^4a=Y^4b=Y^5a=Y^5b=Y^7a=Y^7b=H, Y⁶=Y⁸=D) following the same procedures outlined in Scheme 4a.

[88] Likewise, the meso-diol obtained in Scheme 4b may be converted to 9d

(Y^4a=Y^4b=Y^5a=Y^5b=Y^7a=Y^7b=D, Y⁶=Y⁸=H) in an analogous manner as depicted in Scheme 4d. The use of deuterated solvents such as D₂O or MeOD may be considered to reduce the risk of D to H exchange for ketone containing intermediates.

[89] Use of appropriately deuterated reagents allows deuterium incorporation at the Y^4a, Y^4b, Y^5a, Y^5b, Y⁶, Y^7a, Y^7b, and Y⁸ positions of a compound of Formula I or any appropriate intermediate herein, e.g., about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at any Y^4a, Y^4b, Y^5a, Y^5b, Y⁶, Y^7a, Y^7b, and/or Y⁸.

[90] Appropriately deuterated intermediates 11a-11d, for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents exemplified in Scheme 5 below.

Scheme 5. Synthesis of Benzylamines 11a-11d

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Aug 19, 2015 – BMS–919373, from $BMS for atrial fibrillation #ACSBoston MEDI 1st disclosures @bmsnews pic.twitter.com/y3D4Yv2U7M.

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(2R,4aS,10aR)-4a-Benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-1,2,3,4,4a,9,10,10a-octahydrophenanthren-2-yl dihydrogen phosphate

2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-N-(2-methyl-3-pyridinyl)-4b-(phenylmethyl)-7-(phosphonooxy)-7-(trifluoromethyl)-, (4bS,7R,8aR)-

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Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms

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Ni-Catalyzed C–H Functionalization in the Formation of a Complex Heterocycle: Synthesis of the Potent JAK2 Inhibitor BMS-911543

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without a methyl

with an ethyl

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Fragment-Based Discovery of the Pyrazol-4-yl Urea (AT9283), a Multitargeted Kinase Inhibitor with Potent Aurora Kinase Activity†

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Glioblastoma is the most common form of primary brain cancer

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Antibacterial and Anti-Quorum Sensing Molecular Composition Derived from Quercus cortex (Oak bark) Extract

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2,5-Methanopyrido(1′,2′:4,5)pyrazino(2,1-b)(1,3)oxazepine-10-carboxamide, 2,3,4,5,7,9,13,13a-octahydro-8-hydroxy-7,9-dioxo-N-((2,4,6-trifluorophenyl)methyl)-, (2R,5S,13aR)-

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Fragment-Based Discovery of the Pyrazol-4-yl Urea (AT9283), a Multitargeted Kinase Inhibitor with Potent Aurora Kinase Activity^†