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Mavatrep, JNJ 39439335,

October 25, 2015 9:10 am / Leave a comment

Mavatrep; UNII-F197218T99; Mavatrep (USAN); JNJ-39439335; 956274-94-5;

2-(2-(2-(2-(4-trifluoromethylphenyl)vinyl)-1H-benzimidazol-5-yl)phenyl)propan-2-ol

(E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol

(E)-2-(2-(2-(4-(Trifluoromethyl)styryl)-1H-benzo[d]imidazol-5-yl)phenyl)-propan-2-ol Hydrochloride

Phase I Musculoskeletal pain; Pain

01 Mar 2013 Janssen Research and Development completes a phase I trial in Japanese and Caucasian adult male volunteers in the US (NCT01631487)
01 Mar 2013 Janssen completes enrolment in its phase I trial for Pain (in volunteers) in the USA (NCT01631487)
05 Feb 2013 Janssen Research and Development initiates enrolment in a phase I trial for Pain (Japanese and Caucasian volunteers) in USA (NCT01631487)

Originator Johnson & Johnson Pharmaceutical Research & Development
Developer Janssen Research & Development
Class Analgesics; Benzimidazoles; Small molecules
Mechanism of Action TRPV1 receptor antagonists

ChemSpider 2D Image | Mavatrep | C25H21F3N2O

PHASE 1 Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Public title:	A Clinical Study to Investigate the Effect on Pain Relief of a Single Dose of JNJ-39439335 in Patients With Chronic Osteoarthritis Pain of the Knee

http://clinicaltrials.gov/ct2/show/NCT01006304
http://apps.who.int/trialsearch/trial.aspx?trialid=NCT00933582

http://www.ama-assn.org/resources/doc/usan/mavatrep.pdf SEE STRUCTURE IN THIS FILE

MAVATREP IS JNJ-39439335
—

(E)-2-(2-(2-(4-(trifluoromethyl)styryl)-1H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol hydrochloride

956282-89-6 CAS NO OF HCl SALT

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.5b00271, http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00271

The process development of Mavatrep (1), a potent transient receptor potential vanilloid-1 (TRPV1) antagonist, is described. The two key synthetic transformations are the synthesis of (E)-6-bromo-2-(4-(trifluoromethyl)styryl)1H-benzo[d]imidazole (4) and the Suzuki coupling of 4 with 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol (5). Compound 1a was prepared in four chemical steps in 63% overall yield.

HCl SALT

1a as an off-white solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.35 (d, J = 16.6 Hz, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 8.3 Hz, 2H), 7.80 (dd, J = 8.1, 1.3 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 1.4 Hz, 1H), 7.53 (d, J = 6.6 Hz, 1H), 7.43 (dd,J = 8.4, 1.5 Hz, 1H), 7.39 (ddd, J = 8.1, 7.4, 1.5 Hz, 1H), 7.27 (ddd, J = 7.4, 7.4, 1.3 Hz, 1H), 7.04 (dd, J = 7.5, 1.5, 1H), 1.29 (s, 6H); ¹³C NMR (DMSO-d₆, 125 MHz) δ 147.7 (C), 147.4 (C), 142.3 (C), 140.3 (CH), 139.0 (C), 138.0 (C), 131.7 (CH), 131.1 (C), 130.5 (C), 130.2 (C), 128.7 (2CH), 128.3 (CH), 127.4 (CH), 126.2 (CH), 126.2 (CH), 125.8 (2CH), 124.0 (CF₃), 114.3 (CH), 113.2 (CH), 112.4 (CH), 71.6 (C), 32.4 (2CH₃); Anal. Calcd for C₂₅H₂₂F₃ClN₂O·1.2H₂O: C, 62.49; H, 5.12; Cl, 7.38; F, 11.86; N, 5.83. Found: C, 62.34; H, 4.93; Cl, 7.24; F, 11.61; N, 5.78. Water wt % calcd, 4.50%; found, 4.52% (determined by KF analysis).

Patent

http://www.google.st/patents/US20110190344

CLICK ON IMAGE FOR CLEAR VIEW

Example 10 (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol(Cpd 18)

Step A. 3-(4-trifluoromethyl-phenyl)-acrylic acid

[0278]

A solution of 4-trifluoromethylbenzaldehyde (7.7 mL, 57.7 mmol), malonic acid (12.0 g, 115.4 mmol), 0.567 μL piperidine (5.75 mmol) in 30 mL of pyridine was stirred at 70° C. for 18 h. The reaction solution was cooled to room temperature. Water (300 mL) was added and the resulting mixture was acidified to pH 4 (litmus) using concentrated hydrochloric acid to give a precipitate. The solid was filtered, and washed with water until the filtrate was neutral. The solid product was dried in vacuo to give the title Compound 10a as a white powder (11.2 g, 90%). ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 12.60 (bs, 1H), 7.92 (d, 2H, J=8.2 Hz), 7.77 (d, 2H, J=8.2 Hz), 7.66 (d, 1H, J=16.0 Hz), 6.70 (d, 1H, J=16.0 Hz).
[0000]

Step B. (E)-5-bromo-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazole

[0279]

A solution of Compound 10a (20.6 g, 95.4 mmol) in anhydrous methylene chloride (200 mL) was treated with oxalyl chloride (16.6 mL, 190 mmol) and “3 drops” of anhydrous dimethylformamide. The resulting solution was stirred at room temperature under an argon atmosphere for 18 h. The solvent was concentrated to give 3-(4-trifluoromethyl-phenyl)-acryloyl chloride Compound 10b as a solid, which was used without further purification in the next step.
[0280]

To a solution of 4-bromo-benzene-1,2-diamine (16.1 g, 86.7 mmol) in acetic acid (100 mL) was added dropwise a solution of Compound 10b (assumed 95.4 mmol) in acetic acid (100 mL). The reaction mixture was stirred at 100° C. for 18 h. The reaction mixture was cooled to room temperature, and a mixture of ethyl acetate and hexanes 3:7 (500 mL) was added. The mixture was triturated at room temperature for 3 h to give a precipitate. The solid was filtered, and dried in vacuo to give the title Compound 10c (23.2 g, 73%). ¹H NMR (400 MHz, DMSO-d₆/CDCl₃) δ (ppm): 8.45 (d, 1H, J=16.7 Hz), 7.84-7.90 (m, 1H), 7.74 (d, 2H, J=8.3
[0281]

Hz), 7.56-7.62 (m, 3H), 7.50-7.52 (m, 1H), 7.34 (d, 1H, 16.7 Hz).
[0000]

Step C. 2-(2-bromo-phenyl)-propan-2-ol

[0282]

To a solution of methyl 2-bromobenzoate (20.76 g, 96 mmol) in 120 mL of anhydrous ether under Argon at 0° C. was slowly added methylmagnesium bromide (77 mL, 3.26 M) at a rate that the internal temperature of the mixture was below 20° C. A white suspension resulted, and the mixture was stirred at room temperature for 2 h. The mixture was cooled in an ice-water bath. To the reaction mixture was very slowly added hydrochloric acid (400 mL, 0.5 M). The pH of the final mixture was adjusted to less than about 6 with few drops of 2M hydrochloric acid. The layers were separated, and the aqueous layer was extracted twice with ether. The organic layers were combined and dried over magnesium sulfate. The organic fraction was filtered, and the filtrate was concentrated to yield the title compound as a pale yellow liquid, which was distilled under vacuum to afford the title Compound 10d as a colorless liquid (16.9 g, 82%, b.p. about 65-70° C./0.3 mmHg). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.67 (dd, 1H, J=1.7, 7.9 Hz), 7.58 (dd, 1H, J=1.3, 7.9 Hz), 7.30 (ddd, 1H, J=1.4, 7.4, 7.9 Hz), 7.10 (ddd, 1H, J=1.7, 7.4, 7.8 Hz), 2.77 (br s, 1H), 1.76 (s, 6H).
[0000]

Step D. 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol

[0283]

To a solution of n-BuLi (166 mL, 2.6 M, 432 mmol) in 200 mL of THF at −78° C. under argon was slowly added a solution of Compound 10d (42.2 g, 196 mmol) in 60 mL of THF at a rate that the internal temperature remained below −70° C. The mixture was stirred at −75° C. for 2 h. To the reaction mixture was then added triisopropylborate (59 mL, 255 mmol) in three portions. The mixture was allowed to warm slowly to room temperature overnight. The mixture was then cooled to 0° C., and was carefully quenched with dilute hydrochloric acid (250 mL, 2N). The mixture was then stirred at room temperature for 1 h. The pH of the mixture was checked and adjusted to acidic using additional 2N HCl if prophetic. The two layers were separated, and the aqueous layer was extracted twice with ether. The organic layers were combined, and dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a pale yellow oil. The residue was then diluted with ethyl acetate (400 mL) and, washed with 1N sodium hydroxide solution (150 mL×3). The basic aqueous layers were combined and acidified with 2N HCl. The clear solution turned cloudy when the acid was added. The mixture was extracted with ether (150 mL×3). The organic layers were combined and dried with magnesium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure to yield the title Compound 10e as a colorless oil (26.2 g, 82%) which was used without further purification in the next step. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.00 (s, 1H), 7.66 (dm, 1H, J=7.3 Hz), 7.45 (dt, 1H, J=1.1, 7.7 Hz), 7.40 (dm, 1H, J=7.6 Hz), 7.31 (dt, 1H, J=1.2, 7.1 Hz), 1.44 (s, 6H).
[0000]

Step E. (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol

[0284]

To a mixture of Compound 10e (11.7 g, 71 mmol), Compound 10c (19.9 g, 54 mmol), sodium carbonate (46 g, 435 mmol) and PdCl₂(dppf).CH₂Cl₂(8.9 g, 11 mmol) in a 1 L round bottom flask equipped with water condenser was added 400 mL of anhydrous DME and 200 mL of water. The mixture was evacuated and filled with Argon three times. The mixture was heated to 100° C. for 20 h. The mixture was then cooled to room temperature. The biphasic system was transferred to a 1 L separatory funnel and the two layers were separated. The organic layer was washed with brine (2×300 mL). The aqueous layers were combined and extracted with ethyl acetate once (about 300 mL). The organic layers were combined, dried with sodium sulfate, and filtered. The volume of the filtrate was reduced to about 170 mL under reduced pressure. The mixture was then filtered through a pad of silica gel and the pad was washed with ethyl acetate until the filtrate did not contain any product. After concentration, a light pink/beige solid was obtained. The solid was triturated with 50 mL ethyl acetate, and the mixture was heated to 85° C. for 5 min. The mixture was slowly cooled to r.t., then cooled at 0° C. for 0.5 h. The mixture was filtered, and the solid was washed with cold ethyl acetate twice, and dried under vacuum at 40° C. to yield the title Compound 18 as a light beige solid (7.58 g, 33%). RP-HPLC 95% pure.
¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.73 (m, 1H,), 7.90 (d, 2H, J=8.2 Hz), 7.85 (dd, 1H, J=8.0, 0.6 Hz), 7.78 (d, 2H, J=8.4 Hz), 7.74 (d, 1H, J=16.8 Hz), 7.59-7.47 (m, 1H), 7.41 (s, 1H), 7.37-7.32 (m, 2H), 7.21 (dt, 1H, J=1.2, 7.4 Hz), 7.06 (s, 1H), 7.02 (d, 1H, J=7.4 Hz), 4.85 (s, 1H), 1.21 (s, 6H).
Mass Spectrum (LCMS, APCI pos.) Calcd. For C₂₅H₂₁F₃N₂O: 423.2 (M+H). Found 423.3.
m.p. (uncorr.) 250-251° C.

Example 10.1 Scale Up Preparation of (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol (Cpd 18) Step A. 3-(4-trifluoromethyl-phenyl)-acrylic acid

[0286]

A 2-L 4-neck round bottom flask equipped with an air condenser/argon inlet, mechanical stirrer, thermocouple and a stopper was charged with 4-(trifluoromethyl)benzaldehyde (250 g, 196.2 mL, 1.44 mol), malonic acid (302.6 g, 2.87 mol), and pyridine (750 mL). An exotherm developed (about 38-40° C.), which was maintained for 30 min. Piperidine (14.202 mL, 143.58 mmol) was then added to the reaction and a second exotherm developed (T_maxabout 42° C. after about 10 min.). The reaction was stirred for 30 min and then heated to 60° C. for 18 h (overnight). The reaction appeared to be complete by TLC, and was cooled to about 40° C., diluted into water (2 L; done to prevent reaction freezing), cooled to room temperature, and further diluted with water (4 L, 6 L total). The slurry was acidified to pH=2.0-3.0 with concentrated hydrochloric acid (about 675-700 mL). The material was stirred for 30 min., and a white solid was collected by filtration. The filter cake was washed with water until the filtrate was neutral (pH about 5.5-6, 2.5 L), air-dried in a Buchner funnel for 2 h, and then further dried in a vacuum oven at 60° C. overnight to provide 300.5 g (96%) of the title Compound 10a as a white solid.

Step B. (E)-5-bromo-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazole

[0287]

To a 5-L 4-neck round bottom flask equipped with a magnetic stirrer, argon inlet-argon outlet to a carbonate scrub, two stoppers, and a room temperature water bath was charged with 4-(trifluoromethyl)cinnamic acid (315 g, 1.46 mol) and dichloromethane (3.15 L) to give a slurry. To the slurry was added oxalyl chloride (151.71 mL, 1.75 mol) and DMF (1.13 mL, 14.57 mmol). Upon addition of DMF, gas evolution commenced, and the reaction was continued for about 3 h during which time a solution developed. When the reaction was complete (LC-MS), it was concentrated to dryness to give 342.4 g of 3-(4-trifluoromethyl-phenyl)-acryloyl chloride Compound 10b (>100%) as a yellow oily solid.
[0288]

A 5-L 4-neck round bottom flask equipped with mechanical stirrer, thermocouple, air condenser with argon inlet, and a stopper was charged with 4-bromo-benzene-1,2-diamine (244 g, 1.27 mol) and acetic acid (2.13 L). To this solution was added a solution of Compound 10b (327 g, 1.39 mol) in toluene (237 mL). After this addition, the temperature spiked to 45° C. in about 30 seconds and then subsided. The reaction was then heated to 90° C. for 16 h (overnight). The reaction was cooled to 40° C., and poured into a mixed solution of EtOAc and heptane (about 1:3, 5.75 L) and a precipitate occurred. The resulting slurry was stirred for 3 h, and the solid was collected by filtration, washed with EtOAc:heptane (1:3, 3 L), and then dried in a vacuum oven (60° C.) to give 324.3 g (65%) of the title Compound 10c as a partial acetate salt.

Step C. 2-(2-bromo-phenyl)-propan-2-ol

[0289]

A 12-Liter 4-neck flask equipped with a thermocouple, condenser, septum, addition funnel and overhead mechanical stirrer under argon was charged with methyl-2-bromobenzoate (226.5 g, 1.05 mol) and THF (1.6 L, 19.66 mol). The mixture was cooled to a temperature between 2 and 5° C. with stirring and held for 30 min. To the solution was slowly added methyl magnesium bromide in diethyl ether (3M, 1.05 L; 3.15 mol) via the addition funnel at a rate to maintain the reaction temperature below 15° C. An exotherm was observed during the addition, the reaction temperature warmed from 3 to 15° C. The addition of 1.05 L Grignard was complete in 4 h (approximate feed rate was 4.17 mL/min). The reaction mixture appeared to be off-white/yellow slurry. The reaction was allowed to warm to room temperature and stirred overnight (15 h). The reaction was sampled by HPLC/TLC and showed no starting material present. The ice bath was again applied to the reaction flask and a 0.5 M HCl solution (4.5 L; 2.25 mol) was slowly added over a period of 2 h. The temperature increased dramatically from 0 to 15° C. After the quench was complete, the reaction was stirred at room temperature for 30 min. Additional 2 N HCl (500 mL; 1.00 mol) was slowly added to maintain a pH less than 6. MTBE (1 L) was added to help with the phase split. The reaction was stirred at room temperature for 1 to 2 h to dissolve the solid material into the aqueous phase (most likely Mg(OH)₂which is very basic). The pH must be checked and adjusted with additional acid when necessary. The phases were separated and the aqueous layer was washed with an additional 1 L MTBE (2×500 mL). The organic phases were combined, washed with NaHCO₃solution (2×300 mL), dried over MgSO₄, filtered and the filtrate was concentrated under vacuum to yield the title Compound 10d (220.83 g, 97.48% yield) as a clear yellow oil.

Step D. 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol

[0290]

A 12-Liter 4-neck round bottom flask equipped with a thermocouple, condenser, addition funnel and overhead mechanical stirrer under dry Argon was charged with anhydrous THF, (3 L) and chilled to −70 to −78° C. via a dry ice/acetone bath. n-Butyl lithium (2.5N in hexanes, 860 mL, 2.15 mol) was slowly added via addition funnel. An exotherm was observed as the temperature rose from −78 to −70° C. To the addition funnel was added a solution of Compound 10d (220 g, 979.97 mmol) in anhydrous THF (1 L). The 2-(2-bromophenyl)propan-2-ol solution was slowly added to the n-BuLi solution. The addition took 90 min in order to maintain a reaction temperature below −70° C. After the addition was complete, the reaction mixture was stirred at −70 to −75° C. for 30 min. The triethylborate (230 mL, 1.35 mol) was quickly added in 3 portions at −70° C. An exotherm was observed, the batch temperature rose from −70 to −64° C. The reaction was stirred at −70° C. and slowly warmed to room temperature over night. After the reaction was cooled to 0-5° C., the reaction was slowly quenched with 2 M HCl (1 L, 2.00 mol) added via the addition funnel while maintaining the batch temperature 0-5° C. The reaction mixture was stirred for 1 h. The aqueous phase pH was 9-10. The pH was then adjusted to acidic (4-5) with 2 M HCl (200 mL). The two phases were separated and the aqueous layer was extracted with MTBE (2×500 mL). The combined organic phases were dried with anhydrous magnesium sulfate. The solution was filtered and concentrated to yield a yellow oil. The yellow oil was diluted with MTBE (1.5 L) and washed with 1M NaOH (3×500 mL). The product containing basic aqueous phases were combined and acidified with 2 M HCl (800 mL) (the clear solution turns turbid with the addition of acid). After stirring the turbid solution for 15 min (pH=4-5) (Note 1), it was extracted with MTBE (2×500 mL). The organic phases were combined and dried over MgSO₄. The solution was filtered and the filtrate was concentrated to yield the title Compound 10e as a clear yellow oil (121.78 grams, 77% yield).

Step E. (E)-2-(2-{2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol

A 5-L 4-neck flask equipped with a thermocouple controller, condenser, overhead mechanical stirrer, Firestone Valve® and a nitrogen inlet/outlet was charged with dimethoxyethane (2 L), DI water (1 L) and sodium carbonate (230.9 g, 2.18 mol). The solution was degassed and purged with N₂three times. Compound 10e (71.7 g, 0.35 mol) and Compound 10c (100.0 g, 0.27 mol) were added to the degassed solution. The solution was degassed and purged with N₂three times. PdCl₂(dppf) (44.48 g, 54.4 mmol) was added to the solution, and the solution was degassed and purged with N₂three times. The resulting two-phase suspension was heated to reflux for 18 h, and then cooled to room temperature. The reaction mixture was transferred to a 12-L separatory funnel, and the layers were separated. The organic layer was washed with brine (1 L). The two aqueous layers were combined and extracted with EtOAc (1 L). The combined organic layers were dried (Na₂SO₄), filtered, and the filtrate was concentrated to an oil. Two separate 100 g coupling reactions were combined and purified by chromatography in 10 successive chromatography runs on an ISCO preparative chromatography system (10×1.5 Kg SiO2, 5 column volumes of EtOAc, 250 mL/min flow rate). The combined fractions were transferred to two 22 L 4-neck round bottom flasks, and Silicycle Si-thiol functionalized silica gel (2 g) was added to each solution. The solutions were warmed to 40° C. and aged for 1 h. The solutions were filtered thru a medium glass funnel and washed with EtOAc (4 L) and combined. The filtrate was evaporated to a semi solid, which was transferred to a 2 L round bottom flask, to which EtOAc (0.4 L) was added. The resulting white precipitate slurry was cooled to −5° C. and stirred for 1 h. The slurry was filtered and washed twice with cold EtOAc (100 mL). The solids were dried in a vacuum oven at 40° C. for 40 h to afford 84.0 g (36.5% yield, 98.8 area % purity) of the title Compound 18 as a white solid. Anal. Calcd for C₂₅H₂₁N₂OF₃.0.04% H₂O.0.15 mol MeOH: C, 70.48; H, 5.14: N, 6.42; F, 13.06 Found: C, 70.54; H, 4.83: N, 6.18; F, 13.33

Example 10.2 (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol monosodium salt (Cpd 18)

A 5-L 4-neck flask equipped with a thermocouple controller, an overhead mechanical stirrer, and a nitrogen inlet/outlet was charged with (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol. Compound 18 (125.0 g, 0.510 mol) and MeOH (1.25 L). A solution of sodium methoxide in methanol (0.5 M, 592 mL, 0.3 mol) was added. The reaction was heated to 65° C. for 30 min and all solids dissolved. The solution was cooled and evaporated to dryness. The foam was collected by scraping it out of the flask. The solids were placed in vacuum oven for 24 h at 40° C. to afford 139 g (about 100% isolated yield) of the title Compound 18 monosodium salt as a yellowish solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.80-7.84 (m, 3H), 7.74 (d, 2H, J=8.59 Hz), 7.65 (d, 1H, J=16.4 Hz), 7.40-7.44 (m, 2H), 7.25-7.37 (m, 2H), 7.16-7.20 (m, 1H), 7.01-7.05 (m, 1H), 6.84-6.87 (m, 1H), 1.23 (s, 6H). Mass Spectrum (LCMS, APCI pos.) Calcd. For C₂₅H₂₁F₃N₂O: 423.2 (M+H). Found 423.3. m.p. (uncorr.) 258-259° C.

Example 10.3 (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol hydrochloride salt (Cpd 18)

A 250-mL separatory funnel was charged with (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol. Compound 18 (1.0 g, 2.4 mmol) and EtOAc (20 mL). Aqueous HCl (1M, 20 mL) was added to the white slurry, and the separatory funnel was shaken. The solid product quickly dissolved, and a white precipitate started to form. The organic layer was transferred to a 100 mL round bottom flask equipped with a magnetic stir bar, and was stirred for 2 h. The thick slurry was filtered, rinsed with EtOAc (2×5 mL), and put into a vacuum oven at 40° C. for 36 h to afford 0.95 g (87.5%) of the title Compound 18 hydrochloride salt.

US7951829

Patent	Submitted	Granted
BENZIMIDAZOLE MODULATORS OF VR1 [US2011190344]	2011-08-04
BENZIMIDAZOLE MODULATORS OF VR1 [US2011190364]	2011-08-04
Benzimidazole Modulators of VR1 [US7951829]	2007-11-08	2011-05-31

////////////Phase I, Musculoskeletal pain, Pain, Mavatrep, JNJ 39439335,

FDA grants breakthrough status for Pfizer’s leukaemia drug inotuzumab ozogamicin

October 23, 2015 3:21 am / 2 Comments on FDA grants breakthrough status for Pfizer’s leukaemia drug inotuzumab ozogamicin

Inotuzumab ozogamicin
RN: 635715-01-4
UNII: P93RUU11P7

Pfizer Inc., Oncology Institute Of Southern Switzerland INNOVATOR

http://chem.sis.nlm.nih.gov/chemidplus/rn/635715-01-4

MF 1680.6764
Oncological Treatment

FDA grants breakthrough status for Pfizer’s leukaemia drug inotuzumab ozogamicin
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for Pfizer’s investigational antibody-drug conjugate (ADC) inotuzumab ozogamicin to treat acute lymphoblastic leukaemia (ALL).

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for Pfizer’s investigational antibody-drug conjugate (ADC) inotuzumab ozogamicin to treat acute lymphoblastic leukaemia (ALL).

The breakthrough status was based on data from the Phase III INO-VATE ALL trial, which enrolled 326 adult patients with relapsed or refractory CD22-positive ALL and compared inotuzumab ozogamicin to standard of care chemotherapy………….http://www.pharmaceutical-technology.com/news/newsfda-grants-breakthrough-status-pfizer-leukaemia-drug-inotuzumab-ozogamicin-4697877?WT.mc_id=DN_News

EVER SINCE POST WAS WRITTEN…..FGD APPROVAL Inotuzumab ozogamicin

PFIZER

Image result for inotuzumab ozogamicin

Besponsa		FDA 8/17/2017	To treat adults with relapsed or refractory acute lymphoblastic leukemia Press Release Drug Trials Snapshot

LINK….https://newdrugapprovals.org/2015/10/23/fda-grants-breakthrough-status-for-pfizers-leukaemia-drug-inotuzumab-ozogamicin/

Inotuzumab ozogamicin (CMC-544) is an antibody-drug conjugate for the treatment of cancers.^[1] It consists of the humanized monoclonal antibody inotuzumab (for CD22), linked to a cytotoxic agent from the class of calicheamicins (which is reflected by ‘ozogamicin‘ in the drug’s name).^[2]

This drug is being developed by Pfizer and UCB.

It is undergoing numerous clinical trials,^[3] including two phase II trials for Non-Hodgkin lymphoma (NHL).

A phase III trial in patients with follicular b-cell NHL has been terminated due to poor enrollment.^[4] A Phase III trial in patients with relapsed or refractory CD22+ aggressive non-Hodgkin lymphoma (NHL) who were not candidates for intensive high-dose chemotherapy was terminated for futility.^[5]

Monoclonal antibodies (mAbs) and derivatives are currently the fastest growing class of therapeutic molecules. More than 30 G-type immunoglobulins (IgG) and related agents have been approved over the past 25 years mainly for cancers and inflammatory diseases. In oncology, mAbs are often combined with cytotoxic drugs to enhance their therapeutic efficacy. Alternatively, small anti-neoplastic molecules can be chemically conjugated to mAbs, used both as carriers (increased half-life) and as targeting agents (selectivity). Potential benefits of antibody-drug conjugates (ADCs), strategies, and development challenges are discussed in this review. Several examples of ADCs are presented with emphasis on three major molecules currently in late clinical development as well as next generation thio-mAbs conjugates with improved therapeutic index.

PATENT

http://www.google.com/patents/WO2013088304A1?cl=en

Inotuzumab ozogamicin:

is described in U.S. Patent Application No. 10/428894

U.S. Patent Application No. 10/428894

References

Statement On A Nonproprietary Name Adopted By The Usan Council – Inotuzumab ozogamicin, American Medical Association.
Takeshita, A; Shinjo, K; Yamakage, N; Ono, T; Hirano, I; Matsui, H; Shigeno, K; Nakamura, S; Tobita, T; Maekawa, M (2009). “CMC-544 (inotuzumab ozogamicin) shows less effect on multidrug resistant cells: analyses in cell lines and cells from patients with B-cell chronic lymphocytic leukaemia and lymphoma.”. British journal of haematology 146 (1): 34–43.doi:10.1111/j.1365-2141.2009.07701.x. PMID 19388933.
http://clinicaltrials.gov/ct2/results?term=Inotuzumab+ozogamicin
http://clinicaltrials.gov/ct2/show/NCT00562965
http://pfizer.newshq.businesswire.com/press-release/pfizer-discontinues-phase-3-study-inotuzumab-ozogamicin-relapsed-or-refractory-aggress
http://pubs.rsc.org/en/content/articlelanding/2008/np/b514294f#!divAbstract

Structure of inotuzumab ozogamicin. ABOVE

Inotuzumab ozogamicin^?
Monoclonal antibody
Type	Whole antibody
Source	Humanized (from mouse)
Target	CD22
Identifiers
CAS Registry Number	635715-01-4
ATC code	None
UNII	P93RUU11P7
KEGG	D08933
Chemical data
Formula	C₆₅₁₈H₁₀₀₀₂N₁₇₃₈O₂₀₃₆S₄₂
Molecular mass	150,000 Daltons

//////////

Regulation of Herbal (Traditional) Medicinal Products in the European Union

October 21, 2015 8:29 am / Leave a comment

Regulation of Herbal (Traditional) Medicinal Products in the European Union

Introduction

The European Union (EU) regulatory framework for medicinal products is complex and is based on the need of a marketing authorization before placing medicines in the market. The main objective is to protect public health by assuring quality, efficacy and safety. The requirements and procedures to obtain a marketing authorization are laid down in regulations, directives and scientific guidelines which are contained in the “Rules Governing Medicinal Products in the European Union”. Several volumes are included which are supported by other publications with complementary information such as scientific or Good Manufacturing Practice (GMP) guidelines, between others [1].

Medicinal plants have been used since Ancient times in all parts of the world. Nonetheless, regulation of herbal medicines in a legal environment was introduced in the 20^th century. The EU regulatory framework includes specific requirements for herbal medicinal products (HMP) which are independent from their legal status: traditional herbal medicinal product (THMP) or products based on clinical evidence – well established use (WEU).

Before a HMP is placed in the market, it must be approved by a MS or by the European Commission by one of the existing types of application: full marketing authorization application, well-established use marketing authorization application or Traditional use marketing registration (Table 1).

The applicant has to submit adequate quality, non-clinical and clinical documentation of the product, irrespectively of the procedure used. Quality requirements of the pharmaceutical product are the same, regardless of the type of application, while efficacy documentation differs between them. The full marketing application is chosen for new medicinal products (new chemical entity) and it has to be completed with the results of pharmaceutical tests (quality documentation), nonclinical (toxicological and pharmacological) studies and clinical trials. Safety data have to be of sufficient size according the existing guidelines; efficacy is demonstrated by results from the clinical trials which have to be in conformity with the guidelines of the corresponding therapeutic area. This type of application is open for HMP, but only a few examples of herbal products have obtained a marketing authorization in the EU in this way.

EU Pharmaceutical Legislation for Herbal Medicinal Products for Human Use

Quality requirements

The principles to assure quality of medicinal products are defined mainly in two Directives of volume 1: Directive 2001/83/EC (which was emended by Directive 2004/24/EC) and Directive 2003/63/EC.

The basic legislation lay down in Directive 2001/83/EC describes the general requirements and provides legal definitions of herbal substances, herbal preparations and herbal medicinal products (Table 2). These concepts are essential for setting quality standards for HMP, as they are by definition complex in nature and so quality requirements set for purified compounds are not suitable for herbal products.

According to the Directive 2001/83/EC, monographs in the European Pharmacopoeia (Eur. Ph.) are legally binding and applicable to all substances which are included in it. For substances which do not have a Eur. Ph. monograph, each Member State (MS) may apply its own national pharmacopoeia. Constituents which are not given in any pharmacopoeia shall be described in the form of a monograph under the same headings included in any monograph in the Eur. Ph., i.e., the name of the substance supplemented by any trade or scientific synonyms; the definition of the substance, set down in a form similar to that used in the European Pharmacopoeia; methods of identification and purity tests.

Moreover, all medicinal products have to be manufactured according to the principles and guidelines of GMP for medicinal products. GMP are applicable to both finished HMP and active substances and, according to Article 46 (f) of Directive 2001/83/EC as amended, marketing authorization holders are required to use as starting materials only active substances which have been manufactured in accordance with the guidelines on the GMP for starting materials as adopted by the Community and distributed in accordance with good distribution practices for active substances.

Additional requirements are found in the Directive 2003/63/EC, as Herbal medicinal products differ substantially from conventional medicinal products in so far as they are intrinsically associated with the very particular notion of herbal substances and herbal preparations. It is therefore appropriate to determine specific requirements in respect of these products with regards to the standardized marketing authorization requirements. Then, detailed information on the herbal medicinal product, herbal substances and herbal preparations has to be included, such as the name, address and responsibility of each herbal substance supplier or description of the plant production process, geographical source or drying and storage conditions. The application dossier of a HMP should include specifications and details of all the analytical methods used for testing herbal substances and herbal preparations, results of batch analyses and analytical validation, together with the justification for the specifications.

Most of the quality requirements for HMP are laid down in soft laws (considered as EU measures such as scientific guidelines) which do not have legal force but provide practical harmonization between the MS and the European Medicines Agency (EMA).

The guideline on quality of HMP/THMP covers the general quality aspects of HMP for human and veterinary use, including THMP for human use (EMA, 2014) and indicates which information has to be included in the application dossier. It provides definitions to be taken in account such as genuine (native) herbal preparations, markers, drug to extract ratio (DER) and specifications. Which is more important, it states that the herbal substance or herbal preparation is considered as the whole active substance. In consequence, the quality control of these products has to include appropriate fingerprint analysis to cover not only the content of markers or constituents with known therapeutic activity but also a wider range of chemical constituents.

Efficacy requirements

Before a HMP is placed in the market, it must be approved by a MS or by the European Commission by one of the existing types of application: full authorization application, well-established use authorization application or Traditional use registration (Table 3).

The applicant has to submit adequate quality, non-clinical and clinical documentation of the product, irrespectively of the procedure used. Quality requirements of the pharmaceutical product are the same, regardless of the type of application, while efficacy documentation differs between them. The full marketing application is chosen for new medicinal products (new chemical entity) and it has to be completed with the results of pharmaceutical tests (quality documentation), nonclinical (toxicological and pharmacological) studies and clinical trials. Safety data have to be of sufficient size according the existing guidelines; efficacy is demonstrated by results from the clinical trials which have to be in conformity with the guidelines of the corresponding therapeutic area. This type of application is open for HMP, but only a few examples of herbal products have obtained a marketing authorization in the EU in this way.

The well-established medicinal use (WEU) in the EU can be applied to medicinal products for which there exists a wide clinical experience within the EU (not only HMP). The assessment may be based in published controlled clinical trials, non-clinical studies and epidemiological studies. In this type of application, there are no limitations to the therapeutic indication, as this will be derived from the available documentation.

(Traditional) Herbal Medicinal Products

Under the Traditional use registration for herbal medicinal product (article 16e), there exist some herbal products that not fulfill the efficacy requirements for a marketing authorization but are endorsed with a long tradition of use. In this case, no clinical trials on these products have been conducted and the efficacy is based on the long-standing use and experience. This simplified registration procedure is limited to products which are intended for use without medical supervision, with a specified strength and posology, to be used by oral, external or inhalation ways, and which can demonstrate a period of use equal or superior to 30 years, including at least 15 years within the EU. In this case, therapeutic indications are limited to those which can be considered safe for use without the supervision of a physician such as minor disorders or symptoms that are benign or self- limiting. In case the applicant should consider another kind of indication, the product must be documented with results of clinical and non-clinical studies, so a full application would be necessary.

Simplified registration of THMP is described in Chapter 2a of Directive 2004/24/EC with three main objectives: a) to protect public health by allowing access to safe and high-quality HMP; b) to allow European citizens the access to medicines of their choice, even those HMP with a long tradition of use and which efficacy hasn’t been proved by clinical trials performed according the modern standards; c) to facilitate movement of medicinal products on the European market.

Directive 2004/24/EC has two different dimensions: the evaluation by National Competent Authorities (NCA) of applications submitted by companies at any MS in the EU and at the EMA, and the establishment of advisory scientific opinions on the medicinal use of herbal substances or preparations. The directive on THMP also established a new scientific committee, the Herbal Medicinal Products Committee (HMPC) at the EMA in London, in 2004, to replace the previous Working Party on Herbal Medicinal Products (CPMP) with the following aims: to elaborate Community monographs and List entries for herbal substances/preparations; to publish scientific guidelines useful for the application of European legal framework; to publish its scientific opinion on questions related to herbal medicinal products and coordinate its work with the European Quality group. The HMPC is made up by 33 members, one member (and one alternate) nominated by each MS of the EU and by Iceland and Norway (the EFAEFTA states). Among them, also five experts are included, representing specific fields of expertise as clinical and non-clinical pharmacology, toxicology or pediatrician medicine.

The guidelines and the monographs developed and approved by the HMPC are accepted by both companies and NCAs and are used for TUR and WEU marketing authorizations. This committee plays a key role in the harmonization of the regulation of HMP whereby Community herbal monographs have a fundamental role.

Usage of Community herbal monographs in the EU regulation of traditional HMP

These documents are established for HMP with regards to bibliographic applications (art. 10 a Directive 2001/83/EC) as well as THPMs. Community monographs reflect the scientific opinion of the HMPC on safety and efficacy data concerning a herbal substance. Any single plant or herbal preparation is assessed individually, according to the available information and includes qualitative and quantitative composition, pharmaceutical form(s), therapeutic indication(s), posology and method of administration, contraindications, special warnings and precautions of use, interactions, use in special population (pregnancy, lactation), effects on ability to drive and use machines, undesirable effects, overdose, pharmacological,pharmacodynamics, pharmacokinetic properties and preclinical safety data.

Community list entry

In the EU, a community list of herbal substances, preparations and combinations thereof for use in THMPs has been established. This list is based in the proposals form HMPC and is gradually developed. Substances or preparations which are included in the list have the main advantage that applicants do not need to provide evidence on the safe or traditional use for its registration at the NCA in the intended use and indication.

A Public statement for one herbal substance/preparation is published because of safety reasons or lack of data to comply with the conditions in the Directive 2004/24/EC (the assessment work didn’t allow a monograph to be published) [2].

Community monographs are published by the EMA while list entries are approved and published by the European Commission because they are endorsed with a wider legal status: list entries are legally binding and NCAs should not request additional data on safety and traditional use.

The establishment of monographs and list entries is based on the assessment of the published scientific data, together with the existing products in the market. Most of the assessment work is developed by the Monograph and List Working Party (MLWP) at the HMPC, which was established in 2006. In this working group, a member is designed as rapporteur and is responsible of drafting a monograph and/or list entry which will be later on considered and approved by the HPC and then, by the EMA. The documents are published on the EMA website: Community monographs have to be taken in account by the MS when assessing the application of any company. Monographs are note legally binding and MS are not obliged to follow the monographs.

More than 100 species are included in the priority list with the following data: a) scientific data being assessed (R- Rapporteur assigned); b) evaluation report in progress and discussion in the MLWP (D- Draft under discussion); c) scientific opinion under public consultation (PDraft Published); d) comments after public consultation period being evaluated (PF- Assessment close to finalization – pre-final); e) final opinion adopted (F- Final opinion adopted).

MLWP is also responsible of developing guidelines related to legal requirements for TU and WEU, as well as evaluating hazards and problems related to HMP. For the latter, coordination is established with the Safety Working Party (SWP) from the Committee for Medicinal Products for Human Use (CHMP).

Community herbal monographs to support HMPC authorization

A community monograph reflects the scientific opinion from the HMPC in relation to safety and efficacy of one herbal substance/ preparation for medicinal use. AS stated before, a community monograph may be used by a company for a TU or WEU application. That’s the reason why monographs are divided in to two columns: Well Established Use and Traditional Use (simplified application) (Figure 1). WEU is based in the existence of safety data of sufficient size and efficacy data derived from good-quality clinical trials. Traditional use is accepted for those applications which fulfill the criteria shown in the Directive 2004/24/EC.

Each herbal substance/preparation is assessed individually, as the available information may be different for each one. As a result, some substances/preparations may be included in the WEU side, while others will be included in the TU side. If no enough data are available for the substance/preparation, it won’t be included in the monograph.

The approved draft art he HMPC is published for public consultation for 3 month at the EMA website. Comments received are discussed and taken in account when necessary to achieve the final version of the monograph which will be finally published at the MA website.

By the end of 2014, 126 monographs have been adopted and published by the EMA: 104 of them for TU only; 9 of the monographs refer only to WEU (Aloe vera, Cimicifuga racemosa, Rhamnus frangula, Plantago ovata – seed and tegumentum-, Plantago afra, Rheum palmatum, Cassia senna – leaves and fruits-.among them 13 monograph include both TU and WEU.

The main application of a community monograph is to serve as a reference material for the marketing application, both for TU or WEU. Simplified registration is carried on at a national level, so the company gives the dossier to the NCA. With the aim of improving harmonization, the other MSs should recognize the first authorization granted in the first MS, considering that this is based in the European list.

Directive 2004/24/CE established an adaptation period for those herbal products which were on the European market at the moment the Directive was approved. This seven-year period finalized last April 30^th, 2011 and implies that nowadays those herbal preparations that not fulfill the actual legislation will not be marketed any more.

In the public report form the EMA last June 2014, the status of updating the medicines registration in the EU was shown. The number Traditional use registrations (TUR) and Well-established use marketing authorizations (WEU) grouped for mono component and combination products has increased in the last years (Figure 2).

The European market for HMP is increasing during the last years and even exceeds prescription medicines. The indications approved cover a wide range of therapeutic areas, most of them characteristic of self-medication diseases: the main therapeutic areas are respiratory tract disorders (cough and cold), mental stress and mood disorders, urinary tract and gynecology disorders, sleep disorders and temporary insomnia (Figure 3). Most of the approved THMP until now were updates of existing authorizations and were based on Community monographs. The Summary of Product Characteristics (SoPC) reflects the items in the corresponding monograph [3].

A good correlation between the HMPC work and the evaluation of the dossiers from the companies was detected. The relevance of these documents (as shown by the accepted dossiers) is reflected in the HMPC working plan; as an example, last December 2012, 54 among the 56 species with more than 3 marketing authorizations were listed in the priority list.

Conclusión

European legal framework for medicinal products does also include herbal medicinal products to assure their quality, efficacy and safety. The specific characteristics of these products led to the development of a simplified procedure to assure pharmaceutical quality, while keeping safety and efficacy criteria according to marketing authorization granted.

Although the starting point was quite different for the MS, nowadays there exist Community monographs for most of the herbal substances/ preparations that are used in the European market and which form the basis for a harmonization scenario. Moreover, HMPC acts as an International Regulatory Body for herbal medicinal products in order to achieve global standards for this type of medicines, according to other International organization such as the International Conference on Harmonization (ICH). The main tasks the HMPC has to face are those related to herbal medicinal products which have been previously marketed abroad the EU and the increasing existence of combination products within the MS.

References

Kroes BH (2014) The legal framework governing the quality of (traditional) herbal medicinal products in the European Union. J of Ethnopharmacol 158: 449-453. Chinou I (2014) Monographs, list entries, public statements. J of Ethnopharmacol 158: 458-462. Peschel W (2014) The use of community herbal monographs to facilitate registrations and authorisations of herbal medicinal products in the European Union 2004-2012. J of Eth nopharmacol 158: 471-486.

	Main characteristics	Article n°
Full marketing authorisation	New medicinal product (new chemical substance) Quality documentation Non-clinical studies Clinical trials Efficacy demonstrated by results of clinical trials Adequate safety data	8 (3)
Well-established use	Medicinal products for which there is an extensive clinical experience Quality documentation Substantial clinical experience and scientific data available, so no new data on clinical trials No limitation for therapeutic indications	10 a
Traditional use	Products which not fulfill the efficacy requirements for a marketing authorization = simplified registration Efficacy plausible on the bases of long-standing use and experience Quality documentation Therapeutic indications considered to be safe for use without the supervision of a physician	16 a

Table 1: Types of applications for marketing authorization for a HMP in the EU according the Directive 2001/83/EC.

Herbal medicinal product	Any medicinal product, exclusively containing as active ingredients one or more herbal substances or one or more herbal preparations, or one or more such herbal substances in combination with one or more such herbal preparations.
Herbal substances	All mainly whole, fragmented or cut plants, plant part, algae, fungi, lichen in an unprocessed,, usually dried, but sometimes fresh (…). Herbal substances are precisely defined by the planta part used and the botanical name according to the binomial system (genus, species, variety and author).
Herbal preparations	Preparations obtained by subjecting herbal substances to treatments such as extraction, distillation, expression, fractionation, purification, concentration or fermentation. These include comminuted or powdered herbal substances, tinctures, extracts, essential oils, expressed juices and processed exudates.

Table 2: Definitions applicable to herbal medicinal products (Directive 2001/83/EC).

Herbal medicinal product	Any medicinal product, exclusively containing as active ingredients one or more herbal substances or one or more herbal preparations, or one or more such herbal substances in combination with one or more such herbal preparations.
Herbal substances	All mainly whole, fragmented or cut plants, plant part, algae, fungi, lichen in an unprocessed,, usually dried, but sometimes fresh (…). Herbal substances are precisely defined by the planta part used and the botanical name according to the binomial system (genus, species, variety and author).
Herbal preparations	Preparations obtained by subjecting herbal substances to treatments such as extraction, distillation, expression, fractionation, purification, concentration or fermentation. These include comminuted or powdered herbal substances, tinctures, extracts, essential oils, expressed juices and processed exudates.

Table 3: Definitions applicable to herbal medicinal products (Directive 2001/83/EC).

Figure 1: European Community Monograph for Valeriana officinalis L., radix, for WEU and TU

Ruiz-Poveda OMP^*

Department of Pharmacology, Faculty of Pharmacy, Universidad Complutense de Madrid, 28040 Madrid, Spain

Ruiz-Poveda OMP
Department of Pharmacology, Faculty of Pharmacy
Universidad Complutense de Madrid, Madrid
Ciudad Universitaria s/n. 28040 Madrid, Spain
Tel: 913 941 767
Fax: 913 941 726
E-mail: olgapalomino@farm.ucm.es

Citation: Ruiz-Poveda OMP (2015) Regulation of Herbal (Traditional) Medicinal Products in the European Union. Pharmaceut Reg Affairs 4:142. doi: 10.4172/2167-7689.1000142

/////////Herbal medicines, Good manufacturing practices, Traditional uses

EMA: European Medicines Agency; DER: Drug to Extract Ratio; HMP: Herbal Medicinal Products; THMP: Traditional Herbal Medicinal Products

Dr. Ashok Kumar, President – Research and Development (Chemical) at IPCA LABORATORIES LTD

October 21, 2015 8:25 am / 1 Comment on Dr. Ashok Kumar, President – Research and Development (Chemical) at IPCA LABORATORIES LTD

Dr. Ashok Kumar

PRESIDENT – R&D (Chemical) at IPCA LABORATORIES LTD

LINKS

https://in.linkedin.com/pub/ashok-kumar/16/6a7/903

Intro

The 25-year process patent regime allowed a large number of generic companies in India to reap rich dividends, but there were few who believed in the need to go beyond the horizon of process development to tap into unexplored terrains.

In the year 2000, when Dr Ashok Kumar joined the board of Mumbai-based IPCA Labs, he was determined to implement a different strategy to accelerate IPCA’s R&D initiatives. Having seen IPCA grow from a 350-crore company to one clocking an annual turnover of over 2,500 crore, Dr Ashok Kumar, president- Center for Research and Development, IPCA Labs, is now leaving no stone unturned to exploit the biotech and drug discovery space.

Dr Kumar completed his M Sc in Chemistry from Kumaun University, now in Uttarakhand. He then decided to pursue his PhD in organic chemistry and joined Banaras Hindu University (BHU), but opted out three months later to do PhD from the Central Drug Research Institute (CDRI), Lucknow, under the guidance of the then director of the CDRI, Dr Nityanand.

Dr Kumar did his post doctoral studies from the University of Sussex, UK. “During the 1980s, jobs in scientific research were not available in India. It was always good to go for higher studies abroad,” he says about the reason for going abroad. “Dr Nityanand taught me to be explorative and think of new ways to approach a subject. I still follow that process,” he says. In 1984, Dr Kumar decided to return to India and took up a job at the Imperial Chemical Laboratories (ICI), Mumbai. In 1994, he joined Lupin Labs where he was once again involved in process development of small molecules.

In 2000, he joined IPCA Labs where he immediately focused on bringing about two changes – introducing a library and bringing in systems like a nuclear magnetic resonance (NMR), which at that time was the costliest instrument. “I understood the importance of high-end technologies since my PhD years at the CDRI (which housed a couple of NMRs) and then in the UK. You do not enjoy organic chemistry without an NMR. My main objective at IPCA was cost reduction along with process development.”

In the last few years, IPCA’s R&D team has brought out over 100 products. Under Dr Kumar, IPCA has an R&D center in Mumbai and another parallel R&D center in Ratlam, Madhya Pradesh. “In Mumbai, we have around 60 people. The Mumbai team takes care of basic chemistry and small-scale development. Scaling up is done in Ratlam,” he explains. IPCA is also coming up with a facility at Vadodara, Gujarat, that will look into large-scale manufacture of both organic and biotech drugs. The facility will have a strategic importance for the company. “We are growing at a rate of 20 per cent year-on-year and, next year, we intend to add 500 crore to our revenue. For that, we need more products to come to the market and more volume,” he adds.

Apart from organic chemistry, Dr Kumar is currently aligning his attention to two promising but high risk segments – fermentation-based products and biosimilars. “We are working on five-to-six molecules, mainly active metabolites that are intermediates or biotech drugs,” he adds. IPCA has also collaborated with two companies in India for the development of biosimilars. Currently, there are three biosimilar products in the pipeline.

The R&D team at IPCA ventured into drug discovery three years ago. It has two products in the pipeline; one anti-malarial and the other anti-thrombotic. “We will be filing the investigational new drug application for one molecule this year and for the other next year. The success rate here is 99 per cent,” adds Dr Kumar. IPCA has also joined hands with the CDRI and licensed two molecules in the anti-malarial space. One of these molecules is currently in phase-I stage.

Innogen summit India 2016, 18-19 Aug, Mumbai, India, HOTEL HOLIDAY INN, Mumbai International Airport,Organised by Inventicon Business Intelligence Pvt. Ltd………topic is Supergenerics, Innovation in Generics, commercialization, regulatory, other insights,

Dr. Ashok Kumar, President – Centre for Research & Development, Ipca Laboratories Ltd, at Innogen summit India 2016, 18-19 Aug, Mumbai, India,, HOTEL HOLIDAY INN, Mumbai International Airport,Organised by Inventicon Business Intelligence Pvt. Ltd — with DR ASHOK KUMAR OF IPCA at Holiday Inn-Mumbai Intl Airport.

PANEL DISCUSSION, Dr. Ashok Kumar, President – Centre for Research & Development, Ipca Laboratories Ltd , Dr. Nilima A. Kshirsagar, National Chair Clinical Pharmacology, ICMR Government of India, Yugal Sikri, Chairman – Pharmaceutical Management, School of Business Management, SVKM’s Narsee Monjee Institute of Management Studies — with Yugal Sikri,, Nilima A. Kshirsagarand ASHOK KUMAR OF IPCA at Holiday Inn-Mumbai Intl Airport.

JOURNEY

2005…..PRESIDENT

In 2000, he joined IPCA Labs

1994, he joined Lupin Labs where he was once again involved in process development of small molecules.

1984 Dr Kumar decided to return to India and took up a job at the Imperial Chemical Laboratories (ICI), Mumbai.

Dr Kumar did his post doctoral studies from the University of Sussex, UK.

PhD in organic chemistry and joined Banaras Hindu University (BHU), but opted out three months later to do PhD from the Central Drug Research Institute (CDRI), Lucknow, under the guidance of the then director of the CDRI, Dr Nityanand.

Dr Kumar completed his M Sc in Chemistry from Kumaun University, now in Uttarakhand

DR NITYANAND

DIRECTOR, CDRI, LUCKNOW, INDIA

Experience

PRESIDENT – R&D

IPCA LABORATORIES LTD

2005 – Present (10 years)

Patent 1

chlorthalidone is 3-hydroxy-3-(3′-sulfamyI-4′- chlorophenyl)phtalimidine and is represented by the structural formula shown below.

http://www.google.co.in/patents/WO2005065046A2?cl=en

Chlorthalidone Formula 1

(Scheme 2). The starting material, 2-(4′-chlorobenzoyl) benzoic acid, of Formula (2) and its preparation was reported earlier for example in patents US 4500636, US 30555904, US4379092, US 3764664.

Formula 9 CIS0₃H

Chlorthalidone Formula 10 Formula 1

PATENT 2

https://www.google.co.in/patents/US7847094Quetiapine and its process for preparation is first disclosed in the patent specification EP0240228 and various other processes for the preparation are disclosed in EP0282236, WO0155125, WO9906381, WO2004076431.

PATENT 3

http://www.google.com/patents/US20080009635

. The chemical name of Ondansetron is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl)-1H-imidazole-1-yl)methyl]-4H-carbazol-4-one and is represented by the structural formula given below:

PATENT 4

http://www.google.im/patents/US20100081847

scheme 2.

AT A SEMIMAR

Chemical Research & Development Centre

123-AB, Kandivli Industrial Estate, Kandivli (West)
Mumbai 400 067, Maharashtra

+91 (22) 6647 4755 / 56

+91 (22) 6647 4757

Kumaun University

Imperial Chemical Laboratories (ICI), Mumbai

/////Dr. Ashok Kumar, PRESIDENT, R&D, IPCA LABORATORIES LTD

FDA approves first Factor X concentrate to treat patients with rare hereditary bleeding disorder

October 21, 2015 12:54 am / Leave a comment

FDA approves first Factor X concentrate to treat patients with rare hereditary bleeding disorder

10/20/2015

The U.S. Food and Drug Administration today approved Coagadex, Coagulation Factor X (Human), for hereditary Factor X (10) deficiency. Until today’s orphan drug approval, no specific coagulation factor replacement therapy was available for patients with hereditary Factor X deficiency.

October 20, 2015

Release

In healthy individuals, the Factor X protein activates enzymes to help with normal blood clotting in the body. Factor X deficiency is an inherited disorder, affecting men and women equally, where the blood does not clot as it should. Patients with the disorder are usually treated with fresh-frozen plasma or plasma-derived prothrombin complex concentrates (plasma products containing a combination of vitamin K-dependent proteins) to stop or prevent bleeding. The availability of a purified Factor X concentrate increases treatment options for patients with this rare bleeding disorder.

“The approval of Coagadex is a significant advancement for patients who suffer from this rare but serious disease,” said Karen Midthun, M.D., director of the FDA’s Center for Biologics Evaluation and Research.

Coagadex, which is derived from human plasma, is indicated for individuals aged 12 and older with hereditary Factor X deficiency for on-demand treatment and control of bleeding episodes, and for perioperative (period extending from the time of hospitalization for surgery to the time of discharge) management of bleeding in patients with mild hereditary Factor X deficiency.

The safety and efficacy of Coagadex was evaluated in a multi-center, non-randomized study involving 16 participants (208 bleeding episodes) for treatment of spontaneous, traumatic and heavy menstrual (menorrhagic) bleeding episodes. Coagadex was demonstrated to be effective in controlling bleeding episodes in participants with moderate to severe hereditary Factor X deficiency. Coagadex was also evaluated in five participants with mild to severe Factor X deficiency who were undergoing surgery. The five individuals received Coagadex for perioperative management of seven surgical procedures. Coagadex was demonstrated to be effective in controlling blood loss during and after surgery in participants with mild deficiency. No individuals with moderate or severe Factor X deficiency received Coagadex for perioperative management of major surgery, and no safety concerns were identified in either study.

The FDA granted Coagadex orphan product designation for these uses. Orphan product designation is given to drugs intended to treat rare diseases in order to promote their development. Coagadex was also granted fast track designation and priority review.

Coagadex is manufactured by Bio Products Laboratory Limited in Elstree, Hertfordshire, United Kingdom.

TAK 272, For Hypertension, Takeda’s Next Sartan

October 20, 2015 8:19 am / 1 Comment on TAK 272, For Hypertension, Takeda’s Next Sartan

TAK 272

C27 H41 N5 O4 . Cl H, 536.106

CAS.1202269-24-6. MonoHCl

1202265-90-4 DIHCL

Base cas…1202265-63-1
Metanesulfonate…1202266-34-9

Takeda Pharmaceutical Company Limited, INNOVATOR

see……….http://www.allfordrugs.com/2015/10/21/tak-272-for-hypertension-takedas-next-sartan/
1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)-piperidin-3-yl]-1H-benzimidazole-2-carboxamide

1- (4-methoxybutyl) -N- (2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -lH-benzimidazole-2-carboxamide dihydrochloride

N-Isobutyl-1-(4-methoxybutyl)-N-[5(R)-(morpholin-4-ylcarbonyl)piperidin-3(S)-yl]-1H-benzimidazole-2-carboxamide hydrochloride

1- (4-methoxybutyl) -N- (2- methylpropyl) -N – [(3S, 5R) -5- (morpholin-4-ylcarbonyl) piperidine-3 – yl] -1H- benzimidazole-2-carboxamide hydrochloride,

The compound is used as renin inhibitor for treating diabetic nephropathy and hypertension

Takeda’s TAK-272, was reported to be in phase II in October 2015), an oral renin inhibitor, for treating diabetic nephropathy and hypertension

01 Apr 2015Takeda completes a phase I drug-drug interaction trial in Healthy volunteers in Japan (NCT02370615)
18 Feb 2015Takeda plans a phase I drug-drug interaction trial in Healthy volunteers in Japan (NCT02370615)
13 Feb 2015Takeda plans a phase I pharmacokinetics trial in Renal or Hepatic impairment patients in Japan (NCT02367872)

in Patent Document 1, a method for producing a synthetic intermediate of the above heterocyclic compound, the following methods are disclosed.

In the above method, the acid anhydride (BANC) from chiral dicarboxylic acid monoester ((-) – BMPA) were synthesized and then the carboxylic acid after conversion and hydrolysis reaction of the Z amine by the Curtius rearrangement of the carboxylic acid (BAPC) and it was then performs amidation by the condensation reaction with the amine (morpholine), is synthesized heterocyclic amide compound (BMPC).　Further, Patent Document 2, the preparation of compounds useful as synthetic intermediates of the above heterocyclic compounds are disclosed.

(Wherein each symbol is as described in Patent Document 2.)

　TABLE In the above method, the acid anhydride of the formula (VI), in the presence of a chiral amine with the formula (VIIa) or (VIIb) is to produce a chiral dicarboxylic acid monoester compound, then reacted with an amine (R1-NH-R2) is subjected to amidation to, to produce a heterocyclic amide compound of the formula (VIII).

Patent literature

Patent Document 1: Patent No. 4,800,445 Patent
Patent Document 2: International Publication No. 2007/077005

SYNTHESIS…click on image to get clear view

PATENT

WO2009154300

https://www.google.co.in/patents/WO2009154300A2?cl=en

INTERMEDIATES FOR CONSTRUCTION

USE THIS ONE

Reference Example 31 tert-butyl (3S,5R)-3-[{ [1- (4-methoxybutyl) -lH-benzimidazol-2- yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl)piperidine-l-carboxylate and 1- (4-methoxybutyl) -N-

(2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin-4- ylcarbonyl)piperidin-3-yl]-lH-benzimidazole-2-carboxamide

tert-Butyl (3S, 5R) -3-{ [ ( {2- [ (4- methoxybutyl) amino] phenyl}amino) (oxo) acetyl] (2- methylpropyl) amino} -5- (morpholin-4-ylcarbonyl) piperidine-1- carboxylate (9.11 g) was dissolved in acetic acid (50 ml), and the mixture was stirred at 😯⁰C for 15 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, the residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give tert- butyl (3S, 5R) -3- [ { [1- (4-methoxybutyl) -lH-benzimidazol-2- yl] carbonyl } (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl)piperidine-l-carboxylate (5.85 g) , and a fraction eluted with ethyl acetate-methanol (85:15) was concentrated under reduced pressure to give 1- (4-methoxybutyl) -N- (2- methylpropyl) -N- [ (3S, 5R) -5- (morpholin-4-ylcarbonyl) piperidin- 3-yl] -lH-benzimidazole-2-carboxamide (580 mg) . [0424] tert-butyl (3S,5R)-3-[{ [1- (4-methoxybutyl) -lH-benzimidazol-2- yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl ) piperidine-1-carboxylate 1H-NMR (CDCl₃) δ 0.63-0.80 (2H, m) , 0.89-1.07 (4H, m) , 1.41- 1.59 (9H, m) , 1.59-1.80 (2H, m) , 1.87-2.23 (4H, m) , 2.30-2.98 (3H, m) , 3.21-3. 46 ( 6H, m) , 3.49-3. 91 (1OH, m) , 3. 95-4 . 47 (5H, m) , 7 . 18-7 . 51 (3H, m) , 7. 56-7 . 84 ( IH, m) .

MS (ESI+, m/e) 600 (M+l )

1- (4-methoxybutyl) -N- (2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin- 4-ylcarbonyl)piperidin-3-yl] -lH-benzimidazole-2-carboxamide BASE

¹H-NMR (CDCl₃) δ 0.64-0.74 (2H, m) , 0.95-1.07 (4H, m) , 1.43-

1.74 (3H, m) , 1.84-2.41 (4H, m) , 2.48-2.67 (IH, m) , 2.67-3.01

(3H, m), 3.03-3.44 (8H, m) , 3.47-3.78 (9H, m) , 4.06-4.46 (3H, m) , 7.28-7.47 (3H, m) , 7.62-7.81 (IH, m) . MS (ESI+, m/e) 500 (M+l)

Example 10

1- (4-methoxybutyl) -N- (2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin-

4-ylcarbonyl) piperidin-3-yl] -lH-benzimidazole-2-carboxamide dihydrochloride

tert-Butyl (3S,5R)-3-[{ [1- (4-methoxybutyl) -IH- benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5-

(morpholin-4-ylcarbonyl)piperidine-l-carboxylate (5.85 g) was dissolved in methanol (20 ml) , 4M hydrogen chloride-ethyl acetate (20 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate- methanol (9:1) was concentrated under reduced pressure to give 1- (4-methoxybutyl) -N- (2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin- 4-ylcarbonyl) piperidin-3-yl] -lH-benzimidazole-2-carboxamide (4.40 g) . The obtained 1- (4-methoxybutyl) -N- (2-methylpropyl) – N- [ (3S, 5R) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -IH- benzimidazole-2-carboxamide (2.20 g) was dissolved in ethyl acetate (20 ml) , 4M hydrogen chloride-ethyl acetate (5 ml) and methanol (20 ml) were added, and the mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated under reduced pressure to give the object product (2.52 g).

dihydrochloride

¹H-NMR (DMSO-d₆) δ 0.63-0.76 (2H, m) , 0.85-1.00 (4H, m) , 1.40-

1.60 (2H, m) , 1.68-1.89 (2H, m) , 1.93-2.17 (2H, m) , 2.20-2.44

(2H, m) , 2.81-3.81 (2OH, m) , 4.19-4.39 (3H, m) , 7.23-7.46 (2H, m) , 7.57-7.81 (2H, m) , 8.38-9.77 (2H, m) .

MS (ESI+, m/e) 500 (M+l)

Example 252

1- ( 4-methoxybutyl ) -N- ( 2-methylpropyl ) -N- [ ( 3S ₁. 5R) -5- (morpholin- 4-ylcarbonyl ) piperidin-3-yl ] -lH-benzimidazole-2-carboxamide methanesulfonate

l-(4-Methoxybutyl) -N- (2-methylpropyl) -N- [ (3S,5R)-5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -lH-benzimidazole-2- carboxamide (208 mg) was dissolved in ethyl acetate (2 ml) , a solution of methanesulfonic acid (40 μl) in ethyl acetate (1 ml) was added at 75°C, hexane (1 ml) was added, and the mixture was heated under reflux and stood at room temperature overnight. The precipitated crystals were collected by filtration, and dried at 7O⁰C for 3 hr to give the object product (158 mg) . MS (ESI+, m/e) 500 (M+l) melting point : 144.4⁰C

EXTRAS IF REQD .………….

Example 32

methyl (3R, 5S)-5-[{ [1- (4-methoxybutyl) -lH-benzimidazol-2- yl] carbonyl} (2-methylpropyl) amino] piperidine-3-carboxylate dihydrochloride [0675]

MS (ESI+, m/e) 445 (M+l)

Example 33

(3R, 5S) -5- [ { [1- (4-methoxybutyl) -lH-benzimidazol-2- yljcarbonyl} (2-methylpropyl) amino] piperidine-3-carboxylic acid dihydrochloride

MS (ESI+, m/e) 431 (M+l)

Reference Example 29

{ [ ( 3S , 5R) -1- (tert-butoxycarbonyl ) -5- (morpholin-4- ylcarbonyl ) piperidin-3~yl ] ( 2-itιethylpropyl ) amino } (oxo ) acetic acid

To a solution of tert-butyl (3S,5R)~3-{ [ethoxy (oxo) acetyl] (2-methylpropyl) amino}-5- (morpholin-4- ylcarbonyl) piperidine-1-carboxylate (10.3 g) in ethanol (40 ml) was added 2M aqueous sodium hydroxide solution (22 ml) , and the mixture was stirred at room temperature for 6 hr. The reaction mixture was adjusted to pH 7 with IM hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (10.3 g) .

¹H-NMR (CDCl₃) δ 0.78-0.99 (6H, m) , 1.37-1.52 (9H, m) , 1.79- 2.16 (3H, m) , 2.38-3.86 (14H, m) , 3.93-4.43 (2H, m) . MS (ESI+, m/e) 442 (M+l)

Reference Example 28

tert-butyl (3S, 5R) -3-{ [ethoxy (oxo) acetyl] (2- methylpropyl ) amino } -5- (morpholin-4-ylcarbonyl) piperidine-1- carboxylate

To a solution of tert-butyl (3S, 5R) -3- [ (2- methylpropyl) amino] -5- (morpholin-4-ylcarbonyl) piperidine-1- carboxylate (9.24 g) and diisopropylethylamine (10.5 ml) in DMA (100 ml) was added dropwise ethyl chloroglyoxylate (3.4 ml) at 0°C. The reaction mixture was stirred at room temperature for 15 hr, and the reaction mixture was concentrated. An aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (10.3 g) . 1H-NMR (CDCl₃) δ 0.84-1.00 (6H, m) , 1.37 (3H, q) , 1.42-1.53 (9H, m) , 1.80-2.19 (3H, m) , 2.26-2.42 (IH, m) , 2.59-2.96 (IH, in) , 2.97-3.30 (3H, m) , 3.37-3.92 (9H, m) , 4.01-4.26 (2H, m) , 4.26- 4.40 (2H, m) . MS (ESI4-, m/e) 470 (M+l) ^“

Reference Example 22 tert-butyl (3S, 5R) -3- [ (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl)piperidine-l-carboxylate

[0369] tert-Butyl (3S,5R)-3-{ [ (benzyloxy) carbonyl] aminoJ-5- (morpholin-4-ylcarbonyl)piperidine-l-carboxylate (58 g) and palladium (II) hydroxide-carbon (5 g) were suspended in methanol (400 ml) and the mixture was stirred under a hydrogen atmosphere (1 atom) at room temperature for 16 hr. The palladium catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue and acetic acid (8.8 ml) were dissolved in methanol (400 ml), 2- methylpropanal (14.0 ml) was added, and the mixture was stirred at room temperature for 1 hr. Sodium triacetoxyborohydride (40.4 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the concentrate was basified with 3.5M aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:5) – ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object product (33.3 g) .

¹H-NMR (CDCl₃) δ: 0.90 (6H, d) , 1.46 (9H, s) , 1.54 (IH, d) , 1.69 (IH, dt), 1.96-2.12 (2H, m) , 2.23-2.37 (IH, m) , 2.47 (3H, d) , 2.66 (IH, d) , 3.61 (IH, br s) , 3.55 (2H, d) , 3.69 (5H, ddd) , 4.01-4.46 (2H, m) .

Example 6 1-tert-butyl 3-methyl (3R, 5S) -5-aminopiperidine-l, 3- dicarboxylate [0318]

(3S, 5R) -1- (tert-Butoxycarbonyl) -5-(methoxycarbonyl)piperidine-3-carboxylic acid (2.83 g) was suspended in toluene (36 ml), diphenylphosphoryl azide (2.60 ml) and triethylamine (1.70 ml) were added, and the mixture was stirred at 100°C for 1 hr. The reaction mixture was cooled to room temperature, benzyl alcohol (1.53 ml) and triethylamine (7.00 ml) were added and the mixture was stirred at 80°C for 3 hr. The reaction mixture was concentrated, the residue was dissolved in ethyl acetate, and the solution was washed with water, 0.5M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:3 – 3:1) was concentrated under reduced pressure. The obtained residue was dissolved in methanol (60 ml), 10% palladium carbon (50% in water) (150 mg) was added and the mixture was stirred under a hydrogen pressurization (5 atom) at ambient temperature and normal pressure for 5 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object product (1.83 g) as an oil.

¹H-NMR (CDCl₃) δ 1.22-1.43 (4H, m) , 1.46 (9H, s), 2.27-2.79 (4H, m) , 3.70 (3H, s) , 4.13 (2H, br s) [0320] In the same manner as in the method shown in Reference Example 6, the following compound (Reference Example 7) was obtained.

Reference Example 8

1-tert-butyl 3-methyl (3R, 5S) -5- [ (2- methylpropyl) amino] piperidine-1, 3-dicarboxylate [0325]

1-tert-Butyl 3-methyl (3R, 5S) -5-aminopiperidine-l, 3- dicarboxylate (1.83 g) , isobutyraldehyde (0.78 ml) and acetic acid (0.49 ml) were dissolved in methanol (50 ml), and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (3.80 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 7 hr. The reaction mixture was concentrated under reduced pressure, the concentrate was basified with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1) – ethyl acetate 100% – ethyl acetate- methanol (9:1) was concentrated under reduced pressure to give the object product (1.42 g) as an oil.

¹H-NMR (CDCl₃) δ 0.90 (6H, d) , 1.22-1.38 (3H, m) , 1.46 (9H, s) , 1.69 (IH, dt), 2.23-2.39 (2H, m) , 2.44-2.59 (IH, m) , 2.47 (2H, d) , 2.74 (IH, br s) , 3.69 (3H, s) , 4.18-4.34 (2H, m)

Reference Example 27

N- (4-methoxybutyl) benzene-1, 2-diamine

To a solution of phenylenediamine (10.8 g) and 4- methoxybutyl methanesulfonate (9.11 g) in acetonitrile (100 ml) was added potassium carbonate (20.7 g) , and the mixture was stirred heated under reflux for 15 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (35:65) was concentrated under reduced pressure to give the object product (5.44 g) . 1H-NMR (CDCl₃) δ 1.67-1.82 (4H, m) , 3.13 (2H, t) , 3.24-3.39 (6H, m) , 3 . 38 -3 . 50 ( 2H, m) , 6 . 62 – 6 . 74 ( 3H, m) , 6 . 81 ( IH, in) . MS ( ESI+ , m/e ) 195 (M+l )

Reference Example 146 tert-butyl (3S, 5R) -3- [ { [1- (4-methoxybutyl) -lH-benzimidazol-2- yl]carbonyl} (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl)piperidine-l-carboxylate

A solution of tert-butyl (3S, 5R) -3- [ (lH-benzimidazol-2- ylcarbonyl) (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl)piperidine-l-carboxylate (200 mg) , 4-itιethoxybutyl methanesulfonate (107 mg) and cesium carbonate (254 mg) in N,N-dimethylacetamide (5 ml) was stirred at 60°C for 15 hr. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (10 ml*2) . The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95 – 3:7) was concentrated under reduced pressure to give the object product (190 mg) . 1H-NMR (CDCl₃) δ 0.63-0.80 (2H, m) , 0.89-1.07 (4H, m) , 1.41- 1.59 (9H, m) , 1.59-1.80 (2H, m) , 1.87-2.23 (4H, m) , 2.30-2.98 (3H, m) , 3.21-3.46 (6H, m) , 3.49-3.91 (1OH, m) , 3.95-4.47 (5H, m) , 7.18-7.51 (3H, m) , 7.56-7.84 (IH, m) . MS (ESI+, m/e) 600 (M+l)

ALTERNATE METHOD IN THIS PATENT

Figure imgf000106_0001

Figure imgf000127_0002

Reference Example 61

2- (trichloromethyl) -lH-benzimidazole

O-Phenylenediamine (25 g) was dissolved in acetic acid (750 ml), and methyl 2, 2, 2-trichloroacetimidate (28.5 ml) was added dropwise over 15 min. After stirring at room temperature for 1 hr, the reaction mixture was concentrated to about 150 ml, and poured into water (1500 ml) . The precipitated crystals were collected by filtration, washed with water (1000 ml) and suspended in toluene (500 ml) . The solvent was evaporated under reduced pressure. The residue was again suspended in toluene (500 ml) and the solvent was evaporated under reduced pressure. The residue was dried under reduced pressure to give the object product (51.8 g) . 1H-NMR (CDCl₃) δ 7.31-7.45 (2H, m) , 7.49-7.55 (IH, m) , 7.89 (IH, d) , 9 . 74 ( IH, br s )

Reference Example 64

1-tert-butyl 3-methyl (3R, 5S) -5- [ (lH-benzimidazol-2- ylcarbonyl) (2-methylpropyl) amino] piperidine-1, 3-dicarboxylate

2- (Trichloromethyl) -lH-benzimidazole (19 g) and 1-tert- butyl 3-methyl (3R, 5S) -5- [ (2-methylpropyl) amino] piperidine- 1,3-dicarboxylate (25 g) were dissolved in THF (1200 ml), sodium hydrogen carbonate (67 g) and water (600 ml) were added, and the mixture was stirred at room temperature for 1 hr and at 5O⁰C for 1 hr. After evaporation of the solvent, the residue was extracted 3 times with ethyl acetate (700 ml) . The extract was washed successively with 10%-aqueous citric acid solution (500 ml) and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure.

The residue was dissolved in ethyl acetate (1000 ml), subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (30.6 g) .

¹H-NMR (CDCl₃) δ 0.78-1.09 (6 H, m) , 1.17-1.55 (9 H, m) , 1.77-2.95 (5 H, m) , 3.11-3.79 (6 H, m) , 3.99-4.73 (4 H, m) , 7.24- 7.41 (2 H, m) , 7.45-7.59 (1 H, m) , 7.72-7.88 (1 H, m) , 10.66-10.98 (1 H, m)MS (ESI+, m/e) 459 (M+l)

Reference Example 69

1-tert-butyl 3-methyl (3R, 5S) -5- [ { [1- (4-methoxybutyl) -IH- benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] piperidine-1 , 3-dicarboxylate

1-tert-Butyl 3-methyl (3R, 5S) -5- [ (lH-benzimidazol-2- ylcarbonyl) (2-methylpropyl) amino] piperidine-1, 3-dicarboxylate (30 g) and 4-methoxybutyl methanesulfonate (12.5 g) were dissolved in DMA (600 ml), cesium carbonate (32 g) was added, and the mixture was stirred at 70°C for 12 hr. The reaction mixture was poured into ice water (1000 ml), and the mixture was extracted twice with ethyl acetate (1000 ml) . The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:4 – 1:1) was concentrated under reduced pressure to give the object product (28.7 g) .

¹H-NMR (CDCl₃) δ 0.76 (4H, d) , 1.01 (2H, d) , 1.30-1.52 (9H, m) , 1.58-2.07 (4H, m) , 2.10-2.93 (4H, m) , 3.27-3.75 (12H, m) , 4.06-4.57 (5H, m) , 7.26-7.48 (3H, m) , 7.79 (IH, d) MS (ESI+, m/e) 545 (M+l)

Example 71

1- (4-methoxybutyl) -N- (2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin- 4-ylcarbonyl) piperidin-3-yl] -lH-benzimidazole-2-carboxamide

tert-Butyl (3S, 5R) -3- [{ [1- (4-methoxybutyl) -IH- benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4-ylcarbonyl)piperidine-l-carboxylate (5.85 g) was dissolved in methanol (20 ml) , 4M hydrogen chloride-ethyl acetate (20 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, the residue was diluted with aqueous sodium bicarbonate,…and, the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate- methanol (9:1) was concentrated under reduced pressure to give the object product (4.40 g) . MS (ESI+, m/e) 500 (M+l)

Example 101

1- (5-methoxypentyl) -N- (2-methylpropyl) -N- [ (3S, 5R) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -lH-benzimidazole-2- carboxamide dihydrochloride

[1144] tert-Butyl (3S, 5R) -3- [ { [1- (5-methoxypentyl) -IH- benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4-ylcarbonyl)piperidine-l-carboxylate (123 mg) was dissolved in 4M hydrogen chloride-ethyl acetate (5 ml) , and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was subjected to reversed-phase preparative HPLC and the eluted fraction was concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. 4M Hydrogen chloride-ethyl acetate (1 ml) was added and the mixture was stirred for 5 min. The solvent was evaporated under reduced pressure to give the object product (76 mg) . MS (ESI+, m/e) 514 (M+l)

PATENT

WO2013122260

http://www.google.co.in/patents/WO2013122260A1?cl=en

PATENT

WO 2011158880

http://www.google.co.in/patents/WO2011158880A1?cl=en

Reference Example 1
1- (4-methoxybutyl) -N- (2- methylpropyl) -N – [(3S, 5R) -5- (morpholin-4-ylcarbonyl) piperidin-3-yl] -1H- benzimidazole -2 – carboxamide hydrochloride (A-type crystal)
tert- butyl (3S, 5R) -3 – [{[1- (4- methoxy-butyl) -1H- benzimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl) was suspended dissolved piperidine-1-carboxylate The (300g) in 3N- hydrochloric acid water (1200mL) and Ethyl acetate (60mL), and stirred over 3 h at 25 ~ 35 ℃. After completion of the reaction, it was added ethyl acetate (2400mL) in the same temperature. After the addition, it was added 25% aqueous ammonia (600mL) with cooling. After the addition stirring and extracted the organic layer of 5% aqueous ammonia (600mL) was added and stirred. After stirring, the resulting organic layer it was concentrated until the solvent no longer distilled off. After concentrated, dissolved with ethyl acetate (1500mL), and transferred to solution to the crystallizer vessel, and washed with ethyl acetate (750mL). After washing, it was raised in stirring under 45 ~ 55 ℃. After raising the temperature, at the same temperature 4N- hydrogen chloride – it was dropped ethyl acetate (131.3mL). After dropping, it was to dissolve the precipitate at the same temperature. After dissolution confirmation, it was added heptane (750mL) at 40 ~ 50 ℃, after the addition, then cooled to 25 ~ 35 ℃. After cooling, the addition of A-type crystals of the seed crystals (300mg) which was obtained according to the method described in Example 265 of WO2009 / 154300, and stirred for 30 minutes or more. After stirring, the temperature was raised to 40 ~ 45 ℃, it was dropped heptane (1500mL). After the completion of the dropping, it was stirred at the same temperature. Then gradually cooled to 5 ℃ below, followed by stirring at the same temperature for 1 hour. After stirring, ethyl acetate and filtered crystals – heptane: washed with (1 1,600mL), to obtain a wet crystal. The obtained wet crystals dried under reduced pressure at 50 ℃, 1- (4- methoxybutyl) -N- (2- methylpropyl) -N – [(3S, 5R) -5- (morpholin-4-yl carbonyl) piperidin-3-yl] -1H- obtained a crystalline powder of benzimidazole-2-carboxamide hydrochloride (A-type crystal, 198.82g, 74.1% yield). FINAL PRODUCT

TERT BUTYL DERIVATIVE, N-1

Reference Example 4
tert- butyl (3S, 5R) -3 – [{[1- (4- methoxy-butyl) -1H- benzoimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5- (morpholin-4- ylcarbonyl) piperidine-1-carboxylate 1)

o- nitro aniline (50.0g, 0.362mol), tetrabutylammonium bromide (58.3g, 0.181mol), potassium bromide (43.1g, 0.362mol) in toluene (500mL ) and it was added. At a temperature of 20 ~ 30 ℃ 1- chloro-4-methoxy-butane (66.6g, 0.543mol) and, I was added to 50w / v% sodium hydroxide solution (145mL, 1.81mol). The reaction was heated to a temperature 85 ~ 95 ℃, and stirred for 6 hours. After cooling to a temperature 20 ~ 30 ℃, the reaction mixture water (250mL), 1N- aqueous hydrochloric acid (250mL × 2), 5w / v% aqueous solution of sodium bicarbonate (250mL), it was washed successively with water (250mL). After concentration under reduced pressure the organic layer to Contents (250mL), was added toluene (100mL), was obtained

N- (4- methoxy-butyl) -2-nitroaniline in toluene (350mL, 100% yield).
¹ H-NMR (300MHz, CDCl ₃₎ ^δ 1.64-1.89 (m, 4H), 3.25-3.39 (m, 2H), 3.35 (s, 3H), 3.44 (t, J = 6.1 Hz, 2H), 6.63 ( ddd, J = 8.5, 6.9, 1.2 Hz, 1H), 6.86 (dd, J = 8.5, 1.2 Hz, 1H), 7.43 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 8.07 (br s, 1H ), 8.17 (dd, J = 8.5, 1.5 Hz, 1H).

2) N- (4-methoxy-butyl) -2-10 percent in nitroaniline of toluene solution (350mL) Pd / C (K-type, 50% water-containing product) (10.0g) and toluene (100mL) it was added. Hydrogen pressure of 0.1MPa, it was stirred for 3 hours at a temperature of 20 ~ 30 ℃. A stream of nitrogen, the catalyst was filtered, I was washed with toluene (100mL). After the water in the filtrate was separated off and adding magnesium sulfate (25.0g) at a temperature 20 ~ 30 ℃, and stirred at the same temperature for 30 minutes. Filtered over magnesium sulfate, washed with toluene (100mL), was obtained N- (4- methoxybutyl) -o- toluene solution of phenylenediamine (100% yield).
¹ H NMR (500 MHz, CDCl ₃₎ ^δ1.67-1.78 (m, 4H), 3.12-3.14 (m, 2H), 3.32 (br, 3H), 3.35 (s, 3H), 3.41-3.47 (m, 2H), 6.63-6.69 (m, 2H), 6.69-6.74 (m, 1H), 6.82 (td, J = 7.57, 1.58 Hz, 1H).

3) N- (4- methoxy-butyl) -o- After the toluene solution of phenylenediamine cooled to a temperature 0 ~ 10 ℃, acetic acid (65.2g, 1.09mol) and 2,2,2 trichloroacetimide acid methyl ( 70.3g, 0.398mol) and I were added. After stirring for 30 minutes at a temperature 0 ~ 10 ℃, it was stirred for 3 hours at a temperature of 20 ~ 30 ℃. The reaction was 5w / v% saline (250mL), 2N- aqueous hydrochloric acid / 5w / v% sodium chloride solution: a mixture of (1 1) (250mL × 2), 5w / v% aqueous solution of sodium bicarbonate (250mL), 5w / v It was washed successively with% saline solution (250mL). A stream of nitrogen, was added magnesium sulfate (25.0g) to the organic layer at a temperature 20 ~ 30 ℃, and stirred at the same temperature for 30 minutes. Filtered magnesium sulfate, and washed with toluene (100mL). The filtrate was concentrated under reduced pressure and the amount of contents (150mL). Stir the concentrated solution at a temperature 20 ~ 30 ℃, was allowed to precipitate crystals, was added dropwise heptane (750mL). The crystals bleeding is heated to a temperature 40 ~ 50 ℃, after stirring for 30 min, cooled to a temperature 0 ~ 10 ℃, and the mixture was stirred at the same temperature for 2 hours.The precipitated crystals were collected by filtration, toluene – heptane: was washed with (1 5,150 mL). And dried under reduced pressure at 40 ℃, it was obtained 1- (4-methoxy-butyl) -2-fine brown crystals of trichloromethyl -1H- benzimidazole (96.5g, 82.9% yield from o- nitroaniline).
¹ H-NMR (300MHz, CDCl ₃₎ ^δ: 1.68-1.85 (m, 2H), 1.99-2.17 (m, 2H), 3.37 (s, 3H), 3.48 (t, J = 6.1 Hz, 2H), 4.50 -4.65 (m, 2H), 7.27-7.49 (m, 4H), 7.82-7.93 (m, 1H).
. Anal Calcd _for C ₁₃ H ₁₅ Cl ₃ N ₂ O:. C, 48.55; H, 4.70; N, 8.71; Cl, 33.07 Found: C, 48.30; H, 4.61; N, 8.74; Cl, 33.30.

4) pyridine-3,5-dicarboxylic acid (110g, 0.66mol), it was dropped methanol (660 mL) mixture of concentrated sulfuric acid at a temperature of 50 ℃ or less of (226.0g, 2.30mol). Thereafter, the mixture was stirred and heated to a temperature 55 ~ 65 ℃ 7 hours. The reaction was the temperature 40 ~ 50 ℃, was added water (220mL). And further dropping temperature 40-50 5% aqueous ammonia at ℃ (about 1.10L) was adjusted to pH8.0 ~ 8.5. After stirring at a temperature 40 ~ 50 ℃ 30 minutes and stirred for 1 hour and cooled to a temperature 0 ~ 10 ℃. Was collected by filtration precipitated crystals, methanol – water (1: 3,165mL), and washed successively with water (440mL). To obtain a white crystalline powder pyridine-3,5-dicarboxylic acid dimethyl and dried under reduced pressure at 50 ℃ (105.0g, 82.0% yield).
¹ H-NMR (300 MHz, CDCl ₃₎ ^δ 4.00 (s, 6H), 8.87 (s, 1H), 9.37 (s, 2H).
. Anal Calcd for C ₉ H ₉ NO _4:. C, 55.39; H, 4.65; N, 7.18; O, 32.79 Found: C, 55.42; H, 4.65; N, 7.16.

5) 1 L autoclave pyridine-3,5-dicarboxylic acid dimethyl (100g, 0.51mol) and was charged with dimethylacetamide (400mL), temperature 30 ℃ below with trifluoroacetic acid (59.2mL, after dropping the 0.77mol), 10% Pd-C (PE-type) the (20.0g) it was added. Hydrogen pressure of 0.5 ~ 0.7MPa, it was stirred for 12 hours at a temperature of 55 ~ 65 ℃. The catalyst was filtered off, it was washed with dimethylacetamide (50mL × 2). Triethylamine and the combined filtrates at a temperature 20 ~ 30 ℃ (77.8g, 0.77mol) was added dropwise, and adjusted to pH9.0 ~ 10.0. Temperature 30 ~ 40 ℃ by di -tert- butyl (134g, 0.614mol) was added dropwise and stirred at the same temperature for 2 hours. After the reaction mixture as a 20 ~ 30 ℃, it was added ethyl acetate (600mL), washed with water (900mL). The aqueous layer it was re-extracted with ethyl acetate (400mL). The combined organic layers 5w / v% citric acid -10w / v% sodium chloride solution (600mL), 3% aqueous sodium bicarbonate (600mL), and washed successively with water (600mL). Contents The organic layer (200mL) until it was concentrated under reduced pressure, methanol (250mL) was added to the concentrated solution, and then concentrated under reduced pressure until Contents (200mL). The addition of methanol (250mL) again concentrate, After concentration under reduced pressure until Contents (200mL), was added methanol (2.40L). The solution in water (18.5g, 1.03mol), cesium carbonate (417g, 1.28mol) was added and stirred for about 24 hours at a temperature 55 ~ 65 ℃. The reaction solution was the temperature 20 ~ 30 ℃, concentrated to Contents (700mL), it was added tetrahydrofuran (500mL). The solution temperature at 15 ~ 35 ℃ 2N- hydrochloric acid solution (1.28L, 2.56mol) was added dropwise and adjusted to pH3.0 ~ 3.5, and the mixture was stirred for 30 minutes at a temperature 20 ~ 30 ℃. Extracted with ethyl acetate (750mL × 2), and the organic layer was washed with 10w / v% aqueous sodium chloride solution (500mL × 3). Contents The organic layer (300mL) until it was concentrated under reduced pressure, to obtain a weight content by adding ethyl acetate (650mL).Heating the concentrate to a temperature of 55 ~ 65 ℃, it was added dropwise heptane (500mL). It cooled to a temperature 20 ~ 30 ℃ and stirred for 1 hour. The precipitated crystals were collected by filtration, ethyl acetate – heptane: was washed with (1 1,120mL). Dried under reduced pressure at 50 ℃ 1- (tert- butoxycarbonyl) to give a white crystalline powder of piperidine-3,5-dicarboxylic acid (113.3g, 80.9% yield).
¹ H-NMR (300 MHz, DMSO-d ₆₎ ^δ 1.40 (s, 9H), 1.44-1.61 (m, 1H), 2.21-2.26 (m, 1H), 2.31-2.41 (m, 2H), 4.10- 4.12 (m, 2H).
. Anal Calcd for C ₁₂ H ₁₉ NO _6:. C, 52.74; H, 7.01; N, 5.13; O, 35.13 Found: C, 52.96; H, 6.99; N, 5.39.

6) Under a nitrogen stream, 1- (tert- butoxycarbonyl) piperidine-3,5-dicarboxylic acid (5.00g, 18.3mmol) was suspended in tetrahydrofuran (10.0mL), trifluoroacetic acid anhydride at a temperature 20 ~ 30 ℃ It was dropping things (3.80mL, 27.5mmol). After the completion of the dropping, it was stirred for 1 hour at a temperature of 20 ~ 30 ℃. It was added dropwise heptane (20.0mL) at a temperature 20 ~ 30 ℃ the reaction solution, and stirred for 3 hours then cooled to a temperature 0 ~ 10 ℃. The precipitated crystals were collected by filtration, and washed with heptane (3.00mL). Dried under reduced pressure at 40 ℃ 2,4- dioxo-3-oxa-7-azabicyclo [3,3,1] white crystalline powder of nonane-7-carboxylic acid tert- butyl was obtained (4.03g, yield 86.1%).
¹ H-NMR (300 MHz, CDCl ₃₎ ^δ 1.43 (s, 9H), 1.93-1.99 (m, 1H), 2.40-2.46 (m, 1H), 3.06-3.11 (m, 4H), 4.50-4.54 ( m, 2H).
. Anal Calcd for C ₁₂ H ₁₇ NO _5:. C, 56.46; H, 6.71; N, 5.49; O, 31.34 Found: C, 56.51; H, 6.63; N, 5.69.

7) Under a nitrogen stream, quinidine (69.9g, 0.215mol) and was charged with tetrahydrofuran (200mL), and cooled to a temperature -5 ~ 5 ℃. At the same temperature 2,4-dioxo-3-oxa-7-azabicyclo [3,3,1] nonane-7-carboxylic acid tert- butyl (50.0g, 0.196mol) was added and washed with tetrahydrofuran (50.0mL) crowded. Temperature -5 ~ 5 methanol at ℃ (9.41g, 0.29 4mol) was added dropwise, and the mixture was stirred for 2 hours at a temperature -5 ~ 5 ℃. Ethyl acetate (350mL) to the reaction mixture, was by adding minute solution 20w / v% citric acid aqueous solution (250mL). The aqueous layer it was re-extracted with ethyl acetate (125mL × 2). The organic layers were combined 20w / v% aqueous solution of citric acid (250mL), I was washed successively with water (250mL × 2). The organic layer it was concentrated under reduced pressure. To the residue ethanol (100mL) was added ethyl acetate (450mL) was heated to a temperature 60 ~ 70 ℃, (R) – was added phenethylamine (23.7g, 0.196mol). Temperature 50-60 for one hour at ℃, 1 hour at a temperature of 20 ~ 30 ℃, it was stirred for 1 hour at a temperature of -5 ~ 5 ℃. The precipitated crystals were collected by filtration, ethanol – ethyl acetate: and washed with (2 9,100mL). And dried under reduced pressure at 50 ℃ (3S, 5R) -1- (tert- butoxycarbonyl) -5- (methoxycarbonyl) piperidin-3 to give a white crystalline powder of the carboxylic acid (1R) -1- phenylethylamine salt It was (55.7g, 69.6% yield).
¹ H-NMR (300 MHz, DMSO-d ₆₎ ^δ 1.42 (s, 9H), 1.43-1.51 (m, 3H), 2.06-2.14 (m, 1H), 2.21-2.26 (m, 1H), 2.39- 2.44 (m, 1H), 2.52-2.53 (m, 1H), 2.57 (br s, 2H), 3.64 (s, 3H), 4.12 (br s, 2H), 4.19-4.26 (m, 1H), 7.30- 7.40 (m, 3H), 7.45-7.48 (m, 2H).
. Anal Calcd for C ₂₁ H ₃₂ N ₂ O _6:. C, 61.75; H, 7.90; N, 6.86; O, 23.50 Found: C, 61.54; H, 7.77; N, 6.86.

8) (3S, 5R) -1- (tert- butoxycarbonyl) -5- (methoxycarbonyl) piperidine-3-carboxylic acid (1R) -1- phenylethylamine salt (20.0g, 49.0mmol), methanol (20mL) and it was charged with water (80mL). Temperature 20-30 citric acid at ℃ (11.3g, 58.8mmol) was added dropwise a solution prepared by dissolving in water (20.0mL), and the mixture was stirred 1.5 hours at the same temperature. The precipitated crystals were collected by filtration and washed with water (60mL). And dried under reduced pressure at 50 ℃ (3S, 5R) -1- (tert- butoxycarbonyl) -5- give a white crystalline powder (methoxycarbonyl) piperidine-3-carboxylic acid (13.5g, 96.1% yield ).
¹ H-NMR (300 MHz, CDCl ₃₎ ^δ 1.40 (s, 9H), 1.46-1.59 (m, 1H), 2.22-2.27 (m, 1H), 2.37-2.45 (m, 2H), 2.63-2.73 ( m, 2H), 3.63 (s, 3H), 4.14 (br s, 2H), 12.51 (br s, 1H).
. Anal Calcd for C ₁₃ H ₂₁ NO _6:. C, 54.35; H, 7.37; N, 4.88; O, 33.41 Found: C, 54.14; H, 7.28; N, 4.85.

9) Under a nitrogen stream, (3S, 5R) -1- (tert- butoxycarbonyl) -5- (methoxycarbonyl) piperidine-3-carboxylic acid (30.0g, 104mmol), triethylamine (31.7g, 313mmol) and toluene ( It was charged with 180mL). Diphenylphosphorylazide at a temperature of 15 ~ 35 ℃ (28.7g, 313mmol) I was dropped a toluene (30.0mL) solution. After stirring at a temperature 30 ± 5 ℃ 30 minutes, and the mixture was stirred and heated to a temperature 65 ~ 75 ℃ 30 minutes. Temperature 60 ~ 70 ℃ in the benzyl alcohol (12.4g, 115mmol) it was dropped. To a temperature 80 ~ 90 ℃ was stirred and heated for 3 hours. The reaction mixture was cooled to a temperature 20 ~ 30 ℃, sodium nitrite (7.20g, 104mmol) and after stirring was added a solution prepared by dissolving in water (150mL) 1 hour, the aqueous layer was separated. The organic layer 5w / v% aqueous sodium bicarbonate solution (150mL), 20w / v% aqueous citric acid solution (150mL), washed successively with 5w / v% aqueous sodium chloride solution (150mL), the organic layer was concentrated under reduced pressure. The residue methanol (60.0mL) was added and concentrated under reduced pressure to. The more we went once in the same manner.To the residue was added methanol and the content amount of the (90.0g). Temperature 15 ~ 35 ℃ 2N- aqueous sodium hydroxide (62.6mL, 125mmol) was added and stirred for 1 hour at a temperature 30 ± 5 ℃. Temperature 20 ~ 30 ℃ in methanol (120mL), was added to 20w / v% aqueous citric acid solution (300mL), it was a pH3.0 ~ 3.5. After stirring for 30 minutes at a temperature 50 ~ 60 ℃, cooled to a temperature 20 ~ 30 ℃ and stirred for 1 hour. It was stirred for 1 hour at the temperature 0 ~ 10 ℃. The precipitated crystals were collected by filtration, and washed with water (90.0mL). And dried under reduced pressure at 50 ℃ (3R, 5S) -5 – {[(benzyloxy) carbonyl] amino} -1- (tert- butoxycarbonyl) to yield a white crystalline powder piperidine-3-carboxylic acid (35.0 g, 88.6% yield).
¹ H-NMR (300 MHz, DMSO-d ₆₎ ^δ 1.41 (s, 9H), 2.11 (d, J = 12.4 Hz, 1H), 2.40-2.48 (m, 4H), 2.62 (br s, 1H), 4.08 (t, J = 14.4 Hz, 2H), 5.04 (s, 2H), 7.31-7.41 (m, 5H), 12.53 (br s, 1H).
. Anal Calcd for C ₁₉ H ₂₆ N ₂ O _6:. C, 60.30; H, 6.93; N, 7.40; O, 25.37 Found: C, 60.03; H, 6.99; N, 7.41.

10) Under a nitrogen stream, (3R, 5S) -5 – {[(benzyloxy) carbonyl] amino} -1- (tert- butoxycarbonyl) piperidine-3-carboxylic acid (30.0g, 79.3mmol), morpholine (7.60 g, 87.2mmol), 1- hydroxybenzotriazole monohydrate (2.43g, it was charged with 15.9mmol) and dimethylacetamide (90.0mL). Hydrochloride 1-ethyl at a temperature 20 ~ 30 ℃ -3- (3- dimethylaminopropyl) carbodiimide (16.7g, 87.1mmol) after addition and stirred for 1 hour at a temperature 45 ~ 55 ℃. Temperature 45 ~ 55 ℃ with tetrahydrofuran (90.0mL), sequentially dropwise addition of water (210mL), and stirred for 1 hour. After stirring for 1 hour and cooled to a temperature 20 ~ 30 ℃, were collected by filtration the precipitated crystals, tetrahydrofuran – water: washing with (1 3,120mL). And dried under reduced pressure at 50 ℃ tert- butyl piperidine -1- (3S, 5R) -3 – a white crystalline powder of {[(benzyloxy) carbonyl] amino} -5 (morpholin-4-yl-carbonyl) carboxylate It was obtained (32.7g, 92.3% yield).
¹ H-NMR (300 MHz, DMSO-d ₆₎ ^δ 1.41 (s, 9H), 1.49-1.57 (m, 1H), 1.87 (d, J = 12.3 Hz, 1H), 2.43 (br s, 1H), 2.63-2.71 (m, 1H), 2.79-2.83 (m, 1H), 3.37-3.54 (m, 9H), 3.89 (d, J = 11.5 Hz, 1H), 4.06 (br s, 1H), 5.03 (s , 2H), 7.30-7.38 (m, 5H).
. Anal Calcd for C ₂₃ H ₃₃ N ₃ O _6:. C, 61.73; H, 7.43; N, 9.39; O, 21.45 Found: C, 61.59; H, 7.50; N, 9.43.

11) tert- Butyl piperidin -1- (3S, 5R) -3 – {[(benzyloxy) carbonyl] amino} -5- (morpholin-4-ylcarbonyl) carboxylate (30.0g, 67.0mmol), isobutyraldehyde (7.25g, 101mmol), it was charged with 10% Pd-C (PE type) (1.50g) and methanol (240mL).Hydrogen pressure of 0.2 ~ 0.3MPa, it was stirred for 4 hours at a temperature of 20 ~ 30 ℃. The catalyst is filtered off and washed with methanol (60.0mL). The filtrate was concentrated under reduced pressure, ethyl acetate was added (60.0mL), and concentrated under reduced pressure again. The residue ethyl acetate was added, followed by the amount of contents (360mL). Temperature 45-55 succinate by heating to ℃ (7.90g, 67.0mmol) was added. After stirring for 1 hour at a temperature 45 ~ 55 ℃, cooled to a temperature 20 ~ 30 ℃, and stirred for 1 hour. The precipitated crystals were collected by filtration, and washed with ethyl acetate (90.0mL). And dried under reduced pressure at 50 ℃ tert- butyl (3S, 5R) -3 – [(2- methyl-propyl) amino] -5- (morpholin-4-yl-carbonyl) piperidine – 1-carboxylate white crystals of alert succinate got sex powder (30.2g, 92.5% yield).
¹ H-NMR (300 MHz, D ₂ O) ^δ 1.02 (s, 3H), 1.04 (s, 3H), 1.47 (s, 9H), 1.97-2.09 (m, 2H), 2.26-2.30 (m, 1H ), 2.55 (s, 4H), 2.99 (d, J = 7.0 Hz, 2H), 3.23 (br s, 1H), 3.39-3.45 (m, 2H), 3.53-3.80 (m, 10H), 3.82-3.93 (br s, 1H).
. Anal Calcd for C ₂₃ H ₄₁ N ₃ O _8:. C, 56.66; H, 8.48; N, 8.62; O, 26.25 Found: C, 56.48; H, 8.46; N, 8.39.

12) tert- Butyl (3S, 5R) -3 – [(2- methylpropyl) amino] -5- (morpholin-4-ylcarbonyl) piperidine – 1 – carboxylate succinate (30.3g, 62.2mmol), acetonitrile (60.0mL) and, it was charged with water (40.0mL). Then after stirring was added potassium carbonate (34.4g, 0.249mmol) 10 minutes, 1- (4-methoxybutyl) -2-trichloromethyl -1H- benzimidazole (20.0g, 62.2mmol) was added. After stirring for 2 hours at a temperature of 70 ~ 80 ℃, it was added dimethyl sulfoxide (15.0mL), and the mixture was stirred for 6 hours at a temperature 70 ~ 80 ℃. After cooling the reaction mixture to a temperature 20 ~ 30 ℃, water (120mL), it was separated and by adding toluene (240mL). The organic layer 10w / v% sodium chloride solution (100mL), 10w / v% aqueous solution of citric acid (100mL), it was washed sequentially with 10w / v% sodium chloride solution (100mL). The organic layer of activated carbon Shirasagi A a (1.0g) was added, and the mixture was stirred for 30 minutes at a temperature 20 ~ 30 ℃. Activated carbon was filtered, washed with toluene (40.0mL), and concentrated under reduced pressure of the filtrate to 110 mL. By heating to a temperature 35 ~ 45 ℃ was added dropwise heptane (280mL). At a temperature 35 ~ 45 ℃ tert- butyl (3S, 5R) -3 – [{[1- (4- methoxy-butyl) -1H- benzoimidazol-2-yl] carbonyl} (2-methylpropyl) amino] -5 – and the mixture was stirred for 1 hour at (morpholin-4-ylcarbonyl) piperidine-1-carboxylate was added to the same temperature the crystals (10mg) of the acrylate. Heptane (140mL) was stirred and added dropwise to 30 minutes at a temperature 35 ~ 45 ℃. It was cooled to a temperature 20 ~ 30 ℃ and stirred for 2 hours. The precipitated crystals were collected by filtration, toluene – heptane: was washed with (1 5,40.0mL). And dried under reduced pressure at 50 ℃ tert- butyl (3S, 5R) -3 – [{[1- (4- methoxy-butyl) -1H- benzoimidazol-2-yl] carbonyl} (2-methylpropyl) amino] – 5- (morpholin-4-ylcarbonyl) piperidine-1-carboxylate was obtained a pale yellowish crystalline powder of alert (27.7g, 74.2% yield).
¹ H-NMR (300 MHz, CDCl ₃₎ ^δ 0.68-0.80 (m, 3H), 0.96-1.08 (m, 3H), 1.31 (br s, 5H), 1.49 (s, 4H), 1.61-1.71 (m , 2H), 1.71 (br s, 0.5H), 1.92-2.05 (m, 3H), 2.05-2.24 (m, 2H), 2.45 (br s, 1H), 2.60 (br s, 1H), 2.72-2.96 (m, 2H), 3.26-3.35 (m, 3H), 3.35-3.47 (m, 2H), 3.47-3.73 (m, 10H), 4.02-4.26 (m, 2H), 4.26-4.34 (m, 1H) , 4.34-4.47 (m, 0.5H), 7.25-7.29 (m, 1H), 7.29-7.41 (m, 1H), 7.41-7.53 (m, 1H), 7.64 (br s, 0.5H), 7.79 (d , J = 8.2 Hz, 0.5H).
. Anal Calcd for C ₃₂ H ₄₉ N ₅ O _6:. C, 64.08; H, 8.23; N, 11.68; O, 16.01 Found: C, 63.82; H, 8.12; N, 11.64.

PATENT

WO 2015156346

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=AEE60471E3EF3D2BBE2D20033D4D0CD7.wapp2nC?docId=WO2015156346&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

TAKEDA PHARMACEUTICAL COMPANY LIMITED [JP/JP]; 1-1, Doshomachi 4-chome, Chuo-ku, Osaka-shi, Osaka 5410045 (JP)

Provided is a method for producing a synthetic intermediate of a heterocyclic compound having a renin inhibitory activity and effective as a prophylactic or therapeutic drug against diabetic renal disease, hypertension, and the like. A method for producing a compound represented by formula (III-1a), (III-1b), (III-1c), and/or (III-1d) [where the symbols in the formulas are as defined in the description], or a salt thereof, said method characterized in that a compound represented by formula (Ia) or (Ib) [where the symbols in the formulas are as defined in the description] or a salt thereof is reacted with a compound represented by formula (II) [where the symbols in the formula are as defined in the description] or a salt thereof in the presence of an aluminum compound and a chiral amine compound.

in Patent Document 1, a method for producing a synthetic intermediate of the above heterocyclic compound, the following methods are disclosed.

Formula 2]

(Wherein each symbol is as described in Patent Document 2.)

Prior art documents

Patent literaturePatent Document 1: Patent No. 4,800,445 Patent

Patent Document 2: International Publication No. 2007/077005

Reference Example 1

3-oxabicyclo [3.3.1] nonane-2,4-dione
reaction vessel (1R, 3S) – was added to cyclohexane-1,3-dicarboxylic acid (10g) and THF (20mL), 5 It was cooled to ℃. It was added dropwise trifluoroacetic anhydride (8.19mL), and the mixture was stirred for about 1 hour. The reaction mixture was allowed to warm to room temperature, heptane (20mL) was added, up to 5 ℃ was cooled and stirred for about 30 minutes. The precipitate was filtered off, washed with heptane to give the title compound. Yield (6.7g)

Reference Example 2

(3S, 5R) – tert – butyl 3- (isobutyl-amino) -5- (morpholine-4-carbonyl) piperidine-1-carboxylic acid ester succinate
reactor in THF (240ml), (3S, 5R) -1- (tert – butoxycarbonyl) -5- (morpholine-4-carbonyl) piperidine-3-carboxylic acid (20.0g), triethylamine (12.2mL) and diphenylphosphoryl azide (15.1mL) They were charged and allowed to react for 1 hour at 60 ℃, cooled to 25 ℃. After cooling the THF (60ml) and sodium trimethyl silanolate (19.7g) to charged 0 ℃ separately reaction vessel, was added dropwise to this was allowed to react before the reaction solution over about 1 hour, 0 at 0 ℃. 5 hours it was allowed to react. 0 slowly added dropwise acetic acid (40mL) at ℃, After stirring for 10 minutes, was added ethanol (60ml) and isobutyraldehyde (5.3mL) at 25 ℃, and stirred for 10 minutes. Then added sodium borohydride (1.88g), and the mixture was stirred for 30 minutes, and further addition of sodium borohydride (1.88g) at 25 ℃, and the mixture was stirred for 30 minutes. After completion of the reaction, water (100mL) was added and stirred for 10 minutes at room temperature. The organic layer was concentrated, then added dropwise slowly toluene (140ml) and 5N aqueous sodium hydroxide solution (120ml), the layers were separated. After washing and addition of aqueous 1N sodium hydroxide (100ml) the organic layer was washed 1N aqueous sodium hydroxide (100ml) was added again organic layer. The aqueous layers were combined and extracted by addition of toluene (100ml). The organic layers were combined, washed with 10w / v% aqueous sodium chloride solution (100ml), and the organic layer was concentrated. It was added ethanol (100ml), after it was concentrated under reduced pressure until about 60ml, warmed to 60 ℃ by the addition of ethyl acetate (40ml). Was added succinic acid (6.9g), After stirring for 30 minutes, it was added dropwise ethyl acetate (200ml) at 60 ℃, and stirred for 30 minutes. After stirring for 1 hour at room temperature, and the mixture was stirred for 1 hour at 0 ℃. The crystals were collected by filtration and washed with a mixture of ethyl acetate / n-heptane (6/1) (60mL). The obtained crystals at an external temperature of 50 ℃ to constant weight and then dried under reduced pressure to give the title compound as almost white crystals. Yield (22.8g)

Example 1

(3S, 5R) -1- (tert – butoxycarbonyl) -5- (morpholin-4-ylcarbonyl) piperidine-3-carboxylic acid
the reaction vessel in chlorobenzene (7.5mL) and quinine (0.70g ) is added and stirred, it was added dropwise DIBAL1.0M hexane solution (2.16mL). The reaction mixture was cooled to -40 ℃, tert – butyl 2,4-dioxo-3-oxa-7-azabicyclo [3.3.1] was added nonane-7-carboxylic acid ester (0.50g), about 1 hour stirring. Was added chlorobenzene to another reaction vessel (2.5mL) and morpholine (0.17mL), the resulting solution was cooled to -40 ℃ was added dropwise to the previous reaction solution. After completion of the reaction, the mixture was separated with ethyl acetate and 10w / w% aqueous citric acid solution, and the resulting aqueous layer was re-extracted with ethyl acetate. The organic layers were combined, washed with 10w / w% saline, and concentrated to give the title compound. ¹ H NMR (500 MHz, DMSO-D ₆ ) delta ppm 1.41 (s, 9 H), 1.47 – 1.72 (M, 1 H), 1.89 – 2.10 (M, 1 H), 2.36 – 2.49 (M, 1 H ), 2.55 – 2.83 (m, 3 H), 3.40 – 3.50 (m, 2 H), 3.51 -.. 3.57 (m, 4 H), 3.59 (br s, 2 H), 3.83 – 4.04 (m, 1 H), 4.05 – 4.29 (m, 1 H), 12.52 (s, 1 H) optical purity of 94.3% EE <HPLC analytical conditions> column: CHIRALPAK IC (Co., Ltd. Daicel) column temperature: constant around 15 ℃ Temperature Mobile phase: A solution) 0.02 mol / L KH ₂ PO ₄ buffer solution (pH3.0): acetonitrile = 70: 30　　　　B solution) 0.02 mol / L KH ₂ PO ₄ buffer solution (pH3.0): acetonitrile = 50 : 50 gradient program

Example 30 (1R, 3S) -3- (morpholin-4-ylcarbonyl) cyclopentanecarboxylic acid

(anhydride: 3-oxabicyclo [3.2.1] octane-2,4-dione; Amine: Morpholine ) ¹ H NMR (500 MHz, DMSO-D ₆ ) delta ppm 1.72 – 1.91 (M, 5 H), 2.04 (dt, J = 12.69, 7.84 Hz, 1 H), 2.65 – 2.74 (M, 1 H), 2.99 – 3.07 (m, 1 H), 3.42 – 3.51 (m, 4 H), 3.51 – 3.58 (m, 4 H), 11.96 – 12.17 (m, 1 H) optical purity of 52.3% EE <HPLC analysis conditions > column: CHIRALPAK IF (Co., Ltd. Daicel) column temperature: 15 ℃ constant temperature in the vicinity ofmobile phase: A solution) 0.02 mol / LKH ₂ PO ₄ buffer solution (pH3.0): acetonitrile = 70: 30 　　　　B solution) 0.02 mol / LKH ₂ PO ₄ buffer solution (pH3.0): acetonitrile = 50: 50 gradient Program

WO2010150840A1	24 Jun 2010	29 Dec 2010	Dainippon Sumitomo Pharma Co., Ltd.	N-substituted-cyclic amino derivative
WO2011158880A1	15 Jun 2011	22 Dec 2011	Takeda Pharmaceutical Company Limited	Crystal of amide compound
WO2012062687A1 *	7 Nov 2011	18 May 2012	F. Hoffmann-La Roche Ag	Triazole derivatives and their use for neurological disorders
WO2013122260A1	14 Feb 2013	22 Aug 2013	Takeda Pharmaceutical Company Limited	Tablet
CN103221402B *	7 Nov 2011	17 Jun 2015	霍夫曼-拉罗奇有限公司	三唑衍生物及其用于神经障碍的用途
US8329691	14 Oct 2008	11 Dec 2012	Takeda Pharmaceutical Company Limited	Amide compounds and use of the same
US8389511	19 Dec 2008	5 Mar 2013	Dainippon Sumitomo Pharma Co., Ltd.	Bicyclic heterocyclic derivative
US8658639	24 Jun 2010	25 Feb 2014	Dainippon Sumitomo Pharma Co., Ltd	N-substituted-cyclic amino derivative
US8742097	2 Nov 2011	3 Jun 2014	Hoffmann-La Roche Inc.	Triazole compounds I
US9018374	15 Jun 2011	28 Apr 2015	Takeda Pharmaceutical Company Limited	Crystal of amide compound
US9090601	28 Jan 2010	28 Jul 2015	Millennium Pharmaceuticals, Inc.	Thiazole derivatives

///////////TAK 272, Hypertension

Pramipexole

October 20, 2015 4:28 am / Leave a comment

Pramipexole, (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole, represented by the following formula I (the compound of formula I), is a dopamine D2/D3 agonist used for treatment of Schizophrenia, and particularly for the treatment of Parkinson’s disease.

Pramipexole is marketed in the form of dihydrochloride monohydrate salt under the brand name Mirapex.

Pramipexole (Mirapex, Mirapexin, Sifrol) is a dopamine agonist of the non-ergoline class indicated for treating Parkinson’s disease(PD)^[1] and restless legs syndrome (RLS).^[2]

Formula I

Indian patent application no. 605/MUM/2008 describes a process for the preparation of the dihydrochloride salt of the compound of formula I.

Synthesis

Pramipexole can be synthesized from a cyclohexanone derivative by the following route:

Pramipexole synthesis:^[14]

Research

Pramipexole has been evaluated for the treatment of cluster headache and to counteract problems with sexual dysfunction experienced by some users of selective serotonin reuptake inhibitor (SSRI) antidepressants.^[15] Pramipexole has shown effects on pilot studies in a placebo-controlled proof of concept study in bipolar disorder.^[8]^[16]^[17] It is also being investigated for the treatment of clinical depression and fibromyalgia.^[18]^[19]^[20]

Paper

Org. Process Res. Dev., 2010, 14 (5), pp 1125–1129

DOI: 10.1021/op1000989

http://pubs.acs.org/doi/abs/10.1021/op1000989

Pramipexole is a dopamine D₂ subfamily receptor agonist that is used for the treatment of Parkinson’s disease. We report here on the successful application of the Fukuyama alkylation protocol to the development of a novel and scalable process for synthesis of pramipexole and its pharmaceutically acceptable salts. The synthesis consists of converting the crucial intermediate (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole to (6S)-N-(2-amino-4,5,6,7-tetrahydrobenzothiazole-6-yl)-2-nitrobenzenesulfonamide, which is in turn monoalkylated to (6S)-N-(2-amino-4,5,6,7-tetrahydrobenzothiazole-6-yl)-2-nitro-N-propylbenzenesulfonamide. Deprotection of the latter yields pramipexole base, which is finally converted to a crude pramipexole dihydrochloride monohydrate with a yield of over 50% over four steps. The process allows for the telescoping of the final three steps, has high conversion rates of intermediates, offers ease of purification, and preserves high optical purity throughout all of the stages.

pramipexole dihydrochloride monohydrate 13 (315 g) with a yield of 70% (calculated from 12) and an HPLC purity of 94.4%. ¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J = 7.5 Hz, 3H), 1.62−1.75 (m, J = 7.6 Hz, 2H), 1.87−2.00 (m, 1H), 2.24−2.28 (m, 1H), 2.55−2.67 (m, 2H), 2.71−2.79 (m, 1H), 2.86−2.89 (m, 2H), 2.99−3.06 (m, 1H), 3.47 (m, 1H), 9.50 (m, 2H). ¹³C NMR (300 MHz, DMSO-d₆) 11.1, 19.1, 20.9, 23.5, 24.8, 46.0, 52.3, 111.0, 132.9, 168.7. FT-IR (cm⁻¹): 3150−3450 (NH₂ stretching), 2700−3000 (C−H stretching), 1600−1650 (C═N stretching), 1550−1600 (heteroaromatic ring skeleton).

POSTER

A NEW, EFFICIENT AND ECONOMIC METHOD FOR PREPARATION OF PRAMIPEXOLE.

Roman Balicki , Agnieszka Ciesielska , Michał Odrowąż-Sypniewski

Pharmaceutical Research Institute (IF), Rydygiera 8, Warszawa 01-793, Poland

Abstract

Pramipexole is a novel nonergot dopamine agonist which has high selectivity for interacting with dopamine D₂ receptors. It is effective in early Parkinson,s disease as monotherapy and as adjunctive therapy with L-dopa in advanced stages of the disease.

Known, two-steps method for preparation of pramipexole (3) is based on acylation reaction of diamine 1 with propionic anhydride. The obtained amide 2 is subsequently reduced using borane to give final product 3 with 65% yield.

Now, we present novel, more economic and safe procedure for obtaining pramipexole. Our one-step method requires only alkylation of 1 using n-propyl tosylate. Dangerous reduction with borane is eliminated and the final compound is obtained with similar yield as in a previous method.

Patent

http://www.google.com/patents/US7741490

Pramipexole, of formula (A)

is a dopaminergic agonist, known from U.S. Pat. No. 4,843,086, used in the treatment of Parkinson’s disease in the form of dihydrochloride monohydrate.

US 2002/0103240 discloses inter alia a method for the resolution or the enrichment of (R,S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole in the single (R) or (S) enantiomers, in particular in the (S) enantiomer. The same application illustrates in detail the synthetic routes known for the preparation of pramipexole, in particular those described in U.S. Pat. No. 4,886,812, EP 186087, EP 207696 and J. Med. Chem. 30. 494 (1987). From what reported it is evident that the synthetic pathways up to now available make use of synthetic steps that do not fulfill the requirements for the production of pramipexole on the industrial scale. Therefore there is the need for an improved process, which is simpler, easier to carry out and meets the requirements for the industrial production of pramipexole.

Example 13 Intermediate (VIII) Ra=H; Pramipexole Free Base

A 2 liter reactor under nitrogen is loaded with 53.3 g of, 33.0 g of (S) N-(6-propionylamino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine, 95% sodium borohydride and 260 ml of tetrahydrofuran (THF). A solution of 98.7 g of iodine in 160 ml of THF is dropped therein in about 3 hours, keeping the temperature at approx. 20-25° C. The reaction mixture is kept under stirring for further 2 hours at about 20-25° C. The reaction mixture is poured into a solution of 60.0 g of 37% HCl in 260 ml of water. The mixture is heated to 50-55° C. and left under stirring for an hour. The complete cleavage of the boran-complexes is checked by HPLC. The mixture is added with 250 g of 50% aqueous NaOH, keeping the temperature at about 20-25° C. After that, 315 ml of toluene are added and the mixture is heated to about 30-35° C. Stirring is interrupted and the two phases are separated. The organic phase are washed, concentrated to a residue and dissolved in 420 ml of ethyl acetate.

The solution is concentrated under vacuum at a temperature below 50° C. to about 150 ml volume. The resulting suspension is refluxed, then cooled to about 10-15° C., stirred for further 1-2 hours, then filtered with suction and the precipitate is washed twice with 30 ml of ethyl acetate. The product is dried under vacuum at 40° C. 32 g of (S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole are obtained.

PATENT

https://www.google.sc/patents/WO2008097203A1?cl=en

Example 1

Synthesis of N-(2-amino-4,5, 6, 7-tetrahydrobenzo[d]thiazole-6-yl)-2- n itrobenzenesulfonam ide

o-Nitrobenzenesulfonyl chloride (8.865 g, 40 mmol) was dissolved in 100 ml of THF and during stirring cooled to -10⁰C (ice + salt). Then, first 3 equiv. of triethylamine (Et₃N) (120 mmol, 16.8 ml) and then also 1.1 equiv. of 4,5,6,7-tetrahydrobenzo[J]thiazol-2,6-diamine (7.605 g, 45 mmol) were added. The formed suspension was, during stirring, gradually heated to room temperature and was left standing until the reaction was completed. In the course of the reaction, in addition to a soluble product, also in THF non-soluble Et₃NH⁺Cl^“ was formed, which was, at the end of the reaction, filtered off by suction and the reaction mixture was evaporated to dryness on a rotatory evaporator. The residue was poured over with H₂O (300 ml), whereby on the bottom of a round-bottom flask an orange viscous liquid was obtained. After rubbing with the glass stick a yellow precipitate (N-(2- amino-4,5,6,7-tetrahydrobenzo[^thiazole-6-yl)-2-nitrobenzenesulfonamide) was formed. The precipitate was filtered off and washed with 100 ml of cold ethylether and dried. The yield of the reaction was 95%.

Example 2

Synthesis of N-(2-amino-4,5,6, 7-tetrahydrobenzo[d]thiazole-6-yl)-2-nitro-N- propylbenzenesulfonamide

Process A:

N-(2-amino-4,5,6,7-tetrahydrobenzo[rf]thiazole-6-yl)-2-nitrobenzenesulfonamide (1.770 g, 5 mmol) and K₂CO₃ (2.856 g, 20 mmol) were suspended in acetonitrile (40 ml) and was, during stirring, heated to 60⁰C. Then propylbromide (1.65 ml, 18 mmol) was added and the reaction was left to run over night (the course of the reaction was followed by the use of a suitable method).

After the reaction was completed, the present precipitate was filtered off by suction. The reaction mixture was evaporated to dryness and the residue was dissolved in dichloromethane (150 ml). Organic phase was washed with IM NaOH (3 x 50 ml), saturated NaCl solution (2 x 50 ml) and dried with Na₂SO₄. After evaporation of dichloromethane an orange oily product N-(2-amino-4, 5,6,7- tetrahydrobenzo[^thiazole-6-yl)-2-nitro-Ν-propylbenzenesulfonamide was obtained.

Process B:

N-(2-amino-4,5,6,7-tetrahydrobenzo[rf]thiazole-6-yl)-2-nitrobenzenesulfonamide (1.770 g, 5 mmol), Cs₂CO₃ (3.909 g, 12 mmol) and KI (0.415 g, 2.5 mmol) was suspended in acetonitrile (40 ml) and heated to 60⁰C. Then propyl bromide (0.9 ml, 10 mmol) was added and the course of the reaction was followed by the use of a suitable method.

The process of the isolation was the same as in the process A.

Example 3

Synthesis of lf-propyl-4,5,6, 7-tetrahydrobenzo[d]thiazole-2,6-diamine

Process A:

K₂CO₃ (2.073 g, 15 mmol) was suspended in 20 ml of DMF (stored above molecular sieves), thioglycolic acid (SHCH₂COOH, 0.6 ml, 7.5 mmol) was added and stirred for 30 minutes. Then N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole-6-yl)-2-nitro-N- propylbenzenesulfonamide ( 0,99 g, 2,5 mmol), dissolved in 20 ml of DMF was added and the reaction was left to run over night. After the reaction was completed, DMF was evaporated, the residue was poured over with H₂O (100 ml) and IM NaOH (200 ml). The aqueous phase was then washed with dichloromethane (3 x 80 ml) and the combined organic fractions were dried with z Na₂SO₄. After the evaporation of the solvent an oily residue of orange-red colour (presence of DMF is possible) was obtained.

Process B:

LiOH (0.5 g, 20 mmol) was suspended in 20 ml of DMF (stored above molecular sieves), thioglycolic acid (SHCH₂COOH, 0.6 ml, 7.5 mmol) was added and stirred for 30 minutes. Then N-(2-amino-4,5,6,7-tetrahidrobenzo[cT|thiazole-6-yl)-2-nitro-N- propylbenzenesulfonamide (0.99 g, 2.5 mmol), dissolved in 20 ml of DMF was added and the reaction was left to run over night (the solution was coloured in orange-red).

After the reaction was completed, DMF was evaporated off, the residue was poured over with H₂O (100 ml) and IM NaOH (200 ml). The aqueous phase was then washed with dichloromethane (3 x 80 ml) and the combined organic fractions were dried with Na₂SO₄. After the evaporation of the solvent an oily residue of an orange- red colour was obtained.

Example 4

Pramipexole dihydrochloride monohydrate

(S)-(-)-2-Amino-6-(N-propylamino)-4,5,6,7-tetrahydrobenzothiazole (9.15 g, 43.28 mmol) in 500 ml round-bottom flask was dissolved in 30 ml of ethanol and water (0.78 g, 43.33 mmol) was added. A solution was cooled in an ice bath to 0⁰C and gaseous HCl^₎₁ was blown through whereby a white precipitate fell out. The round- bottomed flask was sealed and it was stirred over night at room temperature. The next day the precipitate was filtered off by suction and washed with a small amount of anhydrous ethanol. The precipitate was transferred into 100 ml round-bottom flask and anhydrous ethanol (50 ml) was added. The suspension was heated to 45°C and ethanol was evaporated on a rotatory evaporator. The process was repeated for another two times in order to drive out all of the excessive HCl_(g). The product was recrystallized from methanol: a salt was dissolved in methanol (70 ml) at 45⁰C, approximately 40 ml of methanol was evaporated and 20 ml of ethanol were added. It was cooled to room temperature and the resulting precipitate was filtered by suction, washed with some cooled anhydrous ethanol and dried in vacuum over P₂O₅ and NaOH. Yield: 11.631 g (89.01 %)

Example •§

Synthesis of N-(2-amino-4, 5, 6, 7-tetrahydrobenzo[d]thiazole-6-yl)-2- nitrobenzenesulfonamide

2-Nitrobenzenesulfonyl chloride (390 g, 1.76 mol) was dissolved in 4 1 of THF. The solution was cooled to approximately -10⁰C. Triethylamine (Et₃N) (740 g, 7.313 mol) and (6S)-4,5,6,7-tetrahydrobenzotiazole-2,6-diamine (327 g, 1.932 mol) were added. The suspension was heated during mixing to approximately 25°C and allowed to react at this temperature for approximately 1 hour.

Precipitated triethylammonium chloride (Et₃NH⁺Cl^“) was filtered off. The filtrate was concentrated to about 1/3 of the volume and water (2 1) was added. Again, approximately 1/2 of the solvent was distilled off. Water (2 1) was added, the mixture was cooled to about 25°C and mixed for about 1 hour. The precipitated product ((6S)- N-(2-amino-4,5,6,7-tetrahydrobenzotiazole-6-yl)-2-nitrobenzenesulfonamide) was separated by filtration or centrifuging.

Example g

Synthesis of (S)-(-)-2-Amino-6-(N-propylamino)-4,5,6, 7-tetrahidrobenzo[d]thiazole dihydrochloride hydrate

Potassium carbonate (1890 g, 13.675 mol), (6S)-N-(2-amino-4,5,6,7- tetrahydrobenzotiazole-6-yl)-2-nitrobenzenesulfonamide (590 g, 1.665 mol) and propyl bromide (1.09 1, 12 mol) were suspended in 4.1 1 of acetonitrile. The mixture was heated during stirring to approximately 60⁰C and mixed at this temperature for about 12 hours. The mixture was cooled to about 25°C. Potassium bromide was removed by filtration. The solution was concentrated to about 1/4 of the volume (not exceeding 60⁰C) and cooled to the room temperature. Methylene chloride (2 1) and 1 M NaOH water solution (2.43 1) were added and the mixture was mixed for about 30 minutes. Phases were separated and water phase was washed again with methylene chloride (1.46 1). Organic phases were collected and concentrated to about 1/10 of the volume. 0.83 1 of ethanol was added and the solution was concentrated to 1/10 of the volume. 3.35 1 of ethanol was added and ethanolic solution of (6S)-N-(2-amino- 4,5 ,6,7-tetrahydrobenzotiazole-6-yl)-2-nitro-Ν-propylbenzenesulfonamide was stored for further reaction.

Ethanol (2.35 1) and of LiOH (288 g, 12 mol) were put into the reactor and the suspension was cooled to 0 – 5°C. During about 30 minutes thioglycolic acid (SHCH₂COOH) (720 g, 7.816 mol) was added (the temperature must not exceed 25°C). The suspension was heated to about 25°C and mixed for about 45 minutes. Ethanolic solution of (6S)-N-(2-amino-4,5,6,7-tetrahydrobenzotiazole-6-yl)-2-nitro-N- propylbenzenesulfonamide was added. The air in the reactor was replaced by nitrogen. The mixture was heated to about 50⁰C and mixed at this temperature for about 4 hours. The mixture was cooled to about 25°C and filtrated. The filtrate was concentrated at 40⁰C to about 1/4 of the volume and cooled to the ambient temperature. Methylene chloride (4.23 1) and of IM aqueous NaOH solution solution (2.53 1) were added and the mixture was mixed for about 30 minutes. Phases were separated and water phase was washed again with 4.23 1 of methylene chloride. Organic phases containing pramipexole were collected and concentrated to about 1/4 of the volume. 5 1 of ethanol was added.

To the ethanolic solution of pramipexole water was added (27.6 ml, 1.53 mol) and solution was cooled to about -10⁰C. Gaseous HCl_(g) was introduced into the solution (200 g). The temperature of the solution and later the suspension must not exceed 25⁰C during addition of gaseous HCl_(g) . After the addition the suspension was heated to about 4O⁰C and concentrated to 2/3 of the volume. 2.65 1 of ethanol was added and the suspension was concentrated to 1/2 of the volume. Again 3.5 1 of ethanol was added and the suspension was concentrated to 1/2 of the volume. The solution was cooled to about -15°C and the product was separated by filtration. The product was dried at 25°C and finally at 40⁰C on air.

PATENT

http://www.google.com/patents/WO2008041240A1?cl=en

(S)-2-amino-6-propylaminio-4,5,6,7- tetrahydrobenzothiazole of formula (I), which is more commonly known as Pramipexole. Pramipexole is the commercial product marketed, in a form of a dihydrochloride salt in a peroral formulation, under several brand names e.g. Mirapexin[TM].

The compound of formula (I) has one symmetric carbon and they may exist either as a single enantiomer or in a mixed or racemic form. The pharmacological activity of compounds of formula (I) is generally connected only or mainly with one isomer thereof. Accordingly, the dopaminergic activity of the (S) isomer is twice as high as that of the (R) enantiomer.

A general process for the preparation of Pramipexole dihydrochloride has been described in US 4886812, EP 186087 and EP 207696. The process comprises the protection of amino function of 4-aminocyclohexanol to give the intermediate compound wherein, Rl is acyl or alkoxycarbonyl and R2 is hydrogen or Rl and R2 together form an amino protective group such as pthalimido group which on oxidation with an oxidising agent, followed by halogenation (preferably bromination) of protected ketone to give alpha halogenatedketone which on reaction with thiourea, followed by deprotection yielded the racemic 2,6-diaminotetrahydrobenzothiazole. Reductive alkylation of diaminotetrahydrobenzothiazole with n-propanal furnished the racemic pramipexole. Although the (S) isomer of pramipexole is mentioned therein, it is not clear at what stage the chiral resolution has been carried out. The general process steps are indicated in Scheme- Ia below.

H₂N

Racemate Resolution

n-Propyl Bromide –

Scheme-la

Another process for preparing optically pure pramipexole dihydrochloride was disclosed in J. Med. Chem. 1987, 30, 494-498, wherein, racemic 2,6-diamino-4,5,6,7- tetrahydrobenzo- thiazole was resolved, using L (+) tartaric acid to give optically pure (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole, which was converted to optically pure pramipexole by reacting (S)- 2,6-diamino-4,5,6,7-tetrahydro benzothiazole with propionic anhydride in THF and followed by reduction with borane THF complex . The reaction steps are shown in Scheme-lb as under:

(VIII) (II)

(CH3CH2CO)₂O

2HCl Scheme- Ib

However, the variants of the above general process prepare only racemate.

Thus, the synthesis of pramipexole by the above process yields R,S(±)-2~amino-6- propylamino-4,5,6,7-tetrahydrobenzothiazole. The above-mentioned acknowledge that the produced racemic compound may be resolved into single enantiomers by classical methods such as chromatography on a chiral phase or fractional crystallization of a salt with an optically active acid. However, even though the S(-)-enantiomer of pramipexole was disclosed and characterized therein, no information is provided how it was prepared; i.e. whether it was prepared by a resolution of racemic pramipexole of form some optically active precursor. Further, no information is provided on how to produce the S(-)- enantiomer of pramipexole.

WO 2006/003677 Al discloses the improved process the preparation of biologically active tetrahydrobenzothiazole derivative. The patent application discloses the process that has tried to solve the problems of prior art. However, much improvement over the prior art process has still been achieved. Moreover, the process discloses the formation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole via an isolated bromo intermediate, which on reaction with thiourea gets converted to tetrahydrobenzothiazole. The isolation of bromo intermediate can also be avoided. The halogenation of the protected cyclohexanone derivative is performed in presence of Lewis acid catalysts like AICI₃, ZnCl₂ or SnCl₂ etc. which will give aluminous waste though increase the yield during the halognation reaction. Moreover, the overall steps of the reaction will increase by performing isolation and work up for bromo intermediate.

US 6,727,637 B2 discloses the monobasic acid addition salts and the mixed salts of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole wherein the monobasic acid includes hydrochloric, hydrobromic, hydroiodic, nitric, benzoic, acetic, methane sulfonic, ethane sulfonic, trifluromethane sulfonic, benzene sulfonic, and p- toluene sulfonic acids. Further the patent US ‘637 B2 discloses the formation of mixed salts like of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole monohydrochloride monotartrate, of 2-amino-6-propylamino -4,5,6,7- tetrahydrobenzothiazole monohydrobromide monotartrate or of 2-amino-6- propylamino-4,5,6,7-tetrahydrobenzothiazole. monomethane sulfonate dibenzoyl-D- tartrate. The process as disclosed in US ‘637 B2 converts the racemic pramipexole into monohydrochloride salt of pramipexole which is then resolved with a optically active auxilliary acid to give mixed salt like of 2-amino-6-propylamino-4,5,6,7-tetrahydro- benzothiazole monohydrochloride monotartrate which is then converted to (S)- pramipexole free base and then to the desired pharmaceutically active ingredient (S)- pramipexole dihydrochloride.

US 6,770,761 B2 also discloses the process for preparation of 2-amino-6(alkyl)- amino-4,5,6,7-tetrahydrobenzothiazoles which includes the bromination of 1,4- cyclohexadione by bromine in an alcoholic solvent, followed by treatment of the reaction mixture with thiourea or N-acylthiourea and isolation of compound (A), that is further treated with an amine R₁-NH₂ or a chiral amine to get an imine intermediate and reducing it by reaction with said reducing agent or by hydrogenation, to yield the compound of formula (B)

(A) (B) Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x- ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid-state forms of a drug, including all polymorphic forms, and to determine the stability^ dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. For a general review of polymorphs and the pharmaceutical applications of polymorphs see G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. ScL, 58, 911 (1969); and J. K. Haleblian, J. Pharm. ScL, 64, 1269 (1975), all of which are incorporated herein by reference.

Example-1: Preparation of 2-amino-6-phthaIimido-4,5,6,7- tetrahydrobenzothiazole A) Preparation of chromic acid:

0.278 kg of chromium trioxide was added in 0.428 L of water at 15⁰C to 35°C. The reaction mixture was cooled to 5⁰C to 1O⁰C. 0.198 L of sulfuric acid Was added slowly within 25 to 30 minutes. 1.0 L of water was added to get the clear solution. B) Preparation of 2-amino-6-phthalimido-4,5,6,7-tetrahydrobenzothiazole via 4- (phthalimido)-cyclohexanone

1.0 Kg of 4-(phthalimido)-cyclohexanol was added in 20.0 L of acetone at 25⁰C to 35⁰C. The reaction mixture was cooled to 5⁰C to 10⁰C and treated with chromic acid solution. 0.2 L of isopropanol was added and stirred for 30 min. The reaction mixture was filtered and washed with acetone (1.0 L). The filtrate was treated with 0.4 kg sodium bicarbonate at 25⁰C to 35⁰C and stirred for 1 h. The reaction mass was again filtered, washed with acetone (1.0 L). Excess of acetone was distilled under vacuum. The residue was treated with 0.5 L ethanol followed by distillation of ethanol under vacuum. The reaction mass was cooled and treated with 3.36 L ethanol at 45⁰C to 25⁰C while gradual cooling. The reaction mixture was further cooled to 15⁰C to 2O⁰C and treated with 0.22 L of bromine and 0.43 Kg of thiourea under stirring for 1 h. The reaction mixture was heated to reflux at 75⁰C to 78⁰C for 6 hrs. The reaction mixture was cooled and stirred for 1 hr at 5⁰C to 1O⁰C. The product was isolated by centrifuge, washing with ethanol 0.66 L and drying under vacuum at 5O⁰C t0 55⁰C. (yield: 0.70 Kg).

ExampIe-2: Preparation of 2, 6-diamino-4,5,6,7-tetrahydrobenzothiazole

1.595 kg of 2-amino-6-phthalimido-4,5,6,7-tetrahydrobenzothiazole was treated with 40% aqueous solution of monomethylamine at 25⁰C to 35⁰C. The reaction mass was allowed to stir for 5-10 minutes and heated at 45°C to 5O⁰C for 1 – 1.5 hr. The reaction mixture was cooled gradually to 5⁰C to 1O⁰C and maintained for 30 minutes. The product thus obtained was filtered, washed with chilled water and dried at 5O⁰C to 55⁰C to obtained racemic 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole. (Yield: 0.522 kg)

Example-3: Preparation of 2, 6-diamino-4,5,6,7-tetrahydrobenzothiazoIe tartrate salt

1.0 Kg of 2, 6-diamino-4,5,6,7-tetrahydrobenzothiazole was added in 9.5 L of water and heated at 75⁰C to 85⁰C. 0.888 Kg of L-(+)-tartaric acid was added to the reaction mixture and maintained for 30 minutes. The reaction mixture was fine filtered at high temperature and washed with 0.5 L of water. The filtrate was gradually cooled to 25⁰C to 30⁰C and maintained for 16 hours. The product was centrifuge and washed with 1 L water. The wet cake was treated with 6.0 L water and heated at 😯⁰C to 9O⁰C with addition of excess water to ensure clear solution. The reaction mass was fine filtered at high temperature and washed with 0.5 L water. The filtrate thus obtained was gradually cooled to 5°C to 1O⁰C and maintained for 2 hrs. The product was centrifuge and washed with 1 L chilled water. The wet cake was treated with 6.0 L water and heated at 😯⁰C to 9O⁰C with addition of excess water to ensure clear solution. The reaction mass was gradually cooled to 95⁰C to 25°C and maintained for 2 hrs. The product was centrifuge, washed with 1 L chilled water, dried at 5O⁰C to 55⁰C and cooled to 25⁰C to 35⁰C. (Yield: 0.70 Kg). ExampIe-4: Preparation of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole

1.0 Kg of 2, 6-diamino-4,5,6,7-tetrahydrobenzothiazole tartrate salt was treated with 1.5 L of water and stirred for 15 minutes at 25°C to 35°C. 0.245 Kg of sodium hydroxide solution in 0.612 L of water was added to adjust the pH 11.0 to 12.0 within 35 to 40 minutes and stirred for 1 hr. The product was centrifuge, washed with 1.0 L water and dried at 50⁰C to 55⁰C. The product was cooled to 20°C-40°C to obtain (S)- 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole. (Yield: 0.37 Kg). Example-5: Preparation of Pramipexole crude

To the solution of 1.0 Kg of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole and 0.1225 Kg of potassium carbonate in 10.0 L isopropanol was added 0.540 L n- propyl bromide. The reaction mixture was stirred for 15 minutes and heated to reflux on a water bath up to 😯⁰C and was maintained for 5 hours. 0.3236 L of n-propyl bromide was further added in two portions at 😯⁰C to 82°C and maintained for 5 hours. The isopropanol was removed completely by distillation under vacuum at 55⁰C to 75⁰C. 7.5 L of process water was added into the reaction mass and stirred for 30 minutes. The reaction mixture was cooled to 25⁰C to 35⁰C. 40% sodium hydroxide solution (0.108 Kg in 0.27 L water) was added to adjust the constant pH 10.0 to 10.5 followed by treatment with 5.0 L methylene dichloride twice and separating the organic layer. The organic layer was treated with 5.0 L of process water and stirred for 30 minutes. The separated organic layer was subjected to distillation to remove methylene dichloride under vacuum. 5.0 L of isopropanol was added at 4O⁰C to 45⁰C and heated up to 6O⁰C to 65⁰C. Acidic isopropanol 0.440L was added to adjust the pH 7.0 to 7.5 and stirred for 1 hour. The reaction mass was cooled to 25⁰C to 35°C. The product was obtained by centrifuge, washing with 0.5 L of isopropanol and drying at 5O⁰C to 55⁰C followed by cooling. (Yield: 1.0 Kg)

ExampIe-6: Preparation of Pramipexole dihydrochloride monohydrate

1.0 Kg of crude Pramipexole was added in 5.0 L of ethanol and heated to reflux using water bath at 80⁰C. The reaction mixture was maintained for 1 hour and cooled to 25⁰C to 35°C and stirred for 1 hour. The product was centrifuge and washed with 0.5 L ethanol. The wet cake thus obtained was further treated with 5.0 L of ethanol and heated to reflux using water bath at 😯⁰C. The reaction mixture was maintained for 1 hour and cooled to 25⁰C to 35⁰C and stirred for 1 hour. The product was centrifuge and washed with 0.5 L ethanol. The wet cake was treated with 5.0 L isopropanol and heated to 6O⁰C to 65°C using water bath. Acidic isopropanol 0.35 L was added to adjust the pH 1.7 to 2.3 and maintained for 1 hour. The product was centrifuge and washed with 1 L of isopropanol and dried in hot air oven at 5O⁰C to 55⁰C to give Pramipexole dihydrochloride pure, which is converted to Pramipexole dihydrochloride monohydrate upon cooling the dried material under airflow. (Purity: 99.5% by HPLC and having known individual impurities less than 0.1% and total impurities less than 1.0%.) Example-7.: Preparation of Pramipexole dihydrochloride monohydrate

1.0 Kg of crude Pramipexole was added in 5.0 L of ethanol and heated to reflux using water bath at 😯⁰C. The reaction mixture was maintained for 1 hour and cooled to 25⁰C to 35⁰C and stirred for 1 hour. The product was centrifuge and washed with 0.5 L ethanol. The wet cake thus obtained was further treated with 5.0 L of ethanol and heated to reflux using water bath at 80⁰C. The reaction mixture was maintained for 1 hour and cooled to 25⁰C to 35⁰C and stirred for 1 hour. The product was centrifuge and washed with 0.5 L ethanol. The wet cake was treated with 5.0 L isopropanol and heated to 60⁰C to 65⁰C using water bath. Isopropanolic HCl (0.35 L) containing water was added to adjust the pH 1.7 to 2.3 and maintained for 1 hour. The product was centrifuge and washed with 1 L of isopropanol and dried at 4O⁰C to 5O⁰C to give Pramipexole dihydrochloride monohydrate

PATENT

New patent, WO 2015155704, An improved process for the preparation of pramipexole dihydrochloride monohydrate

WO 2015155704, An improved process for the preparation of pramipexole dihydrochloride monohydrate

PIRAMAL ENTERPRISES LIMITED [IN/IN]; Piramal Tower, Ganpatrao Kadam Marg Lower Parel Mumbai 400013 (IN)

Inventors:

PATIL, Pravin; (IN).
PANSARE, Prakash; (IN).
JAGTAP, Ashutosh; (IN).
KRISHNAMURTHY, Dhileepkumar; (IN)

Formula I

The compound of formula I is disclosed in US Patent no. 4,886,812 (US ‘812 Patent). The US’ 812 Patent also describes a process for the preparation of the compound of formula I and its dihydrochloride monohydrate salt involving the propylation reaction of the compound of formula II with n-propylbromide as a propylating agent in the presence of potassium carbonate by using methanol as a solvent to provide the reaction mixture. The resulting reaction mixture is then refluxed for 3 hours. After completion of the reaction, water is added to the reaction mixture. The reaction mixture is then extracted with ethyl acetate and concentrated to obtain the residue. The obtained residue is purified by silica gel chromatography and the corresponding fraction is concentrated under reduced pressure to obtain the compound of formula I which is then converted into its dihydrochloride monohydrate salt. Although, US ‘812 Patent describes the process for the preparation of the compound of formula I from the compound of formula II, it does not teach the process for converting the compound of formula I into its dihydrochloride monohydrate salt. Also, the process described in US ‘812 Patent involves propylation of the compound of formula II using 4 molar equivalents of n-propylbromide as the propylating agent. N-propylbromide is known to be carcinogenic compound and its average threshold limit value for 8 hours exposure is 10 parts per million. Therefore, on commercial scale, excess use of such a hazardous reagent is not desirable. Further, propylation of the compound of formula II using the process described in US ‘812 Patent generates one major impurity namely (6S)-2,6-benzothiazolediamine,4,5,6,7-tetrahydro-N²,N⁶-dipropyl. The US ‘812 Patent does not teach any purification method for removal of this impurity.

Indian Patent Application no. 694/MUM/2006 describes a process for the preparation of the dihydrochloride monohydrate salt of the compound of formula I involving treating the alcoholic solution of the compound of formula I with hydrochloric acid and precipitating the dihydrochloride monohydrate salt of the compound of formula I by addition of water. The process disclosed in this patent application does not involve any purification step for the purification of the compound of formula I or its dihydrochloride monohydrate salt and thus, the final active pharmaceutical ingredient (API), the dihydrochloride monohydrate salt of the compound of formula I prepared by this process does not have the desired pharmaceutically acceptable purity.

Indian patent application no. 605/MUM/2008 describes a process for the preparation of the dihydrochloride salt of the compound of formula I. The process for the preparation of the dihydrochloride salt of the compound of formula I involves the propylation reaction of the compound of formula II with n-propanal as a propylating agent by using a mixture of methanol and water as the solvent. To the resulting reaction mixture, glacial acetic acid and sodium borohydride are charged and the reaction mixture is stirred for 30-40 minutes at a temperature of 15 to 20°C. The reaction mixture is then cooled to -5 to 0°C and to the reaction mixture; second lot of n-propanal with methanol and sodium borohydride is added. The resulting reaction mixture is stirred for 30-40 minutes and quenched with brine solution. The reaction mixture is distilled under vacuum to obtain a residue. To the obtained residue, ethyl acetate and water are added. Two layers formed are separated and ethyl acetate layer is concentrated under vacuum to obtain the crude compound of formula I. The resulting crude compound of formula I is then recrystallised by using acetonitrile to yield the pure compound of formula I. To the pure compound of formula I; ethanolic hydrochloric acid solution is added. The reaction mixture is stirred for 1 hour to precipitate the solid. The precipitated solid is filtered and suspended in ethanol. The reaction mixture is then stirred at reflux temperature for 30 minutes and at room temperature for 1 hour to precipitate the dihydrochloride salt of the compound of formula I. The precipitated dihydrochloride salt of the compound of formula I is dissolved in a mixture of ethanol and water; and filtered through hyflo. The filtrate is then distilled under vacuum and recrystallised by using ethanol to obtain the pure dihydrochloride salt of the compound of formula I. The process disclosed in said patent involves the use of 3 molar equivalents of sodium borohydride and n-propanal which renders the process costlier and hence, this process is not viable for scale up.

The general process for producing the dihydrochloride monohydrate salt of the compound of formula I is depicted in the following Scheme I:

(S)-2-amino-6-propinamido-4, 5,6,7- tetrahydrobenzothiazole

sodium borohydride

o e compoun o ormu a

Scheme I

Scheme-II.

methanol-water purification

Scheme-II

Examples

Example 1:

Step A: Synthesis of compound of formula I:

To the reaction flask dichloromethane (1500 ml), methanol (1500 ml) and the compound of formula II (100 gm) were charged at a temperature of 25-30° C. The reaction mixture was cooled to a temperature of 3-8 °C and to the reaction mixture, sulphuric acid (8.69 gm); n-propanal (13.98 ml) and sodium borohydride (2.46 g) were charged. The reaction mixture was stirred for 20-30 minutes at a temperature of 3-8°C. To the reaction mixture, n-propanal (41.94g) followed by sodium borohydride (7.38g) were added in three different lots at a temperature of 3-8°C. After completion of the reaction, the reaction mixture was quenched with brine solution. The quenched reaction mixture was further concentrated up to 15-16 volumes at 50-55°C under vacuum. The reaction mixture was cooled to 15-20°C. To the reaction mixture potassium carbonate (150 g), ethyl acetate (900 ml) and methanol (100 ml) were charged. The two layers formed were separated. The organic layer was then concentrated up to 7 to 8 volumes. To the organic layer ethyl acetate (500 ml) and brine solution (240 g) were added. The two layers formed were separated. The organic layer was treated with activated charcoal and filtered through hyflo. The organic layer was then concentrated under vacuum to obtain residue. To the obtained residue diisopropyl ether (200 ml) was added and reaction mixture was stirred for 20-30 minutes at 45-50°C. The reaction mixture was then cooled at 25-30°C to precipitate solid. The precipitated solid was then filtered and washed with diisopropyl ether (200ml) to obtain the compound of formula I.

Step B: Synthesis of monohydrochlonde salt of the compound of formula I:

To the reaction flask, the compound of formula I (as obtained in the step A) and isopropyl alcohol (900 ml) were charged and the reaction mixture was stirred at a temperature of 25-35°C for 1 hour. The reaction mixture was then filtered through hyflo and washed with isopropyl alcohol (100 ml). To the filtrate cone, hydrochloric acid (42.20 ml) was added to obtain a solid. The obtained solid was then filtered and washed with isopropyl alcohol (200 ml) to yield the monohydrochloride salt of the compound of formula I.

Step C: Purification of the monohydrochloride salt of the compound of formula I:

To the reaction flask, the monohydrochloride salt of the compound of formula I (as obtained in the step B) and the mixture of methanol (300 ml) and water (5.01 ml) were charged and the reaction mixture was stirred at a temperature of 55-60°C for 2 hours. The resulting reaction mixture was then cooled to a temperature of 20-25°C to precipitate solid. The precipitated solid was then filtered and washed with isopropyl alcohol (200 ml) to obtain the pure monohydrochloride salt of the compound of formula I.

Step D: Synthesis of the dihydrochloride monohydrate salt of the compound of formula I:

To the reaction flask, the pure monohydrochloride salt of the compound of formula I (as obtained in the step C), methanol (600 ml) and cone, hydrochloric acid (33.67 ml) were charged and the reaction mass was stirred at a temperature of 3-8°C for 2 hours. To the reaction mass, activated charcoal (4g) was charged and the reaction mass was stirred for 30-45 minutes at temperature of 40-50°C. The activated charcoal was filtered through hyflo and filtrate was concentrated under vacuum to obtain residue. To the residue, isopropyl alcohol (700 ml) was charged and the reaction mass was maintained for 2-3 hours at 15-20°C to precipitate solid. The precipitated solid was then filtered and washed with isopropyl alcohol (100 ml). The solid was then dried under vacuum to yield dihydrochloride monohydrate salt of the compound of formula I. Yield 36%, purity 99.77%.

Details for HPLC analysis:

Column: Inertsil ODS-3, 125 X 4.0 mm, 5μιη

Part No: C/N 5020

Mobile phase

Mobile phase A: Buffer solution

Mobile phase B: Acetonitrile: Buffer (500:500 v/v)

Flow rate: 1.5 ml/min

Injection volume: 5 μΐ

Run time: 25 minutes

Detector: 264 nm.

Column temperature: 40°C

Diluent: Acetonitrile: Buffer (200:800 v/v)

Procedure:

For system suitability inject (5μί) of the system suitability solution. The resolution between Pramipexole (the compound of formula I) related compound and Pramipexole should not be less than 6.0. The tailing factor for Pramipexole should not be more than 2.0. Inject Standard solution in six replicates into the chromatograph. For the Pramipexole peak, the relative standard deviation should not be more than 5.0%.

Inject (5μί) of blank preparation and test solution into the chromatograph, measure the responses of all the peaks and calculate all known impurities and unknown impurities by the formula given below. In the sample chromatogram disregard any peak due to the blank. Retention time and relative retention times are given in the table below.

Calculation :- SPL (Area) Cone STD

% impurities = X X 100

STD (Area) Cone SPL

Where:

SPL (Area) – is area of peak due to impurities in sample preparation.

STD (Area) – is mean area of peak of Pramipexole in reference solution (a) for injections.

Cone SPL – concentration of Pramipexole in test solution in mg/mL

Cone STD – concentration of Pramipexole in test solution in mg/mL

References

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Newman-Tancredi A, Cussac D, Audinot V, et al. (November 2002). “Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor”. The Journal of Pharmacology and Experimental Therapeutics 303 (2): 805–14.doi:10.1124/jpet.102.039875. PMID 12388667.
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Chang, W; Weber M; Breier MR; Saint Marie RL; Hines SR; Swerdlow NR (February 2012). “Stereochemical and neuroanatomical selectivity of pramipexole effects on sensorimotor gating in rats”. Brain Res 1437: 69–76. doi:10.1016/j.brainres.2011.12.007. PMID 22227455.
Zarate CA, Payne JL, Singh J, et al. (July 2004). “Pramipexole for bipolar II depression: a placebo-controlled proof of concept study”. Biol. Psychiatry 56 (1): 54–60.doi:10.1016/j.biopsych.2004.03.013. PMID 15219473.
Corrigan MH, Denahan AQ, Wright CE, Ragual RJ, Evans DL (2000): Comparison of pramipexole, fluoxetine, and placebo in patients with major depression. Depress Anxiety 11:58 –65.
Jump up^ “MedlinePlus Drug Information: Pramipexole (Systemic)”. United States National Library of Medicine. Archived from the original on 2006-09-26. Retrieved 2006-09-27.
“FDA Prescribing Information: Mirapex (pramipexole dihydrochloride)” (PDF). Food and Drug Administration (United States). Retrieved 2008-12-31.
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External links

Mirapex.com – Manufacturer’s website

WO2006003677A1 *	Apr 25, 2005	Jan 12, 2006	Alembic Ltd	Improved process for the preparation of biologically active tetrahydrobenzthiazole derivative
EP0186087A1 *	Dec 16, 1985	Jul 2, 1986	Dr. Karl Thomae GmbH	Tetrahydro-benzothiazoles, their production and their use as intermediates or drugs
EP0207696A1 *	Jun 20, 1986	Jan 7, 1987	Eli Lilly And Company	Dialkylaminotetrahydrobenzothiazoles and oxazoles
EP1731514A1 *	Jun 2, 2005	Dec 13, 2006	Sandoz AG	Process for the preparation of Pramipexole

BOEHRINGER INGELHEIM: “Mirapex“[Online] 2006, pages 4-31, XP002444888 Retrieved from the Internet: URL:http://www.fda.gov/medwaTCH/safety/200 6/Nov_PIs/Mirapex_PI.pdf>
2	*	SCHNEIDER C S ET AL: “Dopamine autoreceptor agonists: resolution and pharmacological activity of 2,6-diaminotetrahydrobenzothiazole and aminothiazole analogue of apomorphine” JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 30, no. 3, March 1987 (1987-03), pages 494-498, XP002186199 ISSN: 0022-2623 cited in the application

Citing Patent	Filing date	Publication date	Applicant	Title
EP2137171A2 *	Mar 14, 2008	Dec 30, 2009	Knopp Neurosciences, Inc.	Synthesis of chirally purified substituted benzothiazole diamines

Pramipexole
Systematic (IUPAC) name


(S)-N ⁶-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine
Clinical data
Trade names	Mirapex, Mirapexin, Sifrol
AHFS/Drugs.com	monograph
MedlinePlus	a697029
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Legal status	℞ (Prescription only)
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	>90%
Protein binding	15%
Biological half-life	8–12 hours
Excretion	Urine (90%), Feces(2%)
Identifiers
CAS Registry Number	104632-26-0
ATC code	N04BC05
PubChem	CID: 119570
IUPHAR/BPS	953
DrugBank	DB00413
ChemSpider	106770
UNII	83619PEU5T
KEGG	D05575
ChEBI	CHEBI:8356
ChEMBL	CHEMBL301265
Chemical data
Formula	C₁₀H₁₇N₃S
Molecular mass	211.324 g/mol

///////////

Update………..

. Compound 1 1H NMR (CD3OD, 300 MHz): δ 3.36–3.41 (m, 1H), 2.70–2.92 (m, 2H), 2.53–2.67 (m, 2H), 2.32–2.40 (m, 1H), 1.78–1.92 (m, 1H), 1.48–1.61 (m, 2H), 0.93 (td, J = 1.1 Hz, 7.4 Hz, 3H).

13C NMR (CD3OD, 100 MHz): 184.04, 178.19, 170.88, 117.92, 61.24, 26.85, 20.83, 11.23.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00182

Synthesis of Impurities of Pramipexole Dihydrochloride

Tianwen Hu^†^‡∥, Feipu Yang^†^‡∥, Tao Jiang^†^‡, Weiming Chen^§, Jian Zhang^§, Jianfeng Li^†, Xiangrui Jiang^*^†, andJingshan Shen^†

^† CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zuchongzhi Road, Shanghai 201203, China

^‡ University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China

^§ Topharman Shanghai Co. Ltd., Shanghai 201209, China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00182

*Fax: +86-21-20231000-2407. Telephone: +86-21-2023100-2407. E-mail: jiangxiangrui@simm.ac.cn.

Abstract

Three impurities of pramipexole dihydrochloride were synthesized, and the possible generation mechanisms and the preparation methods of some impurities were reviewed. The desired configuration at C7 of 3 was built by a Mitsunobu reaction.

Abemaciclib (Bemaciclib)

October 19, 2015 5:00 am / 1 Comment on Abemaciclib (Bemaciclib)

Abemaciclib (Bemaciclib)

N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine

2-Pyrimidinamine, N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)

[5-(4-Ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine

C₂₇H₃₂F₂N₈
M.W.	506.59

Abemaciclib; 1231929-97-7; LY2835219; LY2835219 free base; UNII-60UAB198HK; LY 2835219 (free base);

Treatment of Advanced Cancer

Abemaciclib is an orally available cyclin-dependent kinase (CDK) inhibitor that targets the CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathway, with potential antineoplastic activity. Abemaciclib specifically inhibits CDK4 and 6, thereby inhibiting retinoblastoma (Rb) protein phosphorylation in early G1. Inhibition of Rb phosphorylation prevents CDK-mediated G1-S phase transition, thereby arresting the cell cycle in the G1 phase, suppressing DNA synthesis and inhibiting cancer cell growth. Overexpression of theserine/threonine kinases CDK4/6, as seen in certain types of cancer, causes cell cycle deregulation.

LY2835219 is a potent and selective inhibitor of CDK4 and CDK6 with IC50 of 2 nM and 10 nM, respectively.
IC50 Value: 2 nM(CDK4); 10 nM(CDK6)
Target: CDK4/6
in vitro: LY2835219 is an orally available cyclin-dependent kinase (CDK) inhibitor that targets the CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathway, with potential antineoplastic activity. LY2835219 specifically inhibits CDK4 and 6, thereby inhibiting retinoblastoma (Rb) protein phosphorylation in early G1. Inhibition of Rb phosphorylation prevents CDK-mediated G1-S phase transition, thereby arresting the cell cycle in the G1 phase, suppressing DNA synthesis and inhibiting cancer cell growth. Overexpression of the serine/threonine kinases CDK4/6, as seen in certain types of cancer, causes cell cycle deregulation.
in vivo: LY2835219 saturates BBB efflux with an unbound plasma IC50 of about 95 nM. The percent of dose in brain for LY2835219-MsOH is 0.5–3.9%. In both a subcutaneous and intracranial human glioblastoma model (U87MG), LY2835219-MsOH suppressed tumor growth in a dose-dependent manner both as a single agent, and in combination with temozolomide.

LY2835219 Methane sulfonate

cas 1231930-82-7, C28H36F2N8O3S, 602.7

SYNTHESIS

US20100160340

Example 1

[0112]
Bubble nitrogen into a mixture of 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazole (15.9 g), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (10.85 g), cesium carbonate (32.10 g), tris(dibenzylideneacetone) dipalladium (1.82 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.35 g) in 1,4-dioxane (197.06 mL). Heat the mixture in a pre-heated oil bath at 110° C. for 2 h. Cool to RT, dilute with DCM and filter over a celite pad. Remove the solvent under vacuum and purify by silica gel column chromatography, eluting with DCM/methanol (2%) and then DCM/methanol-NH₃2 M 2% to afford 22.11 g of the title compound. MS (ES⁺): m/z=507 (M+H)⁺.

Example 33

[0135]

a. 1-(6-Bromo-pyridin-3-ylmethyl)-4-ethyl-piperazine

Add neat 1-ethylpiperazine (5.6 kg) to a mixture of 6-bromo-pyridine-3-carbaldehyde (8.3 kg) and DCM (186 kg). Then, add sodium triacetoxyborohydride (10.9 kg) in portions and stir at 20-30° C. for 12 h. Quench the reaction into a mixture of DCM (36 kg) and aqueous solution of sodium hydroxide 2 N (46 kg). Separate the layers and extract twice the aqueous layer with DCM (24×2 kg). Combine the organic layers, wash with brine (50×2 kg) and remove the solvent under vacuum to afford 11.5 kg of the title compound. MS (ES⁺): m/z=285 (M+H)⁺.

b. 5-(4-Ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine

Add liquid ammonia (50.0 kg) to a degassed mixture of 1-(6-bromo-pyridin-3-ylmethyl)-4-ethyl-piperazine (14.2 kg), cuprous oxide (200 g), and MeOH (57 kg) at T≦40° C. Heat the mixture at 65-75° C. overnight. Cool to 20-30° C. and filter over a Celite® pad. Concentrate the filtrate and add DCM (113 kg) and adjust the pH to 12-14 with sodium hydroxide 2N (23 kg) separate the phases and wash the organic phase with DCM (58×2 kg) and combine the organic layers. Filter the mixture through Celite® and concentrate. Dissolve the residue in toluene (9.7 kg) and crystallize by the addition of MtBE (8.3 kg) to give 6.0 kg of the title compound. Obtain further purification through a toluene recrystallization. MS (ES⁺): m/z=221 (M+H)⁺.

c. N-Isopropyl-acetamide

Add potassium carbonate (28 kg) to a solution of 2-propanamine (12 kg) in ethyl acetate (108 kg) at <20° C. Cool the mixture to 5-0° C. and add acetyl chloride (16.7 kg) at about 2-3 kg/h. Stir until complete by gas chromatography. Quench the reaction with water (0.8 kg) and filter the reaction mixture and concentrate to afford 13.4 kg of the title compound. NMR (CDCl₃) 4.06 (m, 1H), 1.94 (s, 3H), 1.14 (d, 6H).

d. N-(4-Bromo-2,6-difluoro-phenyl)-N′-isopropyl-acetamidine

Add phosphoryl chloride (16.0 kg) to a mixture of 4-bromo-2,6-difluoro-phenylamine (14.5 kg), N-isopropyl acetamide (8.5 kg), TEA (10.6 kg) in toluene (115 kg) at <20° C. Stir at 10-20° C. until complete by HPLC. Remove the solvent under vacuum and add MtBE (64 kg). Adjust the pH of the mixture with 10% aq. sodium carbonate (250 kg). Filter the mixture and rinse the cake with MtBE (11×2 kg). Separate the phases and wash the aqueous layer with MtBE (22×2 kg). Combine the organic layers and concentrate, filter and wash with cyclohexane (0.6 kg) and dry to afford 17.2 kg of the title compound. MS (ES⁺): m/z=292 (M+H)⁺.

e. 6-Bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazole

Add potassium tert-butoxide (6.9 kg) in portions to a solution of N-(4-bromo-2,6-difluoro-phenyl)-N′-isopropyl-acetamidine (16.2 kg) in N-methyl formamide (76 kg) while maintaining the temperature at T<30° C. Heat the mixture at 70-75° C. until complete by HPLC. Cool to 20-30° C. and quench by adding into water (227 kg) then extract with MtBE (37×4 kg). Wash the combined organic phases with brine (49×2 kg) and concentrate to 25-30 L, add n-hexane (64 kg) and filter the slurry to give 11 kg of the title compound. MS (ES⁺): m/z=272 (M+H)⁺.
Obtain additional purification by dissolving the crude compound in DCM and filtering through a silica gel and Celite® pad followed by isolation from an MtBE/hexane mixture.

f. 4-Fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazole

Bubble nitrogen into a mixture of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazole (600 g), bis(pinacolato)diboron (843 g), tricyclohexylphosphine (106 g), potassium acetate (652 g), and DMSO (3.6 L). Add palladium acetate (49 g) and heat at 100° C. until complete by HPLC. Cool the reaction mixture and dilute with water (18 L), then filter to isolate the solid. Dissolve the crude material in 1,2-dimethoxyethane (450 mL) and filter through Celite®. Use the filtrate directly in part g.

g. 6-(2-Chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazole

Bubble nitrogen into a mixture of 2,4-dichloro-5-fluoro-pyrimidine (517 g), sodium carbonate (586 g) in water (1.7 L) and 1,2-dimethoxyethane (3.4 L). Add bis(triphenylphosphine)palladium(II) chloride (4.9 g) and heat the reaction at 80±3° C. and add drop wise a solution of 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazole in 1,2-dimethoxyethane from part f (5.1 L). Stir the mixture at 80±3° C. until complete by HPLC. Cool to RT and dilute with cold water (2.1 L, 5° C.). Stir for 1 hour then isolate the crude solid by filtration. Achieve further purification of the solid by trituration with IPA to give 472 g of the title compound. MS (ES⁺): m/z=323 (M+H)⁺.

h. [5-(4-Ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine Crystalline form III

[0144]
Bubble nitrogen into a mixture of 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazole (465 g), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (321 g), potassium carbonate (403 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17 g) in t-amyl alcohol (2.3 L). Heat tris(dibenzylideneacetone) dipalladium (13.2 g) and the mixture at 100±5° C. until complete by HPLC. Cool to RT, dilute with DCM (1.2 L) and filter over a Celite® pad. Extract the filtrate with 4M HCl (2.3 L×2). Combine the aqueous layers and stir with charcoal (32 g). Filter through Celite®, add DCM (1.7 L) and adjust pH with NaOH (28% aq., 1.5 L). Collect the organic layer and wash the aqueous layer with DCM (1.7 L). Combine organic layers, wash with brine (1 L), and dry over magnesium sulphate. Use a solid supported Si-Thiol treatment to remove residual palladium and the solvent is exchanged to acetone. Filter the slurry and dry to give 605 g of crude product as Form I. Mix 605 g of Form I and 4.3 L of dry acetone. Slurry the suspension at 56-57° C. (reflux) for at least 18 hours and then at ambient temperature for 4 hours. Isolate the solid by vacuum filtration, producing a light yellow cake. Dry the solid in a vacuum oven at 35° C. until a constant weight of 570 g is obtained. Confirm the material by XRPD to be Form III of the title compound. MS (ES+): m/z=507 (M+H)⁺.

Synthesis….http://www.joygooo.com/news_110.htm?pageNum=21

OTHERS


Patent	Submitted	Granted
PROTEIN KINASE INHIBITORS [US7855211]	2010-06-24	2010-12-21
Human papilloma virus as predictor of cancer prognosis [US8673972]	2013-08-02	2014-03-18
HUMAN PAPILLOMA VIRUS AS PREDICTOR OF CANCER PROGNOSIS [US2015030587]	2014-02-11	2015-01-29

/////////LY 2835219, Abemaciclib, Bemaciclib

CCN1CCN(CC1)Cc2ccc(nc2)Nc3ncc(c(n3)c4cc5c(c(c4)F)nc(n5C(C)C)C)F

Ribociclib, рибоциклиб , ريبوسيكليب , 瑞波西利

October 19, 2015 3:40 am / 1 Comment on Ribociclib, рибоциклиб , ريبوسيكليب , 瑞波西利

str0

Ribociclib

рибоциклиб , ريبوسيكليب , 瑞波西利

Ribociclib (LEE 011)
CAS: 1211441-98-3

Chemical Formula: C23H30N8O
Exact Mass: 434.25426

7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide

FDA UNII

TK8ERE8P56

Current developer: Novartis /Astex Pharmaceuticals.

Novartis Ag, Astex Therapeutics Ltd.

NMR.http://file.selleckchem.com/downloads/nmr/S744002-LEE011-2-HNMR-Selleck%20.pdf

http://file.selleckchem.com/downloads/hplc/S744002-LEE011-2-HPLC-Selleck.pdf

Ribociclib (LEE011) is an orally available, and highly specific CDK4/6 inhibitor. Phase 3.

CDK4 AND 6
(Cell-free assay)Product Ingredients

NOW FDA APPROVED 2017 since the blog post was written

Kisqali		FDA 3/13/2017	To treat postmenopausal women with a type of advanced breast cancer Drug Trials Snapshot

Image result for RIBOCICLIB

INGREDIENT	UNII	CAS	INCHI KEY
Ribociclib hydrochloride	63YF7YKW7E	1211443-80-9	JZRSIQPIKASMEV-UHFFFAOYSA-N
Ribociclib succinate	BG7HLX2919	1374639-75-4	NHANOMFABJQAAH-UHFFFAOYSA-N

ChemSpider 2D Image | Ribociclib succinate | C27H36N8O5

RIBOCICLIB SUCCINATE

STRUCTURE ….LINK

Ribociclib is in phase III clinical trials by Novatis for the treatment of postmenopausal women with advanced breast cancer.

Phase II clinical trials are also in development for the treatment of liposarcoma, ovarian cancer, fallopian tube cancer, peritoneum cancer, endometrial cancer, and gastrointestinal cancer.

Ribociclib, also known as LEE011, is an orally available cyclin-dependent kinase (CDK) inhibitor targeting cyclin D1/CDK4 and cyclin D3/CDK6 cell cycle pathway, with potential antineoplastic activity. CDK4/6 inhibitor LEE011 specifically inhibits CDK4 and 6, thereby inhibiting retinoblastoma (Rb) protein phosphorylation. Inhibition of Rb phosphorylation prevents CDK-mediated G1-S phase transition, thereby arresting the cell cycle in the G1 phase, suppressing DNA synthesis and inhibiting cancer cell growth. Overexpression of CDK4/6, as seen in certain types of cancer, causes cell cycle deregulation

Orally bioavailable CDK4/6-selective inhibitor that has been tested in Phase III clinical trials for treatment of advanced breast cancer.

CDK full name of cyclin-dependent kinases, there are many other subtypes CDK1-11, capable of binding to cell cycle proteins regulate the cell cycle. Pfizer Palbociclib been submitted for FDA review under phase II clinical data, Novartis Ribociclib (LEE011), Lilly Abemaciclib (LY2835219) the three CDK4 / 6 inhibitors have entered late stage development for the treatment of breast cancer

SYNTHESIS

WO2010020675
US20120115878

WO2010020675

http://www.google.co.in/patents/WO2010020675A1?cl=en

Example 74

7-Cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide

Following Buchwald Method B, then General Procedure A, 2-chloro-7-cyclopentyl-7H- pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (300 mg, 1.02 mmol) and 5-piperazin-1- yl-pyridin-2-ylamine (314 mg, 1.13 mmol) gave 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2- ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (142 mg, 36%). MS(ESI) m/z 435.3 (M+H)⁺

POSTER

str1

SYNTHESIS

str1

Image result for RIBOCICLIB joygooo

TAKEN FROM ….http://www.joygooo.com/news_71.htm?pageNum=21

PCT Int Appl, WO2012061156.

US Pat Appl Publ, US20120115878

PCT Int Appl, WO2011130232 5) Brain, Christopher Thomas et al; Preparation of pyrrolopyrimidine Derivatives for Use as CDK4 / 6 inhibitors;. PCT Int Appl, WO2011101409.

PCT Int Appl, WO2011101417. 7) Besong, Gilbert et al;.

PCT Int Appl, WO2010020675.

PCT Int Appl, WO2007140222.

Route 1

Reference：1. WO2012064805A1 / US20120115878A1.

2. WO2010020675A1 / US8415355B2.

3. WO2011130232A1 / US20130035336A1.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2015-10-17)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT02571829	Not yet recruiting	Liposarcoma\|Soft Tissue Sarcoma	Hadassah Medical Organization	December 2015	Phase 2
NCT02524119	Not yet recruiting	Hepatocellular Carcinoma	University of Texas Southwestern Medical Center\|Novartis …more	November 2015	Phase 2
NCT02494921	Recruiting	Prostate Cancer	Rahul Aggarwal\|University of California, San Francisco	September 2015	Phase 1\|Phase 2
NCT02420691	Recruiting	Gastrointestinal Cancer	M.D. Anderson Cancer Center\|Novartis	August 2015	Phase 2
NCT02431481	Not yet recruiting	Normal Renal Function\|Impaired Renal Function	Novartis Pharmaceuticals\|Novartis	August 2015	Phase 1

Protocols from literature

In vitro protocol::

Pharmacologic growth inhibition: Clin Cancer Res. 2013 Nov 15;19(22):6173-82.

Cell-cycle analysis: Clin Cancer Res. 2013 Nov 15;19(22):6173-82.

Senescence and apoptosis assays: Clin Cancer Res. 2013 Nov 15;19(22):6173-82.

In vivo protocol:

Xenograft therapeutic trials: Clin Cancer Res. 2013 Nov 15;19(22):6173-82

Immunohistochemistry of xenografted neuroblastomas.Clin Cancer Res. 2013 Nov 15;19(22):6173-82

Ribociclib (LEE011) is a Me-Too version of palbociclib. Their structures are compared side-by-side as the following:

Ribociclib (LEE011) is currently being developed by Novartis and Astex. According its Novartis’s website, LEE011 is a novel, orally available, selective inhibitor of CDK4/6 kinases, which induces complete dephosphorylation of Rb and G1 arrest in cancer cells. In preclinical in vitro and in vivo tumor models, LEE011 has been shown active in cancers harboring aberrations that increase CDK4/6 activity, including those directly linked to the kinases as well as activating alterations in the upstream regulators. First-in-human study of LEE011 in patients with solid tumors and lymphoma is currently ongoing. (source: http://www.novartisoncology.us/research/pipeline/lee011.jsp).

Treatment with LEE011 significantly reduced proliferation in 12 of 17 human neuroblastoma-derived cell lines by inducing cytostasis at nanomolar concentrations (mean IC50 = 307 ± 68 nmol/L in sensitive lines). LEE011 caused cell-cycle arrest and cellular senescence that was attributed to dose-dependent decreases in phosphorylated RB and FOXM1, respectively. In addition, responsiveness of neuroblastoma xenografts to LEE011 translated to the in vivo setting in that there was a direct correlation of in vitro IC50 values with degree of subcutaneous xenograft growth delay. Although our data indicate that neuroblastomas sensitive to LEE011 were more likely to contain genomic amplification of MYCN (P = 0.01), the identification of additional clinically accessible biomarkers is of high importance. LEE011 is active in a large subset of neuroblastoma cell line and xenograft models, and supports the clinical development of this CDK4/6 inhibitor as a therapy for patients with this disease. (Clin Cancer Res. 2013 Nov 15;19(22):6173-82)

References

1. Rader J, Russell MR, Hart LS, Nakazawa MS, Belcastro LT, Martinez D, Li Y, Carpenter EL, Attiyeh EF, Diskin SJ, Kim S, Parasuraman S, Caponigro G, Schnepp RW, Wood AC, Pawel B, Cole KA, Maris JM. Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res. 2013 Nov 15;19(22):6173-82. doi: 10.1158/1078-0432.CCR-13-1675. Epub 2013 Sep 17. PubMed PMID: 24045179; PubMed Central PMCID: PMC3844928.

2. Caponigro, Giordano; Stuart, Darrin; Kim, Sunkyu; Loo, Alice; Delach, Scott. Pharmaceutical combinations of a CDK4/6 inhibitor and a B-RAF inhibitor for treatment of proliferative diseases such as cancer. PCT Int. Appl. (2014), WO 2014018725 A1 20140130.

3. Kim, Sunkyu; Doshi, Shivang; Haas, Kristy; Kovats, Steven; Huang, Alan Xizhong; Chen, Yan. Combination therapy comprising a cyclin dependent kinase 4/6 (CDK4/6) inhibitor and a phosphatidylinositol 3-kinase (PI3K) inhibitor for use in the treatment of cancer. PCT Int. Appl. (2013), WO 2013006532 A1 20130110

4. Kim, Sunkyu; Doshi, Shivang; Haas, Kristy; Kovats, Steven. Combination of cyclin dependent kinase 4/6 (CDK4/6) inhibitor and fibroblast growth factor receptor (FGFR) kinase inhibitor for the treatment of cancer. PCT Int. Appl. (2013), WO 2013006368 A1 20130110

5. Calienni, John Vincent; Chen, Guang-Pei; Gong, Baoqing; Kapa, Prasad Koteswara; Saxena, Vishal. Salt(s) of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof. U.S. Pat. Appl. Publ. (2012), US 20120115878 A1 20120510.

6. Borland, Maria; Brain, Christopher Thomas; Doshi, Shivang; Kim, Sunkyu; Ma, Jianguo; Murtie, Josh; Zhang, Hong. Combination comprising a cyclin dependent kinase 4 or cyclin dependent kinase (cdk4/6) inhibitor and an Mtor inhibitor for treating cancer. PCT Int. Appl. (2011), WO 2011130232 A1 20111020

7. Besong, Gilbert; Brain, Christopher Thomas; Brooks, Clinton A.; Congreve, Miles Stuart; Dagostin, Claudio; He, Guo; Hou, Ying; Howard, Steven; Li, Yue; Lu, Yipin; et al. Preparation of pyrrolopyrimidine compounds as CDK inhibitors. PCT Int. Appl. (2010), WO 2010020675 A1 20100225.

CLIP

Cyclin-dependent kinase inhibitors (14 compounds) under clinical evaluation.

Molecules 19 14366 g002 1024

LEE-011 is one of the most selective inhibitors for CDK4 and CDK6 [59] and is being developed by Astex Pharmaceuticals™ and Novartis. In January 2014 this inhibitor entered phase III clinical trials for the treatment of breast cancer [60]. Due to encouraging results LEE-011 has now become the main competing drug-candidate with Pfizer’s PD0332991 (palbociclib), see Figure 3 [59].

Figure 3. Comparison of Astex/Novartis’ LEE-011 and Pfizer’s PD0332991 structures.

Upon comparison of the chemical structure of Novartis’ LEE-011 and Pfizer’s PD0332991, the similarity is evident. The major difference lies in the bicyclic core since LEE-011 possesses a pyrrolo-pyrimidine and PD0332991 a pyridopyrimidine. The “east” part of the structure is also modified. The structural similarities make their analogous CDKs inhibition profiles (high selectivity for CDK4 and CDK6) quite obvious Moreover, both derivatives are orally administered which is pretty advantageous compared with dinaciclib, which is also in phase III clinical trials but is administered intravenously.

http://www.mdpi.com/1420-3049/19/9/14366/htm

Kurt, S. LEE011 CDK Inhibitor Showing Early Promise in Drug-Resistant Cancers. Oncol. Times 2014, 36, 39–40. [Google Scholar]
Macmillan Publishers Limited. CDK inhibitors speed ahead. Nat. Rev. Drug Discov. 2014, 13, 323. [Google Scholar] [CrossRef]

Sources:
1)Rader, JulieAnn et al.;Dual CDK4/CDK6 Inhibition Induces Cell-Cycle Arrest and Senescence in Neuroblastoma;Clinical Cancer Research (2013), 19(22), 6173-6182

2)Tavares, Francis X. and Strum, Jay C.;Preparation of pyrazinopyrrolopyrimidine derivatives and analogs for use as CDK inhibitors;PCT Int. Appl., WO2012061156

3)Calienni, John Vincent et al.;Salt(s) of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof;U.S. Pat. Appl. Publ., US20120115878

4)Borland, Maria et al;Combination comprising a cyclin dependent kinase 4 or cyclin dependent kinase (cdk4/6) inhibitor and an Mtor inhibitor for treating cancer;PCT Int. Appl., WO2011130232

5)Brain, Christopher Thomas et al;Preparation of pyrrolopyrimidine derivatives for use as CDK4/6 inhibitors;PCT Int. Appl., WO2011101409

6)Brain, Christopher Thomas and Perez, Lawrence Blas; Preparation of deuterated pyrrolopyrimidine compounds as inhibitors of CDK4/6 for treating cancer; PCT Int. Appl., WO2011101417

7)Besong, Gilbert et al.;Preparation of pyrrolopyrimidine compounds as CDK inhibitors;PCT Int. Appl., WO2010020675

8)Brain, Christopher Thomas et al.;Preparation of pyrrolopyrimidine compounds as protein kinase inhibitors; PCT Int. Appl., WO2007140222

9)A Randomized Double-blind, Placebo-controlled Study of LEE011 in Combination With Letrozole for the Treatment of Postmenopausal Women With Hormone Receptor Positive, HER2 Negative, Advanced Breast Cancer Who Received no Prior Therapy for Advanced Disease;ClinicalTrials.gov Identifier: NCT01958021

/////////Ribociclib, novartis, LEE011, astex, phase 3, CDK inhibitors

CN(C)C(=O)c1cc2cnc(nc2n1C3CCCC3)Nc4ccc(cn4)N5CCNCC5

VARDENAFIL

October 18, 2015 12:48 pm / 1 Comment on VARDENAFIL

VARDENAFIL

224785-90-4^{CAS NO}

Vardenafil hydrochloride (CAS NO.224785-91-5)

Formula	C₂₃H₃₂N₆O₄S
Mol. mass	488.604 g/mol

4-[2-Ethoxy-5-(4-ethylpiperazin-1-yl)sulfonyl-phenyl]-9-methyl-7-propyl-3,5,6,8-tetrazabicyclo[4.3.0]nona-3,7,9-trien-2-one

Vivanza, Vardenafil (INN), Levitra (TN), STK642629, , LEVITRA

Vardenafil (INN) is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the trade names Levitra (Bayer AG, GSK, and SP) andStaxyn.

Vardenafil was co-marketed by Bayer Pharmaceuticals, GlaxoSmithKline, and Schering-Plough under the trade name Levitra. As of 2005, the co-promotion rights of GSK on Levitra have been returned to Bayer in many markets outside the U.S. In Italy, Bayer sells vardenafil as Levitra and GSK sells it as Vivanza. Thus, because of European Union trade rules, parallel imports might result in Vivanza sold next to Levitra in the EU.

Vardenafil (Levitra) is an oral therapy for the treatment of erectile dysfunction. It is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpus cavernosum. Nitric oxide activates the enzyme guanylate cyclase resulting in increased synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum. The cGMP in turn triggers smooth muscle relaxation, allowing increased blood flow into the penis, resulting in erection. The tissue concentration of cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs). The most abundant PDE in the human corpus cavernosum is the cGMPspecific phosphodiesterase type 5 (PDE5); therefore, the inhibition of PDE5 enhances erectile function by increasing the amount of cGMP.

An orally disintegrating form, marketed as Staxyn, has been gaining approvals in countries such as the United States^[1] and Canada.^[2]

Vardenafil’s indications and contra-indications are the same as with other PDE5 inhibitors; it is closely related in function to sildenafil citrate (Viagra) and tadalafil (Cialis). The difference between the vardenafil molecule and sildenafil citrate is a nitrogen atom’s position and the change of sildenafil’spiperazine ring methyl group to an ethyl group. Tadalafil is structurally different from both sildenafil and vardenafil. Vardenafil’s relatively short effective time is comparable to but somewhat longer than sildenafil’s.

Beyond its indications for erectile dysfunction, vardenafil may be effective in the treatment of premature ejaculation, where it may significantly increase the time from vaginal penetration to ejaculation.^[3]

The common, adverse drug reactions (side-effects) are the same as with other PDE5 inhibitors. The frequent vardenafil-specific side-effect is nausea; the infrequent side-effects are abdominal pain, back pain, photosensitivity, abnormal vision, eye pain, facial edema, hypotension, palpitation,tachycardia, arthralgia, myalgia, rash, itch, and priapism.

One possibly serious, but rare, side-effect with vardenafil is heart attack. Also, in rare cases, vardenafil use may cause priapism, a very painful emergency condition that can cause impotence if left untreated.^[4]

On 18 October 2007, the U.S. Food and Drug Administration (FDA) announced that a warning about possible deafness (sudden hearing loss) would be added to the drug labels of Vardenafil, and other PDE5 inhibitors.^[5]

Vardenafil, as with all PDE5 inhibitors, should not be used by men taking nitrate medications, because combining them with vardenafil might provoke potentially life-threatening hypotension (low blood pressure).

Further, Vardenafil causing lengthening of the QT interval. Therefore it should not be taken by men taking other medications that affect the QT interval (such as amiodarone).

Levitra 20mg Oral Tablet

It is available in 2.5 mg, 5 mg, 10 mg, and 20 mg doses in round orange tablets. The normal starting dose is 10 mg (roughly equivalent to 50 mg of sildenafil). Vardenafil should be taken 1 to 2 hours prior to sexual activity, with a maximum dose frequency of once per day. In some territories, such as the UK, only certain doses may be available.

Vardenafil is also available under the name Staxyn as a tablet which dissolves on the tongue rather than being swallowed in the form of a pill.

STAXYN is an oral therapy for the treatment of erectile dysfunction. This monohydrochloride salt of vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific PDE5.

Vardenafil HCl is designated chemically as piperazine, 1-[[3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-4-ethyl-, monohydrochloride and has the following structural formula:

STAXYN (vardenafil hydrochloride) Structural Formula Illustration

Vardenafil HCl is a nearly colorless, solid substance with a molecular weight of 579.1 g/mol and a solubility of 0.11 mg/mL in water.

LEVITRA

TRIHYDRATE, HCL SALT

US2002137930A

vardenafil hydrochloride is piperazine, 1-[[3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-4-ethyl-, mono -hydrochloride and can be structurally represented by Formula I.

The monohydrochloride salt of vardenafil is a selective inhibitor of cyclic guaosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). It is commercially available in products sold under the brand name LEVITRA formulated as 2.5 mg, 5 mg, 10 mg, 20 mg film-coated tablets.

U.S. Pat. No. 6,362,178 B1 discloses vardenafil, its related compounds and processes for their preparation. The patent describes a process in which vardenafil is obtained by recrystallization in ether in Example 19. Vardenafil produced as per Example 19 is hereinafter referred as “crystalline Form I” of vardenafil. The patent also describes processes for the preparation of its monohydrochloride and dihydrochloride salts, which are formed in a combination of ether and dichloromethane. The patent also describes a process for the preparation of vardenafil monohydrochloride trihydrate.

U.S. Patent Application Publication No. 2005/0203298 also describes a process for the preparation of vardenafil, and its monohydrochloride trihydrate.

Chemical synthesis of vardenafil has mostly been directed to the preparation of the trihydrate of monohydrochloride of vardenafil.

In WO 99/24433, sulphonamide-substituted imidazotriazinones are described as potent inhibitors of either one or more of the cyclic guanosine 3′,5′-monophosphate-metabolizing phosphodiesterases (cGMP PDEs). According to the nomenclature of Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11, 150-155, 1990), these cGMP PDEs are the phosphodiesterase isoenzymes PDE-I, PDE-II and PDE-V.

According to WO 99/24433, the sulphonamide-substituted imidazotriazinones described therein are prepared from corresponding 2-ethoxyphenyl-substituted imidazotriazinones by reaction with chlorosulphonic acid and subsequent reaction with an appropriate amine, as is illustrated by the following scheme (R¹to R⁶here have the meanings indicated in WO 99/24433):

In this process, highly reactive chlorosulphonic acid has to be used as a reagent. Moreover, the imidazotriazinonesulphonyl chlorides formed as intermediates are sensitive to hydrolysis, which, in particular in the conversion of this preparation process to the industrial scale, can lead to not inconsiderable yield variations.

It was therefore the object of the present invention to make available a process for the preparation of sulphonamide-substituted imidazotriazinones in which the disadvantages of the above process known from the prior art are avoided.

This object is achieved according to the present invention by a process as in claim 1. In particular, in the process according to the invention as in claim 1 the use of chlorosulphonic acid is avoided by introduction of the sulphonic acid via a reaction with sulphuric acid and subsequent reaction with thionyl chloride. Moreover, the reaction with thionyl chloride and the subsequent reaction with an amine is carried out in a one-pot process, so that the imidazotriazinonesulphonyl chloride intermediate, which is sensitive to hydrolysis, does not need to be isolated. By means of this, yield variations on account of partial hydrolysis of this intermediate can be excluded. As a result of these advantages, the process according to the invention is much simpler to carry out on the industrial scale than the process described in WO 99/24433.

………………….

SYNTHESIS

US6362178

2-butyrylamino-propionic acid

EXAMPLE 1A 2-Butyrylaminopropionic acid

22.27 g (250 mmol) of D,L-alanine and 55.66 g (550 mmol) of triethylamine are dissolved in 250 ml of dichloromethane, and the solution is cooled to 0° C. 59.75 g (550 mmol) of trimethylsilyl chloride are added dropwise, and the solution is stirred for 1 hour at room temperature and for 1 hour at 40° C. After cooling to −10° C., 26.64 g (250 mmol) of butyryl chloride are added dropwise, and the resulting mixture is stirred for 2 hours at −10° C. and for one hour at room temperature.

With ice-cooling, 125 ml of water are added dropwise and the reaction mixture is stirred at room temperature for 15 minutes. The aqueous phase is evaporated to dryness, the residue is titrated with acetone and the mother liquor is filtered off with suction. The solvent is removed and the residue is chromatographed. The resulting product is dissolved in 3N aqueous sodium hydroxide solution and the resulting solution is evaporated to dryness. The residue is taken up in conc. HCl and once more evaporated to dryness. The residue is stirred with acetone, precipitated solid is filtered off with suction and the solvent is removed under reduced pressure. This gives 28.2 g (71%) of a viscous oil which crystallizes after some time.

200 MHz ¹H-NMR (DMSO-d6): 0.84, t, 3H; 1.22, d, 3H; 1.50, hex, 2H; 2.07, t, 2H; 4.20, quin., 1H; 8.09, d, 1H.

EXAMPLE 3A 2-Ethoxybenzonitrile

25 g (210 mmol) of 2-hydroxybenzonitrile are refluxed with 87 g of potassium carbonate and 34.3 g (314.8 mmol) of ethyl bromide in 500 ml of acetone overnight. The solid is filtered off, the solvent is removed under reduced pressure and the residue is distilled under reduced pressure. This gives 30.0 g (97%) of a colourless liquid.

200 MHz ¹H-NMR (DMSO-d6): 1.48, t, 3H; 4.15, quart., 2H; 6.99, dt, 2H; 7.51, dt, 2H.

2-ethoxybenzamidine hydrochloride

EXAMPLE 4A 2-Ethoxybenzamidine hydrochloride

21.4 g (400 mmol) of ammonium chloride are suspended in 375 ml of toluene, and the suspension is cooled to 0° C. 200 ml of a 2M solution of trimethylaluminium in hexane are added dropwise, and the mixture is stirred at room temperature until the evolution of gas has ceased. After addition of 29.44 g (200 mmol) of 2-ethoxybenzonitrile, the reaction mixture is stirred at 80° C. (bath) overnight.

With ice-cooling, the cooled reaction mixture is added to a suspension of 100 g of silica gel and 950 ml of chloroform, and the mixture is stirred at room temperature for 30 minutes. The mixture is filtered off with suction, and the filter residue is washed with the same amount of methanol. The mother liquor is concentrated, the resulting residue is stirred with a mixture of dichloromethane and methanol (9:1), the solid is filtered off with suction and the mother liquor is concentrated. This gives 30.4 g (76%) of a colourless solid.

200 MHz ¹H-NMR (DMSO-d6): 1.36, t, 3H; 4.12, quart., 2H; 7.10, t, 1H; 7.21, d, 1H; 7.52, m, 2H; 9.30, s, broad, 4H.

EXAMPLE 10A 2-(2-Ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

7.16 g (45 mmol) of 2-butyrylamino-propionic acid and 10.67 g of pyridine are dissolved in 45 ml of THF and, after addition of a spatula tip of DMAP, heated to reflux. 12.29 g (90 mmol) of ethyl oxalyl chloride are slowly added dropwise, and the reaction mixture is refluxed for 3 hours. The mixture is poured into ice-water and extracted three times with ethyl acetate and the organic phase is dried over sodium sulphate and concentrated using a rotary evaporator. The residue is taken up in 15 ml of ethanol and refluxed with 2.15 g of sodium bicarbonate for 2.5 hours. The cooled solution is filtered.

With ice-cooling, 2.25 g (45 mmol) of hydrazine hydrate are added dropwise to a solution of 9.03 g (45 mmol) of 2-ethoxybenzamidine hydrochloride in 45 ml of ethanol, and the resulting suspension is stirred at room temperature for another 10 minutes. The ethanolic solution described above is added to this reaction mixture, and the mixture is stirred at a bath temperature of 70° C. for 4 hours. After filtration, the mixture is concentrated, the residue is partitioned between dichloromethane and water, the organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure.

This residue is dissolved in 60 ml of 1,2-dichloroethane and, after addition of 7.5 ml of phosphorus oxychloride, refluxed for 2 hours. The mixture is diluted with dichloromethane and neutralized by addition of sodium bicarbonate solution and solid sodium bicarbonate. The organic phase is dried and the solvent is removed under reduced pressure. Chromatography using ethyl acetate and crystallization afford 4.00 g (28%) of a colourless solid, R_f=0.42 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H; 1.56, t, 3H; 1.89, hex, 2H; 2.67, s, 3H; 3.00, t, 2H; 4.26, quart., 2H; 7.05, m, 2H; 7.50, dt, 1H; 8.17, dd, 1H; 10.00, s, 1H.

EXAMPLE 15A 4-Ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride

At 0° C., 2.00 g (6.4 mmol) of 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are slowly added to 3.83 ml of chlorosulphonic acid. At room temperature, the reaction mixture is stirred ovemight, and then poured into ice-water and extracted with dichloromethane. This gives 2.40 g (91%) of a colourless foam.

200 MHz ¹H-NMR (CDCl₃): 1.03, t, 3H; 1.61, t, 2H; 1.92, hex, 2H; 2.67, s, 3H; 3.10, t, 2H; 4.42, quart., 2H; 7.27, t, 1H; 8.20, dd, 1H; 8.67, d, 1H; 10.18, s, 1H.

Example 19 2-[2-Ethoxy-5-(4-ethyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

470 mg (1.14 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 20 ml of dichloromethane and cooled to 0° C. 390 mg (3.42 mmol) of N-ethylpiperazine are added, and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed twice with water and dried over sodium sulphate and the solvent is removed under reduced pressure. Crystallization from ether gives 370 mg (66%) of a colourless solid.

400 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H; 1.59, t, 3H; 1.88, hex, 2H; 2.42, quart., 2H; 2.56, m, 4H; 2.63, s, 3H; 3.00, t, 2H; 3.10, m, 4H; 4.33, quart., 2H, 7.17, d, 1H; 7.88, dd, 1H; 8.44, d, 1H; 9.75, s, 1H.

…………………….

US7977478

EXAMPLE 7 Preparation of the Trihydrate of Vardenafil Monohydrochloride

14 g of vardenafil hydrochloride was taken into a round bottom flask followed by the addition of 70 ml water and the pH of the reaction mass was adjusted using sodium hydroxide to 11 at 30° C. 280 ml of dichloromethane was added to the above reaction mass and the layers were separated. The organic layer was dried over sodium sulfate and the organic layer was transferred into a round bottom flask and subjected to heating for distillation at 40° C. for 1.5 hours. The solid material was transferred into a round bottom flask and 36 ml of a mixture of acetone and water in 12:1 ratio was added with stirring, then 2.2 ml of 36% aqueous hydrochloric acid was added with stirring. The reaction mass was heated to a temperature of about 45° C. and the undissolved particles were removed by filtration. The filtrate was taken into a round bottom flask and cooled to 5° C., maintained for 45 minutes at 3 to 5° C. followed by the filtration of the solid which was then subjected to suction drying and finally dried at 40° C. to yield 9.0 g of the trihydrate of vardenafil monohydrochloride.

……………………..

US20050203298

STARTING COMPOUNDS

Example I Preparation of 2-(2-ethoxyphenyl)-5-methyl-7-propyl-3H-imidazo-[5,1-f][2,4]triazin-4-oneIa) Preparation of 2-butyrylaminopropionic acid

A solution of 100 kg of D,L-alanine in aqueous sodium hydroxide solution is reacted in the cold with 119 kg of butyryl chloride. After addition of butyl acetate, the mixture is acidified with hydrochloric acid, the organic phase is separated off and the aqueous phase is re-extracted. The organic phase is dried by azeotropic distillation. The crystallizate is isolated, washed with butyl acetate and dried.

Yield: 132.6 kg (68%)

¹H-NMR: δ=0.8 (t, 3H), 1.25 (d, 3H), 1.5 (m, 2H), 2.1 (t, 2H), 4.2 (q, 1H), 8.1 (d, NH), 12.0-12.7 (s, COOH)

MS: 336 (2M+NH₄, 40), 319 (2M+H, 15), 177 (M+NH₄, 100), 160 (M+H, 20)

Ib) Preparation of 2-ethoxybenzonitrile

260 kg of thionyl chloride are added at 85-95° C. to a suspension of 250 kg of 2-ethoxybenzamide in toluene under metering control. The reaction mixture is stirred in the presence of heat. Thionyl chloride and toluene are then distilled off in vacuo. The product is employed in the subsequent stage as a crude product.

Yield: 228.5 kg (crude product)

¹H-NMR: δ=1.45 (t, 3H), 4.15 (q, 2H), 7.0 (m, 2H, phenyl), 7.5 (m, 2H, phenyl)

MS: 312 (2M+N₄, 35), 165 (M+NH₄, 100), 147 (5)

Ic) Preparation of 2-ethoxy-N-hydroxybenzamidine

111 kg of 2-ethoxybenzonitrile (crude product) from Example Ib are heated under reflux with 164 1 of triethylamine and 73 kg of hydroxylamine hydrochloride in isopropanol. The reaction mixture is treated with water and cooled. The crystallizate is isolated, washed and employed in the subsequent stage as a moist product.

Yield: 92.6 kg (moist product)

¹H-NMR: δ=1.35 (t, 3H), 4.1 (q, 2H), 5.6 (s, 2H), 6.9-7.4 (4H, phenyl), 9.4 (s, 1H, OH)

MS: 361 (2M+H, 30), 198 (M+N, 30), 181 (M+H, 100)

Id) Preparation of 2-ethoxybenzamidine hydrochloride

135 kg of 2-ethoxy-N-hydroxybenzamidine (moist product) from Example Ic are hydrogenated at 50-60° C. in acetic acid using palladium on carbon as a catalyst. For the work-up, the hydrogenation reaction is freed from the catalyst, treated with hydrochloric acid and concentrated. Residual acetic acid and water are removed by azeotropic distillation with toluene. The crystallizate is isolated and dried in vacuo.

Yield: 136.4 kg

H-NMR: 1.35 (t, 3H), 4.15 (q, 2H), 7.1-7.7 (m, 4H, phenyl), 9.1-9.4 (2×s, 3H), 10.5-10.7 (s, 1H)

MS: 329 (2M+H, 10), 165 (M+H, 100)

Ie) Preparation of 2-(2-ethoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one

231 kg of 2-butyrylaminopropionic acid from Example Ia are treated in tetrahydrofuran with 341 kg of pyridine, catalytic amounts of 4-N,N-dimethylaminopyridine and 392 kg of ethyl chloroxalate and stirred with heating under reflux. The reaction mixture is taken up in ethyl acetate, washed with water and the ethyl acetate phase is concentrated. The distillation residue is taken up in methanol and reacted with the following solution.

192 kg of 2-ethoxybenzamidine hydrochloride from Example Id are treated in methanol with 47.5 kg of hydrazine hydrate and the mixture is stirred at room temperature. The solution is combined with the solution of 2-butyrylamino-1-ethoxycarbonylpropenyl ethyl oxalate prepared above. The reaction mixture thus obtained is stirred with heating under reflux. Methanol is removed by distillation and replaced by acetic acid.

Option A:

138.6 kg of phosphorus oxychloride are added and stirred in the presence of heat.

Acetic acid is distilled off in vacuo. The residue is treated with water and dichloromethane or optionally methyl isobutyl ketone and rendered neutral using sodium hydroxide solution. The organic phase is concentrated, and the residue is dissolved in acetone and crystallized with cooling. The crystallizate is isolated, washed and dried.

Option B:

At least 190 kg of acetyl chloride are added and stirred in the presence of heat. Acetic acid is distilled off in vacuo. The distillation residue is treated with acetone and water, and the product is crystallized by rendering neutral with sodium hydroxide solution. The product is isolated, washed and dried.

Yield: 90-160 kg

¹H-NMR: δ=1.0 (t, 3H), 1.6 (t, 3H), 1.9 (m, 2H), 2.8 (s, 3H), 3.3 (t, 2H), 4.3 (q, 2H), 7.0-8.2 (Ar, 4H), 10.3 (CONH, 1H)

MS: 313 (M+H, 100), 149 (25), 151 (40), 121 (15)

HPLC: Kromasil C-18 phase, neutral phosphate buffer, acetonitrile, 233 nm, linear gradient of 30% acetonitrile ->80% acetonitrile (30 min.): 99 area % (R_t19.1)

PREPARATION EXAMPLES Example 1a 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-fl-][1,2,4]triazin-2-yl)benzenesulphonic acid

194 kg of 2-(2-ethoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one from Example Ie are reacted with 504 kg of concentrated sulphuric acid. The reaction mixture is added to water, cooled, and the crystallizate is isolated and dried in vacuo.

Yield: 195.2 kg

¹H-NMR: δ=0.95 (t, 3H), 1.3 (t, 3H), 1.8 (m, 2H), 2.6 (s, 3H), 3.05 (t, 2H), 4.1 (q, 2H), 7.15 (Ar, 1H), 7.75 (m, 2H), 12.3 (SO₂OH)

MS: 393 (M+H, 100), 365 (25), 151 (40)

HPLC: X-Terra C-18 phase, aqueous phosphoric acid, acetonitrile, 242 nm, linear gradient of 10% acetonitrile ->90% acetonitrile (20 min.):

98 area % (R, 9.2)

Example 1b) 2-[2-ethoxy-5-(4-ethlylpiperazin-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

22.5 kg of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]-triazin-2-yl)benzenesulphonic acid from Example 1a are reacted with 74 kg of thionyl chloride and catalytic amounts of dimethylformamide until the evolution of gas has ended. Xylene is repeatedly added to the reaction mixture and thionyl chloride is distilled off. 15.1 kg of N-ethylpiperazine are added to the suspension and it is stirred. After the addition of water, it is adjusted to pH 1 using hydrochloric acid, and the phases are separated. The aqueous phase is treated with acetone and rendered neutral by addition of sodium hydroxide solution. The mixture is cooled, and the crystallizate is isolated, washed and dried in vacuo.

Yield: 26.1 kg

¹H-NMR: δ=1.0 (2×t, 6H), 1.6 (t, 3H), 1.9 (m, 2H), 2.45 (q, 2H), 2.55 (m, 4H), 2.65 (s, 3H), 3.0 (t, 2H), 3.1 (m, 4H), 4.35 (q, 2H), 7.15 (Ar, 1H), 7.9 (Ar, 1H), 8.4 (Ar, 1H), 9.8 (CONH)

MS: 489 (M+H, 100), 345 (10), 313, (10), 285 (10), 113 (20)

HPLC: X-Terra C-18 phase, neutral phosphate buffer, acetonitrile, 242 nm, linear gradient of 20% acetonitrile ->75% acetonitrile (20 min.): 98 area % (R_t16.3)

1 c) 2-[2-ethoxy-5-(4-ethylpiperazin-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-fl][1,2,4]triazin-4-one hydrochloride trihydrate

22.5 kg of 2-[2-ethoxy-5-(4-ethylpiperazin-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one from Example 1b are dissolved in 5.1 kg of concentrated hydrochloric acid and acetone/water (12:1 v/v) in the presence of heat. The clear solution is filtered hot and crystallized by cooling and seeding. The crystallizate is isolated, washed and dried in vacuo at about 30° C. and about 300 mbar.

Yield: 25.4 kg

M.p. (DSC): 192° C.

HPLC: X-Terra C-18 phase, neutral phosphate buffer, acetonitrile, 242 nm, linear gradient of 20% acetonitrile ->75% acetonitrile (20 min.): 99 area % (R_t16.3)

http://www.pharmpro.com/News/Feeds/2010/06/pharmaceutical-companies-bayer-new-erectile-dysfunction-treatment-staxyn-approve/
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A Aversa et al. “Effects of vardenafil administration on intravaginal ejaculatory latency time in men with lifelong premature ejaculation”. Retrieved 2010-12-14.
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Official Levitra website
PubChem Information

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2-1-2013

Synthesis of quinoline derivatives: discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer’s disease.

European journal of medicinal chemistry

PATENTS

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US20060111354 *	Jul 3, 2003	May 25, 2006	Peter Serno	Medicaments containing vardenafil hydrochloride trihydrate
WO2004006894A1 *	Jul 3, 2003	Jan 22, 2004	Bayer Healthcare Ag	Medicaments containing vardenafil hydrochloride trihydrate

US2011269750	11-4-2011	ROFLUMILAST FOR THE TREATMENT OF DIABETES MELLITUS
US8017633	9-14-2011	Roflumilast for the Treatment of Diabetes Mellitus
US2011190495	8-5-2011	N-BUTYRAMIDE, THE PREPARATION METHOD AND USE THEREOF
US2011048980	3-4-2011	Fatty Acid Oxidation Inhibitors Treating Hyperglycemia and Related Disorders
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US2010234388	9-17-2010	SUBSTITUTED PDE5 INHIBITORS
US2010179131	7-16-2010	Combination treatment for diabetes mellitus
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US2009318459	12-25-2009	Therapeutic Compositions Comprising a Specific Endothelin Receptor Antagonist and a PDE5 Inhibitor
US2009291958	11-27-2009	Substituted PDE5 inhibitors
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US2009215836	8-28-2009	Roflumilast for the Treatment of Pulmonary Hypertension
US2009196900	8-7-2009	Use of Phosphodiesterase Inhibitor as a Component of Implantable Medical Devices
US2009163504	6-26-2009	Method for healing a wound using a phosphodiesterase type five inhibitor
US2009074796	3-20-2009	Pde5 inhibitor compositions and methods for immunotherapy
US2009062313	3-6-2009	Pde5 inhibitor compositions and methods for treating cardiac indications
US2008268046	10-31-2008	Formulations with Controlled Release of Active Ingredient
US2008194529	8-15-2008	HIGHLY SELECTIVE and LONG-ACTING PDE5 MODULATORS

US2008187588	8-8-2008	Formulations With Controlled Release Of Active Ingredient
US2008085897	4-11-2008	Use of 2-alkoxyphenyl-substituted imidazotriazinones
US7314871	1-2-2008	2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors, for treatment of hypertension
US2007299088	12-28-2007	Novel Uses of 2-Phenyl-Substituted Imidazotriazinone Derivatives
US7276504	10-3-2007	Use of 2-alkoxyphenyl-substituted imidazotriazinones
US2006264624	11-24-2006	Methods for synthesizing imidazotriazinones
US7122540	10-18-2006	2-Phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
US6998483	2-15-2006	Process for the preparation of sulphonamide-substituted imidazotriazinones
US6930108	8-17-2005	Use of 2-alkoxyphenol-substituted imidazotriazinones
US6890922	5-11-2005	2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors

US2005014756	1-21-2005	Process for the preparation of sulphonamide-substituted imidazotriazinones
US6777551	8-18-2004	Process for the preparation of sulphonamide-substituted imidazotriazinones
US2004152700	8-6-2004	Novel use of 2-phenyl-substituted imidazotriazinones
US2003144296	7-32-2003	Daily treatment for erectile dysfunction using a PDE5 inhibitor
US6566360	5-21-2003	2-phenyl substituted imidatriazinones as phosphodiesterase inhibitors
US6362178	3-27-2002	2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
US2001053780	12-21-2001	Daily treatment for erectile dysfunction using a PDE5 inhibitor
WO9924433	5-21-1999	2-PHENYL SUBSTITUTED IMIDAZOTRIAZINONES AS PHOSPHODIESTERASE INHIBITORS

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EVER SINCE POST WAS WRITTEN…..FGD APPROVAL Inotuzumab ozogamicin

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Patent literaturePatent Document 1: Patent No. 4,800,445 Patent

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Synthesis

Research

Paper

POSTER

A NEW, EFFICIENT AND ECONOMIC METHOD FOR PREPARATION OF PRAMIPEXOLE.

Patent

PATENT

PATENT

PATENT

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Synthesis of Impurities of Pramipexole Dihydrochloride

Abstract

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Abemaciclib (Bemaciclib)

2-Pyrimidinamine, N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)

Treatment of Advanced Cancer

SYNTHESIS US20100160340

Synthesis….http://www.joygooo.com/news_110.htm?pageNum=21

OTHERS

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NOW FDA APPROVED 2017 since the blog post was written

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Inotuzumab ozogamicin
RN: 635715-01-4
UNII: P93RUU11P7

SYNTHESIS

US20100160340