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BI 224436 an investigational new drug under development for the treatment of HIV infection

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Figure imgf000059_0001

 

(2S)-2-tert-butoxy-2-(4-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2- methylquinolin-3-yl)acetic acid

BI 224436

1155419-89-8  cas no

mw

442.51

 

3-​Quinolineacetic acid, 4-​(2,​3-​dihydropyrano[4,​3,​2-​de]​quinolin-​7-​yl)​-​α-​(1,​1-​dimethylethoxy)​-​2-​methyl-​, (αS,​4R)​-

hemi-succinate of (2S)-2-tert-butoxy-2-(4-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-methylquinolin-3-yl)acetic acid)

BI 224436 is an investigational new drug under development for the treatment of HIV infection. BI 224436 is the first non-catalytic site integrase inhibitor (NCINI). It inhibits HIV replication via binding to a conserved allosteric pocket of the HIV integrase enzyme. This makes the drug distinct in mechanism of action compared to raltegravir and elvitegravir, which bind at the catalytic site.[2] In October 2011, Gilead Sciences purchased exclusive rights to develop BI 224436 and several related compounds under investigation in Boehringer Ingelheim’s noncatalytic site integrase inhibitor program.[3][4]

Novel hemi-succinate salt form of (2S)-2-tert-butoxy-2-(4-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-methylquinolin-3-yl)acetic acid (presumed to be BI-224436) and its crystalline forms is desc in WO-2014055618.

Gilead, under license from BI, was developing BI-224436 for the oral treatment of HIV infection. In September 2011, this drug had entered phase 1 trials. Picks up from  WO2012138670, claiming a process for the preparation of the same drug. Also see the concurrently published WO2014055603.  This compound is claimed specifically in WO2009062285 and generically in WO2007131350.

BI 224436 has antiviral EC50 values ranging between 4 and 15 nM against different HIV-1 laboratory strains and CC50 values >90 μM in different cells, including peripheral blood mononuclear cells. BI 224436 also has a low, 2.2-fold shift in antiviral potency in the presence of 50% human serum and by virtue of a steep dose-response curve slope, BI 224436 exhibits serum-shifted EC95 values ranging between 22 and 75 nM. Drug combination studies performed in cell-based antiviral assays have shown that BI 224436 displays, at the least, an additive effect in combination with any of the marketed antiviral classes including INSTIs. BI 224436 has drug-like ADME properties including a Caco-2 cell permeability of 14 .10-6 cm/sec, solubility > 24 mg/ml in the pH range 2.0-6.8 and low cytochrome P450 inhibition. Moreover BI 224436 shows excellent PK profiles in rat (CL=0.7% QH; F= 54%), monkey (CL= 23% QH; F= 82%) and dog (CL= 8%QH; F= 81%).

 

http://www.natap.org/2011/ICAAC/ICAAC_32.htm

……………………

Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1

ACS Med. Chem. Lett., 2014, 5 (4), pp 422–427
DOI: 10.1021/ml500002n

http://pubs.acs.org/doi/abs/10.1021/ml500002n

Abstract Image

 

1H NMR: 12.4 (br, 1H), 8.52 (d, 1H, J = 4.4Hz), 7.94 (d, 1H, J = 7.9 Hz),7.65-7.61 (m, 1H), 7.45 (d,
1H, J = 8.2 Hz), 7.31-7.24 (m, 2H), 7.12 (d, 1H, J = 7.9 Hz), 6.94-6.92 (m, 1H), 4.99 (s, 1H), 4.57-4.47
(m, 2H), 3.37-3.30 (m, 2H), 2.86 (s, 3H), 0.82 (s, 9H).

13C NMR: 172.2, 158.4, 153.1, 150.1, 146.6,
146.1, 145.0, 141.0, 130.8 (br), 130.6 (br), 128.9, 128.0, 127.2, 127.1 (br) 126.4, 125.6, 118.0, 116.7,
109.1, 75.2, 70.8, 65.6, 27.7, 27.5, 24.9.

HRMS: m/z calc. for C27H26N2O4 + H+: 443.1965, m/z found:
443.1951 (-3.2 ppm).

UPLC-MS: rt = 0.68 min, m/z 443.3 [M + H]+, purity: >99.9% @ 254 nm.

http://pubs.acs.org/doi/suppl/10.1021/ml500002n/suppl_file/ml500002n_si_001.pdf

………………………….

http://www.google.com/patents/WO2012138670A1?cl=en

General Scheme IA:

G1 1001

wherein Y is I, Br or CI;

General Scheme 11 A:

 

wherein:

Example 1

 

1 a 1 b

1a (600 g, 4.1 mol) was charged into a dry reactor under nitrogen followed by addition of Ac20 (1257.5 g, 12.3 mol, 3 eq.). The resulting mixture was heated at 40 °C at least for 2 hours. The batch was then cooled to 30 °C over 30 minutes. A suspension of 1b in toluene was added to seed the batch if no solid was observed. After toluene (600 ml_) was added over 30 minutes, the batch was cooled to -5— 10 °C and was held at this temperature for at least 30 minutes. The solid was collected by filtration under nitrogen and rinsed with heptanes (1200 ml_). After being dried under vacuum at room temperature, the solid was stored under nitrogen at least below 20 °C. The product 1 b was obtained with 77% yield. 1H NMR (500 MHz, CDCI3): δ = 6.36 (s, 1 H), 3.68 (s, 2H), 2.30 (s, 3H). Example 2

 

2a 2b

2a (100g, 531 mmol) and 1b (95 g, 558 mmol) were charged into a clean and dry reactor under nitrogen followed by addition of fluorobenzene (1000 mL). After being heated at 35-37 °C for 4 hours, the batch was cooled to 23 °C. Concentrated H2S04 (260.82 g, 2659.3 mmol, 5 eq.) was added while maintaining the batch temperature below 35 °C. The batch was first heated at 30-35 °C for 30 minutes and then at 40- 45 °C for 2 hours. 4-Methyl morpholine (215.19 g, 2127 mmol, 4 eq.) was added to the batch while maintaining the temperature below 50 °C. Then the batch was agitated for 30 minutes at 40-50 °C. eOH (100 mL) was then added while maintaining the temperature below 55 °C. After the batch was held at 50-55 °C for 2 hours, another portion of MeOH (100 mL) was added. The batch was agitated for another 2 hours at 50-55 °C. After fluorobenzene was distilled to a minimum amount, water (1000 mL) was added. Further distillation was performed to remove any remaining fluorobenzene. After the batch was cooled to 30 °C, the solid was collected by filtration with cloth and rinsed with water (400 mL) and heptane (200 mL). The solid was dried under vacuum below 50 °C to reach KF < 0.1%. Typically, the product 2b was obtained in 90% yield with 98 wt%. 1H NMR (500 MHz, DMSO- d6): δ = 10.83 (s, 1 H), 9.85 (s, bs, 1 H), 7.6 (d, 1 H, J

Hz), 6.40 (s, 1 H), 4.00 (s, 2 H), 3.61 (s, 3 H). Example 3

 

2b 3a

2b (20 g, 64 mmol) was charged into a clean and dry reactor followed by addition of THF (140 mL). After the resulting mixture was cooled to 0 °C, Vitride® (Red-AI, 47.84 g, 65 wt%, 154 mmol) in toluene was added while maintaining an internal temperature at 0-5 °C. After the batch was agitated at 5-10 °C for 4 hours, IPA (9.24 g, 153.8 mmol) was added while maintaining the temperature below 10 °C. Then the batch was agitated at least for 30 minutes below 25 °C. A solution of HCI in IPA (84.73 g, 5.5 M, 512 mmol) was added into the reactor while maintaining the temperature below 40 °C. After about 160 mL of the solvent was distilled under vacuum below 40 °C, the batch was cooled to 20-25 °C and then aqueous 6M HCI (60 mL) was added while maintaining the temperature below 40 °C. The batch was cooled to 25 °C and agitated for at least 30 minutes. The solid was collected by filtration, washed with 40 mL of IPA and water (1V/1V), 40 mL of water and 40 mL of heptanes. The solid was dried below 60 °C in a vacuum oven to reach KF < 0.5%. Typically, the product 3a was obtained in 90-95% yield with 95 wt%. 1H NMR (400 MHz, DMSO-d6): δ = 10.7 (s, 1 H), 9.68 (s, 1 H), 7.59 (d, 1 H, J = 8.7 Hz), 6.64 (, 1 H, J = 8.7 Hz), 6.27 (s, 1 H), 4.62 (bs, 1 H), 3.69 (t, 2H, J = 6.3 Hz), 3.21 (t, 2H, J = 6.3 Hz).

Example 4

 

3a (50 g, 174.756 mmol) and acetonitrile (200 mL) were charged into a dry and clean reactor. After the resulting mixture was heated to 65 °C, POCI3 (107.18 g, 699 mmol, 4 eq.) was added while maintaining the internal temperature below 75 °C. The batch was then heated at 70-75 °C for 5-6 hours. The batch was cooled to 20 °C. Water (400 mL) was added at least over 30 minutes while maintaining the internal temperature below 50 °C. After the batch was cooled to 20-25 °C over 30 minutes, the solid was collected by filtration and washed with water (100 mL). The wet cake was charged back into the reactor followed by addition of 1 M NaOH (150 mL). After the batch was agitated at least for 30 minutes at 25-35 °C, it was verified that the pH was greater than 12. Otherwise, more 6M NaOH was needed to adjust the pH >12. After the batch was agitated for 30 minutes at 25-35 °C, the solid was collected by filtration, washed with water (200 mL) and heptanes (200 mL). The solid was dried in a vacuum oven below 50 °C to reach KF < 2%. Typically, the product 4a was obtained at about 75-80% yield. H NMR (400 MHz, CDCI3): δ = 7.90 (d, 1 H, J = 8.4 Hz), 7.16 (s, 1 H), 6.89 (d, 1 H, J = 8.4 Hz), 4.44 (t, 2 H, J = 5.9 Hz), 3.23 (t, 2 H, J = 5.9 Hz). 13C NMR (100 MHz, CDCI3): δ = 152.9, 151.9, 144.9, 144.1 , 134.6, 1 19.1 , 1 17.0, 1 13.3, 1 1 1.9, 65.6, 28.3.

Example 5

 

4a 5a

Zn powder (54 g, 825 mmol, 2.5 eq.) and TFA (100 mL) were charged into a dry and clean reactor. The resulting mixture was heated to 60-65 °C. A suspension of 4a (100 g, 330 mmol) in 150 mL of TFA was added to the reactor while maintaining the temperature below 70 °C. The charge line was rinsed with TFA (50 mL) into the reactor. After 1 hour at 65±5 °C, the batch was cooled to 25-30 °C. Zn powder was filtered off by passing the batch through a Celite pad and washing with methanol (200 mL). About 400 mL of solvent was distilled off under vacuum. After the batch was cooled to 20-25 °C, 20% NaOAc (ca. 300 mL) was added at least over 30 minutes to reach pH 5-6. The solid was collected by filtration, washed with water (200 mL) and heptane (200 mL), and dried under vacuum below 45 °C to reach KF ≤ 2%. The solid was charged into a dry reactor followed by addition of loose carbon (10 wt%) and toluene (1000 mL). The batch was heated at least for 30 minutes at 45-50 °C. The carbon was filtered off above 35 °C and rinsed with toluene (200 mL). The filtrate was charged into a clean and dry reactor. After about 1000 mL of toluene was distilled off under vacuum below 50 °C, 1000 mL of heptane was added over 30 minutes at 40-50 °C. Then the batch was cooled to 0±5 °C over 30 minutes. After 30 minutes, the solid was collected and rinsed with 200 mL of heptane. The solid was dried under vacuum below 45 °C to reach KF≤ 500 ppm. Typically, the product 5a was obtained in about 90-95 % yield. 1H NMR (400 MHz, CDCI3): δ = 8.93 (m, 1 H), 7.91 (dd, 1 H, J = 1.5, 8 Hz), 7.17 (m 1 H), 6.90 (dd, 1 H, J = 1 .6, 8.0 Hz), 4.46-4.43 (m, 2 H), 3.28-3.23 (m, 2 H). 13C NMR (100 MHz, CDCI3): δ = 152.8, 151 .2, 145.1 , 141.0, 133.3, 1 18.5, 1 18.2, 1 14.5, 1 1 1.1 , 65.8, 28.4.

Example 6

 

5a 6a

5a (1.04 kg, 4.16 mol) and toluene (8 L) were charged into the reactor. The batch was agitated and cooled to -50 to -55 °C. BuLi solution (2.5 M in hexanes, 1.69 L, 4.23 mol) was charged slowly while maintaining the internal temperature between – 45 to -50 °C. The batch was agitated at -45 °C for 1 hour after addition. A solution of triisopropyl borate (0.85 kg, 4.5 mol) in MTBE (1 .48 kg) was charged. The batch was warmed to 10 °C over 30 minutes. A solution of 5 N HCI in I PA (1 .54 L) was charged slowly at 10 °C, and the batch was warmed to 20 °C and stirred for 30 minutes. It was seeded with 6a crystal (10 g). A solution of aqueous concentrated HCI (0.16 L) in IPA (0.16 L) was charged slowly at 20 °C in three portions at 20 minute intervals, and the batch was agitated for 1 hour at 20 °C. The solid was collected by filtration, rinsed with MTBE (1 kg), and dried to provide 6a (943 g, 88.7 % purity, 80% yield). 1H NMR (400 MHz, D20): δ 8.84 (d, 1 H, J = 4 Hz)

1 H), 7.68 (d, 1 H, J = 6 Hz), 7.09 (m, 1 H), 4.52 (m, 2H), 3.47 (m, 2H).

Example 7

Iodine stock solution was prepared by mixing iodine (57.4 g, 0.23 mol) and sodium iodide (73.4 g, 0.49 mol) in water (270 mL). Sodium hydroxide (28.6 g, 0.715 mol) was charged into 220 mL of water. 4-Hydroxy-2 methylquinoline 7a (30 g, 0.19 mol) was charged, followed by acetonitrile (250 mL). The mixture was cooled to 10 °C with agitation. The above iodine stock solution was charged slowly over 30 minutes. The reaction was quenched by addition of sodium bisulfite (6.0 g) in water (60 mL). Acetic acid (23 mL) was charged over a period of 1 hour to adjust the pH of the reaction mixture between 6 and 7. The product was collected by filtration, washed with water and acetonitrile, and dried to give 7b (53 g, 98%). MS 286 [M + 1].

Example 8

7b 8a

4-Hydroxy-3-iodo-2-methylquinoline 7b (25 g, 0.09 mol) was charged to a 1-L reactor. Ethyl acetate (250 mL) was charged, followed by triethylamine (2.45 mL, 0.02 mol) and phosphorus oxychloride (12 mL, 0.13 mol). The reaction mixture was heated to reflux until complete conversion (~1 hour), then the mixture was cooled to 22 °C. A solution of sodium carbonate (3 .6 g, 0.3 mol) in water (500 mL) was charged. The mixture was stirred for 20 minutes. The aqueous layer was extracted with ethyl acetate (120 mL). The organic layers were combined and concentrated under vacuum to dryness. Acetone (50 mL) was charged. The solution was heated to 60 °C. Water (100 mL) was charged, and the mixture was cooled to 22 °C. The product was collected by filtration and dried to give 8a (25 g, 97.3 % pure, 91.4 % yield). MS 304 [M + 1].

(Note: 8a is a known compound with CAS # 1033931-93-9. See references: (a) J. Org Chem. 2008, 73, 4644-4649. (b) Molecules 2010, 15, 3171 -3178. (c) Indian J. Chem. Sec B: Org. Chem. Including Med Chem. 2009, 488(5), 692-696.)

Example 9

8a 9a

8a (100 g, 0.33 mol) was charged to the reactor, followed by copper (I) bromide dimethyl sulfide complex (3.4 g, 0.017 mol) and dry THF (450 mL). The batch was cooled to -15 to -12 °C. i-PrMgCI (2.0 M in THF, 173 mL, 0.346 mol) was charged into the reactor at the rate which maintained the batch temperature < -10 °C. In a 2nd reactor, methyl chlorooxoacetate (33 mL, 0.36 mol) and dry THF (150 mL) were charged. The solution was cooled to -15 to -10 °C. The content of the 1 st reactor (Grignard/cuprate) was charged into the 2nd reactor at the rate which maintained the batch temperature < -10 °C. The batch was agitated for 30 minutes at -10 °C. Aqueous ammonium chloride solution ( 0%, 300 mL) was charged. The batch was agitated at 20 – 25 °C for 20 minutes and allowed to settle for 20 minutes. The aqueous layer was separated. Aqueous ammonium chloride solution (10%, 90 mL) and sodium carbonate solution (10%, 135 mL) were charged to the reactor. The batch was agitated at 20 – 25 °C for 20 minutes and allowed to settle for 20 minutes. The aqueous layer was separated. Brine (10%, 240 mL) was charged to the reactor. The batch was agitated at 20 – 25 °C for 20 minutes. The aqueous layer was separated. The batch was concentrated under vacuum to -1/4 of the volume (about 80 mL left). 2-Propanol was charged (300 mL). The batch was concentrated under vacuum to -1/3 of the volume (about 140 mL left), and heated to 50 °C.

Water (70 mL) was charged. The batch was cooled to 20 – 25 °C, stirred for 2 hours, cooled to – 0 °C and stirred for another 2 hours. The solid was collected by filtration, washed with cold 2-propanol and water to provide 58.9 g of 9a obtained after drying (67.8 % yield). 1H NMR (400 MHz, CDCI3): δ 8.08 (d, 1 H, J = 12 Hz), 7.97 (d, 1 H, J = 12 Hz), 7.13 (t, 1 H, J = 8 Hz), 7.55 (t, 1 H, J= 8 Hz), 3.92 (s, 3H), 2.63 (s, 3H). 13C NMR (100 MHz, CDCI3): δ 186.6, 161.1 , 155.3, 148.2, 140.9, 132.0, 129.0, 128.8, 127.8, 123.8, 123.7, 53.7, 23.6.

 

Catalyst preparation: To a suitable sized, clean and dry reactor was charged dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer (800 ppm relative to 9a, 188.5 mg) and the ligand (2000 ppm relative to 9a, 306.1 mg). The system was purged with nitrogen and then 3 ml. of acetonitrile and 0.3 ml_ of triethylamine was charged to the system. The resulting solution was agitated at room temperature for not less than 45 minutes and not more than 6 hours. Reaction: To a suitable sized, clean and dry reactor was charged 9a (1.00 equiv, 100.0 g (99.5 wt%), 377.4 mmol). The reaction was purged with nitrogen. To the reactor was charged acetonitrile (ACS grade, 4 L/Kg of 9a, 400 mL) and

triethylamine (2.50 equiv, 132.8 mL, 943 mmol). Agitation was initiated. The 9a solution was cooled to Tint= -5 to 0 °C and then formic acid (3.00 equiv, 45.2 mL, 1 132 mmol) was charged to the solution at a rate to maintain Tint not more than 20 °C. The batch temperature was then adjusted to Tint= -5 to -0 °C. Nitrogen was bubbled through the batch through a porous gas dispersion unit (Wiimad-LabGlass No. LG-8680-1 0, VWR catalog number 14202-962) until a fine stream of bubbles was obtained. To the stirring solution at Tint= -5 to 0 °C was charged the prepared catalyst solution from the catalyst preparation above. The solution was agitated at Tint= -5 to 0 °C with the bubbling of nitrogen through the batch until HPLC analysis of the batch indicated no less than 98 A% conversion (as recorded at 220 nm, 10-14 h). To the reactor was charged isopropylacetate (6.7 L/Kg of 9a, 670 ml_). The batch temperature was adjusted to Tint= 18 to 23 °C. To the solution was charged water (10 L/Kg of 9a, 1000 mL) and the batch was agitated at Tint= 18 to 23 °C for no less than 20 minutes. The agitation was decreased and or stopped and the layers were allowed to separate. The lighter colored aqueous layer was cut. To the solution was charged water (7.5 L/Kg of 9a, 750 mL) and the batch was agitated at Tint= 18 to 23 °C for no less than 20 minutes. The agitation was decreased and or stopped and the layers were allowed to separate. The lighter colored aqueous layer was cut. The batch was then reduced to 300 mL (3 L/Kg of 9a) via distillation while maintaining Text no more than 65 °C. The batch was cooled to Tint= 35 to 45 °C and the batch was seeded (10 mg). To the batch at Tint= 35 to 45 °C was charged heptane (16.7 L/Kg of 9a, 1670 mL) over no less than 1.5 hours. The batch temperature was adjusted to Tint= -2 to 3 °C over no less than 1 hour, and the batch was agitated at Tint= -2 to 3 °C for no less than 1 hour. The solids were collected by filtration. The filtrate was used to rinse the reactor (Filtrate is cooled to Tint= -2 to 3 °C before filtration) and the solids were suction dried for no less than 2 hours. The solids were dried until the LOD is no more than 4 % to obtain 82.7 g of 10a (99.6- 100 wt%, 98.5% ee, 82.5% yield). 1H-NMR (CDCI3, 400 MHz) δ: 8.20 (d, J= 8.4 Hz, 1 H), 8.01 (d, J= 8.4 Hz, 1 H), 7.73 (t, J= 7.4 Hz, 1 H), 7.59 (t, J= 7.7 Hz, H), 6.03 (s, 1 H), 3.93 (s, 1 H), 3.79 (s, 3H), 2.77 (s, 3H). 13C-NMR (CDCI3, 100 MHz) δ: 173.5, 158.3, 147.5, 142.9, 130.7, 128.8, 127.7, 127.1 , 125.1 , 124.6, 69.2, 53.4, 24.0.

Example 11

 

10a 6a

10a (2.45 kg, 96.8% purity, 8.9 mol), 6a (2.5 kg, 88.7% purity, 8.82 mol), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3, 40 g, 0.044 mol), (S)-3-ieri-butyl- 4-(2,6-dimethoxypheny1 )-2,3-dihydrobenzo[d][1 ,3]oxaphosphole (32 g, 0.01 1 mol), sodium carbonate (1.12 kg, 10.58 mol), 1-pentanol (16.69 L), and water (8.35 L) were charged to the reactor. The mixture was de-gassed by sparging with argon for 10-15 minutes, was heated to 60-63 °C, and was agitated until HPLC analysis of the reaction shows <1 A% (220 nm) of the 6a relative to the combined two atropisomer products (-15 hours). The batch was cooled to 18-23 °C. Water (5 L) and heptane (21 L) were charged. The slurry was agitated for 3 – 5 hours. The solids were collected by filtration, washed with water (4 L) and heptane/toluene mixed solvent (2.5 L toluene/5 L heptane), and dried. The solids were dissolved in methanol (25 L) and the resulting solution was heated to 50 °C and circulated through a CUNO carbon stack filter. The solution was distilled under vacuum to ~ 5 L. Toluene (12 L) was charged. The mixture was distilled under vacuum to ~ 5 L and cooled to 22 °C. Heptane (13 L) was charged to the contents over 1 hour and the resulting slurry was agitated at 20-25 °C for 3 – 4 hours. The solids were collected by filtration and washed with heptanes to provide 2.58 kg of 11a obtained after drying (73% yield). 1H NMR (400 MHz, CDCI3): δ 8.63 (d, 1 H, J = 8 Hz), 8.03 (d, 1 H, J = 12 Hz), 7.56 (t, 1 H, J = 8 Hz), 7.41 (d, 1 H, J = 8 Hz), 7.19 (t, 1 H, J = 8 Hz), 7.09 (m, 2H), 7.04 (d, 1 H, J = 8 Hz), 5.38 (d, 1 H, J = 8 Hz), 5.14 (d, 1 H, J = 8 Hz), 4.50 (t, 2H, J = 4 Hz), 3.40 (s, 3H), 3.25 (t, 2H, J = 4 Hz), 2.91 (s, 3H). 13C NMR (100 MHz, CDCI3): δ 173.6, 158.2, 154.0, 150.9, 147.3, 147.2, 145.7, 141.3, 132.9, 123.0, 129.4, 128.6, 127.8, 126.7, 126.4, 125.8, 1 18.1 , 1 17.3, 109.9, 70.3, 65.8, 52.3, 28.5, 24.0.

Example 12

 

11a 12a

To a suitable clean and dry reactor under a nitrogen atmosphere was charged 11a (5.47 Kg, 93.4 wt%, 1 .00 equiv, 12.8 mol) and fluorobenzene (10 vols, 51.1 kg) following by trifluoromethanesulfonimide (4 mol%, 143 g, 0.51 mol) as a 0.5 M solution in DCM (1.0 Kg). The batch temperature was adjusted to 35-41 °C and agitated to form a fine slurry. To the mixture was slowly charged i-butyl-2,2,2- trichloroacetimidate 12b as a 50 wt% solution (26.0 Kg of f-butyl-2,2,2- trichloroacetimidate (1 19.0 mol, 9.3 equiv), the reagent was -48-51 wt% with the remainder 52-49 wt% of the solution being – 1.8:1 wt:wt heptane: fluorobenzene) over no less than 4 hours at Tint= 35-41 °C. The batch was agitated at Tint= 35-41 °C until HPLC conversion (308 nm) was >96 A%, then cooled to Tint= 20-25 °C and then triethylamine (0.14 equiv, 181 g, 1 .79 mol) was charged followed by heptane (12.9 Kg) over no less than 30 minutes. The batch was agitated at Tint= 20-25 °C for no less than 1 hour. The solids were collected by filtration. The reactor was rinsed with the filtrate to collect all solids. The collected solids in the filter were rinsed with heptane (1 1 .7 Kg). The solids were charged into the reactor along with 54.1 Kg of DM Ac and the batch temperature adjusted to Tint= 70-75 °C. Water ( .2 Kg) was charged over no less than 30 minutes while the batch temperature was maintained at Tint= 65-75 °C. 12a seed crystals (34 g) in water (680 g) was charged to the batch at Tlnt= 65-75 °C. Additional water (46.0 Kg) was charged over no less than 2 hours while maintaining the batch temperature at Tint= 65-75 °C. The batch temperature was adjusted to Tint= 18-25 °C over no less than 2 hours and agitated for no less than 1 hour. The solids were collected by filtration and the filtrate used to rinse the reactor. The solids were washed with water (30 Kg) and dried under vacuum at no more than 45 °C until the LOD < 4% to obtain 12a (5.275 Kg, 99.9 A% at 220 nm, 99.9 wt% via HPLC wt% assay, 90.5% yield). 1H-NMR (CDCI3, 400

MHz) δ: 8.66-8.65 (m, 1 H), 8.05 (d, J= 8.3 Hz, 1 H), 7.59 (t, J= 7.3 Hz, 1 H), 7.45 (d, J= 7.8 Hz, 1 H), 7.21 (t, J= 7.6 Hz, 1 H), 7.13-7.08 (m, 3H), 5.05 (s, 1 H), 4.63-4.52 (m, 2H), 3.49 (s, 3H), 3.41 -3.27 (m, 2H), 3.00 (s, 3H), 0.97 (s, 9H). 13C-NMR (CDCI3, 100 MHz) δ: 172.1 , 159.5, 153.5, 150.2, 147.4, 146.9, 145.4, 140.2, 131.1 , 130.1 , 128.9, 128,6, 128.0, 127.3, 126.7, 125.4, 117.7, 117.2, 109.4, 76.1 , 71.6, 65.8, 51 .9, 28.6, 28.0, 25.4. Example 13

 

To a suitable clean and dry reactor under a nitrogen atmosphere was charged 12a (9.69 Kg, 21.2 mol) and ethanol (23.0 Kg). The mixture was agitated and the batch temperature was maintained at Τίηί= 20 to 25 °C. 2 M sodium hydroxide (17.2 Kg) was charged at Tint= 20 to 25 °C and the batch temperature was adjusted to Tint= 60- 65°C over no less than 30 minutes. The batch was agitated at Tint= 60-65°C for 2-3 hours until HPLC conversion was >99.5% area (12a is <0.5 area%). The batch temperature was adjuted to Tlnt= 50 to 55°C and 2M aqueous HCI (14.54 Kg) was charged. The pH of the batch was adjusted to pH 5.0 to 5.5 (target pH 5.2 to 5.3) via the slow charge of 2M aqueous HCI (0.46 Kg) at Tint= 50 to 55°C. Acetonitrile was charged to the batch (4.46 Kg) at Tint= 50 to 55°C. A slurry of seed crystals (1001 , 20 g in 155 g of acetonitrile) was charged to the batch at Tint= 50 to 55°C. The batch was agitated at Tint= 50 to 55°C for no less than 1 hour (1-2 hours). The contents were vacuum distilled to -3.4 vol (32 L) while maintaining the internal temperature at 45-55°C. A sample of the batch was removed and the ethanol content was determined by GC analysis; the criterion was no more than 10 wt% ethanol. If the ethanol wt% was over 10%, an additional 10% of the original volume was distilled and sampled for ethanol wt%. The batch temperature was adjusted to Tint= 18-22°C over no less than 1 hour. The pH of the batch was verified to be pH= 5 – 5.5 and the pH was adjusted, if necessary, with the slow addition of 2 M HCI or 2 M NaOH aqueous solutions. The batch was agitated at Tint= 18-22°C for no less than 6 hours and the solids were collected by filtration. The filtrate/mother liquid was used to remove all solids from reactor. The cake with was washed with water (19.4 Kg) (water temperature was no more than 20 °C). The cake was dried under vacuum at no more than 60 °C for 12 hours or until the LOD was no more than 4% to obtain 1001 (9.52 Kg, 99.6 A% 220 nm, 97.6 wt% as determined by HPLC wt% assay, 99.0% yield).

…………………

compd 1144

http://www.google.com/patents/WO2009062285A1?cl=en

Figure imgf000127_0001

Figure imgf000146_0001

 

 

……………………

http://www.google.com/patents/WO2012138669A1?cl=en

 

Compound (I), (2S)-2-tert-butoxy-2-(4-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2- methylquinolin-3-yl)acetic acid, is an HIV non-catalytic site integrase inhibitor.

 

Compound (I) falls within the scope of the HIV inhibitors disclosed in WO

2007/131350. Compound (I) is disclosed specifically as compound no. 1144 in WO 2009/062285. Compound (I) can be prepared according to the general procedures found in WO 2007/13 350 and WO 2009/062285, which are hereby incorporated by reference.

Example 1

1 a 1b

1a (600 g, 4.1 mol) was charged into a dry reactor under nitrogen followed by addition of Ac20 (1257.5 g, 12.3 mol, 3 eq.). The resulting mixture was heated at 40 °C at least for 2 hours. The batch was then cooled to 30 °C over 30 minutes. A suspension of 1b in toluene was added to seed the batch if no solid was observed. After toluene (600 mL) was added over 30 minutes, the batch was cooled to -5 ~ -10 °C and was held at this temperature for at least 30 minutes. The solid was collected by filtration under nitrogen and rinsed with heptanes (1200 mL). After being dried under vacuum at room temperature, the solid was stored under nitrogen at least below 20 °C. The product 1b was obtained with 77% yield. 1H NMR (500 MHz, CDCI3): δ = 6.36 (s, 1 H), 3.68 (s, 2H), 2.30 (s, 3H).

Example 2

 

2a (100 g, 531 mmol) and 1 b (95 g, 558 mmol) were charged into a clean and dry reactor under nitrogen followed by addition of fluorobenzene ( 000 mL). After being heated at 35-37 °C for 4 hours, the batch was cooled to 23 °C. Concentrated H2S04 (260.82 g, 2659.3 mmol, 5 eq.) was added while maintaining the batch temperature below 35 °C. The batch was first heated at 30-35 °C for 30 minutes and then at 40- 45 °C for 2 hours. 4-Methyl morpholine (215.19 g, 2127 mmol, 4 eq.) was added to the batch while maintaining the temperature below 50 °C. Then the batch was agitated for 30 minutes at 40-50 °C. MeOH ( 00 mL) was then added while maintaining the temperature below 55 °C. After the batch was held at 50-55 °Cfor 2 hours, another portion of MeOH (100 mL) was added. The batch was agitated for another 2 hours at 50-55 °C. After fluorobenzene was distilled to a minimum amount, water (1000 mL) was added. Further distillation was performed to remove any remaining fluorobenzene. After the batch was cooled to 30 °C, the solid was collected by filtration with cloth and rinsed with water (400 mL) and heptane (200 mL). The solid was dried under vacuum below 50 °C to reach KF < 0.1 %. Typically, the product 2b was obtained in 90% yield with 98 wt%. 1H NMR (500 MHz, DMSO- cfe): δ = 10.83 (s, 1 H), 9.85 (s, bs, 1 H), 7.6 (d, 1 H, J = 8.7 Hz), 6.55 (d, 1 H, J = 8.7 Hz), 6.40 (s, 1 H), 4.00 (s, 2 H), 3.61 (s, 3 H).

Example 3

 

2b 3a

2b (20 g, 64 mmol) was charged into a clean and dry reactor followed by addition of THF (140 mL). After the resulting mixture was cooled to 0 °C, Vitride® (Red-AI, 47.84 g, 65 wt%, 154 mmol) in toluene was added while maintaining an internal temperature at 0-5 °C. After the batch was agitated at 5-10 °C for 4 hours, IPA (9.24 g, 153.8 mmol) was added while maintaining the temperature below 10 °C. Then the batch was agitated at least for 30 minutes below 25 °C. A solution of HCI in IPA (84.73 g, 5.5 M, 512 mmol) was added into the reactor while maintaining the temperature below 40 °C. After about 160 mL of the solvent was distilled under vacuum below 40 °C, the batch was cooled to 20-25 °C and then aqueous 6M HCI (60 mL) was added while maintaining the temperature below 40 °C. The batch was cooled to 25 °C and agitated for at least 30 minutes. The solid was collected by filtration, washed with 40 mL of IPA and water (1 V/1 V), 40 mL of water and 40 mL of heptanes. The solid was dried below 60 °C in a vacuum oven to reach KF < 0.5%. Typically, the product 3a was obtained in 90-95% yield with 95 wt%. 1H NMR (400 MHz, DMSO-c/e): 5 = 10.7 (s, 1 H), 9.68 (s, 1 H), 7.59 (d, 1 H, J = 8.7 Hz), 6.64 (, 1 H, J = 8.7 Hz), 6.27 (s, 1 H), 4.62 (bs, 1 H), 3.69 (t, 2H, J = 6.3 Hz), 3.21 (t, 2H, J = 6.3 Hz).

Example 4

3a 4a

3a (50 g, 174.756 mmol) and acetonitrile (200 mL) were charged into a dry and clean reactor. After the resulting mixture was heated to 65 °C, POC13 (107.18 g, 699 mmol, 4 eq.) was added while maintaining the internal temperature below 75 °C. The batch was then heated at 70-75 °C for 5-6 h. The batch was cooled to 20 °C. Water (400 mL) was added at least over 30 minutes while maintaining the internal temperature below 50 °C. After the batch was cooled to 20-25 °C over 30 minutes, the solid was collected by filtration and washed with water (100 mL). The wet cake was charged back into the reactor followed by addition of 1 M NaOH (150 mL). After the batch was agitated at least for 30 minutes at 25-35 °C, verify that the pH was greater than 12. Otherwise, more 6M NaOH was needed to adjust the pH >12. After the batch was agitated for 30 minutes at 25-35 °C, the solid was collected by filtration, washed with water (200 mL) and heptanes (200 mL). The solid was dried in a vacuum oven below 50 °C to reach KF < 2%. Typically, the product 4a was obtained at about 75-80% yield. 1H NMR (400 MHz, CDCI3): δ = 7.90 (d, 1 H, J = 8.4 Hz), 7.16 (s, 1 H), 6.89 (d, 1 H, J = 8.4 Hz), 4.44 (t, 2 H, J = 5.9 Hz), 3.23 (t, 2 H, J = 5.9 Hz). 13C NMR (100 MHz, CDCI3): δ = 152.9, 151.9, 144.9, 144.1 , 134.6, 119.1 , 1 17.0, 1 13.3, 1 1 1.9, 65.6, 28.3.

Example 5

 

4a 5a

Zn powder (54 g, 825 mmol, 2.5 eq.) and TFA (100 mL) were charged into a dry and clean reactor. The resulting mixture was heated to 60-65 °C. A suspension of 4a (100 g, 330 mmol) in 150 mL of TFA was added to the reactor while maintaining the temperature below 70 °C. The charge line was rinsed with TFA (50 mL) into the reactor. After 1 hour at 65±5 °C, the batch was cooled to 25-30 °C. Zn powder was filtered off by passing the batch through a Celite pad and washing with methanol (200 mL). About 400 mL of solvent was distilled off under vacuum. After the batch was cooled to 20-25 °C, 20% NaOAc (ca. 300 mL) was added at least over 30 minutes to reach pH 5-6. The solid was collected by filtration, washed with water (200 mL) and heptane (200 mL), and dried under vacuum below 45 °C to reach KF ≤ 2%. The solid was charged into a dry reactor followed by addition of loose carbon (10 wt%) and toluene (1000 mL). The batch was heated at least for 30 minutes at 45-50 °C. The carbon was filtered off above 35 °C and rinsed with toluene (200 mL). The filtrate was charged into a clean and dry reactor. After about 1000 mL of toluene was distilled off under vacuum below 50 °C, 1000 mL of heptane was added over 30 minutes at 40-50 °C. Then the batch was cooled to 0±5 °C over 30 minutes. After 30 minutes, the solid was collected and rinsed with 200 mL of heptane. The solid was dried under vacuum below 45 °C to reach KF≤ 500 ppm. Typically, the product 5a was obtained in about 90-95 % yield. 1H NMR (400 MHz, CDCI3): δ = 8.93 (m, 1 H), 7.91 (dd, 1 H, J = 1.5, 8 Hz), 7.17 (m 1 H), 6.90 (dd, 1 H, J = 1.6, 8.0 Hz), 4.46-4.43 (m, 2 H), 3.28-3.23 (m, 2 H). 13C NMR (100 MHz, CDCI3): δ = 152.8, 151 .2, 145.1 , 141.0, 133.3, 1 18.5, 1 18.2, 1 14.5, 1 1 1 .1 , 65.8, 28.4.

Example 6

 

5a (1.04 kg, 4.16 mol) and toluene (8 L) were charged into the reactor. The batch was agitated and cooled to -50 to -55 °C. BuLi solution (2.5 M in hexanes, 1.69 L, 4.23 mol) was charged slowly while maintaining the internal temperature between – 45 to -50 °C. The batch was agitated at -45 °C for 1 hour after addition. A solution of triisopropyl borate (0.85 kg, 4.5 mol) in MTBE (1.48 kg) was charged. The batch was warmed to 10 °C over 30 minutes. A solution of 5 N HCI in IPA (1.54 L) was charged slowly at 10 °C, and the batch was warmed to 20 °C and stirred for 30 minutes. It was seeded with 6a crystal (10 g). A solution of aqueous concentrated HCI (0.16 L) in IPA (0.16 L) was charged slowly at 20 °C in three portions at 20 minute intervals, and the batch was agitated for 1 hour at 20 °C. The solid was collected by filtration, rinsed with MTBE (1 kg), and dried to provide 6a (943 g, 88.7 % purity, 80% yield). 1H NMR (400 MHz, D20): δ 8.84 (d, 1 H, J = 4 Hz), 8.10 (m, 1 H), 7.68 (d, 1 H, J = 6 Hz), 7.09 (m, 1 H), 4.52 (m, 2H), 3.47 (m, 2H).

Example 7

7a 7b

Iodine stock solution was prepared by mixing iodine (57.4 g, 0.23 mol) and sodium iodide (73.4 g, 0.49 mol) in water (270 mL). Sodium hydroxide (28.6 g, 0.715 mol) was charged into 220 mL of water. 4-Hydroxy-2 methylquinoline 7a (30 g, 0.19 mol) was charged, followed by acetonitrile (250 mL). The mixture was cooled to 10 °C with agitation. The above iodine stock solution was charged slowly over 30 minutes. The reaction was quenched by addition of sodium bisulfite (6.0 g) in water (60 mL). Acetic acid (23 mL) was charged over a period of 1 hour to adjust the pH of the reaction mixture between 6 and 7. The product was collected by filtration, washed with water and acetonitrile, and dried to give 7b (53 g, 98%). MS 286 [M + 1].

 

7b 8a

4-Hydroxy-3-iodo-2-methylquinoline 7b (25 g, 0.09 mol) was charged to a 1 -L reactor. Ethyl acetate (250 mL) was charged, followed by triethylamine (2.45 mL, 0.02 mol) and phosphorus oxychloride (12 mL, 0.13 mol). The reaction mixture was heated to reflux until complete conversion (~1 hour), then the mixture was cooled to 22 °C. A solution of sodium carbonate (31.6 g, 0.3 mol) in water (500 mL) was charged. The mixture was stirred for 20 minutes. The aqueous layer was extracted with ethyl acetate (120 mL). The organic layers were combined and concentrated under vacuum to dryness. Acetone (50 mL) was charged. The solution was heated to 60 °C. Water (100 mL) was charged, and the mixture was cooled to 22 °C. The product was collected by filtration and dried to give 8a (25 g, 97.3 % pure, 91.4 % yield). MS 304 [M + 1].

(Note: 8a is a known compound with CAS # 1033931-93-9. See references: (a) J. Org Chem. 2008, 73, 4644-4649. (b) Molcules 2010, 15, 3171-3178. (c) Indian J. Chem. Sec B: Org. Chem. Including Med Chem. 2009, 48B(5), 692-696.)

 

8a (100 g, 0.33 mol) was charged to the reactor, followed by copper (I) bromide dimethyl sulfide complex (3.4 g, 0.017 mol) and dry THF (450 mL). The batch was cooled to – 5 to – 2 °C. i-PrMgCI (2.0 M in THF, 173 mL, 0.346 mol) was charged into the reactor at the rate which maintains the batch temperature < -10 °C.

In a 2nd reactor, methyl chlorooxoacetate (33 mL, 0.36 mol) and dry THF (150 mL) was charged. The solution was cooled to -15 to -10 °C. The content of the 1 st reactor (Grignard/cuprate) was charged into the 2nd reactor at the rate which maintained the batch temperature < -10 °C. The batch was agitated for 30 minutes at -10 °C. Aqueous ammonium chloride solution (10%, 300 mL) was charged. The batch was agitated at 20 – 25 °C for 20 minutes and allowed to settle for 20 minutes. The aqueous layer was separated. Aqueous ammonium chloride solution (10%, 90 mL) and sodium carbonate solution (10%, 135 mL) were charged to the reactor. The batch was agitated at 20 – 25 °C for 20 minutes and allowed to settle for 20 minutes. The aqueous layer was separated. Brine (10%, 240 mL) was charged to the reactor. The batch was agitated at 20 – 25 °C for 20 minutes. The aqueous layer was separated. The batch was concentrated under vacuum to -1/4 of the volume (about 80 mL left). 2-Propanol was charged (300 mL). The batch was concentrated under vacuum to -1/3 of the volume (about 140 mL left), and heated to 50 °C. Water (70 mL) was charged. The batch was cooled to 20 – 25 °C, stirred for 2 hours, cooled to -10 °C and stirred for another 2 hours. The solid was collected by filtration, washed with cold 2-propanol and water to provide 58.9 g of 9a obtained after drying (67.8 % yield). 1H NMR (400 MHz, CDCI3): δ 8.08 (d, 1 H, J = 12 Hz), 7.97 (d, 1 H, J = 12 Hz), 7.13 (t, 1 H, J = 8 Hz), 7.55 (t, 1 H, J = 8 Hz), 3.92 (s, 3H), 2.63 (s, 3H). 13C NMR (100 MHz, CDCI3): δ 186.6, 161.1 , 155.3, 148.2, 140.9, 132.0, 129.0, 128.8, 127.8, 123.8, 123.7, 53.7, 23.6.

Example 10

 

Catalyst preparation: To a suitable sized, clean and dry reactor was charged dichloro(pentamethylcyclopentadienyl)rhodium(lll) dimer (800 ppm relative to 9a, 188.5 mg) and the ligand (2000 ppm relative to 9a, 306.1 mg). The system was purged with nitrogen and then 3 ml_ of acetonitrile and 0.3 ml_ of triethylamine was charged to the system. The resulting solution was agitated at RT for not less than 45 minutes and not more than 6 hours.

Reaction: To a suitable sized, clean and dry reactor was charged 9a (1.00 equiv, 100.0 g (99.5 wt%), 377.4 mmol). The reaction was purged with nitrogen. To the reactor was charged acetonitrile (ACS grade, 4 L/Kg of 9a, 400 ml_) and

triethylamine (2.50 equiv, 132.8 ml_, 943 mmol). Agitation was initiated. The 9a solution was cooled to Tint= -5 to 0 °C and then formic acid (3.00 equiv, 45.2 ml_, 1 132 mmol) was charged to the solution at a rate to maintain Tint not more than 20 °C. The batch temperature was then adjusted to Tlnt= -5 to -0 °C. Nitrogen was bubbled through the batch through a porous gas dispersion unit (Wilmad-LabGlass No. LG-8680-1 10, VWR catalog number 14202-962) until a fine stream of bubbles was obtained. To the stirring solution at Jml= -5 to 0 °C was charged the prepared catalyst solution from the catalyst preparation above. The solution was agitated at Tint= -5 to 0 °C with the bubbling of nitrogen through the batch until HPLC analysis of the batch indicated no less than 98 A% conversion (as recorded at 220 nm, 10-14 h). To the reactor was charged isopropylacetate (6.7 L/Kg of 9a, 670 mL). The batch temperature was adjusted to Tint= 18 to 23 °C. To the solution was charged water (10 L/Kg of 9a, 1000 mL) and the batch was agitated at Tint= 18 to 23 °C for no less than 20 minutes. The agitation was decreased and or stopped and the layers were allowed to separate. The lighter colored aqueous layer was cut. To the solution was charged water (7.5 L/Kg of 9a, 750 mL) and the batch was agitated at Tint= 18 to 23 °C for no less than 20 minutes. The agitation was decreased and or stopped and the layers were allowed to separate. The lighter colored aqueous layer was cut. The batch was then reduced to 300 mL (3 L/Kg of 9a) via distillation while maintaining Text no more than 65 °C. The batch was cooled to Tint= 35 to 45 °C and the batch was seeded ( 0 mg). To the batch at Tint= 35 to 45 °C charged heptane (16.7 L/Kg of 9a, 1670 mL) over no less than 1.5 hours. Adjusted the batch temperature to Tint= -2 to 3 °C over no less than 1 hour, and agitated the batch at Tint= -2 to 3 °C for no less than 1 hour. Collected the solids by filtration. Used the filtrate to rinse the reactor (Filtrate is cooled to

-2 to 3 °C before filtration) and the solids were suction dried for no less than 2 hours. The solids were dried until the LOD was no more than 4 % to obtain 82.7 g of 10a (99.6-100 wt%, 98.5% ee, 82.5% yield). 1H- NMR (CDCI3, 400 MHz) δ: 8.20 (d, J= 8.4 Hz, 1 H), 8.01 (d, J= 8.4 Hz, 1 H), 7.73 (t, J= 7.4 Hz, 1 H), 7.59 (t, J= 7.7 Hz, 1 H), 6.03 (s, 1 H), 3.93 (s, 1 H), 3.79 (s, 3H), 2.77 (s, 3H). 13C-NMR (CDCI3, 100 MHz) δ: 173.5, 158.3, 147.5, 142.9, 130.7, 128.8, 127.7, 127.1 , 125.1 , 124.6, 69.2, 53.4, 24.0.

Example 11

 

10a 6a 11a

10a (2.45 kg, 96.8% purity, 8.9 mol), 6a (2.5 kg, 88.7% purity, 8.82 mol), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3, 40 g, 0.044 mol), (S)-3-iert-butyl-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1 ,3]oxaphosphole (32 g, 0.01 1 mol), sodium carbonate (1.12 kg, 10.58 mol), 1 -pentanol (16.69 L), and water (8.35 L) were charged to the reactor. The mixture was de-gassed by sparging with argon for 10-15 minutes, was heated to 60-63 °C, and was agitated until HPLC analysis of the reaction shows <1 A% (220 nm) of the 6a relative to the combined two atropisomer products (-15 hours). The batch was cooled to 8-23 °C. Water (5 L) and heptane (21 L) were charged. The slurry was agitated for 3 – 5 hours. The solids were collected by filtration, washed with water (4 L) and heptane/toluene mixed solvent (2.5 L toluene/5 L heptane), and dried. The solids were dissolved in methanol (25 L) and the resulting solution was heated to 50 °C and circulated through a CUNO carbon stack filter. The solution was distilled under vacuum to ~ 5 L. Toluene (12 L) was charged. The mixture was distilled under vacuum to – 5 L and cooled to 22 °C. Heptane (13 L) was charged to the contents over 1 hour and the resulting slurry was agitated at 20-25 °C for 3 – 4 hours. The solids were collected by filtration and washed with heptanes to provide 2.58 kg of 11a obtained after drying (73% yield). 1H NMR (400 MHz, CDCI3): δ 8.63 (d, 1 H, J = 8 Hz), 8.03 (d, 1 H, J = 12 Hz), 7.56 (t, 1 H, J = 8 Hz), 7.41 (d, 1 H, J = 8 Hz), 7.19 (t, 1 H, J = 8 Hz), 7.09 (m, 2H), 7.04 (d, 1 H, J = 8 Hz), 5.38 (d, 1 H, J = 8 Hz), 5.14 (d, 1 H, J = 8 Hz), 4.50 (t, 2H, J = 4 Hz), 3.40 (s, 3H), 3.25 (t, 2H, J = 4 Hz), 2.91 (s, 3H). 13C NMR (100 MHz, CDCI3): δ 173.6, 158.2, 154.0, 150.9, 147.3, 147.2, 145.7, 141.3, 132.9, 123.0, 129.4, 128.6, 127.8, 126.7, 126.4, 125.8, 1 18.1 , 1 17.3, 109.9, 70.3, 65.8, 52.3, 28.5, 24.0.

 

To a suitable clean and dry reactor under a nitrogen atmosphere was charged 1a (5.47 Kg, 93.4 wt%, 1 .00 equiv, 12.8 mol) and fluorobenzene (10 vols, 51.1 kg) following by trifluoromethanesulfonimide (4 mol%, 143 g, 0.51 mol) as a 0.5 M solution in DCM (1.0 Kg). The batch temperature was adjusted to 35-41 °C and agitated to form a fine slurry. To the mixture was slowly charged i-butyt-2,2,2- trichloroacetimidate 12b as a 50 wt% solution (26.0 Kg of f-butyl-2,2,2- trichloroacetimidate (119.0 mol, 9.3 equiv), the reagent was -48-51 wt% with the remainder 52-49 wt% of the solution being ~ 1.8:1 wt:wt heptane: fluorobenzene) over no less than 4 hours at Tint= 35-41 °C. The batch was agitated at Tint= 35-41 °C until HPLC conversion (308 nm) was >96 A%, then cooled to Tlnt= 20-25 °C and then triethylamine (0.14 equiv, 181 g, 1.79 mol) was charged followed by heptane (12.9 Kg) over no less than 30 minutes. The batch was agitated at Tint= 20-25 °C for no less than 1 hour. The solids were collected by filtration. The reactor was rinsed with the filtrate to collect all solids. The collected solids in the filter were rinsed with heptane (1 1.7 Kg). The solids were charged into the reactor along with 54.1 Kg of DM Ac and the batch temperature adjusted to Tint= 70-75 °C. Water (1 1.2 Kg) was charged over no less than 30 minutes while the batch temperature was maintained at Tint= 65-75 °C. 12a seed crystals (34 g) in water (680 g) was charged to the batch at Tint= 65-75 °C. Additional water (46.0 Kg) was charged over no less than 2 hours while maintaining the batch temperature at Tint= 65-75 °C. The batch temperature was adjusted to Tint= 18-25 °C over no less than 2 hours and agitated for no less than 1 hour. The solids were collected by filtration and the filtrate used to rinse the reactor. The solids were washed with water (30 Kg) and dried under vacuum at no more than 45 °C until the LOD < 4% to obtain 12a (5.275 Kg, 99.9 A% at 220 nm, 99.9 wt% via HPLC wt% assay, 90.5% yield). H-NMR (CDCI3l 400 MHz) δ: 8.66-8.65 (m, 1 H), 8.05 (d, J= 8.3 Hz, 1 H), 7.59 (t, J= 7.3 Hz, 1 H), 7.45 (d, J= 7.8 Hz, 1 H), 7.21 (t, J= 7.6 Hz, 1 H), 7.13-7.08 (m, 3H), 5.05 (s, H), 4.63-4.52 (m, 2H), 3.49 (s, 3H), 3.41 -3.27 (m, 2H), 3.00 (s, 3H), 0.97 (s, 9H). 13C-NMR (CDCI3, 100 MHz) δ: 172.1 , 159.5, 153.5, 150.2, 147.4, 146.9, 145.4, 140.2, 131.1 , 130.1 , 128.9, 128.6, 128.0, 127.3, 126.7, 125.4, 1 17.7, 1 17.2, 109.4, 76.1 , 71.6, 65.8, 51.9, 28.6, 28.0, 25.4.

Example 13

 

To a suitable clean and dry reactor under a nitrogen atmosphere was charged 12a (9.69 Kg, 21.2 mol) and ethanol (23.0 Kg). The mixture was agitated and the batch temperature was maintained at Tjnt= 20 to 25 °C. 2 M sodium hydroxide (17.2 Kg) was charged at Tint= 20 to 25 °C and the batch temperature was adjusted to Tlnt= 60- 65°C over no less than 30 minutes. The batch was agitated at Tint= 60-65°C for 2-3 hours until HPLC conversion was >99.5% area (12a is <0.5 area%). The batch temperature was adjuted to Tint= 50 to 55°C and 2M aqueous HCI (14.54 Kg) was charged. The pH of the batch was adjusted to pH 5.0 to 5.5 (target pH 5.2 to 5.3) via the slow charge of 2M aqueous HCI (0.46 Kg) at Tint= 50 to 55°C. Acetonitrile was charged to the batch (4.46 Kg) at Τ,ηί= 50 to 55°C. A slurry of seed crystals (1001 , 20 g in 155 g of acetonitrile) was charged to the batch at Tint= 50 to 55°C. The batch was agitated at Tint= 50 to 55°C for no less than 1 hour (1-2 hours). The contents were vacuum distilled to -3.4 vol (32 L) while maintaining the internal temperature at 45-55°C. A sample of the batch was removed and the ethanol content was determined by GC analysis; the criterion was no more than 10 wt% ethanol. If the ethanol wt% was over 10%, an additional 10% of the original volume was distilled and sampled for ethanol wt%. The batch temperature was adjusted to Tint= 8-22°C over no less than 1 hour. The pH of the batch was verified to be pH= 5 – 5.5 and the pH was adjusted, if necessary, with the slow addition of 2 M HCI or 2 M NaOH aqueous solutions. The batch was agitated at Tint= 18-22°C for no less than 6 hours and the solids were collected by filtration. The filtrate/mother liquid was used to remove all solids from reactor. The cake with was washed with water (19.4 Kg) (water temperature was no more than 20 °C). The cake was dried under vacuum at no more than 60 °C for 12 hours or until the LOD was no more than 4% to obtain 1001 (9.52 Kg, 99.6 A% 220 nm, 97.6 wt% as determined by HPLC wt% assay, 99.0% yield). Example 14

Hydrochloride salt of Compound (I), Type A

Compound (I) (263 mg) was added to a vial of ethanol (1.5 ml_), and then 36.5% HCL aqueous solution (59 mg) was added. The mixture was heated to 70 °C; and stirred at this temperature until solid material was obtained. The mixture was cooled to 20 °C over a period of 10 hours. After cooling, isopropanol (400 μΙ_) was added over a period of 3 hours. The resulting solids were collected and characterized as the hydrochloride salt of Compound (I), Type A.

The hydrochloride salt of Compound (I), Type A was prepared analogously to the aforementioned procedure using methyl ethyl ketone, tetrahydrofuran, acetonitrile, ethyl acetate, dichloroethane and methyl-t-buyl ether instead of ethanol.

 

References

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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