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Monday, 4 July 2016

MK-8876

STR1

MK 8876
CAS 1426960-33-9
2-(4-Fluorophenyl)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethanesulfonamido)-1-benzofuran-3-carboxamide
 2-(4-Fluorophenyl)-5-(11-fluoro-6H-pyrido[2',3':5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-[methyl(methylsulfonyl)amino]-3-benzofurancarboxamide
Molecular Formula C32H24F2N4O5S
Molecular Weight 614.62
  • Originator Merck & Co
  • Class Antivirals
  • Phase I Hepatitis C

Most Recent Events

  • 11 Oct 2013 Phase-I clinical trials in Hepatitis C in Germany (PO)
  • 11 Oct 2013 Phase-I clinical trials in Hepatitis C in Moldova (PO)
  • 23 Aug 2013 Preclinical trials in Hepatitis C in USA (PO)
DATA
2-(4-Fluorophenyl)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethanesulfonamido)-1-benzofuran-3-carboxamide
MK-8876 off-white solid
1H NMR (500 MHz, DMSO-d6) δ 8.56 (q, J = 4.7 Hz, 1H), 8.06–8.01 (m, 2H), 8.05 (s, 1H), 7.86 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.46–7.40 (m, 2H), 7.29–7.22 (m, 1H), 7.11 (s, 1H), 6.94 (dd, J = 10.6, 7.9 Hz, 1H), 6.27 (s, 2H), 3.31 (s, 3H), 2.96 (s, 3H), 2.85 (d, J = 4.7 Hz, 3H);
13C NMR (125.7 MHz, DMSO-d6) δ 162.86, 162.82 (d, JC–F = 248.5 Hz), 155.74 (d, JC–F = 246.1 Hz), 153.80, 152.43, 152.28, 147.20, 137.08, 137.00 (d, JC–F = 10.8 Hz), 136.36, 136.20, 132.37, 129.50 (d, JC–F = 8.6 Hz), 127.17, 125.45 (d, JC–F = 3.1 Hz), 125.08, 125.02, 123.70 (d, JC–F = 7.7 Hz), 122.28, 117.23 (d, JC–F = 22.4 Hz), 116.01 (d, JC–F = 21.9 Hz), 113.65, 111.76, 106.90 (d,JC–F = 3.5 Hz), 105.32 (d, JC–F = 18.5 Hz), 94.16, 73.57, 39.39, 37.24, 26.16;
HR-ESI-MS m/zcalcd for C32H25N4O5SF2+ [M + H]+ 615.1514, found 615.1500.
. HPLC Method and Retention Time Data
HPLC Method
columnAscentis Express C18 2.7 μm (fused core), 100 mm × 4.6 mm
detectionUV at 210 nm
column temperature40 °C
flow rate1.8 mL/min
injection volume5.0 μL
gradient90% A to 5% A over 11 min, hold at 5% A for 2 min, 5% A back to 90% A over the next 0.1 min, and then hold at 90% A for 2.9 min
run time16 min
data collectionacquisition for the first 13 min
mobile phasessolvent A: water with 0.1% H3PO4
 solvent B: acetonitrile
Retention Time Data
identitytR (min)
boronic acid 274.24
desbromoarene 285.33
MK-8876 (1)7.89
chloropyridine starting material 28.03
BHT10.22

SYNTHESIS 

Figure imgf000211_0002
Figure imgf000212_0002
Figure imgf000213_0001
STR1
CONTD...............
STR1


STR1
MK 8876
Figure imgf000207_0002
Figure imgf000211_0001
Figure imgf000211_0002
Figure imgf000212_0002
Figure imgf000213_0001
Figure imgf000213_0002
Figure imgf000214_0001
Figure imgf000207_0001
MK 8876
Patent
Scheme 1
Figure imgf000024_0001

Scheme 2
Figure imgf000025_0001

Scheme 3
Figure imgf000026_0001
Q

Scheme 4
Figure imgf000027_0001

EXAMPLES
Example 1
Preparation of Compound 1
Figure imgf000028_0001THIS COMPD HAS ONE FLUORO MISSING, APPLY TO YOUR MK  8876
Step 1 - Synthesis of 2,6-dichloropyridin-3-ol
Figure imgf000028_0002
Η202 (1.60 g, 47.12 mmol) was added slowly to the solution of compound 2,6- dichloropyridin-3-ylboronic acid (3 g, 15.71 mmol) in CH2CI2 (30 mL) at 0 °C. After stirred at room temperature for about 15 hours, the mixture was quenched with sat. Na2S203 aqueous (50 mL) and adjusted to pH < 7 with IN HC1. The mixture was extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (100 mL), dried over Na2S04, filtered and the solvent was evaporated to provide2,6-dichloropyridin-3-ol (2.34 g, yield: 91.4%). 1H-NMR (CDC13, 400 MHz) δ 7.30 (d, / = 8.4 Hz, 1H), 7.19 (d, / = 8.4 Hz, 1H), 5.70 (br, 1H).
- Synthesis of 2,6-dichloro- -methoxypyridine
Figure imgf000028_0003
To a solution of 2,6-dichloropyridin-3-ol (16.3 g, 0.1 mol) and K2C03 (41.4 g, 0.3 mol) in DMF (200 mL) were added Mel (21.3 g, 0.15 mol). The mixture was allowed to stir at 80 °C for 2 hours. The mixture was then diluted with water (200 mL) and extracted with EtOAc (200 mL x 3). The organic layer was washed with brine (200 mL x 3), dried over Na2S04, filtered and the solvent was evaporated to provide 2,6-dichloro-3-methoxypyridine (17.0 g, yield: 96.0%). 1H-NMR (CDC13, 400 MHz) δ 7.12-7.18 (m, 2H), 3.86 (s, 3H). Step 3 - Synthesis of2-(6-chloro-3-methoxypyridin-2-yl)-lH-indole
Figure imgf000029_0001
To a degassed solution of compound 2,6-dichloro-3-methoxypyridine (8.9 g, 0.05 mol), (l-(tert-butoxycarbonyl)-lH-indol-2-yl)boronic acid (13 g, 0.05 mol) and K3PO4 (31.8 g, 3.0 mol) in DMF (100 mL) was added Pd(dppf)Cl2 (3.65 g, 0.005 mol) under N2. The mixture was heated at 60 °C for about 15 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered. The filtrate was washed with H20, brine, dried over Na2S04. After being concentrated in vacuo, the resulting residue was purified using prep-HPLC to provide the desired product of 2-(6-chloro-3-methoxypyridin-2-yl)-lH-indole (9.0 g, yield:
69.8%). 1H-NMR (CDC13, 400 MHz) δ 9.52 (s, 1H), 7.65 (d, / = 7.6 Hz, 1H), 7.38-7.43 (m, 2H), 7.07-7.26 (m, 4H), 4.03 (s, 3H).
Step 4 - Synthesis of6-chlor -2-(lH-indol-2-yl)pyridin-3-ol
Figure imgf000029_0002
BBr3 (0.4 mL, 0.39 mmol) was added to the solution of 2-(6-chloro-3- methoxypyridin-2-yl)-lH-indole (50 mg, 0.194 mmol) in CH2C12 (0.5 mL) at -78 °C under N2. The mixture was allowed to stir at room temperature for 3 hours. The mixture was then quenched with CH3OH (10 mL) at -78 °C. After being concentrated in vacuo, the resulting residue was purified using prep-TLC (PE : EtOAc = 2.5 : 1) to afford the desired product of 6- chloro-2-(lH-indol-2-yl)pyridin-3-ol (40 mg, yield: 85.1%). 1H-NMR (CDC13, 400 MHz) δ 10.09 (s, 1H), 9.72 (s, 1H), 7.50 (d, / = 7.9 Hz, 1H), 7.17-7.32 (m, 3H), 7.08-7.14 (m, 1H), 6.87-6.96 (m, 2H).
Step 5 - Synthesis of 2-chlo -6H-pyrido[2' ,3' : 5 ,6] [ 1 ,3]oxazino[3 ,4-a]indole
Figure imgf000029_0003
To a solution of chloroiodomethane (3.51 g, 20.0 mmol) and K2CO3 (1.38 g, 10.0 mmol) in DMF (50 mL) was allowed to stir at 100 °C, 6-chloro-2-(lH-indol-2-yl)pyridin-3-ol (480 mg, 2.0 mmol) in DMF (50 mL) was added dropwise. After addition, the mixture was allowed to stir for another 0.5 hours. The mixture was then diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine (100 mL x 3), dried over Na2S04 and concentrated. The residue was purified using prep-TLC (PE : EtOAc = 3 1) to afford the desired product of 2-chloro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (260 mg, yield: 50.7%). 1H-NMR (CDC13, 400 MHz) δ 7.63 (d, / = 8.0 Hz, 1H), 7.22-7.27 (m, 3H), 7.19 (d, / = 2.4 Hz, 1H), 7.08-7.12 (m, 2H), 5.86 (s, 2H).
Step 6 - Synthesis of2-(4-fluowphenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(6H- pyridol 2 ',3':5,6][ l, mpound 1 )
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (502 mg, 1.0 mmol), 2-chloro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (256 mg, 1.0 mmol) and K3PO4 (636 mg, 3.0 mmol) in dioxane : H20 (1.5 mL : 0.4 mL) was added Pd2(dba)3 (91 mg, 0.1 mmol) and X-phos (91 mg, 0.2 mmol) under N2. The mixture was heated to 110 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered. The filtrate was washed with H20, brine, dried over Na2S04. After being concentrated in vacuo, the resulting residue was purified using prep-HPLC to provide the desired product of Compound 1 (275 mg, yield: 46.1%). 1H-NMR (CDC13, 400 MHz) δ 7.88-7.94 (m, 3H), 7.61-7.63 (m, 2H), 7.40 (s, 2H), 7.09-7.28 (m, 6H), 5.94 (s, 2H), 5.86 (d, / = 4.4 Hz, 1H), 3.29 (s, 3H), 2.92 (d, / = 5.2 Hz, 3H), 2.65 (s, 3H). MS (M+H)+: 596.
Compounds 2-15, depicted in the table below, were prepared using the method described above.
COMPD 2 IS MK 8876
Figure imgf000031_0001
PATENT
Example 81
Preparation of Compound 2
Figure imgf000207_0001
Synthesis of ethyl 3- 4-fluorophenyl)-3-oxopropanoate
Figure imgf000207_0002
Diethyl carbonate (130 g, 1.1 mol) was dissolved in a suspension ofNaH (60% in oil, 50.2 g, 1.3 mol) in anhydrous tetrahydrofuran (1.5 L), and then l-(4-fluorophenyl)ethanone (150 g, 1.09 mol) was added dropwise at 70 °C. The resulting mixture was stirred at 70 °C for 3 hours. After the reaction mixture was cooled to room temperature and poured into HCl (1 N). The mixture was extracted with EtOAc, the organic phase was dried with anhydrous NaS04 and concentrated in vacuo. The resulting residue was purified using column chromatography (eluted with petroleum ether / EtOAc = 50 / 1) to provide ethyl 3-(4-fluorophenyl)-3-oxopropanoate (217 g, yield: 95%). 1H-NMR (CDC13, 400 MHz) δ 7.92-7.97 (m, 2H), 7.07-7.13 (m, 2H), 4.14-4.20 (m, 2H), 3.93 (s, 2H), 1.22 (d, J= 7.2 Hz, 3H). MS (M+H)+: 211. Step 2 - Synthesis of ethyl 5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate
Figure imgf000207_0003
A solution of ethyl 3-(4-fluorophenyl)-3-oxopropanoate (130 g, 0.6 mol), 4- bromophenol (311 g, 1.8 mol) and FeCl3-6H20 (19.5 g, 0.09 mol) in DCE (700 mL) was heated to reflux, and then 2-(tert-butylperoxy)-2-methylpropane (193 g, 1.32 mol) was added dropwise under nitrogen. After 6 hours of refluxing, the mixture was cooled to RT, quenched with saturated NaHS03 and extracted with dichloromethane. The organic phases were washed with water, brine and dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether / dichloromethane = 15 / 1) to provide the crude product, which was crystallized from cold MeOH to provde ethyl 5-bromo-2- (4-fluorophenyl)benzofuran-3-carboxylate (37 g, yield: 14.3%) as solid. 1H- MR (CDC13, 400 MHz) δ 8.12 (s, 1H), 7.97-8.01 (m, 2H), 7.37 (d, J= 4.0 Hz, 1H), 7.32 (d, J= 8.0 Hz, 1H), 7.11 (t, J= 8.0 Hz, 2H), 4.32-4.38 (m, 2H), 1.36 (t, J= 8.0 Hz, 3H). MS (M+H)+: 363 / 365.
Step 3 - Synthesis of eth l 5-bromo-2-(4-fluorophen -6-nitrobenzofuran-3-carboxylate
Figure imgf000208_0001
To a solution of ethyl 5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate (50 g,
137.6 mmol) in CHC13 (500 mL), fuming HN03 (50 mL) was added dropwise at -15 °C and the mixture was stirred for 0.5 hour. The reaction mixture was poured into ice water and extracted with CH2C12. The organic layer was washed with a.q. sat. NaHC03 and brine, after removed the most of solvent, the resulting residue was crystallized with petroleum ether / dichloromethane = 20 / 1 to provide product of ethyl 5-bromo-2-(4-fluorophenyl)-6-nitrobenzofuran-3-carboxylate (35 g, yield: 66%). 1H- MR (CDC13, 400 MHz) δ 8.36 (s, 1H), 8.02-8.04 (m, 3H), 7.13-7.18 (m, 2H), 4.36-4.41 (m, 2H), 1.37 (t, J= 4.0 Hz, 3H). MS (M+H)+: 408 / 410.
Step 4 - Synthesis of ethyl 6-amino-5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate
Figure imgf000208_0002
A mixture of ethyl 5-bromo-2-(4-fluorophenyl)-6-nitrobenzofuran-3-carboxylate (52 g, 127 mmol), iron filings (21.3 g, 382.2 mmol) and H4C1 (41 g, 764.4 mmol) in MeOH / THF / H20 (2 / 2 / 1, 500 mL) was stirred at reflux for 3 hour. After filtered and concentrated, the resulting residue was purified using column chromatography (petroleum ether / EtOAc / dichloromethane = 20 : 1 : 20) to provide ethyl 6-amino-5-bromo-2-(4-fluorophenyl) benzofuran-3-carboxylate (40 g, yield: 82%). 1H- MR (CDC13, 400 MHz) δ 8.01 (s, 1H), 7.94-7.98 (m, 2H), 7.08 (t, J= 8.0 Hz, 2H), 6.83 (s, 1H), 4.32-4.36 (m, 2H), 4.18 (s, 2H), 1.35 (t, J= 8.0 Hz, 3H). MS (M+H)+: 378 / 380.
Step 5 - Synthesis of 5-Bromo-2-(4-fluoro-phenyl)-6-methanesulfonylamino-benzofuran-3- carboxylic acid eth l ester
Figure imgf000209_0001
MsCI (31.7 g, 277.5 mmol) was added to a solution of ethyl 6-amino-5-bromo-2- (4-fluorophenyl)benzofuran-3-carboxylate (35 g, 92.5 mmol) and pyridine (60 mL) in
dichloromethane (300 mL) at 0 °C. After stirred overnight at room temperature, the mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo, the resulting residue was purified using crystallized with EtOAc to provde the pure product of ethyl 5-bromo-2-(4-fluorophenyl)-6- (methylsulfonamido)benzofuran-3-carboxylate (35 g, yield: 82%). 1H- MR (CDC13, 400 MHz) δ 8.27 (s, 1H), 8.01-8.05 (m, 2H), 7.87 (s, 1H), 7.15-7.19 (m, 2H), 6.87 (s, 1H), 4.38-4.43 (m, 2H), 3.00 (s, 3H), 1.40 (t, J= 40 Hz, 3H). MS (M+H)+: 456 / 458.
Step 6 - Synthesis of 5-Bromo-2-(4-fluoro-phenyl)-6-methanesulfonylamino-benzofuran-3- carboxylic acid
Figure imgf000209_0002
To a solution of ethyl 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido) benzofuran-3-carboxylate (53 g, 0.23 mol) in dioxane / H20 (5 / 1, 600 mL) was added
LiOH-H20 (25 g, 1.17 mol), and the mixture was stirred at 100 °C for 3 hours. After
concentrated, the resulting residue was dissolved in H20, 1 N HCl was added until pH reached 3, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and filtered. The solvent was removed to provide the product of 5-bromo-2-(4- fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (48 g, yield: 96%).1H- MR (DMSO- e, 400 MHz) δ 13.49 (s, 1H), 9.67 (s, 1H), 8.30 (s, 1H), 8.12-8.17 (m, 2H), 7.87 (s, 1H), 7.45-7.50 (m, 2H), 3.16 (s, 3H). MS (M+H)+: 428 / 430. Step 7 - Synthesis of 5-Bromo-2-(4-fluoro-phenyl)-6-methanesulfonylamino-benzofuran-3- carboxylic acid methylamide
Figure imgf000210_0001
A solution of 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido) benzofuran-3- carboxylic acid (33 g, 77 mmol), HOBT (15.6 g, 115.5 mmol) and EDCI (22.2 g, 115.5 mmol) in DMF (250 mL) was stirred at room temperature. After 2 hours, Et3N (50 mL) and CH3 H2 (HC1 salt, 17.7 g, 231 mmol) was added to the mixture, and the mixture was stirred overnight. After the solvent was removed, H20 was added and the mixture was extracted with ethyl acetate. The combined organic layer was washed with H20, brine and concentrated in vacuo. The resulting residue was washed with EtOAc to provide the product of 5-bromo-2-(4-fluorophenyl)-N- methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (32 g, yield: 94%). 1H- MR (DMSO- ck, 400 MHz) δ 9.55 (br s, 1H), 8.46-8.48 (m, 1H), 8.12-8.17 (m, 2H), 7.96 (s, 1H), 7.87 (s, 1H), 7.45-7.50 (m, 2H), 3.16 (s, 3H), 2.93 (d, J= 8.4 Hz, 3H). MS (M+H)+: 441 / 443.
Step 8 - Synthesis of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido benzofuran-3-carboxamide
Figure imgf000210_0002
CH3I (31.6 g, 223 mmol) was added to a mixture of 5-bromo-2-(4-fluorophenyl)- N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (32 g, 74 mmol), K2C03 (25.6 g, 186 mmol) and KI (246 mg, 1.5 mmol) in DMF (150 mL) under N2 protection. The mixture was stirred at 80-90 °C overnight. After concentrated in vacuo, the resulting residue was washed with water (200 mL) and EtOAc (200 mL) to provide the product of 5-bromo-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (31.5 g, 94%). 1H- MR (CDCI3, 400 MHz) δ 8.16 (s, 1H), 7.88-7.92 (m, 2H), 7.70 (s, 1H), 7.18-7.23 (m, 2H), 5.78 (br s, 1H), 3.34 (s, 3H), 3.09 (s, 3H), 3.00 (d, J= 4.8 Hz, 3H). MS (M+H)+: 455 / 457. Step 9 - Synthesis of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4, 4, 5, 5- tetramethyl-1 -dioxaborolan-2-yl)benzofuran-3-carboxamide
Figure imgf000211_0001
a degassed solution of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (1.0 g, 2.2 mmol) and pinacol diborane (2.79 g, 11.0 mmol) in 1,4-Dioxane (25 mL) was added KOAc (647 mg, 6.6 mmol) under N2 and stirred for 4 hours at room temperature. Then Pd(dppf)Cl2 (60 mg) was added, and the mixture was stirred for another 30 minutes. Then the mixture was put into a pre-heated oil-bath at 130 °C and stirred for another 1 hour under N2. The reaction mixture was cooled to room
temperatureand concentrated and extracted with EtOAc. The organic layers were washed with brine, dried over Na2S04. After concentrated, the crude product of the boronic ester was purified using column chromatography (petroleum ether / EtOAc = 5 / 1 to 2 / 1) to obtain 2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzofuran-3-carboxamide as white solid (700 mg, yield: 64%). 1H- MR (CDCI3, 400 ΜΗζ) δ 8.17 (s, 1H), 7.87-7.91 (m, 2H), 7.52 (s, 1H), 7.11 (t, 7= 7.6 Hz, 2H), 5.81 (d, 7= 2.8 Hz, 1H), 3.30 (s, 3H), 2.97 (d, 7= 5.2 Hz, 3H), 2.90 (s, 3H), 1.31 (s, 12H). MS (M+H)+: 503.
Step 10 - Synthesis of tert-butyl 4-fluoro-lH-indole-l -car boxy late
Figure imgf000211_0002
To a solution of 4-fluoro-lH-indole (5 g, 0.11 mol) and DMAP (150 mg, 3%Wt) in THF (50 mL) was added (Boc)20 (8.5 g, 0.04 mol) dropwise. The mixture was stirred at room temperature for 2 hours. The organic solvent was removed in vacuo, and the resulting residue was purified using column chromatography (pure petroleum ether) to provide tert-butyl 4-fluoro- lH-indole-l-carboxylate (8.3 g, yield: 96%). 1H- MR (CDC13, 400 MHz) δ 7.92 (d, J= 8.4 Hz, 1H), 7.55 (d, J= 3.6 Hz, 1H), 7.23 (m, 1H), 6.90 (m, 1H), 6.66 (d, J= 3.6 Hz, 1H), 1.67 (s, 9H). MS (M+H)+: 236.
Step 11 - Synthesis of (l-(tert-butoxycarbonyl)-4-fluoro-lH-indol-2-yl)boronic acid
Figure imgf000212_0001
To a solution of diisopropylamine (7.5 mL, 0.11 mol) in THF (35 mL) at 0 °C was added «-BuLi (21 mL, 0.055 mol) dropwise. The mixture was stirred at 0 °C for 40 minutes. Then the mixture was cooled to -78 °C. Tert-butyl 4-fluoro-lH-indole-l-carboxylate (5 g, 0.02 mol) in THF (13 mL) was added dropwise slowly. After addition, the mixture was stirred at -78 °C for 2 hours. Then triisopropyl borate (3.29 g, 0.03 mol) was added. The mixture was stirred at -78 °C for another 40 minutes. The reaction was monitored using TLC. When the reaction was completed, the mixture was adjusted to pH = 6 with 1 N HC1. After extracted with EtOAc (25 mL x 3), the combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered and concentrated in vacuo. The obtained solid was recrystallized with EtOAc and petroleum ether to provide (l-(tert-butoxycarbonyl)-4-fluoro-lH-indol-2-yl)boronic acid (4.5 g, yield: 76.7%, which might be unstable at high temp, work up, store in fridge). 1H- MR (CDC13, 400 MHz) δ 7.77 (d, J= 8.4 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 2H), 7.24 (m, 1H), 6.90 (m, 1H), 1.66 (s, 9H). MS (M+H)+: 280.
Step 12 - Synthesis of 6-chloro-2-iodopyridin-3-ol
Figure imgf000212_0002
6-chloropyridin-3-ol (5.0 g, 38.6 mmol) was dissolved in water (50 mL) and placed under an N2 atmosphere. Na2C03 (8.2 g, 77.4 mmol) was added followed by iodine (9.8 g, 38.8 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into 1M Na2S203 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04 and concentrated to provide the product of 6-chloro-2- iodopyridin-3-ol (7.0 g, yield: 70.9%). 1H- MR (CDC13, 400 MHz) δ 7.17 (d, J= 8.4 Hz, 1H), 7.06 (d, J= 8.4 Hz, 1H). MS (M+H)+: 256 / 258.
Step 13 - Synthesis of 6-chloro-2-(4-fluoro-lH-indol-2-yl)pyridin-3-ol
Figure imgf000213_0001
A mixture of (l-(tert-butoxycarbonyl)-4-fluoro-lH-indol-2-yl)boronic acid (5 g, 18.0 mmol), 6-chloro-2-iodopyridin-3-ol (3.82 g, 15.0 mol) and NaHC03 (3.78 g, 45.0 mol) in 1, 4-dioxane (76 mL) and water (7 mL) was stirred at room temperature for 15 minutes. Then Pd(PPh3)2Cl2 (527 mg, 0.75 mmol) was added under nitrogen atmosphere, and the mixture was heated at 100 °C under N2 for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), filtered and concentrated in vacuo. The resulting residue was diluted with H20 (60 mL) and EtOAc (30 mL), and the layer was separated, the aqueous layer was extracted with EtOAc (3*30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether / EtOAc = 20 / 1 ~ 3 / 1) to provide 6-chloro-2- (4-fluoro-lH-indol-2-yl)pyridin-3-ol (3 g, yield: 76.5%). 1H- MR (MeOD, 400 MHz) δ 7.36 (s, 1H), 7.23-7.27 (m, 2H), 7.03-7.11 (m, 2H), 6.63-6.68 (m, 1H). MS (M+H)+: 263 / 265.
Ste 14 - Synthesis of 2-chloro-ll-fluoro-6H-pyrido[2',3':5, 6][l,3]oxazino[3,4-a]indole
Figure imgf000213_0002
A solution of 6-chloro-2-(4-fluoro-lH-indol-2-yl)pyridin-3-ol (2 g, 7.6 mmol) and Cs2C03 (7.46 g, 22.89 mmol) in DMF (100 mL) was stirred at 100 °C (internal temperature) for 15 min, and then chloroiodomethane (2.85 g, 15.3 mmol) in DMF (2 mL) was added dropwise. After the reaction was completed, the mixture was filtered and concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether:EA=10: l) to provde 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (1.8 g, yield: 86.1%). 1H- MR (DMSO-i¾, 400 MHz) δ 7.64 (d, J= 8.8 Hz, 1H), 7.39-7.46 (m, 2H), 7.21-7.25 (m, 1H), 7.06 (s, 1H), 6.88-6.92 (m, 1H), 6.18 (s, 2H). MS (M+H)+: 275 / 277. Step 15 - Synthesis of5-(ll-fluoro-6H-pyrido[2 3':5, 6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxam
Figure imgf000214_0001
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (100 mg, 0.199 mmol), 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indole (56 mg, 0.199 mmol) and Κ3Ρ04·3Η20 (159 mg, 0.597 mmol) in dioxane / H20 (0.8 mL / 0.2 mL) was added Pd2(dba)3 (9 mg, 0.01 mmol) and X-Phos (9 mg, 0.02 mmol) under N2. The mixture was heated at 80 °C for 1 hour. The mixture was then diluted with water (30 mL) and extracted with EtOAc (15 mL x 3). The organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether / EtOAc = 1 : 1.5) to provde the pure product of 5-(l l-fluoro-6H- pyrido [2', 3 ' : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (60 mg, 48.8%). 1H- MR (CDC13, 400 MHz) δ: 7.99 (s, 1H), 7.93-7.96 (m, 2H), 7.65 (s, 1H), 7.45-7.50 (m, 2H), 7.17-7.21 (m, 4H), 7.10 (d, J= 8.0 Hz, 1H), 6.81-6.85 (m, 1H), 5.98 (s, 3H), 3.35 (s, 3H), 2.98 (d, J= 4.8 Hz, 3H), 2.72 (s, 3H). MS (M+H)+: 615.

Paper
Abstract Image
We describe the route development and multikilogram-scale synthesis of an HCV NS5B site D inhibitor, MK-8876. The key topics covered are (1) process improvement of the two main fragments; (2) optimization of the initially troublesome penultimate step, a key bis(boronic acid) (BBA)-based borylation; (3) process development of the final Suzuki–Miyaura coupling; and (4) control of the drug substance form. These efforts culminated in a 28 kg delivery of the desired active pharmaceutical ingredient.

Process Development of the HCV NS5B Site D Inhibitor MK-8876

 Department of Process Research and Development, Merck Research Laboratories, Rahway, New Jersey 07065, United States
 Department of Process Chemistry, Merck Sharp & Dohme Ltd., Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, United Kingdom
§ Werthenstein BioPharma GmbH (MSD Switzerland), Industrie Nord 1, CH-6105 Schachen, Switzerland
 WuXi AppTec Co., Ltd., No. 1 Building, #288 FuTe ZhongLu, WaiGaoQiao Free Trade Zone, Shanghai 200131, China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00405
*E-mail: qinghao.chen@merck.com
PAPER
Abstract Image
Using the Teasdale method, purge factor estimates for six impurities identified as mutagenic alerts in the synthesis of MK-8876 are compared to actual measured amounts of these impurities determined via appropriate analytical methods. The results from this comparison illustrate the conservative nature of purge factor estimates, meaning that overprediction of mutagenic impurity purging is unlikely when using this method. Industry and regulatory acceptance of the purge factor estimation method may help minimize analytical burden in pharmaceutical development projects.

Evaluation and Control of Mutagenic Impurities in a Development Compound: Purge Factor Estimates vs Measured Amounts

 Merck and Co., Rahway, New Jersey 07065, United States
 Advanced Polymer Technology, The Dow Chemical Company, 400 Arcola Road, Collegeville, Pennsylvania 19426, United States
Org. Process Res. Dev.201519 (11), pp 1531–1535
DOI: 10.1021/acs.oprd.5b00263
*E-mail: mark_mclaughlin@merck.com.
This article is part of the Genotoxic Impurities 2015 special issue.
WO2004041201A2 *Oct 31, 2003May 21, 2004Viropharma IncorporatedBenzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis c viral infections and associated diseases
WO2011106992A1 *Mar 2, 2011Sep 9, 2011Merck Sharp & Dohme Corp.Inhibitors of hepatitis c virus ns5b polymerase
WO2004041201A2 *Oct 31, 2003May 21, 2004Viropharma IncorporatedBenzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis c viral infections and associated diseases
WO2010030592A1 *Sep 8, 2009Mar 18, 2010Bristol-Myers Squibb CompanyCompounds for the treatment of hepatitis c
WO2011106992A1 *Mar 2, 2011Sep 9, 2011Merck Sharp & Dohme Corp.Inhibitors of hepatitis c virus ns5b polymerase
Citing PatentFiling datePublication dateApplicantTitle
WO2014123794A1 *Feb 3, 2014Aug 14, 2014Merck Sharp & Dohme Corp.Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c
WO2014123795A2 *Feb 3, 2014Aug 14, 2014Merck Sharp & Dohme Corp.Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c
WO2014123795A3 *Feb 3, 2014Oct 30, 2014Merck Sharp & Dohme Corp.Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c
US9242998Feb 3, 2014Jan 26, 2016Merck Sharp & Dohme Corp.Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis C
//////MK-8876, 1426960-33-9, Merck & Co, Antivirals, Phase I,  Hepatitis C
Fc7cccc6c7cc2n6COc1ccc(nc12)c3cc4c(cc3N(C)S(C)(=O)=O)oc(c4C(=O)NC)c5ccc(F)cc5

Sunday, 3 July 2016

SM 934, β-Aminoarteether maleate

str1
STR1

SM 934
  • Ethanamine, 2-[(decahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10-yl)oxy]-, [3R-(3α,5aβ,6β,8aβ,9α,10α,12β,12aR*)]-, (Z)-2-butenedioate (1:1)
  • 3,12-Epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin, ethanamine deriv.
  • SM 934
  • β-Aminoarteether maleate
CAS 133162-25-1
MF C17 H29 N O5 . C4 H4 O4
Ethanamine, 2-​[(decahydro-​3,​6,​9-​trimethyl-​3,​12-​epoxy-​12H-​pyrano[4,​3-​j]​-​1,​2-​benzodioxepin-​10-​yl)​oxy]​-​, (3R,​5aS,​6R,​8aS,​9R,​10S,​11aR)​-​, (2Z)​-​2-​butenedioate (1:1)
TLR7/9 signal transduction modulator
IND FILED
2.5 and 5 mg/kg, ig (MRL/lpr mice);
10 mg·kg−1·d−1, ig (NZB/W F1 mice)
Autoimmune diseases; SLE
SM934, an artemisinin derivative, possesses potent antiproliferative and antiinflammatory properties.
str1
In the present study, we investigated the immunosuppressive effects and underlying mechanisms of beta-aminoarteether maleate (SM934), a derivative of artemisinin, against T cell activation in vitro and in vivo. In vitro, SM934 significantly inhibited the proliferation of splenocytes induced by concanavalin A (Con A), lipopolysaccharide (LPS), mixed lymphocyte reaction (MLR), and anti-CD3 plus anti-CD28 (anti-CD3/28). SM934 significantly inhibited interferon (IFN)-gamma production and CD4(+) T cell division stimulated by anti-CD3/28. SM934 also promoted apoptosis of CD69(+) population in CD4(+) T cells stimulated by anti-CD3/28. Furthermore, SM934 inhibited interleukin (IL)-2 mediated proliferation and survival through blocking Akt phosphorylation in activated T cells. In ovalbumin (OVA)-immunized mice, oral administration of SM934 suppressed OVA-specific T cell proliferation and IFN-gamma production. SM934 treatment also significantly inhibited the sheep red blood cell (SRBC)-induced delayed type hypersensitivity (DTH) reactions in mice. Taken together, SM934 showed potent immunosuppressive activities in vitro and in vivo. Our results demonstrated that SM934 might be a potential therapeutic agent for immune-related diseases.

PATENT
Figure imgb0005
Figure imgb0006
PAPER
Volume 9, Issues 13–14, December 2009, Pages 1509–1517
Inflammatory Mediators Long Term after Sulfur Mustard Exposure (Sardasht-Iran Cohort Study)

SM934, a water-soluble derivative of arteminisin, exerts immunosuppressive functions in vitro and in vivo

  • a State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China
  • b Department of Synthetic Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China
  • c Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People's Republic of China

  • Hou LF, He SJ, Wang JX, Yang Y, Zhu FH, Zhou Y, et al. SM934, a water-soluble derivative of arteminisin, exerts immunosuppressive functions in vitro and in vivoInt Immunopharmacol 2009; 9: 1509–17. | Article |
  • Hou LF, He SJ, Li X, Yang Y, He PL, Zhou Y, et al. Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses. Arthritis Rheum 2011; 63: 2445–55. | Article
  • Hou LF, He SJ, Li X, Wan CP, Yang Y, Zhang XH, et al. SM934 treated lupus-prone NZB x NZW F1 mice by enhancing macrophage interleukin-10 production and suppressing pathogenic T cell development. PLoS One 2012; 7: e 32424.
  • Wu Y, He S, Bai B, Zhang L, Xue L, Lin Z, et al. Therapeutic effects of the artemisinin analog SM934 on lupus-prone MRL/lpr mice via inhibition of TLR-triggered B-cell activation and plasma cell formation. Cell Mol Immunol 2015 Mar 16. doi: 10.1038/cmi.2015.13. [Epub ahead of print].


/////////TLR7/9 signal transduction modulator, SM 934, IND FILED, 133162-25-1, β-Aminoarteether maleate
[C@@H]3(OC1O[C@@]4(CCC2C1(C(CC[C@H]2C)[C@H]3C)OO4)C)OCCN.C(=C/C(=O)O)/C(=O)O

Friday, 1 July 2016

Ripasudil hydrochloride hydrate 塩酸塩水和物 , リパスジル

UNII-016TTR32QF.png
Ripasudil hydrochloride hydrate
4-fluoro-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline;dihydrate;hydrochloride
4-Fluoro-5-[2(S)-methylperhydro-1,4-diazepin-1-ylsulfonyl]isoquinoline hydrochloride dihydrate
cas 223645-67-8 FREE
M.Wt395.88
OR C15H18FN3O2S·HCl·2H2O
FormulaC15H23ClFN3O4S
CAS No887375-67-9 .HCL 2 H2O
016TTR32QF, K 115
LAUNCHED 2014 Kowa
JAPAN 2014-09-26, Glanatec
リパスジル塩酸塩水和物
Ripasudil Hydrochloride Hydrate

C15H18FN3O2S.HCl.2H2O : 395.88
[887375-67-9]
ChemSpider 2D Image | Ripasudil | C15H18FN3O2S

Ripasudil

  • Molecular FormulaC15H18FN3O2S
  • Average mass323.386
CAS 223645-67-8
4-fluoro-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline
CompanyD. Western Therapeutics Institute Inc.
DescriptionSelective rho kinase inhibitor
Molecular TargetRho kinase
Mechanism of ActionRho kinase inhibitor
SEE
NMR ETC
 COA NMR HPLC Datasheet MSDS  CLICK

PAPER

HETEROCYCLES, Vol. 83, No. 8, 2011, pg 1771-1781.
Paper | Regular issue | Vol 83, No. 8, 2011, pp.1771-1781
Published online: 24th May, 2011
DOI: 10.3987/COM-11-12230
■ A Practical Synthesis of Novel Rho-Kinase Inhibitor, (S)-4-Fluoro-5-(2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline
Noriaki Gomi, Tadaaki Ohgiya, Kimiyuki Shibuya,* Jyunji Katsuyama, Masayuki Masumoto, and Hitoshi Sakai
*Pharmaceutical Division, Tokyo New Drug Research Laboratories, Kowa Co., Ltd., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan
Abstract
A practical synthesis of novel Rho-kinase inhibitor, (S)-4-fluoro-5-(2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline hydrochloride dihydrate (1) was achieved in a pilot-scale production. We have demonstrated the regioselective chlorosulfonylation of 4-fluoroisoquinoline in an one-pot reaction to afford 4-fluoroisoquinoline-5-sulfonyl chloride and the asymmetric construction of the (S)-2-methyl-1,4-diazepane moiety as key steps.
White crystalline solid.: mp 258-259 °C (decomp);
 
[]20D –8.82 (c1.00, H2O);
 
IR (KCl) 3406, 2983, 2763, 1588, 1324, 1146, 1129 cm-1; 1H-NMR (DMSO-d6) δ: 1.20 (3H, d,J = 6.6 Hz), 1.98-2.07 (2H, m), 3.06-3.16 (1H, m), 3.22-3.31 (2H, m), 3.35 (4H, s), 3.44 (1H, dd, J = 14.1,4.4 Hz), 3.59-3.74 (2H, m), 4.37-4.47 (1H, m), 7.93 (1H, t, J = 7.8 Hz), 8.32 (1H, d, J = 7.8 Hz), 8.54-8.60(1H, m), 8.72 (1H, d, J = 4.9 Hz), 9.39 (1H, s), 9.51 (2H, br s);
 
13C-NMR (DMSO-d6) δ: 16.6, 26.8, 42.9,45.5, 50.3, 50.9, 120.9 (J = 12.4 Hz), 127.5, 130.7 (J = 1.7 Hz), 132.2, 132.5 (J = 27.3 Hz), 133.2 (J = 5.0Hz), 133.3, 149.8 (J = 5.0 Hz), 152.0 (J = 264.0 Hz);
 
FABMS m/z 324 (M+H–HCl–2H2O)+, Anal. Calcd forC15H23ClFN3O4S: C, 45.51; H, 5.86; Cl, 8.96; F, 4.80; N, 10.61. Found: C, 45.44; H, 5.65; Cl, 8.87; F, 4.68;N, 10.78.
 
WRITEUP

K-115, an isoquinolinesulfonamide compound, is a highly selective and potent (IC50 = 31 nM) Rho-kinase inhibitor; is in Phase II clinical development in patients with POAG or ocular hypertension.Ripasudil hydrochloride hydrate (Glanatec® ophthalmic solution 0.4 %; hereafter referred to as ripasudil) is a small-molecule, Rho-associated kinase inhibitor developed by Kowa Company, Ltd. for the treatment of glaucoma and ocular hypertension. This compound, which was originally discovered by D. Western Therapeutics Institute, Inc., reduces intraocular pressure (IOP) by directly acting on the trabecular meshwork, thereby increasing conventional outflow through the Schlemm's canal.
Ripasudil hydrochloride hydrate was first approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Sept 26, 2014. It was developed and marketed as Glanatek® by Kowa Pharmaceuticals.
Ripasudil hydrochloride hydrate is the first drug that can inhibit the rho-associated, coiled-coil containing protein kinase (ROCK). It is indicated for the treatment of glaucoma and ocular hypertension.
Glanatek® is available as solution (0.4%) for ophthalmic use, containing 4 mg of free Ripasudil per millimeter, and the recommended dose is one drop twice daily.
As a result of this mechanism of action, ripasudil may offer additive effects in the treatment of glaucoma and ocular hypertension when used in combination with agents such as prostaglandin analogues (which increase uveoscleral outflow) and β blockers (which reduce aqueous production).
The eye drop product has been approved in Japan for the twice-daily treatment of glaucoma and ocular hypertension, when other therapeutic agents are not effective or cannot be administered. Phase II study is underway for the treatment of diabetic retinopathy.
K-115 is a Rho-kinase inhibitor as ophthalmic solution originally developed by Kowa and D Western Therapeutics Institute (DWTI). The product candidate was approved and launched in Japan for the treatment of glaucoma and ocular hypertension in 2014.
In 2002, the compound was licensed to Kowa Pharmaceutical by D Western Therapeutics Institute (DWTI) in Japan for the treatment of glaucoma. The compound is currently in phase II clinical trials at the company for the treatment of age-related macular degeneration and diabetic retinopathy.
Use of (S)-(-)-1-(4- fluoro-5-isoquinoline-sulfonyl)-2-methyl-1,4-homopiperazine (ripasudil hydrochloride, first disclosed in WO9920620), in the form of eye drops, for the treatment of retinal diseases, particularly diabetic retinopathy or age-related macular degeneration.
Follows on from WO2012105674 by claiming a combination of the same compound. Kowa, under license from D Western Therapeutics Institute, has developed the Rho kinase inhibitor ripasudil hydrochloride hydrate (presumed to be Glanatek) as an eye drop formulation for the treatment of glaucoma and ocular hypertension which was approved in Japan in September 2014..
The company is also developing the agent for the treatment of diabetic retinopathy, for which it is in phase II trial as of October 2014.
Ripasudil (Glanatec) is a drug used for the treatment of glaucoma and ocular hypertension. It is approved for use in Japan as a 0.4% ophthalmic solution.[1]
Ripasudil, a derivative of fasudil, is a rho kinase inhibitor.[2]

Paper

A Practical Synthesis of (S)-tert-butyl 3-methyl-1,4-diazepane-1-carboxylate, the key intermediate of Rho-kinase inhibitor K-115
Synthesis (Stuttgart) 2012, 44(20): 3171
practical synthesis of (S)-tert-butyl 3-methyl-1,4-di­azepane-1-carboxylate has been established for supplying this key intermediate of Rho–kinase inhibitor K-115 in a multikilogram production. The chiral 1,4-diazepane was constructed by intramolecular Fukuyama–Mitsunobu cyclization of a N-nosyl diamino alcohol starting from the commercially available (S)- or (R)-2-aminopropan-1-ol. In the same manner, an enantiomeric pair of a structural isomer were prepared for demonstration of the synthetic utility.

SEE

PATENT

WO 2012026529
The including prevention and treatment cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, cerebrovascular disorders such as cerebral edema, the present invention relates to a salt thereof or isoquinoline derivatives useful as therapeutic agents, particularly glaucoma.
(S) - (-) -1 - (4 - fluoro-iso-5 - yl) sulfonyl - 2 - methyl -1,4 - diazepane the following formula (1):
Figure JPOXMLDOC01-appb-C000009
It is a compound represented by the particular it is a crystalline water-soluble, not hygroscopic, because it is excellent in chemical stability, it is useful as a medicament has been known for its hydrochloride dihydrate ( refer to Patent Documents 1 and 2). -5 Isoquinoline of these - the sulfonamide compounds, that prophylactic and therapeutic agents for cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, cerebrovascular disorders such as cerebral edema, is useful as a therapeutic agent for preventing and glaucoma in particular is known (1-5 see Patent Document 1).
Conventionally, for example, a method of manufacturing by the method described in Patent Document 1, as shown in the following production process has been reported preparation of said compound (Production Method 1-A).
Figure JPOXMLDOC01-appb-C000010
That is, (S)-1-tert-butoxycarbonyl - 3 - by reacting the presence of triethylamine in methylene chloride-fluoro-isoquinoline (2) - methyl -1,4 - diazepane and 5 (3) - chloro-sulfonyl -4 by adding trifluoroacetic acid in methylene chloride compound (the first step), obtained following (4) to synthesize a compound (4) by deprotection to (second step) the desired compound (1) This is a method of manufacturing.
It is also an important intermediate for preparing the compound (1) (S)-1-tert-butoxycarbonyl - 3 - methyl-1 ,4 - diazepane to (3), for example, in the following manner (; see JP Production Process 1-B) that can be produced is known.
Figure JPOXMLDOC01-appb-C000011
Further, on the other hand, the compound (1) (see Patent Document 1) to be manufactured manufacturing routes such as: Any (Process 2) are known.
Figure JPOXMLDOC01-appb-C000012
WO 1999/20620 pamphlet WO 2006/057397 pamphlet WO 1997/028130 pamphlet JP Patent Publication No. 2006-348028 JP Patent Publication No. 2006-290827
However, it is possible to produce in the laboratory of a small amount scale, but you place the point of view for mass industrial production, environmentally harmful halogenated hydrocarbon solvent in the compound of the above-mentioned process for producing 1-A is ( problem because it is carried out coupling step (3) and 2), giving significant adverse environmental exists.Therefore, solvent of halogenated hydrocarbon other than those listed to the specification of the patent document 1, for example, I tried actually dioxane, tetrahydrofuran and the like, but the present coupling reaction will be some progress indeed, Problems reaction is not completed raw material remained even after prolonged reaction time, yield undesirably stays in at most 30% was found.Furthermore, it is hard to decompose in the environment, elimination is also difficult to dioxane is not preferred irritating to humans, and are known as compounds that potentially harmful brain, kidney and liver .
When we actually produced compound (3) by the above production method 1-B, can be obtained desired compound in good yield merged with reproducibility is difficult has further been found that. That is, in the production path, 1,4 - and is used sodium hydride with dimethyl sulfoxide in forming a diazepane ring, except that I actually doing this step, Tsu than the reproducibility of the desired compound It could not be obtained in high yield Te. Also, that this is due to the synthetic route through the unstable intermediate, that it would be converted into another compound easily found this way. limitations and potential problems of the present production process is exposed since this stability may affect the reproducibility of the reaction.
Meanwhile, an attempt to carry out mass production is actually in the Process 2, it encounters various problems. For example, it is stored as an impurity whenever I repeat step, by-products formed in each stage by tandem production process ranging from step 8 gave more complex impurity profile. Depending, it is necessary to repeat a complicated recrystallization purity obtained as a medicine until the purification, the yield in the laboratory be a good overall yield is significantly reduced in the mass production of actual example be away, it does not have industrial utility of true was found. It can be summarized as follows: Considering from the viewpoint of GMP process control required for pharmaceutical production these problems.
Requires control process and numerous complex ranging 1) to 8 step, 3 2) third step - amino-1 - in the step of reacting a propanol, a difficult to remove positional isomers are mixed, 3) The fourth step water is mixed by the minute liquid extraction operation at the time of return to the free base from oxalate require crystallization purification by oxalate in the removal of contaminants of positional isomers, in 4) fifth step, 5) sixth step The Mitsunobu by reproducibility poor require water control in the Mitsunobu reaction used in the ring closure compounds to (1) compounds in (6), 6) ring closure reaction, departing management of the reagent added or the like is generated, in 7) Seventh Step it takes a complicated purification in impurity removal after the reaction, resulting in a decrease in isolated yield. These are issues that must be solved in order to provide a stable supply of raw material for pharmaceuticals high chemical purity is required.
Thus, gentle salt thereof, or the environment isoquinoline derivative comprising a compound represented by the formula (1), the present invention provides a novel production method having good reproducibility and high purity easily and in high yield I intended.
As a result of intensive studies in view of such circumstances, the present inventors, in the manufacturing process of the final target compound shown by the following expression
Figure JPOXMLDOC01-appb-C000013
(Wherein represents a fluorine, chlorine, bromine or iodine, may, R 3 and 1, R 2 R represents a C 1-4 alkyl group be the same or different from each other, and P, X 1 is a protecting group shows a, 0 to m represents an integer of 3, 0 to n is. represents an integer of 3)
Is a urea-based solvents nitrile solvents, amide solvents, sulfoxide or solvents, the solvent may be preferably used in the coupling step of the compound (III) and (II) are generally very short time With these solvents It has been found that can be converted to the desired product quantitatively. It is possible to carry out the coupling step Volume scale while maintaining a high yield by using these solvents, there is no need to use a halogenated hydrocarbon solvent to give significant adverse environment. In consideration of the process such as removal of the solvent after the reaction was further found that acetonitrile is the best among these solvents. Also, since by using hydrochloric acid with ethyl acetate solvent in step deprotection can be isolated as crystal of hydrochloride desired compound (I), without going through the manipulation of solvent evaporation complicated , it has been found that it is possible to obtain the object compound (I) is a simpler operating procedure. Since there is no need to use a halogenated hydrocarbon solvent in this deprotection step further, there is no possibility of harming the environment.
It has been found that it is possible in mass production of (II), leading to the target compound purity, in high yield with good reproducibility as compared with the conventional method compounds are important intermediates in the coupling step further. That is, was it possible to lead to the intermediate high purity and in high yield by eliminating the production of a harmful halogenated hydrocarbon solvent to the environment in this manner. 1,4 addition - in order to avoid the problems encountered in the reaction using sodium hydride in dimethyl sulfoxide in forming the diazepane ring, in order to allow the cyclization reaction at mild conditions more, as a protecting group By performing the Mitsunobu reaction using Noshiru group instead of the carbobenzyloxy group, in addition to one step shorten the manufacturing process of the whole, without deteriorating the optical purity was successfully obtained the desired compound desired.
SEE
1. WO2012026529A1 / US2015087824A1.
2. WO9920620A1.
3. Synthesis 201244, 3171–3178.

1. Heterocycles 201183, 1771-1781.
2. WO2006057397A1 / US7858615B2.
3. WO9920620A1.
CLIP
Ripasudil hydrochloride hydrate (Glanatec )
Ripasudil hydrochloride hydrate (Glanatec ) was approved in Japan in 2014 for the treatment of glaucoma and ocular hypertension.
219 Originally discovered by D. Western Therapeutics Institute,Inc. and licensed by the Kowa Company, Ltd, ripasudil
functions as a selective Rho-kinase inhibitor and reduces intraocular pressure by stimulation of aqueous humour drainage of the
trabecular meshwork.219–221
While this recent approval allows for use of ripasudil as a twice-daily monotherapy treatment when
other drugs cannot be used or are not effective, clinical trials using ripasudil as a combination therapy with other glaucoma
drugs have shown promising results in the treatment of primary open-angle glaucoma or ocular hypertension.222,223 Currently, the
Kowa Company is also pursuing trials focused on the use of ripasudil for the treatment of diabetic retinopathy and diabetic macular edema.224
While initial synthetic routes to ripasudil were carried out via a stepwise functionalization of 4-fluoroisoquinoline-5-sulfonylchloride (238),225,226 more recent reports describe an efficient route to ripasudil employing a late stage-coupling of Boc-diazepane
(237) with 4-fluoroisoquinoline-5-sulfonyl chloride (238), enabling synthesis on multi-kilogram scale and isolation of the
drug in high purity (Scheme 40).221,227,228 This optimized route to ripasudil begins with 2-nitrobenzene sulfonyl chloride (NsCl)-
mediated protection of (S)-2-amino-1-propanol (234) in 82% yield.
In this case, use of the NaHCO3/THF/H2O conditions were essential for preventing bis-nosylation.228 Alcohol activation with methanesulfonyl chloride (MsCl) in N-methyl morpholine (NMM) took place smoothly to give the corresponding mesylate 235 in 91%
yield. Direct mesylate displacement with 3-aminopropanol and subsequent amine protection as the carbamate ((Boc)2O) in a
one-pot fashion provided the corresponding Boc-amino propanol product 236 in 95% yield over 2 steps.
With the acyclic diazepane precursor 236 in hand, employment of the intramolecular Fukuyama-Mitsunobu N-alkyl cyclization conditions (diisopropylazodicarboxylate (DIAD)/PPh3) allowed generation of the diazepane in 75% yield. Nosyl group cleavage with thiophenol/K2CO3provided the Boc-diazepane 237 in 65% overall yield and 98% purity following a pH-controlled aqueous workup.
Finally, 4-fluoroisoquinoline- 5-sulfonyl chloride (238)—prepared via subjection of 4- fluoroisoquinoline (239, Scheme 41)229 to sulfur trioxide and sulfuric acid followed by treatment with thionyl chloride and finally 4 N HCl in ethyl acetate—was involved in a 1-pot, two-step procedure in which this sulfonyl chloride was coupled with diazepane 237 (TEA/MeCN) to access the ripasudil framework in quantitative yield.
Synthesis of the final drug target by deprotection with 4 MHCl in ethyl acetate followed by neutralization with aqueoussodium hydroxide provided the free base of ripasudil in 93% yield and 99.8% purity. Conversion to the more stable hydrochloride dihydrate form could be performed by treatment of the free base with 1 M HCl/EtOH and subsequent heating of the hydrochloride in H2O/acetone to provide ripasudil hydrochloride dihydrate XXIX in 83% yield.230,231
STR1
STR1
219. Garnock, J. P. K. Drugs 2014, 74, 2211.
220. Isobe, T.; Mizuno, K.; Kaneko, Y.; Ohta, M.; Koide, T.; Tanabe, S. Curr. Eye Res.2014, 39, 813.
221. Sumi, K.; Inoue, Y.; Nishio, M.; Naito, Y.; Hosoya, T.; Suzuki, M.; Hidaka, H.
Bioorg. Med. Chem. Lett. 2014, 24, 831.
222. Mizuno, K. WO Patent 2,012,105,674, 2012.
223. Mizuno, K.; Matsumoto, J. WO Patent 2,007,007,737, 2007.
224. http://clinicaltrials.jp/user/cteDetail.jsp.
225. Gomi, N.; Ohgiya, T.; Shibuya, K. WO Patent 2,012,026,529, 2012.
226. Hidaka, H.; Nishio, M.; Sumi, K. US Patent 20,080,064,681, 2008.
227. Gomi, N.; Kouketsu, A.; Ohgiya, T.; Shibuya, K. Synthesis 2012, 44, 3171.
228. Gomi, N.; Ohgiya, T.; Shibuya, K.; Katsuyama, J.; Masumoto, M.; Sakai, H.Heterocycles 2011, 83, 1771.
229. Sakai, H.; Masunoto, M.; Katsuyama, J.; Onogi, K. WO Patent 2006090783A1,2006.
230. Hidaka, H.; Matsuura, A. WO Patent 1999020620A1, 1999.
231. Ohshima, T.; Hidaka, H.; Shiratsuchi, M.; Onogi, K.; Oda, T. US Patent7858615B2, 2008.
H-NMR spectral analysis
4-fluoro-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline NMR spectra analysis, Chemical CAS NO. 223645-67-8 NMR spectral analysis, 4-fluoro-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline H-NMR spectrum
CAS NO. 223645-67-8, 4-fluoro-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline H-NMR spectral analysis
C-NMR spectral analysis
4-fluoro-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline NMR spectra analysis, Chemical CAS NO. 223645-67-8 NMR spectral analysis, 4-fluoro-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline C-NMR spectrum
CAS NO. 223645-67-8, 4-fluoro-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline C-NMR spectral analysis
·
WO1997028130A1Jan 31, 1997Aug 7, 1997Hiroyoshi HidakaIsoquinoline derivatives and drugs
WO1999020620A1Oct 22, 1998Apr 29, 1999Hiroyoshi HidakaIsoquinoline derivative and drug
WO2006057397A1Nov 29, 2005Jun 1, 2006Hiroyoshi Hidaka(s)-(-)-1-(4-fluoroisoquinolin-5-yl)sulfonyl-2-methyl-1,4­homopiperazine hydrochloride dihydrate
JP2006290827ATitle not available
JP2006348028ATitle not available
JPH11171885A *Title not available
JPS61227581A *Title not available

References

  1.  Garnock-Jones, K. P. (2014). "Ripasudil: First global approval". Drugs 74 (18): 2211–5. doi:10.1007/s40265-014-0333-2.PMID 25414122.
  2.  Tanihara, H; Inoue, T; Yamamoto, T; Kuwayama, Y; Abe, H; Suganami, H; Araie, M; the K-115 Clinical Study Group (2014). "Intra-ocular pressure-lowering effects of a Rho kinase inhibitor, ripasudil (K-115), over 24 hours in primary open-angle glaucoma and ocular hypertension: A randomized, open-label, crossover study". Acta Ophthalmologica: n/a. doi:10.1111/aos.12599PMID 25487877.
Ripasudil
Ripasudil.svg
Systematic (IUPAC) name
4-Fluoro-5-{[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl}isoquinoline
Clinical data
Trade namesGlanatec
Identifiers
PubChemCID 9863672
ChemSpider8039366
SynonymsK-115
Chemical data
FormulaC15H18FN3O2S
Molar mass323.39 g/mol
///////////////// , Ripasudil hydrochloride hydrate, Ripasudil, 223645-67-8,   塩酸塩水和物 , リパスジル
O=S(=O)(c2c1c(F)cncc1ccc2)N3[C@H](CNCCC3)C