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Zelicapavir, Enanta Pharmaceuticals
Alternative Names: EDP-938; EP 023938
cas 2070852-76-3
RSV-IN-7
549.5 g/mol, C27H22F3N7O3
UNII U4OI721DMD
(3S)-3-[[5-[3-morpholin-4-yl-5-(trifluoromethyl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl]amino]-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one
SYN
New England Journal of Medicine (2022), 386(7), 655-666
WO2022157327
WO2018152413
WO2019067864
WO2017015449
PATENT
WO2018152413
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018152413&_cid=P20-M0V26A-30323-1
Step 5 : (<Sf)-3-((5-(3-morpholino-5-(trifluoromethyl)pyridin-2-yl)-1.3.4-oxadiazol-2-
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To a mixture of (5)-2-(3-morpholino-5-(trifluoromethyl)picolinoyl)-N-2-oxo-5-phenyl-2,3-dihydro-lH-benzo[e] [l,4]diazepin-3-yl)hydrazine-l-carboxamide (1.4 kg, 1 eq.) in DCM (11.2 L) in a flask was charged with 4A-MS (1.4 kg) and stirred at 20±5 °C for 2hrs. Then, it was cooled to 0°C, charged with triethylamine (0.62 Kg, 2.5 eq.) and stirred for 10 min. /^-Toluenesulfonyl chloride (0.7 kg, 1.5 eq.) in DCM (1.4 L) solution was dropwise added to the reaction mixture with maintaining below 5°C and stirred at at 0±5 °C for 5 hrs. The reaction mixture was filtered and washed with DCM (2 X 4.2 L). The filtrate was treated with water (4.2 L) at 0°C and stirred between 0 and 10°C for 5 min. After separation, the organic phase was washed with 5% aqueous NaHCC solution (7 L), water (7 L) and brine (7 L) successively and separated. The DCM layer was concentrated in vacuo at below 30°C to leave ~7L of organic layer. MTBE (7 L) was added to organic layer and concentrated in vacuo to leave ~ 7 L of organic layer (This step was repeated once). The organic layer was charged with water (7 L) and stirred at 20±5 °C for 4 hrs. The solid was filtered and washed with MTBE (3 X 2.1 L) and purified water (2.8 L). The wet cake was stirred with ethyl acetate (7 L) for 12 hrs, charged with n-heptane (14 L) and stirred at 20±5 °C for 5 hrs. The solid was filtered, washed with n-heptane (2 X 2.8 L) and dried under vacuum at ambient temperature to provide the title compound (0.776 kg, 99.6% purity by HPLC, 97.8%
chiral purity by chiral HPLC) as a pale yellowish solid. LC-MS(ESI, m/z): 550.17 [M+H]+;
¾ NMR: ( DMSO-c 6400 MHz): δ 10.98 (br-s, 1H), 9.40 (d, J=8.0 Hz, 1H), 8.69 (br-d, J=4.0 Hz, 1H), 7.89 (d, J=4.0 Hz, 1H), 7.68 (dt, J=8.0 and 4.0 Hz, 1H), 7.56-7.51 (m, 3H), 7.49-7.45 (m, 2H), 7.38-7.35 (m, 2H), 7.29 (br-t, J=8.0 Hz, 1H)
5.22 (d, J=8.0 Hz, 1H), 3.75-3.72 (m, 4H), 3.09-3.07 (m, 4H); 13C (DMSO-c¾, 100 MHz): δ 167.3, 167.0, 162.8, 156.4, 147.2, 139.2, 138.7, 138.4, 138.3, 138.0, 132.30, 130.7, 130.5, 129.5, 128.4, 126.2, 124.5, 123.4, 121.5, 71.8, 65.9, 51.0.
SCHEME
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PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US368999603&_cid=P20-M0V2BF-36596-1
Example 253
Example 160 was prepared using a procedure similar to that used to prepare Example 152 where methyl 5-cyano-3-morpholinopicolinate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 507.2 [M+H] +. 1H NMR (400 MHz, DMSO-d 6) δ 3.02-3.04 (m, 4H), 3.71-3.73 (m, 4H), 5.19-5.21 (d, J=8.0 Hz, 1H), 7.26-7.30 (m, 1H), 7.34-7.36 (m, 2H), 7.44-7.55 (m, 5H), 7.65-7.70 (m, 1H), 8.13 (s, 1H), 8.72 (s, 1H), 9.42-9.45 (m, 1H), 10.98 (s, 1H).
//////////////Zelicapavir, EDP-938, EP 023938, EDP 938, RSV-IN-7, ENANTA