Dimethyl Sulfoxide → HCID 59459216, compound

HRID 1874277Notes

Reaction equation

C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:13]=[C:14]([C@:25]([NH:40][C:41]([NH:43][C@@H:44]2[CH2:48][CH2:47][CH2:46][C@H:45]2[OH:49])=[O:42])([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:15]=[C:16]([O:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[CH:17]=1>C(Cl)Cl>[F:11][C:12]1[CH:13]=[C:14]([C@:25]([NH:40][C:41]([NH:43][C:44]2[C:45](=[O:49])[CH2:46][CH2:47][CH:48]=2)=[O:42])([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:15]=[C:16]([O:18][C:19]([F:23])([F:24])[CH:20]([F:21])[F:22])[CH:17]=1.[F:11][C:12]1[CH:13]=[C:14]([C@:25]([NH:40][C:41]([NH:43][C@@H:44]2[CH2:48][CH2:47][CH2:46][C:45]2=[O:49])=[O:42])([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:15]=[C:16]([O:18][C:19]([F:23])([F:24])[CH:20]([F:21])[F:22])[CH:17]=1

Participants

Conditions

Temperature: -78 °C

Procedure

To a solution of oxalyl chloride (2 M in CH2Cl2, 150 uL) at −78° C. was added DMSO (47 mg, 0.60 mmol) dropwise. The reaction mixture was stirred at −78° C. for 15 min, then 1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((1R,2R)-2-hydroxycyclopentyl)urea (Example 246, 113 mg, 0.20 mmol) in CH2Cl2 (1 mL) was added dropwise. The reaction mixture was allowed to warm to rt and stirred for 16 h. The reaction mixture was concentrated under reduced pressure and purified by ISCO flash chromatography with EtOAc and hexane as eluting solvent to yield (R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(5-oxocyclopent-1-enyl)urea (Example 333) as a white solid (15 mg, 14% yield) and 1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((R)-2-oxocyclopentyl)urea (Example 334) as a white solid (66 mg, 60% yield). (R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(5-oxocyclopent-1-enyl)urea: HPLC: RT=3.99 min [M+H] 551.09 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 1.24-1.37 (m, 1H), 1.36-1.58 (m, 1H), 1.68-1.84 (m, 1H), 1.84-2.00 (m, 2H), 2.12-2.30 (m, 3H), 2.48-2.73 (m, 1H), 3.58-4.05 (m, 3H), 5.35-5.52 (m, 1H), 5.64-6.03 (m, 2H), 6.62-6.78 (m, 2H), 6.78-7.02 (m, 5H), 7.04-7.23 (m, 5H). 1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((R)-2-oxocyclopentyl)urea: HPLC: RT=4.09 min [M+H] 549.1 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 1.84-1.94 (m, 2H), 2.43-2.62 (m, 2H) 3.92 (dd, 2H) 5.82 (t, 1H) 6.62-6.78 (m, 2H) 6.79-6.88 (m, 1H) 6.90-7.01 (m, 5H), 7.01-7.15 (m, 3H), 7.14-7.25 (m, 2H), 7.62-7.74 (m, 1H), 8.09-8.25 (m, 1H).

Workup

temperatureto warm to rt
stirringstirred for 16 h
concentrationThe reaction mixture was concentrated under reduced pressure
custompurified by ISCO flash chromatography with EtOAc and hexane
washas eluting solvent

Sources & evidence

ORD record: ord-61d2ba80b6f64f508d4bb62274e6718a
Source dataset: uspto-grants-2012_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08304403B2

Reaction notes

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