Cesium carbonate → 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-[bis-(2-methoxy-ethyl)-carbamoyloxy]-ethyl ester

HRID 882352Notes

Reaction equation

HRID 882352 reaction equation
[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:49][O:50][CH2:51][CH2:52][N:53]([CH2:60][CH2:61][O:62][CH3:63])[C:54](=[O:59])[O:55][CH:56](Cl)[CH3:57]>CN(C)C=O.C(OCC)(=O)C>[CH3:63][O:62][CH2:61][CH2:60][N:53]([CH2:52][CH2:51][O:50][CH3:49])[C:54]([O:55][CH:56]([O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)[CH3:57])=[O:59]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 53358942IdasanutlinHCID 866962971-Chloroethyl bis(2-methoxyethyl)carbamate

Product 1

HCID 717387584-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-[bis-(2-methoxy-ethyl)-carbamoyloxy]-ethyl esterYield 63.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (US20100152190A1, 200 mg, 0.324 mmol) in dimethylformamide (8 mL) was added cesium carbonate (846 mg, 2.6 mmol). After stirring for 10 min, a solution of the above freshly made 1-chloroethyl bis(2-methoxyethyl)carbamate (510 mg, 2.13 mmol) in dimethylformamide (3 mL) was added. The reaction mixture was allowed to stir at room temperature overnight. This reaction mixture was taken up in ethyl acetate, washed with water, brine and concentrated to dryness. The crude material was purified by flash chromatography (hexane/ethyl acetate, 90/10 to 10/90) to give 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-[bis-(2-methoxy-ethyl)-carbamoyloxy]-ethyl ester as a white solid (168 mg, 63% yield). LCMS (ES+) m/z calcd. for C40H47Cl2F2N4O8 [(M+H)+]: 819, found: 819.

Workup

  1. stirringto stir at room temperature overnight
  2. washwashed with water, brine
  3. concentrationconcentrated to dryness
  4. customThe crude material was purified by flash chromatography (hexane/ethyl acetate, 90/10 to 10/90)

Sources & evidence

ORD record
ord-61e70d4774ba497787d53b8522358a7a
Source dataset
uspto-grants-2015_03
Patent number
US08993614B2

Reaction notes

Loading…