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 882352ノート

反応式

HRID 882352 の反応式
[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]

参加物

6

反応物 3

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

生成物 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 ester収率 63.3%

試薬・触媒・溶媒 2

HCID 6228Dimethylformamide溶媒2 回HCID 8857Ethyl Acetate溶媒

実験手順

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.

後処理

  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)

出典と根拠

ORDレコード
ord-61e70d4774ba497787d53b8522358a7a
出典データセット
uspto-grants-2015_03
特許番号
US08993614B2

反応ノート

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