N,N-二异丙基乙胺 → (2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-trifluoromethyl-phenyl)-amide

HRID 1807319

反应方程式

HRID 1807319 反应方程式
[Cl:1][C:2]1[C:3]([F:44])=[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)=[C:33]([C:40]([F:43])([F:42])[F:41])[CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.C[N:46](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.N>O.CN(C=O)C>[C:35]([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:44])[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]2)=[O:29])=[CH:32][C:33]=1[C:40]([F:43])([F:42])[F:41])(=[O:37])[NH2:46]

参与物

7

反应物 4

HCID 81531N,N-二异丙基乙胺HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 12820921氯化铵HCID 533577404-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-(trifluoromethyl)benzoic acid

产物 1

HCID 53357096(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-carbamoyl-3-trifluoromethyl-phenyl)-amide收率 28.6%

试剂、催化剂与溶剂 2

HCID 962聚[6-[4-(4-氰基苯基)苯氧基]己基甲基丙烯酸酯]溶剂HCID 6228N,N-二甲基甲酰胺溶剂

实验过程

In a 25 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-(trifluoromethyl)benzoic acid (42 mg, 64.2 μmol, Eq: 1.00) was combined with DMF (2.50 ml) to give a colorless solution. HATU (36.6 mg, 96.3 μmol, Eq: 1.5) and DIPEA (41.5 mg, 56.0 μl, 321 μmol, Eq: 5) were added. The reaction was stirred for 5 minutes and ammonia hydrochloride (34.3 mg, 642 μmol, Eq: 10) was added. The reaction mixture was stirred for overnight. The reaction mixture was poured into 10 mL of H2O and extracted with EtOAc (3×10 mL). The organic layers were combined, washed with H2O (1×10 mL), saturated NaCl (1×10 mL), dried over Na2SO4 and concentrated in vacuum. The crude material was purified by preparative HPLC (65-100% ACETONITRILE/water). The fractions were combined and freeze dried and triturated with CH2Cl2/hexanes to give a white foam (12 mg, 26% yield). (ES+) m/z Calcd: [(M+H)+]: 653. found: 653.

后处理

  1. customto give a colorless solution
  2. stirringThe reaction mixture was stirred for overnight
  3. extractionextracted with EtOAc (3×10 mL)
  4. washwashed with H2O (1×10 mL), saturated NaCl (1×10 mL)
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated in vacuum
  7. customThe crude material was purified by preparative HPLC (65-100% ACETONITRILE/water)
  8. customfreeze dried
  9. customtriturated with CH2Cl2/hexanes

来源与证据

ORD记录
ord-bcb54ce1744d401983f40faa3f186d35
来源数据集
uspto-grants-2013_01
专利号
US08354444B2

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