Sodium Hydroxide → HCID 87304286、化合物

HRID 1951688ノート

反応式

HRID 1951688 の反応式
[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[O:38][CH2:39][C@@H:40]1[CH2:44][CH2:43][C@@H:42]([CH2:45][O:46]C)[NH:41]1.[OH-].[Na+].B(Br)(Br)Br>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.ClCCl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[OH:38][CH2:39][C@H:40]1[CH2:44][CH2:43][C@@H:42]([CH2:45][OH:46])[N:41]1[C:21]1[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)([CH3:34])[CH3:33])=[C:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH:22]=1.[OH:38][CH2:39][C@@H:40]1[CH2:44][CH2:43][C@@H:42]([CH2:45][OH:46])[N:41]1[C:21]1[N:20]=[CH:19][C:18]([N:16]([CH3:17])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)([CH3:34])[CH3:33])=[C:23]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH:22]=1

参加物

10

反応物 4

HCID 14798Sodium HydroxideHCID 25134Boron tribromideHCID 7019262(S,S)-(+)-2,5-Bis(methoxymethyl)pyrrolidineHCID 235027842-(3,5-Bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(4-fluoro-2-methylphenyl)pyrid-3-yl)-N,2-dimethylpropanamide

生成物 2

HCID 87304286HCID 87304286、化合物収率 2%HCID 87304714HCID 87304714、化合物収率 2%

試薬・触媒・溶媒 4

HCID 5974Hexadecyltrimethylammonium Bromide触媒HCID 178418851HCID 178418851、化合物触媒HCID 1140Toluene溶媒HCID 6344Dichloromethane溶媒2 回

反応条件

温度
90 °C

実験手順

A mixture of 0.30 g (0.56 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 0.11 g (0.68 mmol) (2S,5S)-(−)-2,5-bis(methoxymethyl)pyrrolidine, 5 mg (0.01 mmol) cetyltrimethylammonium bromide, 0.014 g (0.027 mmol) bis(tri-t-butylphosphine)palladium(0), 0.07 ml NaOH 50% and 2 ml toluene was degassed by two freeze-thaw cycles. The reaction mixture was heated under argon at 90° C. over night. After cooling to room temperature the mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 0.09 g of the crude coupling product. This material was dissolved in 2 ml dichloromethane and treated with 1.1 ml (1.1 mmol) of a 1 M solution of boron tribromide in dichloromethane at 0° C. After 15 min. the reaction was quenched by the addition of water, followed by extraction with three portions of dichloromethane. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 7 mg (2%) of (2R,5S)-N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as a light brown solid and 6 mg (2%) of (2S,5S)-N-[6-(2,5-bis-hydroxymethyl-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as a light brown solid.

後処理

  1. customwas degassed by two freeze-thaw cycles
  2. temperatureAfter cooling to room temperature the mixture
  3. additionwas diluted with water
  4. extractionextracted with three portions of tert-butyl methyl ether
  5. dry with materialThe combined organic layers were dried over sodium sulphate
  6. concentrationconcentrated in vacuo
  7. customFlash column chromatography gave 0.09 g of the crude coupling product
  8. customAfter 15 min. the reaction was quenched by the addition of water
  9. extractionfollowed by extraction with three portions of dichloromethane
  10. dry with materialThe combined organic layers were dried over sodium sulphate
  11. concentrationconcentrated in vacuo

出典と根拠

ORDレコード
ord-7f98eddfb3b94a8c8200f17cb5e323ad
出典データセット
uspto-grants-2013_03
特許番号
US08404708B2

反応ノート

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