Sodium Hydroxide → HCID 87304286, 화합물

HRID 1951688노트

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HRID 1951688 반응식
[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

참가 물질

10

반응물 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

생성물 2

HCID 87304286HCID 87304286, 화합물수율 2%HCID 87304714HCID 87304714, 화합물수율 2%

시약·촉매·용매 4

HCID 5974Hexadecyltrimethylammonium Bromide촉매HCID 178418851HCID 178418851, 화합물촉매HCID 1140Toluene용매HCID 6344Dichloromethane용매2회

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온도
90 °C

실험 절차

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.

후처리

  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

출처 및 근거

ORD 기록
ord-7f98eddfb3b94a8c8200f17cb5e323ad
출처 데이터셋
uspto-grants-2013_03
특허 번호
US08404708B2

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