Tetrahydrofuran → 2-(3-Chloro-4-fluorophenyl)-6-cyclopropyl-N5-(3,3-difluoro-1-methylcyclobutyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide

HRID 920833노트

반응식

HRID 920833 반응식
[F:1][C:2]1([F:10])[CH2:5][C:4]([CH3:9])(C(O)=O)[CH2:3]1.C1C=CC(P([N:25]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[C:47]([C:48]([NH2:50])=[O:49])=[C:39]3[CH2:40][NH:41][CH:42]([CH:44]4[CH2:46][CH2:45]4)[CH2:43][N:38]3[N:37]=2)[CH:32]=[CH:33][C:34]=1[F:35].C1[CH2:55][O:54]CC1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[C:47]([C:48]([NH2:50])=[O:49])=[C:39]3[CH2:40][N:41]([C:55]([NH:25][C:4]4([CH3:9])[CH2:3][C:2]([F:1])([F:10])[CH2:5]4)=[O:54])[CH:42]([CH:44]4[CH2:45][CH2:46]4)[CH2:43][N:38]3[N:37]=2)[CH:32]=[CH:33][C:34]=1[F:35]

참가 물질

7

반응물 4

HCID 8028TetrahydrofuranHCID 199401P,P-Diphenylphosphinic azideHCID 234468533,3-Difluoro-1-methylcyclobutane-1-carboxylic acidHCID 1180617232-(3-Chloro-4-fluorophenyl)-6-cyclopropyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

생성물 1

HCID 1180619322-(3-Chloro-4-fluorophenyl)-6-cyclopropyl-N5-(3,3-difluoro-1-methylcyclobutyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide

시약·촉매·용매 2

HCID 1140Toluene용매HCID 8857Ethyl Acetate용매

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온도
80 °C

실험 절차

To a stirred solution of 3,3-difluoro-1-methylcyclobutanecarboxylic acid (0.047 g, 0.311 mmol) in toluene (2.0 mL) was added TEA (0.167 mL, 1.195 mmol), followed by DPPA (0.104 mL, 0.478 mmol) and the reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was cooled to RT and to it was added a solution of Intermediate 3481 (0.08 g, 0.239 mmol) in THF (1.0 mL) and stirred at RT for 14 h. The reaction mixture was diluted with EtOAc (10 mL), washed with water and brine. The organic layer was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 1% MeOH in CHCl3) to afford the racemic compound. The individual isomers were separated by preparative Chiral SFC (Column: Lux cellulose-4 (250×4.6) mm, 5 μm, flow rate 4 mL/min, Mobile Phase A: CO2, Mobile Phase B: 0.2% DEA in methanol, back pressure: 100 bar. Retention time: 3.84 min. and 8.08 min. respectively for Compounds 348 and 349.

후처리

  1. temperatureThe reaction mixture was cooled to RT and to it
  2. stirringstirred at RT for 14 h
  3. washwashed with water and brine
  4. dry with materialThe organic layer was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationthe filtrate concentrated under reduced pressure
  7. customThe crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 1% MeOH in CHCl3)
  8. customto afford the racemic compound
  9. customThe individual isomers were separated by preparative Chiral SFC (Column
  10. customRetention time: 3.84 min. and 8.08 min.

출처 및 근거

ORD 기록
ord-c4802889fb22409992356bb3c88a343d
출처 데이터셋
uspto-grants-2016_03
특허 번호
US09273058B2

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