Methanol → Cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(5-cyclopropylmethylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide

HRID 529758노트

반응식

HRID 529758 반응식
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:35][C@@H:34]4[C@@H:30]([CH2:31][NH:32][CH2:33]4)[CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.[CH:40]1([CH:43]=O)[CH2:42][CH2:41]1.[BH4-].[Na+].CO>FC(F)(F)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][C@@H:30]4[C@@H:34]([CH2:33][N:32]([CH2:43][CH:40]5[CH2:42][CH2:41]5)[CH2:31]4)[CH2:35]3)=[O:27])[N:9]=2)[CH:7]=1

참가 물질

6

반응물 4

HCID 887Methanol2회HCID 123114CyclopropanecarboxaldehydeHCID 4311764Sodium borohydrideHCID 118522653Cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(hexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide

생성물 1

HCID 118522500Cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(5-cyclopropylmethylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide

시약·촉매·용매 1

HCID 64092,2,2-Trifluoroethanol용매

실험 절차

To a solution of cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(hexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide (100 mg, 0.18 mmol) in 2,2,2-trifluoroethanol (3 mL) was added cyclopropanecarbaldehyde (67 μL, 0.90 mmol). After stirring at room temperature for 15 minutes, sodium borohydride (21 mg, 0.54 mmol) was added and the reaction was heated at 90° C. for 2 hours. MeOH was added to quench the reaction and the mixture was loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. Evaporation gave a crude product which was purified by HPLC (Method 1). The pure fractions loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. Evaporation gave the title compound as a free base which was crystallised from MeOH/Et2O and obtained as a yellow solid (55 mg, 50%). LCMS (Method 5) [M+H]+=611.1, RT=3.02 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 10.94-10.88 (m, 1H), 9.57-9.55 (m, 1H), 8.95-8.92 (m, 1H), 8.38-8.35 (m, 1H), 8.29-8.28 (m, 1H), 7.65-7.61 (m, 1H), 7.56-7.54 (m, 1H), 7.47 (d, 1H, J=8.9 Hz), 7.45-7.07 (m, 1H), 7.08 (d, 1H, J=1.9 Hz), 7.02-6.99 (m, 1H), 5.24-5.07 (m, 2H), 3.86-3.52 (m, 5H), 3.52-3.22 (m, 2H), 3.17-3.11 (m, 1H), 3.07-3.00 (m, 2H), 3.00-2.79 (m, 1H), 1.27-1.01 (m, 1H), 0.63-0.56 (m, 2H), 0.42-0.34 (m, 2H).

후처리

  1. temperaturethe reaction was heated at 90° C. for 2 hours
  2. customto quench
  3. customthe reaction
  4. customAfter flushing with MeOH
  5. washthe product was eluted with 2M ammonia in MeOH
  6. customEvaporation
  7. customgave a crude product which
  8. customwas purified by HPLC (Method 1)
  9. customAfter flushing with MeOH
  10. washthe product was eluted with 2M ammonia in MeOH
  11. customEvaporation

출처 및 근거

ORD 기록
ord-a606407ca6674a569000c0646f56ee6e
출처 데이터셋
uspto-grants-2016_05
특허 번호
US09346815B2

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