Sodium cyanoborohydride → {3-(4-{[4-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile

HRID 1426340노트

반응식

HRID 1426340 반응식
C([BH3-])#N.[Na+].O=[C:6]1[CH2:9][C:8]([CH2:32][C:33]#[N:34])([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7]1.[Si:35]([O:52][CH2:53][C:54]1[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[N:57]=[C:56]([O:64][CH:65]2[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]2)[CH:55]=1)([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CO.CCOC(C)=O.[Cl-].[Cl-].[Zn+2].[BH3-]C#N.[Na+].[Cl-].[Cl-].[Zn+2]>[Si:35]([O:52][CH2:53][C:54]1[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[N:57]=[C:56]([O:64][CH:65]2[CH2:66][CH2:67][N:68]([CH:6]3[CH2:7][C:8]([CH2:32][C:33]#[N:34])([N:10]4[CH:14]=[C:13]([C:15]5[C:16]6[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:17]=6[N:18]=[CH:19][N:20]=5)[CH:12]=[N:11]4)[CH2:9]3)[CH2:69][CH2:70]2)[CH:55]=1)([C:48]([CH3:50])([CH3:49])[CH3:51])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1

참가 물질

8

반응물 3

HCID 5003444Sodium cyanoborohydrideHCID 696736304-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-2-(piperidin-4-yloxy)-6-(trifluoromethyl)pyridineHCID 69675509{3-oxo-1-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile

생성물 1

HCID 86666504{3-(4-{[4-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidin-1-yl)-1-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile

시약·촉매·용매 4

HCID 3007855Zincchloride촉매HCID 131717307ZINC chloride sodium cyanoborohydride촉매HCID 887Methanol용매2회HCID 8857Ethyl Acetate용매

실험 절차

Sodium cyanoborohydride (8.8 mg, 0.14 mmol) and zinc dichloride (9.5 mg, 0.070 mmol) were combined in methanol (0.56 mL, 14 mmol) and stirred for 2 hours to generate the reducing solution referenced in JOC 1985, 50, 1927-1932. Subsequently, {3-oxo-1-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile (66 mg, 0.14 mmol, from Step 7 of Example 1a) and 4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-(piperidin-4-yloxy)-6-(trifluoromethyl)pyridine (60. mg, 0.12 mmol, from Step C) were combined in Methanol (2.0 mL) to dissolve, then the above generated reducing mixture was added. The reaction was stirred overnight. An additional 0.3 eq of the prestirred NaCNBH3/ZnCl2 mixture was added. After stirring for 3 hours, the mixture was diluted with EtOAc and was washed with saturated sodium bicarbonate solution, followed by brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-80% EtOAc in hexanes afforded product as a mixture of cis- and trans-isomers (43 mg, 40%). LCMS (M+2H)2+: 461.4.

후처리

  1. dissolutionto dissolve
  2. additionwas added
  3. stirringThe reaction was stirred overnight
  4. stirringAfter stirring for 3 hours
  5. washwas washed with saturated sodium bicarbonate solution
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. washFlash chromatography on silica gel, eluting with a gradient from 0-80% EtOAc in hexanes afforded product as a mixture of cis- and trans-isomers (43 mg, 40%)

출처 및 근거

ORD 기록
ord-2b8a5fee059744a6a07bc4b41e82df3b
출처 데이터셋
uspto-grants-2015_01
특허 번호
US08933085B2

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