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 1426340Notes

Reaction equation

HRID 1426340 reaction equation
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

Participants

8

Reactant 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

Product 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

Reagents, catalysts & solvents 4

HCID 3007855ZincchlorideCatalystHCID 131717307ZINC chloride sodium cyanoborohydrideCatalystHCID 887MethanolSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

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.

Workup

  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%)

Sources & evidence

ORD record
ord-2b8a5fee059744a6a07bc4b41e82df3b
Source dataset
uspto-grants-2015_01
Patent number
US08933085B2

Reaction notes

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