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 717872Notes

Reaction equation

HRID 717872 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 A1) and 4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-(piperidin-4-yloxy)-6-(trifluoromethyl)pyridine (60. mg, 0.12 mmol, from Step D) 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-3ba64ebf198149688971a107bd181ed6
Source dataset
uspto-grants-2015_11
Patent number
US09193733B2

Reaction notes

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