Acetonitrile → 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-hydroxycyclohexylmethyl cyanide

HRID 51564

Reaction equation

HRID 51564 reaction equation
[CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.C(#N)C.[NH2:16][C:17]1[C:18]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)=[CH:24][N:23]([CH:39]3[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40]3)[C:19]=2[N:20]=[CH:21][N:22]=1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[NH2:16][C:17]1[C:18]2[C:25]([C:26]3[CH:27]=[CH:28][C:29]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:30][CH:31]=3)=[CH:24][N:23]([CH:39]3[CH2:40][CH2:41][C:42]([CH2:2][C:1]#[N:4])([OH:45])[CH2:43][CH2:44]3)[C:19]=2[N:20]=[CH:21][N:22]=1

Participants

7

Reactant 4

HCID 6342AcetonitrileHCID 7912DiisopropylamineHCID 22736171Protein kinase inhibitor 9HCID 178418339Butyllithium

Product 1

HCID 227362434-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-hydroxycyclohexylmethyl cyanideYield 15,200%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 12679HexamethylphosphoramideSolvent

Conditions

Temperature
0 °C

Procedure

A solution of diisopropylamine (0.649 g, 0.0050 mol) in tetrahydrofuran (10 mL) was cooled to 0° C. A solution of 1.6 M n-butyl lithium (3.14 mL, 0.0050 mol) in hexanes was added dropwise, keeping the temperature less than 5° C. After the addition was complete, the mixture was stirred for 20 minutes at 0° C. The mixture was cooled to −78° C., and dry acetonitrile (0.175 g, 0.0043 mol) was added, keeping the temperature less than −70° C. After the addition was complete, the mixture was stirred for 20 minutes at −78° C., and a mixture of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone (1.000 g, 0.0025 mmol) in tetrahydrofuran (10 mL) and hexamethylphosphoramide (10 mL) was added, keeping the temperature less than −70° C. After the addition was complete, the mixture was stirred for 30 minutes at −78° C., then stirred at ambient temperature for 18 hours. The mixture was partitioned between dichloromethane and saturated ammonium chloride (aq). The organic phase was washed with water and saturated sodium bicarbonate (aq), and dried over magnesium sulfate. The solvent was removed in vacuo and the cis and trans isomers were separated by flash column chromatography on silica using dichloromethane/methanol (95:5) as an eluent to give less polar 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-hydroxycyclohexylmethyl cyanide (0.120 g, 0.00027 mol) and more polar 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-hydroxycyclohexylmethyl cyanide (0.170 g, 0.00038 mol):

Workup

  1. customthe temperature less than 5° C
  2. additionAfter the addition
  3. temperatureThe mixture was cooled to −78° C.
  4. customthe temperature less than −70° C
  5. additionAfter the addition
  6. stirringthe mixture was stirred for 20 minutes at −78° C.
  7. additionwas added
  8. customthe temperature less than −70° C
  9. additionAfter the addition
  10. stirringthe mixture was stirred for 30 minutes at −78° C.
  11. stirringstirred at ambient temperature for 18 hours
  12. customThe mixture was partitioned between dichloromethane and saturated ammonium chloride (aq)
  13. washThe organic phase was washed with water and saturated sodium bicarbonate (aq)
  14. dry with materialdried over magnesium sulfate
  15. customThe solvent was removed in vacuo
  16. customthe cis and trans isomers were separated by flash column chromatography on silica

Sources & evidence

ORD record
ord-0dfd4308f6d54cbd9db5af920712d17a
Source dataset
uspto-grants-2004_03
Patent number
US06713474B2

Linked notes

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