Acetone Cyanohydrin → HCID 46938169, compound

HRID 655728Notes

Reaction equation

HRID 655728 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([O:18][C@@H:19]([CH2:30][O:31][C@H:32]([CH3:45])[CH2:33][O:34][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[C:20]([NH:22][C:23]3[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=3)=[O:21])=[C:12]2[CH:11]=[N:10]1.C([O-])(=O)C.[Na+].CC(C)(O)[C:53]#[N:54].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(N(C(C)C)CC)(C)C.C(OC)(C)(C)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:53]#[N:54])[C:3]=1[N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([O:18][C@@H:19]([CH2:30][O:31][C@H:32]([CH3:45])[CH2:33][O:34][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[C:20]([NH:22][C:23]3[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=3)=[O:21])[C:12]=2[CH:11]=[N:10]1

Participants

11

Reactant 4

HCID 6406Acetone CyanohydrinHCID 516892Sodium BicarbonateHCID 517045Sodium AcetateHCID 57504702HCID 57504702, compound

Product 1

HCID 46938169HCID 46938169, compoundYield 74%

Reagents, catalysts & solvents 6

HCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent3×HCID 15413tert-Butyl methyl etherSolventHCID 81531DiisopropylethylamineSolvent

Conditions

Temperature
5 °C

Procedure

A solution of (2S)-2-(1-(2-bromo-6-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate BO1) (1 equiv) in inerted* DMF (5 rel vols) and diisopropylethylamine (DIPEA) (1.25 equivs) was kept in an inert atmosphere and was added with stirring to an inerted* mixture of tris(dibenzylideneacetone)dipalladium(0) (0.025 equivs), sodium acetate (0.1 equiv) and 1,1′-bis(diphenylphosphino)ferrocene (0.075 equivs) in DMF (5 rel vols) at 90° C. over 5 minutes. The mixture was stirred for 10 minutes and then an inerted* solution of acetone cyanohydrin (1.4 equivs) in DMF (2 rel vols) was added over 20 hours with stirring. When the reaction was completed the mixture was cooled to 5° C. and diluted with methyl tert-butyl ether (7 rel vols) and then sodium bicarbonate (0.3 equivs) in water (2.5 rel vols). The organic phase was separated and the aqueous phase washed with methyl tert-butyl ether. The combined organic extract and organic washings were evaporated under reduced pressure at 35° C. and the residue was purified by chromatography. Yield 74%. *Nitrogen bubbled through before use.

Workup

  1. additionwas added
  2. stirringwith stirring
  3. customThe organic phase was separated
  4. washthe aqueous phase washed with methyl tert-butyl ether
  5. extractionThe combined organic extract
  6. customorganic washings were evaporated under reduced pressure at 35° C.
  7. customthe residue was purified by chromatography
  8. custom*Nitrogen bubbled through before use

Sources & evidence

ORD record
ord-7bc0914f70884d3a98d440d43ae871d1
Source dataset
uspto-grants-2011_12
Patent number
US08071608B2

Reaction notes

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