2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → tert-butyl 2-(3-fluoro-4-((((1R,2R)-2-(1-(5-(methoxymethyl)pyrimidin-2-yl) piperidin-4-yl)cyclopropyl)methoxy)methyl)phenyl)acetate

HRID 1468876Notes

Reaction equation

HRID 1468876 reaction equation
Br[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][O:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[C:4]([F:29])[CH:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Br-].[C:65]([O:69][C:70](=[O:73])[CH2:71][Zn+])([CH3:68])([CH3:67])[CH3:66]>C1COCC1.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]>[F:29][C:4]1[CH:3]=[C:2]([CH2:71][C:70]([O:69][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:73])[CH:28]=[CH:27][C:5]=1[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[CH:22][C:21]([CH2:24][O:25][CH3:26])=[CH:20][N:19]=2)[CH2:14][CH2:13]1

Participants

6

Reactant 3

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 711160832-(4-((1R,2R)-2-(((4-bromo-2-fluorobenzyl)oxy)methyl)cyclopropyl)piperidin-1-yl)-5-(methoxymethyl)pyrimidineHCID 178451181HCID 178451181, compound

Product 1

HCID 71116106tert-butyl 2-(3-fluoro-4-((((1R,2R)-2-(1-(5-(methoxymethyl)pyrimidin-2-yl) piperidin-4-yl)cyclopropyl)methoxy)methyl)phenyl)acetateYield 98%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

2-(4-((1R,2R)-2-(((4-bromo-2-fluorobenzyl)oxy)methyl)cyclopropyl)piperidin-1-yl)-5-(methoxymethyl)pyrimidine (Step B product, 1.0 g, 2.15 mmol) was dissolved in anhydrous THF (3 ml). The mixture was stirred for 5 min and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.099 g, 0.108 mmol) and X-PHOS (0.103 g, 0.215 mmol) were added, followed by (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (0.5 M solution in ether, 12.92 ml, 6.46 mmol). The mixture was heated at 60° C. overnight. The reaction mixture was quenched with aqueous NH4Cl, and the aqueous layer was extracted with EtOAc. The organic extracts were washed with brine, dried, and evaporated to give the crude product, which was purified by flash column (25 g SNAP, 5˜30% EtOAc in hexane) to afford 1.05 g (98%) of the desired product. Rf was 0.3 @ 20% EtOAc in hexanes (blue spot on CAM stain).

Workup

  1. customThe reaction mixture was quenched with aqueous NH4Cl
  2. extractionthe aqueous layer was extracted with EtOAc
  3. washThe organic extracts were washed with brine
  4. customdried
  5. customevaporated
  6. customto give the crude product, which
  7. customwas purified by flash column (25 g SNAP, 5˜30% EtOAc in hexane)

Sources & evidence

ORD record
ord-0d4496a3c46c4cf99636cc5282518bc8
Source dataset
uspto-grants-2015_04
Patent number
US09006228B2

Reaction notes

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