Tricyclohexylphosphine → HCID 24991554, compound

HRID 1919816Notes

Reaction equation

HRID 1919816 reaction equation
[CH3:1][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)[N:17]([C:31]2[CH:36]=[CH:35][C:34](Br)=[CH:33][CH:32]=2)[C:16]1=[O:38])([C:4]1[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH3:3].[CH:39]1(B(O)O)[CH2:41][CH2:40]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C:2]([NH:14][C@@H:15]1[CH2:19][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)[N:17]([C:31]2[CH:36]=[CH:35][C:34]([CH:39]3[CH2:41][CH2:40]3)=[CH:33][CH:32]=2)[C:16]1=[O:38])([C:4]1[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH3:3]

Participants

8

Reactant 3

HCID 75806TricyclohexylphosphineHCID 2760897Cyclopropylboronic acidHCID 24990102HCID 24990102, compound

Product 1

HCID 24991554HCID 24991554, compoundYield 91.07%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

Dissolve (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-1-(4-bromo-phenyl)-5-(3-trifluoromethoxy-phenyl)-pyrrolidin-2-one (1.25 mmoles; 750 mg), cyclopropylboronic acid (1.62 mmoles; 139 mg), tribasic potassium phosphate N-hydrate (4.36 mmoles; 925 mg), and tricyclohexylphosphine (124.51 μmoles; 34 mg) in toluene (5 mL) and water (275 μL) and degas the solution for 5 minutes then place under a nitrogen atmosphere. Add Pd(OAc)2 (62 μmoles; 14 mg) and heat the mixture at 90° C. overnight. Dilute with ethyl acetate (50 mL) and filter through celite. Wash the filtrate with water, 1N HCl, saturated aqueous sodium bicarbonate, brine, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to a brown residue. Purify the residue by flash chromatography on silica with gradient 0->50% ethyl acetate in hexane to afford the title compound (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-(3-trifluoromethoxy-phenyl)-1-(4-cyclopropyl-phenyl)-pyrrolidin-2-one (1.13 mmoles; 639.00 mg; 91.07% yield). LC/MS m/z 564.2 (M+1), Tr=4.87 min (Method 3).

Workup

  1. customdegas the solution for 5 minutes
  2. filtrationfilter through celite
  3. washWash the filtrate with water, 1N HCl, saturated aqueous sodium bicarbonate, brine
  4. dry with materialdry over anhydrous sodium sulfate
  5. filtrationfilter
  6. concentrationconcentrate in vacuo to a brown residue
  7. customPurify the residue by flash chromatography on silica with gradient 0->50% ethyl acetate in hexane

Sources & evidence

ORD record
ord-da2cb80964884063b5e8ca0f14595cf3
Source dataset
uspto-grants-2012_05
Patent number
US08168659B2

Reaction notes

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