Cesium carbonate → methyl 4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3'-bipyrrolidin-1'-yl}benzoate

HRID 562584Notes

Reaction equation

HRID 562584 reaction equation
[N:1]1([CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:22])[CH2:8][NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:2]1.Br[C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])(O)=O.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].ClCCl>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:10]([NH:9][CH2:8][C:7]([NH:6][C@@H:3]1[CH2:4][CH2:5][N:1]([CH:23]2[CH2:27][CH2:26][N:25]([C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=3)[CH2:24]2)[CH2:2]1)=[O:22])=[O:21]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 12081Methyl 4-bromobenzoateHCID 516892Sodium BicarbonateHCID 67006850N-{2-[(3R)-1,3'-bipyrrolidin-3-ylamino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

Product 1

HCID 16666601methyl 4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3'-bipyrrolidin-1'-yl}benzoateYield 30%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Procedure

A slurry of N-{2-[(3R)-1,3′-bipyrrolidin-3-ylamino]-2-oxoethyl}-3-(trifluoromethyl)benzamide (50 mg, 0.13 mmol), methyl 4-bromobenzoate (35 mg, 0.16 mmol), Pd2(dba)3 (12 mg, 0.013 mmol), cesium carbonate (64 mg, 0.19 mmol) and R-BINAP (8 mg, 0.013 mmol) in toluene was heated at 100° C. overnight. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford, as a mixture of diastereomers, methyl 4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidin-1′-yl}benzoate (20 mg, 30%) as a white solid. 1H-NMR (CDCl3) δ: 1.60-1.76 (m, 1H), 1.86-2.04 (m, 1H), 2.08-2.25 (m, 1H), 2.20-2.44 (m, 2H), 2.60-2.78 (m, 2H), 2.84-3.00 (m, 2H), 3.18 (q, J=8.7 Hz, 1H), 3.32 (q, J=7.5 Hz, 1H), 3.40-3.54 (m, 2H), 3.82 (s, 3H), 4.10 (m, 2H), 4.40-4.56 (m, 1H), 6.44 (d, J=8.7 Hz, 2H), 6.54 (d, J=2.4 Hz, 1H), 7.20-7.35 (m, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.97 (d, J=7.8 Hz, 1H), 8.07 (s, 1H). MS m/z: 519 (M+1)

Workup

  1. customThe organic layer was separated
  2. washthe aqueous layer was washed with an addition portion of dichloromethane (10 mL)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-5c21f22e28494da3ba8e3fa18158ad97
Source dataset
uspto-grants-2011_11
Patent number
US08067415B2

Reaction notes

Loading…