Diisopropylethylamine → rac-[(3R,4S)-4-(3,4-Dichloro-phenyl)-1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester

HRID 587326Notes

Reaction equation

HRID 587326 reaction equation
[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49](=[O:65])[N:50]([C@@H:52]2[C@@H:56]([C:57]3[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=3)[CH2:55][NH:54][CH2:53]2)[CH3:51])=[CH:44][CH:43]=1>CN(C=O)C.C(OCC)(=O)C>[F:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49](=[O:65])[N:50]([C@@H:52]2[C@@H:56]([C:57]3[CH:62]=[CH:61][C:60]([Cl:63])=[C:59]([Cl:64])[CH:58]=3)[CH2:55][N:54]([C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[O:9])[CH2:53]2)[CH3:51])=[CH:44][CH:43]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 219302Oxane-4-carboxylic acidHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 67234230rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester

Product 1

HCID 53244483rac-[(3R,4S)-4-(3,4-Dichloro-phenyl)-1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl esterYield 57%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of tetrahydropyran-4-yl-carboxylic acid (51 mg, 0.39 mmol) in DMF (1 mL) was added ambient temperature 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.36 mmol) and N,N-diisopropyl ethyl amine (125 mg, 0.97 mmol). After stirring for 15 min at this temperature a solution of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (124 mg, 0.32 mol) in DMF (1 mL) was added and stirred for 20 h at ambient temperature. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with aqueous sodium carbonate (1 M, 10 mL), water (10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, ethyl acetate:methanol=98:2 to 85:15) afforded the title compound (92 mg, 57%) as a white oil. MS m/e: 495.3 [M]+.

Workup

  1. additionwas added
  2. washwashed with aqueous sodium carbonate (1 M, 10 mL), water (10 mL) and brine (10 mL)
  3. extractionThe aqueous layers were extracted with ethyl acetate (10 mL)
  4. dry with materialthe combined organic layers were dried over sodium sulfate
  5. concentrationconcentrated
  6. customPurification by chromatography (SiO2, ethyl acetate:methanol=98:2 to 85:15)

Sources & evidence

ORD record
ord-a99da81a87ff4ec6be23943e50462189
Source dataset
uspto-grants-2016_01
Patent number
US09226916B2

Reaction notes

Loading…