Diisopropylethylamine → (2S,3R)-2-(3-Chloro-2-fluoro-benzylcarbamoyl)-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 1527323Notes

Reaction equation

HRID 1527323 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH3:14])[C@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:20]([F:27])=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH3:14])[C@H:9]1[C:15](=[O:17])[NH:26][CH2:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=1[F:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 2773614(3-Chloro-2-fluorophenyl)methanamineHCID 69351760(2S,3R)-1-[(tert-Butoxy)carbonyl]-3-methoxypyrrolidine-2-carboxylic acid

Product 1

HCID 68284261(2S,3R)-2-(3-Chloro-2-fluoro-benzylcarbamoyl)-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

The mixture of (2S,3R)-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (60.0 mg, 0.245 mmol), (3-chloro-2-fluorophenyl)methanamine (0.034 mL, 0.269 mmol), HBTU (139 mg, 0.367 mmol) and DIPEA (0.085 mL, 0.489 mmol) in CH2Cl2 (5 mL) was stirred for 20 h at RT. The reaction mixture was then diluted with CH2Cl2, and the organics were washed subsequently with 0.1N aqueous HCl (3×), aqueous NaHCO3 solution (2×) and brine. The organic layers were dried (Phase separator), concentrated in vacuo and the residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm; flow: 40 mL/min; eluent: 5-100% CH3CN/H2O for 20 min, 100% CH3CN for 2 min, CH3CN and H2O containing 0.1% TFA) to afford the title compound as a white solid. MS (LC/MS): 387 [M+H]+, 331 [MH−tBu]+, 287 [MH−Boc]+; tR (HPLC conditions b): 4.26 min.

Workup

  1. washthe organics were washed subsequently with 0.1N aqueous HCl (3×), aqueous NaHCO3 solution (2×) and brine
  2. customThe organic layers were dried (Phase separator)
  3. concentrationconcentrated in vacuo
  4. customthe residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm; flow: 40 mL/min; eluent: 5-100% CH3CN/H2O for 20 min, 100% CH3CN for 2 min, CH3CN and H2O containing 0.1% TFA)

Sources & evidence

ORD record
ord-b0df195b7b3e42a6af62590c5cdf98eb
Source dataset
uspto-grants-2015_07
Patent number
US09085555B2

Reaction notes

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