Diisopropylethylamine → (2S,3S,4S)-4-fluoro-2-(2-fluoro-3-trifluoromethoxy-phenylcarbamoyl)-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 1527413Notes

Reaction equation

HRID 1527413 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C[C@@H](OC)[C@H](F)[C@H]1C(O)=O)=O)(C)(C)C.ClC(N(C)C)=C(C)C.[F:45][C:46]1[C:52]([O:53][C:54]([F:57])([F:56])[F:55])=[CH:51][CH:50]=[CH:49][C:47]=1[NH2:48].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16](=[O:18])[NH:48][C:47]1[CH:49]=[CH:50][CH:51]=[C:52]([O:53][C:54]([F:55])([F:56])[F:57])[C:46]=1[F:45])=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 6407921-Chloro-N,N-2-trimethylpropenylamineHCID 252105032-Fluoro-3-(trifluoromethoxy)anilineHCID 68283958(2S,3S,4S)-4-Fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl esterHCID 68284081(2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

Product 1

HCID 68283880(2S,3S,4S)-4-fluoro-2-(2-fluoro-3-trifluoromethoxy-phenylcarbamoyl)-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (prepared as described in Scheme B25, 1.00 g, 3.80 mmol) in CH2Cl2 (10 mL) at 0° C. under nitrogen atmosphere was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (609 mg, 4.56 mmol) and the mixture was stirred at this temperature for 1 h. 2-Fluoro-3-(trifluoromethoxy)aniline (0.815 mg, 4.18 mmol) was then added, followed by DIPEA (1.327 mL, 7.60 mmol) and the mixture was stirred at RT for 1 h. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:0 to 1:1) to give (2S,3S,4S)-4-fluoro-2-(2-fluoro-3-trifluoromethoxy-phenylcarbamoyl)-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-d6) 2:1 mixture of rotamers δ (ppm): 10.15 (m, 1H), 7.87 (m, 1/3H), 7.77 (m, 2/3H), 7.31 (m, 2H), 5.29-5.11 (m, 1H), 4.76 (d, 1/3H), 4.70 (d, 2/3H), 4.29 (m, 1H), 3.80-3.53 (m, 2H), 3.39 (m, 3H), 1.39 (s, 3H), 1.31 (s, 6H). MS (UPLC-MS): 441 [M+H]+; tR (HPLC conditions f): 2.14 min.

Workup

  1. stirringthe mixture was stirred at RT for 1 h
  2. customThe crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:0 to 1:1)

Sources & evidence

ORD record
ord-01aff2deee2947729e7d617b652a0bde
Source dataset
uspto-grants-2015_07
Patent number
US09085555B2

Reaction notes

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