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

HRID 1527410Notes

Reaction equation

HRID 1527410 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].[Cl:19][C:20]1[C:21]([F:28])=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24].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>CN(C=O)C.O>[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:24][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([Cl:19])[C:21]=1[F:28])=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

7

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 68283958(2S,3S,4S)-4-Fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

Product 1

HCID 68283934(2S,3S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (500 mg, 1.90 mmol) in DMF (20 mL) were added 3-chloro-2-fluoro-benzylamine (330 mg, 2.1 mmol), HBTU (1.4 g, 3.8 mmol) and DIPEA (1.32 mL, 7.6 mmol). The reaction mixture was stirred at RT for 2 h then was poured into water (50 mL). After extraction with ETOAc (3×30 mL), the organic phases were joined, washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1) to give (2S,3S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester: Rf, TLC (c-hexane/EtOAc 1:1)=0.37; MS (UPLC): 405.1/407.2 [M+H]+, 349.1/351.1 [MH−tBu]+, 449.2/451.2 [M+HCOO]−; tR (HPLC conditions f): 2.12 min. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.59 (m, 1H), 7.48 (m, 1H), 7.37 (m, 1H), 7.20 (m, 1H), 5.20 (br.d, 1H), 4.47-4.26 (m, 3H), 4.19 (ddd, 1H), 3.81-3.65 (m, 1H), 3.54-3.40 (m, 1H), 3.36 (s, 3H), 1.42 and 1.27 (2 s, 9H).

Workup

  1. extractionAfter extraction with ETOAc (3×30 mL)
  2. washwashed with brine
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1)

Sources & evidence

ORD record
ord-98f330414eee47609eef5609db889165
Source dataset
uspto-grants-2015_07
Patent number
US09085555B2

Reaction notes

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