Methanol → (3S,5S)-5-(3-Chloro-2-fluoro-benzylcarbamoyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester

HRID 1527320Notes

Reaction equation

HRID 1527320 reaction equation
Cl[Si](C)(C)C.C[OH:7].[C:8]([O:12][C:13]([N:15]1[CH2:19][C@@H:18]([C:20]#N)[CH2:17][C@H:16]1[C:22](=[O:33])[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[F:32])=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:34](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:35]>C(Cl)Cl>[CH3:34][O:35][C:20]([C@H:18]1[CH2:17][C@@H:16]([C:22](=[O:33])[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=2[F:32])[N:15]([C:13]([O:12][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:14])[CH2:19]1)=[O:7]

Participants

6

Reactant 4

HCID 887MethanolHCID 6397ChlorotrimethylsilaneHCID 90495Di-tert-butyl dicarbonateHCID 68283946(2S,4S)-2-(3-Chloro-2-fluoro-benzylcarbamoyl)-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 68284043(3S,5S)-5-(3-Chloro-2-fluoro-benzylcarbamoyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Chlorotrimethylsilane (5.66 mL, 44.8 mmol) was added dropwise to dry MeOH (7.6 mL) at 0° C. followed by a solution of (2S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (900 mg, 2.36 mmol) in dry CH2Cl2 (6.7 mL) and the resulting mixture was stirred at RT for 5 h. The mixture was cooled to 0° C., quenched with a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×3). To the organic extracts was added di-tert-butyl dicarbonate (514 mg, 2.36 mmol) at RT and the resulting solution was stirred overnight. The reaction mixture was concentrated in vacuo and the crude material purified by flash column chromatography (c-hexane to c-hexane/EtOAc 1:1) to give the expected compound. tR (HPLC conditions a): 3.50 min.

Workup

  1. temperatureThe mixture was cooled to 0° C.
  2. customquenched with a saturated aqueous solution of NaHCO3
  3. extractionextracted with CH2Cl2 (×3)
  4. stirringthe resulting solution was stirred overnight
  5. concentrationThe reaction mixture was concentrated in vacuo
  6. customthe crude material purified by flash column chromatography (c-hexane to c-hexane/EtOAc 1:1)

Sources & evidence

ORD record
ord-6bd16d27bf8e41218f03e5059dcfc77b
Source dataset
uspto-grants-2015_07
Patent number
US09085555B2

Reaction notes

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