Formamide → (3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid amide

HRID 587346Notes

Reaction equation

C[O:2][C:3]([C@H:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][N:7]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6]1)=O.C([NH2:26])=O.C[O-].[Na+]>CN(C=O)C>[CH2:17]([N:7]1[CH2:8][C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C@H:5]([C:3]([NH2:26])=[O:2])[CH2:6]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1

Participants

Conditions

Temperature: 100 °C

Procedure

A solution of (3S,4R)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester (62.82 g, 190.5 mmol) and formamide (22.7 mL, 571.4 mmol) in DMF (75 mL) was heated to 100° C. Then sodium methylate solution (5.4 M in methanol, 17.6 mL, 95.2 mmol) was added dropwise over a period of 50 min. The solution was stirred for 3 h at 100° C. (after 1 h further formamide (11.4 mL, 285.7 mmol) was added). The reaction mixture was cooled to ambient temperature and the resulting suspension was separated between ethyl acetate (1500 mL) and water (1000 mL). The organic layers were washed with brine (500 mL), combined and dried over sodium sulfate. Concentration and trituration with tert-butylmethylether (500 mL) afforded the tittle compound (51.19 g, 85%) as white crystals. MS m/e: 315.2 and 317.3 [M+H]+).

Workup

temperatureThe reaction mixture was cooled to ambient temperature
customthe resulting suspension was separated between ethyl acetate (1500 mL) and water (1000 mL)
washThe organic layers were washed with brine (500 mL)
dry with materialdried over sodium sulfate
concentrationConcentration and trituration with tert-butylmethylether (500 mL)

Sources & evidence

ORD record: ord-c3b239c9f61445969f6e3073029687a5
Source dataset: uspto-grants-2016_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09226916B2

Reaction notes

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