Citric Acid → Ethyl 4-[(3R)-3-(1-tert-butoxycarbonylaminocyclopropyl)-pyrrolidin-1-yl]-2-fluoro-3-methoxybenzoate

HRID 1865173Notes

Reaction equation

HRID 1865173 reaction equation
[C:1]([O:5][C:6]([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[C:28]([O:29][CH3:30])=[C:27](F)[CH:26]=[CH:25][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][N:14]([C:27]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([F:17])[C:28]=3[O:29][CH3:30])[CH2:13]2)[CH2:10][CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 311Citric AcidHCID 8471TriethylamineHCID 11117758(R)-t-Butyl (1-(pyrrolidin-3-yl)cyclopropyl)carbamateHCID 11543054Ethyl 2,4-difluoro-3-methoxybenzoate

Product 1

HCID 11704499Ethyl 4-[(3R)-3-(1-tert-butoxycarbonylaminocyclopropyl)-pyrrolidin-1-yl]-2-fluoro-3-methoxybenzoateYield 76%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Procedure

(3R)-3-(1-Tert-butoxycarbonylaminocyclopropyl)-pyrrolidine (4.75 g, 85% content) was dissolved in dimethylsulfoxide (30 mL). After adding thereto ethyl 2,4-difluoro-3-methoxybenzoate (3.2 g) and triethylamine (3.1 mL), the mixture was stirred at 75° C. After 18 hours, the mixture was allowed to cool, incorporated with 10% aqueous citric acid solution, and extracted with AcOEt. An organic layer was dried with anhydrous sodium sulfate and filtered, and then the solvent was distilled away. The resulting residual crystals (6.22 g) (2-position:4-position=17:83) were subjected to chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound as white crystals (4.75 g).

Workup

  1. additionAfter adding
  2. extractionextracted with AcOEt
  3. dry with materialAn organic layer was dried with anhydrous sodium sulfate
  4. filtrationfiltered
  5. distillationthe solvent was distilled away

Sources & evidence

ORD record
ord-11dc09e6d21845b38082f97fcb23bdd8
Source dataset
uspto-grants-2009_12
Patent number
US07626029B2

Reaction notes

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