Water → 1-(Biphenyl-4-ylcarbamoyl)-cyclopropanecarboxylic acid

HRID 1093709

Reaction equation

HRID 1093709 reaction equation
O[Li].O.C[O:5][C:6]([C:8]1([C:11](=[O:25])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:10][CH2:9]1)=[O:7].C1COCC1.O>CO>[C:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:17]=[CH:18][C:13]([NH:12][C:11]([C:8]2([C:6]([OH:7])=[O:5])[CH2:10][CH2:9]2)=[O:25])=[CH:14][CH:15]=1

Participants

6

Reactant 4

HCID 962WaterHCID 8028TetrahydrofuranHCID 168937Lithium hydroxide, monohydrateHCID 578758101-(Biphenyl-4-ylcarbamoyl)-cyclopropanecarboxylic acid methyl ester

Product 1

HCID 578743681-(Biphenyl-4-ylcarbamoyl)-cyclopropanecarboxylic acidYield 33%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

KOH (420 mg, 7.5 mmol) was added to a solution cyclopropane-1,1-dicarboxylic acid diethyl ester (1 g, 6.3 mmol) in methanol (7 mL). The reaction mixture was stirred for 4 hours at ambient temperature then concentrated. The resulting residue was diluted with water, acidified with conc. HCl and the product was extracted with dichloromethane. The dichloromethane layer was dried over sodium sulfate and concentrated under reduced pressure to afford 680 mg (75%) of cyclopropane-1,1-dicarboxylic acid methyl ester. HOBt (764 mg, 5.6 mmol), DMAP (1.72 g, 14.15 mmol) and EDCI.HCl (1.08 g, 5.6 mmol) followed by biphenyl-4-ylamine (957 mg, 5.6 mmol) were added to a stirred solution of cyclopropane-1,1-dicarboxylic acid methyl ester (680 mg, 4.7 mmol) in DMF (7 mL) and the resulting mixture was stirred at ambient temperature overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethylacetate layer was washed with brine solution and concentrated to afford 1.1 g (79%) of 1-(biphenyl-4-ylcarbamoyl)-cyclopropanecarboxylic acid methyl ester. LiOH.H2O (234 mg, 5.5 mmol) was added to a solution of 1-(biphenyl-4-ylcarbamoyl)-cyclopropanecarboxylic acid methyl ester (1.1 g, 3.7 mmol) in a mixture of methanol (5 mL), THF (11 mL) and H2O (3 mL) and the resulting mixture was stirred for 2 hours at ambient temperature. The reaction mixture was then concentrated and the residue was diluted with water, acidified with conc. HCl. The resulting precipitate was isolated by filtration and dried to afford 340 mg (33%) of 1-(biphenyl-4-ylcarbamoyl)-cyclopropane carboxylic acid.

Workup

  1. concentrationThe reaction mixture was then concentrated
  2. additionthe residue was diluted with water
  3. customThe resulting precipitate was isolated by filtration
  4. customdried

Sources & evidence

ORD record
ord-b90557bbb96743089df95e33fba42774
Source dataset
uspto-grants-2012_03
Patent number
US08129376B2

Linked notes

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