Chloroform → N-(1-methylcyclobutyloxycarbonyl)-phenylalanine methyl ester

HRID 1605183Notes

Reaction equation

HRID 1605183 reaction equation
Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(Cl)(Cl)Cl.Cl[C:20]([O:22][C:23]1([CH3:27])[CH2:26][CH2:25][CH2:24]1)=[O:21]>C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:20]([O:22][C:23]1([CH3:27])[CH2:26][CH2:25][CH2:24]1)=[O:21]

Participants

5

Reactant 3

HCID 6212ChloroformHCID 75736Methyl L-phenylalaninate hydrochlorideHCID 215491141-Methylcyclobutyl Chloroformate

Product 1

HCID 22788824N-(1-methylcyclobutyloxycarbonyl)-phenylalanine methyl ester

Reagents, catalysts & solvents 1

HCID 8471TriethylamineSolvent2×

Procedure

A suspension of 171 mg. (0.74 mM) of phenylalanine methyl ester hydrochloride in 10 ml. of chloroform is cooled to 0°C. and the pH adjusted to 8 by addition of triethylamine. 1-Methylcyclobutyl chloroformate 1.5 mM is added portion-wise at 0°C. and the pH of the reaction is maintained at 8 by addition of triethylamine. Upon completion of the addition, the reaction is stirred overnight at 20°-25°C. The reaction solution is washed successively with 10 ml. portions of a saturated sodium bicarbonate solution, 50% saturated solution of sodium chloride, 0.2 N sulfuric acid saturated with sodium sulfate, 50% saturated solution of sodium chloride (twice), and the chloroform solution is dried over sodium acetate. Removal of the chloroform affords N-(1-methylcyclobutyloxycarbonyl)-phenylalanine methyl ester. Saponification of the above ester is carried out by dissolving the residue in 10 ml. of methanol, water (10 ml.) is added and the pH is adjusted to 12 by addition of 2 N sodium hydroxide. After stirring overnight at 25°C., the pH is adjusted to 7 with 2 N sulfuric acid. The methanol is removed in vacuo and saturated sodium bicarbonate solution is added to the water solution. The aqueous bicarbonate solution is washed two times with ether and then the pH is adjusted to 3 by addition of concentrated hydrochloric acid. The acidified solution is extracted three times with ethyl acetate and the organic extracts combined, washed twice with sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo and trituration with pet ether affords N-(1-methylcyclobutyl-oxycarbonyl)-phenylalanine, which is isolated by filtration.

Workup

  1. additionA suspension of 171 mg
  2. additionUpon completion of the addition
  3. washThe reaction solution is washed successively with 10 ml
  4. dry with materialportions of a saturated sodium bicarbonate solution, 50% saturated solution of sodium chloride, 0.2 N sulfuric acid saturated with sodium sulfate, 50% saturated solution of sodium chloride (twice), and the chloroform solution is dried over sodium acetate
  5. customRemoval of the chloroform

Sources & evidence

ORD record
ord-49db45402f5b430a9946af1af8d98c0a
Source dataset
uspto-grants-1976_04
Patent number
US03948971

Reaction notes

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