Hydrochloric Acid → 2-(3-chloro-4,5-dihydro-1,2-oxazol-5-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)acetic acid

HRID 28241Notes

Reaction equation

HRID 28241 reaction equation
[CH2:1]1[C:5]([Cl:6])=[N:4][O:3][C@@H:2]1[C@H:7]([NH2:11])[C:8]([OH:10])=[O:9].[C:12]1([CH2:25][O:26][C:27](Cl)=[O:28])[C:24]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[K+].Cl>O>[Cl:6][C:5]1[CH2:1][CH:2]([CH:7]([NH:11][C:27]([O:26][CH2:25][CH:12]2[C:24]3[CH:16]=[CH:17][CH:18]=[CH:19][C:23]=3[C:22]3[C:13]2=[CH:14][CH:15]=[CH:20][CH:21]=3)=[O:28])[C:8]([OH:10])=[O:9])[O:3][N:4]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 294641AcivicinHCID 516893Potassium BicarbonateHCID 14261773Fluorenylmethyl chloroformate

Product 1

HCID 3323662-(3-chloro-4,5-dihydro-1,2-oxazol-5-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)acetic acid

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

A mixture of AT-125 (178 mg; 1 mmole), 9 fluorenylmethylchloroformate (285 mg, 1.1 mmole), and potassium bicarbonate (370 mg; 3.7 mmole) in 5 ml of water was stirred for 20 hours at room temperature. The gelatinous mixture is acidified to pH 2 with hydrochloric acid, evaporated to dryness under reduced pressure, and extracted with acetone. The acetone extracts are adsorbed onto silica gel and chromatographed on 40 g of silica gel with methylene chloride:isopropanol:acetic acid (100:3:1). Fractions of 20 ml are collected and monitored by TLC (U.S. visualization). The first 8 fractions contain components derived from the chloroformate reagent only including 9-fluorenylmethyl alcohol. Fractions 11-17 contain 206 mg of chromatographically homogeneous 3-chloro-α-[[(9H-fluoren-9-yl-methoxy)carbonyl]amino]-4,5-dihydro-5-isoxazoleacetic acid, and fractions 21-50 contain 132 mg of chromatographically homogeneous 3-chloro-α-[[(3-chloro-4,5-dihydro-5-isoxazolyl)[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]acetyl]amino]-4,5-dihydro-5-isoxazoleacetic acid. Crystallization of fractions 11-17 from aqueous methanol and recrystallization from acetone-cyclohexane yields 3-chloro-α-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4,5-dihydro-5-isoxazoleacetic acid m.p. 175°-176°.

Workup

  1. customevaporated to dryness under reduced pressure
  2. extractionextracted with acetone
  3. customchromatographed on 40 g of silica gel with methylene chloride:isopropanol:acetic acid (100:3:1)
  4. customFractions of 20 ml are collected
  5. customCrystallization of fractions 11-17
  6. customfrom aqueous methanol and recrystallization from acetone-cyclohexane

Sources & evidence

ORD record
ord-2ba0ad324bd245a7bfcda98f05e8b884
Source dataset
uspto-grants-1980_09
Patent number
US04225720

Reaction notes

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