Allyl bromide → HCID 23079039, compound

Participants

Reaction Conditions

Reaction Steps

The 2-(3-carboxyacetyl-phenyl)-oxazole-4-carboxylic acid methyl ester was prepared from 2-(3-chlorocarbonyl-phenyl)-oxazole-4-carboxylic acid methyl ester [prepared by the following sequence: i.) To a solution of isophthalic acid (16.6 g) and 1,1,3,3-tetramethyl-guanidine (27.7 mL) in DMSO (75 mL) was added at 0° C. allyl bromide (18.6 mL) and the mixture was stirred at 20° C. for 6 h. The mixture was diluted with EtOAc and washed with 2N HCl and brine. The organic layer was dried and evaporated. The remaining oil (21.5 g) was dissolved in DMSO (40 mL) and, after the addition of LiOH hydrate (2.8 g) and H2O (1 mL), the mixture was heated to 60° C. for 3 h. The solution was diluted with EtOAc and then extracted with 5% NaHCO3-solution. The aqueous layer was acidified with 25% HCl and the precipitated product was extracted with EtOAc to give isophthalic acid monoallyl ester (23.1 g) as white crystals. ii.) To a solution of this material (15.5 g) in DMF (350 mL) were added at −35° C. 88% 1-hydroxy-benzotriazole (15.4 g) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (19.2 g) and the mixture was stirred for 30 min. L-Serine methyl ester hydrochloride (14.0 g) was added at −50° C. followed by the addition of a solution of NEt3 (12.5 mL) in DMF (50 mL) over 2 min. The mixture was allowed to warm up to 20° C. over 2 h and stirring was continued for 19 h. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed successively with 0.5 N HCl, sat. NaHCO3-solution and brine, dried over Na2SO4 and evaporated in vacuum to give (S)-3-[N-(1-methoxycarbonyl-2-hydroxy)-aminocarbonyl]-benzoic acid allyl ester (20.6 g) as a crystallizing oil. iii.) To a solution of this material (20.6 g) in THF (0.4 L) was added methoxycarbonylsulfamoyl-triethylammonium hydroxide inner salt (17.6 g) and the mixture was stirred at 70° C. for 1 h. The mixture was evaporated in vacuum and the residue was purified by chromatography using EtOAc/hexane (1:1) as eluent to give (S)-2-(3-allyloxycarbonyl-phenyl)-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (16.7 g) as a yellow oil. iv.) To a solution of this material (14.7 g) in a mixture of acetonitrile (75 mL) and pyridine (75 mL) was added at 0° C. CCl4 (14.4 mL) and subsequently DBU (15.0 mL). The mixture was stirred at 20° C. for 0.5 h, diluted with EtOAc and washed with 2N HCl and brine. The organic layer was dried and evaporated to give 2-(3-allyloxycarbonyl-phenyl)-oxazole-4-carboxylic acid methyl ester (10.1 g) as light-brown crystals, mp 104-107° C. v.) This material (10.1 g) was subjected to the palladium-catalysed allylester cleavage according to general procedure G (method b) to give 2-(3-carboxy-phenyl)-oxazole-4-carboxylic acid methyl ester (7.0 g) as light-brown crystals, mp 209-210° C. (dec.). vi.) This carboxylic acid (1.26 g) was heated with thionyl chloride in toluene and the resulting carboxylic acid chloride was used directly in the next step.] (1.35 g) and bis(trimethylsilyl)malonate with n-BuLi in ether at −60° C. to 0° C. according to general procedure K (method c2). The crude material was transformed into the title compound by stirring in isopropenyl acetate and conc. H2SO4 according to general procedure L (method a). Obtained as pale-yellow crystals (1.4 g).

Provenance & Evidence