Synthesis Of α-hydroxy Benzenebutanoic Acid And It's Analog

(R)-2-hydroxy-4-phenylbutyric acid ((R)-HPBA) is a key intermediate for the syntheses of angiotensin converting enzyme inhibitor(ACEI), which are widely used in clinic as the therapy of hypertesion and congestive heart failure. In this paper, we expediently, simply synthesized the racemic HPBA, prepared (R)-HPBA which using chemical resolution and were engaged in studying the asymmetric synthesis of (?)-4-phenyl-1,1,1-trichloro-2- butanol((?)-TCPB) which using the chiral phase-transfer catalyst. When studying the synthesis of HPBA, we ameliorated existing synthesis method on the base of literature, at the same time, and invented the new method of one-pot synthesis ofα-hydroxy acids under the microwave irradiation. The main points were as follows:1. Intermedia 4-phenyl-1,1,1-trichloro-2-butanol was prepared from hydrocinnamaldehyde and trichloromethide anion made by trichloroacetic acid and trichloroacetic sodium undergoing addition in dimethyl formamide(DMF) at room temperature, then was hydrolyzed with strong alkali to form target 2-hydroxy-4-phenylbutyric acid. And the key step of hydrolysis was optimized, thus with 4-phenyl-1,1,1-trichloro-2-butanol and sodium hydroxide in molar ratio 1 : 20, water and dimethoxyethane (DME) in volume ratio 1 : 1, the velocity of stirring 550 r/min, and time of hydrolysis 24 h, yield of hydrolysis was 57%, total yield of two steps was 54%.2. Herein, we describe a rapid, simple and practical procedure for the phase transfer catalytic(PTC) synthesis of a wide range ofα-hydroxy acids by means of a microwave-assisted addition reaction in one pot. The route involves two sides. 1) A convenient and efficient formation of trichloromethyl carbinols from carbonyl compounds: In a LWMC-205 MW oven to the three-neck flask equipped with a glass stir-bar was added carbonyl compound, sodium trichloroacetate, tetrabutylammonium bromide, water and chloroform. The mixture was irradiated under low power for the needed time with vigorous stirring. Trichloromethyl carbinol intermedias was obtained. 2) The PTC hydrolysis of trichloromethyl carbinol intermedia under microwave irradiation: After cooling, NaOH powder was added to flask, then refluxed for the needed time under certain power. The reaction mixture was diluted with water and washed with chloroform. After the aqueous layer was treated with active charcoal, the filtrate and was acidified to pH=1 with HCl and turned into cloudy. It was extracted with ether and combined organic phases were washed with sat. brine, dried (MgSO4) and concentrated to afford product. Compared with the general synthesis method ofα-hydroxy acids, this route embodies some traits that the first addition reaction may take place in the water system and neutral environment to avoid the trouble of anhydrous operations and side-reactions.