Recovery And Transformation Of (S)-2-Hydroxy-4-Phenylbutyric Acid

(R)-2-hydroxy-4-phenylbutyric acid ((R)-HPBA) is the critical chiral intermediate for the synthesis of various angiotensin-converting enzyme inhibitor (ACEI). The classical chemical resolution is usually used for large-scale production of (R)-HPBA due to its convenience in operation. However, it is not so satisfactory because of low yield, high cost and production of by-product (S)-2-hydroxy-4-phenylbutyric acid ((S)-HPBA). Recovery of (S)-HPBA and transformation into (R)-HPBA will be useful for the (R)-HPBA preparation process. In this paper, the recovery and transformation of (S)-HPBA were investigatied systematically, as well as the recovery and reuse of the resolving agent, N-Octyl-D-glucamine.The dissociation constant (pKa) of (S)-HPBA was determined at 298.2 K by potentiometric titration, and (S)-HPBA exhibits a pKa value of 3.81. The solubility of (S)-HPBA in different pure solvents (ethyl acetate, water, toluene) and its solubility at different pH values in aqueous solutions were detemined by the steady-state method: The former was well correlated with temperature and the later was well correlated with pH value. Water was found to be a fine alternative to toluene for crystallizing (S)-HPBA, and ethyl acetate, to be a suitable extraction solvent of (S)-HPBA in the pharmaceutical industry. A appropriate separation and purifcaiton process of (S)-HPBA was suggested to be composed of reactive crystallization by acidification and recrystallization by cooling in water. In this way,98% (S)-HPBA could be obtained with an overall yield of 68.7%.Ethyl (S)-2-hydroxy-4-phenylbutanoate ((S)-HPBE) (obtained by esterification of (S)-HPBA) could be racemized with sodium hydride or sodium ethoxide as catalyst. In the pharmaceutical industry, sodium ethoxide is more applicable than sodium hydride, and the racemization could be accomplished under the reaction temperature of 70～90℃, and catalyst relative mole ratio of 9%～15%. Racemization without any solvent was better than racemization in toluene and the racemization could be accomplished under reaction temperature of 70～90℃, and catalyst relative mole ratio of 6%～9%, with yields more than 80%. A kinetic model of racemization without any solvent was founded for correlation of reaction rate with temperature and relative mole ratio of catalyst, with a correlation coefficient of 0.996, a root-mean-square deviation of 0.00135 and an average relative deviation of 5.6%. (S)-HPBA could be racemized in the presence of sodium acetate and acetic anhydride, and the complete racemization time decreased with the increase of temperature and the increase of acetic anhydride. It was found that the racemizaiton could be completed in 2 h when the reaction temperature was at 140℃ and the amount of acetic anhydride was 3-4 times as much as the moles of (S)-HPBA.(S)-HPBA could be transformed into (R)-HPBA by configuration inversion through esterification, sulfonylation, nucleophilic substitution and hydrolysis. A appropriate condition was suggested as follows:triethylamine as acid binding agent, toluene-4-sulfonyl chloride as sulfonylation reagent, and potassium propionate as nucleophilic reagent. Under this condtion, a conversion ratio of 66.3% and an overall yield of 72.4% were obtained.Resolving agent, N-Octyl-D-glucamine was recovered and purified by reactive crystallization with an overall yield of 89.8% and a purity of 99.9%. The concentration of NaOH, the base adding rate and the final pH value are best controlled at lmol/L, 0.1mL/min, and 12, respectively. The regular cuboid crystalline powder of N-Octyl-D-glucamine was obtained, which was the same as its standard sample. (R)-HPBA was prepared by resolution using recovered N-Octyl-D-glucamine with a yield of 28.3%, and specific rotation of 7.0°, which were similar with the industrial results. Therefore, the recovered N-Octyl-D-glucamine is appropriate for circularly resolution.