Study On Synthesis, Resolution And Racemization Of α-cyclohexyl-mandelic Acid

Chiral compound α-cyclohexyl-mandelic acid is an important intermediate ofmedicine. It can be used to prepare chiral medicine such as Oxybutynin and has greatdemand in the market. Because the different enatiomers of a medicine have differentbiological activity, researching and producing of the more potent single enatiomer ofchiral medicine have become increasingly important. If the single enatiomer ofα-cyclohexyl-mandelic acid is available, it can be esterified directly into chiralmedicine. Since the resolution of α-cyclohexyl-mandelic acid is simple in processingand moderate in reaction conditions, not only its synthesis but also its resolution werediscussed here. Because there are two enatiomers in the product, the racemization ofthe single enatiomer of α-cyclohexyl-mandelic acid, which was then recycled intoresolution process to increase the overall yield, was also discussed here.During the course of resolution not only the method of formation ofdiastereoisomeric salts but also the method of resolution by HPLC were studied.Further more, the synthesis of resolving agents such as L-tyrosine methyl esterhydrochloride. L-tyrosine methyl ester and L-2-pheylglycine methyl esterhydrochloride were also studied.α-cyclohexyl-mandelic acid was synthesized by Grignard reaction. Methylphenylglyoxylate was reacted with cyclohexylmagnesium chloride to get methylphenylcyclohexylglycolate which then was converted into α-cyclohexyl-mandelicacid by hydrolysis. The premium conditions: During the preparation of Grignardreagent water in the reactant must be lower than 0.03%. THF was used as the solvent.Molar ratio of chlorocyclohexane to THF was 1:10. In the Grignard reaction thetemperature was controlled at 10~20℃. After the reaction the pH value of the mixturewas adjusted to 2~3 by 10%~15% HCl. During the hydrolysis, reflux time wascontrolled at 2~3 hours and the pH value of water phase was adjusted to 7~7.5 by HCl.The yield of α-cyclohexyl-mandelic acid was 22.15%, and the purity was nearly100%.During the resolution by HPLC α-cyclohexyl- mandelic acid was successfullyresolved on C18 column with β-cyclodextrin as an ingredient in the mobile phaseavoiding the use of expensive chiral column. The premium conditions: V(KH2PO4aqueous solution (0.075mol/L)): V(ethanol) : V(acetonitrile) =65:20:15. Theconcentration of β-cyclodextrin was 9.5mmol/L. UV wavelength: 220nm. Flow rate:1ml/min. The retention time was 7~10 minutes which was about ten times shorter thannoted in the prior literature.In the synthesis of resolving agents, L-tyrosine methyl ester hydrochloride wasprepared by esterification of L-tyrosine with methanol. The use of SOCl2 as catalystgave much higher yield. The best reflux time in the esterification process was 2 hours.Reusing the mother liquor in production made the overall yield nearly 100% andmade it possible to be industrialized and exported. Neutralization of L-tyrosine methylester hydrochloride with alkali could get L-tyrosine methyl ester. Similarly,L-2-pheylglycine could be esterified into L-2-pheylglycine methyl ester hydrochloride iAbstractwith methanol using SOCl2 as catalyst.In the resolution through formation of diastereoisomeric salts, L-tyrosine methylester was selected as the best resolving agent. The yield was increased throughinitiating the reaction at a lower temperature and heating the mixture to reflux afterthe reaction had been completed. The premium conditions: the crystallizationtemperature was 0℃, the solvent was about 10 wt% water in acetonitrile, the molarratio of α-cyclohexyl-mandelic acid to L-tyrosine methyl ester was 1:0.75, thecrystallization time was 4 hours. The optical purity of S-α-cyclohexyl-mandelic acidobtained was above 98% and the yield was 83.2%(calculated on the product), while inthe literature it was 60%.The method of racemization of S- and R-α-cyclohexyl-mandelic acid wassuccessfully found out. It was completed in 16 hours using H2SO4 as catalyst.