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Study On The Optical Resolution Of Mandelic Acid And The Asymmetric Synthesis Of R-(-)-α-Cyclohexyl-mandelic Acid

Posted on:2006-06-30Degree:MasterType:Thesis
Country:ChinaCandidate:J ZangFull Text:PDF
GTID:2121360155464648Subject:Chemical Engineering
Abstract/Summary:PDF Full Text Request
In the asymmetric synthesis of a variety of medicinal agents, chiral mandelic acid and α-cyclohexyl-mandelic acid are important intermediate compounds. Optically active mandelic acid has a good biology resolvability. It is focused more attention in the acidic resolving agents at present. Most racemic amines or amino acids can be optical resolved by it. In addition, it can be used in intermediate medicament as side-chain. Such as R-(-)-mandelic acid can be used in cefamandole (CMD). The need of single enantiomer of mandelic acid is increased up to 10% every year. So it is a more important intermediate compound in fine chemical now. Chiral a-cyclohexyl-mandelic acid can be used in synthesizing convulsion antagonist medicaments or muscarinic receptor antagonists. For example, oxybutynin and its metabolite desethyloxybutynin, oxyphenonium bromide and oxphencyclimine. They display improved therapeutic profiles compared to theirs racemic counterparts. So it has a long-range foreground in market. In foreign country, it had been a focus how to develop a simple and efficient method of asymmetry synthesis since 1960. On the contrary, there were no more reports in our country. For making the chiral productions to be industrialized and exported, not only the optical resolution of mandelic acid but also the asymmetric synthesis of R-(-)-α-cyclohexyl-mandelic acid was discussed here. At the same time, the synthesis of D-(-)-phenylglycine butyl ester and its hydrochloride were disclosed.The resolution through formation of diastereoisomeric salts was studied here. The author used D-phenylglycine butyl ester hydrochloride as the resolving agent. The mol ratio was 1.0—1.2 to the racemic mandelic acid. Both of them were dissolved in water at 10 ℃ . With stirring, NaOH solution was dripped in them. The diastereoisomeric salt (D-phenylglycine butyl ester.R-mandelic acid) was separated out. After acidification and extraction with ether, R-(-)-mandelic acid was gotten. The yield was 98.9% and the optical purity was 32%. At the same time, S-(+)-mandelic acid was obtained in mother liquor. The yield was 90% and the optical purity was 67%. In addition, the author recycled the mother liquor of the resolution. It increased the overall yield and decreased the whole productioncost.In the synthesis of resolving agents, D-(-)-phenylglycine butyl ester hydrochloride was prepared by D-(-)-phenylglycine and 1-butanol. The catalyst of esterification was SOCI2. With stirring, SOC12 was dripped in them at 5 °C. Then, all of them reacted for about one hour at home temperature. Finally, they were heated up to reflux. The best reflux time was 70 minutes. Reusing the mother liquor made the overall yield over 85% and the optical purity over 98.1%. D-phenylglycine butyl ester was prepared by neutralization of D-phenylglycine butyl ester hydrochloride using NaOH under 5°C. Be careful in accommodating the PH during 7 and 8. Twenty minutes later, it was extracted three times with the mixture of n-hexane and dichloromethane (2/1, V/V). The yield and the optical purity were 74.1% and 98.4%.The raw materials of the asymmetric synthesis of R-(-)-a-cyclohexyl-mandelic acid were R-(-)-mandelic acid and iso-butyraldehyde. The reaction solvent was the mixture of n-hexane and ether (4/1, V/V). The catalyst was methanesulfonic acid. They allowed reflux about 4 hours. The water generated in the reaction was separated with a Dean-Stark trap. Four recrystallization of crude solid from the mixture of n-hexane and ether (4/1, V/V) yielded cis-(2R,5R)-2-isopropyl-5-phenyl-l,3-dioxolan-4-one( I). The yield and the optical purity were 43.6% and 93.6%. To a -78°C solution of lithium bis(trimethylsilyl)-amide in THF was added cis-(2R,5R)-2-isopropyl-5-phenyl-l,3-dioxolan-4-one( I). The reaction mixture was allowed to stir to produce enol under nitrogen, followed by the addition of neat cyclohexanone as electrophilic agent. Then, the reaction solution was added thionyl chloride (SOCI2), followed by pyridine. Sulfur impurity was washed by the addition of saturated NH4CI solution. Next, 5.5N NaOH was added to hydrolyze. After acidification, white solids were precipitated. It was R-cyclohex-1-enyl-hydroxy-phenyl-acetic acid(IV). The yield was 55.2%. After recrystallization, the white solid dissolved in methanol, followed by the addition of 10% Pd/C. The reaction was subjected to 1 atm of hydrogen and was allowed to stir for 14 hours at 50 °C. The yield and the optical purity were 61.2% and 81.1%. After recrystallization from n-hexane, the purity R-(-)-CHPGA was gotten.The method of the synthesis of D-phenylglycine butyl ester and its hydrochloride was successfully found out. It was satisfied with the yield and the optical purity. The process ofthe optical resolution of mandelic acid by D-phenylglycine butyl ester was improved on, and two optical isomers were gained. The yield was increased and the cost was saved through reusing mother liquor. In our actual condition, pilot study of the asymmetric synthesis of R-(-)-CHPGA from cheapness iso-butyraldehyde was experimentized. The final product R-(-)-CHPGA was gotten and some optimized operation conditions were found out. But some aspect of the problem in yield or reaction steps could be improved.
Keywords/Search Tags:Mandelic acid, D-(-)-Phenylglycine butyl ester, R-(-)-|á-Cyclohexyl-mandelicacid, Iso-butyraldehyde, Resolution, Asymmetric synthesis
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