Dissertation > Industrial Technology > Chemical Industry > Pharmaceutical chemical industry > Production of organic compounds in drug > Aliphatic compounds, drugs

The Research on Synthesis of R-(-)3-quinuclidinol

Author LiShuBin
Tutor ShenYongCun
School Wuhan University of Technology
Course Pharmacy
Keywords 3-quinuclidinone hydrochloride R-3-quinuclidinol resolution L-tartaric acid
CLC TQ463.2
Type Master's thesis
Year 2008
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More than 50% of the commercial drug available worldwide have stereogenic centers and most of them are marketed as racemates at present. Increased understanding of the pharmacokinetics and mechanism of action of these chemicals in biological system has led to the development of drug in optically pure form. Resolution of racemates into enantiomers is an important way of obtaining optically pure chemical compounds.R-3-quinuclidinol is important intermediate of many Anticholinergic drugs. For instance, Solifenacin and Revatropate are new Anticholinergic drugs which are made from R-3-quinuclidinol and can cure Incontinence; and COPD. In this thesis, Synthesis and resolution of 3-quinuclidinol have been studied, Recycle and use of S-3-quinuclidinol and tartaric acid also have been studied.Synthesis of 3-quinuclidinol:3-quinuclidinol was synthesized by reduction of 3-quinuclidinone hydrochloride. Al(OPr-i)3 was used as reducing agent after studying Al(OPr-i)3、Na、KBH4. After many factors such as temperature、the molecular ratio of reducing agent to 3-quinuclidinone hydrochloride、recrystallization etc have been studied,we concluded that the best conditions were as follows:3-quinuclidinone hydrochloride was reacted with 2eqv Al(OPr-i)3 in isopropanol at 100℃, after 4 hour, the reaction was terminated by HC1.3-quinuclidinol was got by resolving 3-quinuclidinol hydrochloride with NaOH, in the end,3-quinuclidinol was recrystallizated with acetone. As a result, the yield of reduction reaction is 80.6%, product has been confirmed by mp and IR.Resolution of 3-quinuclidinol:Resolution of 3-quinuclidinol with L-tartaric acid, After studying affecting factors such as solvent, the molecular ratio of racemate to resolving agent, crystallization temperature and crystallization time, we concluded the best conditions were as follows:3-quinuclidinol was reacted with 1.05eqv L-tartaric acid in water and ethanol(ratio of volume in 3:7) at 50℃, R-3-quinuclidinol was got when temperature reached room temperature (25℃) slowly, in the end, we must recrystallizate with the same solvent. As a result, the yield of reduction reaction is 35.1%, ee is 99%. Product has been confirmed by mp and IRRecycle of S-3-quinuclidinol:3-quinuclidinone was synthesized by oxidizating S-3-quinuclidinol. DMSO-Ac2O is used as oxidation agent after studying DMSO-Ac2O, PCC, KMnO4, After studying many factors such as temperature, the molecular ratio of oxidization agent to S-3-quinuclidinol etc, best conditions were as follows:S-3-quinuclidinol reacted with 1.2eqv DMSO-Ac2O about 6 hours, 3-quiclidinone was obtained after distillization with yield 85%. Product has been confirmed by’H NMR and IRRecycle of tartaric acid:we use BaCl2 to recycle of tartaric acid. After studying mang fators such as temperature and reagent etc, the best conditions are as follows: put 1 eq BaCl2 into water containing tartaric acid, barium tartrate can be obtained after filtration. Then, treat barium tartrate with sulfonic acid in water, tartaric acid was crystallized at 25℃to give a pure product, yield is 72.5%.

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