Study On The Synthesis Process Of Butorphanol Tartrate

Butorphanol Tartrate,as a kind of central analgesic developed by Bristol-Myers Squibb company was approved by US FDA in 1978.It was widely used in clinical relief of the pain caused by operation and cancer.The systhesis and quality research of butorphanol tartrate were demonstrated in our study.This paper can be divided into the following two parts:1.Butorphanol Tartrate was obtained through acylation,epoxidation,hydrolysis,reduction,cyclization,demethylation and deprotection salt using(R)-1-methoxybenzyl-1,2,3,4,5,6,7,8-octahydroiso-quinolineace tate 2 as raw material.(1)To achieve the simplicity and safety of operation during the synthesis process of compound 4,m-CPBA was chosen as oxidant instead of CF3CO3H/CH3CO3H.(2)For compound 7 synthesis,the yield increased to more than 84%with the optimization of reaction temperature and shorten of reaction time.(3)Using ethanol as a substitute of acetone/methanol was found to increase the recrystallization yield from 56.5%to 70%.The purity of butorphanol was higher than 99%in HPLC.(4)Ethanol was chosen as solvent instead of methanol in the purification of butorphanol.The total yield was 90%,far more than 46.6%,which was reported in literature.The purity of the product was higher than 99%in HPLC.(5)Crystals of butorphanol,intermediate 6 and butorphanol tartrate were cultivated for the confirm of their absolute configurations.The overall yield was improved to 30.1%from reported 14.4%through 7 steps.The purity of butorphanol tartrate was>99.9%.The ee value was>99.9%with the single impurity content was<0.1%.The structure of butorphanol tartrate was characterized by MS and NMR data.2.Studies were performed to investigate the impurities occurred during the synthesis and degrading process of butorphanol tartrate.Eight impurities were synthesized based on their source.The final synthesis impurities were characterized through MS and NMR spectra.Four intermediates impurities and four impurities of the end-product were synthesized.The stability test of butorphanol tartrate was studied under the condition of acid,alkali and oxidation.The alkaline-degradation impurity was 1-C.The produce of oxidation-degradation impurity 1-D was due to the oxidization of N.