| Atorvastatin calcium is a synthetic HMG-Co A reductase inhibitor,discovered and developed by Warner-Lambert(Now merged with Pfizer)from August 1985.It can lower plasma cholesterol,low density lipoprotein(LDL)cholesterol,apolipoprotein B and triglyceride level at the same time.It is a effective drug for the treatment of hyperlipidemia and can reduce the rate of mortality in coronary patients.It plays an important role in the primary and secondary prevention of cardiovascular and cerebrovascular disease.4-Fluoro-?-[2-methyl-1-oxopropyl]-?-oxo-N,?-diphenylbenzene butyramide(1)is known as the nucleus of atorvastatin calcium.Hence,the synthesis of compound1 was systematically investigated in this paper,and an efficient synthetic route of compound 1 from methyl isopropyl ketone and phenylacetic acid via six steps of ester condensation(yield 88%),N-acylation(yield 91.9%),chloromylation(yield97%),Friedel-Crafts reaction(yield 92%),bromination(yield 88%),nucleophilic substitution(yield 80%)was successfully established.The reaction parameters for each related reaction were optimized,under the optimized reaction conditions,compound 1 was obtained in the overall yield of 62.8% as compared with 51.4%reported in literature.Two impurities generated by the aldol condensation of methyl isopropyl ketone were identified by GC-MS and their generation can be inhibited by reducing the mixing time of methyl isopropyl ketone and NaH and the work-up of the reaction was improved.Removal of the formed methanol during the reaction is a prerequisite for obtaining high yield of compound 3 in shorter time and using trimethylamine instead of ethylene to avoid the side reaction.One oxybromination protocol with hydrogen peroxide was employed to make the best of bromine.A debromination byproduct was isolated and confirmed by 1H NMR,13 C NMR and HRMS and its generation mechanism was discussed.The impurity can be inhibited by protecting the reaction from light and easily removed by recrystallization. |
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