Study On Synthesis Of Dutasteride

Dutasteride is the achievement of research of GSK. It is a kind of 5α-2 reducing enzyme inhibitor and was applied to clinical experience in January 2003 after receiving validation in America. Its chemical name is(N-(2,5-bis'(Trifluoromethyl))phenyl.Dutasteride belongs to the 4-azasteroid structure class of compounds which can selectively and competively inhibit the activity of 5α- reducing enzyme. The course of testosterone(T) changing into dihydrotestosterone(DHT) needs the participation of this kind of nicotinamide adenine dinucleotide phosphate(NADPH) dependent enzyme. Dutasteride can specially inhibit typeⅡisoenzyme of 5α-2 reducing enzyme, and the latter is mainly synthesized in parastata glandulosa. The inhibition of dutasteride may cause serum DHT decreasing by 60%-80%, and prostatic DHT decreasing by 90% above. The serum prostate specific antigen(PSA) of BPH patients treated with dutasteride is obviously decreased, but the average ratio of the free PSA with gross PSA is not affected. Dutasteride may induce the contraction of parastata glandulosa by means of atrophy and programmed cell death. These changes are seen first in endothelial cell, then in interstitial substance. We have known that the inhibition of dutasteride to 5α-reducing enzyme in endothelial cell is stronger than that in interstitial substance. The histomorphological change induced by drugs is seen 6 months after treatment: the IPSS score, serum DHT, serum PSA all decreased; the volume of parastata glandulosa reduced; the detrusor pressure decreased, in addition, they all lie in a stable level.We choose cheap ,easy acquired ketopregnene as incipient raw material, via amidation,oxidizing ring cleavage, ring closure, selective catalytic hydrogenation and△1 dehydrogenation to obtain target compound.This synthetic line is the short correspondingly,it reduced the reaction steps.At choosing of the amidation, we put it on the first step and use the cheap Dichlorosulfoxide to produce acylchloride,then with 2 , 5 -bis'(Trifluoromethyl) phenyl-amine to generate amide, finally we get the N-2 , 5-bis'(Trifluoromethyl) ) phenyl-3-oxo-4- androstene-17β- carboxamide.We reduce the reactive steps and avoid using the costly2,2'-dithiopyridine ,4-dimethylamino Pyridine or possible adverse reaction of A-ring in the position of 4. The reaction of oxidized plat catalyzed hydrogenation were put to the reciprocal second step,thus the using of the expensive oxidized plat was decreased in synthesis. The cost of synthesis are significantly lowed. Cheap,nontoxic 2,3-Dichloro-5,6- dicyanben -zoquinine (DDQ) and N,O-bis-(Trimethylsilyl) tnfluorin -eacetaminde (BSTFA) take the place of great noxious,costly Benzene seleninic anhydride in the selective dehydrogenation when dehydrogenize reaction proceed of the N-2 , 5-bis'(Trifluoromethyl) phenyl-3-oxo-4-androstene-17β- carboxamide. This method not only decreased toxicity of the production technology and risk of it,but also reduced the cost and diminished the side effect. Critical intermedium and the final compound were identified with element analysis,mass spectrum,nuclear magnetic resonance hydro-spectrum and carbo-spectrum.Bulk drug of Dutasteride carried out the study of the quality control standard according to the norm of《Chinese Pharmacopoeia2000》.it showed that:the self-made bulk drug of Dutasteride is qualified of norm. it can be guaranteed for its efficacy and safety.The study of synthesis of Dutasteride provided optimized synthetic route and safe reliable quality criteria with industrial application of it. Therefore, the feasibility of industry of the medicine was ensured.The method we metioned provide less noxious and more simple Dutasteride synthesis technology, Moreover it decrease effectively the costs of the bulk drug. Thus it is possible of realization of serving for much more patients of benign prostatic hyperplasia(BPH).Accordingly, the research and development of the Dutasteride will bring about greateeconomic returns and social benefit.