Synthesis Of The New Anti-HBV Agent Entecavir And The Key Intermediate Of The New Antihypertensive Agent ALK

The first part of this dissertation relates to a research into a route of synthesizing a new anti-HBV agent Entecavir. Entecavir is a novel carbocyclic 2'-deoxyguanosine analog, which can effectively inhibite the hepatitis B virus replication. This product was researched by Bristol-Myers Squibb Co., and it was marketed in America in March this year initially.Herein we described the synthesis of Entecavir. We started from dicyclopentadieneand eventually finished the total synthesis work (including the synthesis of one sidechain) in a fifteen-step sequence of reactions including depolymerization, alkylation,asymmetric hydroboration-oxidation, epoxidation, benzyl protection, ring-opening of. epoxide, p-methoxyphenyldiphenylmethyl protection, oxidation, methylenation, etc.In the synthesis of the key intermediate (1S,2R)-2-[(benzyloxy)methyl]-3-cyclopent en-1-ol (D), we replaced 92%ee (1R)-(+)- α -pinene with much cheaper 84%ee (1R)-(+)- α -pinene, and made progress the conditions of reactions, making the overall yield improve from 28% to 69%. While preparing (1S,2R,3S,5R)-2-[(benzyloxy)meth yl]-6-oxabicyclo[3. 1. 0]hexan-3-ol (E) from D, we used indigenous 3mol/L t-butyl hydroperoxide in dichloromethane instead of imported 3mol/L t-butyl hydroperoxide in 2, 2, 4-trimethylpentane, and improved the yield to 81.5%. Starting from the common key intermediate D, we designed a new synthetic route to manufacture (lS,2S,3S,5S)-5-(2-amino-6-benzyloxy-9H-purin-9-yl)-3-benzyloxy-2-[(benzyloxy)m ethyl]cyclopentanol(G), and improved the overall yield from 32.4% to 38.2%. When synthesizing (1S,2S3S,5S)-5-[2-[[(4-methoxyphenyl)diphenylmethyl]amino]-6-benzy loxy-9H-purin-9-yl]-3-benzyloxy-2-[(benzyloxy)methyl]cyclopentanol (H) from G, we pretreated the correlative reagents before conducting the reaction, not only making the process become simpler, but also enhancing the yield from 82% to 95.4%. By aforementioned improvements, the overall yield of the whole synthetic route became higher, and the cost was lower. At the same time, the process is simple and suitable for large-scale production.The second part of this dissertation is on the synthesis of the key intermediate of ALK, a new Antihypertensive agent. ALK is the first novel non-peptidic oral renin inhibitor. It proved to be very effective for treatment for essential hypertension. The product has been in phase III from January 2004 to now.(2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl chloride (1) is the key intermediate of ALK, we designed a new synthetic route to prepare it.Herein we describe the new synthetic route. Started from isovanillin, the key intermediate 1 of ALK was synthesized by a nine-step sequence of reactions including etherification, reduction, bromination, condensation, hydrolyzation and decarboxyla-tion of diester, resolution, reduction(-COOH) and chlorination. This route is successful without using pseudoephedrine and a series of expensive reagents, such as (4R)-3-isovaleryl-4-benzyl-oxazolidin-2-one (Evans reagent), LiHMDS, LDA, asymmetric hydrogenation catalyst-complex Rh/(S, S)BPPM and orgnoboron reagents. In a word, the process is very simple and the cost is quite low, so this route is very suitable for large-scale production.