【药物名称】Vapiprost hydrochloride, SN-309, GR-32191B
化学结构式(Chemical Structure):
参考文献No.147137
标题:VAPIPROST HYDROCHLORIDE < Rec INNM; BAN >
作者:Lumley, P.; Finch, H.; Collington, E.W.C.; Humphrey, P.P.A.
来源:Drugs Fut 1990,15(11),1087
合成路线图解说明:

Resolution of bicyclo[3.2.0]hept-2-en-6-one (I) via the R-(+)-alpha-methylbenzylamine-bisulfite (A) addition complex provides the 1S-(-)-enantiomer (II), which affords the 3-endo-acetoxy-2-exo-bromobicyclo[3.2.0]heptan-6-one (III) on treatment with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH). Reaction with piperidine followed by hydrolysis gives the hydroxynorbornanone (IV), which is alkylated with biphenylmethylbromide (B) under phase-transfer catalysis to yield the norbornanone (V). Baeyer-Villiger oxidation followed by partial reduction with diisobutylaluminum hydride (Dibal) gives the aldehyde (VII), which is then homologated to the aldehyde (VIII) using methoxymethylene-phosphorane and subsequent treatment with 2N HCl. Condensation of (VIII) with carboxypropyltriphenylphosphorane in tetrahydrofuran followed by esterification with tritylchloride gives the ester (IX). The alcohol stereochemistry in (IX) is inverted via oxidation with pyridine-sulfur trioxide complex in dimethylsulfoxide followed by reduction with Dibal in the presence of 2,6-di-tert-butyl-4-methylphenol. Finally, the ester is hydrolyzed with hydrochloric acid to give the required acid.

参考文献No.562882
标题:Baeyer-villiger oxidation of 5-endo-(biphenyl-4-ylmethoxy)-7-anti-piperidinobicyclo[2.2.1] process development and scale-Up
作者:Coleman, M.J.; et al.
来源:Org Process Res Dev 1997,1(1),20
合成路线图解说明:

Resolution of bicyclo[3.2.0]hept-2-en-6-one (I) via the R-(+)-alpha-methylbenzylamine-bisulfite (A) addition complex provides the 1S-(-)-enantiomer (II), which affords the 3-endo-acetoxy-2-exo-bromobicyclo[3.2.0]heptan-6-one (III) on treatment with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH). Reaction with piperidine followed by hydrolysis gives the hydroxynorbornanone (IV), which is alkylated with biphenylmethylbromide (B) under phase-transfer catalysis to yield the norbornanone (V). Baeyer-Villiger oxidation followed by partial reduction with diisobutylaluminum hydride (Dibal) gives the aldehyde (VII), which is then homologated to the aldehyde (VIII) using methoxymethylene-phosphorane and subsequent treatment with 2N HCl. Condensation of (VIII) with carboxypropyltriphenylphosphorane in tetrahydrofuran followed by esterification with tritylchloride gives the ester (IX). The alcohol stereochemistry in (IX) is inverted via oxidation with pyridine-sulfur trioxide complex in dimethylsulfoxide followed by reduction with Dibal in the presence of 2,6-di-tert-butyl-4-methylphenol. Finally, the ester is hydrolyzed with hydrochloric acid to give the required acid.

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