新产品编号:196677

合成路线:Title compound has been prepared by several related ways.Alkylation of methyl acetoacetate (I) with n-heptyl bromide (II) in the presence of NaOMe in refluxing MeOH yielded (III),which was brominated in CHCl3 at 0 C to give (IV).Subsequent reaction with triphenylmethyl mercaptan (V) and tetrabutyl ammonium hydroxide in toluene at r.t.provided (XI).Alternatively,beta-ketoester (XI) was prepared from a-mercaptoacetic acid (VI).Thus,protection as the S-trityl compound (VIII) by treatment with triphenylcarbinol (VII) and TFA,followed by condensation with N,O-dimethyl hydroxylamine in the presence of EDC and HOBt afforded N-methoxyamide (IX).Then,Claisen condensation with methyl nonanoate (X) using LDA as the base in THF at -78 C provided ketoester (XI).In order to avoid b-ketoacid decarboxylation,ketone (XI) was reduced to alcohol (XV) with NaBH4 in MeOH at 0 C.This hydroxyester was also prepared by a related route,consisting of protection of methyl mercaptoacetate (XII) as the S-trityl compound (XIII),followed by reduction to aldehyde (XIV) with DIBAL-H and condensation with methyl nonanoate (X).Saponification of methyl ester (XV) with KOH yielded hydroxyacid (XVI).Subsequent coupling with tert-butylglycine amide (XVII) using EDC and HOBt as the condensing agents produced amide (XVIII).Ketoamide (XX) was then obtained by oxidation with Dess-Martin periodinane (XIX).Finally,deprotection of the S-trityl group was effected by trifluoroacetic acid treatment under reducing conditions with triethyl silane to provide the target compound.

参考文献标题:Novel inhibitors of metalloproteases,pharmaceutical compsns.comprising same and methods of their use
文献作者:Campbell,D.A.; Patel,D.V.; Xiao,X.Y.(Affymax Technologies,NV)
参考来源:WO 9640738


合成路线:Title compound has been prepared by several related ways.Alkylation of methyl acetoacetate (I) with n-heptyl bromide (II) in the presence of NaOMe in refluxing MeOH yielded (III),which was brominated in CHCl3 at 0 C to give (IV).Subsequent reaction with triphenylmethyl mercaptan (V) and tetrabutyl ammonium hydroxide in toluene at r.t.provided (XI).Alternatively,beta-ketoester (XI) was prepared from a-mercaptoacetic acid (VI).Thus,protection as the S-trityl compound (VIII) by treatment with triphenylcarbinol (VII) and TFA,followed by condensation with N,O-dimethyl hydroxylamine in the presence of EDC and HOBt afforded N-methoxyamide (IX).Then,Claisen condensation with methyl nonanoate (X) using LDA as the base in THF at -78 C provided ketoester (XI).In order to avoid b-ketoacid decarboxylation,ketone (XI) was reduced to alcohol (XV) with NaBH4 in MeOH at 0 C.This hydroxyester was also prepared by a related route,consisting of protection of methyl mercaptoacetate (XII) as the S-trityl compound (XIII),followed by reduction to aldehyde (XIV) with DIBAL-H and condensation with methyl nonanoate (X).Saponification of methyl ester (XV) with KOH yielded hydroxyacid (XVI).Subsequent coupling with tert-butylglycine amide (XVII) using EDC and HOBt as the condensing agents produced amide (XVIII).Ketoamide (XX) was then obtained by oxidation with Dess-Martin periodinane (XIX).Finally,deprotection of the S-trityl group was effected by trifluoroacetic acid treatment under reducing conditions with triethyl silane to provide the target compound.
参考文献标题:Malonyl alpha-mercaptoketones and alpha-mercaptoalcohols,a new class of matrix metalloproteinase inhibitors
文献作者:Campbell,D.A.; Xiao,X.Y.; Harris,D.; Ida,S.; Mortezaei,R.; Ngu,K.; Shi,L.; Tien,D.; Wang,Y.; Navre,M.; Patel,D.V.; Sharr,M.A.; DiJoseph,J.F.; Killar,L.M.; Leone,C.L.; Levin,J.I.; Skotnicki,J.S.
参考来源:Bioorg Med Chem Lett 1998,8(10),1157