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【结 构 式】

【药物名称】

【化学名称】N-[1-[4-Aminothieno[3,2-c]pyridin-2-ylmethyl]-2-(4-methyl-1-piperidinyl)-2-oxoethyl]-7-methoxy-2-naphthalenesulfonamide hydrochloride

【CA登记号】

【 分 子 式 】C27H31ClN4O4S2

【 分 子 量 】575.15352

【开发单位】Akzo Nobel (Originator)

【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Thrombin Inhibitors

合成路线1

The reaction of 4-chlorothieno[3,2-c]pyridine (I) with KOH in phenol at 140 C followed by ammonium acetate at 155 C gives thieno[3,2-c]pyridine-4-amine (II), which is benzoylated with benzoyl anhydride in pyridine yielding the benzamide (III). The formylation of (III) with DMF and LDA, followed by reduction with NaBH4 in methanol/THF affords the hydroxymethyl compound (IV), which is converted into the mesylate (V) with MsCl and TEA in dichloromethane. The reaction of (V) with LiCl in THF provides the chloromethyl compound (VI), which is condensed with the protected aminomalonate (VII) by means of sodium ethoxide in ethanol/dioxane to give the adduct (VIII). The selective decarboxylation and deprotection of (VIII) with HCl in hot acetic acid yields the amino acid (IX), which is esterified with SOCl2 and methyl to the corresponding methyl ester (X). The condensation of (X) with 7-methoxynaphthalen-2-ylsulfonyl chloride (XI) by means of TEA in dichloromethane affords the sulfonamide (XII), which is finally condensed with 4-methylpiperidine (XIII) by means of NaOH and TBTU in DMF. Alternatively, the protection of the amino acid (IX) with Boc2O and TEA in methanol gives the carbamate (XIV), which is condensed with 4-methylpiperidine (XIII) by means of NaOH and TBTU in DMF yielding the piperidide (XV). Finally, this compound is deprotected with TFA and condensed with sulfonyl chloride (XI) and TEA to afford the target compound.

1 Rewinkel, J.B.M.; et al.; Design, synthesis and testing of amino-bicycloaryl based orally bioavailable thrombin inhibitors. Bioorg Med Chem Lett 1999, 9, 19, 2837.
2 Van Galen, P.J.M.; Rewinkel, J.B.M.; Van Boeckel, C.A.A. (Akzo Nobel N.V.); Heterocyclic derivs. and their use as antithrombotic agents. EP 0975600; WO 9847876 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 38321 4-chlorothieno[3,2-c]pyridine C7H4ClNS 详情 详情
(II) 38322 thieno[3,2-c]pyridin-4-amine; thieno[3,2-c]pyridin-4-ylamine C7H6N2S 详情 详情
(III) 38323 N-thieno[3,2-c]pyridin-4-ylbenzamide C14H10N2OS 详情 详情
(IV) 38324 N-[2-(hydroxymethyl)thieno[3,2-c]pyridin-4-yl]benzamide C15H12N2O2S 详情 详情
(V) 38325 N-[2-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)thieno[3,2-c]pyridin-4-yl]benzamide C18H18N2O2S2 详情 详情
(VI) 38326 N-[2-(chloromethyl)thieno[3,2-c]pyridin-4-yl]benzamide C15H11ClN2OS 详情 详情
(VII) 30060 diethyl 2-[(tert-butoxycarbonyl)amino]malonate C12H21NO6 详情 详情
(VIII) 38327 diethyl 2-[[4-(benzoylamino)thieno[3,2-c]pyridin-2-yl]methyl]-2-[(tert-butoxycarbonyl)amino]malonate C27H31N3O7S 详情 详情
(IX) 38328 3-(4-aminothieno[3,2-c]pyridin-2-yl)alanine C10H11N3O2S 详情 详情
(X) 38329 methyl 2-amino-3-(4-aminothieno[3,2-c]pyridin-2-yl)propanoate C11H13N3O2S 详情 详情
(XI) 31666 7-methoxy-2-naphthalenesulfonyl chloride C11H9ClO3S 详情 详情
(XII) 38333 methyl 3-(4-aminothieno[3,2-c]pyridin-2-yl)-2-[[(7-methoxy-2-naphthyl)sulfonyl]amino]propanoate C22H21N3O5S2 详情 详情
(XIII) 10192 4-Methylpiperidine; gamma-Pipecoline 626-58-4 C6H13N 详情 详情
(XIV) 38331 3-(4-aminothieno[3,2-c]pyridin-2-yl)-N-(tert-butoxycarbonyl)alanine C15H19N3O4S 详情 详情
(XV) 38332 tert-butyl 1-[(4-aminothieno[3,2-c]pyridin-2-yl)methyl]-2-(4-methyl-1-piperidinyl)-2-oxoethylcarbamate C21H30N4O3S 详情 详情
Extended Information