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【结 构 式】

【药物名称】Terutroban Sodium, S-18204(racemate), S-18886

【化学名称】3-[6-(4-Chlorophenylsulfonamido)-2-methyl-5,6,7,8-tetrahydronaphth-1-yl]propionic acid sodium salt

【CA登记号】

【 分 子 式 】C20H21ClNNaO4S

【 分 子 量 】429.90147

【开发单位】Servier (Originator)

【药理作用】Antiplatelet Therapy, Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Prostanoid TP (Thromboxane A2) Antagonists

合成路线1

Reductive amination of 4,4-diethoxycyclohexanone (I) with benzylamine in the presence of sodium triacetoxyborohydride provided amino ketal (II). Subsequent benzyl group hydrogenolysis in (II) yielded the primary amine (III), which was acylated by 4-chlorobenzenesulfonyl chloride (IV) affording sulfonamide (V). Claisen condensation of ketone (V) with ethyl formate furnished the hydroxymethylene ketone (VI). This was subjected to a Wittig reaction with (methoxycarbonylmethylene)triphenylphosphorane to produce ester (VII). Intramolecular cyclization of (VII) under acidic conditions gave rise to the benzopyranone (VIII). Diels-Alder cycloaddition between methyl butynoate (IX) and benzopyranone (VIII) led to a mixture of two regioisomeric tetrahydronaphthalenes (X) and (XI). Reduction of this mixture of esters by means of LiAlH4 yielded the desired alcohol (XII) along with its regioisomer, which were further oxidized to the corresponding aldehydes employing 4-benzylpyridinium dichromate. Separation of the resultant mixture by column chromatography furnished the desired aldehyde (XIII).

1 Cimetière, B.; Dubuffet, T.; Muller, O.; Descombes, J.-J.; Simonet, S.; Verbeuren, T.J.; Laubie, M.; Lavielle, G.; Synthesis and biological evaluation of new tetrahydronaphthalene derivatives as thromboxane receptor antagonists. Bioorg Med Chem Lett 1998, 8, 11, 1375.
2 Lavielle, G.; Dubuffet, T.; Muller, O.; Laubie, M.; Verbeuren, T.; Simonet, S.; Descombes, J.-J. (ADIR et Cie.); 1,2,3,4-Tetrahydronaphthalene, chroman and thiochroman derivs. as antithrombotic agents. CA 2118102; EP 0648741; FR 2711139; JP 1995188155 .
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) 19576 4,4-diethoxycyclohexanone C10H18O3 详情 详情
(II) 19577 N-benzyl-4,4-diethoxycyclohexanamine; N-benzyl-N-(4,4-diethoxycyclohexyl)amine C17H27NO2 详情 详情
(III) 19578 4,4-diethoxycyclohexanamine; 4,4-diethoxycyclohexylamine C10H21NO2 详情 详情
(IV) 15787 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride 98-60-2 C6H4Cl2O2S 详情 详情
(V) 19580 4-chloro-N-(4-oxocyclohexyl)benzenesulfonamide C12H14ClNO3S 详情 详情
(VI) 19583 4-chloro-N-[3-[(Z)-hydroxymethylidene]-4-oxocyclohexyl]benzenesulfonamide C13H14ClNO4S 详情 详情
(VII) 19585 methyl 3-(5-[[(4-chlorophenyl)sulfonyl]amino]-2-oxocyclohexylidene)propanoate C16H18ClNO5S 详情 详情
(VIII) 19586 4-chloro-N-(2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)benzenesulfonamide C15H14ClNO4S 详情 详情
(IX) 51405 2-Butynoic acid methyl ester; Methyl 2-butynoate; Tetrolic acid methyl ester; Methyl tetrolate 23326-27-4 C5H6O2 详情 详情
(X) 58536 methyl 6-{[(4-chlorophenyl)sulfonyl]amino}-1-methyl-5,6,7,8-tetrahydro-2-naphthalenecarboxylate C19H20ClNO4S 详情 详情
(XI) 58537 methyl 6-{[(4-chlorophenyl)sulfonyl]amino}-2-methyl-5,6,7,8-tetrahydro-1-naphthalenecarboxylate C19H20ClNO4S 详情 详情
(XII) 58535 ethyl 2-[7-(1H-imidazol-1-yl)-2,3-dioxo-3,4-dihydro-1(2H)-quinoxalinyl]acetate C15H14N4O4 详情 详情
(XIII) 58539 4-chloro-N-(5-formyl-6-methyl-1,2,3,4-tetrahydro-2-naphthalenyl)benzenesulfonamide C18H18ClNO3S 详情 详情

合成路线2

Wittig condensation of aldehyde (XIII) with (methoxycarbonylmethylene)triphenylphosphorane gave the conjugated ester (XIV). This was further reduced to the saturated ester (XV) by using either samarium iodide or sodium borohydride/cobaltous chloride. Finally, saponification of the methyl ester function of (XV) afforded the title sodium carboxylate salt.

1 Cimetière, B.; Dubuffet, T.; Muller, O.; Descombes, J.-J.; Simonet, S.; Verbeuren, T.J.; Laubie, M.; Lavielle, G.; Synthesis and biological evaluation of new tetrahydronaphthalene derivatives as thromboxane receptor antagonists. Bioorg Med Chem Lett 1998, 8, 11, 1375.
2 Lavielle, G.; Dubuffet, T.; Muller, O.; Laubie, M.; Verbeuren, T.; Simonet, S.; Descombes, J.-J. (ADIR et Cie.); 1,2,3,4-Tetrahydronaphthalene, chroman and thiochroman derivs. as antithrombotic agents. CA 2118102; EP 0648741; FR 2711139; JP 1995188155 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 58539 4-chloro-N-(5-formyl-6-methyl-1,2,3,4-tetrahydro-2-naphthalenyl)benzenesulfonamide C18H18ClNO3S 详情 详情
(XIV) 58540 methyl (E)-3-(6-{[(4-chlorophenyl)sulfonyl]amino}-2-methyl-5,6,7,8-tetrahydro-1-naphthalenyl)-2-propenoate C21H22ClNO4S 详情 详情
(XV) 58541 methyl 3-(6-{[(4-chlorophenyl)sulfonyl]amino}-2-methyl-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate C21H24ClNO4S 详情 详情
Extended Information