Terutroban Sodium, S-18204(racemate), S-18886, -Drug Synthesis Database

【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 合成路线2

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).

参考文献中间体

【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.

参考文献中间体

【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	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