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【结 构 式】

【药物名称】S-35031

【化学名称】3-[6-(4-Chlorophenylsulfonamido)-3-[2-(4-methylpiperazin-1-yl)phenoxymethyl]-5,6,7,8-tetrahydronaphthalen-1-yl]propionic acid

【CA登记号】

【 分 子 式 】C31H36ClN3O5S

【 分 子 量 】598.16667

【开发单位】Servier (Originator)

【药理作用】Antiplatelet Therapy, CARDIOVASCULAR DRUGS, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Hypertension, Treatment of, 5-HT2A Antagonists, Prostanoid TP (Thromboxane A2) Antagonists

合成路线1合成路线2合成路线3

合成路线1

Bromination of the coumarin derivative (I) with Br2 in DMF afforded the bromo coumarin (II). Diels-Alder cycloaddition between bromo coumarin (II) and ethyl 3-(trimethylsilyl)propiolate (III) with concomitant decarboxylation furnished the tetrahydronaphthalene (IV). After desilylation of (IV) with trifluoroacetic acid, the resultant ester (V) was reduced to alcohol (VI) using the combination LiAlH4-AlCl3. Further oxidation of the alcohol function of (VI) to aldehyde (VII) was performed with 4-benzylpyridinium dichromate (BPDC) in CH2Cl2. Wittig reaction of aldehyde (VII) with methyl (triphenylphosphoranylidene)acetate produced the arylacrylate ester (VIII), which was then reduced to the saturated ester (IX) employing NaBH4 in the presence of CoCl2.

参考文献 中间体
【1】 Cimetiere, B.; et al.; Discovery of new combined 5-HT2 and TP-receptor antagonists. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 57.
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) 19586 4-chloro-N-(2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)benzenesulfonamide C15H14ClNO4S 详情 详情
(II) 19587 N-(3-bromo-2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)-4-chlorobenzenesulfonamide C15H13BrClNO4S 详情 详情
(III) 23898 ethyl 3-(trimethylsilyl)-2-propynoate 29394-58-9 C8H14O2Si 详情 详情
(IV) 49920 ethyl 3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-2-(trimethylsilyl)-5,6,7,8-tetrahydro-1-naphthalenecarboxylate C22H27BrClNO4SSi 详情 详情
(V) 49921 ethyl 3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenecarboxylate C19H19BrClNO4S 详情 详情
(VI) 19590 N-[7-bromo-5-(hydroxymethyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-4-chlorobenzenesulfonamide C17H17BrClNO3S 详情 详情
(VII) 19591 N-(7-bromo-5-formyl-1,2,3,4-tetrahydro-2-naphthalenyl)-4-chlorobenzenesulfonamide C17H15BrClNO3S 详情 详情
(VIII) 49922 methyl (E)-3-(3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenyl)-2-propenoate C20H19BrClNO4S 详情 详情
(IX) 49923 methyl 3-(3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate C20H21BrClNO4S 详情 详情

合成路线2

Heck reaction of aryl bromide (IX) with vinyl tributyltin (X) in the presence of palladium catalyst gave the vinyl tetrahydronaphthalene (XI), which was subjected to oxidative double-bond cleavage to aldehyde (XII) using NaIO4 in the presence of a catalytic amount of OsO4. Aldehyde reduction with NaBH4 provided alcohol (XIII). This was then converted to the corresponding bromide (XIV) by treatment with carbon tetrabromide and triphenylphosphine.

参考文献 中间体
【1】 Cimetiere, B.; et al.; Discovery of new combined 5-HT2 and TP-receptor antagonists. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 57.
【2】 Verbeuren, T.; Simonet, S.; Descombes, J.-J.; Cimetiere, B.; Lavielle, G. (ADIR et Cie.); Benzenesulfonamide derivs., process for their preparation and pharmaceutical compsns. containing them. EP 1118610; FR 2803848; JP 2001226353 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 49923 methyl 3-(3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate C20H21BrClNO4S 详情 详情
(X) 24920 tributyl(vinyl)stannane；Tributylvinylstannane;Vinyltributylstannane 7486-35-3 C14H30Sn 详情 详情
(XI) 49924 methyl 3-(6-[[(4-chlorophenyl)sulfonyl]amino]-3-vinyl-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate C22H24ClNO4S 详情 详情
(XII) 49925 methyl 3-(6-[[(4-chlorophenyl)sulfonyl]amino]-3-formyl-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate C21H22ClNO5S 详情 详情
(XIII) 49926 methyl 3-[6-[[(4-chlorophenyl)sulfonyl]amino]-3-(hydroxymethyl)-5,6,7,8-tetrahydro-1-naphthalenyl]propanoate C21H24ClNO5S 详情 详情
(XIV) 49927 methyl 3-(3-(bromomethyl)-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate C21H23BrClNO4S 详情 详情

合成路线3

Acylation of 2-(1-piperazinyl)phenol (XV) with ethyl chloroformate produced the carbamate (XVI). After protection of the phenolic hydroxyl of (XVI) as the corresponding tosylate (XVII), reduction of the carbamate group of (XVII) with LiAlH4 gave rise to the N-methylpiperazine (XVIII). The tosylate group of (XVIII) was then removed by hydrolysis with KOH in aqueous ethanol, yielding phenol (XIX). The Williamson's ether synthesis between phenol (XIX) and bromide (XIV) provided adduct (XX). Finally, basic hydrolysis of the ester group of (XX) furnished the title carboxylic acid

参考文献 中间体
【1】 Cimetiere, B.; et al.; Discovery of new combined 5-HT2 and TP-receptor antagonists. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 57.
【2】 Verbeuren, T.; Simonet, S.; Descombes, J.-J.; Cimetiere, B.; Lavielle, G. (ADIR et Cie.); Benzenesulfonamide derivs., process for their preparation and pharmaceutical compsns. containing them. EP 1118610; FR 2803848; JP 2001226353 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIV) 49927 methyl 3-(3-(bromomethyl)-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate C21H23BrClNO4S 详情 详情
(XV) 49928 2-(1-piperazinyl)phenol C10H14N2O 详情 详情
(XVI) 49929 ethyl 4-(2-hydroxyphenyl)-1-piperazinecarboxylate C13H18N2O3 详情 详情
(XVII) 49930 ethyl 4-(2-[[(4-methylphenyl)sulfonyl]oxy]phenyl)-1-piperazinecarboxylate C20H24N2O5S 详情 详情
(XVIII) 49931 2-(4-methyl-1-piperazinyl)phenyl 4-methylbenzenesulfonate C18H22N2O3S 详情 详情
(XIX) 49932 2-(4-methyl-1-piperazinyl)phenol C11H16N2O 详情 详情
(XX) 49933 methyl 3-(6-[[(4-chlorophenyl)sulfonyl]amino]-3-[[2-(4-methyl-1-piperazinyl)phenoxy]methyl]-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate C32H38ClN3O5S 详情 详情
Extended Information