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【结 构 式】 
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【药物名称】S-32080 【化学名称】3-[6-(4-Chlorophenylsulfonamido)-2-propyl-3-(3-pyridylmethyl)- 5,6,7,8-tetrahydronapthalen-1-yl]propionic acid 【CA登记号】 【 分 子 式 】C28H31ClN2O4S 【 分 子 量 】527.08727 |
【开发单位】Servier 【药理作用】HEMATOLOGIC DRUGS, ANTIPLATELET THERAPY |
合成路线1
The intermediate 4-(4-chlorophenylsulfonyl)aminocyclohexanone (V) was prepared by two synthetic ways: 1) Reductive condensation of 4,4-diethoxycyclohexanone (I) with benzylamine in the presence of sodium triacetoxyborohydride and AcOH provided the benzylcyclohexylamine (II). Further hydrogenolysis of the N-benzyl group of (III) in the presence of Pd/C and oxalic acid yielded cyclohexylamine (III) as the oxalate salt. Sulfonamide (V) was then obtained by condensation with 4-chlorophenylsulfonyl chloride (IV), followed by hydrolysis of the diethyl acetal with aqueous HCl. 2) Alternatively, treatment of trans-4-aminocyclohexanol hydrochloride (VI) with sulfonyl chloride (IV) in the presence of Et3N provided the sulfonamide (VII), which was subsequently oxidized with chromic anhydride and H2SO4 to the target ketone (V). 3) Condensation of this intermediate with ethyl formate in the presence of NaH produced the hydroxymethylene cyclohexanone (VIII), which was submitted to a Wittig reaction with phosphorane (IX) to give the cyclohexylidenpropanoic ester (X). Cyclization of this compound using anhydrous p-toluenesulfonic acid in refluxing toluene furnished pyranone (XI), which by subsequent bromination in acetic acid yielded the 3-bromopyranone (XII) (1). The key tetrahydronaphthalene system (XIV) was then obtained by Diels-Alder reaction with refluxing methyl hexynoate (XIII) with concomitant decarboxylation. The ester function of (XIV) was reduced to alcohol (XV) with LiAlH4.
| 【1】 Cimetière, B.; Dubuffet, T.; Landras, C.; Descombes, J.J.; Simonet, S.; Verbeuren, T.J.; Lavielle, G.; New tetrahydronaphthalene derivatives as combined thromboxane receptor antagonists and thromboxane synthase inhibitors. Bioorg Med Chem Lett 1998, 8, 11, 1381. |
| 【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) | 19581 | trans-4-Aminocyclohexanol；trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol; | 27489-62-9 | C6H13NO | 详情 | 详情 |
| (VII) | 19582 | 4-chloro-N-(4-hydroxycyclohexyl)benzenesulfonamide | C12H16ClNO3S | 详情 | 详情 | |
| (VIII) | 19583 | 4-chloro-N-[3-[(Z)-hydroxymethylidene]-4-oxocyclohexyl]benzenesulfonamide | C13H14ClNO4S | 详情 | 详情 | |
| (IX) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (X) | 19585 | methyl 3-(5-[[(4-chlorophenyl)sulfonyl]amino]-2-oxocyclohexylidene)propanoate | C16H18ClNO5S | 详情 | 详情 | |
| (XI) | 19586 | 4-chloro-N-(2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)benzenesulfonamide | C15H14ClNO4S | 详情 | 详情 | |
| (XII) | 19587 | N-(3-bromo-2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)-4-chlorobenzenesulfonamide | C15H13BrClNO4S | 详情 | 详情 | |
| (XIII) | 19609 | methyl 2-hexynoate | 18937-79-6 | C7H10O2 | 详情 | 详情 |
| (XIV) | 19610 | methyl 3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-2-propyl-5,6,7,8-tetrahydro-1-naphthalenecarboxylate | C21H23BrClNO4S | 详情 | 详情 | |
| (XV) | 19611 | N-[7-bromo-5-(hydroxymethyl)-6-propyl-1,2,3,4-tetrahydro-2-naphthalenyl]-4-chlorobenzenesulfonamide | C20H23BrClNO3S | 详情 | 详情 |
合成路线2
Then group of (XV) was oxidized with 4-benzylpyridinium dichromate to the aldehyde (XVI). 3-(Tributylstannylmethyl)pyridine (XVIII), prepared from lithiated 3-picoline (XVII) and Bu3SnCl in the presence of HMPA, was coupled to bromotetrahydronaphthalene (XVI) under palladium catalysis to provide the pyridylmethyl derivative (XIX). Wittig reaction of (XIX) with phosphorane (IX) gave acrylate (XX), which was reduced with SmI2 or with NaBH4 and CoCl2 to the tetrahydronaphthylpropionic ester (XXI). Finally, the ester group of (XXI) was hydrolyzed with NaOH in MeOH-H2O to give the title acid.
| 【1】 Cimetière, B.; Dubuffet, T.; Landras, C.; Descombes, J.J.; Simonet, S.; Verbeuren, T.J.; Lavielle, G.; New tetrahydronaphthalene derivatives as combined thromboxane receptor antagonists and thromboxane synthase inhibitors. Bioorg Med Chem Lett 1998, 8, 11, 1381. |
| 【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 |
|---|---|---|---|---|---|---|
| (IX) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (XV) | 19611 | N-[7-bromo-5-(hydroxymethyl)-6-propyl-1,2,3,4-tetrahydro-2-naphthalenyl]-4-chlorobenzenesulfonamide | C20H23BrClNO3S | 详情 | 详情 | |
| (XVI) | 19612 | N-(7-bromo-5-formyl-6-propyl-1,2,3,4-tetrahydro-2-naphthalenyl)-4-chlorobenzenesulfonamide | C20H21BrClNO3S | 详情 | 详情 | |
| (XVII) | 19592 | (3-pyridinylmethyl)lithium | C6H6LiN | 详情 | 详情 | |
| (XVIII) | 19572 | 3-[(tributylstannyl)methyl]pyridine | C18H33NSn | 详情 | 详情 | |
| (XIX) | 19615 | 4-chloro-N-[5-formyl-6-propyl-7-(3-pyridinylmethyl)-1,2,3,4-tetrahydro-2-naphthalenyl]benzenesulfonamide | C26H27ClN2O3S | 详情 | 详情 | |
| (XX) | 19616 | methyl (E)-3-[6-[[(4-chlorophenyl)sulfonyl]amino]-2-propyl-3-(3-pyridinylmethyl)-5,6,7,8-tetrahydro-1-naphthalenyl]-2-propenoate | C29H31ClN2O4S | 详情 | 详情 | |
| (XXI) | 19617 | methyl 3-[6-[[(4-chlorophenyl)sulfonyl]amino]-2-propyl-3-(3-pyridinylmethyl)-5,6,7,8-tetrahydro-1-naphthalenyl]propanoate | C29H33ClN2O4S | 详情 | 详情 |