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【结 构 式】 
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【分子编号】19583 【品名】4-chloro-N-[3-[(Z)-hydroxymethylidene]-4-oxocyclohexyl]benzenesulfonamide 【CA登记号】 |
【 分 子 式 】C13H14ClNO4S 【 分 子 量 】315.7772 【元素组成】C 49.45% H 4.47% Cl 11.23% N 4.44% O 20.27% S 10.15% |
合成路线1
该中间体在本合成路线中的序号：(VI)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
该中间体在本合成路线中的序号：(VIII)The intermediate 4-(4-chlorophenylsulfonyl)aminocyclohexanone (V) was prepared by two synthetic ways. 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 (II) 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. lternatively, 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). Condensation of this intermediate (V) 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). The key tetrahydronaphthalene system (XIV) was then obtained by Diels-Alder reaction with methyl propiolate (XIII) with concomitant decarboxylation at 200 C. Finally, 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 | |
| (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) | 19588 | methyl propiolate | 922-67-8 | C4H4O2 | 详情 | 详情 |
| (XIV) | 19589 | methyl 3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenecarboxylate | C18H17BrClNO4S | 详情 | 详情 | |
| (XV) | 19590 | N-[7-bromo-5-(hydroxymethyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-4-chlorobenzenesulfonamide | C17H17BrClNO3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)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 |