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【结 构 式】 
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【分子编号】51405 【品名】2-Butynoic acid methyl ester; Methyl 2-butynoate; Tetrolic acid methyl ester; Methyl tetrolate 【CA登记号】23326-27-4 |
【 分 子 式 】C5H6O2 【 分 子 量 】98.10144 【元素组成】C 61.22% H 6.16% O 32.62% |
合成路线1
该中间体在本合成路线中的序号：(I)The cyclization of 2-butynoic acid methyl ester (I) with 2-(2-chlorobenzylidene)-3-oxobutyric acid ethyl ester (II) and benzylamine (III) in refluxing toluene gives the N-benzylated dihydropyridine (IV), which is debenzylated by reduction with formic acid over Pd/C in refluxing methanol to yield the dihydropyridine (V). The bromination of (V) with C5H5NH+ HBr3- in dichloromethane affords the bromomethyl compound (VI), which is condensed with 2-azidoethanol (VII) by means of NaH in ethyl ether to provide the 2-azidoethoxymethyl compound (VIII). Finally, the azido group of (VIII) is reduced with Zn and HCl in methanol to furnish the desired 2-aminoethoxymethyl compound.
| 【1】 Kim, S.-C.; et al.; Synthesis of amlodipine using aza Diels-Alder reaction. Bull Korean Chem Soc 2002, 23, 1, 143. |
| 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) | 51405 | 2-Butynoic acid methyl ester; Methyl 2-butynoate; Tetrolic acid methyl ester; Methyl tetrolate | 23326-27-4 | C5H6O2 | 详情 | 详情 |
| (II) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (III) | 51406 | ethyl (Z)-2-acetyl-3-(2-chlorophenyl)-2-propenoate | C13H13ClO3 | 详情 | 详情 | |
| (IV) | 51407 | 3-methyl 5-propyl 1-benzyl-4-(2-chlorophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate | C26H28ClNO4 | 详情 | 详情 | |
| (V) | 51408 | 3-ethyl 5-methyl 4-(2-chlorophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate | C18H20ClNO4 | 详情 | 详情 | |
| (VI) | 51409 | 3-ethyl 5-methyl 2-(bromomethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C18H19BrClNO4 | 详情 | 详情 | |
| (VII) | 24111 | 2-azido-1-ethanol | C2H5N3O | 详情 | 详情 | |
| (VIII) | 51410 | 5-methyl 3-propyl 2-[(2-azidoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C21H25ClN4O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)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3
该中间体在本合成路线中的序号：(I)Arglabin (I) was isolated from the extracts of Artemisia glabella and was purified by column chromatography followed by crystallization from hexane. Conjugate addition of dimethylamine to the methylene lactone system of (I) provided the target dimethylamino derivative, which was finally converted to the corresponding hydrochloride salt.
| 【1】 Adekenov, S.M. (Paracure, Inc.); Pharmaceutical compsns. of arglabin and arglabin derivs.. US 5902809; WO 9848789 . |
| 【2】 Shaikenov, T.E. (International Phytochemistry Research Laboratory Ltd.); Farnesyl-protein transferase inhibitors. WO 9943314 . |