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【结 构 式】 
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【分子编号】12380 【品名】2,3-Dihydroxybenzaldehyde 【CA登记号】24677-78-9 |
【 分 子 式 】C7H6O3 【 分 子 量 】138.12284 【元素组成】C 60.87% H 4.38% O 34.75% |
合成路线1
该中间体在本合成路线中的序号：(II)The demethylation ot o-vanillin (I) with AlCl3 dissolved in pyridine gives 2,3 dihydroxybenzaldehyde (II). Subsequent alkylation by means of hexyl bromide with NaH gives 3-hexyloxy-2-hydroxybenzaldehyde (III), which is then condensed with malononitrile and piperidine, yielding 3-cyano-8-hexyloxycromen-2-one (IV), a needle-like yellow crystalline substance. Finally, compound (IV) is treated with sodium azide and AlCl3 in refluxing THF, yielding the formation of the tetrazole ring.
| 【1】 Tasaka, K.; KP-136. Drugs Fut 1988, 13, 10, 915. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 | |
| 11108 | n-Hexyl bromide; 1-Bromohexane | 111-25-1 | C6H13Br | 详情 | 详情 | |
| (I) | 12620 | o-Vanillin; 2-Hydroxy-3-methoxybenzaldehyde | 148-53-8 | C8H8O3 | 详情 | 详情 |
| (II) | 12380 | 2,3-Dihydroxybenzaldehyde | 24677-78-9 | C7H6O3 | 详情 | 详情 |
| (III) | 23096 | 3-(hexyloxy)-2-hydroxybenzaldehyde | C13H18O3 | 详情 | 详情 | |
| (IV) | 23097 | 8-(hexyloxy)-2-oxo-2H-chromene-3-carbonitrile | C16H17NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The cyclization of 2,3-dihydroxybenzaldehyde (I) with dibromomethane by means of KF in hot DMF gives 2,3-methylenedioxybenzaldehyde (II), which is condensed with ethyl acetoacetate (III) by means of piperidine and acetic acid in refluxing benzene to afford ethyl 2-acetyl-3-(2,3-methylenedioxyphenyl)acrylate (IV). Finally, this compound is cyclized with methyl 3-aminocrotonate (V) in hot isopropanol.
| 【1】 Galiano Ramos, J.A.; Verde Casanova, M.J. (IIDQB (Madrid); Laboratoires Delagrange); Calcium antagonists. BE 0902016; CH 663020; DE 3510762; EP 0158211; FR 2562069; GB 2156809; JP 1985248671; US 4722931 . |
| 【2】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; Oxodipine. Drugs Fut 1987, 12, 7, 633. |
| 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) | 12380 | 2,3-Dihydroxybenzaldehyde | 24677-78-9 | C7H6O3 | 详情 | 详情 |
| (II) | 13329 | 2,3-(Methylenedioxy)benzaldehyde; 1,3-Benzodioxole-4-carbaldehyde | 7797-83-3 | C8H6O3 | 详情 | 详情 |
| (III) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (IV) | 28848 | ethyl 2-(1,3-benzodioxol-4-ylmethyl)-3-oxobutanoate | C14H16O5 | 详情 | 详情 | |
| (V) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Two minor metabolites of mosapride 4-amino-5-chloro-2-ethoxy-3-hydroxy-N-(5-oxo-2-morpholinylmethyl)benzamide (A) and 4-amino-5-chloro-2-ethoxy-3-hydroxy-N-(2-morpholinylmethyl)benzamide (B) have been synthesized as follows: 1) The alkylation of 2,3-dihydroxybenzaldehyde (I) with NaH and ethyl iodide in DMSO gives 2-ethoxy-3-hydroxybenzaldehyde (II), which is nitrated with HNO3 in acetic acid yielding 2-ethoxy-3-hydroxy-4-nitrobenzaldehyde (III). The oxidation of (III) with AgNO3 in methanol/water affords the expected benzoic acid (IV), which is condensed with 2-(aminomethyl)morpholin-5-one (V) by means of carbonyldiimidazole (CDI) in THF giving the corresponding benzamide (VI). The hydrogenation of the nitro group of (VI) with H2 over Pd/C in aqueous ethanol yields 4-amino-2-ethoxy-3-hydroxy-N-(5-oxo-2-morpholinylmethyl)benzamide (VII), which is finally chlorinated to the metabolite (A) with N-chlorosuccinimide in hot DMF. 2) The reaction of the benzoic acid (IV) with SOCl2 in refluxing dichloromethane gives the corresponding acyl chloride (VIII), which is condensed with 2-(aminomethyl)-4-(4-fluorobenzyl)morpholine (IX) by means of triethylamine in dichloromethane to yield the expected amide (X). The debenzylation of (X) with 1-chloroethyl chloroformate (ACE-Cl) and reprotection with di-tert-butyl carbonate affords N-[4-(tert-butoxycarbonyl)morpholin-2-ylmethyl]-2-ethoxy-3-hydroxy-4-nitrobenzamide (XI), which is submitted to a reductive acetylation (H2 over Pd/C in acetic anhydride) giving 4-acetamido-N-[4-(tert-butoxycarbonyl)morpholin-2-ylmethyl]-2-ethoxy-3-hydroxybenzamide (XII). The chlorination of (XII) with N-chlorosuccinimide (NCS) in chloroform/DMS yields the corresponding 5-chlorobenzamide (XIII), which is finally deprotected with refluxing aqueous HCl to afford metabolite (B).
| 【1】 Kato, S.; Morie, T.; Yoshida, N.; Synthesis and biological activity of 4-amino-5-chloro-2-ethoxy-3-hydroxybenzamides, metabolites of a new gastroprokinetic agent, mosapride. Chem Pharm Bull 1996, 44, 8, 1484. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 12393 | 4-Amino-5-chloro-2-ethoxy-3-hydroxy-N-[(5-oxo-1,4-oxazinan-2-yl)methyl]benzamide | C14H18ClN3O5 | 详情 | 详情 | |
| (B) | 12394 | 4-Amino-5-chloro-2-ethoxy-3-hydroxy-N-(1,4-oxazinan-2-ylmethyl)benzamide | C14H20ClN3O4 | 详情 | 详情 | |
| (I) | 12380 | 2,3-Dihydroxybenzaldehyde | 24677-78-9 | C7H6O3 | 详情 | 详情 |
| (II) | 12381 | 2-Ethoxy-3-hydroxybenzaldehyde | C9H10O3 | 详情 | 详情 | |
| (III) | 12382 | 2-Ethoxy-3-hydroxy-4-nitrobenzaldehyde | C9H9NO5 | 详情 | 详情 | |
| (IV) | 12383 | 2-Ethoxy-3-hydroxy-4-nitrobenzoic acid | C9H9NO6 | 详情 | 详情 | |
| (V) | 12367 | 6-(Aminomethyl)-3-morpholinone | C5H10N2O2 | 详情 | 详情 | |
| (VI) | 12385 | 2-Ethoxy-3-hydroxy-4-nitro-N-[(5-oxo-1,4-oxazinan-2-yl)methyl]benzamide | C14H17N3O7 | 详情 | 详情 | |
| (VII) | 12386 | 4-Amino-2-ethoxy-3-hydroxy-N-[(5-oxo-1,4-oxazinan-2-yl)methyl]benzamide | C14H19N3O5 | 详情 | 详情 | |
| (VIII) | 12387 | 2-Ethoxy-3-hydroxy-4-nitrobenzoyl chloride | C9H8ClNO5 | 详情 | 详情 | |
| (IX) | 12336 | [4-(4-Fluorobenzyl)-1,4-oxazinan-2-yl]methylamine; [4-(4-Fluorobenzyl)-1,4-oxazinan-2-yl]methanamine; 2-Aminomethyl-4-(4-fluorobenzyl)morpholine | 112914-13-3 | C12H17FN2O | 详情 | 详情 |
| (X) | 12389 | 2-Ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]-3-hydroxy-4-nitrobenzamide | C21H24FN3O6 | 详情 | 详情 | |
| (XI) | 12390 | tert-butyl 2-[[(2-ethoxy-3-hydroxy-4-nitrobenzoyl)amino]methyl]-4-morpholinecarboxylate | C19H27N3O8 | 详情 | 详情 | |
| (XII) | 12391 | tert-butyl 2-([[4-(acetamido)-2-ethoxy-3-hydroxybenzoyl]amino]methyl)-4-morpholinecarboxylate | C21H31N3O7 | 详情 | 详情 | |
| (XIII) | 12392 | tert-butyl 2-([[4-(acetamido)-5-chloro-2-ethoxy-3-hydroxybenzoyl]amino]methyl)-4-morpholinecarboxylate | C21H30ClN3O7 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)Elgodipine can be obtained in three main steps: The alkylation of N-methyl-2-aminoethanol (I) with 4-fluorobenzyl chloride (II) gives 2-[N-(4-fluorobenzyl)-N-methylamino]ethanol (III), which is esterified with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (IV) yielding the corresponding acetoacetic ester (V). The condensation of (V) with 2,3-methylenedioxybenzaldehyde (VI) affords 2-[N-(4-fluorobenzyl)-N-methylamino]ethyl 2-(2,3-methylenedioxybenzylidene]acetoacetate (VII), which is finally cyclized with isopropyl 3-aminocrotonate (VIII). The intermediate aldehyde (VI) is obtained starting from 2,3-dimethoxybenzaldehyde (X), which by demethylation with HCl or HBr yields 2,3-dihydroxybenzaldehyde (XI). Finally, this compound is converted into (VI) in the usual way. The intermediate crotonate (VIII) is obtained by reaction of isopropyl acetoacetate (IX) with ammonia.
| 【1】 Galiano, A.; Elgodipine Hydrochloride. Drugs Fut 1995, 20, 3, 231. |
| 【2】 Fernandez Torija, C.; Galiano Ramos, J.A. (IIDQB (Madrid)); 1,4-Dihydropyridines, process for their preparation and their use as medicaments. AU 8820330; BE 1001055; CH 675999; EP 0302980; GB 2208861; JP 1989294675; US 4952592 . |
| 【3】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; Oxodipine. Drugs Fut 1987, 12, 7, 633. |
| 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) | 13324 | 2-Methylaminoethanol; 2-(Methylamino)-1-ethanol | 109-83-1 | C3H9NO | 详情 | 详情 |
| (II) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
| (III) | 13333 | 2-[(4-Fluorobenzyl)(methyl)amino]-1-ethanol | C10H14FNO | 详情 | 详情 | |
| (IV) | 13327 | 2,2,6-Trimethyl-4H-1,3-dioxin-4-one；2,2,6-trimethyl-1,3-dioxin-4-one；2,2,6-trimethyl-m-Dioxin-4-one;3-(1-hydroxy-1-methylethoxy)-d-lactone Crotonicacid | 5394-63-8 | C7H10O3 | 详情 | 详情 |
| (V) | 13328 | 2-[(4-fluorobenzyl)(methyl)amino]ethyl 3-oxobutanoate | C14H18FNO3 | 详情 | 详情 | |
| (VI) | 13329 | 2,3-(Methylenedioxy)benzaldehyde; 1,3-Benzodioxole-4-carbaldehyde | 7797-83-3 | C8H6O3 | 详情 | 详情 |
| (VII) | 13330 | 2-[(4-fluorobenzyl)(methyl)amino]ethyl (Z)-2-acetyl-3-(1,3-benzodioxol-4-yl)-2-propenoate | C22H22FNO5 | 详情 | 详情 | |
| (VIII) | 13331 | isopropyl (E)-3-amino-2-butenoate | 143093-33-8 | C7H13NO2 | 详情 | 详情 |
| (IX) | 13332 | isopropyl 3-oxobutanoate; Isopropyl acetoacetate | 542-08-5 | C7H12O3 | 详情 | 详情 |
| (X) | 17615 | 2,3-Dimethoxybenzaldehyde | 86-51-1 | C9H10O3 | 详情 | 详情 |
| (XI) | 12380 | 2,3-Dihydroxybenzaldehyde | 24677-78-9 | C7H6O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)Methylation of phenylpyruvic acid (I) with iodomethane and DBU affords the methyl phenylpyruvate (II). Subsequent condensation of keto ester (II) with 2,3-dihydroxybenzaldehyde (III) in the presence of DBU, followed by acidic quenching provides the target furanone derivative
| 【1】 Weber, V.; et al.; Novel 4,5-diaryl-3-hydroxy-2(5H)-furanones as anti-oxidants and anti-inflammatory agents. Bioorg. Med. Chem. 2002, 10, 6, 1647. |