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【结 构 式】 
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【分子编号】12336 【品名】[4-(4-Fluorobenzyl)-1,4-oxazinan-2-yl]methylamine; [4-(4-Fluorobenzyl)-1,4-oxazinan-2-yl]methanamine; 2-Aminomethyl-4-(4-fluorobenzyl)morpholine 【CA登记号】112914-13-3 |
【 分 子 式 】C12H17FN2O 【 分 子 量 】224.2782632 【元素组成】C 64.26% H 7.64% F 8.47% N 12.49% O 7.13% |
合成路线1
该中间体在本合成路线中的序号：(VII)The starting compounds (IV) and (VII) are obtained as follows: a) Methyl 4-acetylamino-2-hydroxybenzoate (I) is converted to the 2-ethoxy derivative (II) with ethyl iodide, and then chlorination of (II) with N-chlorosuccinimide followed by alkaline hydrolysis of (III) gives benzoic acid (IV). b) The reaction of 2-[(4-fluorobenzyl)amino]ethanol (V) with N-(2,3-epoxypropyl)phthalimide (VI), followed by treatment with concentrated sulfuric acid, affords intermediate (VII). The condensation of 4-Amino-5-chloro-2-ethoxybenzoic acid (IV) with 4-(4-fluorobenzyl)-2-(methylamino) morpholine (VII) by means of ethyl chloroformate and triethylamine in CHCl3 gives 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl] benzamide, which is converted to mosapride citrate, by treatment with citric acid.
| 【1】 Kato, S.; Yoshida, N.; Ito, T.; Mosapride Citrate. Drugs Fut 1993, 18, 6, 513. |
| 【2】 Kato, S.; Morie, T.; Hino, K.; Kon, T.; Naruto, S.; Yoshida, N.; Karasawa, T.; Matsumoto, J.; Novel benzamides as selective and potent gastrokinetic agents. 1. Synthesis and structure-activity relationships of N[4-(2-morpholinyl)alkyl]benzamides. J Med Chem 1990, 33, 5, 1406-13. |
| 【3】 Kato, S.; Morie, T.; Hino, K.; Kon, T.; Naruto, S.; Yoshida, N.; Karasawa, T.; Matsumoto, J.; Novel benzamides as selective and potent gastrokinetic agents. 1. Synthesis and structure-activity relationships of N[4-(2-morpholinyl)alkyl]benzamides. J Med Chem 1990, 33, 5, 1406-13. |
| 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) | 12330 | methyl 4-(acetamido)-2-hydroxybenzoate | C10H11NO4 | 详情 | 详情 | |
| (II) | 12331 | Methyl 4-acetamido-2-ethoxybenzoate; methyl 4-(acetamido)-2-ethoxybenzoate | 59-06-3 | C12H15NO4 | 详情 | 详情 |
| (III) | 12332 | methyl 4-(acetamido)-5-chloro-2-ethoxybenzoate | C12H14ClNO4 | 详情 | 详情 | |
| (IV) | 12333 | 4-Amino-5-chloro-2-ethoxybenzoic acid | C9H10ClNO3 | 详情 | 详情 | |
| (V) | 12334 | 2-[(4-Fluorobenzyl)amino]-1-ethanol | C9H12FNO | 详情 | 详情 | |
| (VI) | 12335 | 2-(2-Oxiranylmethyl)-1H-isoindole-1,3(2H)-dione; N-(2,3-Epoxypropyl)phtalimide | 5455-98-1 | C11H9NO3 | 详情 | 详情 |
| (VII) | 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 |
合成路线2
该中间体在本合成路线中的序号：(IX)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 |