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【结 构 式】 
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【分子编号】12421 【品名】4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide 【CA登记号】364-62-5 |
【 分 子 式 】C14H22ClN3O2 【 分 子 量 】299.8004 【元素组成】C 56.09% H 7.4% Cl 11.83% N 14.02% O 10.67% |
合成路线1
该中间体在本合成路线中的序号：(I)By acylation of metoclopramide (I) with 2-(4-chlorophenoxy)acetic acid (II) by means of POCl3 in refluxing chloroform.
| 【1】 Metz, G.; Specker, M.; Anti-inlammatory N-acyl substituted benzamides. BE 0854683; CH 633259; DE 2623228; FR 2352791; GB 1555723; US 4146637 . |
| 【2】 Metz, G.; Chen, H.L.; Pindell, M.H.; Cloxacepride and related compounds: A new series of orally active antiallergic compounds. J Med Chem 1983, 26, 7, 1065-70. |
| 【3】 Serradell, M.N.; Castaner, J.; Cloxacepride. Drugs Fut 1984, 9, 5, 322. |
合成路线2
该中间体在本合成路线中的序号：(VII)A new synthesis for [14C]-labeled batanopride has been described: The starting material is 4-amino-2-hydroxybenzoic acid labeled with [14C] at the carboxy group (I). The methylation of (I) in the usual way gives 4-amino-2-methoxybenzoic acid methyl ester (II), which is treated with acetic anhydride to yield the corresponding acetamido derivative (III). Chlorination of (III) with Cl2 in acetic acid affords 4-acetamido-5-chloro-2-methoxybenzoic acid methyl ester (IV), which is hydrolyzed with aqueous NaOH to 4-amino-5-chloro-2-methoxybenzoic acid (V). The condensation of (V) with 2-(diethylamino)ethylamine (VI) by means of triethylamine and isobutyl chloroformate in THF gives the corresponding amide (VII), which is demethylated with sodium ethanethiolate in DMF to yield the phenolate (VIII). The condensation of (VIII) with 3-chloro-2-butanone (IX) in DMF affords batanopride free base (X), which is finally treated with HCl in acetone - water.
| 【1】 Standridge, R.T.; Swigor, J.E.; Synthesis of 4-amino-5-chloro-N[2-(diethylamino)ethyl]-2-[(butan-2-on-3-yl)oxy]-[carbonyl-C-14]benzamide hydrochloride (C-14-batanopride). J Label Compd Radiopharm 1991, 29, 9, 983. |
| 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) | 12415 | 4-Aminosalicylic Acid; 4-Amino-2-hydroxybenzoic acid | 65-49-6 | C7H7NO3 | 详情 | 详情 |
| (I) | 45126 | 4-amino-2-hydroxybenzoic acid | C7H7NO3 | 详情 | 详情 | |
| (II) | 12416 | methyl 4-amino-2-methoxybenzoate | 27492-84-8 | C9H11NO3 | 详情 | 详情 |
| (II) | 45127 | methyl 4-amino-2-methoxybenzoate | C9H11NO3 | 详情 | 详情 | |
| (III) | 12417 | methyl 4-(acetamido)-2-methoxybenzoate; Methyl 4-acetamido-2-methoxybenzoate | 4093-28-1 | C11H13NO4 | 详情 | 详情 |
| (III) | 45128 | methyl 4-(acetamido)-2-methoxybenzoate | C11H13NO4 | 详情 | 详情 | |
| (IV) | 12418 | 4-Acetamido-5-chloro-2-methoxy methyl benzoate; methyl 4-(acetamido)-5-chloro-2-methoxybenzoate; Methyl 4-acetamido-5-chloro-2-methoxybenzoate; 4-Acetamido-5-chloro-2-methoxybenzoic acid methyl ester; 4-Acetamido-5-chloro-o-anisic acid methyl ester | 4093-31-6 | C11H12ClNO4 | 详情 | 详情 |
| (IV) | 45129 | methyl 4-(acetamido)-5-chloro-2-methoxybenzoate | C11H12ClNO4 | 详情 | 详情 | |
| (V) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (V) | 45130 | 4-amino-5-chloro-2-methoxybenzoic acid | C8H8ClNO3 | 详情 | 详情 | |
| (VI) | 12420 | N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine | 100-36-7 | C6H16N2 | 详情 | 详情 |
| (VII) | 12421 | 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide | 364-62-5 | C14H22ClN3O2 | 详情 | 详情 |
| (VII) | 45131 | 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide | C14H22ClN3O2 | 详情 | 详情 | |
| (VIII) | 12422 | sodium 5-amino-4-chloro-2-([[2-(diethylamino)ethyl]amino]carbonyl)benzenolate | C13H19ClN3NaO2 | 详情 | 详情 | |
| (VIII) | 45132 | sodium 5-amino-4-chloro-2-([[2-(diethylamino)ethyl]amino]carbonyl)benzenolate | C13H19ClN3NaO2 | 详情 | 详情 | |
| (IX) | 12423 | 3-Chloro-2-butanone | 4091-39-8 | C4H7ClO | 详情 | 详情 |
| (X) | 12424 | 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(1-methyl-2-oxopropoxy)benzamide | C17H26ClN3O3 | 详情 | 详情 | |
| (X) | 45133 | 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(1-methyl-2-oxopropoxy)benzamide | C17H26ClN3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The demethylation of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide (I) with EtS-Na in hot DMF gives the hydroxy compound (II), which is acylated with 3-chloro-2-butanone (III) by means of K2CO3 and NaI in DMF to yield 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(1-methyl-2-oxopropoxy)benzamide (IV). Finally, this compound is treated with HCl to furnish the target hydrochloride. Alternatively, the alkylation of the hydroxy compound (II) can also be performed by reaction of (II) with tetrabutylammonium bisulfate and NaOH to give the tetrabutylammonium phenolate (V), which is alkylated with the chlorobutanone (III) to give (IV).
| 【1】 Monkovic, I.; NEW BENZAMIDE ANTI-EMETICS. Drugs Fut 1989, 14, 1, 41. |
| 【2】 Monkovic, I.; Willner, D.; Adam, M.A.; Brown, M.; Crenshaw, R.R.; Fuller, C.E.; Juby, P.F.; Luke, G.M.; Matiskella, J.A.; Montzka, T.A.; Substituted benzamides. 1. Potential nondopaminergic antagonists of chemotherapy-induced nausea and emesis. J Med Chem 1988, 31, 8, 1548-58. |
| 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) | 12421 | 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide | 364-62-5 | C14H22ClN3O2 | 详情 | 详情 |
| (II) | 43739 | 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide | C13H20ClN3O2 | 详情 | 详情 | |
| (III) | 12423 | 3-Chloro-2-butanone | 4091-39-8 | C4H7ClO | 详情 | 详情 |
| (IV) | 12424 | 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(1-methyl-2-oxopropoxy)benzamide | C17H26ClN3O3 | 详情 | 详情 | |
| (V) | 43740 | N,N,N-tributyl-1-butanaminium 5-amino-4-chloro-2-([[2-(diethylamino)ethyl]amino]carbonyl)benzenolate | C29H55ClN4O2 | 详情 | 详情 |