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【结 构 式】 
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【药物名称】Sulpiride [L-(-)], Levosulpiride, RV-12309, Levopraid 【化学名称】(S)-5-(Aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methoxybenzamide 【CA登记号】23672-07-3, 77111-58-1 (HCl) 【 分 子 式 】C15H23N3O4S 【 分 子 量 】341.43226 |
【开发单位】Abbott (Originator), Ravizza (Originator) 【药理作用】Antipsychotic Drugs, Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, PSYCHOPHARMACOLOGIC DRUGS, Dopamine D2 Antagonists |
合成路线1
This compound is obtained by condensation of 2(S)-(aminomethyl)-1-ethylpyrrolidine (I) with 5-(aminosulfonyl)-2-methoxybenzoyl chloride (II) by means of K2CO3 in acetone. The starting compounds (I) and (II) are obtained as follows: a) The acylation of 2(S)-(hydroxymethyl)pyrrolidine (III) with acetic anhydride in refluxing methanol gives 1-acetyl-2(S)-(hydroxymethyl)pyrrolidine (IV), which by reaction with SOCl2 in CHCl3 is converted into 1-acetyl-2(S)-(chloromethyl)pyrrolidine (V). The reaction of (V) with sodium azide in hot DMF affords the corresponding azide (VI), which is reduced with LiAlH4 in refluxing THF to yield the desired product (I). b) The methylation of 2-hydroxybenzaldehyde (VII) with dimethyl sulfate and K2SO3 in refluxing acetone gives 2-methoxybenzaldehyde (VIII), which is oxidized with KMnO4 in hot aqueous NaOH affording 2-methoxybenzoic acid (IX). The sulfonation of (IX) with hot chlorosulfonic acid yields 5-(chlorosulfonyl)-2-methoxybenzoic acid (X), which is finally treated with 28% aqueous NaOH to give the desired product (II).
| 【1】 Al-Koutayni-Rifai, M.; Jamet, G.; Kerr, R.R.; Jung, L.; Koffel, J.C.; Synthesis of D3-sulpiride and its (R) and (S) isomers. J Label Compd Radiopharm 1989, 27, 7, 811. |
| 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) | 21345 | (2S)-1-Ethyl-2-(aminomethyl)pyrrolidine; [(2S)-1-Ethylpyrrolidinyl]methanamine | C7H16N2 | 详情 | 详情 | |
| (II) | 21346 | 5-(aminosulfonyl)-2-methoxybenzoyl chloride | C8H8ClNO4S | 详情 | 详情 | |
| (III) | 21347 | (2S)pyrrolidinylmethanol | 23356-96-9 | C5H11NO | 详情 | 详情 |
| (IV) | 21348 | 1-[(2S)-2-(hydroxymethyl)pyrrolidinyl]-1-ethanone | C7H13NO2 | 详情 | 详情 | |
| (V) | 21349 | 1-[(2S)-2-(chloromethyl)pyrrolidinyl]-1-ethanone | C7H12ClNO | 详情 | 详情 | |
| (VI) | 21350 | 1-[(2S)-2-(azidomethyl)pyrrolidinyl]-1-ethanone | C7H12N4O | 详情 | 详情 | |
| (VII) | 21351 | 2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde | 90-02-8 | C7H6O2 | 详情 | 详情 |
| (VIII) | 12568 | 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde | 135-02-4 | C8H8O2 | 详情 | 详情 |
| (IX) | 13926 | 2-Methoxybenzoic acid; o-Methoxybenzoic Acid | 579-75-9 | C8H8O3 | 详情 | 详情 |
| (X) | 21354 | 5-(chlorosulfonyl)-2-methoxybenzoic acid | C8H7ClO5S | 详情 | 详情 | |
| (XI) | 21355 | 5-(aminosulfonyl)-2-methoxybenzoic acid; 2-methoxy-5-sulfamoylbenzoic acid | 22117-85-7 | C8H9NO5S | 详情 | 详情 |
合成路线2
Optically active sulpiride is prepared by converting levo-proline (I) to the correspondig levorotatory acetylproline (II), followed by reduction, chlorination and amination to afford levorotatory N-ethyl-2-aminomethylpyrrolidine (V), which, upon treatment with an ester of 2-methoxy-5-sulfamoylbenzoic acid (VI), yields N-(1-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-sulfamoylbenzamide, that is, the levorotatory enantiomer of sulpiride.
| 【1】 Forgione, A.; Levosulpiride. Drugs Fut 1987, 12, 10, 944. |
| 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) | 16731 | L-proline | 147-85-3 | C5H9NO2 | 详情 | 详情 |
| (II) | 28022 | (2S)-1-acetyl-2-pyrrolidinecarboxylic acid | 68-95-1 | C7H11NO3 | 详情 | 详情 |
| (III) | 28023 | [(2S)-1-ethylpyrrolidinyl]methanol | C7H15NO | 详情 | 详情 | |
| (IV) | 28024 | (2S)-2-(chloromethyl)-1-ethylpyrrolidine | C7H14ClN | 详情 | 详情 | |
| (V) | 21345 | (2S)-1-Ethyl-2-(aminomethyl)pyrrolidine; [(2S)-1-Ethylpyrrolidinyl]methanamine | C7H16N2 | 详情 | 详情 | |
| (VI) | 28025 | methyl 5-(aminosulfonyl)-2-methoxybenzoate | 33045-52-2 | C9H11NO5S | 详情 | 详情 |