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【结 构 式】 
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【分子编号】21345 【品名】(2S)-1-Ethyl-2-(aminomethyl)pyrrolidine; [(2S)-1-Ethylpyrrolidinyl]methanamine 【CA登记号】 |
【 分 子 式 】C7H16N2 【 分 子 量 】128.21752 【元素组成】C 65.57% H 12.58% N 21.85% |
合成路线1
该中间体在本合成路线中的序号：(III)The reaction of 3-chloro-5-ethyl-2,6-dimethoxybenzoic acid (I) with SOCl2 gives the corresponding acyl chloride (II), which is condensed with N-ethyl-2-(aminomethyl)pyrrolidine (III) in refluxing CHCl3 yielding N-ethyl-2-(3-chloro-5-ethyl-2,6-dimethoxybenzamidomethyl)pyrrolidine (IV). Finally, this compound is treated with BBr3 in methylene chloride.
| 【1】 Florvall, G.L.; Lundstroem, J.O.G.; Raemsby, S.I.; Oegren S.O. (AstraZeneca plc); Benzamido-derivatives. DD 201886; EP 0060235; JP 57159762; US 4789683 . |
| 【2】 Serradell, M.N.; Castaner, J.; Eticlopride Hydrochloride. Drugs Fut 1985, 10, 4, 286. |
| 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) | 29113 | 3-chloro-5-ethyl-2,6-dimethoxybenzoic acid | C11H13ClO4 | 详情 | 详情 | |
| (II) | 29114 | 3-chloro-5-ethyl-2,6-dimethoxybenzoyl chloride | C11H12Cl2O3 | 详情 | 详情 | |
| (III) | 21345 | (2S)-1-Ethyl-2-(aminomethyl)pyrrolidine; [(2S)-1-Ethylpyrrolidinyl]methanamine | C7H16N2 | 详情 | 详情 | |
| (IV) | 29115 | 3-chloro-5-ethyl-N-[[(2S)-1-ethylpyrrolidinyl]methyl]-2,6-dimethoxybenzamide | C18H27ClN2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The bromination of 2,6-dimethoxybenzoic acid (I) with Br2 in dioxane gives 3-bromo-2,6-dimethoxy benzoic acid (II), which is treated with refluxing SOCl2 yielding the corresponding acyl chloride (III). Finally, this compound is condensed with (-)-(S)-1-ethyl 2-(aminomethyl)pyrrolidine (IV).
| 【1】 Florvall, L.; Ogren, S.O.; Potential neuroleptic agents. 2,6-dialkoxybenzamide derivatives with potent dopamine receptor blocking activities. J Med Chem 1982, 25, 11, 1280. |
| 【2】 Prous, J.; Castaner, J.; Remoxipride. Drugs Fut 1986, 11, 11, 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) | 24193 | 2,6-dimethoxybenzoic acid | 1466-76-8 | C9H10O4 | 详情 | 详情 |
| (II) | 24194 | 3-bromo-2,6-dimethoxybenzoic acid | 73219-89-3 | C9H9BrO4 | 详情 | 详情 |
| (III) | 24195 | 3-bromo-2,6-dimethoxybenzoyl chloride | C9H8BrClO3 | 详情 | 详情 | |
| (IV) | 21345 | (2S)-1-Ethyl-2-(aminomethyl)pyrrolidine; [(2S)-1-Ethylpyrrolidinyl]methanamine | C7H16N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The reaction of 3,5-dichloro-6-methoxysaliclic acid (I) with refluxing SOCl2 gives the corresponding acyl chloride (II), which is condensed with 1-ethyl-2-(aminomethyl)pyrrolidine (III) in methylene chloride yielding the amide (IV). Finally, this compound is partially demethylated with BBr3 in methylene chloride ether.
| 【1】 de Paulis, T.; et al.; Potential neuroleptic agents. 4. Chemistry, behavioral pharmacology, and inhibition of [3H]spiperone binding of 3,5-disubstituted N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamides. J Med Chem 1986, 29, 1, 61. |
| 【2】 Florvall, G.L.; Lundstroem, J.O.G.; Raemsby, S.I.; Oegren S.O. (AstraZeneca plc); Benzamido-derivatives. DD 201886; EP 0060235; JP 57159762; US 4789683 . |
| 【3】 Prous, J.; Castaner, J.; Raclopride. Drugs Fut 1986, 11, 5, 387. |
| 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) | 24010 | 3,5-Dichloro-6-methoxysaliclic acid; 3,5-Dichloro-2,6-dimethoxybenzoic acid | 73219-91-7 | C9H8Cl2O4 | 详情 | 详情 |
| (II) | 24011 | 3,5-dichloro-2,6-dimethoxybenzoyl chloride | C9H7Cl3O3 | 详情 | 详情 | |
| (III) | 21345 | (2S)-1-Ethyl-2-(aminomethyl)pyrrolidine; [(2S)-1-Ethylpyrrolidinyl]methanamine | C7H16N2 | 详情 | 详情 | |
| (IV) | 24013 | 3,5-dichloro-N-[[(2R)-1-ethylpyrrolidinyl]methyl]-2,6-dimethoxybenzamide | C16H22Cl2N2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)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5
该中间体在本合成路线中的序号：(V)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 |
合成路线6
该中间体在本合成路线中的序号：(VII)This compound has been obtained by three related ways: 1. The lithiation of N-(1-ethylpyrrolidin-2(S)-ylmethyl)-2,3-dimethoxybenzamide (I) with n-BuLi gives the dilithium salt (II), which by reaction with tosyl azide yields 6-azido-N-(1-ethylpyrrolidin-2(S)-ylmethyl)-2,3-dimethoxybenzamide (III). The reduction of the azido group of (III) with SnCl2 yields the corresponding amino derivative (IV), which is finally brominated with Br2 to afford the target compound. 2. The reaction of N-(3,4-dimethoxyphenyl)carbamic acid tert-butyl ester (V) with n-BuLi and CO2 gives 6-(tert-butoxycarbonyl)-2,3-dimethoxybenzoic acid (VI), which is condensed with (S)-1-ethylpyrrolidin-2-ylmethylamine (VII) by means of SOCl2, yielding the already reported 2-aminobenzamide (IV). 3. The intermediate carboxylic acid (VI) can also be first brominated with Br2 to give 5-bromo-6-(tert-butoxycarbonyl)-2,3-dimethoxybenzoic acid (VIII), which is finally condensed with (S)-1-ethylpyrrolidin-2-ylmethylamine (VII) by means of SOCl2, yielding the target compound.
| 【1】 Hogberg, M.; Novel substituted salicylamides and benzamides as selective dopamine D2-receptor antagonists. Drugs Fut 1991, 16, 4, 333. |
| 【2】 Bengtsson, S.; Hogberg, T.; Secondary beta-aminobenzamide and heteroatom directed lithiation in the synthesis of 5,6-dimethoxyanthranilamides and related compounds. J Org Chem 1989, 54, 4549-4553. |
| 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) | 42899 | N-[[(2S)-1-ethylpyrrolidinyl]methyl]-2,3-dimethoxybenzamide | C16H24N2O3 | 详情 | 详情 | |
| (II) | 42900 | lithium [2-[([[(2S)-1-ethylpyrrolidinyl]methyl]imino)(oxido)methyl]-3,4-dimethoxyphenyl]lithium | C16H22Li2N2O3 | 详情 | 详情 | |
| (III) | 42901 | 6-azido-N-[[(2S)-1-ethylpyrrolidinyl]methyl]-2,3-dimethoxybenzamide | C16H23N5O3 | 详情 | 详情 | |
| (IV) | 42902 | 6-amino-N-[[(2S)-1-ethylpyrrolidinyl]methyl]-2,3-dimethoxybenzamide | C16H25N3O3 | 详情 | 详情 | |
| (V) | 42903 | tert-butyl 3,4-dimethoxyphenylcarbamate | C13H19NO4 | 详情 | 详情 | |
| (VI) | 42904 | 6-[(tert-butoxycarbonyl)amino]-2,3-dimethoxybenzoic acid | C14H19NO6 | 详情 | 详情 | |
| (VII) | 21345 | (2S)-1-Ethyl-2-(aminomethyl)pyrrolidine; [(2S)-1-Ethylpyrrolidinyl]methanamine | C7H16N2 | 详情 | 详情 | |
| (VIII) | 42905 | 3-bromo-2-[(tert-butoxycarbonyl)amino]-5,6-dimethoxybenzoic acid | C14H18BrNO6 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)The alkylation of L-proline (I) with ethyl iodide (II) and K2CO3 gives N-ethylproline ethyl ester (III), which is treated with ammonia in methanol to afford N-ethyl-L-prolinamide (IV). The reduction of (IV) with LiAlH4 yields (S)-1-ethylpyrrolidin-2-ylmethylamine (V), which is condensed with 3-bromo-2,5,6-trimethoxybenzoyl chloride (VI) to provide the corresponding amide (VII). Finally, this compound is partially demethylated with BBr3 to provide the target compound.
| 【1】 Hogberg, M.; Novel substituted salicylamides and benzamides as selective dopamine D2-receptor antagonists. Drugs Fut 1991, 16, 4, 333. |
| 【2】 Ramsby, S.; Hogberg, T.; Strom, P.; Efficient stereoconservative syntheses of 1-substituted (S)- and (R)-2-aminomethylpyrrolidines. Acta Chem Scand 1989, 43, 660-664. |
| 【3】 Hogberg, T.; Ramsby, S.; Strom, P.; Ebner, M.; Cyanide as an efficient and mild catalyst in the aminolysis of esters. J Org Chem 1987, 52, 2033-2036. |
| 【4】 Hogberg, T.; et al.; Potential antipsychotic agents. 5. Synthesis and antidopaminergic properties of substituted 5, 6-dimethoxysalicylamides and related compounds. J Med Chem 1990, 33, 1155-63. |
| 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) | 10925 | Iodoethane;ethyl iod | 75-03-6 | C2H5I | 详情 | 详情 |
| (III) | 42895 | ethyl (2S)-1-ethyl-2-pyrrolidinecarboxylate | C9H17NO2 | 详情 | 详情 | |
| (IV) | 42896 | (2S)-1-ethyl-2-pyrrolidinecarboxamide | 55446-83-8 | C7H14N2O | 详情 | 详情 |
| (V) | 21345 | (2S)-1-Ethyl-2-(aminomethyl)pyrrolidine; [(2S)-1-Ethylpyrrolidinyl]methanamine | C7H16N2 | 详情 | 详情 | |
| (VI) | 42897 | 3-bromo-2,5,6-trimethoxybenzoyl chloride | C10H10BrClO4 | 详情 | 详情 | |
| (VII) | 42898 | 3-bromo-N-[[(2S)-1-ethylpyrrolidinyl]methyl]-2,5,6-trimethoxybenzamide | C17H25BrN2O4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(V)The alkylation of L-proline (I) with ethyl iodide (II) and K2CO3 gives N-ethylproline ethyl ester (III), which is treated with ammonia in methanol to afford N-ethyl-L-prolinamide (IV). The reduction of (IV) with LiAlH4 yields (S)-1-ethylpyrrolidin-2-ylmethylamine (V), which is condensed with 3-iodo-2,5,6-trimethoxybenzoyl chloride (VI) to provide the corresponding amide (VII). Finally, this compound is partially demethylated with BBr3 to provide the target compound.
| 【1】 Hogberg, T.; Ramsby, S.; Strom, P.; Ebner, M.; Cyanide as an efficient and mild catalyst in the aminolysis of esters. J Org Chem 1987, 52, 2033-2036. |
| 【2】 Ramsby, S.; Hogberg, T.; Strom, P.; Efficient stereoconservative syntheses of 1-substituted (S)- and (R)-2-aminomethylpyrrolidines. Acta Chem Scand 1989, 43, 660-664. |
| 【3】 Hogberg, M.; Novel substituted salicylamides and benzamides as selective dopamine D2-receptor antagonists. Drugs Fut 1991, 16, 4, 333. |
| 【4】 Hogberg, T.; et al.; Potential antipsychotic agents. 5. Synthesis and antidopaminergic properties of substituted 5, 6-dimethoxysalicylamides and related compounds. J Med Chem 1990, 33, 1155-63. |
| 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) | 10925 | Iodoethane;ethyl iod | 75-03-6 | C2H5I | 详情 | 详情 |
| (III) | 42895 | ethyl (2S)-1-ethyl-2-pyrrolidinecarboxylate | C9H17NO2 | 详情 | 详情 | |
| (IV) | 42896 | (2S)-1-ethyl-2-pyrrolidinecarboxamide | 55446-83-8 | C7H14N2O | 详情 | 详情 |
| (V) | 21345 | (2S)-1-Ethyl-2-(aminomethyl)pyrrolidine; [(2S)-1-Ethylpyrrolidinyl]methanamine | C7H16N2 | 详情 | 详情 | |
| (VI) | 42906 | 3-iodo-2,5,6-trimethoxybenzoyl chloride | C10H10ClIO4 | 详情 | 详情 | |
| (VII) | 42907 | N-[[(2S)-1-ethylpyrrolidinyl]methyl]-3-iodo-2,5,6-trimethoxybenzamide | C17H25IN2O4 | 详情 | 详情 |