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【结 构 式】 
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【药物名称】Vigabatrin;M071754;RMI-71890((+)-enantiomer); GVG;MDL-71754;RMI-71754;Sabrilex;Sabril 【化学名称】4-Amino-5-hexenoic acid;gamma-Vinyl GABA;(RS)-4-Amino-5-hexenoic acid 【CA登记号】60643-86-9 【 分 子 式 】C6H11NO2 【 分 子 量 】129.16007 |
【开发单位】Aventis Pharma (Originator), Novartis (Licensee), Ovation Pharmaceuticals (Licensee) 【药理作用】Antiepileptic Drugs, NEUROLOGIC DRUGS, Treatment of Alcohol Dependency, Treatment of Cocaine Dependency, TREATMENT OF POISONING, DRUG ABUSE & DEPENDENCY, Treatment of Substance Dependency, GABA Aminotransferase Inhibitors |
合成路线1
The synthesis of [14C]-labeled vigabatrin has been described: The reduction by known methods of pyroglutamic acid (I) to the alcohol (II) and its acylation with p-toluenesulfonyl chloride gives 5-(tosyloxymethyl)pyrrolidin-2-one (III), which by reaction with [14C]-labeled sodium cyanide in hot DMF yields 5-([14C]-cyanomethyl)pyrrolidin-2-one (IV). The reduction of (VI) with H2 over Pd/Al2O3 and treatment with dimethylamine affords 5-[2-(dimethylamino)ethyl]pyrrolidin-2-one (VI), which is oxidized with H2O2 in water to the N-oxide (VI). The treatment of (VI) with K2CO3 in refluxing xylene affords 5-([14C]-vinyl)pyrrolidin-2-one (VII), which is finally submitted to ring opening with hot 5 M aqueous HCl, followed by neutralization with triethylamine.
| 【1】 Wagner, E.R.; Schuster, A.J.; Synthesis of carbon-14 labeled vigabatrin. J Label Compd Radiopharm 1993, 33, 3, 213. |
| 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) | 10078 | Pyrrolidonecarboxylic acid; 5-Oxo-proline; 5-Oxo-2-pyrrolidinecarboxylic acid | 149-87-1 | C5H7NO3 | 详情 | 详情 |
| (II) | 10079 | 5-(Hydroxymethyl)-2-pyrrolidinone | 62400-75-3 | C5H9NO2 | 详情 | 详情 |
| (III) | 10080 | (5-Oxo-2-pyrrolidinyl)methyl phenylmethanesulfonate | C12H15NO4S | 详情 | 详情 | |
| (IV) | 10081 | 2-(5-Oxo-2-pyrrolidinyl)acetonitrile | C6H8N2O | 详情 | 详情 | |
| (IV) | 44576 | 2-(5-oxo-2-pyrrolidinyl)acetonitrile | C6H8N2O | 详情 | 详情 | |
| (V) | 10082 | 5-[2-(Dimethylamino)ethyl]-2-pyrrolidinone | C8H16N2O | 详情 | 详情 | |
| (V) | 44577 | 5-[2-(dimethylamino)ethyl]-2-pyrrolidinone | C8H16N2O | 详情 | 详情 | |
| (VI) | 10083 | dimethyl[2-(5-oxo-2-pyrrolidinyl)ethyl]ammoniumolate | C8H16N2O2 | 详情 | 详情 | |
| (VI) | 44578 | dimethyl[2-(5-oxo-2-pyrrolidinyl)ethyl]ammoniumolate | C8H16N2O2 | 详情 | 详情 | |
| (VII) | 10084 | 5-Vinyl-2-pyrrolidinol | C6H11NO | 详情 | 详情 | |
| (VII) | 44579 | 5-vinyl-2-pyrrolidinol | C6H11NO | 详情 | 详情 |
合成路线2
An efficient new synthesis for [14C]-labeled vigabatrin has been described: The reaction of triphenylphosphine (I) with [14C]-labeled methyl iodide (II) in benzene gives the corresponding phosphonium salt (III), which is submitted to a Wittig condensation with 1-(1-butenyl)-5-oxopiperidin-2-carbaldehyde (IV) to afford the vinylpyrrolidone (V). Finally, this compound is hydrolyzed with 6N HCl at 95 C.
| 【1】 Gill, H.S.; An efficient synthesis of carbon-14 labelled vigabatrin. J Label Compd Radiopharm 1995, 36, 5, 425. |
合成路线3
This compound can be prepared in two different ways: 1) The reaction of 1,4-dichloro-2-butene (I) with diethyl malonate (II) by means of sodium ethoxide in refluxing ethanol gives 1,1-bis(ethoxycarbonyl)-2-vinylcyclopropane (III), which by reaction with ammonia gas in DMF at 120 C is converted into 3-carboxamido-5-vinyl-2-pyrrolidone (IV). Finally, this compound is treated with concentrated HCl in refluxing acetic acid. 2) The treatment of (IV) with sodium ethoxide in refluxing ethanol gives 3-carboxy-5-vinyl-2-pyrrolidone (V), which is decarboxylated by treatment with refluxing acetic acid to afford 5-vinyl-2-pyrrolidone (VI). The bromination of (VI) with Br2 in CCl4 yields 5-(1,2-dibromoethyl)-2-pyrrolidone (VII), which by treatment with Na in liquid NH3 in a pressure vessel at 25 C is converted into 4-aminohex-5-inoic acid (VIII). Finally, this compound is partially reduced with H2 over a suitable catalyst.
| 【1】 Gittos, M.W.; Leterre, G.J.; Process for making 4-aminohex-5-enoic acid. FR 2415630; GB 2013205; JP 54112860; US 4178463 . |
| 【2】 Metcalf, B.W.; Jung, M.; Olefinic derivatives of amino acids. US 4039549 . |
| 【3】 Metcalf, B.W.; Jung, M.; Olefinic derivatives of amino acids. CA 1077487; FR 2304329; GB 1472525; JP 76125320; US 3960927 . |
| 【4】 Blancafort, P.; Paton, D.M.; Serradell, M.N.; Castaner, J.; RMI-71,754. Drugs Fut 1981, 6, 6, 363. |
| 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) | 32186 | (E)-1,4-dichloro-2-butene | 110-57-6 | C4H6Cl2 | 详情 | 详情 |
| (II) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (III) | 32187 | Diethyl 2-vinyl-1,1-cyclopropanedicarboxylate | C11H16O4 | 详情 | 详情 | |
| (IV) | 32188 | 2-Oxo-5-vinyl-3-pyrrolidinecarboxamide; 3-Carboxamido-5-vinyl-2-pyrrolidone | 71107-19-2 | C7H10N2O2 | 详情 | 详情 |
| (V) | 32189 | 2-oxo-5-vinyl-3-pyrrolidinecarboxylic acid | C7H9NO3 | 详情 | 详情 | |
| (VI) | 32190 | 5-Vinyl-2-pyrrolidinone | C6H9NO | 详情 | 详情 | |
| (VII) | 32191 | 5-(1,2-dibromoethyl)-2-pyrrolidinone | C6H9Br2NO | 详情 | 详情 | |
| (VIII) | 32192 | 4-amino-5-hexynoic acid | C6H9NO2 | 详情 | 详情 |
合成路线4
The enantiocontrolled addition of phthalimide (I) to 1,3-butadiene monoepoxide (II) with a chiral palladium catalyst and Na2CO3 in dichloromethane gives N-(2-hydroxy-1(S)-vinylethyl)phthalimide (III), which is treated with triflic anhydride and TEA in dichloromethane to yield the triflate (IV). The condensation of (IV) with dimethyl malonate (V) by means of NaH in THF affords the alkylated malonate (VI), which is finally decarboxylated and deprotected by a treatment with aqueous refluxing HCl. Note that the synthesis of the biologically active (S)-enantiomer simply requires a change in the chirality of the Pd catalyst used in the first step of the synthesis.
| 【1】 Trost, B.M.; et al.; Dynamic kinetic asymetric transformation of diene monoepoxides: A practical asymmetric synthesis of vinylglycinol, vigabatrin, and ethambutol. J Am Chem Soc 2000, 122, 25, 5968. |
| 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) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
| (II) | 32805 | 2-vinyloxirane | 930-22-3 | C4H6O | 详情 | 详情 |
| (III) | 38039 | 2-[(1S)-1-(hydroxymethyl)-2-propenyl]-1H-isoindole-1,3(2H)-dione | C12H11NO3 | 详情 | 详情 | |
| (IV) | 38040 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-butenyl trifluoromethanesulfonate | C13H10F3NO5S | 详情 | 详情 | |
| (V) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (VI) | 38041 | dimethyl 2-[(2R)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-butenyl]malonate | C17H17NO6 | 详情 | 详情 |
合成路线5
The reaction of 3-aminotetrahydrofuran-2-one (I) with benzyloxycarbonyl chloride (II) and TEA in chloroform gives the carbamate (III), which is reduced to the lactol (IV) by means of DIBAL in toluene. It has been observed that lactol (IV) is in equilibrium with its tautomeric open chain aldehydic form.(V). The reaction of (IV)??(V) with phosphonium bromide (VI) by means of Bu-Li in THF yields 3-amino-4-penten-1-ol (VII), which is reprotected with benzyloxycarbonyl chloride (II) and TEA to afford the carbamate (VIII). The reaction of (VIII) with CBr4 and PPh3 in dichloromethane provides the pentenyl bromide (IX), which is treated with LiCN in THF to give 4-(benzyloxycarbonylamino)-5-hexenenitrile (X). Finally this compound is hydrolyzed with conc. HCl to yield the target 4-amino-5-hexenoic acid.
| 【1】 Zhang, Z.; Ding, Y.S.; Studenov, A.R.; Gerasimov, M.R.; Ferrieri, R.A.; Novel synthesis of [1-11C]gamma-vinyl-gamma-aminobutyric acid ([1-11C]GVG) for pharmacokinetic studies of addiction treatment. J Label Compd Radiopharm 2002, 45, 3, 199. |
| 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) | 59984 | 3-aminodihydro-2(3H)-furanone | C4H7NO2 | 详情 | 详情 | |
| (II) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (III) | 59985 | benzyl 2-oxotetrahydro-3-furanylcarbamate | C12H13NO4 | 详情 | 详情 | |
| (IV) | 59986 | benzyl 2-hydroxytetrahydro-3-furanylcarbamate | C12H15NO4 | 详情 | 详情 | |
| (V) | 59987 | benzyl 1-formyl-3-hydroxypropylcarbamate | C12H15NO4 | 详情 | 详情 | |
| (VI) | 59988 | methyl(triphenyl)phosphonium | C19H18P | 详情 | 详情 | |
| (VII) | 59989 | 3-amino-4-penten-1-ol | C5H11NO | 详情 | 详情 | |
| (VIII) | 59990 | benzyl 1-(2-hydroxyethyl)-2-propenylcarbamate | C13H17NO3 | 详情 | 详情 | |
| (IX) | 59991 | benzyl 1-(2-bromoethyl)-2-propenylcarbamate | C13H16BrNO2 | 详情 | 详情 | |
| (X) | 59992 | benzyl 1-(2-cyanoethyl)-2-propenylcarbamate | C14H16N2O2 | 详情 | 详情 |
合成路线6
The reaction of 3-aminotetrahydrofuran-2-one (I) with benzyloxycarbonyl chloride (II) and TEA in chloroform gives the carbamate (III), which is reduced to the lactol (IV) by means of DIBAL in toluene. It has been observed that lactol (IV) is in equilibrium with its tautomeric open chain aldehydic form (V). The reaction of (IV)??(V) with phosphonium bromide (VI) by means of Bu-Li in THF yields 3-amino-4-penten-1-ol (VII), which is reprotected with benzyloxycarbonyl chloride (II) and TEA to afford the carbamate (VIII). The reaction of (VIII) with CBr4 and PPh3 in dichloromethane provides the pentenyl bromide (IX), which is treated with 11C labeled LiCN in THF to give 4-(benzyloxycarbonylamino)-5-hexenenitrile (X). Finally this compound is hydrolyzed with conc. HCl to yield the target 11C labeled 4-amino-5-hexenoic acid.
| 【1】 Zhang, Z.; Ding, Y.S.; Studenov, A.R.; Gerasimov, M.R.; Ferrieri, R.A.; Novel synthesis of [1-11C]gamma-vinyl-gamma-aminobutyric acid ([1-11C]GVG) for pharmacokinetic studies of addiction treatment. J Label Compd Radiopharm 2002, 45, 3, 199. |
| 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) | 59984 | 3-aminodihydro-2(3H)-furanone | C4H7NO2 | 详情 | 详情 | |
| (II) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (III) | 59985 | benzyl 2-oxotetrahydro-3-furanylcarbamate | C12H13NO4 | 详情 | 详情 | |
| (IV) | 59986 | benzyl 2-hydroxytetrahydro-3-furanylcarbamate | C12H15NO4 | 详情 | 详情 | |
| (V) | 59987 | benzyl 1-formyl-3-hydroxypropylcarbamate | C12H15NO4 | 详情 | 详情 | |
| (VI) | 59988 | methyl(triphenyl)phosphonium | C19H18P | 详情 | 详情 | |
| (VII) | 59989 | 3-amino-4-penten-1-ol | C5H11NO | 详情 | 详情 | |
| (VIII) | 59990 | benzyl 1-(2-hydroxyethyl)-2-propenylcarbamate | C13H17NO3 | 详情 | 详情 | |
| (IX) | 59991 | benzyl 1-(2-bromoethyl)-2-propenylcarbamate | C13H16BrNO2 | 详情 | 详情 | |
| (X) | 59992 | benzyl 1-(2-cyanoethyl)-2-propenylcarbamate | C14H16N2O2 | 详情 | 详情 | |
| (X) | 59993 | benzyl 1-(2-cyanoethyl)-2-propenylcarbamate | C14H16N2O2 | 详情 | 详情 |
合成路线7
加拿大Alberta大学Knaus研究小组将谷氨酸选择性保护为单酯（II），并将氨基保护后，游离羧酸被还原为一级醇（IV）.Swern氧化将IV转化为醛（V），后者立即进行Witting反应，产生烯烃（VI）.最后，用TMSI脱除氨基保护基，并用3mol/L盐酸水解酯，即得到（S）-Vi-gabatrin （VII）.
| 【1】 Wei ZY, Knaus EE. 1993.A short efficient synthesis of (S)-4-amino-5-hexenoic acid[(8-Vigabatrin)].J Org Chem, 58: 1586-1588. |
| 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) | 12005 | L-2-Amino propane dicarboxylic acid; (-)-2-Aminoglutaric acid; L-2-Aminopentanoic acid; L-Glutamic acid | 56-86-0 | C5H9NO4 | 详情 | 详情 |
| (II) | 69497 | C7H15NO8S | 详情 | 详情 | ||
| (III) | 69498 | (R)-5-ethoxy-2-((methoxycarbonyl)amino)-5-oxopentanoic acid | C9H15NO6 | 详情 | 详情 | |
| (IV) | 69499 | (R)-ethyl 5-hydroxy-4-((methoxycarbonyl)amino)pentanoate | C9H17NO5 | 详情 | 详情 | |
| (V) | 69500 | (R)-ethyl 4-((methoxycarbonyl)amino)-5-oxopentanoate | C9H15NO5 | 详情 | 详情 | |
| (VI) | 69501 | (R)-ethyl 4-((methoxycarbonyl)amino)hex-5-enoate | C10H17NO4 | 详情 | 详情 |
合成路线8
台湾的一个研究小组以吡咯-4-酮(I)为原料来合成Vigabatrin.首先，mCPBA对酮(I)进行Baeyer-Villiger氧化，生成内痔（II）。（II）被氢化锂铝还原成醇（III），其中（III）位氨基的立体构型与Vigabatrin一致。接着，PCC将醇（III)氧化成醛（IV）后，进行Witting反应，并经Jones氧化，得到羧酸（V）。最后，去除氨基保护基，生成Vigabatrin。
| 【1】 Chang MY, Lin CY, Ong CW.2006.Synthesis of Vigabatrin.Heterocycles, 68:2031-2036. |
| 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) | 69502 | (R)-1-tosyl-5-vinylpyrrolidin-3-one | C13H15NO3S | 详情 | 详情 | |
| (II) | 69503 | (R)-3-tosyl-4-vinyl-1,3-oxazinan-6-one | C13H15NO4S | 详情 | 详情 | |
| (III) | 69504 | (R)-N-(5-hydroxypent-1-en-3-yl)-4-methylbenzenesulfonamide | C12H17NO3S | 详情 | 详情 | |
| (IV) | 69505 | (R)-4-methyl-N-(5-oxopent-1-en-3-yl)benzenesulfonamide | C12H15NO3S | 详情 | 详情 | |
| (V) | 69506 | (R)-4-(4-methylphenylsulfonamido)hex-5-enoic acid | C13H17NO4S | 详情 | 详情 |
合成路线9
印度国家化学实验室在钴催化下对消旋化环氧化物（I）进行水解动力学拆分，得到98%的手性环氧化物（II）。区域选择性对（II）开环，生成稀醇（III）。（III）中的羟基被叠氮基取代后，再被还原为氨基，并被保护为乙酰胺（V）。脱去（V）中的PMB保护基后，所生成的醇被氧化为相应的羧酸（VII）。水合肼去除乙酰基后，即产生（S）-Vigabatrin(VIII).
| 【1】 Raj IVP, Sudalai A.2008.Asymmetric synthesis of (S)-vigabatrin and (S)-dihydrokavain via cobalt catalyzed hydrolytic kinetic resolution of epoxides. Tetrahedron Lett, 49:2646-2648. |
| 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) | 69507 | 2-(3-((4-methoxybenzyl)oxy)propyl)oxirane | C13H18O3 | 详情 | 详情 | |
| (II) | 69508 | (R)-2-(3-((4-methoxybenzyl)oxy)propyl)oxirane | C13H18O3 | 详情 | 详情 | |
| (III) | 69509 | (R)-6-((4-methoxybenzyl)oxy)hex-1-en-3-ol | C14H20O3 | 详情 | 详情 | |
| (IV) | 69510 | (R)-1-(((4-azidohex-5-en-1-yl)oxy)methyl)-4-methoxybenzene | C14H19N3O2 | 详情 | 详情 | |
| (V) | 69511 | (R)-N-(6-((4-methoxybenzyl)oxy)hex-1-en-3-yl)acetamide | C16H23NO3 | 详情 | 详情 | |
| (VI) | 69512 | (R)-N-(6-hydroxyhex-1-en-3-yl)acetamide | C8H15NO2 | 详情 | 详情 | |
| (VII) | 69513 | (R)-4-acetamidohex-5-enoic acid | C8H13NO3 | 详情 | 详情 |