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【结 构 式】 
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【药物名称】Lamotrigine, BW-430C, Labileno, Lamictal 【化学名称】6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine 【CA登记号】84057-84-1 【 分 子 式 】C9H7Cl2N5 【 分 子 量 】256.09564 |
【开发单位】GlaxoSmithKline (Originator), FAES (Licensee) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Antiepileptic Drugs, Bipolar Disorder, Treatment of, Mood Disorders, Treatment of, NEUROLOGIC DRUGS, Neuropathic Pain, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Glutamate Release Inhibitors, Sodium Channel Blockers |
合成路线1
The Grignard condensation of 2,3-dichloroiodobenzene (I) with CO2 by means of Mg / ether gives 2,3-dichlorobenzoic acid (II), which is converted to the corresponding acyl chloride (III) by refluxing with SOCl2.The reaction of (III) with cuprous cyanide and KI in refluxing xylene yields 2,3-dichlorobenzoyl cyanide (IV). Finally, this compound is cyclized with aminoguanidine (V) in DMSO.
| 【1】 Baxter, M.G.; Elphick, A.R.; Miller, A.A.; Sawyer, D.A. (Glaxo Wellcome plc); 1,2,4-Triazine derivs., process for preparing such cpds., pharmaceutical compsns. and intermediates utilized for this process. CA 1133938; EP 0021121 . |
| 【2】 Castaner, J.; Prous, J.; Lamotrigine. Drugs Fut 1986, 11, 6, 456. |
| 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) | 24006 | 1,2-dichloro-3-iodobenzene | 2401-21-0 | C6H3Cl2I | 详情 | 详情 |
| (II) | 24007 | 2,3-dichlorobenzoic acid | 50-45-3 | C7H4Cl2O2 | 详情 | 详情 |
| (III) | 24008 | 2,3-dichlorobenzoyl chloride | 2905-60-4 | C7H3Cl3O | 详情 | 详情 |
| (IV) | 24009 | 2-(2,3-dichlorophenyl)-2-oxoacetonitrile; 2,3-Dichlorobenzoylcyanide | 77668-42-9 | C8H3Cl2NO | 详情 | 详情 |
| (V) | 10015 | 1-Hydrazinecarboximidamide; Hydrazinecarboximidamide | 79-17-4 | CH6N4 | 详情 | 详情 |
合成路线2
Condensation of 2,3-dichlorobenzoyl cyanide (I) with aminoguanidine (II) by means of PPA in hot acetonitrile yields 2,3-dichlorobenzoyl cyanide amidinohydrazone (III), which is cyclized to the target 1,2,4-triazine by heating in refluxing propanol with or without DMSO.
| 【1】 Nadaka, V.; Lexner, J.; Kaspi, J. (Chemagis Ltd.); Process for preparing substd. benzoyl cyanide amidinohydrazones. EP 1127873 . |
| 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) | 24009 | 2-(2,3-dichlorophenyl)-2-oxoacetonitrile; 2,3-Dichlorobenzoylcyanide | 77668-42-9 | C8H3Cl2NO | 详情 | 详情 |
| (II) | 10015 | 1-Hydrazinecarboximidamide; Hydrazinecarboximidamide | 79-17-4 | CH6N4 | 详情 | 详情 |
| (III) | 52654 | 2-[cyano(phenyl)methylidene]-1-hydrazinecarboximidamide | C9H9N5 | 详情 | 详情 |
合成路线3
Hydrogenation of 2,3-dichloronitrobenzene (I) with H2 over Ra-Ni in methanol gives 2,3-dichloroaniline (II), which is diazotized with NaNO2 and HCl and treated with CuCN to yield 2,3-dichlorobenzonitrile (III). Hydrolysis of the nitrile (III) with NaOH in refluxing methanol/water affords 2,3-dichlorobenzoic acid (IV), which is treated with hot SOCl2 to provide the corresponding acyl chloride (V). Reaction of (V) with CuCN and KI in refluxing chlorobenzene gives 2,3-dichlorobenzoyl cyanide (VI), which is condensed with aminoguanidine (VII) by means of H2SO4/TsOH in hot toluene to yield 2,3-dichlorobenzoyl cyanide amidinohydrazone (VIII). Finally, this compound is cyclized by treatment with NaOMe in refluxing methanol.
| 【1】 Srivastava, A.R.; Sasikumar, T.M.; Radhakrishnan, T.V. (RPG Life Sciences Ltd); A process for the preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, commonly known as lamotrigine. WO 0149669 . |
| 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) | 52655 | 2,3-Dichloronitrobenzene; 1,2-Dichloro-3-Nitrobenzene; Nitro-o-dichlorobenzene | 3209-22-1 | C6H3Cl2NO2 | 详情 | 详情 |
| (II) | 28562 | 2,3-dichlorophenylamine | 608-27-5 | C6H5Cl2N | 详情 | 详情 |
| (III) | 30204 | 2,3-dichlorobenzonitrile | 6574-97-6 | C7H3Cl2N | 详情 | 详情 |
| (IV) | 24007 | 2,3-dichlorobenzoic acid | 50-45-3 | C7H4Cl2O2 | 详情 | 详情 |
| (V) | 24008 | 2,3-dichlorobenzoyl chloride | 2905-60-4 | C7H3Cl3O | 详情 | 详情 |
| (VI) | 24009 | 2-(2,3-dichlorophenyl)-2-oxoacetonitrile; 2,3-Dichlorobenzoylcyanide | 77668-42-9 | C8H3Cl2NO | 详情 | 详情 |
| (VII) | 10015 | 1-Hydrazinecarboximidamide; Hydrazinecarboximidamide | 79-17-4 | CH6N4 | 详情 | 详情 |
| (VIII) | 52654 | 2-[cyano(phenyl)methylidene]-1-hydrazinecarboximidamide | C9H9N5 | 详情 | 详情 |
合成路线4
The reaction of 2,3-dichlorobenzoic acid (I) with oxalyl chloride in dichloromethane gives the acyl chloride (II), which is condensed with labeled copper cyanide (III) by means of KI in refluxing xylene to yield the 2,3-dichlorobenzoyl cyanide (IV). The condensation of (IV) with labeled aminoguanidine (V) by means of sulfuric acid in acetonitrile/water affords adduct (VI), which is finally cyclized by refluxing under the conditions of the preceding reaction to provide the target labeled diaminotriazine. The intermediate labeled copper cyanide (III) has been obtained by reaction of CuSO4 with labeled potassium cyanide (VII) and Na2S2O5 in hot water. The intermediate labeled aminoguanidine (V) has been obtained by methylation of thiourea (VIII) with dimethyl sulfate in boiling water to give S-methylisothiourea (IX), which is finally treated with hydrazine (X) and NaOH in water.
| 【1】 Manning, C.O.; et al.; Synthesis of stable isotopically labelled versions of lamotrigine and its methylated metabolite. J Label Compd Radiopharm 2002, 45, 7, 611. |
| 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) | 24007 | 2,3-dichlorobenzoic acid | 50-45-3 | C7H4Cl2O2 | 详情 | 详情 |
| (II) | 24008 | 2,3-dichlorobenzoyl chloride | 2905-60-4 | C7H3Cl3O | 详情 | 详情 |
| (III) | 56856 | Copper (I) cyanide; Cuprous cyanide | 544-92-3 | CCuN | 详情 | 详情 |
| (III) | 56861 | cyanocopper | CCuN | 详情 | 详情 | |
| (IV) | 24009 | 2-(2,3-dichlorophenyl)-2-oxoacetonitrile; 2,3-Dichlorobenzoylcyanide | 77668-42-9 | C8H3Cl2NO | 详情 | 详情 |
| (IV) | 56862 | 2-(2,3-dichlorophenyl)-2-oxoacetonitrile | C8H3Cl2NO | 详情 | 详情 | |
| (V) | 56857 | CH6N4 | 详情 | 详情 | ||
| (V) | 56866 | CH6N4 | 详情 | 详情 | ||
| (VI) | 56858 | 1,2-dichloro-3-{cyano[(Z)-2-(diaminomethylene)hydrazono]methyl}benzene | C9H7Cl2N5 | 详情 | 详情 | |
| (VI) | 56867 | 1,2-dichloro-3-{cyano[(Z)-2-(diaminomethylene)hydrazono]methyl}benzene | C9H7Cl2N5 | 详情 | 详情 | |
| (VII) | 56859 | Potassium cyanide | 151-50-8 | CKN | 详情 | 详情 |
| (VII) | 56860 | cyanopotassium | CKN | 详情 | 详情 | |
| (VIII) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VIII) | 56863 | thiourea | CH4N2S | 详情 | 详情 | |
| (IX) | 10272 | [[Amino(imino)methyl]sulfanyl]methane | 2986-19-8 | C2H6N2S | 详情 | 详情 |
| (IX) | 56864 | {[amino(imino)methyl]sulfanyl}methane | C2H6N2S | 详情 | 详情 | |
| (X) | 27344 | hydrazine | 302-01-2 | H4N2 | 详情 | 详情 |
| (X) | 56865 | hydrazine | H4N2 | 详情 | 详情 |