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【结 构 式】 
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【药物名称】Levamisole hydrochloride, KW-2299, R-12, 564, Ergamisol 【化学名称】6(S)-Phenyl-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole hydrochloride 【CA登记号】16595-80-5, 14769-73-4 (free base) 【 分 子 式 】C11H13ClN2S 【 分 子 量 】240.75666 |
【开发单位】Janssen (Originator), Kyowa Hakko (Licensee) 【药理作用】Oncolytic Drugs |
合成路线1
The cyclization of (S)-(+)-phenylethylenediamine (I) with CS2 in alkaline water gives (S)-(+)-4-phenyl-2-mercaptoimidazolidine (II), which is then cyclized again with 1,2-dibromoethane (A) in alkaline isopropanol-water.
| 【1】 Castañer, J.; Hopkins, S.J.; Blancafort, P.; Serradell, M.N.; Levamisole hydrochloride. Drugs Fut 1979, 4, 6, 420. |
| 【2】 Raeymaekers, A.H.M.; et al.; Absolute configurations of the optical isomers of the broad spectrum anthelmintic tetramisole. Tetrahedron Lett 1967, 16, 1467-70. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (I) | 39497 | (1S)-1-phenyl-1,2-ethanediamine; (1S)-2-amino-1-phenylethylamine | C8H12N2 | 详情 | 详情 | |
| (II) | 39498 | (4S)-4-phenyl-4,5-dihydro-1H-imidazole-2-thiol; (4S)-4-phenyl-4,5-dihydro-1H-imidazol-2-ylhydrosulfide | C9H10N2S | 详情 | 详情 |
合成路线2
The reaction of beta-chloroethylamine (III) with ammonium thiocyanate (B) gives beta-aminoethylthiocyanate (IV), which is alkylated with alpha,beta-dichloroethylbenzene (V) in hot benzene yielding the secondary amine (VI). The cyclization of (VI) in hot aqueous NaOH affords racemic levamisole, which is finally resolved in its optical isomers through the d-10-camphorsulfonate or N-benzene (or p-toluene)sulfonyl-L-(+)-glutamic salt.
| 【1】 Bullock, M.W.; DE 1645975 . |
| 【2】 Dick, P.R.; Rombi, M.; FR 2183313 . |
| 【3】 Castañer, J.; Hopkins, S.J.; Blancafort, P.; Serradell, M.N.; Levamisole hydrochloride. Drugs Fut 1979, 4, 6, 420. |
| 【4】 US 3579530 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 39499 | ammonium thiocyanate | 1762-95-4 | CH4N2S | 详情 | 详情 |
| (rac)-(XII) | 39503 | 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole | C11H12N2S | 详情 | 详情 | |
| (III) | 33455 | 2-chloro-1-ethanamine; 2-chloroethylamine | C2H6ClN | 详情 | 详情 | |
| (IV) | 39500 | 2-amino-1-ethanesulfenyl cyanide | C3H6N2S | 详情 | 详情 | |
| (V) | 39501 | 1-(1,2-dichloroethyl)benzene | 1074-11-9 | C8H8Cl2 | 详情 | 详情 |
| (VI) | 39502 | 2-[(2-chloro-2-phenylethyl)amino]-1-ethanesulfenyl cyanide | C11H13ClN2S | 详情 | 详情 |
合成路线3
The reaction of phenacyl bromide (VII) with 2-aminothiazoline (VIII) in MeCN at 100 C gives 2-imino-3-phenacylthiazolidine (IX), which is reduced to the corresponding alcohol (X) with NaBH4 in methanol. Finally, this compound is cyclized with SOCl2 and refluxing acetic anhydride giving the racemic levamisole which is resolved resolved in its optical isomers through the d-10-camphorsulfonate, N-benzene (or p-toluene)sulfonyl-L-(+)-glutamic salt. Compound (X) can be acetylated under milder conditions than before giving the N-acetyl compound (XI), which is cyclized SOCl2 and refluxing acetic anhydride.
| 【1】 Janssen Pharm. N.V.; US 3274209 . |
| 【2】 US 3579530 . |
| 【3】 Castañer, J.; Hopkins, S.J.; Blancafort, P.; Serradell, M.N.; Levamisole hydrochloride. Drugs Fut 1979, 4, 6, 420. |
| 【4】 Bullock, M.W.; DE 1645975 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac)-(XII) | 39503 | 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole | C11H12N2S | 详情 | 详情 | |
| (VII) | 10315 | 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone | 70-11-1 | C8H7BrO | 详情 | 详情 |
| (VIII) | 39504 | 4,5-dihydro-1,3-thiazol-2-ylamine; 4,5-dihydro-1,3-thiazol-2-amine | 1779-81-3 | C3H6N2S | 详情 | 详情 |
| (IX) | 39505 | 2-(2-imino-1,3-thiazolidin-3-yl)-1-phenyl-1-ethanone | C11H12N2OS | 详情 | 详情 | |
| (X) | 39506 | 2-(2-imino-1,3-thiazolidin-3-yl)-1-phenyl-1-ethanol | C11H14N2OS | 详情 | 详情 | |
| (XI) | 39507 | N-[3-(2-hydroxy-2-phenylethyl)-1,3-thiazolidin-2-yl]acetamide | C13H18N2O2S | 详情 | 详情 |
合成路线4
The inactive d-(+)-levamisole can be isomerized by reaction with a strong nonaqueous base such as potassium tert-butylate, sodium amide or sodium hydride with or without solvent (DMF, DMSO). The racemic mixture obtained is resolved in its optical isomers through the d-10-camphorsulfonate, N-benzene (or p-toluene)sulfonyl-L-(+)-glutamic salt.
| 【1】 US 3579530 . |
| 【2】 Bullock, M.W.; DE 1645975 . |
| 【3】 Castañer, J.; Hopkins, S.J.; Blancafort, P.; Serradell, M.N.; Levamisole hydrochloride. Drugs Fut 1979, 4, 6, 420. |
| 【4】 Bullock, M.W.; Hand, J.J.; US 3673206 . |