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【结 构 式】 
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【药物名称】Mizolastine, MKC-431, SL-85.0324, Zolistam, Zolistan, Mizolen, Zolim, Mizollen 【化学名称】2-[N-[1-[1-(4-Fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methylamino]pyrimidin-4(3H)-one 【CA登记号】108612-45-9 【 分 子 式 】C24H25FN6O 【 分 子 量 】432.50485 |
【开发单位】Sanofi-synthélabo (Originator), Angelini (Licensee), Ferrer (Licensee), Mitsubishi Chemical (Licensee) 【药理作用】Allergic Skin Disorders, Treatment for, DERMATOLOGIC DRUGS, Drugs for Allergic Rhinitis, RESPIRATORY DRUGS, Treatment of Upper Respiratory Tract Disorders, Urticaria, Treatment for, Histamine H1 Antagonists |
合成路线1
Mizolastine can be obtained by two related ways: 1) The condensation of 2-chloro-1-(4-fluorobenzyl)benzimidazole (I) with N-(4-piperidyl)carbamic acid ethyl ester (II) by means of NaOCH3 at 14 C gives N-[1-[1-(4-fluorobenzyl)benzimidazol-2-yl]piperidin-4-yl]carbamic acid ethyl ester (III), which is methylated with methyl iodide and NaH in DMF to yield the corresponding N-methyl derivative (IV). The decarboxylative hydrolysis of (IV) with 48% HBr in acetic acid affords N-[1-[1-(4-fluorobenzyl)benzimidazol-2-yl]piperidin-4-yl]-N-methylamine (V), which is finally condensed with 2-(methylsulfanyl)pyrimidin-4(3H)-one (VI) by heating at 170 C. 2) Compound (V) can also be obtained by direct condensation of 2-chloro-1-(4-fluorobenzyl)benzimidazole (I) with 4-(methylamino)piperidine (VII) by means of K2CO3 in refluxing isoamyl alcohol.
| 【1】 Mealy, N.; Ngo, J.; Castaner, J.; Mizolastine. Drugs Fut 1996, 21, 8, 799. |
| 【2】 Manoury, P.; Binet, J.; Defosse, G. (Sanofi-Synthelabo ); EP 217700, FR 2587029, JP 87061979, US 4820710. EP 0217700; FR 2587029; JP 1987061979; US 4820710 . |
| 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) | 12043 | 1-(4-Fluorobenzyl-2-chlorobenzimidazol; 2-Chloro-1-(4-fluorobenzyl)-1H-benzimidazole; 1-(4-Fluorobenzyl)-2-chlorobenzimidazole | 84946-20-3 | C14H10ClFN2 | 详情 | 详情 |
| (II) | 12044 | ethyl N-(4-piperidinyl)carbamate | C8H16N2O2 | 详情 | 详情 | |
| (III) | 12045 | ethyl N-[1-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]carbamate | C22H25FN4O2 | 详情 | 详情 | |
| (IV) | 12046 | ethyl N-[1-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methylcarbamate | C23H27FN4O2 | 详情 | 详情 | |
| (V) | 12047 | 1-[1-(4-Fluorobenzyl)-1H-benzimidazol-2-yl]-N-methyl-4-piperidinamine; N-[1-[1-(4-Fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methylamine | C20H23FN4 | 详情 | 详情 | |
| (VI) | 12048 | 2-(Methylsulfanyl)-4(3H)-pyrimidinone | C5H6N2OS | 详情 | 详情 | |
| (VII) | 12049 | N-Methyl-N-(4-piperidinyl)amine; N-Methyl-4-piperidinamine | C6H14N2 | 详情 | 详情 |