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【结 构 式】 
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【药物名称】 【化学名称】3-Cyano-4-hydroxy-N'-[4-(4-isopropylbenzyloxy)-3,5-dimethoxybenzylidene]benzohydrazide 【CA登记号】219681-70-6 【 分 子 式 】C27H27N3O5 【 分 子 量 】473.53334 |
【开发单位】Anadys (Originator), Novo Nordisk (Originator), Pfizer (Originator) 【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Glucagon Antagonists |
合成路线1
Methyl 4-hydroxybenzoate (I) is iodinated by means of iodine monochloride in hot AcOH, producing (II). Displacement of the aryl iodide (II) with CuCN gives nitrile (III). Then, ester group saponification in (III) leads to 3-cyano-4-hydroxybenzoic acid (IV). Coupling of (IV) with tert-butyl carbazate produces the N-Boc hydrazide (V), which is further deprotected to (VI) by treatment with trifluoroacetic acid
| 【1】 Ling, A.; Plewe, M.; Gonzalez, J.; et al.; Human glucagon receptor antagonists based on alkylidene hydrazides. Bioorg Med Chem Lett 2002, 12, 4, 663. |
| 【2】 Gonzales, J.; Sams, C.; Teng, M. (Alanex Corp.; Novo Nordisk A/S); Glucagon antagonists/inverse agonists. EP 0994848; WO 9901423 . |
| 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) | 10251 | methyl 4-hydroxybenzoate; Methyl p-hydroxybenzoate | 99-76-3 | C8H8O3 | 详情 | 详情 |
| (II) | 60844 | methyl 4-hydroxy-3-iodobenzoate | C8H7IO3 | 详情 | 详情 | |
| (III) | 60845 | methyl 3-cyano-4-hydroxybenzoate | C9H7NO3 | 详情 | 详情 | |
| (IV) | 60846 | 3-cyano-4-hydroxybenzoic acid | C8H5NO3 | 详情 | 详情 | |
| (V) | 60847 | tert-butyl 2-(3-cyano-4-hydroxybenzoyl)-1-hydrazinecarboxylate | C13H15N3O4 | 详情 | 详情 | |
| (VI) | 60848 | 3-cyano-4-hydroxybenzohydrazide | C8H7N3O2 | 详情 | 详情 |
合成路线2
Alkylation of 4-hydroxy-3,5-dimethoxybenzaldehyde (VII) with 4-isopropylbenzyl chloride (VIII) affords the benzyloxy benzaldehyde (IX). Then, condensation of aldehyde (IX) with hydrazide (VI) furnishes the target N-acyl hydrazone
| 【1】 Ling, A.; Plewe, M.; Gonzalez, J.; et al.; Human glucagon receptor antagonists based on alkylidene hydrazides. Bioorg Med Chem Lett 2002, 12, 4, 663. |
| 【2】 Gonzales, J.; Sams, C.; Teng, M. (Alanex Corp.; Novo Nordisk A/S); Glucagon antagonists/inverse agonists. EP 0994848; WO 9901423 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 60848 | 3-cyano-4-hydroxybenzohydrazide | C8H7N3O2 | 详情 | 详情 | |
| (VII) | 49243 | 3,5-Dimethoxy-4-hydroxybenzaldehyde; 4-Hydroxy-3,5-dimethoxybenzaldehyde; Syringaldehyde | 134-96-3 | C9H10O4 | 详情 | 详情 |
| (VIII) | 33769 | 1-(chloromethyl)-4-isopropylbenzene | 2051-18-5 | C10H13Cl | 详情 | 详情 |
| (IX) | 60849 | 4-[(4-isopropylbenzyl)oxy]-3,5-dimethoxybenzaldehyde | C19H22O4 | 详情 | 详情 |