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【结 构 式】 
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【药物名称】NO-aspirin, m-NO-ASA, NO-ASA, NCX-4016 【化学名称】2-Acetoxybenzoic acid 3-(nitrooxymethyl)phenyl ester 【CA登记号】175033-36-0, 190442-10-5 (deleted CAS) 【 分 子 式 】C16H13NO7 【 分 子 量 】331.28451 |
【开发单位】NicOx (Originator) 【药理作用】Antiplatelet Therapy, CARDIOVASCULAR DRUGS, Cerebrovascular Diseases, Treatment of, Chemopreventive Agents, Coagulation Disorders Therapy, ENDOCRINE DRUGS, HEMATOLOGIC DRUGS, NEUROLOGIC DRUGS, ONCOLYTIC DRUGS, Peripheral Vascular Disease, Treatment of, Restenosis Treatment of, Stroke, Treatment of, Treatment of Diabetic Complications, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Cyclooxygenase Inhibitors, Nitric Oxide Donors, Non-Steroidal Antiinflammatory Drugs |
合成路线1
A mixture of 3-hydroxybenzyl alcohol (I) with 48% hydrobromic acid in dichloromethane is stirred at room temperature to give the corresponding benzyl bromide (II), which is immediately dissolved in acetonitrile. Silver nitrate is added proportionally to the crude solution (II) at room temperature to obtain derivative (III). A mixture of (III), potassium carbonate and ethyl acetate is cooled under nitrogen at 0 C and slowly treated with a solution of O-acetylsalicyloyl chloride (IV) in ethyl acetate to yield crude NCX-4016. The pure product is obtained by crystallization from isopropyl ether. The three-step prepaation is described in the Scheme 25203601a.
| 【1】 Cirino, G.; et al.; NCX-4016. Drugs Fut 1997, 22, 11, 1231. |
| 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) | 17296 | 3-Hydroxybenzyl alcohol; 3-(hydroxymethyl)phenol | 620-24-6 | C7H8O2 | 详情 | 详情 |
| (II) | 17297 | 3-(bromomethyl)phenol | C7H7BrO | 详情 | 详情 | |
| (III) | 17298 | 3-[(nitrooxy)methyl]phenol | C7H7NO4 | 详情 | 详情 | |
| (IV) | 16900 | 2-(chlorocarbonyl)phenyl acetate; Acetylsalicyloyl chloride | 5538-51-2 | C9H7ClO3 | 详情 | 详情 |
合成路线2
Basic treatment of 3-hydroxybenzyl alcohol (I) with either NaOH in dichloromethane, Et3N in toluene or K2CO3 in acetone, followed by reaction with acetylsalicyloyl chloride (II) in the respective solvents, gives 2-acetoxybenzoic acid 3-(hydroxymethyl)phenyl ester (III). NCX-4016 is obtained by nitration of compound (III) with steaming nitric acid in dichloromethane in the presence of either sulfuric acid, acetic anhydride or methanesulfonic acid.
| 【1】 Benedini, F.; Razzetti, G.; Castaldi, G.; Oldani, E. (NicOx SA); A process for obtaining (nitroxymethyl)phenyl esters of salicylic acid derivs.. WO 0104082 . |
合成路线3
Alternatively, coupling of 3-hydroxybenzaldehyde (I) with acetylsalicyloyl chloride (II) by means of Et3N in dichloromethane affords 2-acetoxybenzoic acid 3-formyl-phenyl ester (IV), which is then reduced by hydrogenation over Pd/C in ethyl acetate to provide alcohol (III). Chlorination of alcohol (III) by treatment with thionyl chloride in DMF gives the chloromethyl derivative (V), which is finally converted to NCX-4016 by treatment with AgNO3 in refluxing acetonitrile.
| 【1】 Garufi, M.; Del Soldato, P. (NicOx SA); Synthesis method of nitroxymethylphenyl esters of aspirin derivs.. WO 0044705 . |
| 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) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (II) | 16900 | 2-(chlorocarbonyl)phenyl acetate; Acetylsalicyloyl chloride | 5538-51-2 | C9H7ClO3 | 详情 | 详情 |
| (III) | 51713 | 3-(hydroxymethyl)phenyl 2-(acetoxy)benzoate | C16H14O5 | 详情 | 详情 | |
| (IV) | 51714 | 3-formylphenyl 2-(acetoxy)benzoate | C16H12O5 | 详情 | 详情 | |
| (V) | 51715 | 3-(chloromethyl)phenyl 2-(acetoxy)benzoate | C16H13ClO4 | 详情 | 详情 |