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【结 构 式】 
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【药物名称】Naproxen nitroxybutyl ester;Nitronaproxen;AZD-3582;ZD-3582;NO-naproxen;HCT-3012;Naproxcinod;AR-P900758XX (former code name);AZ-3582 (former code name) 【化学名称】2(S)-(6-Methoxynaphthalen-2-yl)propionic acid 4-(nitrooxy)butyl ester 【CA登记号】170591-17-0 (undefined isomer);163133-43-5 【 分 子 式 】C18H21NO6 【 分 子 量 】347.37117 |
【开发单位】NicOx (Originator) 【药理作用】Nonsteroidal Anti-Inflammatory Agent;Cyclooxygenase-Inhibiting NO Donor |
合成路线1
Chlorination of (S)-naproxen (I) with SOCl2 by means of Et3N in cyclohexane at 60 °C affords the acyl chloride (II) , which is condensed with 4-hydroxybutyl nitrate (III) in CH2Cl2 at 40 °C directly or after pretreatment of nitrate (III) with K2CO3 in CH2Cl2 or toluene, or CaCO3 or CaAl2Si2O8 in CH2Cl2 .
By treatment of (S)-naproxen (I) with KHCO3 in DMF followed by condensation with either 4-nitrooxybutyl tosylate (IVa) or 4-bromobutyl nitrate (IVb) in the presence of KI .
Esterification of (S)-naproxen (I) with 1,4-butanediol (V) in the presence of H2SO4 or NaHSO4·H2O in toluene at 80 °C gives (S)-naproxen 4-hydroxybutyl ester (VI), which is then converted to: a) the mesylate (VII) by mesylation with MsCl by means of Et3N or Nmethylmorpholine (NMM) in toluene; b) the tosylate (IXa) by reaction with tosyl chloride (VIIIa) by means of either DMAP and Et3N in toluene or NMM in EtOAc; and c) the chlorobenzenesulfonate (IXb) by treatment with 4-chlorobenzenesulfonyl chloride (VIIIb) by means of NMM in acetonitrile. Finally, esters (VII), (IXa) and (IXb) are nitrated with NaNO3 or LiNO3 in the presence or absence of Bu4NNO3 or Bu4NHSO4 in various solvents, such as N-methylpyrrolidone (NMP), sulfolane and tetramethylurea, among others .
| 【1】 Hack, A., Weingartner, G., Kramer, M. (NicOX SA). Process for preparing 1,4-butanediol mononitrate. WO 2009000723. |
| 【2】 Benedini, F., Tarquini, A., Castaldi, G., Oldani, E. (NicOX SA). Process for the preparation of naproxene nitroxyalkylesters. CA 2380116, EP 1200386, EP 1384707, JP 2003506425, US 2005119339, US 6700011, US 7238829, WO 2001010814. |
| 【3】 Del Soldato, P., Santus, G., Benedini, F. (NicOX SA). Process for preparing nitrooxyderivative of naproxen. CA 2497187, EP 1532098, JP 2005536558, US 2006173005, US 7199258, WO2004020384. |
| 【4】 Belli, A., Cannata, V., Villa, M., Hedberg, M., Westermark, A., Fonduca, T. (AstraZeneca AB). New process. CA 2465697, EP 1451140, JP 2005510557, US 2005234123, WO 2003045896. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa) | 69254 | 4-(nitrooxy)butyl 4-methylbenzenesulfonate | C11H15NO6S | 详情 | 详情 | |
| (IVb) | 69255 | 4-bromobutyl nitrate;4-Nitrooxybutyl bromide;4-bromo-1-Butanol nitrate | 146563-40-8 | C4H8BrNO3 | 详情 | 详情 |
| (VIIIa) | 13975 | p-Toluenesulfonyl chloride;p-tosyl chloride;Toluene-4-sulfonyl chloride;4-Toluene sulfochloride;tosyl chloride; 4-Methylbenzenesulfonyl chloride | 98-59-9 | C7H7ClO2S | 详情 | 详情 |
| (VIIIb) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (IXa) | 69258 | (S)-4-(tosyloxy)butyl 2-(6-methoxynaphthalen-2-yl)propanoate | C25H28O6S | 详情 | 详情 | |
| (IXb) | 69259 | (S)-4-(((4-chlorophenyl)sulfonyl)oxy)butyl 2-(6-methoxynaphthalen-2-yl)propanoate | C24H25ClO6S | 详情 | 详情 | |
| (I) | 30839 | (2S)-2-(6-methoxy-2-naphthyl)propionic acid;(S)-naproxen;(S)-6-Methoxy-alpha-methyl-2-naphthaleneacetic acid | 22204-53-1 | C14H14O3 | 详情 | 详情 |
| (II) | 69252 | (S)-2-(6-methoxynaphthalen-2-yl)propanoyl chloride | C14H13ClO2 | 详情 | 详情 | |
| (III) | 69253 | 4-hydroxybutyl nitrate | C4H9NO4 | 详情 | 详情 | |
| (V) | 43160 | 1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol | 110-63-4 | C4H10O2 | 详情 | 详情 |
| (VI) | 69256 | (S)-4-hydroxybutyl 2-(6-methoxynaphthalen-2-yl)propanoate | C18H22O4 | 详情 | 详情 | |
| (VII) | 69257 | (S)-4-((methylsulfonyl)oxy)butyl 2-(6-methoxynaphthalen-2-yl)propanoate | C19H24O6S | 详情 | 详情 |
合成路线2
Intermediates (III), (IVa) and (IVb) can be synthesized as follows. Esterification of butyric acid (X) with 1,4-butanediol (V) in the presence of TsOH·H2O in refluxing n-octane gives 1,4-butanediol monobutyrate (XI), which is then nitrated with HNO3/H2SO4 in CH2Cl2, yielding nitrate ester (XII). Selective saponification of the carboxylate of ester of (XII) with NaOH in MeOH/H2O, followed by acidification with H2SO4, furnishes 4-hydroxybutyl nitrate (III) .
| 【1】 Hack, A., Weingartner, G., Kramer, M. (NicOX SA). Process for preparing 1,4-butanediol mononitrate. WO 2009000723. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 69253 | 4-hydroxybutyl nitrate | C4H9NO4 | 详情 | 详情 | |
| (V) | 43160 | 1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol | 110-63-4 | C4H10O2 | 详情 | 详情 |
| (X) | 53267 | Butanoic acid; Butyric acid; N-Butanic acid; N-Butanoic acid; n-Butyric acid; N-Ethylacetic acid; N-Propanecarboxylic acid; N-Propylformic acid | 107-92-6 | C4H8O2 | 详情 | 详情 |
| (XI) | 69260 | 1,4-butanediol monobutyrate;4-hydroxybutyl butyrate | C8H16O3 | 详情 | 详情 | |
| (XII) | 69261 | 4-(nitrooxy)butyl butyrate | C8H15NO5 | 详情 | 详情 |
合成路线3
Tosylation of 4-bromobutan-1-ol (XIII) by treatment with TsCl in pyridine gives tosylate (XIV), which without isolation is then nitrated with AgNO3 in acetonitrile to afford 4-nitroxybutyl tosylate (IVa). Nitration of 4-bromobutan-1-ol (XIII) with H2SO4/HNO3 provides 4-bromobutyl nitrate (IVb) .
| 【1】 Del Soldato, P., Santus, G., Benedini, F. (NicOX SA). Process for preparing nitrooxyderivative of naproxen. CA 2497187, EP 1532098, JP 2005536558, US 2006173005, US 7199258, WO2004020384. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVb) | 69255 | 4-bromobutyl nitrate;4-Nitrooxybutyl bromide;4-bromo-1-Butanol nitrate | 146563-40-8 | C4H8BrNO3 | 详情 | 详情 |
| (IVa) | 69254 | 4-(nitrooxy)butyl 4-methylbenzenesulfonate | C11H15NO6S | 详情 | 详情 | |
| (XIII) | 50608 | Tetramethylene Bromohydrin; 4-Bromo-1-butanol;4-bromobutan-1-ol | 33036-62-3 | C4H9BrO | 详情 | 详情 |
| (XIV) | 69262 | 4-bromobutyl 4-methylbenzenesulfonate | C11H15BrO3S | 详情 | 详情 |
合成路线4
The sodium salt (II), prepared from racemic naproxen (I), was alkylated with 1-bromo-4-chlorobutane (III) in DMF to produce the 4-chlorobutyl ester (IV). Chloride displacement in (IV) by silver nitrate in hot acetonitrile gave rise to the target nitrate ester.
| 【1】 Del Soldato, P.; Nitric esters having anti-inflammatory and/or analgesic activity and process for their preparation. WO 9509831 . |
| 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) | 42596 | 2-(6-methoxy-2-naphthyl)propionic acid | 23981-80-8 | C14H14O3 | 详情 | 详情 |
| (II) | 56161 | sodium 2-(6-methoxy-2-naphthyl)propanoate | C14H13NaO3 | 详情 | 详情 | |
| (III) | 16141 | 1-bromo-4-chlorobutane | 6940-78-9 | C4H8BrCl | 详情 | 详情 |
| (IV) | 56162 | 4-chlorobutyl 2-(6-methoxy-2-naphthyl)propanoate | C18H21ClO3 | 详情 | 详情 |