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【结 构 式】

【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
Extended Information