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【结 构 式】 
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【分子编号】69255 【品名】4-bromobutyl nitrate;4-Nitrooxybutyl bromide;4-bromo-1-Butanol nitrate 【CA登记号】146563-40-8 |
【 分 子 式 】C4H8BrNO3 【 分 子 量 】198.016 【元素组成】C 24.26% H 4.07% Br 40.35% N 7.07% O 24.24% |
合成路线1
该中间体在本合成路线中的序号：(IVb)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
该中间体在本合成路线中的序号：(IVb)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 |