4-hydroxybutyl nitrate -Drug Synthesis Database

【结构式】

【分子编号】69253

【品名】4-hydroxybutyl nitrate

【CA登记号】　

【分子式】C₄H₉NO₄

【分子量】135.12

【元素组成】C 35.56% H 6.71% N 10.37% O 47.36%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(III)

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 .

参考文献中间体

合成目标

【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：(III)

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) .

参考文献中间体

合成目标

【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

Extended Information