奈诺沙星关键中间体2,4-二氟-3-甲氧基苯甲酸的合成
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摘要
以2-甲基四氢呋喃代替四氢呋喃作溶剂,间二氟苯(2)与正丁基锂、硼酸三甲酯反应得2,6-二氟苯硼酸(3),在确保收率的前提下,减少了溶剂的用量,同时使正丁基锂、硼酸三甲酯的摩尔量分别由1.14和2.16减少至1.05和1.1。然后以水代替乙醚作溶剂,3与双氧水反应得2,6-二氟苯酚(4),反应更安全。以硫酸二甲酯代替碘甲烷作甲基化试剂,与4在2-甲基四氢呋喃与水的混合溶剂中反应得2,6-二氟苯甲醚(5),收率89.9%。最后5与正丁基锂和二氧化碳反应得奈诺沙星关键中间体2,4-二氟-3-甲氧基苯甲酸,纯度99.3%,总收率72.6%。该工艺原料价廉易得,反应收率高,已实现工业化生产。
1,3-Difluorobenzene(2) reacted with n-butyllithium and trimethyl borate to give(2,6-difluorophenyl)-boronic acid(3) by using 2-methyl tetrahydrofuran(MeTHF) rather than tetrahydrofuran as solvent. Under the premise of ensuring yield, the amount of solvent was reduced, and the molar amounts of n-butyl lithium and trimethyl borate were reduced from 1.14 and 2.16 to 1.05 and 1.1, respectively. Then, compound 3 reacted with hydrogen peroxide in water to give 2,6-difluorophenol(4), which was subjected to a methylation with dimethyl sulfate instead of iodomethane in a mixed solvent of MeTHF and water to afford 2,6-difluoroanisole(5) in 89.9% yield. Finally, 5 reacted with n-butyllithium and carbon dioxide in MeTHF to prepare the key intermediate of nemonoxacin 2,4-difluoro-3-methoxyl benzoic acid with an overall yield of 72.6%, and a purity of 99.3%. The process has the advantages of low cost, easy availability of raw materials and high yield, and it has been applied in industrial production.
1,3-Difluorobenzene(2) reacted with n-butyllithium and trimethyl borate to give(2,6-difluorophenyl)-boronic acid(3) by using 2-methyl tetrahydrofuran(MeTHF) rather than tetrahydrofuran as solvent. Under the premise of ensuring yield, the amount of solvent was reduced, and the molar amounts of n-butyl lithium and trimethyl borate were reduced from 1.14 and 2.16 to 1.05 and 1.1, respectively. Then, compound 3 reacted with hydrogen peroxide in water to give 2,6-difluorophenol(4), which was subjected to a methylation with dimethyl sulfate instead of iodomethane in a mixed solvent of MeTHF and water to afford 2,6-difluoroanisole(5) in 89.9% yield. Finally, 5 reacted with n-butyllithium and carbon dioxide in MeTHF to prepare the key intermediate of nemonoxacin 2,4-difluoro-3-methoxyl benzoic acid with an overall yield of 72.6%, and a purity of 99.3%. The process has the advantages of low cost, easy availability of raw materials and high yield, and it has been applied in industrial production.
引文
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[2]袁其亮,张佳炳,徐鹏飞,等.1-环丙基-4-氧代-7-氟-8-甲氧基-1,4-二氢喹啉-3-羧酸的合成方法:中国,103819401[P].2014-05-28.
[3]ZHANGL J,ZHENG J,HU J B.2-Chloro-2,2-difluoroacetophenone:a non-ODS-based difluorocarbene precursor and its use in the difluoromethylation of phenol derivatives[J].J Org Chem,2006,71(26):9845-9848.
[4]BRADBU RY B J,WILES J A,WANG QP,et al.8-Methoxy-9H-isothiazolo[5,4-b]quinoline-3,4-diones and related compounds as anti-infective agents:WO,2007014308[P].2007-02-01.
[5]YANG Y G,CHEN H,TANG G,et al.Synthesis and mesomorphic properties of some fluorinated benzoate liquid crystals[J].Mol Cryst And Liq Cryst,2002,11:1-15.
[6]LEDOUSSAL B,ALMSTEAD J K,GRAY J L,et al.Antimicrobial quinolones,their compositions and uses:WO,9914214[P].1999-03-25.
[7]LEDOUSSAL B,ZHENG X M,ALMSTEAD J K,et al.Process for making certain benzoic acid compounds:WO,9935117[P].1999-07-15.
[8]WROBEL J E,DIETRICH A J,LI Z N.11-Aryl-benzo[b]-naphtho[2,3-d]furans and 11-aryl-benzo[b]naphtho[2,3-d]-thiophenes useful in the treatment of insulin resistance and hyperglycemia:WO,9958521[P].1999-11-18.
[9]ROE A M,BURTON R A,WILLEY G L,et al.The synthesis and activity of some 2,6-difluorophenyl-substituted compounds[J].J Med Chem,1968,11(4):814-819.
[10]BARNARD S,STORR R C,ONEILL P M,et al.The effect of fluorine substitution on the physicochemical progerties and the analgesic activity of paracetamol[J].J Pharm Pharmacol,1993,45:736-744.