巴洛沙星的合成研究
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摘要
巴洛沙星是由日本中外制药公司的Nagano H等人合成，并于1999年完成Ⅲ期临床的一种新型氟喹诺酮类抗菌药，化学名为1-环丙基-6-氟-8-甲氧基-7-[(3-甲氨基)哌啶-1-基]-1,4-二氢-4-氧代喹啉-3-羧酸二水合物(Balofloxacin，Q-35·2H_2O)。鉴于国内尚无该产品上市，为实现该产品的国产化，依据现有资料，本文对该产品的合成路线进行了深入研究。即以3-氨基吡啶为起始原料合成3-甲氨基哌啶中间体，以及以1-环丙基-6,7-二氟-8-甲氧基-1，4-二氢-4-氧代喹啉-3-羧酸乙酯(DFQ-Et)为起始原料用硼螯合物法制备巴洛沙星。这为巴洛沙星的新的合成生产路线奠定了坚实的基础。
(1)研究了3-氨基吡啶上3位氨基的保护情况，重点考察了投料方式、反应时间对目标产物3-(对甲苯磺酰氨基)吡啶收率的影响，不同浓度的乙醇溶液对3-(对甲苯磺酰氨基)吡啶重结晶的影响，优化了的氨基保护工艺：投料方式为先加入对甲苯磺酰氯(TsCl)、吡啶搅拌完全溶解后，缓慢加入3-氨基吡啶，做薄层色谱(TLC)跟踪反应进程，确定了最佳反应时间为2h，收率为91.2％，选用80％乙醇作为重结晶溶剂，收率为87.3％，熔点为192.6～193.4℃。
(2)考察了NaOH与3-(对甲苯磺酰氨基)吡啶的摩尔比、硫酸二甲酯与3-(对甲苯磺酰氨基)吡啶的摩尔比对甲基化的影响确立了甲基化反应的优化工艺为NaOH:3-(对甲苯磺酰氨基)吡啶=7:1(摩尔比)、硫酸二甲酯:3-(对甲苯磺酰氨基)吡啶=2.1:1(摩尔比)，收率为49.5％。
(3)在以硼螯合物法制备1-环丙基-6,7-二氟-8-甲氧基-1，4-二氢-4-氧代喹啉-3-羧酸根·二乙酸根合硼(DFQ-B(OAc)_2)螯合物的过程中，重点考察了反应时间、温度、干燥条件、洗涤溶剂的影响，确立了合成DFQ-B(OAc)_2的优化工艺：做薄层色谱(TLC)跟踪反应进程，确定了最佳反应时间为3h，用高压液相色谱法对DFQ-B(OAc)_2进行含量分析，确定了反应温度为90℃，干燥条件：真空度为—0.065MPa、温度为45℃，用蒸馏水洗涤，制得DFQ-B(OAc)_2的含量为98.00％，收率为90.4％。
(4)在合成1-环丙基-6-氟-7-(3-甲氨基哌啶-1-基)-8-甲氧基-1，4-二氢-4-氧代-3-喹啉羧酸(Q-35)的工艺过程中重点考察了反应时间、温度、溶剂的影响以及以50％乙醇作为重结晶溶剂对Q-35重结晶的影
响，确立了合成及精制Q一35的优化工艺:做薄层色谱(TLC)跟踪反应
进程，确定了最佳反应时间sh，用高压液相色谱(HPLC)法对Q一35进
行含量分析，确立了反应温度为60℃，以乙睛作为反应溶剂，Q一35
的含量为85.71%;精品Q一35的含量为90.62%，同时对精制品进行
紫外吸收光谱(UV)、元素分析、红外吸收光谱(FT一IR)、核磁共振氢
谱(’H~NMR)、核磁共振碳谱(，，C.NM丑)、质谱(Ms)、热重分析(TG)
等表征，结果表明产品的化学结构与巴洛沙星实际的化学结构相符。
Balofloxacin, 1 -cyclopropyl-6-fluoro-8-methoxy-7-[(3-methylamino) piperidin-1 -yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid dehydrates, is one of the new fluoroquinolones, which had been synthesized by Nagano H etc. in the Chugai Pharmaceutical company of Japan and had been phased III in 1999. This product has not been marketed and produced domestically in this time. The synthesis of intermediate of 3-methylaminopiperidine from 3-aminopyridine as raw material and the synthesis of Balofloxacin from DFQ-Et by means of the borate chelate were deeply studied in this paper. All these work will contribute to the new synthesis of Balofloxacin, especially the study on the synthesis of borate chelate.
The optimum reaction conditions were studied during the protection of the amino group at the 3-position of 3-aminopyridine. The 3-aminopyridine was added slowly to the mixture of p-toluenesulfonyl chloride and pyridine. The 3-(p-toluenesulfonylamino)pyridine was obtained with the yield of 91.2% for 2h, characterized by the TLC spectra. The recrystallization of 3-(p-Toluenesulfonylamino)pyridine was obtained with the yield of 87.3 % by the use of 80 % ethanol as recrystling solvent; m.p.l92.6~193.4℃. With the molar ratio of NaOH to 3-(p-toluenesulfonylamino)pyridine being 7 '. 1 and the molar ratio of 3-(p-toluenesulfonylamino)pyridine to Me2SO4 being 1 '. 2.1, the 3N,3N-(methyl-p-toluenesulfonylamino)pyridine was obtained with the yield of 49.5%.
The DFQ-B(OAc)2 was obtained with the yield of 90.4 % for 3h at 90℃, washed with water, then dried up at 45℃ under reduced pressure of-0.065MPa, being the purity of 98.00%, The synthesis of Q-35 was carried out at 60℃ for 5h with CH3CN being solvent, being the purity of 85.71%. The refined Q-35 was obtained with the purity of 90.62%, characterized by the TLC spectra and the HPLC spectra. The refined product was characterized by UV spectra, the elemental analysis, IR spectra,1H-NMR spectra, 13C-NMR spectra, MS spectra and the analysis of TG. The results showed that the structure of the refined product was
the same to the theoretical structure of Balofloxacin.
(1)研究了3-氨基吡啶上3位氨基的保护情况，重点考察了投料方式、反应时间对目标产物3-(对甲苯磺酰氨基)吡啶收率的影响，不同浓度的乙醇溶液对3-(对甲苯磺酰氨基)吡啶重结晶的影响，优化了的氨基保护工艺：投料方式为先加入对甲苯磺酰氯(TsCl)、吡啶搅拌完全溶解后，缓慢加入3-氨基吡啶，做薄层色谱(TLC)跟踪反应进程，确定了最佳反应时间为2h，收率为91.2％，选用80％乙醇作为重结晶溶剂，收率为87.3％，熔点为192.6～193.4℃。
(2)考察了NaOH与3-(对甲苯磺酰氨基)吡啶的摩尔比、硫酸二甲酯与3-(对甲苯磺酰氨基)吡啶的摩尔比对甲基化的影响确立了甲基化反应的优化工艺为NaOH:3-(对甲苯磺酰氨基)吡啶=7:1(摩尔比)、硫酸二甲酯:3-(对甲苯磺酰氨基)吡啶=2.1:1(摩尔比)，收率为49.5％。
(3)在以硼螯合物法制备1-环丙基-6,7-二氟-8-甲氧基-1，4-二氢-4-氧代喹啉-3-羧酸根·二乙酸根合硼(DFQ-B(OAc)_2)螯合物的过程中，重点考察了反应时间、温度、干燥条件、洗涤溶剂的影响，确立了合成DFQ-B(OAc)_2的优化工艺：做薄层色谱(TLC)跟踪反应进程，确定了最佳反应时间为3h，用高压液相色谱法对DFQ-B(OAc)_2进行含量分析，确定了反应温度为90℃，干燥条件：真空度为—0.065MPa、温度为45℃，用蒸馏水洗涤，制得DFQ-B(OAc)_2的含量为98.00％，收率为90.4％。
(4)在合成1-环丙基-6-氟-7-(3-甲氨基哌啶-1-基)-8-甲氧基-1，4-二氢-4-氧代-3-喹啉羧酸(Q-35)的工艺过程中重点考察了反应时间、温度、溶剂的影响以及以50％乙醇作为重结晶溶剂对Q-35重结晶的影
响，确立了合成及精制Q一35的优化工艺:做薄层色谱(TLC)跟踪反应
进程，确定了最佳反应时间sh，用高压液相色谱(HPLC)法对Q一35进
行含量分析，确立了反应温度为60℃，以乙睛作为反应溶剂，Q一35
的含量为85.71%;精品Q一35的含量为90.62%，同时对精制品进行
紫外吸收光谱(UV)、元素分析、红外吸收光谱(FT一IR)、核磁共振氢
谱(’H~NMR)、核磁共振碳谱(，，C.NM丑)、质谱(Ms)、热重分析(TG)
等表征，结果表明产品的化学结构与巴洛沙星实际的化学结构相符。
Balofloxacin, 1 -cyclopropyl-6-fluoro-8-methoxy-7-[(3-methylamino) piperidin-1 -yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid dehydrates, is one of the new fluoroquinolones, which had been synthesized by Nagano H etc. in the Chugai Pharmaceutical company of Japan and had been phased III in 1999. This product has not been marketed and produced domestically in this time. The synthesis of intermediate of 3-methylaminopiperidine from 3-aminopyridine as raw material and the synthesis of Balofloxacin from DFQ-Et by means of the borate chelate were deeply studied in this paper. All these work will contribute to the new synthesis of Balofloxacin, especially the study on the synthesis of borate chelate.
The optimum reaction conditions were studied during the protection of the amino group at the 3-position of 3-aminopyridine. The 3-aminopyridine was added slowly to the mixture of p-toluenesulfonyl chloride and pyridine. The 3-(p-toluenesulfonylamino)pyridine was obtained with the yield of 91.2% for 2h, characterized by the TLC spectra. The recrystallization of 3-(p-Toluenesulfonylamino)pyridine was obtained with the yield of 87.3 % by the use of 80 % ethanol as recrystling solvent; m.p.l92.6~193.4℃. With the molar ratio of NaOH to 3-(p-toluenesulfonylamino)pyridine being 7 '. 1 and the molar ratio of 3-(p-toluenesulfonylamino)pyridine to Me2SO4 being 1 '. 2.1, the 3N,3N-(methyl-p-toluenesulfonylamino)pyridine was obtained with the yield of 49.5%.
The DFQ-B(OAc)2 was obtained with the yield of 90.4 % for 3h at 90℃, washed with water, then dried up at 45℃ under reduced pressure of-0.065MPa, being the purity of 98.00%, The synthesis of Q-35 was carried out at 60℃ for 5h with CH3CN being solvent, being the purity of 85.71%. The refined Q-35 was obtained with the purity of 90.62%, characterized by the TLC spectra and the HPLC spectra. The refined product was characterized by UV spectra, the elemental analysis, IR spectra,1H-NMR spectra, 13C-NMR spectra, MS spectra and the analysis of TG. The results showed that the structure of the refined product was
the same to the theoretical structure of Balofloxacin.
引文
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[2] 陈新谦，金有豫．新编药物学．第14版．北京：人民卫生出版社，1997．91．
[3] 陈瑞红，梁建华，张文革．第四代氟喹诺酮类药物的研究与应用发展[J]．中国药房，2001，12(2)，114．
[4] 张致平， 喹诺酮类抗菌药研究的进展[J]．中国抗生素杂志，1992，17(2)：87．
[5] 张致平，喹诺酮类抗菌药研究的进展[J]．中国抗生素杂志，1995，20(2)：79．
[6] 周伟澄，张秀平．氟喹诺酮类药物研究的新进展[J]．中国医药工业杂志，1997，28(2)：75．
[7] 张致平，喹诺酮类抗菌药研究的进展[J]．中国抗生素杂志，1999，24(1)：61．
[8] 周伟澄，张秀平．氟喹诺酮类药物研究新进展[J]．中国新药杂志，2000，9(10)：667．
[9] 张致平．氟喹诺酮类抗菌药的新进展[J]．国外医药抗生素分册，2001，22(6)：241．
[10] 陈杖榴，肖田安．人工合成抗菌药—氟喹诺酮类[J]．中国家禽，2002，24(11)：35．
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