甲磺酸帕珠沙星的合成
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摘要
甲磺酸帕珠沙星属于国外开发上市的第四代喹诺酮类药物,在国内属于三类新药。目前与国内市场上销售额最高的三个喹诺酮类药物左旋氧氟沙星、氧氟沙星和环丙沙星相比在抵抗体外细菌的活性和药理毒性方面都具有很大的优势,在国内市场上具有极大的生产和销售潜力。所以帕珠沙星的工业化生产具有很大的经济价值和市场前景。
本文参照文献报道的合成路线作了以下几个方面的研究:
1.以左旋氧氟沙星中间体((S)-9,10-二氟-3-甲基-2,3-二氢-7-氧代-7-H-吡啶并[1,2,3-de][1,4]苯并噁嗪-6-羧酸乙酯)为起始原料,经亲核取代、选择性脱羧、环丙化、水解、经典Hofmann重排和成盐单元反应合成甲磺酸帕珠沙星,总收率42.46%。其化学结构利用红外光谱、质谱和核磁共振光谱等技术进行确证。
2.采用高效层析硅胶板对第一步亲核反应进程进行监控。以甲醇:氯仿:乙酸乙酯:浓氨水=3:7:0.5:0.5混合溶剂作为展开剂,采用光学检测进行定性分析。
3.对各步反应机理进行分析,重点研究了亲核取代反应和Hofmann重排反应。课题选用DBDMH- Hg(OAC)2作为Hofmann重排反应试剂,反应条件温和,收率大大提高,适合工业化生产。
Pazufloxacin mesilate is the fourth generation of quinolone antibacterial agents that has been come into overseas market recently, and is the third kinds of new pharmaceutical in China. Comparing to the three quinolone antibacterial agents of Levofloxacin, ofloxacin and ciprofloxacin, which have the best sale in home market, pazufloxacin mesilate has the obvious advantages in both of resisting the active bacteric and pharmacological toxicity. So it has huge potential of production and selling in home market,and its industrialization production has the prodigious economy value and market prospect.
Referring to the synthesis routes of reference literature, the following three main areas of study have been carried out in the research of this paper.
1.Pazufloxacin mesilate was synthesized from (s)-9, 10–difluoro-3-methly-7-oxo-2, 3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylate, by nuclephilic substitution, selective decarboxylation, cyclic addition, hydrolysis, Hofmann recomposition and salt formation, the overall yield was 42.46%. Technologies, such as infrared spectrum, mass spectrum and nucleus magnetism spectrum, were applied to identify the chemic structure of this compound.
2. A method, which adopting high effect chromatography TLC plate was used to monitor the process of nuclephilic reaction, was put forward. Using mixture of carbinol : chloroform : ethyl acetate : ammonia=3:7:0.5:0.5 as developer, using optical test to make the qualitative analysis.
3. Analyzing the reaction mechanism of every process, especially the nuclephilic substitution reaction and Hofmann recomposition reaction were studied. Using DBDMH- Hg (OAC) 2 as reaction reagent of Hofmann recomposition with the mild reaction condition in the research, and the yield has increased greatly, it is be applicable to industrialization production.
本文参照文献报道的合成路线作了以下几个方面的研究:
1.以左旋氧氟沙星中间体((S)-9,10-二氟-3-甲基-2,3-二氢-7-氧代-7-H-吡啶并[1,2,3-de][1,4]苯并噁嗪-6-羧酸乙酯)为起始原料,经亲核取代、选择性脱羧、环丙化、水解、经典Hofmann重排和成盐单元反应合成甲磺酸帕珠沙星,总收率42.46%。其化学结构利用红外光谱、质谱和核磁共振光谱等技术进行确证。
2.采用高效层析硅胶板对第一步亲核反应进程进行监控。以甲醇:氯仿:乙酸乙酯:浓氨水=3:7:0.5:0.5混合溶剂作为展开剂,采用光学检测进行定性分析。
3.对各步反应机理进行分析,重点研究了亲核取代反应和Hofmann重排反应。课题选用DBDMH- Hg(OAC)2作为Hofmann重排反应试剂,反应条件温和,收率大大提高,适合工业化生产。
Pazufloxacin mesilate is the fourth generation of quinolone antibacterial agents that has been come into overseas market recently, and is the third kinds of new pharmaceutical in China. Comparing to the three quinolone antibacterial agents of Levofloxacin, ofloxacin and ciprofloxacin, which have the best sale in home market, pazufloxacin mesilate has the obvious advantages in both of resisting the active bacteric and pharmacological toxicity. So it has huge potential of production and selling in home market,and its industrialization production has the prodigious economy value and market prospect.
Referring to the synthesis routes of reference literature, the following three main areas of study have been carried out in the research of this paper.
1.Pazufloxacin mesilate was synthesized from (s)-9, 10–difluoro-3-methly-7-oxo-2, 3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylate, by nuclephilic substitution, selective decarboxylation, cyclic addition, hydrolysis, Hofmann recomposition and salt formation, the overall yield was 42.46%. Technologies, such as infrared spectrum, mass spectrum and nucleus magnetism spectrum, were applied to identify the chemic structure of this compound.
2. A method, which adopting high effect chromatography TLC plate was used to monitor the process of nuclephilic reaction, was put forward. Using mixture of carbinol : chloroform : ethyl acetate : ammonia=3:7:0.5:0.5 as developer, using optical test to make the qualitative analysis.
3. Analyzing the reaction mechanism of every process, especially the nuclephilic substitution reaction and Hofmann recomposition reaction were studied. Using DBDMH- Hg (OAC) 2 as reaction reagent of Hofmann recomposition with the mild reaction condition in the research, and the yield has increased greatly, it is be applicable to industrialization production.
引文
[1]戴德银,实用新药特药手册,人民军医出版社,1977
[2]解斌,实用新药手册,人民卫生出版社,1979
[3]Tsutomu I., Seigo S., Satoshi M.,et al, EP 195316,1986
[4]Mich T.F., Sanchez J.P., Domagala J.M., EP 153828,1986
[5]Chu D.T.W., Fernandes P.B., Claibrone A.K., et al, J Med Chem, 1985,28:1558
[6]Domagala J.M., Bridges A.J., Culbertson T.P., et al, J.Med.Chem.1991,34:1142
[7]Gerster J.F., Rohlfing S.R., Pecore S.E., et al. J.Med.Chem.,1987,30:839
[8]Mitscher L.A., Sharma P.N., Chu D.T.W., J.Med.Chem.,1986,29:2044
[9]Ohta M.and Koga H., J.Med.Chem., 1991,34:131
[10]郭惠元,顾慧儿,中国抗生素杂志,1995,20:85
[11]张洪化,新喹诺酮类抗菌药合成路线概述,中国医药工业杂志,1991,22(1):37-44
[12]郭惠元,孙兰英,汤云等,吡酮酸类抗菌类药物的研究,药学学报,1998,23(8):566
[13]Hirosato K., Fumio S., Kiyotaka K., et al, J.Med.Chem., 1998,31:221
[14]李卓荣,郭惠元,张致平,吡酮酸类抗菌类药物的研究,药学学报,1991,26(2):111
[15]Uno T., Takamatsu M., Inoue Y., et al, J.Med.Chem., 1987,30:2163
[16]Istvan H., Geza K., Lelle V., et al, WO 8807993,1998
[17]Istvan H., Geza K., Lelle V., et al, WO 07998,1998
[18]Istvan H., Geza K., Lelle V., et al, WO 10253,1998
[19]Sanchez J.P., Domagala J.M., Hagen S.E., et al, J.Med.Chem.,1998,31:983
[20]穆永琪,郭惠元,吡酮酸类抗菌类药物的定量构效关系,抗生素,1987,12(4):311
[21]刘明亮,郭惠元,国外新药-合成药、生化药、制剂手册,1996,17(5):272
[22]朱玉洁,郭惠元,国外新药-抗生素手册,1999,20(3):109
[23]钟倩,抗菌药甲磺酸帕珠沙星,世界临床药物,2004,25 (2): 122-123
[24]日本化学疗法学会,Pazufloxacin (T-3761)特集[J],日本化学疗法学会杂志,1995,43 (Suppl2 ):1
[25] Tetsuro Muratani, Matsuhisa Inoue, Susumu Mitsuhashi,In vitro activity of T-3761, a new fluoroquinolone[J],Antimicarobial Agents and Chemotherapy, 1992, 36(10):2293-2303
[26]Fukuoka Y, Ikeda Y, Yamash iro Y, et al,In vitro and in vivo antibacterial activitives of T -3761, a new quinolone derivative[J], Antimicrob Agents Chemother, 1993, 37 (3):384-392
[27]石和鹏,刘浚,氟唆诺酮类抗菌剂帕珠沙星[J],四川生理科学杂志,2003, 25 (4):159-160
[28]日本公开特许,117238,1993 (CA 1993, V119:225848h)
[29]Todo Y, Nitta J, Migajima M, et al, Chem Pharm Bull, 1994,42(12):2063
[30]US 4990508,1991 (CA 1991, V113:78417n)
[31]日本公开特许,133983,1991 (CA 1991, V115:214833r)
[32]日本公开特许,264724,1990 (CA 1991, V114:247292w)
[33]Todo Y, Takaji H, Iino F, et al, Chem Pharm Bull, 1994,42(12):2569
[34]Todo Y, Takaji H, Iino F, et al, Chem Pharm Bull, 1994,42(12):2629
[35]王宏,黄东临,世界临床药物,2003,24(5):119
[36]日本公开特许,41070,1996 (CA 1996, V124:343319n)
[37]Todo Y, Takagi H. Synthesis and structure activity relationship of 3-substituted-10-(1-ami-nocylopropyl)-9-fluoro-7-oxo-2,3-dihydro-7-H-pyrido [1,2,3-de]-1,4-benzoxazine-6-carboxylic acids. Chem Pharm Bull,1994,42(12):2569-2574
[38]C,C research laboratories, Method for producing 10-(1-aminocyclopropyl)-7-oxo-2,3-dihydropyrido [1,2,32de]-1,4-benzoxazine-6-carboxylic acid derivative and related analog as antibactetial agent[P]. JP:1996-02-13
[39]闻韧,药物合成反应[M],北京:化学工业出版社,1988,92
[40]张文治,束家有,帕珠沙星合成中的Hofmann重排反应[J],中国医药工业杂志,2003,34(12):593-594
[2]解斌,实用新药手册,人民卫生出版社,1979
[3]Tsutomu I., Seigo S., Satoshi M.,et al, EP 195316,1986
[4]Mich T.F., Sanchez J.P., Domagala J.M., EP 153828,1986
[5]Chu D.T.W., Fernandes P.B., Claibrone A.K., et al, J Med Chem, 1985,28:1558
[6]Domagala J.M., Bridges A.J., Culbertson T.P., et al, J.Med.Chem.1991,34:1142
[7]Gerster J.F., Rohlfing S.R., Pecore S.E., et al. J.Med.Chem.,1987,30:839
[8]Mitscher L.A., Sharma P.N., Chu D.T.W., J.Med.Chem.,1986,29:2044
[9]Ohta M.and Koga H., J.Med.Chem., 1991,34:131
[10]郭惠元,顾慧儿,中国抗生素杂志,1995,20:85
[11]张洪化,新喹诺酮类抗菌药合成路线概述,中国医药工业杂志,1991,22(1):37-44
[12]郭惠元,孙兰英,汤云等,吡酮酸类抗菌类药物的研究,药学学报,1998,23(8):566
[13]Hirosato K., Fumio S., Kiyotaka K., et al, J.Med.Chem., 1998,31:221
[14]李卓荣,郭惠元,张致平,吡酮酸类抗菌类药物的研究,药学学报,1991,26(2):111
[15]Uno T., Takamatsu M., Inoue Y., et al, J.Med.Chem., 1987,30:2163
[16]Istvan H., Geza K., Lelle V., et al, WO 8807993,1998
[17]Istvan H., Geza K., Lelle V., et al, WO 07998,1998
[18]Istvan H., Geza K., Lelle V., et al, WO 10253,1998
[19]Sanchez J.P., Domagala J.M., Hagen S.E., et al, J.Med.Chem.,1998,31:983
[20]穆永琪,郭惠元,吡酮酸类抗菌类药物的定量构效关系,抗生素,1987,12(4):311
[21]刘明亮,郭惠元,国外新药-合成药、生化药、制剂手册,1996,17(5):272
[22]朱玉洁,郭惠元,国外新药-抗生素手册,1999,20(3):109
[23]钟倩,抗菌药甲磺酸帕珠沙星,世界临床药物,2004,25 (2): 122-123
[24]日本化学疗法学会,Pazufloxacin (T-3761)特集[J],日本化学疗法学会杂志,1995,43 (Suppl2 ):1
[25] Tetsuro Muratani, Matsuhisa Inoue, Susumu Mitsuhashi,In vitro activity of T-3761, a new fluoroquinolone[J],Antimicarobial Agents and Chemotherapy, 1992, 36(10):2293-2303
[26]Fukuoka Y, Ikeda Y, Yamash iro Y, et al,In vitro and in vivo antibacterial activitives of T -3761, a new quinolone derivative[J], Antimicrob Agents Chemother, 1993, 37 (3):384-392
[27]石和鹏,刘浚,氟唆诺酮类抗菌剂帕珠沙星[J],四川生理科学杂志,2003, 25 (4):159-160
[28]日本公开特许,117238,1993 (CA 1993, V119:225848h)
[29]Todo Y, Nitta J, Migajima M, et al, Chem Pharm Bull, 1994,42(12):2063
[30]US 4990508,1991 (CA 1991, V113:78417n)
[31]日本公开特许,133983,1991 (CA 1991, V115:214833r)
[32]日本公开特许,264724,1990 (CA 1991, V114:247292w)
[33]Todo Y, Takaji H, Iino F, et al, Chem Pharm Bull, 1994,42(12):2569
[34]Todo Y, Takaji H, Iino F, et al, Chem Pharm Bull, 1994,42(12):2629
[35]王宏,黄东临,世界临床药物,2003,24(5):119
[36]日本公开特许,41070,1996 (CA 1996, V124:343319n)
[37]Todo Y, Takagi H. Synthesis and structure activity relationship of 3-substituted-10-(1-ami-nocylopropyl)-9-fluoro-7-oxo-2,3-dihydro-7-H-pyrido [1,2,3-de]-1,4-benzoxazine-6-carboxylic acids. Chem Pharm Bull,1994,42(12):2569-2574
[38]C,C research laboratories, Method for producing 10-(1-aminocyclopropyl)-7-oxo-2,3-dihydropyrido [1,2,32de]-1,4-benzoxazine-6-carboxylic acid derivative and related analog as antibactetial agent[P]. JP:1996-02-13
[39]闻韧,药物合成反应[M],北京:化学工业出版社,1988,92
[40]张文治,束家有,帕珠沙星合成中的Hofmann重排反应[J],中国医药工业杂志,2003,34(12):593-594