卡德沙星主要相关杂质的分析和鉴定卡德沙星主要相关杂质的分析和鉴定

目的卡德沙星原料药中相关杂质的分离及结构鉴定。方法用液相色谱-质谱联用技术分离并鉴定卡德沙星原料药中的主要相关杂质,并合成了化合物:1-环丙基-8-二氟甲氧基-6-氟-1,4-二氢-7-(1-哌嗪基)-4-氧代-3-喹啉羧酸(简称DMCA)。比较合成的化合物与原料药中相关杂质的液相色谱、紫外吸收光谱及质谱。结果相关杂质的分子量比卡德沙星少14,即一个亚甲基,推测该杂质可能为卡德沙星中3-甲基哌嗪的去甲基化合物,合成的DMCA的液相色谱、紫外吸收光谱及质谱分析结果与原料药中相关杂质一致。结论确证了该相关杂质的结构为1-环丙基-8-二氟甲氧基-6-氟-1,4-二氢-7-(1-哌嗪基)-4-氧代-3-喹啉羧酸。     

钰均泰

[通用名称] gatifloxacin,甲磺酸加替沙星葡萄糖注射液 ［化学名称］　(±)-1-环丙基-6-氟-8-甲氧基-7-(3-甲基-1-哌嗪基)-1,4-二氢-4-氧代-3-喹啉羧酸.     

环丙氟哌酸

1-环丙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)喹啉-3-羧酸     

加替沙星葡萄糖注射液与丹参类药物之间存在配伍禁忌

加替沙星为8-甲氧氟喹诺酮类外消旋合物,其化学名称为：（±）-1-环丙基-6-氟-8-甲氧基-7-（3-甲基-1-哌嗪基）-1,4-二氢-4-氧代-3-喹啉羧酸。续点时遇到5%葡萄糖250ml冠心宁20ml时当即出现药液混浊,约1min后出现絮状物,当即停止输液,撤换输液管患者未发生不良反应。     

1-环丙基-6,7-二氟-1,4-二氢-8-羟基-4-氧代喹啉-3-羧酸乙酯的合成

1-环丙基-6,7-二氟-1,4-二氢-8-甲氧基-4-氧代喹啉-3-羧酸乙酯(2)经40%氢溴酸水解得到1-环丙基-6,7-二氟-1,4-二氢-8-羟基-4-氧代喹啉-3-羧酸(4),再在三甲基氯硅烷存在下经乙醇酯化得1-环丙基-6,7-二氟-1,4-二氢-8-羟基-4-氧代喹啉-3-羧酸乙酯(1),总收率为52.1%。也可用2在无水三氯化铝作用下水解直接得到1,收率66.9%。     

新氟喹诺酮抗菌剂AT—4140

化学名 5-氨基-1-环丙基-6,8-二氟-1,4-二氢-7-(顺-3,5-二甲基-1-哌嗪)-4-氧代喹啉-3-羧酸合成五氟苯甲酰乙酸乙酯(Ⅰ)和原甲酸三乙酯在酸酐中回流反应后与环丙胺(Ⅱ)于醚中反应得氨基甲叉衍生物(Ⅲ),后者用氢化钠于四氢呋喃中环合得5,6,7,8-四氟-1-环丙基-4-氧代-1,4-二氢喹啉-3-羧酸乙酯(Ⅳ)、(Ⅳ)和苄胺(Ⅴ)借助于K_2CO_3在乙腈中回流反应生成苄胺衍生物(Ⅵ)。再于乙醇中经Pd/C氢化还原脱去保护基得到5-氨基-1-环丙基-6,7,8-三     

盐酸洛美沙星光降解的部分杂质研究

目的确定控制盐酸洛美沙星光降解杂质的必要性。方法用液相色谱/质谱联用技术分离并鉴定盐酸洛美沙星的两个光降解杂质,并化学合成了两个化合物:脱羧洛美沙星[（±）-1-乙基-6,8-二氟-1,4-二氢-7-（3-甲基-1-哌嗪基）-4-氧代喹啉（简称DCLM）]和氯代洛美沙星[（±）-1-乙基-6-氟-8-氯-1,4-二氢-7-（3-甲基-1-哌嗪基）-4-氧代喹啉-3-羧酸（简称CLLM）]。比较DCLM和CLLM与盐酸洛美沙星相应光降解杂质的液相色谱和质谱。测试洛美沙星、DCLM及CLLM体外细胞毒性。结果化学合成的DCLM和CLLM的液相色谱和质谱分析结果分别与盐酸洛美沙星相应光降解杂质一致。洛美沙星、DCLM和CLLM的IC₅₀分别为1.9mmol/L,2.2mmol/L,0.7mmol/L。结论确证了盐酸洛美沙星的两个光降解杂质分别为:DCLM和CLLM。DCLM的体外细胞毒性与洛美沙星相近;CLLM的体外细胞毒性显著强于洛美沙星,可能是导致洛美沙星临床不良反应的物质。     

氟哌酸原料药中微量脱羧物生成的另一途径

提出了氟哌酸原料药中微量脱羧物作为杂质6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)喹啉(1)产生的另一途径是:7-氯-6-氟-4-羟基喹啉-3-羧酸乙酯(2)乙基化时生成的副产物4被水解成羧酸5,5与哌嗪缩合的同时脱羧,生成1。并用~1HNMR方法测定了用不同烷化剂所得乙基化产物中4的含量。     

环丙沙星合成路线图解

环丙沙星(ciprofloxacin,1)又名环丙氟哌酸,化学名为1-环丙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)喹啉-3-羧酸,系1981年由西德拜尔药厂所研制,为含氟喹诺酮类抗菌药中的最佳品种,疗效与第三代头孢菌素     

乳酸环丙沙星的制备

乳酸环丙沙星(ciprofloxacin lactate)的化学名是1-环丙基-6-氟-1,4-二氢-4-氧代-7-(1-哌嗪基)-3-喹啉羧酸乳酸盐,为一合成的高效抗菌药。其注射液已由德国拜     

1H定量核磁共振波谱法测定盐酸莫西沙星及其杂质7-氨基莫西沙星喹啉羧酸的含量

目的:建立采用1 H定量核磁共振波谱(1H quantitative nuclear magnetic resonance,1H qNMR)法测定盐酸莫西沙星及其杂质7-氨基莫西沙星喹啉羧酸对照品含量的方法.方法:采用核磁共振波谱法,使用Bruker Ascend 600超导核磁共振谱仪,以氘代二甲基亚砜(DMSO-d...     

盐酸环丙沙星纯化中微量有机杂质的分离与结构研究

用液相色谱法检测盐酸环丙沙星原药，发现一杂质峰。该杂质经分离，确证其结构为７－氯－１－环丙基－６－（１－哌嗪基）－１，４－二氢－４－氧代喹啉－３－羧酸盐酸盐（３）。     

Structural identification and characterization of impurities in moxifloxacin

In the synthesis of Moxifloxacin four prominent impurities were detected in HPLC analysis. These impurities were detected in gradient HPLC method. They were isolated from enriched mother liquors and were characterized as 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(S,S)-N-methyl-2,8-diazabicyclo (4,3,0) non-8yl]-4-oxo-3-quinoline carboxylic acid (Impurity-1), methyl-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(S,S)-2,8-diazabicyclo(4,3,0)non-8-yl]-4-oxo-3-quinoline carboxylate (impurity-2), and 1-cyclopropyl-6-fluoro-1,4 dihydro-8-hydroxy-7-[(S,S)-2,8-diazobicyclo(4,3,0)non-8-yl]-4-oxo-3-quinoline carboxylicacid (impurity-3), 1-cyclopropyl-6,7-difluoro-8-hydroxy-4-oxo-1,4 dihydro-3-quinoline carboxylicacid (impurity-4) by means of ¹H, ¹³C NMR, DEPT, IR and mass spectral data. Structural elucidation by spectral data was discussed.     

Quinolone antibacterial agents. Synthesis and structure-activity relationships of a series of amino acid prodrugs of racemic and chiral 7-(3-amino-1-pyrrolidinyl)quinolones. Highly soluble quinolone prodrugs with in vivo pseudomonas activity.

A series of amino acid prodrugs of racemic and chiral 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1,8-naphthyridine-3-carboxylic acids, 1-cyclopropyl-6,8-difluoro-3-quinolinecarboxylic acids, 1-cyclopropyl-6-fluoro-3-quinolinecarboxylic acids, and 5-amino-1-cyclopropyl-6,8-difluoro-3-quinolinecarboxylic acids have been prepared and evaluated for comparative antibacterial activity. Compounds were prepared by acylation of the 3-amino group of the pyrrolidine with common amino acids using standard peptide chemistry. This series has been compared with the parent compounds for antibacterial activity in vitro and in vivo as well as for comparative solubility. The amino acid analogues were less active in vitro, but had equal or increased efficacy in vivo. Indeed, it was proven that these compounds, which were stable to acid and base under the reaction conditions for their preparation, were rapidly cleaved in serum to give the parent quinolones. The amino acid derivatives showed a 3-70 times improved solubility when compared to the parent compounds. The most active compound of the series was [S-(R*,R*)]-7-[3-[(2-amino-1-oxopropyl)-amino]-1-pyrrolidinyl]-1- cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (PD 131112).     

3-甲胺基哌啶合成工艺

在(±)-1-环丙基-6-氟-8-甲氧基-7-[3-(甲胺基)哌啶-1-基]-4-氧代-1,4-二氢喹啉-3-羧酸二水合物(即巴洛沙星)的合成过程中,关键中间体3-甲胺基哌啶的收率问题决定着合成巴洛沙星的成本。关键中间体3-甲胺基哌啶可以以3-溴吡啶为原料,用甲胺取代,再经催化氢化等反应合成得到,收率约为48%。     

7-(7-氨甲基-5-氮杂螺［2,4］庚烷-5-基)-1-环丙基-6-氟-8-甲氧基-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物的合成与抗菌作用7-(7-氨甲基-5-氮杂螺［2,4］庚烷-5-基)-1-环丙基-6-氟-8-甲氧基-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物的合成与抗菌作用

目的寻找新的广谱、高效、低毒喹诺酮类抗菌药物。方法设计合成7-(7-氨甲基-5-氮杂螺［2,4］庚烷-5-基)-1-环丙基-6-氟-8-甲氧基-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物,测定其体内外活性。结果共合成了20个新化合物,经¹HNMR,MS和HRMS确证其结构。其中5个目标化合物(22～26)有广谱活性,尤其对革兰氏阳性菌具有很强的活性。其中化合物24对所试的13株革兰氏阳性菌的MIC值均0.03 mg·L^-1,其活性优于对照药克林沙星和加替沙星,对所试的6株革兰氏阴性菌,其活性相当于或低于对照药。结论化合物(22～26)值得进一步评价。     

Synthesis and antibacterial activity of 2-substituted 6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids.

A series of 2-substituted 6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids was prepared and evaluated for antibacterial activity. The 6-fluoro-2-methyl-1-prenyl-1,4-dihydro-7-(3,5-dimethylpiperazinyl)-4-oxo-3-quinolinecarboxylic acid (14f) exhibited the most potent antibacterial activity against gram-positive bacteria among the total 32 derivatives. The synthetic strategies involve the use of well known keto ester condensation of benzoyl chloride and reductive cyclization of intermediates (4a-d) to afford 4-hydroxy-1,2-dihydro-2-oxo-quinoline derivatives (5a,b) or 1-hydroxy-1,4-dihydro-4-oxo-quinoline derivatives (6a,b).     

New quinolone antibacterial agents. Synthesis and biological activity of 7-(3,3- or 3,4-disubstituted-1-pyrrolidinyl)quinoline-3-carboxylic acids

A series of 7-(3-amino- or 3-aminomethyl-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-o xo-3-quinolinecarboxylic acids was synthesized and tested for antibacterial activity. Unique to these quinolones was the presence of a methyl or phenyl group in the pyrrolidine ring. Although the in vitro activity of these agents was usually equal to or less than that of their unsubstituted counterparts, one quinolone, 7-[3-(aminomethyl)-3-methyl-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-1 ,4-dihydro-4-oxo-3-quinolinecarboxylic acid, displayed exceptional potency both in vitro and in vivo, particularly against Gram-positive organisms.