WO2009121304A1 - 尤利沙星光学异构体的制备方法 - Google Patents
尤利沙星光学异构体的制备方法 Download PDFInfo
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- WO2009121304A1 WO2009121304A1 PCT/CN2009/071137 CN2009071137W WO2009121304A1 WO 2009121304 A1 WO2009121304 A1 WO 2009121304A1 CN 2009071137 W CN2009071137 W CN 2009071137W WO 2009121304 A1 WO2009121304 A1 WO 2009121304A1
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- dimethyl sulfoxide
- ulifloxacin
- ulyfloxacin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- the present invention is based on the Chinese Patent Application No. 200810027212, filed on Apr. 3, 2008, the content of which is hereby incorporated by reference.
- the invention relates to a preparation method in the field of chemical medicine, in particular to 6-fluoro-1-methyl-4-oxo-(1-piperazinyl)-1H,4H-[1,3]thiazepine
- Eulerfloxacin internationally known as Ulifloxacm, is a quinolone with a significant anti-infective effect. Its chemical name is (6)-fluoro-1-methyl-4-oxo-(1-piperazinyl). -1H,4H-[1,3]thiazepine-[3,2-a]quinoline-3-carboxylic acid having the formula:
- Eulerfloxacin has a broad-spectrum antibacterial effect against Gram-positive and Gram-negative bacteria, especially against bacteria such as Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, Serratia marcescens, and Pseudomonas aeruginosa. effect. Both in vitro and in vivo experiments show that Euler has not only broad antibacterial spectrum, but also strong activity in vivo, and it has excellent bactericidal effect and antibiotic effect, low cytotoxicity, and migration to the central nervous system compared with ciprofloxacin and ofloxacin. Less advantages.
- Eulerfloxacin contains a chiral carbon atom which produces optically active isomers (s) - uleshafloxacin, of the formula 2 and (R) - uleshafloxacin, of the formula 3, (S) -
- the in vitro antibacterial activity of eufloxacin is 3-10 times that of (R)-Ulyfloxacin and more than twice that of (Shi)-Ulyfloxacin.
- the technical solution employed is: taking 6-fluoro-1-methyl-4-oxo-(1-piperazinyl)-1H,4H-[1,3]sulfur Azetidinazo[3,2-a]quinoline-3-carboxylic acid is dissolved in dimethyl sulfoxide, and D-tartaric acid in dimethyl sulfoxide solution is added dropwise with stirring, at room temperature 20 ⁇ 40 °C After stirring for 20 hours, (S)-Ulyfloxacin-D-tartrate precipitate was obtained, and the salt was recrystallized from dimethyl sulfoxide as a solvent, and the crystal was suspended in 30 times of water, and the pH was adjusted with an aqueous NaOH solution while stirring.
- the preparation process of the optical isomer of uleshafloxacin provided by the invention is simple and has no special equipment requirements, and is advantageous for industrial mass production, and the obtained optical active body has high purity.
- the following examples further illustrate the technical solutions and benefits. detailed description
- Test method Determine the minimum inhibitory concentration (MIC) by agar dilution method, add different concentrations of antibacterial drugs to the quantitative agar medium, mix them, and make solid plates, so that each plate can be used.
- concentration of the antibacterial drug is different by two times, and then the bacteria to be tested are added to the antibacterial drug.
- the surface of the agar medium was cultured, and the results were judged based on the growth of the bacteria. According to the standards of the American Committee for Clinical Laboratory Standardization, the plate was placed on the surface of a dark, non-reflective object to judge the end point of the test.
- the minimum drug concentration for aseptic growth was the minimum inhibitory concentration (MIC) of the bacteria in the strain, in all experiments. All of them were judged by the MIC of the quality control strain to meet the quality control standards of the American Clinical Laboratory Standardization Committee.
- Ciprofloxacin, levofloxacin, and sulphate were commercially available samples as control drugs.
- S - Julishacin
- R -Ulyfloxacin are all made in accordance with the examples of this patent.
- test bacteria were Klebsiella pneumoniae (strain number CMCC 46114-8), Pseudomonas aeruginosa (strain number CMCC10104, ATCC 27853), Escherichia coli (strain number ATCC8739, CMCC44102, ATCC25922), golden yellow Staphylococcus (strain numbers CMCC 26003, ATCC6538, ATCC25925), other experimental beads for the isolation of sputum, throat swabs or urine in patients with acute bacterial respiratory or urinary tract infections in hospitals, and hospital-identified bacteria.
- test drug corresponding to 96 mg of uleshafloxacin was accurately weighed and dissolved in sterile distilled water to a volume of 50 ml; Levofloxacin injection and ciprofloxacin lactate sodium chloride injection were diluted with sterile distilled water to a concentration of 192 ( ⁇ g / ml).
- concentration of 192 ⁇ g / ml
- the optical isomer preparation process of the Euler have been provided by the present invention, and the optically active body obtained by the process has high purity and optical purity e.e.>95%.
- the antibacterial activity of (S)-Ulyfloxacin obtained by splitting is 3 to 10 times that of (R)-Ulyfloxacin and 2 times or more that of (Shi)-Ulyfloxacin.
- the method of the invention is simple, has no special equipment requirements, is advantageous for industrial mass production, and has industrial applicability.
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Description
尤利沙星光学异构体的制备方法
技术领域 本发明基于申请日为 2008年 4月 3日的中国专利申请 200810027212. 3,该 申请的内容作为参考引入本文。
本发明涉及化学药物领域的制备方法, 具体涉及 6-氟 -1-甲基 -4-氧代- ( 1- 哌嗪基) -1H,4H-[1,3]硫氮杂环丁垸并 [3, 2-a]喹啉 -3-羧酸光异构体的制备方法。 背景技术
尤利沙星, 国际通用名为 Ulifloxacm, 是一种抗感染效果显著的喹诺酮类 药物, 其化学名称为 (士) 6-氟 -1-甲基 -4-氧代- ( 1-哌嗪基) -1H,4H-[1,3]硫氮 杂环丁垸并 [3, 2-a]喹啉 -3-羧酸, 其结构式如下式 1 :
1
尤利沙星对革兰阳性菌和革兰阴性菌具有广谱抗菌作用,特别是对金黄色 葡萄球菌、 肺炎链球菌、 粪肠球菌、 粘液沙雷菌、 绿脓杆菌等细菌显示出强大 的抗菌效果。 体内外实验均表明,尤利沙星不仅抗菌谱广,体内活性强,而且较之 环丙沙星和氧氟沙星具有优良的杀菌作用和抗生素后效应、 细胞毒性低、 向中 枢神经系统移动移行少等优点。
尤利沙星含有一手性碳原子,它可以产生旋光性不同的光学异构体(s ) -尤 利沙星, 结构式如下式 2和 (R) -尤利沙星, 结构式如下式 3, ( S) -尤利沙星 的体外抗菌活性是 (R) -尤利沙星的 3-10倍, 是 (士) -尤利沙星的 2倍以上。
日本研究者 Jun Segawa等 [Chem.Pharm.Bull.43(7) 1238-1240]利用高效液相 色谱法, 将尤利沙星的中间体 6, 7-二氟 -1-甲基 -4-氧代 -1H,4H-[1,3]硫氮杂环丁 垸并 [3, 2-a]喹啉 -3-羧酸乙酯 (简称 P8 ) 进行手性拆分分离, 得到 (+ ) -P8 和 (一) -P8, 然后由 (+ ) -P8和 (一) -P8开始, 分别经过两歩化学合成反 应得到( + ) -和(一) -尤利沙星; 并且通过单晶 X-射线分析确证( + ) -和(一) -尤利沙星的 C-1绝对构型分别为 R和 S。显然上述用于制备尤利沙星光学异构 体的方法存在设备投入大, 产量低, 仅适合于学术研究, 而无法应用于工业规 模生产。 因此有必要进一歩研究新的适合产业化生产制备 (S) -尤利沙星的方 法。
发明内容 本发明的目的是采用一种适合产业化的方法制备尤利沙星的光学旋光异构 体。
为达到本发明的目的, 所采用的技术方案是: 取 (士) 6-氟 -1-甲基 -4-氧代- ( 1-哌嗪基) -1H,4H-[1,3]硫氮杂环丁垸并 [3, 2-a]喹啉 -3-羧酸溶解于二甲基亚 砜, 搅拌下滴加 D-酒石酸的二甲基亚砜溶液, 在室温 20~40°C搅拌 20小时, 得到(S) -尤利沙星 -D-酒石酸盐沉淀, 此盐用二甲基亚砜为溶剂重结晶, 再将 结晶悬浮于 30倍的水中,搅拌下用 NaOH水溶液调节 pH值至 7-8,得沉淀物, 过滤,滤饼干燥,得到如下结构式的(S) -尤利沙星 2,光学纯度: e.e.大于 95%; 或将(士) 6-氟 -1-甲基 -4-氧代- ( 1-哌嗪基) -1H,4H-[1,3]硫氮杂环丁垸并 [3, 2-a] 喹啉 -3-羧酸溶解于二甲基亚砜,搅拌下滴加 L-酒石酸的二甲基亚砜溶液,在室 温 20~40°C搅拌 20小时, 得到 (R) -尤利沙星 -L-酒石酸盐沉淀, 此盐在二甲 基亚砜溶剂中重结晶, 过滤, 将滤饼悬浮于 30倍的水中, 搅拌下用 NaOH水
溶液调节 pH值至 7-8, 得沉淀物, 过滤, 滤饼干燥, 得到如下结构式的 (R) - 尤利沙星 3, 光学纯度: e.e.大于 95%。
本发明所提供的尤利沙星光学异构体制备工艺, 方法简便, 无特殊设备 要求, 利于工业化批量生产, 所得光学活性体纯度高。 以下实施例进一歩阐述 技术方案和有益效果。 具体实施方式
实施例 1 (S) -尤利沙星的制备
将消旋的尤利沙星 105克溶解于 1500mL的二甲基亚砜中,搅拌下滴加 27 克 D-酒石酸溶解于 405mL 二甲基亚砜的溶液, 出现浑浊和沉淀, 室温下搅拌 20小时, 沉淀过滤, 所得固体在真空下干燥得 86克, 将此固体于二甲基亚砜 中重结晶, 得到左旋尤利沙星 -D-酒石酸盐 37克, 经过元素分析
C49.08%,H5.06%,N9.50%,S7.44% (分子组成: C16H16FN303S · 1/2C4H606 · ¾0, 计算值 C48.86%,H4.78,N9.50%,S7.25%; 将此盐加入水成悬浮液, 搅拌下用 2%NaOH水溶液调节 pH值到 7-8, 沉淀过滤干燥, 得到 (S) -尤利沙星 24.5 克, 比旋度 [ :。=—143.4° (c=0.15, O.lmol/LNaOH); JH-NMR (DMSO-d6) δ 2.11(3Η, d, j=6.2Hz) , 2.85~3.20(8H, m) , 6.40(1H, q, j=6.2Hz) , 6.89(1H, d, j=7.4Hz) , 7.79(1H, d, j=13.9Hz), 光学纯度 e.e.〉95%。
实施例 2 (R) -尤利沙星
将消旋的尤利沙星 105克溶解于 1500mL的 DMSO中, 搅拌下滴加 27 克 L-酒石酸溶解于 405mL DMSO的溶液, 出现浑浊和沉淀, 室温下搅拌 20小 时, 过滤, 得到的固体于真空下干燥得 82克, 将此固体于 DMSO中重结晶纯 化得到到右旋尤利沙星 -L-酒石酸盐 34克, 将此盐加入水成悬浮液, 搅拌下用 2%NaOH水溶液调节 pH值到 7-8, 过滤干燥, 得到 (R) -尤利沙星 22克, 比 旋度 [ "] ^= + 139.2° (c=0.15, O.lmol/LNaOH) , 光学纯度 e.e.〉95%。
实施例 3 体外抗菌试验
试验方法: 采用琼脂稀释法进行最小抑菌浓度 (MIC) 的测定, 将不同浓 度的抗菌药物, 分别加入到定量的琼脂培养基中, 混匀, 制成固体平皿, 使每 一各平皿中所含抗菌药物的浓度相差二倍, 再把待测细菌点种到加含有抗菌药
物的琼脂培养基的表面上, 培养, 根据细菌生长情况判读结果。 根据美国临床 实验室标准化委员会标准,将平板置于暗色、无反光物体表面上判断试验终点, 以无菌生长的最低药物浓度为对该株细菌的最低抑菌浓度 (MIC), 在全部实验 中均以质控菌株的 MIC判断是否符合美国临床实验室标准化委员会质控标准。
如果出现有 2个以上菌落生长于含药浓度高于终点水平的琼脂平板上, 或 低浓度药物琼脂平板上不长而高浓度药物琼脂平板上生长现象, 则应检查培养 物纯度或重复试验。
试验样品: 环丙沙星、 左氧氟沙星、 (士) 尤利沙星为市售样品, 作为对 照药。 (S) -尤利沙星、 (R) -尤利沙星均为按本专利实施例自制。
测试菌为肺炎克雷伯菌(菌株号为 CMCC 46114-8)、 铜绿假单胞菌(菌株 号为 CMCC10104、 ATCC 27853 )、 大肠埃希菌 (菌株号为 ATCC8739、 CMCC44102、 ATCC25922 )、 金黄色葡萄球菌 (菌株号为 CMCC 26003、 ATCC6538, ATCC25925), 其他实验菌珠为医院临床急性细菌性呼吸道或泌尿 道感染患者的痰、 咽拭子或尿中分离, 并经医院鉴定的细菌。
将 (S) -尤利沙星、 (R) -尤利沙星等供试品按标示量校正后精密称取相 当于 96mg 尤利沙星的受试药物, 用灭菌蒸馏水溶解定容至 50ml; 盐酸左氧氟 沙星注射液、 乳酸环丙沙星氯化钠注射液, 均用灭菌蒸馏水稀释至浓度为 192(^g/ml的溶液。 体外抗菌实验结果见表 1。
表 1、 体外抗菌试验 MIC ( μ g/ml)
工业实用性 本发明所提供的尤利沙星光学异构体制备工艺, 该工艺所得光学活性体纯 度高, 光学纯度 e.e.〉95%。 且拆分得到的 (S) -尤利沙星的抗菌活性是 (R) -尤利沙星的 3〜10倍, 是 (士) -尤利沙星的 2倍或以上。 本发明方法简便, 无特殊设备要求, 利于工业化批量生产, 具有工业实用性。
Claims
1、 一种尤利沙星光学异构体的制备方法, 其特征在于:
取 (士) 6-氟 -1-甲基 -4-氧代- ( 1-哌嗪基) -1H,4H-[1,3]硫氮杂环丁垸并 [3, 2-a] 喹啉 -3-羧酸溶解于二甲基亚砜,搅拌下滴加 D-酒石酸的二甲基亚砜溶液,在室 温 20~40°C搅拌 20小时, 得到 (S) -尤利沙星 -D-酒石酸盐沉淀, 此盐用二甲 基亚砜为溶剂重结晶, 再将结晶悬浮于 30倍的水中, 搅拌下用 NaOH水溶液 调节 pH值至 7-8, 得沉淀物, 过滤, 滤饼干燥, 得到如下结构式的 (S) -尤利 沙星 (2), 或将 (士) 6-氟 -1-甲基 -4-氧代- ( 1-哌嗪基) -1H,4H-[1,3]硫氮杂环 丁垸并 [3, 2-a]喹啉 -3-羧酸溶解于二甲基亚砜, 搅拌下滴加 L-酒石酸的二甲基 亚砜溶液, 在室温 20~40°C搅拌 20小时, 得到 (R) -尤利沙星 -L-酒石酸盐沉 淀, 此盐在二甲基亚砜溶剂中重结晶, 过滤, 将滤饼悬浮于 30倍的水中, 搅
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SEGAWA, J. ET AL.: "Studies on pyridonecarboxylic acids. IV Synthesis and antibacterial activity evaluation of S-(-)- and R-(+)-6-fluoro-1-methyl-4-oxo-7-(1- piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acids", CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 43, no. 7, 1995, pages 1238 - 1240 * |
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