WO2021120063A1 - Method for continuously synthesizing tazobactam intermediate - Google Patents
Method for continuously synthesizing tazobactam intermediate Download PDFInfo
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- WO2021120063A1 WO2021120063A1 PCT/CN2019/126377 CN2019126377W WO2021120063A1 WO 2021120063 A1 WO2021120063 A1 WO 2021120063A1 CN 2019126377 W CN2019126377 W CN 2019126377W WO 2021120063 A1 WO2021120063 A1 WO 2021120063A1
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- the invention relates to the field of organic synthesis, in particular to a continuous synthesis method of tazobactam intermediates.
- Tazobactam is currently recognized as the ⁇ -lactamase inhibitor with the broadest antibacterial spectrum, the best resistance, the best clinical application effect, and the most promising. Due to the excellent properties of tazobactam, the research on its synthesis and clinical application has been very active at home and abroad. With the continuous improvement of the level of organic synthesis, its synthesis route and technology have been continuously improved. However, due to its long synthetic steps and complex synthetic technology, it is still a hot spot in synthetic research. The synthetic route of tazobactam is as follows:
- the main purpose of the present invention is to provide a continuous synthesis method of tazobactam intermediates, so as to solve the problem of poor product selectivity when synthesizing tazobactam intermediates by using existing synthetic methods, thereby causing low yield.
- tazobactam intermediate has the structure shown in formula (I):
- the device used in the above continuous synthesis method includes: a continuous reaction device and a heat exchange device, the heat exchange device is used to adjust the reaction temperature of the continuous reaction device;
- the continuous synthesis method includes: penicillane sulfoxide diphenyl methyl ester and 2 -Mercaptobenzothiazole is continuously transported to the continuous reaction device for ring-opening reaction, and the tazobactam intermediate is continuously discharged; the temperature of the ring-opening reaction is 80-160°C, the residence time of the material is 10-100min, and the reaction The pressure is 0-10MPa.
- reaction temperature of the ring-opening reaction is 140-150°C
- residence time of the materials is 10-20 min
- reaction pressure is 0-10 MPa.
- the molar ratio of diphenylmethyl penicillane sulfoxide to 2-mercaptobenzothiazole is 1: (0.8-2.0).
- the molar ratio of diphenylmethyl penicillane sulfoxide to 2-mercaptobenzothiazole is 1: (0.98 to 1.05).
- the continuous synthesis method includes adding a solvent during the ring-opening reaction, and the amount of the solvent is 10-100 mL/g relative to the amount of diphenylmethyl penicillane sulfoxide.
- the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, acetone, acetonitrile, N , N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, isopropanol, two Methyl chloride, biphenyl, ethylene glycol, hexamethyl triamine phosphate, phenol, pyridine, m-xylene, o-xylene, diphenyl ether, cyclohexanone, cyclohexanol, o-cresol, diethyl carbonate, One or more of the group consisting of diethyl oxalate.
- the continuous reaction device is selected from a tubular continuous reactor or a columnar reactor.
- the above-mentioned continuous synthesis method further includes: under the action of a liquid pump, transporting a mixture of penicillane sulfoxide diphenylmethyl ester, 2-mercaptobenzothiazole and a solvent to the continuous reaction device, and using back pressure
- the valve and pressure sensor regulate the pressure in the continuous reaction device.
- the device used in the above continuous synthesis method further includes: a temperature detection device, a pressure detection device and an online process analysis device, the temperature detection device is used to monitor the reaction temperature in the continuous reaction device; the pressure detection device is used to monitor the continuous reaction The reaction pressure in the device, the online process analysis device is used to detect the product composition of the continuous reaction device.
- the device used in the continuous synthesis method also includes an automated control system, which is electrically connected to the liquid pump, back pressure valve, pressure sensor, heat exchange device, temperature detection device, pressure detection device and online process analysis device.
- the continuous reaction has many advantages such as high heat exchange efficiency, precise and controllable reaction time, and easy to scale-up production.
- the continuous reaction process and continuous reaction equipment are used to instantly heat the raw materials to a predetermined reaction temperature, and the product system after the reaction is instantaneously reduced to a specific temperature.
- the reaction temperature and reaction time By precisely controlling the reaction temperature and reaction time, the production of isomers due to over-temperature or prolonged reaction time can be effectively avoided in the kettle-type process, the selectivity and yield of the reaction are significantly improved, and scale-up production is easy to realize.
- the device used in the above continuous synthesis method includes: a continuous reaction device and a heat exchange device, the heat exchange device is used to adjust the reaction temperature of the continuous reaction device;
- the continuous synthesis method includes: penicillane sulfoxide diphenyl methyl ester and 2 -Mercaptobenzothiazole is continuously transported to the continuous reaction device for ring-opening reaction, and the tazobactam intermediate is continuously discharged; the temperature of the ring-opening reaction is 80-160°C, the residence time of the material is 10-100min, and the reaction The pressure is 0-10MPa.
- the continuous reaction Compared with the traditional kettle-type reaction, the continuous reaction has many advantages such as high heat exchange efficiency, precise and controllable reaction time, and easy to scale-up production.
- the continuous reaction process and continuous reaction equipment are used to instantly heat the raw materials to the predetermined reaction temperature, and the product system after the reaction is instantaneously reduced to a specific temperature.
- the reaction temperature and reaction time By precisely controlling the reaction temperature and reaction time, the production of isomers due to over-temperature or prolonged reaction time in the kettle-type process can be effectively avoided, the selectivity and yield of the reaction are significantly improved, and the scale-up production is easy to realize.
- the reaction temperature of the ring-opening reaction is 140-150°C
- the residence time of the materials is 10-20 min
- the reaction pressure is 0-10 MPa.
- the reaction temperature, the residence time of the materials and the reaction pressure include but are not limited to the above-mentioned ranges, and limiting them within the above-mentioned ranges is beneficial to further increase the selectivity of the product, and thus to further increase the yield of the tazobactam intermediate.
- the molar ratio of diphenylmethyl penicillane sulfoxide to 2-mercaptobenzothiazole is 1: (0.8-2.0). Compared with other ranges, limiting it to the above range is beneficial to increase the conversion rate of the reaction raw materials. In order to further increase the conversion rate of the reaction raw materials, it is more preferable that the molar ratio of diphenylmethyl penicillane sulfoxide to 2-mercaptobenzothiazole is 1: (0.98 to 1.05).
- the above-mentioned continuous synthesis method includes adding a solvent during the ring-opening reaction, and the amount of the solvent is 10-100 mL/g relative to the amount of diphenylmethyl penicillane sulfoxide. Adding a solvent while limiting the amount of the solvent within the above range is beneficial to improve the compatibility of the reaction raw materials, thereby making the reaction more complete.
- the above-mentioned solvent includes but is not limited to tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene , Xylene, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, dimethylsulfoxide, Methanol, ethanol, isopropanol, dichloromethane, biphenyl, ethylene glycol, hexamethyltriamine phosphate, phenol, pyridine, m-xylene, o-xylene, diphenyl ether, cyclohexanone, cyclohexanol, One or more of the group consisting of o-cresol, diethyl carbonate and diethyl
- the continuous reaction device includes but is not limited to a tubular continuous reactor or a column reactor.
- the use of the above two continuous reaction devices is beneficial to further improve the heat exchange efficiency, so that the temperature in the continuous reaction device can be controlled more accurately, thereby improving the selectivity of the ring-opening reaction.
- the continuous synthesis method further includes: under the action of a liquid pump, the penicillane sulfoxide diphenylmethyl ester, 2-mercapto group
- the mixed liquid of benzothiazole and solvent is delivered to the continuous reaction device, and the pressure in the continuous reaction device is adjusted by using a back pressure valve and a pressure sensor.
- the above-mentioned continuous synthesis method includes: under the action of a liquid pump, transporting a mixture of penicillane sulfoxide diphenylmethyl ester and a solvent to the continuous reaction device; in another liquid pump Under the action of, the mixture of 2-mercaptobenzothiazole and solvent is delivered to the continuous reaction device, and the pressure in the continuous reaction device is adjusted by a back pressure valve and a pressure sensor.
- the device used in the above continuous synthesis method further includes: a temperature detection device, a pressure detection device and an online process analysis device (PAT device), the temperature detection device is used to monitor the reaction temperature in the continuous reaction device
- the pressure detection device is used to monitor the reaction pressure in the continuous reaction device
- the online process analysis device is used to detect the product composition of the continuous reaction device.
- the setting of temperature detection device and pressure detection device can monitor the reaction temperature and reaction pressure in the continuous reaction device in real time.
- the online process analysis device is helpful for real-time monitoring of the product composition of the continuous reaction device, thereby controlling its reaction time.
- the apparatus used in the above-mentioned continuous synthesis method It also includes an automated control system, which is electrically connected with a liquid pump, a back pressure valve, a pressure sensor, a heat exchange device, a temperature detection device, a pressure detection device, and an online process analysis device.
- the product contains (R)-2-[2-(benzothiazol-2-yldisulfanyl)-4-oxo-azetidin-1-yl]-3-methyl-
- the purity of the but-3-enoic acid benzhydryl ester is 96%, and the yield is 95%; and the above-mentioned reaction equipment can continue to operate and realize online replacement of equipment without stopping the machine.
- Example 1 The difference from Example 1 is: the temperature of the ring-opening reaction is 100°C, the residence time of the materials is 60 min, and the reaction pressure is 2 to 3 MPa.
- the product contains (R)-2-[2-(benzothiazol-2-yldisulfanyl)-4-oxo-azetidin-1-yl]-3-methyl-
- the purity of but-3-enoic acid benzhydryl ester was 84.3%, and the yield was 78.1.wt%.
- Example 1 The difference from Example 1 is that the reaction is carried out under normal pressure, the temperature of the ring-opening reaction is 100°C, the residence time of the materials is 60 min, and the reaction pressure is 0 MPa.
- the product contains (R)-2-[2-(benzothiazol-2-yldisulfanyl)-4-oxo-azetidin-1-yl]-3-methyl-
- the purity of but-3-enoic acid benzhydryl ester was 84.1%, and the yield was 77.9 wt%.
- Example 1 The difference from Example 1 is that the molar ratio of diphenylmethyl penicillane sulfoxide to 2-mercaptobenzothiazole is 1:0.8.
- the product contains (R)-2-[2-(benzothiazol-2-yldisulfanyl)-4-oxo-azetidin-1-yl]-3-methyl-
- the purity of benzhydryl but-3-enoate was 83.7%, and the yield was 78.8% by weight.
- Example 2 The difference from Example 1 is that the continuous reaction device is a columnar continuous reactor.
- the product contains (R)-2-[2-(benzothiazol-2-yldisulfanyl)-4-oxo-azetidin-1-yl]-3-methyl-
- the purity of but-3-enoic acid benzhydryl ester was 90.4%, and the yield was 87.0% by weight.
- the use of heat exchange devices and continuous reaction devices can instantly heat the raw materials to a predetermined reaction temperature, and the product system after the reaction can instantly drop to a specific temperature.
- the reaction temperature and reaction time By precisely controlling the reaction temperature and reaction time, the production of isomers due to over-temperature or prolonged reaction time in the kettle-type process can be effectively avoided, the selectivity and yield of the reaction are significantly improved, and the scale-up production is easy to realize.
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Abstract
Provided is a method for continuously synthesizing a tazobactam intermediate. The devices used in the continuous synthesis method comprise: a continuous reaction device and a heat exchange device, the heat exchange device being used to adjust the reaction temperature of the continuous reaction device. The method comprises: continuously delivering penicillane sulfoxide diphenylmethyl ester and 2-mercaptobenzothiazole into a continuous reaction device for a ring-opening reaction, and continuously discharging a tazobactam intermediate; the temperature of the ring-opening reaction is 80-160℃, the material retention time is 10-100 min, and the reaction pressure is 0-10 MPa. By using the heat exchange device and the continuous reaction device, raw materials can instantly be heated to a predetermined reaction temperature, and a product system after reaction can instantly be reduced to a specific temperature. By precisely controlling the reaction temperature and reaction time, the generation of isomers due to the temperature of a reaction being excessive or reaction time being prolonged in a kettle-type process can be effectively prevented. Moreover, the selectivity and yield of a reaction are significantly improved, and scaled-up production can be easily achieved.
Description
本发明涉及有机合成领域,具体而言,涉及一种他唑巴坦中间体的连续合成方法。The invention relates to the field of organic synthesis, in particular to a continuous synthesis method of tazobactam intermediates.
β-内酰胺抑制剂和不耐酶的β-内酰胺抗生素的联合应用,增强了后者的抗菌活性,扩大了抗菌谱,已成为提高β-内酰胺类抗生素疗效的重要手段。他唑巴坦是目前公认的抗菌谱最广、抗性最好、临床应用效果最好、最具有前途的β-内酰胺酶抑制剂。由于他唑巴坦的优异性能,目前国内外对其合成及临床应用的研究一直十分活跃,随着有机合成水平的不断提高,它的合成路线及工艺不断得到完善。但由于其合成步骤较长,合成技术复杂,至今仍是合成研究的热点,他唑巴坦的合成路线如下:The combined application of β-lactam inhibitors and enzyme intolerant β-lactam antibiotics enhances the antibacterial activity of the latter, expands the antibacterial spectrum, and has become an important means to improve the efficacy of β-lactam antibiotics. Tazobactam is currently recognized as the β-lactamase inhibitor with the broadest antibacterial spectrum, the best resistance, the best clinical application effect, and the most promising. Due to the excellent properties of tazobactam, the research on its synthesis and clinical application has been very active at home and abroad. With the continuous improvement of the level of organic synthesis, its synthesis route and technology have been continuously improved. However, due to its long synthetic steps and complex synthetic technology, it is still a hot spot in synthetic research. The synthetic route of tazobactam is as follows:
在他唑巴坦的合成中,(R)-2-[2-(苯并噻唑-2-基二硫烷基)-4-氧代-氮杂环丁烷-1-基]-3-甲基-丁-3-烯酸二苯甲基酯是合成过程中关键的中间体之一,分子式:C
28H
24N
2O
3S
3,分子量:532.70,结构式如下所示:
In the synthesis of tazobactam, (R)-2-[2-(benzothiazol-2-yldisulfanyl)-4-oxo-azetidin-1-yl]-3- Methyl-but-3-enoic acid benzhydryl ester is one of the key intermediates in the synthesis process, molecular formula: C 28 H 24 N 2 O 3 S 3 , molecular weight: 532.70, the structural formula is as follows:
现有文献报道了以反应釜作为反应场所,以青霉烷亚砜酸二苯甲酯和2-巯基苯并噻唑为初始原料,甲苯为溶剂,制备(R)-2-[2-(苯并噻唑-2-基二硫烷基)-4-氧代-氮杂环丁烷-1-基]-3-甲基-丁-3-烯酸二苯甲基酯的方法。通过实验发现该反应在反应过程中会生成双键异构体,产物在T>50℃时开始缓慢转化成异构体,导致收率和选择性降低(收率低于70wt%)。异构体转化过程如下:Existing literature reports that the reaction kettle is used as the reaction site, and diphenylmethyl penicillane sulfoxide and 2-mercaptobenzothiazole are used as starting materials, and toluene is used as the solvent to prepare (R)-2-[2-(benzene Thiazol-2-yldisulfanyl)-4-oxo-azetidin-1-yl]-3-methyl-but-3-enoic acid benzhydryl ester method. It is found through experiments that this reaction will generate double bond isomers during the reaction, and the product will slowly transform into isomers when T>50°C, resulting in a decrease in yield and selectivity (yield is less than 70wt%). The isomer conversion process is as follows:
发明内容Summary of the invention
本发明的主要目的在于提供一种他唑巴坦中间体的连续合成方法,以解决采用现有合成方法合成他唑巴坦中间体时存在产物选择性差,进而造成其产率低的问题。The main purpose of the present invention is to provide a continuous synthesis method of tazobactam intermediates, so as to solve the problem of poor product selectivity when synthesizing tazobactam intermediates by using existing synthetic methods, thereby causing low yield.
为了实现上述目的,根据本发明提供了一种他唑巴坦中间体的连续合成方法,他唑巴坦中间体具有式(Ⅰ)所示的结构:In order to achieve the above objective, according to the present invention, a continuous synthesis method of tazobactam intermediate is provided. The tazobactam intermediate has the structure shown in formula (I):
上述连续合成方法采用的装置包括:连续化反应装置和换热装置,换热装置用于调节连续化反应装置的反应温度;该连续合成方法包括:将青霉烷亚砜二苯甲酯和2-巯基苯并噻唑连续地输送至连续化反应装置中进行开环反应,并连续排出他唑巴坦中间体;开环反应的温度为80~160℃,物料的停留时间为10~100min,反应压力为0~10MPa。The device used in the above continuous synthesis method includes: a continuous reaction device and a heat exchange device, the heat exchange device is used to adjust the reaction temperature of the continuous reaction device; the continuous synthesis method includes: penicillane sulfoxide diphenyl methyl ester and 2 -Mercaptobenzothiazole is continuously transported to the continuous reaction device for ring-opening reaction, and the tazobactam intermediate is continuously discharged; the temperature of the ring-opening reaction is 80-160℃, the residence time of the material is 10-100min, and the reaction The pressure is 0-10MPa.
进一步地,开环反应的反应温度为140~150℃,物料的停留时间为10~20min,反应压力为0~10MPa。Further, the reaction temperature of the ring-opening reaction is 140-150°C, the residence time of the materials is 10-20 min, and the reaction pressure is 0-10 MPa.
进一步地,青霉烷亚砜酸二苯甲酯与2-巯基苯并噻唑的摩尔比为1:(0.8~2.0)。Further, the molar ratio of diphenylmethyl penicillane sulfoxide to 2-mercaptobenzothiazole is 1: (0.8-2.0).
进一步地,青霉烷亚砜酸二苯甲酯与2-巯基苯并噻唑的摩尔比为1:(0.98~1.05)。Further, the molar ratio of diphenylmethyl penicillane sulfoxide to 2-mercaptobenzothiazole is 1: (0.98 to 1.05).
进一步地,连续合成方法包括在开环反应过程中加入溶剂,相对于青霉烷亚砜酸二苯甲酯的用量,溶剂的用量为10~100mL/g。Further, the continuous synthesis method includes adding a solvent during the ring-opening reaction, and the amount of the solvent is 10-100 mL/g relative to the amount of diphenylmethyl penicillane sulfoxide.
进一步地,溶剂选自四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、乙二醇二甲醚、二乙二醇二甲醚、苯、甲苯、二甲苯、丙酮、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜、甲醇、乙醇、异丙醇、二氯甲烷、联苯、乙二醇、六甲基磷酸三胺、苯酚、吡啶、间二甲苯、邻二甲苯、二苯醚、环己酮、环己醇、邻甲酚、碳酸二乙酯、草酸二乙酯组成的组中的一种或多种。Further, the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, acetone, acetonitrile, N , N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, isopropanol, two Methyl chloride, biphenyl, ethylene glycol, hexamethyl triamine phosphate, phenol, pyridine, m-xylene, o-xylene, diphenyl ether, cyclohexanone, cyclohexanol, o-cresol, diethyl carbonate, One or more of the group consisting of diethyl oxalate.
进一步地,连续化反应装置选自管式连续反应器或柱状反应器。Further, the continuous reaction device is selected from a tubular continuous reactor or a columnar reactor.
进一步地,上述连续合成方法还包括:在液体泵的作用下,将青霉烷亚砜二苯甲酯、2-巯基苯并噻唑及溶剂的混合液输送至连续化反应装置,并采用背压阀和压力传感器调节连续化反应装置中的压力。Further, the above-mentioned continuous synthesis method further includes: under the action of a liquid pump, transporting a mixture of penicillane sulfoxide diphenylmethyl ester, 2-mercaptobenzothiazole and a solvent to the continuous reaction device, and using back pressure The valve and pressure sensor regulate the pressure in the continuous reaction device.
进一步地,上述连续合成方法采用的装置还包括:温度检测装置、压力检测装置和在线过程分析装置,温度检测装置用于监测连续化反应装置中的反应温度;压力检测装置用于监测连续化反应装置中的反应压力,在线过程分析装置用于检测连续化反应装置的产物组成。Further, the device used in the above continuous synthesis method further includes: a temperature detection device, a pressure detection device and an online process analysis device, the temperature detection device is used to monitor the reaction temperature in the continuous reaction device; the pressure detection device is used to monitor the continuous reaction The reaction pressure in the device, the online process analysis device is used to detect the product composition of the continuous reaction device.
进一步地,连续合成方法采用的装置还包括自动化控制系统,自动化控制系统与液体泵、背压阀、压力传感器、换热装置、温度检测装置、压力检测装置和在线过程分析装置电连接。Further, the device used in the continuous synthesis method also includes an automated control system, which is electrically connected to the liquid pump, back pressure valve, pressure sensor, heat exchange device, temperature detection device, pressure detection device and online process analysis device.
应用本发明的技术方案,相比于传统釜式反应,连续性反应具有热交换效率高、反应时间精准可控、易于放大生产等诸多优点。在换热装置的作用下,采用连续性反应工艺和连续反应设备,可将原料瞬间加热到预定的反应温度,反应后的产物体系瞬间降至特定温度。通过精准控制反应温度和反应时间,可有效避免釜式工艺中由于反应超温或延长时间导致异构体的产生,显著提高了反应的选择性和收率,且易于实现放大生产。By applying the technical scheme of the present invention, compared with the traditional kettle-type reaction, the continuous reaction has many advantages such as high heat exchange efficiency, precise and controllable reaction time, and easy to scale-up production. Under the action of the heat exchange device, the continuous reaction process and continuous reaction equipment are used to instantly heat the raw materials to a predetermined reaction temperature, and the product system after the reaction is instantaneously reduced to a specific temperature. By precisely controlling the reaction temperature and reaction time, the production of isomers due to over-temperature or prolonged reaction time can be effectively avoided in the kettle-type process, the selectivity and yield of the reaction are significantly improved, and scale-up production is easy to realize.
需要说明的是,在不冲突的情况下,本申请中的实施例及实施例中的特征可以相互组合。下面将结合实施例来详细说明本发明。It should be noted that the embodiments in the application and the features in the embodiments can be combined with each other if there is no conflict. The present invention will be described in detail below in conjunction with embodiments.
正如背景技术所描述的,采用现有合成方法合成他唑巴坦中间体时存在产物选择性差,进而造成其产率低的问题。为了解决上述技术问题,本申请提供了一种他唑巴坦中间体的连续合成方法,他唑巴坦中间体具有式(Ⅰ)所示的结构:As described in the background art, the use of existing synthetic methods to synthesize tazobactam intermediates has poor product selectivity, which in turn causes the problem of low yield. In order to solve the above technical problems, this application provides a continuous synthesis method of tazobactam intermediate, the tazobactam intermediate has the structure shown in formula (I):
上述连续合成方法采用的装置包括:连续化反应装置和换热装置,换热装置用于调节连续化反应装置的反应温度;该连续合成方法包括:将青霉烷亚砜二苯甲酯和2-巯基苯并噻唑连续地输送至连续化反应装置中进行开环反应,并连续排出他唑巴坦中间体;开环反应的温度为80~160℃,物料的停留时间为10~100min,反应压力为0~10MPa。The device used in the above continuous synthesis method includes: a continuous reaction device and a heat exchange device, the heat exchange device is used to adjust the reaction temperature of the continuous reaction device; the continuous synthesis method includes: penicillane sulfoxide diphenyl methyl ester and 2 -Mercaptobenzothiazole is continuously transported to the continuous reaction device for ring-opening reaction, and the tazobactam intermediate is continuously discharged; the temperature of the ring-opening reaction is 80-160℃, the residence time of the material is 10-100min, and the reaction The pressure is 0-10MPa.
相比于传统釜式反应,连续性反应具有热交换效率高、反应时间精准可控、易于放大生产等诸多优点。在换热装置的作用下,采用连续性反应工艺和连续反应设备,可将原料瞬间 加热到预定的反应温度,反应后的产物体系瞬间降至特定温度。通过精准控制反应温度和反应时间,可有效避免釜式工艺中由于反应超温或延长时间导致异构体的产生,显著提高了反应的选择性和收率,且易于实现放大生产。Compared with the traditional kettle-type reaction, the continuous reaction has many advantages such as high heat exchange efficiency, precise and controllable reaction time, and easy to scale-up production. Under the action of the heat exchange device, the continuous reaction process and continuous reaction equipment are used to instantly heat the raw materials to the predetermined reaction temperature, and the product system after the reaction is instantaneously reduced to a specific temperature. By precisely controlling the reaction temperature and reaction time, the production of isomers due to over-temperature or prolonged reaction time in the kettle-type process can be effectively avoided, the selectivity and yield of the reaction are significantly improved, and the scale-up production is easy to realize.
在一种优选的实施例中,开环反应的反应温度为140~150℃,物料的停留时间为10~20min,反应压力为0~10MPa。反应温度、物料的停留时间和反应压力包括但不限于上述范围,而将其限定在上述范围内有利于进一步提高产物的选择性,进而有利于进一步提高他唑巴坦中间体的收率。In a preferred embodiment, the reaction temperature of the ring-opening reaction is 140-150°C, the residence time of the materials is 10-20 min, and the reaction pressure is 0-10 MPa. The reaction temperature, the residence time of the materials and the reaction pressure include but are not limited to the above-mentioned ranges, and limiting them within the above-mentioned ranges is beneficial to further increase the selectivity of the product, and thus to further increase the yield of the tazobactam intermediate.
在一种优选的实施例中,青霉烷亚砜酸二苯甲酯与2-巯基苯并噻唑的摩尔比为1:(0.8~2.0)。相比于其他范围,将其限定在上述范围内有利于提高反应原料的转化率。为了进一步提高反应原料的转化率,更优选地,青霉烷亚砜酸二苯甲酯与2-巯基苯并噻唑的摩尔比为1:(0.98~1.05)。In a preferred embodiment, the molar ratio of diphenylmethyl penicillane sulfoxide to 2-mercaptobenzothiazole is 1: (0.8-2.0). Compared with other ranges, limiting it to the above range is beneficial to increase the conversion rate of the reaction raw materials. In order to further increase the conversion rate of the reaction raw materials, it is more preferable that the molar ratio of diphenylmethyl penicillane sulfoxide to 2-mercaptobenzothiazole is 1: (0.98 to 1.05).
在一种优选的实施例中,上述连续合成方法包括在开环反应过程中加入溶剂,相对于青霉烷亚砜酸二苯甲酯的用量,溶剂的用量为10~100mL/g。加入溶剂,同时将溶剂的量限定在上述范围内有利于提高反应原料的相容性,从而使其反应的更加充分。In a preferred embodiment, the above-mentioned continuous synthesis method includes adding a solvent during the ring-opening reaction, and the amount of the solvent is 10-100 mL/g relative to the amount of diphenylmethyl penicillane sulfoxide. Adding a solvent while limiting the amount of the solvent within the above range is beneficial to improve the compatibility of the reaction raw materials, thereby making the reaction more complete.
在一种优选的实施例中,上述溶剂包括但不限于四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、乙二醇二甲醚、二乙二醇二甲醚、苯、甲苯、二甲苯、丙酮、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜、甲醇、乙醇、异丙醇、二氯甲烷、联苯、乙二醇、六甲基磷酸三胺、苯酚、吡啶、间二甲苯、邻二甲苯、二苯醚、环己酮、环己醇、邻甲酚、碳酸二乙酯和草酸二乙酯组成的组中的一种或多种。相比于其它溶剂,上述几种溶剂对青霉烷亚砜酸二苯甲酯及2-巯基苯并噻唑的溶解性更优异。In a preferred embodiment, the above-mentioned solvent includes but is not limited to tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene , Xylene, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, dimethylsulfoxide, Methanol, ethanol, isopropanol, dichloromethane, biphenyl, ethylene glycol, hexamethyltriamine phosphate, phenol, pyridine, m-xylene, o-xylene, diphenyl ether, cyclohexanone, cyclohexanol, One or more of the group consisting of o-cresol, diethyl carbonate and diethyl oxalate. Compared with other solvents, the above-mentioned solvents have better solubility for penicillane sulfoxide diphenylmethyl and 2-mercaptobenzothiazole.
在一种优选的实施例中,连续化反应装置包括但不限于管式连续反应器或柱状反应器。相比于其它连续化反应装置,采用上述两种连续化反应装置有利于进一步提高换热效率,从而能够更加精准的控制连续化反应装置中温度,进而提高开环反应的选择性。In a preferred embodiment, the continuous reaction device includes but is not limited to a tubular continuous reactor or a column reactor. Compared with other continuous reaction devices, the use of the above two continuous reaction devices is beneficial to further improve the heat exchange efficiency, so that the temperature in the continuous reaction device can be controlled more accurately, thereby improving the selectivity of the ring-opening reaction.
为了更加精准的控制反应原料的用量以及反应压力,在一种优选的实施例中,该连续合成方法还包括:在液体泵的作用下,将青霉烷亚砜二苯甲酯、2-巯基苯并噻唑及溶剂的混合液输送至连续化反应装置,并采用背压阀和压力传感器调节连续化反应装置中的压力。在另一种优选的实施例中,上述连续合成方法包括:在液体泵的作用下,将青霉烷亚砜二苯甲酯与溶剂的混合液输送至连续化反应装置;在另一液体泵的作用下,将2-巯基苯并噻唑与溶剂的混合液输送至连续化反应装置,并采用背压阀和压力传感器调节连续化反应装置中的压力。In order to more accurately control the amount of reaction raw materials and the reaction pressure, in a preferred embodiment, the continuous synthesis method further includes: under the action of a liquid pump, the penicillane sulfoxide diphenylmethyl ester, 2-mercapto group The mixed liquid of benzothiazole and solvent is delivered to the continuous reaction device, and the pressure in the continuous reaction device is adjusted by using a back pressure valve and a pressure sensor. In another preferred embodiment, the above-mentioned continuous synthesis method includes: under the action of a liquid pump, transporting a mixture of penicillane sulfoxide diphenylmethyl ester and a solvent to the continuous reaction device; in another liquid pump Under the action of, the mixture of 2-mercaptobenzothiazole and solvent is delivered to the continuous reaction device, and the pressure in the continuous reaction device is adjusted by a back pressure valve and a pressure sensor.
在一种优选的实施例中,上述连续合成方法采用的装置还包括:温度检测装置、压力检测装置和在线过程分析装置(PAT装置),温度检测装置用于监测连续化反应装置中的反应温度,压力检测装置用于监测连续化反应装置中的反应压力,在线过程分析装置用于检测连续化反应装置的产物组成。设置温度检测装置和压力检测装置能够实时监控连续化反应装置中 的反应温度和反应压力。设置在线过程分析装置有利于实时监测连续化反应装置的产物组成,从而控制其反应时间。In a preferred embodiment, the device used in the above continuous synthesis method further includes: a temperature detection device, a pressure detection device and an online process analysis device (PAT device), the temperature detection device is used to monitor the reaction temperature in the continuous reaction device The pressure detection device is used to monitor the reaction pressure in the continuous reaction device, and the online process analysis device is used to detect the product composition of the continuous reaction device. The setting of temperature detection device and pressure detection device can monitor the reaction temperature and reaction pressure in the continuous reaction device in real time. The online process analysis device is helpful for real-time monitoring of the product composition of the continuous reaction device, thereby controlling its reaction time.
为了进一步提高上述连续化反应的自动化程度,同时更加精准的控制反应条件,以使他唑巴坦中间体获得更高的收率,在一种优选的实施例中,上述连续合成方法采用的装置还包括自动化控制系统,自动化控制系统与液体泵、背压阀、压力传感器、换热装置、温度检测装置、压力检测装置和在线过程分析装置电连接。In order to further increase the degree of automation of the above-mentioned continuous reaction, and at the same time more precisely control the reaction conditions, so as to obtain a higher yield of the tazobactam intermediate, in a preferred embodiment, the apparatus used in the above-mentioned continuous synthesis method It also includes an automated control system, which is electrically connected with a liquid pump, a back pressure valve, a pressure sensor, a heat exchange device, a temperature detection device, a pressure detection device, and an online process analysis device.
以下结合具体实施例对本申请作进一步详细描述,这些实施例不能理解为限制本申请所要求保护的范围。The application will be further described in detail below in conjunction with specific embodiments, and these embodiments should not be understood as limiting the scope of protection claimed by the application.
实施例1Example 1
他唑巴坦中间体的合成路线如下:The synthetic route of tazobactam intermediate is as follows:
在室温下,将青霉烷亚砜二苯甲酯(2.0kg,5.22mol)溶于20L甲苯中,记为溶液A;将2-巯基苯并噻唑(0.87kg,5.22mol)溶于20L DMF中,记为溶液B;分别用泵将溶液A和溶液B连续地送入管式连续反应器中,反应器控温145℃,反应器出口备压0.5~0.8MPa,保留时间15min,出口取样HPLC分析,原料剩余为≤0.5%。At room temperature, dissolve penicillane sulfoxide diphenylmethyl ester (2.0kg, 5.22mol) in 20L of toluene and record it as solution A; dissolve 2-mercaptobenzothiazole (0.87kg, 5.22mol) in 20L DMF , Marked as solution B; use pumps to continuously send solution A and solution B into the tubular continuous reactor. The temperature of the reactor is controlled at 145℃, the pressure at the reactor outlet is 0.5~0.8MPa, the retention time is 15min, and the outlet sampling HPLC analysis showed that the remaining raw material was ≤0.5%.
合成结束后,产物中(R)-2-[2-(苯并噻唑-2-基二硫烷基)-4-氧代-氮杂环丁烷-1-基]-3-甲基-丁-3-烯酸二苯甲基酯的纯度为96%,收率为95%;且上述反应设备可以持续运行并实现不停机在线更换设备。After the synthesis, the product contains (R)-2-[2-(benzothiazol-2-yldisulfanyl)-4-oxo-azetidin-1-yl]-3-methyl- The purity of the but-3-enoic acid benzhydryl ester is 96%, and the yield is 95%; and the above-mentioned reaction equipment can continue to operate and realize online replacement of equipment without stopping the machine.
实施例2Example 2
与实施例1的区别为:开环反应的温度为100℃,物料的停留时间为60min,反应压力2~3MPa。The difference from Example 1 is: the temperature of the ring-opening reaction is 100°C, the residence time of the materials is 60 min, and the reaction pressure is 2 to 3 MPa.
合成结束后,产物中(R)-2-[2-(苯并噻唑-2-基二硫烷基)-4-氧代-氮杂环丁烷-1-基]-3-甲基-丁-3-烯酸二苯甲基酯的纯度为84.3%,收率为78.1.wt%。After the synthesis, the product contains (R)-2-[2-(benzothiazol-2-yldisulfanyl)-4-oxo-azetidin-1-yl]-3-methyl- The purity of but-3-enoic acid benzhydryl ester was 84.3%, and the yield was 78.1.wt%.
实施例3Example 3
与实施例1的区别为:反应在常压下进行,开环反应的温度为100℃,物料的停留时间为60min,反应压力为0MPa。The difference from Example 1 is that the reaction is carried out under normal pressure, the temperature of the ring-opening reaction is 100°C, the residence time of the materials is 60 min, and the reaction pressure is 0 MPa.
合成结束后,产物中(R)-2-[2-(苯并噻唑-2-基二硫烷基)-4-氧代-氮杂环丁烷-1-基]-3-甲基-丁-3-烯酸二苯甲基酯的纯度为84.1%,收率为77.9.wt%。After the synthesis, the product contains (R)-2-[2-(benzothiazol-2-yldisulfanyl)-4-oxo-azetidin-1-yl]-3-methyl- The purity of but-3-enoic acid benzhydryl ester was 84.1%, and the yield was 77.9 wt%.
实施例4Example 4
与实施例1的区别为:青霉烷亚砜酸二苯甲酯与2-巯基苯并噻唑的摩尔比为1:0.8。The difference from Example 1 is that the molar ratio of diphenylmethyl penicillane sulfoxide to 2-mercaptobenzothiazole is 1:0.8.
合成结束后,产物中(R)-2-[2-(苯并噻唑-2-基二硫烷基)-4-氧代-氮杂环丁烷-1-基]-3-甲基-丁-3-烯酸二苯甲基酯的纯度为83.7%,收率为78.8wt%。After the synthesis, the product contains (R)-2-[2-(benzothiazol-2-yldisulfanyl)-4-oxo-azetidin-1-yl]-3-methyl- The purity of benzhydryl but-3-enoate was 83.7%, and the yield was 78.8% by weight.
实施例5Example 5
与实施例1的区别为:连续化反应装置为柱状连续反应器。The difference from Example 1 is that the continuous reaction device is a columnar continuous reactor.
合成结束后,产物中(R)-2-[2-(苯并噻唑-2-基二硫烷基)-4-氧代-氮杂环丁烷-1-基]-3-甲基-丁-3-烯酸二苯甲基酯的纯度为90.4%,收率为87.0wt%。After the synthesis, the product contains (R)-2-[2-(benzothiazol-2-yldisulfanyl)-4-oxo-azetidin-1-yl]-3-methyl- The purity of but-3-enoic acid benzhydryl ester was 90.4%, and the yield was 87.0% by weight.
从以上的描述中,可以看出,本发明上述的实施例实现了如下技术效果:From the above description, it can be seen that the above-mentioned embodiments of the present invention achieve the following technical effects:
采用换热装置和连续化反应装置可将原料瞬间加热到预定的反应温度,反应后的产物体系瞬间降至特定温度。通过精准控制反应温度和反应时间,可有效避免釜式工艺中由于反应超温或延长时间导致异构体的产生,显著提高了反应的选择性和收率,且易于实现放大生产。The use of heat exchange devices and continuous reaction devices can instantly heat the raw materials to a predetermined reaction temperature, and the product system after the reaction can instantly drop to a specific temperature. By precisely controlling the reaction temperature and reaction time, the production of isomers due to over-temperature or prolonged reaction time in the kettle-type process can be effectively avoided, the selectivity and yield of the reaction are significantly improved, and the scale-up production is easy to realize.
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。The above are only preferred embodiments of the present invention and are not used to limit the present invention. For those skilled in the art, the present invention can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
- 一种他唑巴坦中间体的连续合成方法,其特征在于,所述他唑巴坦中间体具有式(Ⅰ)所示的结构:A continuous synthesis method of tazobactam intermediate, characterized in that the tazobactam intermediate has the structure shown in formula (I):所述连续合成方法采用的装置包括:连续化反应装置和换热装置,所述换热装置用于调节所述连续化反应装置的反应温度;The devices used in the continuous synthesis method include: a continuous reaction device and a heat exchange device, and the heat exchange device is used to adjust the reaction temperature of the continuous reaction device;所述连续合成方法包括:The continuous synthesis method includes:将青霉烷亚砜二苯甲酯和2-巯基苯并噻唑连续地输送至连续化反应装置中进行开环反应,并连续排出所述他唑巴坦中间体;Continuously transporting penicillane sulfoxide diphenylmethyl ester and 2-mercaptobenzothiazole to a continuous reaction device for ring-opening reaction, and continuously discharging the tazobactam intermediate;所述开环反应的温度为80~160℃,物料的停留时间为10~100min,反应压力为0~10MPa。The temperature of the ring-opening reaction is 80-160°C, the residence time of the materials is 10-100 min, and the reaction pressure is 0-10 MPa.
- 根据权利要求1所述的连续合成方法,其特征在于,所述开环反应的反应温度为140~150℃,物料的停留时间为10~20min,所述反应压力为0~10MPa。The continuous synthesis method according to claim 1, wherein the reaction temperature of the ring-opening reaction is 140-150°C, the residence time of the materials is 10-20 min, and the reaction pressure is 0-10 MPa.
- 根据权利要求2所述的连续合成方法,其特征在于,所述青霉烷亚砜酸二苯甲酯与所述2-巯基苯并噻唑的摩尔比为1:(0.8~2.0)。The continuous synthesis method according to claim 2, wherein the molar ratio of the diphenylmethyl penicillane sulfoxide to the 2-mercaptobenzothiazole is 1:(0.8-2.0).
- 根据权利要求3所述的连续合成方法,其特征在于,所述青霉烷亚砜酸二苯甲酯与2-巯基苯并噻唑的摩尔比为1:(0.98~1.05)。The continuous synthesis method according to claim 3, wherein the molar ratio of the diphenylmethyl penicillane sulfoxide to 2-mercaptobenzothiazole is 1:(0.98-1.05).
- 根据权利要求1至4中任一项所述的连续合成方法,其特征在于,所述连续合成方法包括在所述开环反应过程中加入溶剂,相对于所述青霉烷亚砜酸二苯甲酯的用量,所述溶剂的用量为10~100mL/g。The continuous synthesis method according to any one of claims 1 to 4, wherein the continuous synthesis method comprises adding a solvent during the ring-opening reaction, relative to the penicillane sulfoxide diphenyl The amount of methyl ester, the amount of the solvent is 10-100 mL/g.
- 根据权利要求5所述的连续合成方法,其特征在于,所述溶剂选自四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、乙二醇二甲醚、二乙二醇二甲醚、苯、甲苯、二甲苯、丙酮、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜、甲醇、乙醇、异丙醇、二氯甲烷、联苯、乙二醇、六甲基磷酸三胺、苯酚、吡啶、间二甲苯、邻二甲苯、二苯醚、环己酮、环己醇、邻甲酚、碳酸二乙酯、草酸二乙酯组成的组中的一种或多种。The continuous synthesis method according to claim 5, wherein the solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether. Ether, benzene, toluene, xylene, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, two Methyl sulfoxide, methanol, ethanol, isopropanol, dichloromethane, biphenyl, ethylene glycol, hexamethyl triamine phosphate, phenol, pyridine, m-xylene, o-xylene, diphenyl ether, cyclohexanone , Cyclohexanol, o-cresol, diethyl carbonate, and diethyl oxalate.
- 根据权利要求5所述的连续合成方法,其特征在于,所述连续化反应装置选自管式连续反应器或柱状反应器。The continuous synthesis method according to claim 5, wherein the continuous reaction device is selected from a tubular continuous reactor or a column reactor.
- 根据权利要求5所述的连续合成方法,其特征在于,所述连续合成方法还包括:The continuous synthesis method according to claim 5, wherein the continuous synthesis method further comprises:在液体泵的作用下,将所述青霉烷亚砜二苯甲酯、所述2-巯基苯并噻唑及所述溶剂的混合液输送至所述连续化反应装置,并采用背压阀和压力传感器控制所述连续化反应装置中的压力。Under the action of a liquid pump, the mixed liquid of the penicillane sulfoxide diphenylmethyl ester, the 2-mercaptobenzothiazole and the solvent is transported to the continuous reaction device, and a back pressure valve and The pressure sensor controls the pressure in the continuous reaction device.
- 根据权利要求8所述的连续合成方法,其特征在于,所述连续合成方法采用的装置还包括:The continuous synthesis method according to claim 8, wherein the device used in the continuous synthesis method further comprises:温度检测装置,所述温度检测装置用于监测所述连续化反应装置中的反应温度;A temperature detection device, the temperature detection device is used to monitor the reaction temperature in the continuous reaction device;压力检测装置,所述压力检测装置用于监测所述连续化反应装置中的反应压力;A pressure detection device, which is used to monitor the reaction pressure in the continuous reaction device;在线过程分析装置,所述在线过程分析装置用于检测所述连续化反应装置的产物组成。An online process analysis device, which is used to detect the product composition of the continuous reaction device.
- 根据权利要求9所述的连续合成方法,其特征在于,所述连续合成方法采用的装置还包括自动化控制系统,所述自动化控制系统与所述液体泵、所述背压阀、所述压力传感器、所述换热装置、所述温度检测装置、所述压力检测装置和所述在线过程分析装置电连接。The continuous synthesis method according to claim 9, wherein the device used in the continuous synthesis method further comprises an automatic control system, the automatic control system and the liquid pump, the back pressure valve, and the pressure sensor , The heat exchange device, the temperature detection device, the pressure detection device and the online process analysis device are electrically connected.
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