WO2021120063A1

WO2021120063A1 - Method for continuously synthesizing tazobactam intermediate

Info

Publication number: WO2021120063A1
Application number: PCT/CN2019/126377
Authority: WO
Inventors: 洪浩; 卢江平; 包登辉; 刘超杰; 王学智
Original assignee: 凯莱英医药集团（天津）股份有限公司
Priority date: 2019-12-18
Filing date: 2019-12-18
Publication date: 2021-06-24

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

Continuous synthesis method of tazobactam intermediate

Technical field

The invention relates to the field of organic synthesis, in particular to a continuous synthesis method of tazobactam intermediates.

Background technique

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:

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:

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:

Summary of the invention

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.

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):

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.

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.

Further, the molar ratio of diphenylmethyl penicillane sulfoxide to 2-mercaptobenzothiazole is 1: (0.8-2.0).

Further, the molar ratio of diphenylmethyl penicillane sulfoxide to 2-mercaptobenzothiazole is 1: (0.98 to 1.05).

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.

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.

Further, the continuous reaction device is selected from a tubular continuous reactor or a columnar reactor.

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.

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.

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.

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.

Detailed ways

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.

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):

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

Example 1

The synthetic route of tazobactam intermediate is as follows:

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%.

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.

Example 2

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.

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%.

Example 3

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.

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%.

Example 4

The difference from Example 1 is that the molar ratio of diphenylmethyl penicillane sulfoxide to 2-mercaptobenzothiazole is 1:0.8.

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.

Example 5

The difference from Example 1 is that the continuous reaction device is a columnar continuous reactor.

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.

From the above description, it can be seen that the above-mentioned embodiments of the present invention achieve the following technical effects:

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.

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

A continuous synthesis method of tazobactam intermediate, characterized in that the tazobactam intermediate has the structure shown in formula (I):

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;

The continuous synthesis method includes:

Continuously transporting penicillane sulfoxide diphenylmethyl ester and 2-mercaptobenzothiazole to a continuous reaction device for ring-opening reaction, and continuously discharging the tazobactam intermediate;

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.
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.
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).
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).
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.
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.
The continuous synthesis method according to claim 5, wherein the continuous reaction device is selected from a tubular continuous reactor or a column reactor.
The continuous synthesis method according to claim 5, wherein the continuous synthesis method further comprises:

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.
The continuous synthesis method according to claim 8, wherein the device used in the continuous synthesis method further comprises:

A temperature detection device, the temperature detection device is used to monitor the reaction temperature in the continuous reaction device;

A pressure detection device, which is used to monitor the reaction pressure in the continuous reaction device;

An online process analysis device, which is used to detect the product composition of the continuous reaction device.
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.