CN111004231A - Continuous synthesis method of tazobactam intermediate - Google Patents
Continuous synthesis method of tazobactam intermediate Download PDFInfo
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Abstract
The invention provides a continuous synthesis method of a tazobactam intermediate. The device adopted by the continuous synthesis method comprises the following steps: the continuous reaction device comprises a continuous reaction device and a heat exchange device, wherein the heat exchange device is used for adjusting the reaction temperature of the continuous reaction device; the method comprises the following steps: continuously conveying the penam sulfoxide diphenylmethyl ester and the 2-mercaptobenzothiazole into a continuous reaction device for ring opening reaction, and continuously discharging a tazobactam intermediate; the temperature of the ring-opening reaction is 80-160 ℃, the retention time of the materials is 10-100 min, and the reaction pressure is 0-10 MPa. The heat exchanger and the continuous reactor can heat the material to preset reaction temperature and the reacted product system is lowered to specific temperature. By accurately controlling the reaction temperature and the reaction time, the generation of isomers caused by over-temperature reaction or prolonged reaction time in the kettle type process can be effectively avoided, the selectivity and yield of the reaction are obviously improved, and the large-scale production is easy to realize.
Description
Technical Field
The invention relates to the field of organic synthesis, and particularly relates to a continuous synthesis method of a tazobactam intermediate.
Background
β -lactam inhibitor and β -lactam antibiotic which is not enzyme-resistant, the combined application of the latter enhances the antibacterial activity of the latter and enlarges the antibacterial spectrum, which has become an important means for improving the curative effect of β -lactam antibiotic, tazobactam is the β -lactamase inhibitor which is widely recognized at present, has the best resistance and clinical application effect and is promising at present, the synthesis and clinical application of tazobactam are actively researched at home and abroad due to the excellent performance of tazobactam, and the synthesis route and the process of the tazobactam are continuously improved along with the continuous improvement of the organic synthesis level.
In the synthesis of tazobactam, (R) -2- [2- (benzothiazol-2-yl disulfanyl) -4-oxo-azetidin-1-yl]-3-methyl-but-3-enoic acid benzhydryl ester is one of the key intermediates in the synthesis process, formula: c28H24N2O3S3Molecular weight: 532.70, the structural formula is shown below:
the prior literature reports a method for preparing (R) -2- [2- (benzothiazol-2-yl disulfanyl) -4-oxo-azetidin-1-yl ] -3-methyl-but-3-enoic acid benzhydryl ester by using a reaction kettle as a reaction site, using penicillanic sulfoxide acid benzhydryl ester and 2-mercaptobenzothiazole as initial raw materials and toluene as a solvent. It was found by experiment that this reaction generates double bond isomers during the reaction, and the product starts to be slowly converted into isomers at T > 50 ℃, resulting in a decrease in yield and selectivity (yield less than 70 wt%).
The isomer conversion process is as follows:
disclosure of Invention
The invention mainly aims to provide a continuous synthesis method of a tazobactam intermediate, which aims to solve the problem that the yield is low due to poor product selectivity when the tazobactam intermediate is synthesized by adopting the conventional synthesis method.
In order to achieve the above object, according to the present invention, there is provided a continuous synthesis method of a tazobactam intermediate having a structure represented by formula (i):
the device adopted by the continuous synthesis method comprises the following steps: the continuous reaction device comprises a continuous reaction device and a heat exchange device, wherein the heat exchange device is used for adjusting the reaction temperature of the continuous reaction device; the continuous synthesis method comprises the following steps: continuously conveying the penam sulfoxide diphenylmethyl ester and the 2-mercaptobenzothiazole into a continuous reaction device for ring opening reaction, and continuously discharging a tazobactam intermediate; the temperature of the ring-opening reaction is 80-160 ℃, the retention time of the materials is 10-100 min, and the reaction pressure is 0-10 MPa.
Furthermore, the reaction temperature of the ring-opening reaction is 140-150 ℃, the retention time of the materials is 10-20 min, and the reaction pressure is 0-10 MPa.
Furthermore, the molar ratio of the penicillanic sulfoxide acid diphenylmethyl ester to the 2-mercaptobenzothiazole is 1 (0.8-2.0).
Furthermore, the molar ratio of the penicillanic sulfoxide acid diphenylmethyl ester to the 2-mercaptobenzothiazole is 1 (0.98-1.05).
Further, the continuous synthesis method comprises the step of adding a solvent in the ring-opening reaction process, wherein the dosage of the solvent is 10-100 mL/g relative to the dosage of the penicillanic sulfoxide acid diphenylmethyl ester.
Further, the solvent is one or more selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, isopropanol, dichloromethane, biphenyl, ethylene glycol, hexamethylphosphoric triamide, phenol, pyridine, m-xylene, o-xylene, diphenyl ether, cyclohexanone, cyclohexanol, o-cresol, diethyl carbonate, and diethyl oxalate.
Further, the continuous reaction device is selected from a tubular continuous reactor or a column reactor.
Further, the continuous synthesis method further comprises: under the action of a liquid pump, conveying the mixed liquid of the penam sulfoxide diphenyl methyl ester, the 2-mercaptobenzothiazole and the solvent to a continuous reaction device, and adjusting the pressure in the continuous reaction device by adopting a back pressure valve and a pressure sensor.
Further, the apparatus used in the continuous synthesis method further comprises: the device comprises a temperature detection device, a pressure detection device and an online process analysis device, wherein the temperature detection device is used for monitoring the reaction temperature in the continuous reaction device; the pressure detection device is used for monitoring the reaction pressure in the continuous reaction device, and the on-line process analysis device is used for detecting the product composition of the continuous reaction device.
Furthermore, the device adopted by the continuous synthesis method also comprises an automatic control system, and the automatic control system is electrically connected with the liquid pump, the back pressure valve, the pressure sensor, the heat exchange device, the temperature detection device, the pressure detection device and the online process analysis device.
Compared with the traditional kettle type reaction, the continuous reaction has the advantages of high heat exchange efficiency, accurate and controllable reaction time, easiness in scale-up production and the like. Under the action of the heat exchanger, the continuous reaction process and the continuous reaction equipment are adopted, the raw materials can be instantly heated to a preset reaction temperature, and the product system after reaction is instantly cooled to a specific temperature. By accurately controlling the reaction temperature and the reaction time, the generation of isomers caused by over-temperature reaction or prolonged reaction time in the kettle type process can be effectively avoided, the selectivity and yield of the reaction are obviously improved, and the large-scale production is easy to realize.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail with reference to examples.
As described in the background art, the synthesis of tazobactam intermediates by the existing synthesis methods has the problems of poor product selectivity and low yield. In order to solve the technical problems, the application provides a continuous synthesis method of a tazobactam intermediate, wherein the tazobactam intermediate has a structure shown in a formula (I):
the device adopted by the continuous synthesis method comprises the following steps: the continuous reaction device comprises a continuous reaction device and a heat exchange device, wherein the heat exchange device is used for adjusting the reaction temperature of the continuous reaction device; the continuous synthesis method comprises the following steps: continuously conveying the penam sulfoxide diphenylmethyl ester and the 2-mercaptobenzothiazole into a continuous reaction device for ring opening reaction, and continuously discharging a tazobactam intermediate; the temperature of the ring-opening reaction is 80-160 ℃, the retention time of the materials is 10-100 min, and the reaction pressure is 0-10 MPa.
Compared with the traditional kettle type reaction, the continuous reaction has the advantages of high heat exchange efficiency, accurate and controllable reaction time, easy amplification production and the like. Under the action of the heat exchanger, the continuous reaction process and the continuous reaction equipment are adopted, the raw materials can be instantly heated to a preset reaction temperature, and the product system after reaction is instantly cooled to a specific temperature. By accurately controlling the reaction temperature and the reaction time, the generation of isomers caused by over-temperature reaction or prolonged reaction time in the kettle type process can be effectively avoided, the selectivity and yield of the reaction are obviously improved, and the large-scale production is easy to realize.
In a preferred embodiment, the reaction temperature of the ring-opening reaction is 140-150 ℃, the residence time of the material 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 ranges, and limiting the reaction pressure within the above ranges is advantageous for further improving the selectivity of the product, and thus for further improving the yield of the tazobactam intermediate.
In a preferred embodiment, the molar ratio of the penicillanic acid diphenylmethyl ester to the 2-mercaptobenzothiazole is 1 (0.8-2.0). It is advantageous to limit the reaction raw material conversion rate to the above range as compared with other ranges. In order to further increase the conversion rate of the reaction raw materials, the molar ratio of the penicillanic acid diphenylmethyl ester to the 2-mercaptobenzothiazole is more preferably 1 (0.98-1.05).
In a preferred embodiment, the continuous synthesis method comprises adding a solvent during the ring-opening reaction, wherein the amount of the solvent is 10-100 mL/g relative to the amount of the benzhydryl penam sulfoxide. The addition of the solvent while limiting the amount of the solvent to the above range is advantageous for improving the compatibility of the reaction raw materials, thereby allowing the reaction thereof to be more complete.
In a preferred embodiment, the solvent includes, but is not limited to, one or more of the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, isopropanol, dichloromethane, biphenyl, ethylene glycol, hexamethylphosphoric triamide, phenol, pyridine, m-xylene, o-xylene, diphenyl ether, cyclohexanone, cyclohexanol, o-cresol, diethyl carbonate, and diethyl oxalate. The solvents described above are more excellent in solubility for diphenylmethyl penam sulfoxylate and 2-mercaptobenzothiazole than other solvents.
In a preferred embodiment, the continuous reaction apparatus includes, but is not limited to, a tubular continuous reactor or a column reactor. Compared with other continuous reaction devices, the two continuous reaction devices are favorable for further improving the heat exchange efficiency, so that the temperature in the continuous reaction device can be more accurately controlled, and the selectivity of the ring-opening reaction is further improved.
In order to control the amount of the reaction raw materials and the reaction pressure more precisely, in a preferred embodiment, the continuous synthesis method further comprises: under the action of a liquid pump, conveying the mixed liquid of the penam sulfoxide diphenyl methyl ester, the 2-mercaptobenzothiazole and the solvent to a continuous reaction device, and adjusting the pressure in the continuous reaction device by adopting a back pressure valve and a pressure sensor. In another preferred embodiment, the above continuous synthesis method comprises: under the action of a liquid pump, conveying the mixed solution of the penam sulfoxide diphenyl methyl ester and the solvent to a continuous reaction device; and under the action of another liquid pump, conveying the mixed liquid of the 2-mercaptobenzothiazole and the solvent to a continuous reaction device, and adjusting the pressure in the continuous reaction device by adopting a back pressure valve and a pressure sensor.
In a preferred embodiment, the apparatus used in the continuous synthesis method further comprises: the continuous reaction device comprises a temperature detection device, a pressure detection device and an online process analysis device (PAT device), wherein the temperature detection device is used for monitoring the reaction temperature in the continuous reaction device, the pressure detection device is used for monitoring the reaction pressure in the continuous reaction device, and the online process analysis device is used for detecting the product composition of the continuous reaction device. The temperature detection device and the pressure detection device are arranged to monitor the reaction temperature and the reaction pressure in the continuous reaction device in real time. The online process analysis device is favorable for monitoring the product composition of the continuous reaction device in real time, so that the reaction time of the continuous reaction device is controlled.
In order to further improve the automation degree of the continuous reaction and more precisely control the reaction conditions so as to obtain a higher yield of the tazobactam intermediate, in a preferred embodiment, the continuous synthesis method further comprises an automatic control system, wherein the automatic control system is electrically connected with the liquid pump, the back pressure valve, the pressure sensor, the heat exchange device, the temperature detection device, the pressure detection device and the on-line process analysis device.
The present application is described in further detail below with reference to specific examples, which should not be construed as limiting the scope of the invention as claimed.
Example 1
The synthetic route of the tazobactam intermediate is as follows:
penicillium sulfoxide diphenylmethyl ester (2.0kg, 5.22mol) was dissolved in 20L of toluene at room temperature and designated as solution A; 2-mercaptobenzothiazole (0.87kg,5.22mol) was dissolved in 20L of DMF and denoted as solution B; and (3) continuously feeding the solution A and the solution B into a tubular continuous reactor by using pumps respectively, controlling the temperature of the reactor to be 145 ℃, keeping the pressure of an outlet of the reactor to be 0.5-0.8 MPa, keeping the pressure for 15min, sampling the outlet, and analyzing by HPLC (high performance liquid chromatography), wherein the residual amount of the raw materials is less than or equal to 0.5%.
After the synthesis is finished, the purity of (R) -2- [2- (benzothiazol-2-yl disulfanyl) -4-oxo-azetidin-1-yl ] -3-methyl-butyl-3-olefine acid benzhydryl ester in the product is 96 percent, and the yield is 95 percent; and the reaction equipment can continuously run and realize the on-line replacement of the equipment without stopping.
Example 2
The differences from example 1 are: the temperature of the ring-opening reaction is 100 ℃, the retention time of the materials is 60min, and the reaction pressure is 2-3 MPa.
After the synthesis was complete, (R) -2- [2- (benzothiazol-2-yldisulfanyl) -4-oxo-azetidin-1-yl ] -3-methyl-but-3-enoic acid benzhydryl ester in the product had a purity of 84.3% and a yield of 78.1. wt.%.
Example 3
The differences from example 1 are: the reaction is carried out under normal pressure, the temperature of the ring-opening reaction is 100 ℃, the retention time of the materials is 60min, and the reaction pressure is 0 MPa.
After the synthesis was complete, (R) -2- [2- (benzothiazol-2-yldisulfanyl) -4-oxo-azetidin-1-yl ] -3-methyl-but-3-enoic acid benzhydryl ester in the product had a purity of 84.1% and a yield of 77.9. wt.%.
Example 4
The differences from example 1 are: the molar ratio of the penicillanic sulfoxide acid diphenylmethyl ester to the 2-mercaptobenzothiazole is 1: 0.8.
After the synthesis was complete, (R) -2- [2- (benzothiazol-2-yldisulfanyl) -4-oxo-azetidin-1-yl ] -3-methyl-but-3-enoic acid benzhydryl ester in product purity 83.7% with a yield of 78.8 wt%.
Example 5
The differences from example 1 are: the continuous reaction device is a columnar continuous reactor.
After the synthesis was complete, (R) -2- [2- (benzothiazol-2-yldisulfanyl) -4-oxo-azetidin-1-yl ] -3-methyl-but-3-enoic acid benzhydryl ester in the product had a purity of 90.4% and a yield of 87.0 wt%.
From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:
the heat exchanger and the continuous reactor can heat the material to preset reaction temperature and the reacted product system is lowered to specific temperature. By accurately controlling the reaction temperature and the reaction time, the generation of isomers caused by over-temperature reaction or prolonged reaction time in the kettle type process can be effectively avoided, the selectivity and yield of the reaction are obviously improved, and the large-scale production is easy to realize.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A continuous synthesis method of a tazobactam intermediate, which is characterized in that the tazobactam intermediate has a structure shown as a formula (I):
the continuous synthesis method adopts a device comprising: the device comprises a continuous reaction device and a heat exchange device, wherein the heat exchange device is used for adjusting the reaction temperature of the continuous reaction device;
the continuous synthesis method comprises the following steps:
continuously conveying the penam sulfoxide diphenylmethyl ester and the 2-mercaptobenzothiazole into a continuous reaction device for ring opening reaction, and continuously discharging the tazobactam intermediate;
the temperature of the ring-opening reaction is 80-160 ℃, the retention time of the materials is 10-100 min, and the reaction pressure is 0-10 MPa.
2. The continuous synthesis method according to claim 1, wherein the reaction temperature of the ring-opening reaction is 140-150 ℃, the residence time of the material is 10-20 min, and the reaction pressure is 0-10 MPa.
3. The continuous synthesis method according to claim 2, wherein the molar ratio of the penicillanic acid diphenylmethyl ester to the 2-mercaptobenzothiazole is 1 (0.8-2.0).
4. The continuous synthesis method according to claim 3, wherein the molar ratio of the penicillanic acid diphenylmethyl ester to the 2-mercaptobenzothiazole is 1 (0.98-1.05).
5. The continuous synthesis process according to any one of claims 1 to 4, wherein the continuous synthesis process comprises adding a solvent during the ring-opening reaction, wherein the amount of the solvent is 10 to 100mL/g relative to the amount of the benzhydryl penam sulfoxylate.
6. The continuous synthesis method according to claim 5, wherein the solvent is one or more selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, dimethylsulfoxide, methanol, ethanol, isopropanol, dichloromethane, biphenyl, ethylene glycol, hexamethylphosphoric triamide, phenol, pyridine, m-xylene, o-xylene, diphenyl ether, cyclohexanone, cyclohexanol, o-cresol, diethyl carbonate, and diethyl oxalate.
7. The continuous synthesis process according to claim 5, characterized in that the continuous reaction device is selected from tubular continuous reactors or cylindrical reactors.
8. The continuous synthesis method of claim 5, further comprising:
and under the action of a liquid pump, conveying the mixed solution of the penam sulfoxide diphenylmethyl ester, the 2-mercaptobenzothiazole and the solvent to the continuous reaction device, and controlling the pressure in the continuous reaction device by adopting a back pressure valve and a pressure sensor.
9. The continuous synthesis method according to claim 8, wherein the apparatus used in the continuous synthesis method further comprises:
the temperature detection device is used for monitoring the reaction temperature in the continuous reaction device;
a pressure detection device for monitoring the reaction pressure in the continuous reaction device;
an online process analysis device for detecting a product composition of the continuous reaction device.
10. The continuous synthesis method of claim 9, wherein the apparatus employed in the continuous synthesis method further comprises an automated control system electrically connected to the liquid pump, the back pressure valve, the pressure sensor, the heat exchange device, the temperature detection device, the pressure detection device, and the on-line process analysis device.
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| CN113666945A (en) * | 2021-10-22 | 2021-11-19 | 凯莱英医药集团（天津）股份有限公司 | Preparation method of 2 beta-azido methyl penicillanic acid diphenylmethyl ester, tazobactam intermediate and tazobactam |
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Application publication date: 20200414 |