CN110790790A

CN110790790A - Continuous preparation method of penem intermediate MAP

Info

Publication number: CN110790790A
Application number: CN201911033478.3A
Authority: CN
Inventors: 洪浩; 詹姆斯·盖吉; 陈朝勇; 卢江平; 蒋勇; 陶建; 罗勇
Original assignee: Asymchem Laboratories Jilin Co Ltd
Current assignee: Asymchem Laboratories Jilin Co Ltd
Priority date: 2019-10-28
Filing date: 2019-10-28
Publication date: 2020-02-14

Abstract

The invention provides a continuous preparation method of intermediate MAP of penem. The continuous preparation method comprises the following steps: step S1, catalyzing (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl with a rhodium-loaded catalyst in a column type continuous reactor]-3 oxo-pentanoate undergoes a ring closing reaction to form a first intermediate, wherein the supported rhodium catalyst is loaded in the column type continuous reactor, and the supported rhodium catalyst has the following structural formula:

step S2, carrying out esterification reaction on the first intermediate, diphenyl chlorophosphate and diisopropylethylamine in a second continuous reactor to obtain a product system containing a penem intermediate MAP; and step S3, carrying out crystallization treatment on the product system to obtain a penem intermediate MAP. Column continuous reactor and rhodium-loaded reactorThe catalyst enables the ring closing reaction to be carried out efficiently at a lower temperature, thereby reducing the energy consumption.

Description

Continuous preparation method of penem intermediate MAP

Technical Field

The invention relates to the technical field of preparation of a penem intermediate, and particularly relates to a continuous preparation method of a penem intermediate MAP.

Background

The penem antibiotic, namely the carbapenem antibiotic, belongs to β -lactam antibacterial drugs, has strong antibacterial activity and wide antibacterial spectrum, and is clinically suitable for treating the following moderate and severe infections caused by sensitive bacteria, namely complicated abdominal cavity infection, complicated skin soft tissue infection, community acquired pneumonia, complicated urinary tract infection, acute pelvic cavity infection, serious enterobacteriaceae bacterial infection and the like, so the drug has wide application prospect.

The current industrial scale-up production technology mainly uses batch chemical technology (namely batch reaction production), a solvent, a raw material and a rhodium catalyst are sequentially put into a reaction kettle, the temperature is raised for carrying out a ring closing reaction, the obtained intermediate is cooled and then is sequentially added with diphenyl chlorophosphate and diisopropylethylamine, and the esterification reaction is carried out at a low temperature. The system is subjected to post-treatment operations such as quenching, crystallization and the like to obtain the penem intermediate MAP. The patent application with the application publication number of CN108948086A discloses a process for continuously synthesizing penem antibiotic parent nucleus MAP, wherein methyl tert-butyl ketone is adopted as a solvent to dissolve (3S,4R) -3-, [ 2 ]

-1-hydroxyethyl group]-4- [ (1R) -1-methyl-3-diazo-3-p-nitrobenzyloxyformyl-2-one-propyl]-2-azetidinone, using rhodium octanoate dimer as catalyst, carrying out continuous reaction in a first-stage pipeline reactor to prepare intermediate; mixing diphenyl chlorophosphate with N, N-diisopropylethylamine to form a mixture II, cooling the intermediate, and continuously reacting with the mixture II in a secondary pipeline reactorAnd preparing the mother nucleus MAP of the penem antibiotic. However, in the process, the reaction temperature in the primary pipeline reactor is 80-100 ℃ to achieve higher product yield, but the reaction temperature in the secondary pipeline reactor is-25 to-5 ℃, and the temperature difference between the two is large, so that the intermediate needs to be cooled, the energy consumption is high, particularly when the process is amplified to industrial application, the production cost of MAP is high, and the economic benefit of a producer is reduced.

Disclosure of Invention

The invention mainly aims to provide a continuous preparation method of a penem intermediate MAP, which aims to solve the problem of high energy consumption of the continuous preparation process of the penem intermediate MAP in the prior art.

In order to achieve the above object, according to one aspect of the present invention, there is provided a continuous preparation method of intermediate MAP of penem, comprising: step S1, catalyzing (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl with a rhodium-loaded catalyst in a column type continuous reactor]-3 oxo-pentanoate undergoes a ring closing reaction to form a first intermediate, wherein the supported rhodium catalyst is loaded in the column type continuous reactor, and the supported rhodium catalyst has the following structural formula:

wherein R is¹Represents any one of C1-C10 alkyl; P-COO-represents a residue of the polymer after hydrogen removal, and x represents an arbitrary number of 0.1 to 4.0; step S2, carrying out esterification reaction on the first intermediate, diphenyl chlorophosphate and diisopropylethylamine in a second continuous reactor to obtain a product system containing a penem intermediate MAP; and step S3, carrying out crystallization treatment on the product system to obtain a penem intermediate MAP.

Further, the column type continuous reactor comprises a reaction column, wherein the reaction column comprises a reaction part which is arranged from bottom to top: the feeding section is provided with a liquid inlet, and a liquid distribution device is arranged above the liquid inlet; the reaction section is isolated from the feeding section by a porous bottom plate, inert filler and a rhodium-loaded catalyst are filled in the reaction section, the reaction section is provided with a plurality of first partition plates which are circumferentially arranged, and each first partition plate extends along the vertical direction to divide the inner cavity of the reaction section into a plurality of first reaction chambers; the discharge section is isolated from the reaction section through a porous top plate and is provided with a liquid product outlet and an exhaust port.

Furthermore, a second clapboard is also arranged in the inner cavity of the reaction section, the second clapboard is a cylindrical clapboard which is coaxially arranged with the reaction column, the second clapboard divides the inner cavity of the reaction section into an inner reaction chamber and an outer reaction chamber, and the first clapboard is arranged in the outer reaction chamber and divides the outer reaction chamber into a plurality of first reaction chambers.

Further, in the above structural formula, R¹Represents C1-C10 alkyl, preferably methyl, ethyl, tert-butyl, n-hexyl or n-heptyl.

Further, the step S1 includes: dissolving (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl ] -3-oxopentanoate in a first organic solvent to form a first raw material solution, the first organic solvent being selected from any one or more of the group consisting of ethyl acetate, methyl acetate, tetrahydrofuran, dichloromethane, chloroform, and methyl isobutyl ketone; feeding the first raw material liquid into a column type continuous reactor, and catalyzing (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl ] -3 oxopentanoate to perform a ring-closing reaction at 30-60 ℃ by using a supported rhodium catalyst to form a first intermediate system containing a first intermediate, wherein the retention time of the first raw material liquid in the column type continuous reactor is preferably 2-40 min, and preferably 4-20 min.

Further, the step S2 includes: pre-cooling the second continuous reactor to-32-12 ℃; and (2) respectively feeding the first intermediate system, the diphenyl chlorophosphate solution and the diisopropylethylamine solution into a pre-cooled second continuous reactor for esterification to obtain a product system containing the penem intermediate MAP, wherein a solvent in the diphenyl chlorophosphate solution and a solvent in the diisopropylethylamine solution are respectively and independently selected from any one or more of the group consisting of ethyl acetate, methyl acetate, tetrahydrofuran, dichloromethane, trichloromethane and methyl isobutyl ketone, preferably before the step S2, the first intermediate system obtained in the step S1 is collected into a receiving device and pre-cooled to-12-25 ℃, and the collecting device is connected with the column type continuous reactor and the second continuous reactor.

Further, the second continuous reactor is a one-stage coil continuous reactor or a continuous reactor with multiple stages of coils connected in series, and the retention time of the reactants in the second continuous reactor is 2-40 min, preferably 4-20 min.

Further, the step S3 includes: sending the product system, a quenching agent and a crystallization liquid into a third continuous reactor for continuous crystallization to obtain a crystallization system, wherein the quenching agent is selected from any one or more of pure water, potassium dihydrogen phosphate buffer solution, potassium hydrogen phosphate buffer solution, sodium dihydrogen phosphate buffer solution and sodium hydrogen phosphate buffer solution, and the crystallization liquid is selected from any one or more of hexane, heptane, octane, methylcyclopentane and petroleum ether; and carrying out solid-liquid separation on the crystallization system to obtain the intermediate MAP of the penem.

Further, the third continuous reactor is a one-stage coil continuous reactor or a continuous reactor with a plurality of series-connected coils.

Further, the step S3 includes: sending the product system into a quenching agent for quenching, and then sending a crystallization liquid into the product system for crystallization to obtain a crystallization system, wherein the quenching agent is selected from any one or more of the group consisting of pure water, a potassium dihydrogen phosphate buffer solution, a potassium hydrogen phosphate buffer solution, a sodium dihydrogen phosphate buffer solution and a sodium hydrogen phosphate buffer solution, and the crystallization liquid is selected from any one or more of the group consisting of hexane, heptane, octane, methylcyclopentane and petroleum ether; and carrying out solid-liquid separation on the crystallization system to obtain the intermediate MAP of the penem.

By applying the technical scheme of the invention, the column type continuous reactor is used as a place where the loop closing reaction is generated, and the loop closing reaction forms a gaseous product while forming a first intermediate, and the gaseous product forms a disturbance effect on a loaded rhodium catalyst in the rising process of the gaseous product in the column type continuous reactor, so that the high-efficiency contact of (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl ] -3-oxopentanoate ((R) -4-nitrobenzyl 2-diazo-4- ((2R,3S) -3- ((R) -1-hydroxyethaneyl) -4-oxoazetidin-2-yl) -3-oxopentanoate) and the catalyst is facilitated to improve the catalytic effect, in addition, the rhodium-loaded catalyst has higher mechanical property and catalytic activity and is easy to recover due to the fact that the polymer is used as the carrier. Under the synergistic effect of above-mentioned column type continuous reactor and load rhodium catalyst for the ring closing reaction of this application can high-efficiently go on under lower temperature, has reduced the difference in temperature of ring closing reaction and esterification reaction, thereby has reduced the required cold source of first midbody cooling, and then has reduced the energy consumption, is particularly useful for the industrialization and uses.

Drawings

The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:

FIG. 1 shows a schematic structural view of a column type continuous reactor employed according to an embodiment of the present invention;

FIG. 2 shows a transverse cross-sectional view of the reaction section of the reaction column of the column-type continuous reactor shown in FIG. 1;

FIG. 3 shows the HPLC profile of the product MAP purity and content test of example 18;

FIG. 4 shows the HPLC profile of the α -isomer test in the product of example 18;

FIG. 5 shows the IR spectrum of MAP in the product of example 18;

FIG. 6 shows a thermogravimetric analysis profile of the product of example 18;

figure 7 shows the XRD spectrum of the product of example 18; and

figure 8 shows the GC spectrum of the solvent residue detection in the product of example 18.

Wherein the figures include the following reference numerals:

11. a feeding section; 111. a liquid inlet; 12. a reaction section; 121. an inert filler; 122. a first separator; 123. a second separator; 13. a discharging section; 131. a liquid product outlet; 132. an exhaust port; 14. a perforated base plate; 15. a perforated top plate.

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 below with reference to the embodiments with reference to the attached drawings.

As described in the background of the application, in the prior art, in the process for continuously preparing the intermediate MAP in the penem, a large amount of cold sources are consumed for cooling due to the high temperature of the first-step cyclization reaction, so that the energy consumption is high. In order to solve the problem, the application provides a continuous preparation method of intermediate MAP in penem. In one exemplary embodiment, the continuous production process comprises: step S1, catalyzing (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl with a rhodium-loaded catalyst in a column type continuous reactor]-3 oxo-pentanoate undergoes a ring closing reaction to form a first intermediate, wherein the supported rhodium catalyst is loaded in the column type continuous reactor, and the supported rhodium catalyst has the following structural formula:

The main reaction formulas of the ring closing reaction and the esterification reaction of the preparation method are as follows:

the method utilizes the column type continuous reactor as a place for loop closing reaction, and the loop closing reaction forms a gaseous product while forming a first intermediate, and the gaseous product forms a disturbance effect on a loaded rhodium catalyst in the rising process of the column type continuous reactor, so that the method is favorable for the efficient contact of (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl ] -3-oxopentanoate ((R) -4-nitrobenzyl 2-diaza-4- ((2R,3S) -3- ((R) -1-hydroxyethaneyl) -4-oxoazetidin-2-yl) -3-oxopentanoate) and the catalyst to improve the catalytic effect, in addition, the rhodium-loaded catalyst has higher mechanical property and catalytic activity and is easy to recover due to the fact that the polymer is used as the carrier. Under the synergistic effect of above-mentioned column type continuous reactor and load rhodium catalyst for the ring closing reaction of this application can high-efficiently go on under lower temperature, has reduced the difference in temperature of ring closing reaction and esterification reaction, thereby has reduced the required cold source of first midbody cooling, and then has reduced the energy consumption, is particularly useful for the industrialization and uses.

In a preferred embodiment of the present application, as shown in fig. 1 and 2, the column type continuous reactor comprises a reaction column, the reaction column comprises a feeding section 11, a reaction section 12 and a discharging section 13 arranged from bottom to top, the feeding section 11 is provided with a liquid inlet 111, and a liquid distribution device is arranged above the liquid inlet 111; the reaction section 12 and the feeding section 11 are isolated by a porous bottom plate 14, an inert filler 121 and a loaded rhodium catalyst are filled in the reaction section 12, the reaction section 12 is provided with a plurality of first clapboards 122 which are circumferentially arranged, and each first clapboard 122 extends along the vertical direction to divide the inner cavity of the reaction section 12 into a plurality of first reaction chambers; the discharge section 13 is separated from the reaction section 12 by a porous top plate 15, and the discharge section 13 has a liquid product outlet 131 and an exhaust port 132.

The reaction column of the column type continuous reactor can realize continuous feeding and continuous discharging so as to realize continuous reaction; a liquid distribution device is provided above the liquid inlet 111 so that the reaction physics are fed in a uniform manner; the first partition plate 122 arranged in the reaction section 12 divides the reaction cavity into reaction chambers with small volumes, and the reaction chambers are internally provided with fillers for dispersing the loaded rhodium catalyst arranged therein during the reaction, thereby avoiding the problem of overlarge pressure drop in the reaction column caused by the upward accumulation of the loaded rhodium catalyst driven by the upward flow of the gas by-product; when liquid reaction materials enter each reaction chamber, gaseous byproducts generated by the reaction cannot excessively concentrate to cause transitional impact on the filler and the loaded rhodium catalyst to form large-area cavities because the volume of each reaction chamber is small, and the presence of the filler can further prevent the supported rhodium catalyst from channeling and bypassing due to the impact described above, so that the mass transfer between the liquid phase and the solid phase is uniform in the reaction process, the flow of the gas phase in the liquid phase and the solid phase is also uniform, thereby improving the catalytic efficiency of the rhodium-loaded catalyst, and leading (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl ] -3 oxo valerate to be capable of efficiently carrying out the cyclization reaction at a lower temperature.

The feeding section 11, the reaction section 12 and the discharging section 13 of the reaction column can be arranged in the integrally arranged reaction column, and the sections can also be connected through connecting pieces. And the column type continuous reactor can be used in series in multiple stages in order to improve the productivity.

Further, as shown in fig. 2, it is preferable that a second partition plate 123 is further disposed in the inner cavity of the reaction section 12, the second partition plate 123 is a cylindrical partition plate disposed coaxially with the reaction column, the second partition plate 123 partitions the inner cavity of the reaction section 12 into an inner reaction chamber and an outer reaction chamber, and the first partition plate 122 is disposed in the outer reaction chamber and partitions the outer reaction chamber into a plurality of first reaction chambers. The second baffle 123 and the first baffle 122 are combined to further separate the inner cavity of the reaction section 12, so that the mass transfer between the liquid phase and the solid phase is more uniform. Preferably, the second partition 123 is a cylindrical partition parallel to the side wall of the reaction section 12. For example, as shown in fig. 1, the cylindrical second partition 123 is combined with the first partition 122 to form a first reaction chamber without dead space, so that the material flows more smoothly in the respective reaction chambers and the contact between the materials is more uniform.

Further, the inner diameter of the inner reaction chamber is preferably 1/4 to 1/3 of the inner diameter of the reaction section 12. So that the volumes of the inner reaction chamber and each first reaction chamber are relatively uniform, and the reactions in each reaction chamber are relatively synchronous.

In order to maintain the pressure drop in each reaction chamber of the reaction column 10 stable, it is preferable that the reaction section 12 employs a pipeline of DN10 to DN800, and the length-diameter ratio of the reaction section 12 is 0.05: 1-50: 1; preferably 0.2:1 to 20: 1.

Preferably, in the above formula, R¹Represents C1-C10, preferably methyl, ethyl, tert-butyl, n-hexyl or n-heptyl. So as to reduce the synthesis difficulty of the catalyst carrier.

The supported rhodium catalyst of the present application can be prepared by using a supported rhodium catalyst of the prior art or by using a preparation method of the prior art, such as the supported rhodium catalyst disclosed in patent No. 201410459708.3 or by using a preparation method thereof.

There are various ways of carrying out the above-mentioned loop closing reaction using the above-mentioned column type continuous reactor, and it is preferable that the step S1 includes: dissolving (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl ] -3-oxopentanoate in a first organic solvent to form a first raw material solution, the first organic solvent being selected from any one or more of the group consisting of ethyl acetate, methyl acetate, tetrahydrofuran, dichloromethane, chloroform, and methyl isobutyl ketone. The first raw material liquid is formed by stirring at 10 to 40 ℃. Feeding the first raw material liquid into a column type continuous reactor, and catalyzing (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl ] -3 oxopentanoate to perform a ring-closing reaction at 30-60 ℃ by using a supported rhodium catalyst to form a first intermediate system containing a first intermediate, wherein the retention time of the first raw material liquid in the column type continuous reactor is preferably 2-40 min, and preferably 4-20 min. Preparing (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl ] -3 oxo valerate into a solution in advance, and then feeding the solution into a column type continuous reactor to facilitate the control of a ring closing reaction process. The cyclization reaction can occur at 30-60 ℃, and is greatly reduced compared with the prior art at 80-100 ℃; in addition, due to the improvement of the catalytic efficiency, the retention time of the first raw material liquid in the column type continuous reactor can be relatively shortened, for example, within the range of 2-40 min, even within the range of 4-20 min, and a higher yield of the first intermediate can be obtained.

Preferably, the content of (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl ] -3 oxopentanoate in the first raw material solution is 0.2-0.6 mmol/mL.

In another embodiment of the present application, since the temperature of the esterification reaction is low, in order to improve the preparation efficiency, it is preferable that the above step S2 includes: pre-cooling the second continuous reactor to-32-12 ℃; and respectively feeding the first intermediate system, the diphenyl chlorophosphate solution and the diisopropylethylamine solution into a pre-cooled second continuous reactor for esterification reaction to obtain a product system containing the intermediate MAP of the penem, wherein the retention time of reactants in the second continuous reactor is 2-40 min, preferably 4-20 min, and preferably, the solvent in the diphenyl chlorophosphate solution and the solvent in the diisopropylethylamine solution are respectively and independently selected from one or more of the group consisting of ethyl acetate, methyl acetate, tetrahydrofuran, dichloromethane, trichloromethane and methyl isobutyl ketone. The second continuous reactor is pre-cooled to-32-12 ℃ in advance, so that the materials can enter the second continuous reactor (PFR) to quickly enter a reaction state, and the preparation efficiency is improved.

For simplicity of operation, it is preferred that the solvent in the solution of diphenyl chlorophosphate and the solvent in the solution of diisopropylethylamine are the same as the first organic solvent in which (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl ] -3-oxopentanoate is dissolved. Preferably, the content of diphenyl chlorophosphate in the diphenyl chlorophosphate solution is 0.6-3.0 mmol/mL; the content of diisopropylethylamine in the solution of diisopropylethylamine is 0.6-3.0 mmol/mL. In order to increase the utilization rate of each substance, the flow ratio of the first raw material liquid, the first intermediate system, the diphenyl chlorophosphate solution, and the diisopropylethylamine is preferably 1: 0.5-2.0: 0.1 to 1.0: 0.1 to 1.0.

The second continuous reactor is a one-stage coil continuous reactor or a continuous reactor with a plurality of stages of coils connected in series. The continuous reactor in which the multi-stage coil pipes are connected in series can improve the production efficiency. When the coil continuous reactor is used, the applicable temperature range of the esterification reaction is wider and is easier to control, and the retention time can be relatively shortened to 2-40 min, even 4-20 min.

Before the step S2, the first intermediate system obtained in the step S1 may be collected in a receiving device such as a storage tank or an enamel kettle and pre-cooled to-12 to 25 ℃ (preferably-10 to 10 ℃), the collecting device is connected with the column type continuous reactor and the second continuous reactor, and then the reaction in the step S2 is performed after a certain amount of the first intermediate system is collected, so as to further ensure the continuity and stability of the process.

Step S3 of the present application is to separate the product MAP for crystallization, and the crystallization method applicable to the present application may be continuous crystallization or batch crystallization, and in one embodiment, the step S3 includes: sending the product system, a quenching agent and a crystallization liquid into a third continuous reactor for continuous crystallization to obtain a crystallization system, wherein the quenching agent is selected from any one or more of pure water, potassium dihydrogen phosphate buffer solution, potassium hydrogen phosphate buffer solution, sodium dihydrogen phosphate buffer solution and sodium hydrogen phosphate buffer solution, and the crystallization liquid is selected from any one or more of hexane, heptane, octane, methylcyclopentane and petroleum ether; and carrying out solid-liquid separation on the crystallization system to obtain the intermediate MAP of the penem. The buffer solution such as the potassium dihydrogen phosphate buffer solution adopts a conventional mass concentration of 2-10%.

And a continuous crystallization mode is adopted, so that the production efficiency can be improved. At the beginning of step S3, the product system and the quenching agent may be fed into the third continuous reactor to quench, and then the crystallization liquid is fed into the third continuous reactor, and during normal operation, the three are fed simultaneously, and the feeding speeds of the three may be controlled to control the quenching and crystallization effects and rates, for example, the flow ratio of the first raw material liquid, the product system, the quenching agent and the crystallization liquid is controlled to be 1: 0.7-4.0: 0.5-5.0: 0.5 to 5.0. The third continuous reactor is a one-stage coil continuous reactor or a continuous reactor with a plurality of stages of coils connected in series.

In another embodiment, the step S3 includes: sending the product system into a quenching agent for quenching, and then sending a crystallization liquid into the product system for crystallization to obtain a crystallization system, wherein the quenching agent is selected from any one or more of the group consisting of pure water, a potassium dihydrogen phosphate buffer solution, a potassium hydrogen phosphate buffer solution, a sodium dihydrogen phosphate buffer solution and a sodium hydrogen phosphate buffer solution, and the crystallization liquid is selected from any one or more of the group consisting of hexane, heptane, octane, methylcyclopentane and petroleum ether; and carrying out solid-liquid separation on the crystallization system to obtain the intermediate MAP of the penem. The batch crystallization mode is adopted, and the crystallization efficiency and the product purity are improved by adopting the mode of quenching before crystallization.

The solid-liquid separation mode in the two embodiments can be filtration, suction filtration or centrifugation, and specific operation conditions can be referred to the prior art and are not described herein again.

The advantageous effects of the present application will be further described below with reference to examples and comparative examples.

(1) Respectively dissolving (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl ] -3 oxo valerate, diphenyl chlorophosphate and diisopropylethylamine in ethyl acetate to respectively obtain a first raw material solution, a diphenyl chlorophosphate solution and a diisopropylethylamine solution; the content of the (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl ] -3 oxopentanoate solution in the first raw material liquid is 0.2-0.6 mmol/mL; the concentration of the diphenyl chlorophosphate solution is 0.6-3.0 mmol/mL; the concentration of the diisopropylethylamine solution is 0.6-3.0 mmol/mL.

(2) Pumping the first raw material solution prepared in the step (1) into a column type continuous reactor shown in figures 1 and 2 for reaction, wherein the residence time of the column type continuous reactor is 2-40 min, the reaction temperature is 30-60 ℃, a ring-closing reaction is carried out under the catalysis of a supported rhodium catalyst to generate a first intermediate system containing a first intermediate, the first intermediate system flows out of the column type continuous reactor and enters a receiving device, the inner diameter of an inner reaction chamber of the column type continuous reactor is 1/4-1/3 of the inner diameter of a reaction section, and the length-diameter ratio of the reaction section is 0.05: 1-50: 1; preferably 0.2:1 to 20: 1.

(3) The first intermediate system is sent into a multi-stage coil type continuous reactor; and (2) simultaneously, feeding the diphenyl chlorophosphate solution and the diisopropylethylamine solution prepared in the step (1) into the multistage coiled continuous reactor, and allowing the first intermediate system, the diphenyl chlorophosphate solution and the diisopropylethylamine solution to enter the multistage coiled continuous reactor precooled to-32-12 ℃ for esterification reaction, wherein the retention time of each reactant in the multistage coiled continuous reactor is 2-40 min.

(4) Continuous crystallization: sending the product system flowing out of the multi-stage coil type continuous reactor into another multi-stage coil type continuous reactor, sending 2-10% of potassium dihydrogen phosphate buffer solution into the reactor for mixing and quenching, then sending heptane for continuous crystallization to obtain a crystallization system, and centrifugally separating the crystallization system after flowing out of the multi-stage coil type continuous reactor to finally obtain a product, namely a penem intermediate MAP ((4R,5R,6S) -3- [ (diphenyloxyphenyl) oxy ] -6- [ (1R) -1-hydroxyethenyl ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] pt-2-ene-2-carboxylic acid (4-nitrophenyl) methyl ester);

or (4) batch crystallization: quenching a product system flowing out of the multistage coiled continuous reactor in a 2-10% monopotassium phosphate buffer solution prepared in advance, adding heptane into the solution for crystallization to obtain a crystallization system, and performing centrifugal separation on the crystallization system to finally obtain a product, namely a culture intermediate MAP ((4R,5R,6S) -3- [ (dioxy) oxy ] -6- [ (1R) -1-hydroxyethoxy ] -4-methyl-7-oxo-1-azabicyclo [3.2.0] pt-2-ene-2-carboxylic acid (4-nitrophenyl) methyl ester);

the flow ratio of the first raw material solution, the first intermediate system, the diphenyl chlorophosphate solution, the diisopropylethylamine solution, the product system, the potassium dihydrogen phosphate buffer solution, and heptane per unit time is 1: 0.5-2.0: 0.1 to 1.0: 0.1 to 1.0: 0.7-4.0: 0.5-5.0: 0.5 to 5.0.

Example 1

Preparing a penem intermediate MAP by adopting the process, wherein in the step (1), in the first raw material liquid, (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl]-the content of the 3-oxopentanoate solution is 0.5 mmol/mL; the concentration of the diphenyl chlorophosphate solution is 2.5 mmol/mL; the concentration of diisopropylethylamine in the solution was 2.5 mmol/mL. The supported rhodium catalyst is

Compound 61 of patent No. 201410459708.3. The retention time of the step (1) is 10min, the reaction temperature is 40 ℃, and the column type continuous reaction is carried outThe inner diameter of the inner reaction chamber of the reactor is 1/3 of the inner diameter of the reaction section, and the length-diameter ratio of the reaction section is 10: 1. and (2) adopting a coil pipe continuous reactor, controlling the retention time to be 10min and the reaction temperature to be-5 ℃. The concentration of the potassium dihydrogen phosphate buffer solution in the step (3) is 5%. The flow ratio of the first raw material liquid, the first intermediate system, the diphenyl chlorophosphate solution, the diisopropylethylamine solution, the product system, the potassium dihydrogen phosphate buffer solution and the heptane in unit time is 1: 1.0: 0.3: 0.3: 1.6: 2.5: 3.0.

example 2

Compound 61 of patent No. 201410459708.3. The retention time of the step (1) is 20min, the reaction temperature is 40 ℃, the inner diameter of the inner reaction chamber of the column type continuous reactor is 1/3 of the inner diameter of the reaction section, and the length-diameter ratio of the reaction section is 10: 1. and (2) adopting a coil pipe continuous reactor, controlling the retention time to be 10min and the reaction temperature to be-5 ℃. The concentration of the potassium dihydrogen phosphate buffer solution in the step (3) is 5%. The flow ratio of the first raw material liquid, the first intermediate system, the diphenyl chlorophosphate solution, the diisopropylethylamine solution, the product system, the potassium dihydrogen phosphate buffer solution and the heptane in unit time is 1: 1.0: 0.3: 0.3: 1.6: 2.5: 3.0.

example 3

Compound 61 of patent No. 201410459708.3. The retention time of the step (1) is 40min, the reaction temperature is 40 ℃, the inner diameter of the inner reaction chamber of the column type continuous reactor is 1/3 of the inner diameter of the reaction section, and the length-diameter ratio of the reaction section is 10: 1. and (2) adopting a coil pipe continuous reactor, controlling the retention time to be 10min and the reaction temperature to be-5 ℃. The concentration of the potassium dihydrogen phosphate buffer solution in the step (3) is 5%. The flow ratio of the first raw material liquid, the first intermediate system, the diphenyl chlorophosphate solution, the diisopropylethylamine solution, the product system, the potassium dihydrogen phosphate buffer solution and the heptane in unit time is 1: 1.0: 0.3: 0.3: 1.6: 2.5: 3.0.

example 4

Compound 61 of patent No. 201410459708.3. The retention time of the step (1) is 4min, the reaction temperature is 40 ℃, the inner diameter of the inner reaction chamber of the column type continuous reactor is 1/3 of the inner diameter of the reaction section, and the length-diameter ratio of the reaction section is 10: 1. and (2) adopting a coil pipe continuous reactor, controlling the retention time to be 10min and the reaction temperature to be-5 ℃. The concentration of the potassium dihydrogen phosphate buffer solution in the step (3) is 5%. The flow ratio of the first raw material liquid, the first intermediate system, the diphenyl chlorophosphate solution, the diisopropylethylamine solution, the product system, the potassium dihydrogen phosphate buffer solution and the heptane in unit time is 1: 1.0: 0.3: 0.3: 1.6: 2.5: 3.0.

example 5

Preparing a penem intermediate MAP by adopting the process, wherein in the step (1), in the first raw material liquid, (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidine-4-keto-2-yl]-the content of the 3-oxopentanoate solution is 0.5 mmol/mL; the concentration of the diphenyl chlorophosphate solution is 2.5 mmol/mL; the concentration of diisopropylethylamine in the solution was 2.5 mmol/mL. The supported rhodium catalyst is

Compound 61 of patent No. 201410459708.3. The retention time of the step (1) is 10min, the reaction temperature is 30 ℃, the inner diameter of the inner reaction chamber of the column type continuous reactor is 1/3 of the inner diameter of the reaction section, and the length-diameter ratio of the reaction section is 10: 1. and (2) adopting a coil pipe continuous reactor, controlling the retention time to be 10min and the reaction temperature to be-5 ℃. The concentration of the potassium dihydrogen phosphate buffer solution in the step (3) is 5%. The flow ratio of the first raw material liquid, the first intermediate system, the diphenyl chlorophosphate solution, the diisopropylethylamine solution, the product system, the potassium dihydrogen phosphate buffer solution and the heptane in unit time is 1: 1.0: 0.3: 0.3: 1.6: 2.5: 3.0.

example 6

Compound 61 of patent No. 201410459708.3. The retention time of the step (1) is 10min, the reaction temperature is 60 ℃, the inner diameter of the inner reaction chamber of the column type continuous reactor is 1/3 of the inner diameter of the reaction section, and the length-diameter ratio of the reaction section is 10: 1. and (2) adopting a coil pipe continuous reactor, controlling the retention time to be 10min and the reaction temperature to be-5 ℃. The concentration of the potassium dihydrogen phosphate buffer solution in the step (3) is 5%. The flow ratio of the first raw material liquid, the first intermediate system, the diphenyl chlorophosphate solution, the diisopropylethylamine solution, the product system, the potassium dihydrogen phosphate buffer solution and the heptane in unit time is 1: 1.0: 0.25: 0.25: 1.5: 2.0: 2.5.

example 7

Compound 61 of patent No. 201410459708.3. The retention time of the step (1) is 10min, the reaction temperature is 40 ℃, the inner diameter of the inner reaction chamber of the column type continuous reactor is 1/3 of the inner diameter of the reaction section, and the length-diameter ratio of the reaction section is 10: 1. and (2) adopting a coil pipe continuous reactor, controlling the retention time to be 10min and the reaction temperature to be-32 ℃. The concentration of the potassium dihydrogen phosphate buffer solution in the step (3) is 5%. The flow ratio of the first raw material liquid, the first intermediate system, the diphenyl chlorophosphate solution, the diisopropylethylamine solution, the product system, the potassium dihydrogen phosphate buffer solution and the heptane in unit time is 1: 1.0: 0.3: 0.3: 1.6: 2.5: 3.0.

example 8

Compound 61 of patent No. 201410459708.3. The retention time of the step (1) is 10min, the reaction temperature is 40 ℃, the inner diameter of the inner reaction chamber of the column type continuous reactor is 1/3 of the inner diameter of the reaction section, and the length-diameter ratio of the reaction section is 10: 1. and (2) adopting a coil pipe continuous reactor, controlling the retention time to be 10min and the reaction temperature to be-10 ℃. The concentration of the potassium dihydrogen phosphate buffer solution in the step (3) is 5%. First raw material liquid, secondAn intermediate system, a diphenyl chlorophosphate solution, a diisopropylethylamine solution, a product system, a potassium dihydrogen phosphate buffer solution and heptane, wherein the flow ratio of the intermediate system, the diphenyl chlorophosphate solution, the diisopropylethylamine solution, the product system, the potassium dihydrogen phosphate buffer solution and the heptane in unit time is 1: 1.0: 0.3: 0.3: 1.6: 2.5: 3.0.

example 9

Preparing a penem intermediate MAP by adopting the process, wherein in the step (1), in the first raw material liquid, (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl]-the content of the 3-oxopentanoate solution is 0.5 mmol/mL; the concentration of the diphenyl chlorophosphate solution is 2.5 mmol/mL; the concentration of diisopropylethylamine in the solution was 2.5 mmol/mL. The supported rhodium catalyst isCompound 61 of patent No. 201410459708.3. The retention time of the step (1) is 10min, the reaction temperature is 40 ℃, the inner diameter of the inner reaction chamber of the column type continuous reactor is 1/3 of the inner diameter of the reaction section, and the length-diameter ratio of the reaction section is 10: 1. and (2) adopting a coil pipe continuous reactor, controlling the retention time to be 10min and the reaction temperature to be 12 ℃. The concentration of the potassium dihydrogen phosphate buffer solution in the step (3) is 5%. The flow ratio of the first raw material liquid, the first intermediate system, the diphenyl chlorophosphate solution, the diisopropylethylamine solution, the product system, the potassium dihydrogen phosphate buffer solution and the heptane in unit time is 1: 1.0: 0.3: 0.3: 1.6: 2.5: 3.0.

example 10

Compound 61 of patent No. 201410459708.3. The retention time of the step (1) is 10min, the reaction temperature is 40 ℃, and the inner diameter of the inner reaction chamber of the column type continuous reactor is a reaction section1/3 for the inner diameter, the length to diameter ratio of the reaction section is 10: 1. and (2) adopting a coil pipe continuous reactor, controlling the retention time to be 40min and the reaction temperature to be-5 ℃. The concentration of the potassium dihydrogen phosphate buffer solution in the step (3) is 5%. The flow ratio of the first raw material liquid, the first intermediate system, the diphenyl chlorophosphate solution, the diisopropylethylamine solution, the product system, the potassium dihydrogen phosphate buffer solution and the heptane in unit time is 1: 1.0: 0.3: 0.3: 1.6: 2.5: 3.0.

example 11

Compound 61 of patent No. 201410459708.3. The retention time of the step (1) is 10min, the reaction temperature is 40 ℃, the inner diameter of the inner reaction chamber of the column type continuous reactor is 1/3 of the inner diameter of the reaction section, and the length-diameter ratio of the reaction section is 10: 1. and (2) adopting a coil pipe continuous reactor, controlling the retention time to be 20min and the reaction temperature to be-5 ℃. The concentration of the potassium dihydrogen phosphate buffer solution in the step (3) is 5%. The flow ratio of the first raw material liquid, the first intermediate system, the diphenyl chlorophosphate solution, the diisopropylethylamine solution, the product system, the potassium dihydrogen phosphate buffer solution and the heptane in unit time is 1: 1.0: 0.3: 0.3: 1.6: 2.5: 3.0.

example 12

Preparing a penem intermediate MAP by adopting the process, wherein in the step (1), in the first raw material liquid, (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl]-the content of the 3-oxopentanoate solution is 0.5 mmol/mL; the concentration of the diphenyl chlorophosphate solution is 2.5 mmol/mL; the concentration of diisopropylethylamine in the solution was 2.5 mmol/mL. The supported rhodium catalyst isCompound 61 of patent No. 201410459708.3. The retention time of the step (1) is 10min, the reaction temperature is 40 ℃, the inner diameter of the inner reaction chamber of the column type continuous reactor is 1/3 of the inner diameter of the reaction section, and the length-diameter ratio of the reaction section is 10: 1. and (2) adopting a coil pipe continuous reactor, controlling the retention time to be 4min and the reaction temperature to be-5 ℃. The concentration of the potassium dihydrogen phosphate buffer solution in the step (3) is 5%. The flow ratio of the first raw material liquid, the first intermediate system, the diphenyl chlorophosphate solution, the diisopropylethylamine solution, the product system, the potassium dihydrogen phosphate buffer solution and the heptane in unit time is 1: 1.0: 0.3: 0.3: 1.6: 2.5: 3.0.

example 13

Preparing a penem intermediate MAP by adopting the process, wherein in the step (1), in the first raw material liquid, (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl]-the content of the 3-oxopentanoate solution is 0.6 mmol/mL; the concentration of the diphenyl chlorophosphate solution is 3.0 mmol/mL; the solution concentration of the diisopropylethylamine is 3.0mmol/mL, and the supported rhodium catalyst is

Compound 62 of patent No. 201410459708.3. The retention time of the step (1) is 40min, the reaction temperature is 40 ℃, the inner diameter of the inner reaction chamber of the column type continuous reactor is 1/3 of the inner diameter of the reaction section, and the length-diameter ratio of the reaction section is 10: 1. and (2) adopting a coil pipe continuous reactor, controlling the retention time to be 40min and the reaction temperature to be-5 ℃. The concentration of the potassium dihydrogen phosphate buffer solution in the step (3) is 5%. The flow ratio of the first raw material liquid, the first intermediate system, the diphenyl chlorophosphate solution, the diisopropylethylamine solution, the product system, the potassium dihydrogen phosphate buffer solution and the heptane in unit time is 1: 1.0: 0.3: 0.3: 1.6: 2.5: 3.0.

example 14

Preparing a penem intermediate MAP by adopting the process, wherein in the step (1), in the first raw material liquid, (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl]Of solutions of (E) -3 oxopentanoateThe content is 0.2 mmol/mL; the concentration of the diphenyl chlorophosphate solution is 0.6 mmol/mL; the solution concentration of the diisopropylethylamine is 0.6mmol/mL, and the supported rhodium catalyst is

I.e. compound 63 of patent No. 201410459708.3. The retention time of the step (1) is 2min, the reaction temperature is 40 ℃, the inner diameter of the inner reaction chamber of the column type continuous reactor is 1/3 of the inner diameter of the reaction section, and the length-diameter ratio of the reaction section is 10: 1. and (2) adopting a coil pipe continuous reactor, controlling the retention time to be 2min and controlling the reaction temperature to be-5 ℃. The concentration of the potassium dihydrogen phosphate buffer solution in the step (3) is 5%. The flow ratio of the first raw material liquid, the first intermediate system, the diphenyl chlorophosphate solution, the diisopropylethylamine solution, the product system, the potassium dihydrogen phosphate buffer solution and the heptane in unit time is 1: 1.0: 0.3: 0.3: 1.6: 2.5: 3.0.

example 15

Preparing a penem intermediate MAP by adopting the process, wherein in the step (1), in the first raw material liquid, (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl]-the content of the 3-oxopentanoate solution is 0.5 mmol/mL; the concentration of the diphenyl chlorophosphate solution is 2.5 mmol/mL; the solution concentration of the diisopropylethylamine is 2.5mmol/mL, and the supported rhodium catalyst isCompound 64 in patent No. 201410459708.3. The retention time of the step (1) is 10min, the reaction temperature is 40 ℃, the inner diameter of the inner reaction chamber of the column type continuous reactor is 1/3 of the inner diameter of the reaction section, and the length-diameter ratio of the reaction section is 10: 1. and (2) adopting a coil pipe continuous reactor, controlling the retention time to be 10min and the reaction temperature to be-5 ℃. The concentration of the potassium dihydrogen phosphate buffer solution in the step (3) is 5%. The flow ratio of the first raw material liquid, the first intermediate system, the diphenyl chlorophosphate solution, the diisopropylethylamine solution, the product system, the potassium dihydrogen phosphate buffer solution and the heptane in unit time is 1: 1.0: 0.3: 0.3: 1.6: 2.5: 3.0.

example 16

Compound 61 of patent No. 201410459708.3. The retention time of the step (1) is 10min, the reaction temperature is 40 ℃, the inner diameter of the inner reaction chamber of the column type continuous reactor is 1/3 of the inner diameter of the reaction section, and the length-diameter ratio of the reaction section is 10: 1. and (2) adopting a coil pipe continuous reactor, controlling the retention time to be 10min and the reaction temperature to be-5 ℃. The concentration of the potassium dihydrogen phosphate buffer solution in the step (3) is 5%. The flow ratio of the first raw material liquid, the first intermediate system, the diphenyl chlorophosphate solution, the diisopropylethylamine solution, the product system, the potassium dihydrogen phosphate buffer solution and the heptane in unit time is 1: 1.0: 0.3: 0.3: 1.6: 2.5: 3.0.

example 17

Preparing a penem intermediate MAP by adopting the process, wherein in the step (1), in the first raw material liquid, (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl]-the content of the 3-oxopentanoate solution is 0.4 mmol/mL; the concentration of the diphenyl chlorophosphate solution was 1.0 mmol/mL; the concentration of diisopropylethylamine in the solution was 1.0 mmol/mL. The supported rhodium catalyst is

Compound 61 of patent No. 201410459708.3. The retention time of the step (1) is 10min, the inner diameter of the inner reaction chamber of the column type continuous reactor with the reaction temperature of 20 ℃ is 1/3 of the inner diameter of the reaction section, and the length-diameter ratio of the reaction section is 10: 1. and (2) adopting a coil pipe continuous reactor, controlling the retention time to be 10min and the reaction temperature to be-5 ℃. The concentration of the potassium dihydrogen phosphate buffer solution in the step (3) is 5%. First raw material solution, first intermediate system, diphenyl chlorophosphate solutionThe flow ratio of the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution and the heptane in unit time is 1: 1.0: 0.4: 0.4: 1.8: 1.6: 2.1.

example 18

Preparing a penem intermediate MAP by adopting the process, wherein in the step (1), in the first raw material liquid, (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl]-the content of the 3-oxopentanoate solution is 0.45 mmol/mL; the concentration of the diphenyl chlorophosphate solution was 1.1 mmol/mL; the concentration of diisopropylethylamine in the solution was 1.1 mmol/mL. The supported rhodium catalyst is

Compound 61 of patent No. 201410459708.3. The retention time of the step (1) is 10min, the reaction temperature is 40 ℃, the inner diameter of the inner reaction chamber of the column type continuous reactor is 1/3 of the inner diameter of the reaction section, and the length-diameter ratio of the reaction section is 10: 1. and (2) adopting a coil pipe continuous reactor, controlling the retention time to be 10min and the reaction temperature to be-5 ℃. The concentration of the potassium dihydrogen phosphate buffer solution in the step (3) is 5%. The flow ratio of the first raw material liquid, the first intermediate system, the diphenyl chlorophosphate solution, the diisopropylethylamine solution, the product system, the potassium dihydrogen phosphate buffer solution and the heptane in unit time is 1: 1.0: 0.4: 0.4: 1.8: 1.8: 2.3.

the products of the above examples were identified and it was determined that the target product, MAP, was obtained and the yields are reported in Table 4. HPLC detection is carried out on the products obtained in each example to determine the purity and isomers, infrared test is carried out on the products to identify the structures, thermogravimetric analysis is carried out to further analyze the purity of the products, X-ray diffraction analysis is carried out to confirm the crystal structures, GC test is carried out to analyze the residual solvents in the products, wherein the HPLC test results of the purity and the isomers of the example 18 are shown in a figure 3 and a figure 4, the infrared test results are shown in a figure 5, the TG and DTG curves of the thermogravimetric analysis results are shown in a figure 6, the XRD spectrogram is shown in a figure 7, and the GC spectrogram is shown in a figure 8, wherein the data corresponding to the figure 3 are shown in a table 1.

TABLE 1

The corresponding data description of fig. 4 is shown in table 2.

TABLE 2

The corresponding data description of fig. 8 is shown in table 3.

TABLE 3

According to the test result of fig. 6, it can be seen that the weight loss is 0.011mg and the weight loss rate is 0.059% when the steel is heated to 150 ℃.

TABLE 4

	Yield (%)		Yield (%)
				Example 1	87	Example 10	87
Example 2	85	Example 11	85
				Example 3	88	Example 12	86
Example 4	86	Example 13	89
				Example 5	87	Example 14	87
Example 6	83	Example 15	85
				Example 7	85	Example 16	86
Example 8	88	Example 17	81
				Example 9	85	Example 18	87

According to the results of the above examples, it can be seen that the first step of the cyclization reaction is performed at a relatively low temperature (30-60 ℃) due to the column reactor and the supported rhodium catalyst, so that the high yield of the final product MAP can be ensured.

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

according to the method, a column type continuous reactor is used as a place where a loop closing reaction occurs, a gaseous product is formed while a first intermediate is formed through the loop closing reaction, and the gaseous product forms a disturbance effect on a supported rhodium catalyst in the rising process of the gaseous product in the column type continuous reactor, so that the high-efficiency contact of (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl ] -3 oxopentanoate and the catalyst is facilitated, the catalytic effect is improved, and the supported rhodium catalyst has high mechanical performance and catalytic activity and is easy to recycle due to the fact that a polymer is used as a carrier. Under the synergistic effect of above-mentioned column type continuous reactor and load rhodium catalyst for the ring closing reaction of this application can high-efficiently go on under lower temperature, has reduced the difference in temperature of ring closing reaction and esterification reaction, thereby has reduced the required cold source of first midbody cooling, and then has reduced the energy consumption, is particularly useful for the industrialization and uses.

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

1. A continuous preparation method of intermediate MAP of penem is characterized by comprising the following steps:

step S1, catalyzing (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl ] -3 oxopentanoate to perform a cyclization reaction in a column type continuous reactor by using a supported rhodium catalyst to form a first intermediate, wherein the supported rhodium catalyst is loaded in the column type continuous reactor and has the following structural formula:

wherein R is¹Represents any one of C1-C10 alkyl; P-COO-represents a residue of the polymer after hydrogen removal, and x represents an arbitrary number of 0.1 to 4.0;

step S2, carrying out esterification reaction on the first intermediate, diphenyl chlorophosphate and diisopropylethylamine in a second continuous reactor to obtain a product system containing a penem intermediate MAP; and

and step S3, carrying out crystallization treatment on the product system to obtain the penem intermediate MAP.

2. The continuous production method according to claim 1, wherein the column type continuous reactor comprises a reaction column, and the reaction column comprises from bottom to top:

the feeding section (11) is provided with a liquid inlet (111), and a liquid distribution device is arranged above the liquid inlet (111);

the reaction section (12) is separated from the feeding section (11) through a porous bottom plate (14), an inert filler (121) and the loaded rhodium catalyst are filled in the reaction section (12), the reaction section (12) is provided with a plurality of first partition plates (122) which are circumferentially arranged, and each first partition plate (122) extends along the vertical direction to divide the inner cavity of the reaction section (12) into a plurality of first reaction chambers;

a discharge section (13), the discharge section (13) being isolated from the reaction section (12) by a porous top plate (15), the discharge section (13) having a liquid product outlet (131) and an exhaust port (132).

3. The continuous production method according to claim 2, wherein a second partition plate (123) is further disposed in the inner cavity of the reaction section (12), the second partition plate (123) is a cylindrical partition plate disposed coaxially with the reaction column, the second partition plate (123) divides the inner cavity of the reaction section (12) into an inner reaction chamber and an outer reaction chamber, and the first partition plate (122) is disposed in the outer reaction chamber and divides the outer reaction chamber into a plurality of the first reaction chambers.

4. The continuous production method according to claim 1, wherein R in the formula¹Represents C1-C10 alkyl, preferably methyl, ethyl, tert-butyl, n-hexyl or n-heptyl.

5. The continuous production method according to claim 2, wherein the step S1 includes:

dissolving the (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl ] -3 oxopentanoate in a first organic solvent selected from any one or more of the group consisting of ethyl acetate, methyl acetate, tetrahydrofuran, dichloromethane, chloroform, and methyl isobutyl ketone to form a first feedstock;

and feeding the first raw material liquid into the column type continuous reactor, and catalyzing (R) -4-nitrobenzyl-2-diazo-4- [ (2R,3S) -3- ((R) -1-hydroxyethyl) -azetidin-4-one-2-yl ] -3-oxo valerate to perform a ring-synthesizing reaction at 30-60 ℃ by using the supported rhodium catalyst to form a first intermediate system containing a first intermediate, wherein the retention time of the first raw material liquid in the column type continuous reactor is preferably 2-40 min, and preferably 4-20 min.

6. The continuous production method according to claim 1, wherein the step S2 includes:

pre-cooling the second continuous reactor to-32-12 ℃;

and (2) respectively feeding the first intermediate system, the diphenyl chlorophosphate solution and the diisopropylethylamine solution into the pre-cooled second continuous reactor for esterification to obtain a product system containing a penem intermediate MAP, wherein a solvent in the diphenyl chlorophosphate solution and a solvent in the diisopropylethylamine solution are respectively and independently selected from any one or more of ethyl acetate, methyl acetate, tetrahydrofuran, dichloromethane, chloroform and methyl isobutyl ketone, preferably before step S2, collecting the first intermediate system obtained in step S1 into a receiving device, pre-cooling the first intermediate system to-12-25 ℃, and connecting the collecting device with the column type continuous reactor and the second continuous reactor.

7. The continuous preparation method according to claim 1, wherein the second continuous reactor is a one-stage coil continuous reactor or a multi-stage coil continuous reactor in series, and the retention time of the reactants in the second continuous reactor is 2-40 min, preferably 4-20 min.

8. The continuous production method according to claim 1, wherein the step S3 includes:

sending the product system, a quenching agent and a crystallization liquid into a third continuous reactor for continuous crystallization to obtain a crystallization system, wherein the quenching agent is selected from any one or more of pure water, potassium dihydrogen phosphate buffer solution, potassium hydrogen phosphate buffer solution, sodium dihydrogen phosphate buffer solution and sodium hydrogen phosphate buffer solution, and the crystallization liquid is selected from any one or more of hexane, heptane, octane, methylcyclopentane and petroleum ether;

and carrying out solid-liquid separation on the crystallization system to obtain the intermediate MAP of the penem.

9. The continuous production method according to claim 8, wherein the third continuous reactor is a one-stage coil continuous reactor or a multi-stage coil continuous reactor in series.

10. The continuous production method according to claim 1, wherein the step S3 includes:

sending the product system into a quenching agent for quenching, and then sending a crystallization liquid into the product system for crystallization to obtain a crystallization system, wherein the quenching agent is selected from any one or more of the group consisting of pure water, a potassium dihydrogen phosphate buffer solution, a potassium hydrogen phosphate buffer solution, a sodium dihydrogen phosphate buffer solution and a sodium hydrogen phosphate buffer solution, and the crystallization liquid is selected from any one or more of the group consisting of hexane, heptane, octane, methylcyclopentane and petroleum ether;