CN112501217A - Continuous preparation method of S- (+) -2, 2-dimethylcyclopropane carboxylic acid - Google Patents
Continuous preparation method of S- (+) -2, 2-dimethylcyclopropane carboxylic acid Download PDFInfo
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Abstract
The invention provides aSA continuous preparation method of (+) -2, 2-dimethylcyclopropane carboxylic acid. The continuous preparation method comprises the following steps: in a continuous reactor, carrying out continuous hydrolysis reaction on reaction raw materials containing 2, 2-dimethyl cyclopropane ethyl formate under the catalytic action of immobilized enzyme to obtainS- (+) -2, 2-dimethylcyclopropanecarboxylic acid, wherein the immobilized enzyme is packed in the continuous reactor. The continuous preparation method avoids the stirring effect on the immobilized enzyme, thereby greatly reducing the crushing probability of the immobilized enzyme; on the other hand, the concentrated immobilized enzyme improves the reaction efficiency to a great extent and shortens the reaction time. And the adoption of the continuous preparation method can ensure thatSThe yield of the (+) -2, 2-dimethylcyclopropanecarboxylic acid reaches 80 percent. Meanwhile, the continuous preparation method is not limited by the size of the reaction scale, and is easy to realize large-scale production.
Description
Technical Field
The invention relates toSThe technical field of preparation of (+) -2, 2-dimethylcyclopropanecarboxylic acid, in particular toSA continuous preparation method of (+) -2, 2-dimethylcyclopropane carboxylic acid.
Background
S- (+) -2, 2-dimethylcyclopropanecarboxylic acid (C)S- (+) -DMCPA) is an important chiral intermediate for preparing cilastatin. Cilastatin is a renal dehydrodipeptidase inhibitor, and a complexing agent prepared from cilastatin and imipenem is the first novel carbapenem antibiotic applied to clinic, has extremely strong broad-spectrum antibacterial activity and also hasβLactamase inhibiting effect, which is one of the first choice drugs and global marketable drugs for resisting serious infection at present.
SThe preparation method of the (+) -DMCPA mainly comprises a chemical method and a biological method. Wherein, the chemical method has lower yield, lower optical purity of the product, expensive chiral catalyst and harsher reaction condition. The biological method has the advantages of high selectivity, high catalytic efficiency, environmental friendliness and the like, which are increasingly paid attention to, but the biological method has longer reaction time and fragile immobilized enzyme in batch kettles, so that the overall reaction efficiency is reduced, and the requirement on stirring is high, so that the biological method is not suitable for industrial mass production. The types of immobilized enzymes are Lipase F-AP, L-1754, Lipase PS-D, Novozyme 435 and the like, and the immobilization technology for forming the immobilized enzymes is a technology for binding enzyme molecules by means of chemistry or physics and the like for repeated use, and can be roughly divided into a carrier binding method, a crosslinking method and an embedding method.
Disclosure of Invention
The invention mainly aims to provideSA continuous preparation method of (+) -2, 2-dimethylcyclopropane carboxylic acid, which aims at solving the problemIn the prior artSThe preparation method of (+) -DMCPA has the problem of low reaction efficiency.
To achieve the above object, according to one aspect of the present invention, there is provided a method of manufacturing a semiconductor deviceSA continuous process for the preparation of (+) -2, 2-dimethylcyclopropanecarboxylic acid which comprises: in a continuous reactor, carrying out continuous hydrolysis reaction on reaction raw materials containing 2, 2-dimethyl cyclopropane ethyl formate under the catalytic action of immobilized enzyme to obtainS- (+) -2, 2-dimethylcyclopropanecarboxylic acid, wherein the immobilized enzyme is packed in the continuous reactor.
Further, the mass ratio of the immobilized enzyme to the ethyl 2, 2-dimethylcyclopropanecarboxylate is 20-25: the feeding speed of the 1, preferably 2, 2-dimethyl cyclopropane ethyl formate into the continuous reactor is 0.2-1 g/min.
Further, the retention time of the ethyl 2, 2-dimethylcyclopropanecarboxylate in the continuous reactor is 15-120 min.
Further, in the continuous hydrolysis reaction process, the pH value of the reaction system is adjusted to be between 7 and 8, preferably, a sodium hydroxide solution/potassium hydroxide solution is used as a pH regulator to adjust the pH value of the reaction system, preferably, the continuous reactor is configured with an online pH adjusting device, the online pH adjusting device comprises a pH monitor and a pH regulator supply device which are electrically connected, the pH monitor is arranged in the continuous reactor and used for monitoring the pH value of the reaction system in real time, and the pH regulator supply device receives a detection result of the pH monitor and automatically adds the pH regulator to the continuous reactor according to the detection result.
Further, the temperature of the continuous hydrolysis reaction is 38-42 ℃.
Furthermore, a temperature control jacket is arranged outside the continuous reactor.
The reaction raw material further comprises a buffer solution, preferably the buffer solution is one or more selected from sodium phosphate aqueous solution, potassium phosphate aqueous solution, disodium hydrogen phosphate aqueous solution and dipotassium hydrogen phosphate aqueous solution, and the mass ratio of the buffer solution to the 2, 2-dimethyl cyclopropane ethyl formate is preferably 10-12: 1.
further, the buffer solution and the ethyl 2, 2-dimethylcyclopropanecarboxylate are mixed and then enter a continuous reactor for continuous hydrolysis reaction.
Further, the continuous reactor is a continuous reaction column or a continuous reaction tube, and preferably, the continuous reactor is two to five continuous reaction columns connected in series.
Further, the packing in the continuous reactor is selected from any one or more of pall ring packing, ladder ring packing and Raschig ring packing.
The technical scheme of the invention is applied in the applicationSThe continuous preparation method of the (+) -2, 2-dimethylcyclopropane carboxylic acid has the advantages that on one hand, reaction raw materials flow through the immobilized enzyme loaded in the continuous reaction device, so that the stirring effect on the immobilized enzyme is avoided, and the probability of crushing the immobilized enzyme is greatly reduced; on the other hand, the concentration of the immobilized enzyme catalyst in a local reaction system is improved by the concentrated immobilized enzyme, so that reaction raw materials are sufficiently catalyzed, the reaction efficiency is improved to a great extent, and the reaction time is shortened. And the adoption of the continuous preparation method can ensure thatSThe yield of the (+) -2, 2-dimethylcyclopropane formic acid reaches more than 80 percent. Meanwhile, the continuous preparation method is not limited by the size of the reaction scale, and is easy to realize large-scale production.
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 method provided in accordance with embodiment 1 of the present inventionSFIG. of a continuous reaction apparatus for preparing (+) -2, 2-dimethylcyclopropanecarboxylic acid.
Wherein the figures include the following reference numerals:
01. a supply of ethyl 2, 2-dimethylcyclopropanecarboxylate; 02. a buffer solution supply device; 03. a mixer; 04. a continuous reaction column; 05. an on-line pH adjusting device.
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 analyzed by the background of the inventionSThe preparation method of the (+) -DMCPA has the problem of low reaction efficiency, and in order to solve the problem, the invention provides a method for preparing the (+) -DMCPASA continuous reaction device of (+) -2, 2-dimethyl cyclopropane formic acid and a preparation method thereof.
In an exemplary embodiment of the present application, there is provided a method of operating a computer systemSA continuous process for the preparation of (+) -2, 2-dimethylcyclopropanecarboxylic acid which comprises: in a continuous reactor, carrying out continuous hydrolysis reaction on reaction raw materials containing 2, 2-dimethyl cyclopropane ethyl formate under the catalytic action of immobilized enzyme to obtainS- (+) -2, 2-dimethylcyclopropanecarboxylic acid, wherein the immobilized enzyme is packed in the continuous reactor.
In this applicationSThe continuous preparation method of the (+) -2, 2-dimethylcyclopropane carboxylic acid has the advantages that on one hand, reaction raw materials flow through the immobilized enzyme loaded in the continuous reaction device, so that the stirring effect on the immobilized enzyme is avoided, and the probability of crushing the immobilized enzyme is greatly reduced; on the other hand, the concentration of the immobilized enzyme catalyst in a local reaction system is improved by the concentrated immobilized enzyme, so that reaction raw materials are sufficiently catalyzed, the reaction efficiency is improved to a great extent, and the reaction time is shortened. And the adoption of the continuous preparation method can ensure thatSThe yield of the (+) -2, 2-dimethylcyclopropane formic acid reaches more than 80 percent. Meanwhile, the continuous preparation method is not limited by the size of the reaction scale, and is easy to realize large-scale production.
The immobilized enzyme used in the continuous reaction of the present application may be one commonly used in the batch-tank reaction of the prior art, and the immobilized enzymes such as those described above may be used in the present application.
In order to fully exert the catalytic action of the immobilized enzyme on the 2, 2-dimethyl cyclopropane ethyl formate, the mass ratio of the immobilized enzyme to the 2, 2-dimethyl cyclopropane ethyl formate is preferably 20-25: 1. Preferably, the feeding speed of the ethyl 2, 2-dimethylcyclopropanecarboxylate into the continuous reactor is 0.2-1 g/min.
In order to ensure that the ethyl 2, 2-dimethylcyclopropanecarboxylate is continuously hydrolyzed as sufficiently as possible and to ensure high reaction efficiency, the retention time of the ethyl 2, 2-dimethylcyclopropanecarboxylate in the continuous reactor is preferably 15-120 min.
In order to optimize the hydrolysis condition of the reaction system and thus improve the yield of the continuous hydrolysis reaction, the pH value of the reaction system is preferably adjusted to 7-8 in the continuous hydrolysis reaction process, and a sodium hydroxide solution/potassium hydroxide solution is preferably used as a pH regulator to adjust the pH value of the reaction system.
Further, in order to control the pH value of the reaction system as accurately as possible, it is preferable that the continuous reactor is provided with an on-line pH adjusting device including a pH monitor and a pH adjusting agent supply means which are electrically connected, the pH monitor being provided in the continuous reactor for monitoring the pH value of the reaction system in real time, the pH adjusting agent supply means receiving a detection result of the pH monitor and automatically adding a pH adjusting agent to the continuous reactor according to the detection result. The pH regulator supply device can adjust the pH value of the continuous hydrolysis reaction to be 7-8 of the pH value of a reaction system in real time, so that the continuous hydrolysis reaction is carried out efficiently.
The temperature of the continuous hydrolysis reaction in the present application may refer to the temperature of the batch reaction in the prior art, or may be selected within a temperature range with a higher enzyme activity, so as to improve the efficiency of the continuous hydrolysis reaction, and preferably, the temperature of the continuous hydrolysis reaction is 38 to 42 ℃.
In one embodiment of the present application, the continuous reactor is externally provided with a temperature control jacket. The continuous reactor is externally provided with a temperature control jacket which can keep the continuous hydrolysis reaction to be carried out at a preset reaction temperature, thereby ensuring the product yield of the continuous hydrolysis reaction.
In order to provide a stable pH value of the initial reaction system as much as possible, it is preferable that the above reaction raw materials further include a buffer solution, and it is preferable that the buffer solution is selected from any one or more of an aqueous sodium phosphate solution, an aqueous potassium phosphate solution, an aqueous disodium hydrogen phosphate solution, and an aqueous dipotassium hydrogen phosphate solution.
In order to ensure the mixing uniformity of the buffer solution and the ethyl 2, 2-dimethylcyclopropanecarboxylate and improve the efficiency of the continuous hydrolysis reaction, the buffer solution and the ethyl 2, 2-dimethylcyclopropanecarboxylate are preferably mixed and then enter a continuous reactor for the continuous hydrolysis reaction.
The continuous reactor used in the present application may adopt continuous reaction equipment commonly used in the prior art, and is preferably a continuous reaction column or a continuous reaction tube, in order to facilitate the filling and fixing of the immobilized enzyme and improve the contact effect of the reactant and the immobilized enzyme, and the continuous reactor has a high length-diameter ratio, so that the uniformity of the contact of the reactant and the immobilized enzyme can be controlled. The continuous reactor is preferably two to five continuous reaction columns connected in series, so that the treatment capacity of the continuous hydrolysis reaction can be further improved.
In some embodiments, in order to improve the utilization rate of the immobilized enzyme, the immobilized enzyme is dispersed in the packing, and in order to improve the loading effect of the immobilized enzyme on the packing and reduce the side effect of the packing on the continuous hydrolysis reaction as much as possible, the packing in the continuous reactor is preferably selected from any one or more of pall ring packing, cascade ring packing and raschig ring packing.
The advantageous effects of the present application will be described below with reference to specific examples and comparative examples.
Example 1
At room temperature, 2-dimethyl cyclopropane ethyl formate is simultaneously pumped into a mixer 03 at the speed of 0.42g/min through 2, 2-dimethyl cyclopropane ethyl formate supply equipment 01 and the speed of 4.61g/min through buffer solution supply equipment 02, then the mixture enters two continuous reaction columns 04 filled with L-1754 immobilized enzyme catalyst (150 g) for continuous hydrolysis reaction, the filler in the continuous reaction columns 04 is pall ring filler, and the mass ratio of the L-1754 immobilized enzyme catalyst to the 2, 2-dimethyl cyclopropane ethyl formate is controlledIs 22: adjusting the pH value of the continuous hydrolysis reaction to 7.5, controlling the temperature of a jacket of a continuous reaction column 04 to be 40 ℃, stabilizing the pH value of the system to 7.5 by utilizing a sodium hydroxide solution through an online pH adjusting device 05, controlling the retention time of the 2, 2-dimethyl cyclopropane ethyl formate in the continuous reaction column 04 to be 50min, sampling at an outlet, and carrying out HPLC analysis to obtain the compoundSThe purity of the (+) -2, 2-dimethylcyclopropanecarboxylic acid product is 90%,Sthe yield of the product, - (+) -2, 2-dimethylcyclopropanecarboxylic acid, was 85%.SFIG. 1 shows a schematic diagram of a continuous reaction apparatus for preparing (+) -2, 2-dimethylcyclopropanecarboxylic acid.
Example 2
Example 2 differs from example 1 in that the mass ratio of L-1754 immobilized enzyme catalyst to ethyl 2, 2-dimethylcyclopropanecarboxylate is 20: 1, finally obtainingS- (+) -2, 2-dimethylcyclopropanecarboxylic acid product.
Example 3
Example 3 differs from example 1 in that the mass ratio of L-1754 immobilized enzyme catalyst to ethyl 2, 2-dimethylcyclopropanecarboxylate is 25:1, finally obtainingS- (+) -2, 2-dimethylcyclopropanecarboxylic acid product.
Example 4
Example 4 differs from example 1 in that the mass ratio of L-1754 immobilized enzyme catalyst to ethyl 2, 2-dimethylcyclopropanecarboxylate is 18: 1, finally obtainingS- (+) -2, 2-dimethylcyclopropanecarboxylic acid product.
Example 5
Example 5 differs from example 1 in that the feeding rate of ethyl 2, 2-dimethylcyclopropanecarboxylate into the continuous reaction column was 0.2g/min, the retention time was 120min, and the final product was obtainedS- (+) -2, 2-dimethylcyclopropanecarboxylic acid product.
Example 6
Example 6 differs from example 1 in that the feeding rate of ethyl 2, 2-dimethylcyclopropanecarboxylate into the continuous reaction column was 1g/min, the retention time was 30min, and the final product was obtainedS- (+) -2, 2-dimethylcyclopropanecarboxylic acid product.
Example 7
Example 7 differs from example 1 in that 2, 2-dimethylcyclopropane methylThe feeding speed of the ethyl acetate entering the continuous reaction column is 2g/min, the retention time is 15min, and the ethyl acetate is finally obtainedS- (+) -2, 2-dimethylcyclopropanecarboxylic acid product.
Example 8
Example 8 differs from example 1 in that the retention time of ethyl 2, 2-dimethylcyclopropanecarboxylate in the continuous reaction column was 30min, and the final product was obtainedS- (+) -2, 2-dimethylcyclopropanecarboxylic acid product.
Example 9
Example 9 differs from example 1 in that the retention time of ethyl 2, 2-dimethylcyclopropanecarboxylate in the continuous reaction column was 60min, and the final product was obtainedS- (+) -2, 2-dimethylcyclopropanecarboxylic acid product.
Example 10
Example 10 differs from example 1 in that the retention time of ethyl 2, 2-dimethylcyclopropanecarboxylate in the continuous reaction column was 25min, and the final product was obtainedS- (+) -2, 2-dimethylcyclopropanecarboxylic acid product.
Example 11
Example 11 differs from example 1 in that the pH of the continuous hydrolysis reaction was 7.0 and the final product was obtainedS- (+) -2, 2-dimethylcyclopropanecarboxylic acid product.
Example 12
Example 12 differs from example 1 in that the pH of the continuous hydrolysis reaction was 8.0 and the final product was obtainedS- (+) -2, 2-dimethylcyclopropanecarboxylic acid product.
Example 13
Example 13 differs from example 1 in that the pH of the continuous hydrolysis reaction was 6.0 and the final product was obtainedS- (+) -2, 2-dimethylcyclopropanecarboxylic acid product.
Example 14
Example 14 differs from example 1 in that the temperature of the continuous hydrolysis reaction was 38 ℃ and the final product was obtainedS- (+) -2, 2-dimethylcyclopropanecarboxylic acid product.
Example 15
Example 15 differs from example 1 in that the temperature of the continuous hydrolysis reaction was 42 ℃ and the final product was obtainedS- (+) -2, 2-dimethylcyclopropanecarboxylic acid product。
Example 16
Example 16 differs from example 1 in that the temperature of the continuous hydrolysis reaction was 45 ℃ and the final product was obtainedS- (+) -2, 2-dimethylcyclopropanecarboxylic acid product.
Example 17
Example 17 differs from example 1 in that the buffer solution is an aqueous solution of dipotassium hydrogen phosphate to give the final productS- (+) -2, 2-dimethylcyclopropanecarboxylic acid product.
Comparative example 1
Comparative example 1 differs from example 1 in that 6.82g of ethyl 2, 2-dimethylcyclopropanecarboxylate and 204.55g of L-1754 immobilized enzyme catalyst were subjected to hydrolysis reaction in a reaction kettle at room temperature for 40 hours, the pH value of the hydrolysis was 7.1, the reaction temperature was 40 ℃, and HPLC analysis was performed by sampling from an outlet to obtainSThe purity of the (+) -2, 2-dimethylcyclopropanecarboxylic acid product is 90%,Sthe yield of the product, - (+) -2, 2-dimethylcyclopropanecarboxylic acid, was 85%.
Obtained from the above-mentioned examples 1 to 17 and comparative example 1SSampling HPLC analysis of the product of- (+) -2, 2-dimethylcyclopropanecarboxylic acid and analysis of examples 1 to 17 and comparative example 1SThe yields, retention/reaction times of the (+) -2, 2-dimethylcyclopropanecarboxylic acid product are shown in table 1, wherein the time of examples 1 to 17 represents the retention time and the time of comparative example 1 represents the reaction time.
From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:
in this applicationSThe continuous preparation method of the (+) -2, 2-dimethylcyclopropane carboxylic acid has the advantages that on one hand, reaction raw materials flow through the immobilized enzyme loaded in the continuous reaction device, so that the stirring effect on the immobilized enzyme is avoided, and the probability of crushing the immobilized enzyme is greatly reduced; on the other hand, the concentration of the immobilized enzyme catalyst in a local reaction system is increased by the concentrated immobilized enzyme, so that reaction raw materials are sufficiently catalyzed, and further, the reaction raw materials are fully catalyzedThe reaction efficiency is improved to a great extent, and the reaction time is shortened. And the adoption of the continuous preparation method can ensure thatSThe yield of the (+) -2, 2-dimethylcyclopropane formic acid reaches more than 80 percent. Meanwhile, the continuous preparation method is not limited by the size of the reaction scale, and is easy to realize large-scale production.
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 (15)
1. A kind ofSA continuous production method of (+) -2, 2-dimethylcyclopropanecarboxylic acid, characterized in that the continuous production method comprises:
in a continuous reactor, carrying out continuous hydrolysis reaction on reaction raw materials containing 2, 2-dimethyl cyclopropane ethyl formate under the catalytic action of immobilized enzyme to obtain the productS- (+) -2, 2-dimethylcyclopropanecarboxylic acid, wherein the immobilized enzyme is packed in the continuous reactor.
2. The continuous production method according to claim 1, wherein the mass ratio of the immobilized enzyme to the ethyl 2, 2-dimethylcyclopropanecarboxylate is 20 to 25: 1.
3. the continuous production method according to claim 1, wherein the feeding speed of the ethyl 2, 2-dimethylcyclopropanecarboxylate into the continuous reactor is 0.2-1 g/min.
4. The continuous production method according to any one of claims 1 to 3, wherein the retention time of the ethyl 2, 2-dimethylcyclopropanecarboxylate in the continuous reactor is 15-120 min.
5. The continuous production method according to any one of claims 1 to 3, wherein the pH value of the reaction system is adjusted to 7 to 8 during the continuous hydrolysis reaction.
6. The continuous production method according to claim 5, wherein the pH of the reaction system is adjusted by using a sodium hydroxide solution/potassium hydroxide solution as a pH adjuster.
7. The continuous production method according to claim 6, wherein the continuous reactor is provided with an online pH adjusting device, the online pH adjusting device comprises a pH monitor and a pH adjusting agent supply device which are electrically connected, the pH monitor is arranged in the continuous reactor and is used for monitoring the pH value of the reaction system in real time, and the pH adjusting agent supply device receives the detection result of the pH monitor and automatically adds a pH adjusting agent to the continuous reactor according to the detection result.
8. The continuous production method according to claim 1, wherein the temperature of the continuous hydrolysis reaction is 38 to 42 ℃.
9. The continuous preparation method according to claim 1, wherein a temperature control jacket is arranged outside the continuous reactor.
10. The continuous production method according to claim 1, wherein the reaction raw material further comprises a buffer solution.
11. The continuous production method according to claim 10, wherein the buffer solution is one or more selected from the group consisting of an aqueous sodium phosphate solution, an aqueous potassium phosphate solution, an aqueous disodium hydrogen phosphate solution, and an aqueous dipotassium hydrogen phosphate solution.
12. The continuous production method according to claim 10 or 11, wherein the buffer solution and the ethyl 2, 2-dimethylcyclopropanecarboxylate are mixed and then enter the continuous reactor to perform the continuous hydrolysis reaction.
13. The continuous production method according to claim 1, wherein the continuous reactor is a continuous reaction column or a continuous reaction tube.
14. The continuous production method according to claim 13, wherein the continuous reactor comprises two to five continuous reaction columns connected in series.
15. The continuous production method according to claim 1, wherein the packing in the continuous reactor is selected from any one or more of pall ring packing, ladder ring packing and Raschig ring packing.
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| CN115141871A (en) * | 2022-07-25 | 2022-10-04 | 福建未来药业有限公司 | Preparation method of peramivir intermediate |
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