CN114315862A - Method for preparing penicillin sulfoxide ester by continuous flow - Google Patents

Method for preparing penicillin sulfoxide ester by continuous flow Download PDF

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CN114315862A
CN114315862A CN202011056618.1A CN202011056618A CN114315862A CN 114315862 A CN114315862 A CN 114315862A CN 202011056618 A CN202011056618 A CN 202011056618A CN 114315862 A CN114315862 A CN 114315862A
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penicillin
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周龙
柴宝山
邢久歌
王云华
韩涛
曹贺
焦佳媛
王志强
鄢冬茂
王珂
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Shenyang Research Institute of Chemical Industry Co Ltd
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Abstract

The invention belongs to the technical field of chemistry and chemical engineering, and particularly relates to a method for preparing penicillin sulfoxide ester by continuous flow. The method has the advantages of simple operation, improved safety of the reaction unit, sustainability, high productivity per unit area compared with the traditional intermittent reaction mode, environmental friendliness and the like, the conversion rate of the preparation method reaches 100%, the selectivity reaches 99%, the separation yield reaches 96%, the content is more than 99.5%, and the single impurity content index reaches the original process standard.

Description

Method for preparing penicillin sulfoxide ester by continuous flow
The technical field is as follows:
the invention belongs to the technical field of chemistry and chemical engineering. In particular to a method for preparing penicillin sulfoxide ester by continuous flow.
Technical background:
cephalosporin antibiotics are a widely used class of antibiotics. The penicillin sulfoxide ester (GESO) is used as an important intermediate for synthesizing cephalosporin antibiotics, and has wide application value and wide market prospect. In 1963, American Gift company utilizes penicillin to synthesize cephalosporin drugs, and penicillin G potassium is used as a starting material to synthesize penicillin sulfoxide ester through esterification and peroxyacetic acid oxidation. In the eighties of the last century, salt-wild-type companies in Japan designed an additional route to cephalosporin, penicillin sulfoxide esters of which were synthesized in the same way as lead. In 2011, KUMAR Rajiv et al invented a method for synthesizing penicillin sulfoxide ester by using hydrogen peroxide as an oxidant and sodium tungstate as a catalyst.
As a classic oxidant, hydrogen peroxide is widely applied to oxidation reactions such as oxidation of thioether into sulfoxide and sulfone, oxidation of alcohol into aldehyde ketone, olefin epoxidation, dihydroxylation and the like. The reaction of oxidizing thioether into sulfoxide with hydrogen peroxide has the problem of low selectivity, and in order to improve the selectivity, the proper catalyst is selected more importantly besides the requirement of controlling the addition of hydrogen peroxide. In recent years, heteropolyacid catalysts are widely applied to the reaction of oxidizing thioether with hydrogen peroxide and have ideal selectivity and conversion rate. The metal heteroatoms (metals such as tungsten, vanadium, molybdenum, titanium, etc.) participate in catalysis as peracid formers (Materials Science & Engineering C,110(2020) 110577).
The invention uses hydrogen peroxide as oxidant to prepare penicillin sulfoxide ester (GESO) by continuous flow method, the scheme has no literature report at present, and the selectivity of the reaction is greatly improved by optimizing the using conditions of the catalyst and the phase transfer catalyst, so that the sulfone content of the transition oxidation product is less than 1%, and the penicillin sulfoxide ester (GESO) is prepared under the conditions of high conversion rate, high selectivity, high purity and mild condition.
The invention content is as follows:
the invention provides a method for preparing penicillin sulfoxide ester by continuous flow, which is simple to operate and has sustainability, wherein the conversion rate of raw materials reaches 100%, the selectivity of products reaches 99%, the separation yield reaches 96%, and the content is more than 99.5%.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a continuous flow preparation method of penicillin sulfoxide ester comprises the steps of carrying out continuous flow oxidation reaction on an oxidant and penicillin G potassium ester, carrying out continuous flow quenching reaction on an oxidation reaction solution after the reaction through a sodium bisulfite aqueous solution, and carrying out post-treatment to obtain penicillin sulfoxide ester; wherein the oxidant is a mixed solution of hydrogen peroxide and a catalyst solution;
the catalyst is Keggin type heteropoly acid catalyst and phase transfer catalyst.
The catalyst solution consists of a Keggin type heteropoly acid catalyst, a phase transfer catalyst and water, wherein the mass of the Keggin type heteropoly acid catalyst accounts for 0.1-10% of the mass of the catalyst aqueous solution, and the mass of the phase transfer catalyst accounts for 0.5-10% of the mass of the catalyst aqueous solution;
the mass ratio of the hydrogen peroxide to the catalyst solution is 2-15: 1.
the catalyst Keggin type heteropoly acid HnAM12O40·xH2The O catalyst is phosphomolybdic acid H3[PMo12O40]Phosphotungstic acid H3[PW12O40]Silicotungstic acid H4[SiW12O40]Or silicomolybdic acid H4[SiMo12O40]。
The phase transfer catalyst is benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride or tetradecyltrimethylammonium chloride. The molar ratio of the fed amount of potassium penicillin G ester to the fed amount of the oxidizing agent is 1:1-2, preferably 1: 1.05-1.2.
The molar ratio of the sodium bisulfite aqueous solution to the oxidant is 0.05-0.3: 1.
the concentration of the hydrogen peroxide is 20-50%, and the preferred concentration of the hydrogen peroxide is 27.5-50%.
The reaction temperature of the continuous flow oxidation reaction is 0-80 ℃, and the preferable reaction temperature is 40-70 ℃.
The pressure of the continuous flow oxidation reaction is 0.1-1.0MPa, and the preferable reaction pressure is 0.3-0.8 MPa.
The time of the continuous flow oxidation reaction is 0.5-10min, and the preferable reaction time is 4-9 min.
The concentration of the sodium bisulfite aqueous solution is 1 to 33 percent, and the concentration of the sodium bisulfite aqueous solution is preferably 5 to 15 percent.
The continuous flow quenching reaction temperature is 0-30 ℃, and the preferred quenching reaction temperature is 15-20 ℃.
And the post-treatment comprises the steps of collecting the quenched reaction liquid, separating and extracting, washing an organic phase with a small amount of water, concentrating, crystallizing the concentrated solution with methanol, and drying in vacuum at 40 ℃ to obtain a target product, wherein the post-treatment can ensure that no side reaction occurs after the reaction is finished.
The preparation method of the penicillin G potassium ester compound comprises the step of carrying out esterification reaction on penicillin G potassium serving as a raw material and dichloromethane serving as a solvent and p-nitrobenzyl bromide.
Compared with the prior art, the invention has the advantages that:
1. the method disclosed by the invention is simple to operate, improves the safety of the reaction unit, and has the advantages of sustainability, high productivity per unit area compared with the traditional batch reaction mode, environmental friendliness and the like.
2. The preparation method of the invention has the advantages that the conversion rate reaches 100%, the selectivity reaches 99%, the separation yield reaches 96%, the content is more than 99.5%, and the single impurity content index reaches the original process standard.
3. The invention combines Keggin type heteropoly acid catalyst and phase transfer catalyst to exert the function of Keggin type heteropoly acid catalyst to the maximum extent, reduces the usage amount of heteropoly acid, greatly improves the process economy, greatly improves the selectivity of the reaction by optimizing the using conditions of the catalyst and the phase transfer catalyst, ensures that the sulfone amount of a transition oxidation product is less than 1 percent, and prepares penicillin sulfoxide ester (GESO) under the conditions of high conversion rate, high selectivity, high purity and mild condition.
4. The Keggin type heteropoly acid catalyst and the phase transfer catalyst used in the invention are cheap and easily available, and the usage amount is small.
Drawings
FIG. 1 is a schematic view of a continuous process and apparatus of the present invention, wherein 101 is a first reactor, 102 is a second reactor, 103 is a third reactor, 201 is a storage tank, 301 is a first pipeline, 302 is a second pipeline, 303 is a third pipeline, 304 is a fourth pipeline, 305 is a fifth pipeline, 306 is a sixth pipeline, and 307 is a seventh pipeline;
t1, T2 and T3 are temperature sensors; p1 and P2 are pressure sensors.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings.
As shown in fig. 1, the apparatus of the present invention comprises a storage tank 201, a plurality of reactors and a plurality of pipelines, wherein the reactors are provided with two input ends and an output end, a first pipeline 301 for inputting catalyst and phase transfer catalyst and a second pipeline 302 for inputting hydrogen peroxide are respectively connected with different input ends of a first reactor 101, the output end of the first reactor 101 is connected with a first input end of a second reactor 102 through a third pipeline, a fourth pipeline 304 for inputting penicillin G potassium esterification solution is connected with a second input end of the second reactor 102, the output end of the second reactor 102 is connected with a first input end of a third reactor 103 through a fifth pipeline 305, a sixth pipeline 306 for inputting sodium bisulfite is connected with a second input end of the third reactor 103, the output end of the third reactor 103 is connected with the storage tank 201 through a seventh pipeline 307, the first pipeline 301, the second pipeline 302, the fourth pipeline 304 and the sixth pipeline 306 are all provided with a feeding pump, the third pipeline 303 and the fifth pipeline 305 are both provided with temperature sensors (T1 and T2) and pressure sensors (P1, P2 and P3), and the seventh pipeline 307 is provided with a temperature sensor (T3) and a back pressure valve. The temperature sensor, pressure sensor and each reactor are well known in the art and are commercially available products.
The working principle of the invention is as follows: the feeding amount of a feeding pump is proportionally set, and Keggin type heteropoly acid HnAM12O40·xH2The O and the aqueous solution of the phase transfer catalyst enter a first reactor 101 through a first pipeline 301, hydrogen peroxide enters the first reactor 101 through a second pipeline 302 to be mixed and prepared into an oxidant, the discharging temperature is controlled to be 10 ℃, the discharged material directly enters a second reactor 102, the treated penicillin G potassium esterified substance solution enters the second reactor 102 through a fourth pipeline 304 to be subjected to oxidation reaction with the oxidant, the reaction temperature and the reaction pressure are controlled, the reaction product enters a third reactor 103 to be subjected to quenching reaction, sodium bisulfite enters the third reactor 103 through a sixth pipeline 306 to be subjected to quenching reaction on the reaction product in the previous step, the quenching reaction temperature is controlled, the discharged material enters a material storage tank 201, adjusting pH value to 7-8, separating liquid, extracting water phase with dichloromethane, combining organic phases, washing organic phases with a small amount of water, concentrating, and crystallizing concentrated solution with methanol to obtain the final product.
Example (b):
penicillin G potassium ester synthesis:
4L of dichloromethane, 2Kg of penicillin G potassium, 1.165K G of p-nitrobenzyl bromide and 100G of triethyl benzyl ammonium chloride are sequentially added into a 10L glass reaction kettle. Stirring and heating, refluxing for 6-7 hours, performing HPLC tracking, cooling to room temperature after the reaction is finished, adding 2L of water, stirring uniformly, standing for 30 minutes, and discharging an organic phase. The aqueous phase is extracted twice with 0.5L of dichloromethane, the organic phases are combined, the organic phase is rinsed twice with 0.5L of water, the rinsed organic phase is ready for use, the concentration of the potassium penicillin G ester is 27.66%
The continuous flow preparation method of penicillin sulfoxide ester comprises the following steps:
the above apparatus was used, wherein the first reactor 101, the second reactor 102, and the third reactor 103 were purchased from corning reactor technologies, inc, model: lab Reactor & LFR.
Hydrogen peroxide and a catalyst are mixed in a first reactor 101 to prepare an oxidant, the oxidant and the penicillin G potassium ester undergo continuous flow oxidation reaction in a second reactor 102, the oxidation reaction liquid undergoes continuous flow quenching reaction in a third reactor 103 by using a sodium bisulfite aqueous solution, and then the reaction liquid enters a storage tank 201, and penicillin sulfoxide ester (GESO) is obtained through post-treatment.
And the post-treatment comprises the steps of adjusting the pH value of the quenching reaction solution to 7-8, separating liquid, extracting a water phase by using dichloromethane, combining organic phases, washing the organic phases with a small amount of water, concentrating, and crystallizing the concentrated solution by using methanol to obtain a final product.
The specific charge, reaction effect and reaction conditions for the continuous flow preparation of penicillin sulfoxide esters of examples 1-10 and comparative examples 1-2 are detailed in tables 1-4.
Table 1: continuous preparation oxidant batching table
Figure BDA0002711037040000041
Figure BDA0002711037040000051
Note: the error of the flow of the feeding pump is +/-0.5 g/min; trace amount of hydrogen peroxide is not measured.
Table 2: batch meter for continuously preparing penicillin sulfoxide ester
Figure BDA0002711037040000052
Note: the prepared sodium bisulfite must be filtered and then enters a reactor; .
Table 3: reaction result for continuous preparation of penicillin sulfoxide ester
Figure BDA0002711037040000053
Figure BDA0002711037040000061
Note: in all the examples, continuous peroxyacetic acid experiments were performed, in order to find the concentration of peroxyacetic acid, after detection by the method of GB/T19104-2008 peroxyacetic acid solution, two-step continuous reactions were performed by the corresponding method. The indicated yields are measured as potassium penicillin G.
Table 4: continuous flow process conditions
Figure BDA0002711037040000062
Figure BDA0002711037040000071
Note: the error of the temperature sensor is +/-1 ℃; reactor pressure is related to reaction temperature and material flow rate; the error of the inner diameter of the channel of the reactor is +/-0.2 mm.
As can be seen from the above examples 1-10 and comparative examples 1-2, the results of conversion, selectivity, yield, etc. of the Keggin-type heteropolyacid catalysts of examples 1-10 used in combination with a phase transfer catalyst are significantly superior to those of the single catalyst and other catalysts used in combination.
Comparative example 3 (batch process):
the treated penicillin G potassium esterified solution is put into a reaction kettle, and 10.76G of sodium tungstate dihydrate and 10.76G of triethyl benzyl ammonium chloride are added. Stirring and cooling to 10-20 ℃, slowly dripping 995g of 30% hydrogen peroxide for about 30-60 min, and controlling the temperature of the reaction solution to be between 10 and 20 ℃. And (3) monitoring the reaction by liquid phase tracking, monitoring by TLC, reducing the temperature to 0 ℃ after the reaction is finished, and dropwise adding a sodium bisulfite solution, wherein the color of the starch potassium iodide test paper is not developed. And standing, separating, extracting the water phase with a small amount of dichloromethane, combining the organic phases, placing the organic phases in a reaction kettle, stirring, adjusting the pH value to 7-8 with a saturated sodium bicarbonate solution, standing, layering, extracting the water phase with a small amount of dichloromethane, combining the organic phases, concentrating, and crystallizing the concentrated solution with methanol to obtain the final product. The two-step reverse conversion rate is 90%, the selectivity is 95%, and 2.25kg of product with the content of 99.0% is obtained after drying, and the separation yield is 85.73%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and alternatives falling within the spirit and principles of the present invention are intended to be included therein.

Claims (8)

1. A continuous flow process for the preparation of penicillin sulfoxide esters,
continuously oxidizing an oxidizing agent and a penicillin G potassium ester compound, carrying out continuous flow quenching reaction on the oxidized reaction liquid after the reaction by a sodium bisulfite aqueous solution, and then carrying out post-treatment to obtain penicillin sulfoxide ester; wherein the oxidant is a mixed solution of hydrogen peroxide and a catalyst solution;
the catalyst is Keggin type heteropoly acid catalyst and phase transfer catalyst.
2. The method of claim 1,
the catalyst solution consists of a Keggin type heteropoly acid catalyst, a phase transfer catalyst and water, wherein the mass of the Keggin type heteropoly acid catalyst accounts for 0.1-10% of the mass of the catalyst aqueous solution, and the mass of the phase transfer catalyst accounts for 0.5-10% of the mass of the catalyst aqueous solution;
the mass ratio of the hydrogen peroxide to the catalyst solution is 2-15: 1.
3. the method of claim 1,
the Keggin type heteropolyacid catalyst is phosphomolybdic acid H3[PMo12O40]Phosphotungstic acid H3[PW12O40]Silicotungstic acid H4[SiW12O40]Or silicomolybdic acid H4[SiMo12O40]；
The phase transfer catalyst is benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride or tetradecyltrimethylammonium chloride.
4. The process according to claim 1, characterized in that the molar ratio of penicillin G potassium ester to oxidizing agent is 1: 1-2;
the molar ratio of the sodium bisulfite aqueous solution to the oxidant is 0.05-0.3: 1.
5. the method according to claim 1, wherein the concentration of the hydrogen peroxide is 20-50%.
6. The method of claim 1, wherein the continuous flow oxidation reaction is carried out at a reaction temperature of 0-80 ℃, a reaction pressure of 0.1-1.0MPa, and a reaction time of 0.5-10 min.
7. The method according to claim 1, wherein the concentration of the aqueous solution of sodium bisulfite is 1 to 33%, and the temperature of the quenched reaction solution is 0 to 30 ℃.
8. The method as claimed in claim 1, wherein the post-treatment comprises collecting the quenched reaction solution, separating and extracting, washing the organic phase with water, concentrating, crystallizing the concentrated solution with methanol, and vacuum drying to obtain the penicillin sulfoxide ester.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115445534A (en) * 2022-09-21 2022-12-09 上海应用技术大学 Device for continuously preparing penicillin G p-nitrobenzyl ester and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101434609A (en) * 2008-12-19 2009-05-20 齐鲁天和惠世制药有限公司 Catalytic oxidation system and use thereof in tazobactam synthesis
CN102432627A (en) * 2011-09-19 2012-05-02 江苏九九久科技股份有限公司 Method for producing p-nitrobenzyl penicillin G sulfoxide ester
CN105777780A (en) * 2015-10-10 2016-07-20 浙江沙星医药化工有限公司 Method for preparing thiazoline enol ester
CN111233892A (en) * 2018-11-28 2020-06-05 江苏悦新药业有限公司 Method for synthesizing penicillin G sulfoxide by using continuous flow reactor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101434609A (en) * 2008-12-19 2009-05-20 齐鲁天和惠世制药有限公司 Catalytic oxidation system and use thereof in tazobactam synthesis
CN102432627A (en) * 2011-09-19 2012-05-02 江苏九九久科技股份有限公司 Method for producing p-nitrobenzyl penicillin G sulfoxide ester
CN105777780A (en) * 2015-10-10 2016-07-20 浙江沙星医药化工有限公司 Method for preparing thiazoline enol ester
CN111233892A (en) * 2018-11-28 2020-06-05 江苏悦新药业有限公司 Method for synthesizing penicillin G sulfoxide by using continuous flow reactor

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115445534A (en) * 2022-09-21 2022-12-09 上海应用技术大学 Device for continuously preparing penicillin G p-nitrobenzyl ester and application thereof
CN115445534B (en) * 2022-09-21 2024-01-26 上海应用技术大学 Device for continuously preparing penicillin G p-nitrobenzyl ester and application thereof

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