CN114315862B - Method for preparing penicillin sulfoxide ester by continuous flow - Google Patents
Method for preparing penicillin sulfoxide ester by continuous flow Download PDFInfo
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- CN114315862B CN114315862B CN202011056618.1A CN202011056618A CN114315862B CN 114315862 B CN114315862 B CN 114315862B CN 202011056618 A CN202011056618 A CN 202011056618A CN 114315862 B CN114315862 B CN 114315862B
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Abstract
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. The catalyst is a heteropolyacid catalyst and a phase transfer catalyst, the method is simple to operate, the safety of the reaction unit is improved, the method has the advantages of sustainability, higher productivity per unit area than the traditional batch reaction mode, environmental friendliness and the like, 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 grinding process standard.
Description
Technical field:
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 one of the antibiotics widely used. Penicillin sulfoxide ester (GESO) is an important intermediate for synthesizing cephalosporin antibiotic drugs, and has wide application value and broad market prospect. In 1963, the American Gift company synthesized cephalosporin drugs with penicillin G potassium as the starting material and synthesized penicillin sulfoxide esters by esterification and peracetic acid oxidation. In the eighties of the last century, the salt wild company in japan designed an exception route for the synthesis of cephalosporins, which synthesized penicillin sulfoxide esters in the same way as the gift company. 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.
Hydrogen peroxide is used as a classical oxidant and is widely applied to oxidation reactions such as oxidation of thioether into sulfoxide and sulfone, oxidation of alcohol into aldehyde ketone, epoxidation of olefin, dihydroxylation and the like. The reaction of oxidizing thioether with hydrogen peroxide into sulfoxide has the problem of low selectivity, and in order to improve the selectivity, it is more important to select a proper catalyst except for controlling the addition amount of hydrogen peroxide. In recent years, the heteropolyacid catalyst is widely applied to the oxidation of thioether by hydrogen peroxide and has ideal selectivity and conversion rate. Metal heteroatoms (e.g., metals such as tungsten, vanadium, molybdenum, titanium, etc.) of the metal are involved in catalysis as peracid formers (Materials Science & Engineering C,110 (2020) 110577).
The method for preparing penicillin sulfoxide ester (GESO) by using hydrogen peroxide as an oxidant and using a continuous flow method has no literature report at present, and the selectivity of the reaction is greatly improved through optimizing the use conditions of a catalyst and a phase transfer catalyst, so that the sulfone amount of a transitional oxidation product is less than 1%, and the penicillin sulfoxide ester (GESO) is prepared under the mild conditions with high conversion rate, high selectivity and high purity.
The invention comprises the following steps:
the invention provides a method for preparing penicillin sulfoxide ester by continuous flow, which is simple to operate, has sustainability, the raw material conversion rate reaches 100%, the product selectivity reaches 99%, the separation yield reaches 96%, and the content is more than 99.5%.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
a method for preparing penicillin sulfoxide ester by continuous flow 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 oxidation reaction liquid by sodium bisulphite aqueous solution after the reaction, 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 a Keggin type heteropoly acid catalyst and a phase transfer catalyst.
The catalyst solution consists of a Keggin type heteropolyacid catalyst, a phase transfer catalyst and water, wherein the mass of the Keggin type heteropolyacid 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 heteropolyacid H n AM 12 O 40 ·xH 2 O catalyst is phosphomolybdic acid H 3 [PMo 12 O 40 ]Phosphotungstic acid H 3 [PW 12 O 40 ]Silicotungstic acid H 4 [SiW 12 O 40 ]Or silicomolybdic acid H 4 [SiMo 12 O 40 ]。
The phase transfer catalyst is benzyl triethyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium bisulfate, trioctyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride or tetradecyl trimethyl ammonium chloride. The molar ratio of penicillin G potassium esterified substance to oxidant is 1:1-2, preferably 1:1.05-1.2.
The molar ratio of the sodium bisulphite aqueous solution to the oxidant is 0.05-0.3:1.
the concentration of the hydrogen peroxide is 20-50%, preferably 27.5-50%.
The reaction temperature of the continuous flow oxidation reaction is 0-80 ℃, preferably 40-70 ℃.
The pressure of the continuous flow oxidation reaction is 0.1-1.0MPa, and the preferable reaction pressure is 0.3-0.8MPa.
The continuous flow oxidation reaction time is 0.5-10min, preferably 4-9min.
The concentration of the sodium bisulphite aqueous solution is 1-33%, and the concentration of the sodium bisulphite aqueous solution is 5-15% preferably.
The continuous flow quenching reaction temperature is 0-30 ℃, and the quenching reaction temperature is 15-20 ℃ preferably.
The post-treatment is to collect the quenched reaction liquid, separate liquid extraction, wash the organic phase with a small amount of water, concentrate, crystallize the concentrate with methanol, and dry in vacuum at 40 ℃ to obtain the 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 esterified substance is to take penicillin G potassium as a raw material and take methylene dichloride as a solvent to carry out esterification reaction with p-nitrobenzyl bromide.
Compared with the prior art, the invention has the advantages that:
1. the method is simple to operate, improves the safety of the reaction unit, and has the advantages of high productivity per unit area, environmental friendliness and the like compared with the traditional batch reaction mode.
2. 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 grinding process standard.
3. The invention selects specific catalyst to achieve corresponding effect, the Keggin type heteropolyacid catalyst and phase transfer catalyst are matched to play the role of Keggin type heteropolyacid catalyst to the maximum extent, meanwhile, the use amount of heteropolyacid is reduced, the process economy is greatly improved, the selectivity of the reaction is greatly improved through optimizing the use conditions of the catalyst and the phase transfer catalyst, the sulfone amount of the transition oxidation product is less than 1%, and penicillin sulfoxide (GESO) is prepared under the conditions of high conversion rate, high selectivity and high purity.
4. The Keggin type heteropolyacid catalyst and the phase transfer catalyst used in the invention are low in cost and easy to obtain, and the use amount is small.
Drawings
FIG. 1 is a schematic diagram of a continuous apparatus and process 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 invention is described in further detail below with reference to the accompanying drawings.
As shown in fig. 1, the device 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 one output end, a first pipeline 301 for inputting a catalyst and a phase transfer catalyst and a second pipeline 302 for inputting hydrogen peroxide are respectively connected with different input ends of the first reactor 101, the output end of the first reactor 101 is connected with the first input end of the second reactor 102 through a third pipeline, a fourth pipeline 304 for inputting penicillin G potassium esterified substance solution is connected with the second input end of the second reactor 102, the output end of the second reactor 102 is connected with the first input end of the third reactor 103 through a fifth pipeline 305, a sixth pipeline 306 for inputting sodium bisulphite is connected with the 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 feed pump, and the temperature sensors (T1, T2 and P2) are provided with a pressure sensor and a pressure sensor (T2, T2 and P2). The temperature sensor, pressure sensor and each reactor are well known in the art and commercially available.
The working principle of the invention is as follows: setting the feeding quantity of a feeding pump according to a proportion, and carrying out Keggin type heteropolyacid H n AM 12 O 40 ·xH 2 The aqueous solution of O and the phase transfer catalyst enters the 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 aqueous solution directly enters the second reactor 102 after discharging, 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 is controlled, and the flow rate and the reaction pressure are controlledAnd (3) enabling the reaction product to enter a third reactor 103 for quenching reaction, enabling sodium bisulphite to enter the third reactor 103 through a sixth pipeline 306 for quenching reaction of the reaction product of the previous step, controlling the quenching reaction temperature, discharging, entering a storage tank 201, adjusting the pH value to 7-8, separating liquid, extracting aqueous phase with dichloromethane, merging organic phases, washing the organic phases with a small amount of water, concentrating, and crystallizing the concentrated solution with methanol to obtain the final product.
Examples:
penicillin G potassium esterified compound synthesis:
into a 10 liter glass reactor, 4L of methylene chloride, 2Kg of penicillin G potassium, 1.165. 1.165K G of p-nitrobenzyl ammonium chloride and 100G of triethylbenzyl ammonium chloride were successively added. Stirring and heating, refluxing for 6-7 hours, tracking by HPLC, cooling to room temperature after the reaction is finished, adding 2L of water, uniformly stirring, standing for 30 minutes, and discharging an organic phase. The aqueous phase was extracted twice with 0.5L of dichloromethane, the organic phases were combined, the organic phases were rinsed twice with 0.5L of water, the rinsed organic phases were ready for use, and the penicillin G potassium ester concentration was 27.66%
A method for continuously preparing penicillin sulfoxide ester, which comprises the following steps:
with the device, the first reactor 101, the second reactor 102 and the third reactor 103 are purchased from corning reactor technology limited company, model: lab Reactor & LFR.
The hydrogen peroxide and the catalyst are mixed in the first reactor 101 to prepare an oxidant, the oxidant and the penicillin G potassium ester are subjected to continuous flow oxidation reaction in the second reactor 102, the oxidation reaction liquid is subjected to continuous flow quenching reaction by sodium bisulphite aqueous solution in the third reactor 103, and then the reaction liquid enters the storage tank 201 to be subjected to post-treatment to obtain penicillin sulfoxide ester (GESO).
The post-treatment is to adjust the pH value of the quenching reaction liquid to 7-8, separate the liquid, extract the water phase with methylene dichloride, combine the organic phases, wash the organic phases with a little water, concentrate, and crystallize the concentrate with methanol to obtain the final product.
Examples 1-10, comparative examples 1-2 the specific dosing, reaction effects and reaction conditions for continuous flow preparation of penicillin sulfoxide esters are detailed in tables 1-4.
Table 1: batching table for continuously preparing oxidant
Note that: the flow error of the feed pump is +/-0.5 g/min; the decomposition of the trace hydrogen peroxide is not metered.
Table 2: batching table for continuously preparing penicillin sulfoxide ester
Note that: the prepared sodium bisulphite must be filtered and then enter the reactor; .
Table 3: reaction results of continuous preparation of penicillin sulfoxide esters
Note that: in all examples, a peracetic acid continuous experiment was performed first, in order to find the concentration of peracetic acid, and after detection by the method of GB/T19104-2008 "peracetic acid solution", a two-step continuous reaction was performed by using the corresponding method. The yields shown are measured as penicillin G potassium.
Table 4: continuous flow process conditions
Note that: the error of the temperature sensor is +/-1 ℃; the reactor pressure is related to the reaction temperature and the material flow rate; the error of the inner diameter of the reactor channel is +/-0.2 mm.
As can be seen from the above examples 1 to 10 and comparative examples 1 to 2, the results of conversion, selectivity, yield and the like of the Keggin-type heteropolyacid catalysts of examples 1 to 10 used in combination with the phase transfer catalyst are significantly better than those of the single catalyst and other kinds of catalysts used in combination.
Comparative example 3 (batch process):
the treated penicillin G potassium esterified substance solution is placed in a reaction kettle, and 10.76G of sodium tungstate dihydrate and 10.76G of triethylbenzyl 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 between 10-20 ℃. The liquid phase is followed and monitored for reaction, TLC monitoring is carried out, the temperature is reduced to 0 ℃ after the reaction is finished, sodium bisulphite solution is dripped, and the starch potassium iodide test paper does not develop color. Standing for separating, extracting aqueous phase with a small amount of dichloromethane, mixing organic phases, placing the organic phases in a reaction kettle, stirring, regulating pH value to 7-8 with saturated sodium bicarbonate solution, standing for layering, extracting aqueous phase with a small amount of dichloromethane, mixing organic phases, concentrating, crystallizing concentrated solution with methanol to obtain the final product. The inversion rate of the two steps is 90%, the selectivity is 95%, and the product is 2.25kg, the content is 99.0% and the separation yield is 85.73% after drying.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is to be construed as including any modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (6)
1. A method for preparing penicillin sulfoxide ester by continuous flow is characterized in that,
oxidizing agent and penicillin G potassium ester continuous flow, carrying out continuous flow quenching reaction on the oxidized reaction liquid after the reaction by sodium bisulphite 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 a Keggin type heteropoly acid catalyst and a phase transfer catalyst;
the Keggin type heteropoly acid catalyst is phosphomolybdic acid H 3 [PMo 12 O 40 ]Phosphotungstic acid H 3 [PW 12 O 40 ]Silicotungstic acid H 4 [SiW 12 O 40 ]Or silicomolybdic acid H 4 [SiMo 12 O 40 ]；
The phase transfer catalyst is benzyl triethyl ammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bisulfate, trioctyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride or tetradecyl trimethyl ammonium chloride;
the catalyst solution consists of a Keggin type heteropolyacid catalyst, a phase transfer catalyst and water, wherein the mass of the Keggin type heteropolyacid 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.
2. the method according to claim 1, wherein the molar ratio of penicillin G potassium ester to oxidant is 1:1-2;
the molar ratio of the sodium bisulphite aqueous solution to the oxidant is 0.05-0.3:1.
3. the method of claim 1, wherein the hydrogen peroxide concentration is 20-50%.
4. The process according to 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 0.5-10min.
5. The method according to claim 1, wherein the concentration of the aqueous solution of sodium bisulphite is 1-33%, and the temperature of the quenching reaction solution is 0-30 ℃.
6. The method according to claim 1, wherein the post-treatment is collecting the quenched reaction solution, liquid-separated extraction, washing the organic phase with water, concentrating, crystallizing the concentrate with methanol, and vacuum drying to obtain penicillin sulfoxide ester.
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Citations (4)
| 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 |
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| 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 |
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