CN111100088B - Method for continuously synthesizing ethyl dithiahydroxamate - Google Patents
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- CN111100088B CN111100088B CN201911359740.3A CN201911359740A CN111100088B CN 111100088 B CN111100088 B CN 111100088B CN 201911359740 A CN201911359740 A CN 201911359740A CN 111100088 B CN111100088 B CN 111100088B
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
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Abstract
The invention discloses a method for continuously synthesizing amisothiazolate ethyl ester, belonging to the field of synthesis of cephalo-type drugs. The method comprises the steps of utilizing a continuous reaction device, adding 4-chloro-2-methoxyimino ethyl acetoacetate reaction liquid and thiourea solution into a reactor according to a certain proportion, keeping a certain temperature, adjusting the pH value by using soda solution, overflowing the reaction liquid to a cooler for cooling, and filtering and washing to obtain the product, wherein the purity of a liquid phase is more than 99.5%, and the yield is 85-93%. The method has the advantages that the continuous reaction is realized for the synthesis of the ethyl aminothiazoly loximate, the variable control in the reaction process is more efficient and timely, the product quality stability is obviously improved, meanwhile, the heat in the reaction process is effectively controlled due to the realization of the continuous reaction, the energy can be effectively saved, the production cost is reduced, and the method is suitable for industrial large-scale production.
Description
Technical Field
The invention belongs to the field of drug synthesis, relates to a synthesis technology of ethyl dithiaoximate, and particularly relates to a method for continuously synthesizing ethyl dithiaoximate.
Background
The chemical name of the ethyl aminothiazolyloximate is (Z) -2- (2-amino-4-thiazole) -2-methoxy iminoacetic acid ethyl ester, the ethyl aminothiazolyloximate is an important raw material for synthesizing the cephalosporin of the aminothiazolyloximic acid, the curative effect of the cephalosporin of the aminothiazolyloximic acid is dozens of times of that of penicillin, and the toxicity and the side effect of the cephalosporin of the aminothiazolyloximic acid to human bodies are small.
At present, the production process of ethyl aminothiazolyloximate generally adopts ethyl acetoacetate as a raw material and is prepared by oximation, alkylation, distillation, halogenation and cyclization reactions, but the traditional route and process still have more problems, such as complex operation, low automation level, large yield fluctuation, unstable product quality and the like in the synthesis process; in addition, reducing production costs is a major problem facing industrial production; although the prior art reports some optimization of the synthetic route of ethyl aminothiazoloxime ate, most researches are carried out on the synthetic process, and the optimization of engineering technology is rarely involved.
The Liu Zheng Qiang [ CN106632137A preparation method of ethyl aminothiazolyloxime acid ] reports a method for preparing ethyl aminothiazolyloxime acid in the same reactor, but the cyclization reaction still adds halide dropwise into thiourea solution, still belongs to the intermittent operation category, and does not significantly improve the reduction of the production cost, and the Wang Meng [ CN104478825A synthesis method of aminothiazolyloxime acid ] provides a synthesis method of the aminothiazolyloxime acid, wherein the cyclization reaction uses sodium acetate as buffer salt, but the cost of the sodium acetate is higher, and the difficulty of wastewater treatment is increased. In addition, the raw materials adopted by the two methods are bromides, so that the method has higher cost in industrial production.
Zhaoqi (a new process for synthesizing aminothiazoly loximate) CN107857741A provides a new process for synthesizing aminothiazoly loximate, which relates to a synthesis method of aminothiazoly loximate, wherein 4-chloro-2-methoxyimino-ethyl acetoacetate and sodium carbonate solution are simultaneously dropped into thiourea solution, the reaction adopts chloride as raw material, but the addition amount of thiourea is larger, and tetramethylammonium bromide is added as phase transfer catalyst to increase mass transfer, so that the content of organic matters in waste water is larger, and the difficulty in waste water treatment is increased.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the continuous synthesis method of the ethyl aminothiazolyloximate has the advantages of easily obtained raw materials, stable product yield and quality, no need of adding a catalytic reagent and simpler wastewater treatment.
In order to solve the technical problems, the technical scheme of the invention is as follows:
a method for continuously synthesizing the ethyl dithiahydroxamate comprises the following steps:
continuously introducing 4-chloro-2-methoxyimino ethyl acetoacetate, thiourea solution and soda ash solution into a continuous reactor for reaction, then overflowing from the continuous reactor into a cooler, and carrying out post-treatment to obtain the ethyl aminothiazolyloximate;
the continuous reactor is formed by connecting a plurality of reactors with overflow ports in series in sequence, the 4-chloro-2-methoxyimino ethyl acetoacetate and thiourea solution are introduced into the first-stage reactor, and the soda solution is introduced into all the reactors.
The method takes 4-chloro-2-methoxyimino ethyl acetoacetate as a raw material, continuously pumps the raw material and thiourea solution into a continuous reaction device, strictly controls the temperature and the pH value, and prepares the ethyl aminothiazolyloximate, the yield and the quality of the obtained ethyl aminothiazolyloximate are obviously improved, and the specific reaction formula is as follows:
in the invention, the material concentration is one of key factors influencing the mass transfer efficiency of the reaction, and preferably, the content of 4-chloro-2-methoxyimino ethyl acetoacetate is 65-70%, the content of thiourea solution is 10-20%, the content of soda solution is 25-35%, and the content of 4-chloro-2-methoxyimino ethyl acetoacetate is as follows by mass percent: the feed flow rate ratio of the thiourea solution is 1: 1.5-1.8, and dropwise adding a soda solution according to the pH value of the reaction system.
In the present invention, the 4-chloro-2-methoxyimino acetoacetic acid ethyl ester can be reacted without using a raw material having a high purity, for example, a crude product of a chlorination reaction in industrial production may be directly used as a raw material (specifically, see CN107857741A), and the raw material may be diluted with an appropriate solvent according to the liquid phase purity thereof at the time of charging. Preferably, the solvent used for dilution is aqueous methanol; further, the mass ratio of methanol to water in the methanol water solution is 1-1.5: 1, the reaction has higher conversion and selectivity.
In the invention, the solvent of the thiourea solution is also a combination of methanol and water, and the mass ratio of the methanol to the water is preferably 1-1.5: 1.
preferably, the reaction temperature is controlled to be 35-40 ℃, and the pH value is controlled to be 4.5-6.
Preferably, the reaction time of the 4-chloro-2-methoxyimino acetoacetic acid ethyl ester and the thiourea in the continuous reactor is 3 to 5 hours, and then the reaction solution overflows into the cooler.
Preferably, the continuous reactor is a custom-made overflow glass reactor, the volume of the reactor is 1000ml, the number of the reactors is 3-5 according to the residence time, and the temperature reducer is a 2000ml three-port jacket reactor.
Preferably, the temperature of the materials in the cooler is 15-20 ℃, and the reaction liquid is cooled to the temperature, so that a product with high purity can be obtained.
Preferably, the washing liquid used for filtering and washing is a methanol water solution, and the mass percentage concentration of the methanol water solution is 75-85%.
Compared with the prior art, the invention has the beneficial effects that:
(1) the synthetic raw material of the ethyl aminothiazolyloximate is metered and pumped into the continuous reaction device by using a liquid-phase pump, so that the control of the reaction raw material is more efficient;
(2) the synthesis of the ethyl aminothiazoly loximate realizes continuous feeding and discharging through a continuous reaction device, the heat release in each reaction stage is more stable, and the temperature is easier to control;
(3) the continuous synthesis of the ethyl aminothiazoly loximate ensures that the production automation is easier to realize and the manual operation is reduced.
Drawings
FIG. 1 is a flow chart of the production process of the method for continuously synthesizing ethyl dithiahydroxamate according to the invention,
FIG. 2 is a connection diagram of a reaction device for continuously synthesizing the ethyl aminothiazoloximate.
Detailed Description
In order that those skilled in the art will better understand the present invention, the following examples are provided to further illustrate the present invention, but the scope of the present invention is not limited by these examples.
Example 1
Setting the flow rate of 4-chloro-2-hydroxyimine-ethyl acetoacetate (the concentration is 68%, the liquid phase purity is shown in table 1, the solvent is methanol aqueous solution, the mass ratio of methanol to water is 1.45:1, and the solvent is diluted to 68% for use) to be 3.95g/min, the flow rate of thiourea solution (the concentration is 14.9%, the solvent is methanol aqueous solution, the mass ratio of methanol to water is 1.45:1) to be 6.70g/min, the flow rate ratio is 1:1.7, and the solution is pumped into a continuous reactor together for reaction, wherein the continuous reactor is a 4-stage overflow device, and the volume of each overflow device is a reaction bottle of 1000 ml; controlling the temperature to be 35-40 ℃, dropwise adding the soda solution into a reaction bottle by using a peristaltic pump according to the pH change condition in the reaction bottle, controlling the pH to be 4.5-6, reacting for 4 hours, overflowing to a cooler, cooling to 15-20 ℃, filtering, washing by using a methanol solution with the concentration of 80% to obtain the ethyl aminothiazolyloximate, and continuously operating for 24 hours to obtain 3665.5g of the ethyl aminothiazolyloximate, wherein the molar yield is 85.7%, and the purity of a product liquid phase is 99.7%.
Table 1 raw material liquid phase detection dataa
Example 2
Setting 4-chloro-2-hydroxyimine-ethyl acetoacetate (the concentration is 65 percent, the liquid phase purity is shown in table 2, the solvent is a methanol aqueous solution, the mass ratio of methanol to water is 1.45:1), the reaction liquid is 2.63g/min, thiourea solution (the concentration is 14.9 percent, the solvent is a methanol aqueous solution, the mass ratio of methanol to water is 1.45:1) flow rate is 4.71g/min, the flow rate ratio is 1:1.8, the mixture is pumped into a continuous reactor together for reaction, the continuous reactor is a 3-level overflow device, the temperature is controlled to be 35-40 ℃, pure alkali solution is dripped into a reaction bottle by a peristaltic pump according to the pH change condition in the reaction bottle, the pH value is controlled to be 4.5-6, the mixture is fed into a cooler after 5 hours of reaction, the temperature is controlled to be 15-20 ℃, filtering is carried out, the mixture is washed by using 80 percent methanol solution to obtain pure product of aminothiazoline oxime acid ethyl ester, the mixture is continuously operated for 24 hours, 2509.1g of pure product of the ethyl aminothiazoly loximate is obtained, the molar yield is 92.1 percent, and the liquid phase purity of the product is 99.6 percent.
Table 2 raw material liquid phase detection data
Example 3
Setting 4-chloro-2-hydroxyimine-ethyl acetoacetate (the concentration is 65%, the liquid phase purity is shown in Table 3, the solvent is methanol aqueous solution, the mass ratio of methanol to water is 1.45:1), 3.95g/min of reaction liquid, 14.9% of thiourea solution (the concentration is 14.9%, the solvent is methanol aqueous solution, the mass ratio of methanol to water is 1.45:1), the flow rate is 5.93g/min, the flow rate ratio is 1:1.5, the reaction liquid and the thiourea solution are pumped into a continuous reactor together for reaction, the continuous reactor is a 3-stage overflow device, the temperature is controlled to be 35-40 ℃, according to the pH change condition in the reaction bottle, a peristaltic pump is used for dropping soda solution into the reaction bottle, the pH value is controlled to be 4.5-6, the reaction liquid enters a cooler after 4.5h, the temperature is controlled to be 15-20 ℃, the filtration is carried out, the washing is carried out by using 80% methanol solution, the pure product of the aminothiazolme acid ethyl acetate is obtained, the continuous operation is carried out for 12h, 1875.8g of pure product of the ethyl aminothiazoly loximate is obtained, the molar yield is 91.7 percent, and the liquid phase purity of the product is 99.6 percent.
TABLE 3 raw material liquid phase detection data
Comparative example 1
According to patent CN107857741A, preparing ethyl aminothiazolyloximate according to the cyclization process provided by the patent;
weighing 151g of 4-chloro-2-hydroxyimine-ethyl acetoacetate (the concentration is 65%, the liquid phase purity is shown in table 1, the solvent is methanol aqueous solution, the mass ratio of methanol to water is 1.45:1), adding 72g of thiourea into 450g of mixed solution of methanol and water with the specific gravity of 0.92, adding 1.5g of tetramethylammonium bromide, starting dropwise adding a sodium carbonate solution and a 4-chloro-2-hydroxyimine-ethyl acetoacetate (the content is 65%) reaction solution, controlling the temperature of a reaction system to be 32-35 ℃ after 2h of dropwise adding, continuously preserving heat for 2.5h, adjusting the pH to 7.5, precipitating the ethyl aminothiazolime, and washing by using a methanol solution with the concentration of 80% to obtain a product with the molar yield of 95.6g of 88% and the product purity of 97.5%.
Table 4 raw material liquid phase detection data
Comparative example 2
Preparing ethyl aminothiazoly loximate according to a cyclization process provided by a patent CN 107857741A;
weighing 151g of 4-chloro-2-hydroxyimine-ethyl acetoacetate (the concentration is 65%, the liquid phase purity is shown in Table 5, the solvent is methanol aqueous solution, the mass ratio of methanol to water is 1.45:1), adding 72g of thiourea into 450g of mixed solution of methanol and water with the specific gravity of 0.92, beginning to dropwise add the reaction solution of sodium carbonate solution and 4-chloro-2-hydroxyimine-ethyl acetoacetate (the content is 65%), controlling the temperature of the reaction system to be 32-35 ℃ after 2h of dropwise addition, continuing to preserve heat for 2.5h, adjusting the pH to 7.5, precipitating ethyl aminothiazoloxime ate, and washing by using methanol solution with the concentration of 80%, so as to obtain 89.8g of a product with the molar yield of 82.85% and the product purity of 97.7%.
TABLE 5 raw material liquid phase detection data
The results of the examples 1-3 and the comparative examples 1-2 show that the yield and the reaction efficiency of the reaction can be improved by adopting the continuous process, and the target product can be obtained by only simply cooling and crystallizing after the reaction is finished.
Claims (7)
1. A method for continuously synthesizing the ethyl dithiahydroxamate is characterized by comprising the following steps:
continuously introducing 4-chloro-2-methoxyimino ethyl acetoacetate, thiourea solution and soda ash solution into a continuous reactor for reaction, then overflowing from the continuous reactor into a cooler, and performing post-treatment to obtain the ethyl aminothiazolyloximate;
the continuous reactor is formed by sequentially connecting a plurality of reactors with overflow ports in series, the 4-chloro-2-methoxyimino ethyl acetoacetate and thiourea solution are pumped into a first-stage reactor, and the soda ash solution is pumped into all the reactors;
by mass percentage, the content of the 4-chloro-2-methoxyimino ethyl acetoacetate is 65-70%, the content of the thiourea solution is 13-26%, and the content of the soda solution is 25-35%;
in each reactor, the reaction temperature is 35-40, the pH value is 4.5-6, and the pH value is controlled by the adding speed of a soda solution;
the total reaction time of the 4-chloro-2-methoxyimino ethyl acetoacetate and the thiourea in the continuous reactor is 3-5h, and then the reaction solution overflows into a cooler.
2. The method for continuously synthesizing ethyl aminothiazolinehydroxamate according to claim 1, wherein the solvent for dissolving the ethyl 4-chloro-2-methoxyiminoacetoacetate and the thiourea is a mixed solvent of methanol and water, and the mass ratio of the methanol to the water is 1-1.5: 1.
3. The method for continuously synthesizing ethyl dithiahydroxamate according to claim 1, wherein the mass ratio of the 4-chloro-2-methoxyiminoacetoacetate solution: the feed flow rate ratio of the thiourea solution is 1:1.5 to 1.8.
4. The method for continuously synthesizing ethyl dithiahydroxamate according to claim 1, wherein the number of the reactors connected in series is 3-5, and the volume of each reactor is 1000 ml;
the temperature reducer is a 2000ml three-port jacket reactor.
5. The method for continuously synthesizing ethyl dithiahydroxamate according to claim 1, wherein the temperature of the material in the cooler is 15-20 ℃.
6. The method for continuously synthesizing ethyl dithiahydroxamate according to claim 1, wherein the post-treatment comprises filtration and washing, and the washing solution used for washing is methanol aqueous solution.
7. The method for continuously synthesizing ethyl aminothiazolyloximate according to claim 6, wherein the mass percent concentration of the methanol aqueous solution in the washing solution is 75-85%.
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| CN112457271A (en) * | 2020-11-18 | 2021-03-09 | 河北合佳医药科技集团股份有限公司 | Continuous flow synthesis method of aminothiazoly loximate intermediate |
| CN113354597A (en) * | 2021-06-29 | 2021-09-07 | 上海应用技术大学 | Continuous refining method of anhydrous aminothiazoly loximate |
| CN113979965B (en) * | 2021-10-27 | 2023-07-28 | 陕西中杰科仪化学科技有限公司 | Continuous production method of 4, 5-dichloro-2-octyl-4-isothiazolin-3-ketone |
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