CN112661719B - Clean preparation process of aminothiazoly loximate - Google Patents
Clean preparation process of aminothiazoly loximate Download PDFInfo
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Abstract
The invention discloses a clean preparation process of aminothiazoly loximate, belonging to the technical field of organic synthesis. The method comprises the following steps: (1) Adding sulfuric acid into ethyl acetoacetate and calcium nitrite for oximation, separating out calcium sulfate solid, filtering, washing calcium sulfate wet powder to obtain calcium sulfate, adding sodium carbonate into washing liquid and filtrate, and adding dimethyl sulfate dropwise for oximation methylation; (2) After finishing phase separation, dehydrating an organic phase, then halogenating, adding water for quenching and phase separation, wherein the water phase is strong-acid water, the organic phase is a halide, dropwise adding the halide into thiourea for cyclization, adding trichloromethane after finishing the cyclization, and removing the water phase by phase separation to obtain an ethyl aminothiazolyloximate trichloromethane solution; (3) Dropwise adding liquid caustic soda, hydrolyzing, splitting phase after the reaction is finished, removing an organic phase, decoloring a water phase, and dropwise adding the water phase obtained by quenching until the aminothiazoly loximate is completely separated out. The method has the advantages of less three wastes, realization of resource recycling, high product yield, simple operation and easy realization.
Description
Technical Field
The invention relates to a preparation method of green and clean aminothiazoly loximate, belonging to the technical field of organic synthesis.
Background
The cefotaxime acid is a raw material for synthesizing the third-generation cephalosporin, and the third-generation cephalosporin has the advantages of low toxicity, long curative effect, tens of times higher curative effect than penicillin and the like, and is effective to some drug-resistant bacteria and infection caused by pathogenic bacteria which are difficult to control. The main varieties of cephalo-type medicaments using the ainothiazoly loximate comprise cefpodoxime, cefotaxime, cefodizime, cefotaxime, ceftriaxone, and the like.
Many documents have reported on the synthesis of the ainothiazoly loximate, the production of the ainothiazoly loximate generally adopts the steps of oximation, etherification, halogenation and cyclization of ethyl acetoacetate to prepare an intermediate ainothiazoly loximate ethyl ester, and then the ainothiazoly loximate ethyl ester is subjected to hydrolysis of ethanol under alkaline conditions to prepare the ainothiazoly loximate, wherein the reaction equation is as follows:
the traditional production process, oximation, etherification and hydrolysis, are the main links for generating three wastes, wherein: in the oximation step, a large amount of pure water dissolves sodium nitrite, and sodium salt wastewater with high concentration is generated under acidic conditions; a large amount of purified water in the etherification step is used for dissolving sodium carbonate, and high-concentration sodium salt wastewater is generated after the reaction is finished; and (3) dissolving a large amount of alkali liquor in the hydrolysis step into the ethyl aminothiazolyloxime acid, and adding acid for crystal adjustment after the reaction is finished to generate high-concentration sodium salt wastewater. In addition, after the reaction in the halogenation step is finished, pure water is needed for quenching, and high-concentration acidic wastewater is generated.
The method for recycling the wastewater of the aminothiazoly loximate proposed by patent CN 103012312 only mentions that the mother liquor and the washing liquor generated in the hydrolysis step are applied to the oximation process of the first step, but the wastewater generated in the fifth step of the process is applied to the first step, so that more impurities are easily introduced.
At present, the traditional technology for preparing the ainothiazoly loximate has the following defects:
the amount of waste water generated in the process production process is large, and more than 30t of high-concentration salt-containing waste water can be generated when 1 ton of products are produced;
the process steps are long, the steps of phase splitting, mother liquor separation and the like are more, and the product yield is wasted.
Disclosure of Invention
Aiming at the technical problems in the prior art, the invention aims to solve the technical problem of providing a clean preparation process of aminothiazoly loximate, calcium nitrite is used as an oximation reagent, and byproduct salt is directly separated out in a crystallization form, so that the waste water amount of oximation and etherification processes is greatly reduced, and the generation amount of three wastes and the treatment difficulty are reduced; in the cyclization process, trichloromethane is adopted to extract ethyl aminothiazolyloxime into an organic phase, an alkali solution is added into the organic phase to be directly hydrolyzed into a salt to enter a water phase, and acid water generated by halogenated quenching is used for regulating crystals to separate the ethyl aminothiazolyloxime, so that the operation steps of crystallizing, separating, centrifuging and washing the ethyl aminothiazolyloxime are eliminated, the acidic wastewater is recycled, and the flow chart is as follows.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows: clean preparation process of aminothiazoly loximate
A clean preparation process of aminothiazoly loximate comprises the following steps:
(1) Ethyl acetoacetate and calcium nitrite aqueous solution, dropwise adding sulfuric acid under stirring to oximate to separate out calcium sulfate solid, filtering the separated calcium sulfate after the reaction is finished, washing wet calcium sulfate powder by using trichloromethane to obtain white solid powder by-product calcium sulfate, adding sodium carbonate into washing liquid and filtrate, and dropwise adding dimethyl sulfate to carry out oxime methylation;
(2) After the methylation reaction of oxime is finished, phase separation is carried out, an organic phase is dehydrated and then is dropwise added with a halogenating reagent for halogenation, water is added for quenching after the halogenation is finished, the phase separation is carried out, a water phase is strong-acid water, an organic phase is a halide, the halide is dropwise added into a thiourea aqueous solution, the pH is controlled for cyclization reaction, trichloromethane is added after the reaction is finished until all solids are dissolved, the dissolving temperature is 30-45 ℃, and the phase separation is carried out to remove the water phase, so that an ethyl aminothiazolyloximate trichloromethane solution is obtained;
(3) And (3) dropwise adding liquid alkali into the ethyl aminothiazolyloxime acid trichloromethane solution, stirring at a controlled temperature for hydrolysis, splitting phases after the reaction is finished, removing an organic phase, adding activated carbon into an aqueous phase for decolorization, dropwise adding the water phase obtained by quenching after the halogenation in the step (2) until the aminothiazolyloxime acid is completely separated out, filtering, washing and drying to obtain an aminothiazolyloxime acid product.
And (2) washing the calcium sulfate with trichloromethane in the step (1) until the washing liquid has no yellow color.
The molar ratio of the ethyl acetoacetate to the calcium nitrite is 1.1-1.5.
In the step (1), sulfuric acid is dripped until calcium nitrate is completely converted into calcium sulfate, and the temperature is controlled to be-5-10 ℃ in the process.
The concentration of the liquid caustic soda dropped into the solution of the ethyl aminothiazolyloximate and the trichloromethane is 10 to 30 percent
The liquid alkali is sodium hydroxide solution, and the molar ratio of sodium hydroxide to ethyl aminothiazoly loximate is 1.0-1.5.
The hydrolysis temperature in the step (3) is controlled to be 35-50 ℃.
The invention has the beneficial effects that:
(1) Calcium nitrite is used as an oximation reagent, sulfuric acid is used as an acidic reagent, calcium sulfate precipitate is generated in the reaction process, and high-quality calcium sulfate byproduct can be obtained by filtering and washing, so that the difficulty in extracting waste solids in the oximation process is reduced;
(2) Because the salt in the oximation process is extracted and the water in the oximation reaction liquid does not contain salt basically, the etherification process can be carried out by directly adding sodium carbonate solid without phase separation and discharging wastewater, the water is not used in the etherification process any more, and the total wastewater discharge amount is reduced by about 10t/t product.
(3) The ethyl aminothiazolyloximate generated after the reaction in the traditional cyclization procedure is required to be cooled, crystallized, separated, filtered and washed, and the ethyl aminothiazolyloximate is put into a reaction kettle for the next hydrolysis reaction. After cyclization is finished, trichloromethane is added, ethyl aminothiazoly loximate is dissolved in an organic solvent, phase separation and wastewater separation are carried out, and liquid alkali is added into an organic phase for hydrolysis to produce the aminothiazoly loximate. The solid-liquid separation and washing processes of the ethyl aminothiazoly loximate are avoided, the product waste and the generated wastewater amount in the mother liquor are reduced, and the working difficulty is reduced.
(4) In the traditional halogenation process, because an excessive amount of a halogenation reagent is used, strong acid is generated in the reaction process, water is quenched after the reaction is finished, and the separated wastewater contains high-concentration acidic components, the general treatment mode is alkali neutralization and post-treatment discharge.
Drawings
FIG. 1 is a conventional production route for aminothiazoly loximate;
FIG. 2 is a production line of aminothiazoly loximate of the present invention.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitation of the present invention.
Example 1
Adding 60g of ethyl acetoacetate, 240ml of water and 40g of calcium nitrite into a 500ml four-mouth bottle, controlling the temperature to be 0-2 ℃, slowly dripping 30% sulfuric acid, detecting that the residue of triethyl acetate (ethyl acetoacetate is abbreviated as the following) is less than or equal to 1.0% after 5 hours, filtering, washing a filter cake by 80ml of trichloromethane, and drying to obtain a white calcium sulfate byproduct; adding 40g of sodium carbonate into the filtrate and the washing liquid, controlling the temperature to be 20 ℃, stirring to dissolve, dropwise adding 60ml of dimethyl sulfate, detecting that the residue of the oxime compound is less than or equal to 1.0%, standing for layering, and taking an organic phase.
Adding 5g of magnesium sulfate into the organic phase obtained in the previous step for dehydration, introducing liquid chlorine for halogenation, adding 200ml of water for quenching after the halogenation is finished, carrying out phase splitting, extracting the water phase by using 20ml of trichloromethane for reservation, slowly dropwise adding the organic phase into a prepared thiourea solution, wherein the dosage of thiourea is 28g, the solution is 200ml of a 1.
Adding 100ml of 10% liquid alkali into a trichloromethane solution of ethyl aminothiazolime, controlling the temperature at 40 ℃ for hydrolysis reaction, detecting that the residue of ethyl aminothiazolime is less than or equal to 1.0%, then using acid water generated by halogenated quenching to adjust the pH value to 6.5, splitting phases, taking the water phase for decolorization, controlling the temperature at 15 ℃, dropwise adding acid water generated by halogenated quenching to adjust the pH value to 2.5, filtering, washing and drying to obtain 58.6g of the ethyl aminothiazolime.
Example 2
Adding 60g of ethyl acetoacetate, 240ml of water and 45g of calcium nitrite into a 500ml four-mouth bottle, controlling the temperature to be 5-8 ℃, slowly dripping 30% sulfuric acid for 2 hours, detecting triethyl (the residue is less than or equal to 1.0%, filtering, washing a filter cake by 80ml of trichloromethane, drying to obtain a white calcium sulfate byproduct, adding 38g of sodium carbonate into filtrate and washing liquid, controlling the temperature to be 20 ℃, stirring for dissolving, dripping 60ml of dimethyl sulfate, detecting the residue of an oxime compound is less than or equal to 1.0%, standing for layering, and taking an organic phase.
Adding 5g of magnesium sulfate into the organic phase obtained in the previous step for dehydration, introducing liquid chlorine for halogenation, after the halogenation is finished, adding 150ml of water for quenching, carrying out phase separation, extracting the water phase by using 20ml of trichloromethane for reservation, slowly dropwise adding the organic phase into a prepared thiourea solution, wherein the dosage of thiourea is 28g, the solution is 160ml of a methanol aqueous solution of 1.
Adding 100ml of 10% liquid caustic soda into a trichloromethane solution of ethyl aminothiazoly loximate, controlling the temperature to be 35 ℃ for hydrolysis reaction, detecting that the residue of ethyl aminothiazoly loximate is less than or equal to 1.0%, adjusting the pH to 6.5 by using acid water generated by halogenated quenching, carrying out phase separation, taking a water phase for decolorization, controlling the temperature to be 5 ℃, dropwise adding the acid water generated by halogenated quenching to adjust the pH to 2.5, filtering, washing and drying to obtain 57.8g of the aminothiazoly loximate.
Example 3
Adding 60g of ethyl acetoacetate, 240ml of water and 38g of calcium nitrite into a 500ml four-mouth bottle, controlling the temperature to be 10 ℃, slowly dripping 30% sulfuric acid, taking 2 hours, detecting triethyl (the residue is less than or equal to 1.0%, filtering, washing a filter cake by 80ml of trichloromethane, drying to obtain a white calcium sulfate byproduct, adding 42g of sodium carbonate into filtrate and washing liquid, controlling the temperature to be 20 ℃, stirring for dissolving, dripping 64ml of dimethyl sulfate, detecting the residue of an oxime compound is less than or equal to 1.0%, standing for layering, and taking an organic phase.
Adding 5g of magnesium sulfate into the organic phase obtained in the previous step for dehydration, introducing liquid chlorine for halogenation, after the halogenation is finished, adding 150ml of water for quenching, carrying out phase splitting, extracting the water phase with 20ml of trichloromethane for reservation, slowly dropwise adding the organic phase into the prepared thiourea solution, wherein the dosage of thiourea is 28g, the solution is 100ml of a 1.
Adding 100ml of 10% liquid caustic soda into a trichloromethane solution of ethyl aminothiazoly loximate, controlling the temperature to 50 ℃ for hydrolysis reaction, detecting that the residue of ethyl aminothiazoly loximate is less than or equal to 1.0%, adjusting the pH to 6.5 by using acid water generated by halogenated quenching, carrying out phase separation, taking a water phase for decolorization, controlling the temperature to 10 ℃, dropwise adding the acid water generated by halogenated quenching to adjust the pH to 2.5, filtering, washing and drying to obtain 58.2g of the aminothiazoly loximate.
Claims (4)
1. A clean preparation process of aminothiazoly loximate is characterized in that: the method comprises the following steps:
(1) Ethyl acetoacetate and calcium nitrite aqueous solution are added dropwise with sulfuric acid under stirring for oximation to separate out calcium sulfate solid, the separated calcium sulfate is filtered after the reaction is finished, the wet powder of the calcium sulfate is washed by trichloromethane to obtain white solid powder byproduct calcium sulfate, sodium carbonate is added into the washing liquid and the filtrate, and dimethyl sulfate is added dropwise to carry out oxime methylation;
(2) After the methylation reaction of oxime is finished, phase separation is carried out, an organic phase is dehydrated and then is dropwise added with a halogenating reagent for halogenation, water is added for quenching after the halogenation is finished, the phase separation is carried out, a water phase is strong-acid water, an organic phase is a halide, the halide is dropwise added into a thiourea aqueous solution, the pH is controlled for cyclization reaction, trichloromethane is added after the reaction is finished until all solids are dissolved, the dissolving temperature is 30 to 45 ℃, and the phase separation is carried out to remove the water phase, so that an ethyl aminothiazolyloxime trichloromethane solution is obtained;
(3) Dropwise adding liquid alkali into an ethyl aminothiazolyloxime acid trichloromethane solution, stirring and hydrolyzing at a controlled temperature, splitting phases after the reaction is finished, removing an organic phase, adding activated carbon into an aqueous phase for decoloring, dropwise adding the halogenated compound obtained in the step (2), quenching the obtained aqueous phase until the aminothiazolyloxime acid is completely separated out, filtering, washing and drying to obtain an aminothiazolyloxime acid product; the liquid alkali is a sodium hydroxide solution, the concentration is 10-30%, and the molar ratio of sodium hydroxide to ethyl aminothiazoly loximate is 1.0-1.5.
2. A clean process for the preparation of aminothiazoly loximate according to claim 1, wherein: the molar ratio of the ethyl acetoacetate to the calcium nitrite is 1.1-1.5.
3. A clean process for the preparation of aminothiazoly loximate according to claim 1, wherein: in the step (1), sulfuric acid is dripped until calcium nitrate is completely converted into calcium sulfate, and the temperature is controlled to be-5-10 ℃ in the process.
4. A clean process for the preparation of aminothiazoly loximate according to claim 1, wherein: and (4) controlling the hydrolysis temperature in the step (3) to be 35 to 50 ℃.
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Denomination of invention: A Clean Preparation Process for Ammonium Thioxime Acid Effective date of registration: 20230904 Granted publication date: 20221014 Pledgee: China CITIC Bank Co.,Ltd. Shijiazhuang Branch Pledgor: HEBEI HEJIA PHARMATECH GROUP CO.,LTD. Registration number: Y2023980055239 |