CN112441978B - Preparation method of 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester - Google Patents
Preparation method of 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester Download PDFInfo
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Abstract
The invention relates to a preparation method of 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester. DEMME is taken as a raw material or a mixture of DEMME and EMME is taken as a raw material, and after amination reaction and cyclization reaction, 1-methyl-5-hydroxypyrazole-4-ethyl carboxylate is prepared. According to the invention, DEMM is used as a raw material or a mixture of DEMM and EMME is used as a raw material, the raw material is easy to obtain, the conversion rate of an intermediate DEMM is not required to be pursued, high-purity EMME is not required to be obtained, the reaction time is shortened, the production cost is reduced, and meanwhile, the yield of the preparation method is more than 90%, the product purity is more than 96%, the product yield is high, the purity is high, and the preparation method is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of organic compound preparation, in particular to a preparation method of a pesticide intermediate, and especially relates to a preparation method of a synthetic herbicide topramezone intermediate 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester.
Background
1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester (MHPE) is an important pesticide intermediate, and can be used as a lead compound to react with ketal, acetal and the like to obtain a series of pyrazole pesticides, such as herbicide Topramezone (Topramezone). The chemical structure is as follows:
according to published patents JP19820019170, JP19820019171, JP19830051299, JP19860038898, JP2002371067 and the like, MHPE is mainly prepared by cyclization reaction of methylhydrazine with ethoxymethylene malonic acid diethyl ester (EMME) with the main by-product being its isomer ethyl 1-methyl-3-hydroxypyrazole-4-carboxylate. The reaction formula is as follows:
EMME is used as a key raw material for preparing MHPE, researchers at home and abroad make a great deal of research on the preparation of the MHPE, and at present, EMME is mainly generated by condensation reaction of diethyl malonate and triethyl orthoformate under the catalysis of Lewis acid. An intermediate product, diethyl Diethoxymethylmalonate (DEMME), is present during the reaction, and DEMME is subsequently converted to EMME under certain conditions.
Therefore, the yield of EMME is determined by the conversion rate of DEMM, the use of a catalyst, the control of temperature or the use of a solvent in the process are closely related to the conversion rate, and the EMME and the DEMM mixture are difficult to separate by rectification and the like. If DEMM is not completely converted into EMME, the problems of low yield and low purity of EMME products and the like can be caused; when high-purity EMME is to be obtained, DEMM conversion is required to be thorough, which may cause problems such as long reaction time, more high-boiling by-products, and low product yield.
The prior literature discloses that EMME is obtained by reacting diethyl malonate, triethyl orthoformate and acetic anhydride under the catalysis of anhydrous zinc chloride, and the yield is 74 percent after reduced pressure collection. Then EMME reacts with methylhydrazine hydrate, and the final product yield is 70% (see "synthesis of novel pyrazole derivative 1-methyl-4-ethoxycarbonyl-5-hydroxypyrazole", Wang Shu et al, Fine chemical intermediate "volume 39, phase 4, 2009, 8 months). However, when preparing EMME, a large amount of acetic anhydride is used to drive the reaction to the right, and even this produces only 74% yield of pure EMME product.
In the prior art, the problem of how to prepare the raw material of MHPE rapidly, efficiently and at low cost is not solved. Therefore, there is a need for a new raw material that can be easily and inexpensively prepared to provide a more efficient route for synthesizing MHPE to obtain high yield and high quality MHPE.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a preparation method of 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester, which has the advantages of easily available raw materials, no need of using a pure product EMME which is difficult to prepare, high product yield, capability of effectively reducing the production cost and suitability for industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of 1-methyl-5-hydroxypyrazole-4-ethyl carboxylate takes DENME as a raw material or a mixture of DENME and EMME as a raw material, and MHPE is prepared after amination reaction and cyclization reaction.
The raw materials used by the invention are the mixture of DEMME and EMME or the single DEMME, so that the conversion rate of the intermediate DEMME is not required to be pursued in the preparation process, the high-purity EMME is not required to be obtained, the preparation difficulty is reduced, and the reaction time is shortened.
As a preferred technical scheme of the invention, the raw material is a mixture of DEMME and EMME.
Preferably, in the mixture of DEMME and EMME, the molar ratio of DEMME to EMME is (0.25-4): 1, and can be, for example, 0.25:1, 0.35:1, 0.55:1, 0.75:1, 1:1, 1.25:1, 1.5:1, 2:1, 2.5:1, 3:1 or 4: 1.
As a preferred technical scheme of the invention, the preparation method of the 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester comprises the following steps:
(1) dissolving a mixture of raw materials DEMME and EMME or single DEMME in a solvent, and carrying out amination reaction on the mixture and ammonia water to obtain a first reaction liquid;
(2) mixing the first reaction liquid with methylhydrazine to perform cyclization reaction to obtain a second reaction liquid;
(3) and neutralizing the second reaction solution with acid, filtering and washing to obtain the 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester.
In the present invention, the main reaction process can be represented by the following reaction formula:
in a preferred embodiment of the present invention, the solvent in step (1) is water.
Preferably, the ammonia water is added in a dropwise manner in the step (1).
Preferably, the dropping time is 0.5-1.5 h, for example, 0.5h, 0.75h, 1h, 1.25h or 1.5 h.
Preferably, the temperature of the amination reaction in step (1) is 0 to 50 ℃, and may be, for example, 0 ℃, 5 ℃, 10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃ or 50 ℃, preferably 0 to 20 ℃.
Preferably, the amination reaction time in the step (1) is 1-5 h, for example, 1h, 1.25h, 1.5h, 2h, 3h, 4h or 5h, preferably 1-2 h.
In a preferred embodiment of the present invention, the time for mixing the first reaction solution and methylhydrazine in step (2) is 0.5 to 1.5 hours, for example, 0.5 hour, 0.75 hour, 1 hour, 1.25 hour or 1.5 hour.
Preferably, the temperature during the mixing in step (2) is-10 to 50 ℃, for example, -10 ℃, 0 ℃, 10 ℃, 20 ℃, 30 ℃, 35 ℃, 38 ℃, 40 ℃, 42 ℃, 45 ℃ or 50 ℃, preferably 0 to 35 ℃.
Preferably, the temperature of the cyclization reaction in step (2) is 40 to 90 ℃, and may be, for example, 40 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃ or 90 ℃.
Preferably, the cyclization reaction time in the step (2) is 4-12 h, for example, 4h, 5h, 6h, 7h, 7.5h, 8h, 9h, 10h, 11h or 12 h.
As a preferred embodiment of the present invention, the temperature of the acid neutralization in the step (3) is 30 ℃ or lower, and may be, for example, 0 ℃, 5 ℃, 10 ℃, 15 ℃, 20 ℃, 25 ℃ or 30 ℃.
Preferably, the acid is hydrochloric acid.
Preferably, the molar ratio of the hydrochloric acid to the ammonia water in the step (1) is (1-1.5): 1, and for example, may be 1:1, 1.2:1, 1.3:1, 1.4:1 or 1.5:1.
Preferably, step (3) further comprises the step of cooling after acid neutralization.
Preferably, the second reaction solution is neutralized with an acid, cooled to 0-5 ℃, and then filtered after heat preservation for 1-3 hours, for example, the cooling temperature can be 0 ℃,1 ℃, 2 ℃, 3 ℃, 4 ℃ or 5 ℃, and the heat preservation time can be 1 hour, 1.5 hours, 1.8 hours, 2 hours, 2.3 hours, 2.5 hours, 2.8 hours or 3 hours.
Preferably, the solution used for the filtration in step (3) is ice water.
As a preferable technical scheme of the invention, the DENME and EMME mixture is obtained by reacting diethyl malonate, triethyl orthoformate and acetic anhydride under the catalysis of nickel sulfate.
According to a preferred embodiment of the present invention, the molar ratio of the raw material, ammonia water and methylhydrazine to be fed is 1:1.1 to 3:1.02 (1.02 to 2), and may be, for example, 1:1.1:1.02, 1:1.1:1.05, 1:1.1:1.2, 1:1.2:1.02, 1:1.2:1.05, 1:1.2:1.2, 1:1.2:1.5, 1:1.5:1.1, 1:1.5:1.2, 1:1.5:1.5, 1:2:1.05, 1:2:1.2, 1:2: 1.5: 1.02, 1:2:1.05, 1:2.5:1.2, 1:3:1.02, 1:3:1.05, 1:1.2:1.05, 1: 2.2: 1.2: 1.1.1.05, 1:2: 1.1.1.05, or 1:1.1: 1.2: 1.1.1.2: 1.05 (1: 1.1: 2: 1.1.2: 1.05).
As a preferred technical scheme of the invention, the preparation method comprises the following steps:
(1) dissolving DEMME or a mixture of DEMME and EMME in water, dropwise adding ammonia water at 0-50 ℃, continuously reacting for 1-5 hours while keeping the temperature, and obtaining a first reaction solution;
(2) controlling the temperature of the first reaction liquid to be-10-50 ℃, dropwise adding methyl hydrazine, finishing dropping within 0.5-1.5 h, raising the temperature to 40-90 ℃, and carrying out heat preservation reaction for 4-12 h to obtain a second reaction liquid;
(3) and cooling the second reaction liquid, keeping the temperature below 30 ℃, dropwise adding hydrochloric acid for neutralization, cooling to 0-5 ℃, preserving heat for 1-3 h, filtering, and washing a filter cake with ice water to obtain the ethyl 1-methyl-5-hydroxypyrazole-4-carboxylate.
The recitation of numerical ranges herein includes not only the above-recited values, but also any values between any of the above-recited numerical ranges not recited, and for brevity and clarity, is not intended to be exhaustive of the specific values encompassed within the range.
Compared with the prior art, the invention provides a method for preparing MHPE by amination reaction of a mixture of DENME and EMME or DENME and ammonia water and cyclization reaction of the DENME and methylhydrazine. Therefore, the preparation method does not need to pursue the conversion rate of the intermediate DEMME, simplifies the operation steps, thereby reducing the preparation time, and simultaneously, the yield of MHPE products prepared by the preparation method is more than 90 percent, and the product purity is more than 96 percent.
Detailed Description
The invention is further described with reference to specific examples, but the scope of the invention is not limited thereby.
In the following examples, DEMME and EMME mixtures or DEMME can be prepared by known methods of preparation, and exemplary DEMME and EMME mixtures and DEMME are prepared as follows:
the synthesis steps of the DEMME/EMME mixed ester are as follows: adding 80.8g of diethyl malonate, 224.3g of triethyl orthoformate, 1.55g of acetic anhydride and 0.13g of nickel sulfate hexahydrate into a 500mL three-necked bottle, heating, extracting ethanol when the temperature of a reaction solution rises to 135 ℃, extracting ethanol while reacting, slowly raising the temperature of a kettle to 155 ℃, sampling, carrying out gas chromatographic analysis, and stopping reaction when the raw material diethyl malonate completely reacts. Filtering to remove catalyst, distilling the filtrate under low vacuum and reduced pressure to recover excessive triethyl orthoformate, and distilling the mixed product of DEMM/EMME under high vacuum and reduced pressure to obtain a product with the content sum of more than 99% (quantitative analysis by gas chromatography internal standard method, the molar ratio is about 0.55: 1) and the yield of more than 95%.
The pure DENME can be prepared by the following method (refer to the synthesis method of the patent US 4091040): adding 108g of EMME into a 250ml three-neck bottle, controlling the temperature of the reaction solution to be 40 ℃, slowly dropwise adding a sodium ethoxide ethanol solution (prepared by adding 0.6g of sodium into 60ml of absolute ethanol), keeping the temperature at 35-40 ℃ after dropwise adding, reacting for 1h, and then adjusting the pH of the reaction solution to be 6.5 by adding acetic acid. 109.8g of DEMM was then obtained by distillation, the content of which was greater than 99% by quantitative analysis by internal calibration on gas chromatography, the yield being 83%.
In the following examples, a certain molar ratio of DEMME/EMME mixed ester may be obtained by mixing DEMME and EMME, for example, by mixing DEMME and EMME in a molar ratio of 0.25:1 to obtain a mixed ester having a molar ratio DEMME/EMME of 0.25, and so on.
In the following examples, the final product characterization method was: using melting point determination, liquid chromatography/mass spectrometry (LC/MS) and NMR hydrogen spectroscopy: (1H-NMR), comparing with the structural characterization of MHPE reported in literature, and if the structural characterization of the final product is the same as the literatureAnd if the reports are consistent, the product is confirmed to be MHPE.
The characterization of the product MHPE obtained in example 1 below is:
the melting point is 136.7-138.2 deg.C (which is the average value obtained by testing 3 samples of the same product for 3 times) (see Chemistry of Heterocyclic compounds, 1981,17(11), 1102-1104, which discloses that the melting point of MHPE is 137-137.5 deg.C, and the melting point of its isomer is 161-162 deg.C, which can confirm that the product is MHPE);
LC/MS：m/z：171[M+H]+,169[M-H]-；
1H-NMR(CDCl3，400MHz),δ(ppm)1.34(t,J＝7.1Hz,3H,CH3),3.64(s,3H,1-Me),4.29(q,J＝7.1Hz,2H,CH2),7.55(s,1H,H-3),7.98(br s,1H,OH).
the products prepared in examples 1-11 below were all structurally characterized and were confirmed to be MHPE.
In the following examples, the final product content was quantitatively determined by liquid chromatography external standard method.
Example 1:
(1) adding 70.4g of DEMM/EMME mixed ester (molar ratio: DEMM/EMME is 0.55) and 120mL of water into a 500mL three-necked bottle, stirring, controlling the reaction temperature to be 20 ℃, dropwise adding 61.2g of ammonia water with the mass fraction of 25%, dropwise adding the ammonia water for 1h, and continuing to perform heat preservation reaction for 1h after dropwise adding;
(2) controlling the temperature of the reaction solution to be-10 ℃, dripping 41.4g of 40% methylhydrazine aqueous solution, dripping methylhydrazine for 1h, heating to 60 ℃ after finishing dripping, keeping the temperature for 7h, performing sampling liquid chromatography for central control, and stopping the reaction, wherein the aminated intermediate is less than 0.5%;
(3) and (3) reducing the temperature, controlling the temperature to be 30 ℃, slowly dripping 91.25g of hydrochloric acid with the mass fraction of 36%, reducing the temperature to 0 ℃ after dripping, preserving the temperature for 1h, filtering, washing a filter cake with 2 x 60mL of ice water, drying to obtain a final product, determining the final product to be MHPE through qualitative analysis to obtain 49.15g of the final product MHPE, and quantitatively analyzing the final product by liquid chromatography to obtain the final product MHPE with the content of 96.5% and the yield of 93%.
Example 2:
(1) adding 79.4g of pure DENME and 120mL of water into a 500mL three-necked bottle, stirring, controlling the reaction temperature to be 20 ℃, dropwise adding 30.6g of ammonia water with the mass fraction of 25%, dropwise adding the ammonia water for 1h, and continuing to perform heat preservation reaction for 2h after dropwise adding;
(2) controlling the temperature of the reaction liquid to be 30 ℃, dripping 41.4g of methylhydrazine aqueous solution with the mass fraction of 40%, dripping the methylhydrazine for 1h, heating to 60 ℃ after finishing dripping, keeping the temperature for 7h, controlling the sampling liquid chromatogram, and stopping the reaction, wherein the amination intermediate is less than 0.5%;
(3) and (3) cooling, controlling the temperature to be 30 ℃, slowly dripping 45.63g of hydrochloric acid with the mass fraction of 36%, cooling to 0 ℃ after dripping, preserving heat for 1h, filtering, washing a filter cake with 2 x 60mL of ice water, drying to obtain a final product, determining the final product to be MHPE through qualitative analysis to obtain 48.9g of the final product MHPE, and quantitatively analyzing the final product to obtain the final product with the content of 97.5% and the yield of 93.5% through liquid chromatography.
Example 3:
(1) adding 68.24g of DEMM/EMME mixed ester (molar ratio: DEMM/EMME is 0.25) and 120mL of water into a 500mL three-necked bottle, stirring, controlling the reaction temperature to be 20 ℃, dropwise adding 30.6g of ammonia water with the mass fraction of 25%, dropwise adding the ammonia water for 1h, and continuing to perform heat preservation reaction for 1h after dropwise adding;
(2) controlling the temperature of the reaction liquid to be 30 ℃, dripping 41.4g of methylhydrazine aqueous solution with the mass fraction of 40%, dripping the methylhydrazine for 1h, heating to 60 ℃ after finishing dripping, keeping the temperature for 7h, controlling the sampling liquid chromatogram, and stopping the reaction, wherein the amination intermediate is less than 0.5%; (ii) a
(3) And (3) cooling, controlling the temperature to be 25 ℃, slowly dripping 54.75g of hydrochloric acid with the mass fraction of 36%, cooling to 0 ℃ after dripping, preserving heat for 1h, filtering, washing a filter cake with 2 x 60mL of ice water, drying to obtain a final product, determining the final product to be MHPE through qualitative analysis to obtain 48.85g of the final product MHPE, and quantitatively analyzing the final product to obtain the final product with the content of 97.3% and the yield of 93.2% through liquid chromatography.
Example 4:
(1) adding 76.6g of DEMM/EMME mixed ester (the molar ratio is DEMM/EMME is 4) and 120mL of water into a 500mL three-necked bottle, stirring, controlling the reaction temperature to be 20 ℃, dropwise adding 30.6g of ammonia water with the mass fraction of 25%, dropwise adding the ammonia water for 1h, and continuing to perform heat preservation reaction for 1h after dropwise adding;
(2) controlling the temperature of the reaction liquid to be 30 ℃, dripping 41.4g of methylhydrazine aqueous solution with the mass fraction of 40%, dripping the methylhydrazine for 1h, heating to 60 ℃ after finishing dripping, keeping the temperature for 7h, controlling the sampling liquid chromatogram, and stopping the reaction, wherein the amination intermediate is less than 0.5%;
(3) cooling, controlling the temperature to be 20 ℃, slowly dripping 45.63g of hydrochloric acid with the mass fraction of 36%, cooling to 2 ℃ after dripping, preserving heat for 1h, filtering, washing a filter cake with 2 x 60mL of ice water, drying to obtain a final product, determining the final product to be MHPE through qualitative analysis to obtain 49.06g of the final product MHPE, and quantitatively analyzing the final product by liquid chromatography to obtain the final product MHPE with the content of 97.5% and the yield of 93.8%.
Example 5:
(1) adding 70.4g of DEMM/EMME mixed ester (molar ratio: DEMM/EMME is 0.55) and 120mL of water into a 500mL three-necked bottle, stirring, controlling the reaction temperature to be 20 ℃, dropwise adding 30.6g of ammonia water with the mass fraction of 25%, dropwise adding the ammonia water for 1h, and continuing to perform heat preservation reaction for 1h after dropwise adding;
(2) controlling the temperature of the reaction solution to be 30 ℃, dripping 35.19g of methylhydrazine aqueous solution with the mass fraction of 40%, dripping methylhydrazine for use for 1h, heating to 60 ℃ after finishing dripping, keeping the temperature for 12h, performing sampling liquid chromatography central control, and stopping reaction when the amination intermediate is less than 0.5%;
(3) cooling, controlling the temperature to be 10 ℃, slowly dripping 68.45g of hydrochloric acid with the mass fraction of 36%, cooling to 2 ℃ after dripping, preserving heat for 1h, filtering, washing a filter cake with 2 x 60mL of ice water, drying to obtain a final product, determining the final product to be MHPE through qualitative analysis to obtain 47.18g of the final product MHPE, and quantitatively analyzing the final product by liquid chromatography to obtain the final product with the content of 97.5% and the yield of 90.2%.
Example 6:
(1) adding 70.4g of DEMM/EMME mixed ester (molar ratio: DEMM/EMME is 0.55) and 120mL of water into a 500mL three-necked bottle, stirring, controlling the reaction temperature to be 20 ℃, dropwise adding 30.6g of ammonia water with the mass fraction of 25%, dropwise adding the ammonia water for 1h, and continuing to perform heat preservation reaction for 1h after dropwise adding;
(2) controlling the temperature of the reaction solution to be 30 ℃, dripping 69g of methylhydrazine aqueous solution with the mass fraction of 40%, dripping methylhydrazine for using for 1h, heating to 60 ℃ after finishing dripping, keeping the temperature for 4h, performing central control on a sampling liquid chromatogram, and stopping the reaction, wherein the amination intermediate is less than 0.5%;
(3) and (3) cooling, controlling the temperature to be 30 ℃, slowly dripping 45.63g of hydrochloric acid with the mass fraction of 36%, cooling to 2 ℃ after dripping, preserving heat for 1h, filtering, washing a filter cake with 2 x 60mL of ice water, drying to obtain a final product, determining the final product to be MHPE through qualitative analysis to obtain 49.27g of the final product MHPE, and quantitatively analyzing the final product to obtain the final product with the content of 97.1% and the yield of 93.8% through liquid chromatography.
Example 7:
(1) adding 70.4g of DEMM/EMME mixed ester (molar ratio: DEMM/EMME is 0.55) and 120mL of water into a 500mL three-necked bottle, stirring, controlling the reaction temperature to be 20 ℃, dropwise adding 22.44g of ammonia water with the mass fraction of 25%, dropwise adding the ammonia water for 1h, and continuing to perform heat preservation reaction for 5h after dropwise adding;
(2) controlling the temperature of the reaction liquid to be 30 ℃, dripping 41.4g of methylhydrazine aqueous solution with the mass fraction of 40%, dripping the methylhydrazine for 1h, heating to 60 ℃ after finishing dripping, keeping the temperature for 7h, controlling the sampling liquid chromatogram, and stopping the reaction, wherein the amination intermediate is less than 0.5%;
(3) and (3) reducing the temperature, controlling the temperature to be 30 ℃, slowly dripping 33.46g of hydrochloric acid with the mass fraction of 36%, reducing the temperature to 2 ℃ after dripping, preserving the temperature for 1h, filtering, washing a filter cake with 2 x 60mL of ice water, drying to obtain a final product, determining the final product to be MHPE through qualitative analysis to obtain 47.85g of the final product MHPE, and quantitatively analyzing the final product to ensure that the content of the final product MHPE is 97.0% through liquid chromatography and the yield is 91.0%.
Example 8:
(1) adding 70.4g of DEMM/EMME mixed ester (molar ratio: DEMM/EMME is 0.55) and 120mL of water into a 500mL three-necked bottle, stirring, controlling the reaction temperature to be 0 ℃, dropwise adding 30.6g of ammonia water with the mass fraction of 25%, dropwise adding the ammonia water for 0.5h, and continuing to perform heat preservation reaction for 5h after dropwise adding;
(2) controlling the temperature of the reaction solution to be 30 ℃, dripping 41.4g of methylhydrazine aqueous solution with the mass fraction of 40%, dripping the methylhydrazine for 0.5h, heating to 60 ℃ after finishing dripping, keeping the temperature for 7h, performing central control on a sampling liquid chromatogram, and stopping the reaction, wherein the aminated intermediate is less than 0.5%;
(3) and (3) cooling, controlling the temperature to be 30 ℃, slowly dripping 45.63g of hydrochloric acid with the mass fraction of 36%, cooling to 2 ℃ after dripping, preserving heat for 1h, filtering, washing a filter cake with 2 x 60mL of ice water, drying to obtain a final product, determining the final product to be MHPE by qualitative analysis to obtain 48.75g of the final product MHPE, and quantitatively analyzing the final product by liquid chromatography to obtain the final product with the content of 97.6% and the yield of 93.3%.
Example 9:
(1) adding 70.4g of DEMM/EMME mixed ester (molar ratio: DEMM/EMME is 0.55) and 120mL of water into a 500mL three-necked bottle, stirring, controlling the reaction temperature to be 50 ℃, dropwise adding 30.6g of ammonia water with the mass fraction of 25%, dropwise adding the ammonia water for 1h, and continuing to perform heat preservation reaction for 1h after dropwise adding;
(2) controlling the temperature of the reaction liquid to be 30 ℃, dripping 41.4g of methylhydrazine aqueous solution with the mass fraction of 40%, dripping the methylhydrazine for 1h, heating to 60 ℃ after finishing dripping, keeping the temperature for 7h, controlling the sampling liquid chromatogram, and stopping the reaction, wherein the amination intermediate is less than 0.5%;
(3) cooling and controlling the temperature to be 30 ℃, slowly dripping 45.63g of hydrochloric acid with the mass fraction of 36%, cooling to 5 ℃ after dripping, preserving heat for 3 hours, filtering, washing a filter cake with 2 x 60mL of ice water and drying to obtain a final product, determining the final product to be MHPE by qualitative analysis to obtain 48.65g of the final product MHPE, and quantitatively analyzing the final product by liquid chromatography to obtain the final product MHPE with the content of 97.5% and the yield of 93.0%.
Example 10:
(1) adding 70.4g of DEMM/EMME mixed ester (molar ratio: DEMM/EMME is 0.55) and 120mL of water into a 500mL three-necked bottle, stirring, controlling the reaction temperature to be 20 ℃, dropwise adding 30.6g of ammonia water with the mass fraction of 25%, dropwise adding the ammonia water for 1h, and continuing to perform heat preservation reaction for 1h after dropwise adding;
(2) controlling the temperature of the reaction liquid to be 30 ℃, dripping 41.4g of 40% methylhydrazine aqueous solution, dripping methylhydrazine for 1h, heating to 40 ℃ after finishing dripping, keeping the temperature for 12h, controlling the sampling liquid chromatogram, and stopping the reaction, wherein the amination intermediate is less than 0.5%;
(3) cooling, controlling the temperature to be 25 ℃, slowly dripping 45.63g of hydrochloric acid with the mass fraction of 36%, cooling to 5 ℃ after dripping, preserving heat for 2h, filtering, washing a filter cake with 2 x 60mL of ice water, drying to obtain a final product, determining the final product to be MHPE through qualitative analysis to obtain 48.54g of the final product MHPE, and quantitatively analyzing the final product by liquid chromatography to obtain the final product with the content of 97.4% and the yield of 92.7%.
Example 11:
(1) adding 70.4g of DEMM/EMME mixed ester (molar ratio: DEMM/EMME is 0.55) and 120mL of water into a 500mL three-necked bottle, stirring, controlling the reaction temperature to be 20 ℃, dropwise adding 30.6g of ammonia water with the mass fraction of 25%, dropwise adding the ammonia water for 1.5h, and continuing to perform heat preservation reaction for 1h after dropwise adding;
(2) controlling the temperature of the reaction solution to be 50 ℃, dripping 41.4g of methylhydrazine aqueous solution with the mass fraction of 40%, dripping the methylhydrazine for use for 1.5h, heating to 90 ℃ after finishing dripping, keeping the temperature for 4h, performing central control on a sampling liquid chromatogram, and stopping the reaction, wherein the aminated intermediate is less than 0.5%;
(3) and (3) cooling, controlling the temperature to be 30 ℃, slowly dripping 45.63g of hydrochloric acid with the mass fraction of 36%, cooling to 5 ℃ after dripping, preserving heat for 1h, filtering, washing a filter cake with 2 x 60mL of ice water, drying to obtain a final product, determining the final product to be MHPE through qualitative analysis to obtain 47.38g of the final product MHPE, and quantitatively analyzing the final product to obtain the final product with the content of 97.2% and the yield of 90.3% through liquid chromatography.
Comparative example 1:
in comparison with example 1, in comparative example 1, only the reaction raw material was replaced with EMME 65.45g, and the remaining conditions were the same as in example 1, to finally obtain 48.85g of a product with a content of 97.4% and a yield of 93.3%.
The preparation method of the EMME comprises the following steps:
adding 80.8g of diethyl malonate, 224.3g of triethyl orthoformate, 1.55g of acetic anhydride and 0.067g of zinc chloride into a 500mL three-necked bottle, heating, extracting ethanol when the temperature of a reaction solution rises to 135 ℃, extracting ethanol while reacting, slowly raising the temperature of a kettle to 155 ℃, and carrying out gas chromatographic analysis by sampling, wherein the reaction is stopped when raw materials of diethyl malonate and DENME are completely reacted. The catalyst is filtered out, the filtrate is distilled under low vacuum and reduced pressure to recover excessive triethyl orthoformate, then 81.8g of EMME product is distilled out under high vacuum and reduced pressure, the content is more than 99 percent by quantitative analysis of a gas chromatography internal standard method, and the yield is 75 percent.
Therefore, as can be seen from example 1 and comparative example 1, the raw materials used in the examples can be prepared from the base raw materials simply and in high yield; and the yield and purity of the MHPE prepared by the method are equivalent to those of the MHPE prepared by using pure EMME as a raw material.
As can be seen from the above examples, the preparation method used in the present invention can make the yield of MHPE product more than 90% and the product purity more than 96%.
The applicant states that the present invention is illustrated by the above examples to show the detailed process equipment and process flow of the present invention, but the present invention is not limited to the above detailed process equipment and process flow, i.e. it does not mean that the present invention must rely on the above detailed process equipment and process flow to be implemented. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (25)
1. The preparation method of the 1-methyl-5-hydroxypyrazole-4-ethyl carboxylate is characterized in that DEMM is used as a raw material or a mixture of DEMM and EMME is used as a raw material, and the 1-methyl-5-hydroxypyrazole-4-ethyl carboxylate is prepared through amination reaction and cyclization reaction;
the preparation method comprises the following steps:
(1) dissolving a mixture of raw materials DEMME and EMME or single DEMME in a solvent, and carrying out amination reaction on the mixture and ammonia water to obtain a first reaction liquid;
(2) mixing the first reaction liquid with methylhydrazine to perform cyclization reaction to obtain a second reaction liquid;
(3) and neutralizing the second reaction solution with acid, filtering and washing to obtain the 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester.
2. The method of claim 1, wherein the feedstock is a mixture of DEMME and EMME.
3. The preparation method according to claim 1, wherein the molar ratio of DEMME to EMME in the mixture is (0.25-4): 1.
4. The method according to claim 1, wherein the solvent in the step (1) is water.
5. The production method according to claim 1, wherein the aqueous ammonia is added dropwise in the step (1).
6. The preparation method according to claim 5, wherein the dropping time is 0.5 to 1.5 hours.
7. The method according to claim 1, wherein the temperature of the amination in the step (1) is 0 to 50 ℃.
8. The method according to claim 7, wherein the temperature of the amination in the step (1) is 0 to 20 ℃.
9. The preparation method according to claim 1, wherein the amination is carried out for 1 to 5 hours in step (1).
10. The method according to claim 9, wherein the amination is carried out for 1 to 2 hours in step (1).
11. The method according to claim 1, wherein the first reaction solution is mixed with methylhydrazine in step (2) for 0.5 to 1.5 hours.
12. The method according to claim 11, wherein the temperature during the mixing in the step (2) is-10 to 50 ℃.
13. The method according to claim 12, wherein the temperature during the mixing in the step (2) is 0 to 35 ℃.
14. The process according to claim 1, wherein the temperature of the cyclization reaction in the step (2) is 40 to 90 ℃.
15. The method according to claim 1, wherein the cyclization reaction in step (2) is carried out for 4 to 12 hours.
16. The method according to claim 1, wherein the temperature of the acid neutralization in the step (3) is 30 ℃ or lower.
17. The method of claim 16, wherein the acid is hydrochloric acid.
18. The preparation method according to claim 17, wherein the molar ratio of the hydrochloric acid to the ammonia water in the step (1) is (1-1.5): 1.
19. The method according to claim 1, wherein the step (3) further comprises a step of cooling after neutralization with an acid.
20. The preparation method according to claim 1, wherein the second reaction solution is neutralized with an acid, cooled to 0 to 5 ℃, kept warm for 1 to 3 hours, and then filtered.
21. The method according to claim 1, wherein the solution used for the filtration in the step (3) is ice water.
22. The process according to claim 1, wherein the mixture of DEMME and EMME is obtained by reacting diethyl malonate, triethyl orthoformate and acetic anhydride under the catalysis of nickel sulfate.
23. The method according to claim 1, wherein the molar ratio of the raw material, ammonia water and methylhydrazine is 1 (1.1-3) to 1.02-2.
24. The method according to claim 23, wherein the molar ratio of the raw material, the ammonia water and the methylhydrazine is 1 (1.2-2) to 1.05-1.2.
25. The method of claim 1, comprising the steps of:
(1) dissolving DEMME or a mixture of DEMME and EMME in water, dropwise adding ammonia water at 0-50 ℃, continuously reacting for 1-5 hours while keeping the temperature, and obtaining a first reaction solution;
(2) controlling the temperature of the first reaction liquid to be-10-50 ℃, dropwise adding methyl hydrazine, finishing dropping within 0.5-1.5 h, raising the temperature to 40-90 ℃, and carrying out heat preservation reaction for 4-12 h to obtain a second reaction liquid;
(3) and cooling the second reaction liquid, keeping the temperature below 30 ℃, dropwise adding hydrochloric acid for neutralization, cooling to 0-5 ℃, preserving heat for 1-3 h, filtering, and washing a filter cake with ice water to obtain the ethyl 1-methyl-5-hydroxypyrazole-4-carboxylate.
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| JPS59122488A (en) * | 1982-12-28 | 1984-07-14 | Nissan Chem Ind Ltd | Pyrazolesulfonyl urea derivative, its preparation and herbicide containing the same |
| JPS58174369A (en) * | 1983-03-26 | 1983-10-13 | Nissan Chem Ind Ltd | 1-methyl-5-hydroxypyrazole-4-carboxylic lower alkyl ester and its preparation |
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