CN111138289B - Compound and process for synthesizing 5-acetyl-1H-pyrazole-3-carboxylic acid by using same - Google Patents
Compound and process for synthesizing 5-acetyl-1H-pyrazole-3-carboxylic acid by using same Download PDFInfo
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Abstract
The invention belongs to the field of chemical synthesis of substances, and discloses a compound, application and a process for synthesizing 5-acetyl-1H-pyrazole-3-carboxylic acid by using the compound, wherein a compound 2, 3-butanedione is used as an initial raw material to synthesize a compound intermediate III, and the compound intermediate III is separated out from a system, so that the product conversion is promoted, the purification purpose can be achieved by filtering, the conversion rate reaches 95%, and the yield is improved; synthesizing an intermediate IV, namely taking an intermediate III and a hydrazine compound as raw materials, adjusting the pH value of a system, improving the yield, reducing the production of impurities, finishing the reaction, concentrating and filtering, wherein the yield reaches 98 percent, and the HPLC purity is more than 98.5 percent; by the operation, high-purity V was obtained. The method has the advantages of simple and safe process, high yield, suitability for industrialization, contribution to impurity control and reduction of quality risk.
Description
Technical Field
The invention belongs to the field of chemical synthesis of substances, and particularly relates to a compound and a process for synthesizing 5-acetyl-1H-pyrazole-3-carboxylic acid by using the compound.
Background
Pyrazoles have a wide range of biological activities, and many pyrazoles have been developed and used as fungicides, herbicides, and insecticides, for example: tebufenpyrad (MK-239). In the biological and pharmaceutical fields, representative pyrazole drugs are: celecoxib, sildenafil, rimonabant, and the drug Darolutamide approved by the U.S. FDA for the treatment of prostate cancer (NMCRPC) in 7 months of 2019, which is an oral nonsteroidal androgen receptor antagonist. In addition, the pyrazole compounds are widely concerned as N-heterocyclic carbene precursors and metal ligands, so that the development of a new and effective synthetic method suitable for industrial production has very important significance and application prospect.
5-acetyl-1H-pyrazole-3-carboxylic acid (V) as a molecular fragment can be used for synthesizing various heterocyclic compounds, and derivatives thereof also have good biological activity, such as derivatives of 5-substituted-1H-pyrazole-3-carboxylic acid as nicotinic acid receptor RUP25 agonists for treating dyslipidemia and related diseases. 5-acetyl-1H-pyrazole-3-carboxylic acid and its derivative 5- (1- (tert-butyldimethylsilyloxy) ethyl) -1H-pyrazole-3-carboxylic acid are important fragments for the synthesis of Darolutamide (WO 2011051540, WO2016162604, WO 2016120530)
The synthesis of 5-acetyl-1H-pyrazole-3-carboxylic acid is reported in related patents and literatures. For example, WO2004032928 discloses the use of diethyl oxalate in refluxing reaction with 3, 3-dimethoxybutan-2-one in an ethanolic solvent to give intermediate 4, followed by the addition of hydrazine hydrochloride and H 2 And O, obtaining a crude product of the target product 5. The crude product of the target product 5 is purified by a preparation liquid phase, and only 26 percent of separation yield is obtained. Preparation of compound V, WO2004032928 reports the general procedure: after 5-substituted-1H-pyrazole-3-carboxylic ester (2.56 mmol) is hydrolyzed, ethyl acetate (200 vol) is used for extraction, drying and concentration, the whole synthesis route is synthesized, a compound 5 system is disordered, the product is difficult to separate, the yield is low, a large amount of solvents are used, and the method is not suitable for industrial production.
WO2012139930 reports that ethyl diazoacetate is in InCl 3 The pyrazole compound is prepared by reacting with 3-butyne-2-ketone under catalysis, and the process not only uses an explosive reagent ethyl diazoacetate, but also uses toxic and flammable 3-butyne-2-ketone. In addition, a transition metal catalyst InCl was used 3 Industrial sewage is generated, and a large amount of cost is increased by post-treatment. In the last hydrolysis reaction, the dosage reported by the patent is only 50mg, and the method has no reference to industrial production. We have found that compound V after hydrolysis is readily soluble in water and difficult to isolate by extraction.
WO201808130 reports that compound V is synthesized from ethyl diazoacetate, an explosive reagent, as a raw material through two diazo intermediates 11 and 12. It is well known that diazo compounds are unstable and are very susceptible to decomposition or even explosion when exposed to heat. The process has great safety risk when being used for industrial production. The two-step reaction of the route needs to be carried out at a low temperature (-78 ℃), needs low-temperature equipment and generates great energy consumption, and is not beneficial to the control of the production cost.
Tetrahedron Letters, 2018, 59(51), 4462-. The reaction is only carried out on a 1mmol scale, and the oxidizing reagent Oxone is used, and the use of diazo compounds cannot be avoided. The other substrate ethyl acrylate belongs to 2B carcinogens, and the acrylate compounds are inflammable, explosive and easy to polymerize. Therefore, the method is not suitable for industrial production.
The reported preparation method of the compound V has the defects of flammable, explosive and toxic reagents, harsh process conditions, low product yield, difficulty in purifying the product and the like. The invention aims to provide a simple, safe and low-cost synthetic process for preparing a compound V, which is suitable for industrial production.
Disclosure of Invention
The invention aims to overcome the defects of flammable, explosive and toxic reagents, low yield of intermediates and products, more impurities, difficulty in purification, difficulty in industrial production and the like in the conventional preparation method of 5-acetyl-1H-pyrazole-3-carboxylic acid.
In view of the above object, the present invention provides, in a first aspect, a compound having the formula:
the invention also provides a preparation method of the compound, which takes the compound 2, 3-butanedione as a starting raw material, and the reaction process is as follows:
the process for synthesizing the compound III comprises the following specific operation steps:
s-1, mixing 2, 3-butanedione, trialkyl orthoformate and p-toluenesulfonic acid monohydrate, heating the system to 20-60 ℃, and reacting;
s-2, concentrating the reaction system, controlling the pressure of the system to be 15-75mmHg, the temperature of the system to be 15-45 ℃, and taking the rest system as an intermediate I;
s-3, mixing the compound II, a solvent and a base;
s-4, adding the intermediate I obtained by the S-2 into the S-3, and reacting at the temperature of 5-80 ℃;
and S-5, adding water into the system, stirring, filtering, washing a filter cake, and drying to obtain a compound III.
The invention also provides a process for synthesizing 5-acetyl-1H-pyrazole-3-carboxylic acid by adopting the compound III, which comprises the following steps:
The process for synthesizing 5-acetyl-1H-pyrazole-3-carboxylic acid by adopting the compound III comprises the following specific operation steps:
s-6, mixing the compound III, a solvent and a hydrazine compound, adjusting the pH to be less than 7, and heating to react, wherein the temperature is controlled to be 30-110 ℃; or mixing the compound III with a solvent, adjusting the pH to be less than 7 to obtain a compound III', adding a hydrazine compound, and heating to react at the temperature of 30-110 ℃;
s-7, adjusting the pH value to 7-8, concentrating the system, adding water, filtering and washing to obtain an intermediate IV;
s-8, mixing the intermediate IV, a solvent and a sodium hydroxide aqueous solution, controlling the temperature to be 5-80 ℃ and reacting;
and (4) after the S-9 reaction is finished, separating liquid to remove an organic phase, adjusting the pH value to 1-5, separating out solids, filtering and drying to obtain the product.
According to the technical scheme, the compound 2, 3-butanedione is used as an initial raw material, the intermediate III is synthesized and separated out from a system, so that the product conversion is promoted, the purification purpose can be achieved through filtration, the conversion rate reaches 95%, and the yield is improved; synthesizing an intermediate IV, namely taking compounds of III and hydrazine as raw materials, adjusting the pH value of a system, improving the yield, reducing the production of impurities, finishing the reaction, concentrating and filtering, wherein the yield reaches 98 percent, and the purity of HPLC is more than 98.5 percent; by the operation, high-purity V was obtained. The method has the advantages of simple and safe process, high yield, suitability for industrialization, contribution to impurity control and reduction of quality risk.
Preferably, the molar ratio of 2, 3-butanedione to trialkyl orthoformate is 1: 1-1: 5 further preferably 1: 1.1.
preferably, the mass concentration of the p-toluenesulfonic acid monohydrate is 1wt% to 2 wt%.
Preferably, the system pressure in the step S-2 is 15 to 75mmHg, preferably 50 to 60 mmHg.
Preferably, the temperature of the system in step S-2 is 15 to 45 ℃, preferably 20 to 30 ℃.
Preferably, the solvent in step S-3 refers to n-heptane, methyl tert-butyl ether, tetrahydrofuran, ethanol, preferably n-heptane or methyl tert-butyl ether.
Preferably, the volume ratio of the solvent to the intermediate I in step S-3 is 5 to 20, preferably 10 to 15.
Preferably, the molar ratio of base to intermediate I in step S-3 is 3: 1-1: 1, preferably 2: 1; more preferably 1.8: 1; the alkali is sodium methoxide, sodium ethoxide, potassium tert-butoxide, potassium hydride, sodium hydride, calcium hydride,
The intermediate III corresponding to the magnesium ethoxide is sodium salt, potassium salt, calcium salt and magnesium salt.
Preferably, the reaction temperature in step S-4 is from 5 to 80 deg.C, preferably from 15 to 20 deg.C.
Preferably, the molar ratio of compound II to intermediate I is 3: 1-1: 1, further preferably 1.5: 1.
preferably, the reaction time in step S-4 is 4 to 36 hours, more preferably 5 to 8 hours.
Preferably, the drying mode in the step S-5 adopts vacuum drying at 45-55 ℃.
Preferably, the solvent in step S-6 may be one or more of alcohol, toluene, tetrahydrofuran and methyl tert-butyl ether, preferably ethanol, and the volume ratio of the solvent to the intermediate III is 10.
Preferably, the hydrazine compound in step S-6 is hydrazine hydrate, hydrazine monohydrochloride, hydrazine dihydrochloride, hydrazine sulfate.
Preferably, the molar ratio of hydrazine compound to intermediate III in step S-6 is 1.5: 1-1: 1, preferably 1.15: 1-1: 1, more preferably 1.1: 1, molar ratios in excess of 1.15 produce significant impurities.
Preferably, the solvent in step S-8 is one or a mixture of several of methyl tert-butyl ether, tetrahydrofuran and water, and further preferably tetrahydrofuran and water.
Preferably, the volume ratio of the solvent to the intermediate IV in step S-8 is 10: 1-2: 1, preferably 6: 1 volume.
Preferably, the molar ratio of sodium hydroxide to intermediate IV in step S-8 is 5: 1-1: 1, more preferably 3: 1.
preferably, the reaction temperature in step S-8 is 5 to 80 ℃.
Through the implementation of the technical scheme, the invention has the following beneficial effects:
1. the invention provides a synthesis process of a 5-acetyl-1H-pyrazole-3-carboxylic acid compound. The whole process is suitable for industrial production, avoids the use of flammable, explosive and dangerous reagents, and has mild reaction conditions, high yield and low cost. Meanwhile, the process is beneficial to impurity control, and the quality risk of the product is reduced.
2. Intermediate I: by controlling the pressure and temperature of the post-treatment concentration, the obtained product can be directly used for the next reaction.
3. Intermediate III: the reaction can be operated at room temperature, avoiding energy consumption. The product can be purified by filtration, washing, etc.
4. Intermediate IV: IV was obtained in 98% yield, greater than 98.5% purity. The whole process is simple to operate, high in yield and high in purity, and compared with the method disclosed by the literature, the yield (26%) of the IV is greatly improved.
5. Compound V: the reports in the prior literature only stay on the milligram to gram scale, but are not representative. By using the operation, the compound V can be obtained with high efficiency, and the HPLC purity is as high as 98.5%.
Detailed Description
The present invention will be described in further detail with reference to the following embodiments, and the present invention is not limited to the following examples. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, which is set forth in the following claims. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art, except for those specifically mentioned below, and the present invention is not particularly limited.
EXAMPLE 1 preparation of intermediate I
A1L three-necked flask was charged with 200.0g (2.32mol, 1.0eq.) of 2, 3-butanedione, 271.0g (2.56mol, 1.1eq.) of trimethyl orthoformate and 4.0g (2.0 wt.%) of p-toluenesulfonic acid monohydrate in this order, and reacted at 20 to 30 ℃ for 24 hours, with NMR monitoring showing 2, 3-butanedione: the reaction was stopped when the yield was less than 1.0%, and methyl formate was removed by concentration under reduced pressure (50-60 mmHg) at 20-25 ℃ to give 269g of 3, 3-dimethoxy-2-butanone in 88.0% yield.
EXAMPLE 2 preparation of intermediate I
A1L three-necked flask was charged with 200.0g (2.32mol, 1.0eq.) of 2, 3-butanedione, 271.0g (2.56mol, 1.1eq.) of trimethyl orthoformate and 4.0g (2.0 wt.%) of p-toluenesulfonic acid monohydrate in this order, and reacted at 35-40 ℃ for 6 hours, with NMR monitoring showing 2, 3-butanedione: the reaction was stopped when the yield was less than 1.0%, and methyl formate was removed by concentration under reduced pressure (65-75 mmHg) at 20-25 ℃ to give 274g of 3, 3-dimethoxy-2-butanone in a yield of 89.5%.
EXAMPLE 3 preparation of intermediate III
Adding 510ml (10vol) of methyl tert-butyl ether and 100.8g (0.69mol, 1.8eq.) of diethyl oxalate into a 2L three-neck flask, adding 39.4g (0.58mol, 1.5eq.) of sodium ethoxide into the mixture at the temperature of between 20 and 30 ℃ under stirring, dropwise adding 51g (0.386mol) of 3, 3-dimethoxy-2-butanone, continuing to react for 8 hours at the temperature of between 15 and 20 ℃, monitoring the raw material by NMR to be less than 3.0 percent, adding 150ml (3 vol) of water into the system, stirring for 1.0 hour, stopping the reaction, filtering to obtain a solid product, and performing vacuum drying at the temperature of between 50 and 55 ℃ for 7 hours to obtain 84g of a light yellow solid with the yield of 85 percent.
Preparation of intermediate III other examples:
the molar ratio of the alkali to the I is 1.5:1, b the molar ratio of the alkali to the I is 1.0:1, c the molar ratio of alkali to I is 3.0:1
EXAMPLE 15 preparation of intermediate IV
A1L three-necked flask was charged with 50g (0.20mol, 1.0eq.) of intermediate III (M = Na), 500ml (10 vol.) of ethanol, and an aqueous solution of hydrazine monohydrochloride (15.7 g, 0.23mol, 1.15eq., H, 15 g, hydrazine monohydrochloride) 2 O50 ml, 1vol), stirring, adjusting pH =2-3 with 12N hydrochloric acid, heating to 70-80 ℃, reacting for 5 hours, monitoring completion of the reaction by TLC, cooling to 20-30 ℃, adjusting pH =7-8 with 30% NaOH aqueous solution, concentrating to 2-3vol, adding H 2 O250 ml (5vol), concentrated to 6 volumes, filtered, washed once with 1.5 vol water, dried under vacuum at 50-55 ℃ for 8 hours to give 35.8g of an off-white solid in 98.1% yield and 98.75% purity.
Preparation of intermediate IV other examples:
EXAMPLE 23 preparation of intermediate IV
A 1L three-necked flask was charged with 50g (0.20mol, 1.0eq.) of intermediate III (M = Na), 500ml (10vol) of ethanol, 12N hydrochloric acid to adjust pH =2-3 to obtain an ethanol solution of III', and an aqueous hydrazine monohydrochloride solution (15.7 g, 0.23mol, 1.15eq., H, 15 g, 0.23mol, 1.15 eq.) was added 2 O50 ml, 1vol), stirring, heating to 70-80 ℃, reacting for 6 hours, monitoring the reaction completion by TLC, cooling to 20-30 ℃, adjusting pH =7-8 by 30% NaOH aqueous solution, concentrating to 2-3vol, adding H 2 O250 ml (5vol), concentrated to 6 volumes, filtered, washed once with 1.5 vol water, dried under vacuum at 50-55 ℃ for 8 hours to give 35.1g of an off-white solid in 96.5% yield and 98.50% purity.
EXAMPLE 24 preparation of Compound V
A 1L three-necked flask was charged with 50g of intermediate IV (0.27mol, 1.0eq.), 300ml THF (6vol), 159g of 20% NaOH aqueous solution (0.81mol, 3.0eq.), heated to 60-65 ℃, reacted for 2 hours, TLC monitored disappearance of reaction raw materials, cooled to room temperature, separated, adjusted aqueous phase pH =2 with 12N HCl aqueous solution, stirred for 2 hours, filtered, and vacuum dried at 50-55 ℃ for 8 hours to give a pale yellow solid V, 35.4g, yield 85.1%, CP purity 99.16%.
Claims (13)
1. The process for synthesizing 5-acetyl-1H-pyrazole-3-carboxylic acid is characterized by comprising the following operation steps:
s-1, mixing 2, 3-butanedione, trialkyl orthoformate and p-toluenesulfonic acid monohydrate, heating the system to 20-60 ℃, and reacting;
s-2, concentrating a reaction system, controlling the system pressure to be 15-75mmHg and the system temperature to be 15-45 ℃, and enabling the residual system to be an intermediate I;
s-3, mixing the compound II, a solvent and a base, wherein the base is sodium ethoxide, potassium tert-butoxide and calcium hydride;
s-4, adding the intermediate I obtained by the S-2 into the S-3, and reacting at the temperature of 5-80 ℃;
s-5, adding water into the system, stirring, filtering, washing a filter cake, and drying to obtain a compound III;
s-6, mixing the compound III, a solvent and a hydrazine compound, adjusting the pH to be less than 7, and heating to react, wherein the temperature is controlled to be 30-110 ℃; or mixing the compound III with a solvent, adjusting the pH to be less than 7 to obtain a compound III', adding a hydrazine compound, and heating to react at the temperature of 30-110 ℃;
s-7, adjusting the pH value to 7-8, concentrating the system, adding water, filtering and washing to obtain an intermediate IV;
s-8, mixing the intermediate IV, a solvent and a sodium hydroxide aqueous solution, controlling the temperature to be 5-80 ℃, and reacting;
s-9, after the reaction is finished, separating liquid to remove an organic phase, adjusting the pH value to 1-5, separating out solids, filtering and drying to obtain a product;
the reaction formula is as follows:
alternatively, the first and second electrodes may be,
；
wherein M = Na, K,1/2 Ca; r1= Me, Et; r2= Me, Et, Pr, i-Pr, Bn.
2. The process of claim 1, wherein the molar ratio of 2, 3-butanedione to trialkyl orthoformate is 1: 1-1: 5.
3. The process of claim 1, wherein the concentration of p-toluenesulfonic acid monohydrate is 1 to 2 wt.%.
4. The process according to claim 1, wherein the solvent in step S-3 is n-heptane, methyl tert-butyl ether, tetrahydrofuran, ethanol.
5. The process according to claim 1 or 4, wherein the volume ratio of solvent to intermediate I in step S-3 is 5 to 20.
6. The process of claim 1, wherein the molar ratio of base to intermediate I in step S-3 is
The ratio is 3: 1-1: 1.
7. the process according to claim 1, wherein the molar ratio of compound II to intermediate I is 3: 1-1: 1.
8. the process of claim 1, wherein the solvent in step S-6 is one or more of alcohol, toluene, tetrahydrofuran, and methyl tert-butyl ether.
9. The process according to claim 1, wherein the hydrazine compound in step S-6 is hydrazine hydrate, hydrazine monohydrochloride, hydrazine dihydrochloride or hydrazine sulfate.
10. The process according to claim 1 or 9, characterized in that the molar ratio of hydrazine compound to intermediate III in step S-6 is 1.5: 1-1: 1.
11. the process of claim 1, wherein the solvent in step S-8 is one or more of methyl tert-butyl ether, tetrahydrofuran, and water.
12. The process according to claim 1 or 11, wherein the volume ratio of solvent to intermediate IV in step S-8 is 10: 1-2: 1.
13. the process according to claim 1, wherein the molar ratio of sodium hydroxide to intermediate IV in step S-8 is 5: 1-1: 1.
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Correction item: Applicant|Address|Applicant Correct: Aoruite Pharmaceutical (Tianjin) Co.,Ltd.|300457 19 Haixing street, Tianjin Economic and Technological Development Zone|AURISCO PHARMACEUTICAL CO.,LTD. False: Aoruite Pharmaceutical (Tianjin) Co.,Ltd.|300457 19 Haixing street, Tianjin Economic and Technological Development Zone|AURISCO PHARMACEUTICAL CO.,LTD. Number: 20-01 Volume: 36 Correction item: Applicant|Address|Applicant Correct: Aoruite Pharmaceutical (Tianjin) Co.,Ltd.|300457 19 Haixing street, Tianjin Economic and Technological Development Zone|AURISCO PHARMACEUTICAL CO.,LTD. False: Aoruite Pharmaceutical (Tianjin) Co.,Ltd.|300457 19 Haixing street, Tianjin Economic and Technological Development Zone|AURISCO PHARMACEUTICAL CO.,LTD. Number: 20-01 Page: The title page Volume: 36 |
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