Background
The 3-acetyl pyrazole is a special heterocyclic compound which can be used as a key active molecular block to participate in the preparation of positive allosteric modulators of metabotropic glutamate receptor subtype 4 (mGluR 4 receptor) for treating gastroesophageal reflux disease, lower-stage esophageal disease and gastrointestinal tract disease and relieving pain of patients; at the same time, it is also a key intermediate for preparing monoacylglyceroyl esterase 2 (MGAT 2) inhibitor, which is used for treating obesity and type II diabetes caused by metabolic disorder.
Regarding the synthesis of 3-acetylpyrazoles, there are many reports in the prior art, mainly three of (1) using a direct-splice ring strategy: the 3-alkynyl-2-butanone reacts with trimethyl silanized diazomethane or diazomethane to obtain 3-acetyl pyrazole, the method has the advantages that the price of the raw materials is higher, the required solvent is diethyl ether solvent, the danger is high and the cost is high when the large-scale production is enlarged, and the method is not suitable for popularization [ Organic Letters,2019, vol.21, #22, p.8957-8961], WO20126760[ Journal of pHysical Organic Chemistry, 2002, vol.15, #5, p.247-257]; (2) employing an amino protection strategy: the pyrazole-3-carboxylic acid is amidated by weinreb, protected by Boc and then reacted with a format reagent to obtain 3-acetyl pyrazole, the method needs complicated group protection steps, each step needs column chromatography purification, the solvent cost is high, the lattice test reaction needs ultralow temperature conditions, the operation is complicated, the energy consumption is high, the reaction yield is low, and the application of the method is limited [ ACS Medicinal Chemistry Letters,2020, vol.11, #7, p.1476-1483], [ [ PLoS ONE, 2016, vol.11, #5, art. No. E0155209]; (3) employing a carbonyl protection strategy: the 2, 3-butanedione is connected with a protecting group under an acidic condition, then is subjected to condensation reaction with DMF-DMA, and then is subjected to condensation cyclization with hydrazine to obtain the 3-acetyl pyrazole. Compared with the prior art, the invention provides a novel method for synthesizing the nitrogen-unsubstituted 3-acetyl pyrazole, which has the advantages of no complex and complicated group protection steps, simple and convenient operation, safe process, good purity and yield of the final product, and certain technical enlightenment effect on the synthesis of nitrogen-unsubstituted pyrazole acetyl compounds by the technicians in the field.
Disclosure of Invention
The invention aims to provide a synthesis method of 3-acetyl pyrazole, which aims to solve the problems in the background technology.
A synthesis method of 3-acetyl pyrazole, wherein the synthesis method of 3-acetyl pyrazole comprises the following steps of compound 1, compound 2, compound 3 and compound 4:
preferably, the compound 1 is pyrazole-3-carboxylic acid; the compound 4 is 3-acetyl pyrazole.
Preferably, the synthesis method of the 3-acetyl pyrazole comprises the following specific steps:
(1) Dissolving a compound 1 in the solvent 1, wherein the ratio of the solvent 1 to the compound 1 is 5-15 mL/g, dropwise adding N, N-dimethylformamide at 2-3 mL/min, wherein the ratio of the N, N-dimethylformamide to the compound 1 is 0.1mL/g, dropwise adding acyl chloride at 3-10 mL/min at room temperature, and the molar ratio of the compound 1 to the acyl chloride reagent is 1: (1-5) reacting for 10-12 h at 15-30 ℃ to obtain a crude compound 2;
(2) Dissolving anhydrous magnesium chloride, dimethyl malonate and alkali 1 in a solvent 2, adding pyridine alkali to prepare a reaction solution 1, dissolving a crude compound 2 in a solvent 3, and preparing the reaction solution 2, wherein the ratio of the solvent 3 to the crude compound 2 is 2-4 mL/g; dropwise adding the reaction solution 2 into the reaction solution 1 at the concentration of 8-15 mL/min, wherein the ratio of the solvent 2 to the crude compound 2 is 5-10 mL/g, and reacting at the temperature of 15-30 ℃ for 0.5-2 h to obtain a compound 3;
(3) Mixing 5-15% alkali 2 water solution with compound 3, reacting at 50-100 deg.c for 10-12 hr to obtain compound 4.
Preferably, in the step (1): the solvent 1 is one or more of dichloromethane, 1, 2-dichloroethane and toluene; the acyl chloride reagent is one or more of thionyl chloride, phosgene and oxalyl chloride.
Preferably, in the step (2): the alkali 1 is one or more of triethylamine, pyridine, N-diisopropylethylamine, potassium carbonate and sodium carbonate; the solvent 2 is one or more of acetonitrile, N-dimethylformamide, dichloromethane, 1, 2-dichloroethane and tetrahydrofuran; the solvent 3 is one or more of acetonitrile, N-dimethylformamide, dichloromethane, 1, 2-dichloroethane and tetrahydrofuran; the pyridine base is one or more of 4-pyrrolidinyl pyridine, 4-dimethylamino pyridine and 2, 6-dimethyl pyridine.
Preferably, in the step (2): the molar ratio of the crude compound 2 to anhydrous magnesium chloride, diethyl malonate, alkali 1 and pyridine alkali is 1: (1-1.3): (1.1-1.5): (2-5): (0.1-0.5).
Preferably, in the step (3): the alkali 2 is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; the molar ratio of compound 3 to base 2 is 1: (3-6).
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a synthesis method of 3-acetyl pyrazole, which is different from the group protection strategy adopted in the prior art, and has a certain technical teaching effect on synthesizing a pyrazole acetyl compound without substitution on nitrogen by a person skilled in the art; the main synthesis steps are as follows: pyrazole-3-formic acid is taken as a raw material, and is subjected to acyl chlorination without radical protection to prepare a compound 2; acylating the compound 2 with dimethyl malonate to obtain a compound 3; decarboxylation of compound 3 by strong base gives 3-acetyl pyrazole.
Firstly, as no substituent exists on pyrazole nitrogen and an active site exists, in the actual preparation, more byproducts 1- (1H-pyrazole-3-carbonyl) -1H-pyrazole-3-carbonyl chloride are detected to be generated in the step of preparing the compound 2, the byproducts are directly added without purification, and in the step of preparing the compound 3, the byproduct 2- (1- (1H-pyrazole-3-carbonyl) -1H-pyrazole-3-carbonyl) dimethyl malonate is correspondingly generated, so that impurities are increased in the reaction, the product is difficult to purify, and the reaction yield is lower; in the step of preparing the compound 3, pyridine base is added, and a byproduct 1- (1H-pyrazole-3-carbonyl) -1H-pyrazole-3-carbonyl chloride can be decomposed in a reaction liquid, react with dimethyl malonate to generate a target intermediate dimethyl 2- (1H-pyrazole-3-carbonyl) malonate, and can be further converted into a final product 3-acetyl pyrazole, so that the yield and purity of the final product are improved.
And meanwhile, as the third step of decarboxylation is carried out, the impurities such as salts generated in the continuous casting process can be completely dissolved, and after the intermediate conversion is finished, the target product does not need to be purified and can be directly extracted by an organic solvent, so that the 3-acetyl pyrazole which is a pure product can be obtained easily for industrial expansion production of the 3-acetyl pyrazole.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention and the accompanying drawings, and it is obvious that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
A synthesis method of 3-acetyl pyrazole comprises the following steps:
(1) Compound 1 (600 g,5.36mol,1 eq) was dissolved in 6L of methylene chloride, 60mL of anhydrous N, N-dimethylformamide was added dropwise at 2mL/min, oxalyl chloride (1.7 kg,13.39mol,2.5 eq) was added dropwise at 9.5mL/min at 15℃and reacted at 15℃for 10 hours, and the solvent was distilled off under reduced pressure to give 700g of crude compound 2;
(2) Anhydrous magnesium chloride (567 g,5.97mol,1.11 eq), dimethyl malonate (1.16 kg,7.24mol,1.35 eq), triethylamine (1.63 kg,16.11mol,3 eq) were dissolved in 5L of acetonitrile at 0 ℃, reacted at 15 ℃ for 0.5h, 4-pyrrolidinylpyridine (200 g,1.35mol,0.25 eq) was added, and stirred uniformly to obtain a reaction solution 1, and crude compound 2 (700 g) was dissolved in 2L of acetonitrile to obtain a reaction solution 2; dropwise adding the reaction solution 2 into the reaction solution 1 at 15mL/min, reacting for 1h at 15 ℃, filtering, concentrating the filtrate under reduced pressure, and drying by an oil pump to obtain 1.21kg of a compound 3;
(3) Sodium hydroxide (1.1 kg,27.5mmol,5 eq) was dissolved in 9L of water, then compound 3 (1.21 kg) was added, the mixture was heated at 100℃for reaction for 10 hours, cooled to room temperature, and pH was adjusted to 10 with hydrochloric acid, extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, and distilled off under reduced pressure, and petroleum ether was added to pulp 506g of compound 4.
Example 2
A synthesis method of 3-acetyl pyrazole comprises the following steps:
(1) Compound 1 (60 g,0.54mol,1 eq) was dissolved in 600mL of methylene chloride, 6mL of anhydrous N-N, dimethylformamide was added dropwise at 3mL/min, thionyl chloride (162.5 g,1.37mol,2.5 eq) was added dropwise at 4mL/min at 20℃and reacted at a constant temperature for 11h, and the solvent was distilled off under reduced pressure to give 75g of crude compound 2;
(2) Anhydrous magnesium chloride (57.0 g,0.60mol,1.1 eq), dimethyl malonate (116.80 g,7.24mol,1.35 eq), triethylamine (160 g,1.6mol,3 eq) were dissolved in 500mL of acetonitrile at 0 ℃, reacted at 20 ℃ for 0.5h, 4-pyrrolidinylpyridine (8 g,54mmol,0.10 eq) was added and stirred uniformly to obtain a reaction solution 1, and crude compound 2 (75 g) was dissolved in 200mL of acetonitrile to obtain a reaction solution 2; dropwise adding the reaction solution 2 into the reaction solution 1 at 8mL/min, reacting for 1h at 20 ℃, filtering, concentrating the filtrate under reduced pressure, and drying by an oil pump to obtain 130g of compound 3;
(3) Sodium hydroxide (110 g,2.75mol,5 eq) was dissolved in 900mL of water, then compound 3 (130 g) was added, the mixture was heated at 90℃for reaction for 11h, cooled to room temperature, pH was adjusted to 11 with hydrochloric acid, extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, distilled off under reduced pressure, and slurried with petroleum ether to give 41.2g of compound 4.
Example 3
A synthesis method of 3-acetyl pyrazole comprises the following steps:
(1) Compound 1 (60.4 g,0.54mol,1 eq) was dissolved in 600mL of methylene chloride, 6mL of anhydrous N-N, dimethylformamide was added dropwise at 3mL/min, thionyl chloride (139.6 g,1.10mol,2.0 eq) was added dropwise at 4mL/min at 25℃and reacted under heat preservation for 12 hours, and the solvent was distilled off under reduced pressure to give 68.8g of crude compound 2;
(2) Anhydrous magnesium chloride (57.0 g,0.60mol,1.1 eq), dimethyl malonate (117.0 g,7.30mol,1.35 eq), triethylamine (160.3 g,1.6mol,3 eq) were dissolved in 500mL of acetonitrile at 0 ℃, reacted at 25 ℃ for 0.5h, 4-pyrrolidinylpyridine (40 g,27mmol,0.50 eq) was added, and stirred uniformly to obtain a reaction solution 1, and crude compound 2 (68.8 g) was dissolved in 200mL of acetonitrile to obtain a reaction solution 2; dropwise adding the reaction solution 2 into the reaction solution 1 at 8mL/min, reacting for 1h at 25 ℃, filtering, concentrating the filtrate under reduced pressure, and drying by an oil pump to obtain 125g of compound 3;
(3) Sodium hydroxide (110 g,2.75mol,5 eq) was dissolved in 900mL of water, then compound 3 (125 g) was added, the reaction was heated at 100 ℃ for 12h, cooled to room temperature, the reaction solution was adjusted to pH 11 with hydrochloric acid, extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, distilled off the solvent under reduced pressure, and slurried with petroleum ether to give 47.45g of compound 4.
Comparative example 1
A synthesis method of 3-acetyl pyrazole comprises the following steps:
(1) 60.3g of Compound 1 (1 eq) was dissolved in 600mL of methylene chloride, 6mL of anhydrous N-N, dimethylformamide was added dropwise at 2mL/min, 169.5g of oxalyl chloride (2.5 eq) was added dropwise at 3mL/min at 20℃and reacted under heat preservation for 11h, and 72g of crude Compound 2 was obtained by distillation under reduced pressure;
(2) 57.3g of anhydrous magnesium chloride (1.11 eq), 96.4g of dimethyl malonate (1.35 eq), 160g of triethylamine (3 eq) are dissolved in 500mL of acetonitrile at 0 ℃ to react for 0.5h to obtain a reaction liquid 1, 72g of crude compound 2 (1 eq) is dissolved in 200mL of acetonitrile to obtain a reaction liquid 2, the reaction liquid 2 is dropwise added into the reaction liquid 1 at 8mL/min, the reaction is carried out for 1h at 25 ℃, the filtration and the concentration of the filtrate under reduced pressure are carried out, and the oil pump is pulled to dryness to obtain 101g of compound 3;
(3) 150.25g of potassium hydroxide (5 eq) was dissolved in 100mL of water, 101g of crude compound 3 (1 eq) was added, the mixture was heated at 100℃for reaction for 11h, cooled to room temperature, pH was adjusted to 8 with hydrochloric acid, extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, distilled off under reduced pressure, and slurried with petroleum ether to give 25.83g of compound 4.
Effect example
The following table 1 gives the results of analyses of the yields and purities of compound 4 in examples 1,2, 3 and comparative example 1 according to the present invention.
TABLE 1
| Compound 4 | Purity (%) | Yield (%) |
| Example 1 | 99 | 85 |
| Example 2 | 93 | 65 |
| Example 3 | 94 | 75 |
| Comparative example 1 | 89 | 39 |
Comparing the experimental data of examples 1,2 and 3 with those of comparative example 1, it is obvious that in the method for synthesizing 3-acetyl pyrazole in examples 1,2 and 3, the cheap pyrazole-3-formic acid is taken as a raw material, is not protected by a functional group, is directly subjected to acyl chlorination, is acylated in the presence of pyridine base, and is further decarboxylated to obtain a compound 4, and the acylated part is used for efficiently converting a reaction byproduct into a required intermediate and further into a product through the addition of pyridine base, so that the reaction yield is improved, the purity of the product is improved, and complicated operations of protecting groups and removing protecting groups are avoided in the synthesis process.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.