CN114380747A - Synthetic method of 3-acetyl pyrazole - Google Patents
Synthetic method of 3-acetyl pyrazole Download PDFInfo
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- CN114380747A CN114380747A CN202111419126.9A CN202111419126A CN114380747A CN 114380747 A CN114380747 A CN 114380747A CN 202111419126 A CN202111419126 A CN 202111419126A CN 114380747 A CN114380747 A CN 114380747A
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- BHTZCIGVYSJBQB-UHFFFAOYSA-N 1-(1h-pyrazol-5-yl)ethanone Chemical compound CC(=O)C=1C=CNN=1 BHTZCIGVYSJBQB-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000010189 synthetic method Methods 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 29
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 12
- KOPFEFZSAMLEHK-UHFFFAOYSA-N 1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1C=CNN=1 KOPFEFZSAMLEHK-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000002252 acyl group Chemical group 0.000 claims abstract description 5
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 28
- 239000000243 solution Substances 0.000 claims description 26
- 229940125782 compound 2 Drugs 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 229940126214 compound 3 Drugs 0.000 claims description 18
- 230000002194 synthesizing effect Effects 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 229940125904 compound 1 Drugs 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 10
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 150000001263 acyl chlorides Chemical class 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 239000006227 byproduct Substances 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000006114 decarboxylation reaction Methods 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 230000010933 acylation Effects 0.000 abstract 2
- 238000005917 acylation reaction Methods 0.000 abstract 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 238000011403 purification operation Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 6
- -1 pyrazole acetyl compound Chemical class 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical compound CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 101710186725 2-acylglycerol O-acyltransferase 2 Proteins 0.000 description 1
- 102100024296 Alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase Human genes 0.000 description 1
- 102100038354 Metabotropic glutamate receptor 4 Human genes 0.000 description 1
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 description 1
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 101000938686 Rattus norvegicus Carboxylesterase 1C Proteins 0.000 description 1
- BOGSOFADOWIECK-UHFFFAOYSA-N [N].C=1C=NNC=1 Chemical compound [N].C=1C=NNC=1 BOGSOFADOWIECK-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 208000028299 esophageal disease Diseases 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 108010038422 metabotropic glutamate receptor 4 Proteins 0.000 description 1
- 150000002759 monoacylglycerols Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940126027 positive allosteric modulator Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
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Abstract
The invention discloses a synthesis method of 3-acetyl pyrazole, and relates to the field of organic synthesis. The invention takes pyrazole-3-formic acid as raw material, and the target compound 3-acetyl pyrazole is obtained through the steps of acyl chlorination, acylation and decarboxylation; in the acylation step, the pyridine base is added, so that the reaction by-product can be effectively converted into a target compound, the reaction yield is improved, and the purification operation is simplified; meanwhile, the method is simple and convenient to operate and treat, mild in reaction conditions, energy-saving and environment-friendly, high in comprehensive yield and safer, and is a technological synthesis route which has high cost performance and is suitable for industrial large-scale production.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a method for synthesizing 3-acetyl pyrazole.
Background
The 3-acetyl pyrazole is a special heterocyclic compound, can be used as a key active molecular building block to participate in the preparation of a metabotropic glutamate receptor subtype 4(mGluR4 receptor) positive allosteric modulator, is used for treating gastroesophageal reflux disease, lower esophageal disease and gastrointestinal tract disease, and relieves the pain of patients; it is also a key intermediate in the preparation of monoacylglycerol esterase 2(MGAT2) inhibitors for the treatment of obesity and type ii diabetes caused by metabolic disorders.
With respect to the synthesis of 3-acetylpyrazole, the prior art reports a lot, and the three are mainly as follows (1) a direct ring closing strategy is adopted: 3-alkynyl-2-butanone reacts with trimethylsilylated diazomethane or diazomethane to obtain 3-acetyl pyrazole, the price of the raw materials used in the method is high, the needed solvent is an ether solvent, and the method has high danger and high cost and is not suitable for popularization [ Organic Letters,2019, vol.21, #22, p.8957-8961], WO20126760[ Journal of physiological Organic Chemistry, 2002, vol.15, #5, p.247-257 ]; (2) adopting an amino protection strategy: pyrazole-3-carboxylic acid is amidated by weinreb, protected by Boc, and then reacts with a lattice reagent to obtain 3-acetylpyrazole, the method needs complicated group protection steps, each step needs column chromatography purification, the cost of a solvent is higher, the lattice 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) the carbonyl protection strategy is adopted: the method uses butanedione and hydrazine as raw materials of tube products, has high danger, also undergoes complicated group protection steps, is difficult in intermediate purification, and directly and continuously puts the crude intermediate which is not purified, so that the yield of the final product is obviously reduced, the production cost is increased, and the method is not suitable for large-scale process amplification. Different from the prior art, the invention provides a novel method for synthesizing the nitrogen-unsubstituted 3-acetylpyrazole, which has the advantages of no complicated and fussy group protection step, simple and convenient operation, safe process and good purity and yield of the final product, and has a certain technical inspiration effect on the synthesis of the nitrogen-unsubstituted pyrazole acetyl compound by the technical personnel in the field.
Disclosure of Invention
The present invention aims to provide a method for synthesizing 3-acetylpyrazole, which solves the problems in the background art.
A method for synthesizing 3-acetylpyrazole, wherein the method for synthesizing the 3-acetylpyrazole comprises the following steps of:
preferably, the compound 1 is pyrazole-3-carboxylic acid; the compound 4 is 3-acetyl pyrazole.
Preferably, the synthesis method of the 3-acetylpyrazole comprises the following specific steps:
(1) dissolving a compound 1 in a solvent 1, wherein the ratio of the solvent 1 to the compound 1 is 5-15 mL/g, dropwise adding N, N-dimethylformamide at a rate of 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 a rate of 3-10 mL/min at room temperature, and the molar ratio of the compound 1 to an 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 base to prepare a reaction solution 1, dissolving a crude product compound 2 in a solvent 3, wherein the ratio of the solvent 3 to the crude product compound 2 is 2-4 mL/g, and preparing a reaction solution 2; dropwise adding the reaction solution 2 into the reaction solution 1 at a rate 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 15-30 ℃ for 0.5-2 h to obtain a compound 3;
(3) and (3) blending 5-15% by mass of an alkali 2 aqueous solution with the compound 3, and reacting at 50-100 ℃ for 10-12 h to obtain a compound 4.
Preferably, in the step (1): the solvent 1 is one or more of dichloromethane, 1, 2-dichloroethane and toluene; the acyl chlorination 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-pyrrolidinylpyridine, 4-dimethylaminopyridine and 2, 6-dimethylpyridine.
Preferably, in the step (2): the molar ratio of the crude compound 2 to the anhydrous magnesium chloride, diethyl malonate, alkali 1 and pyridine base 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 synthetic method of 3-acetyl pyrazole, which is different from a group protection strategy adopted in the prior art and has a certain technical inspiration effect on the synthesis of a pyrazole acetyl compound unsubstituted on nitrogen by a person skilled in the art; the main synthesis steps are as follows: pyrazole-3-formic acid is used as a raw material, and is subjected to acyl chlorination without group protection to prepare a compound 2; acylating the compound 2 with dimethyl malonate to obtain a compound 3; decarboxylation of the compound 3 with strong base to obtain 3-acetyl pyrazole.
Firstly, because no substituent exists on pyrazole nitrogen and an active site exists, in the actual preparation, more byproduct 1- (1H-pyrazole-3-carbonyl) -1H-pyrazole-3-carbonyl chloride is detected to be generated in the step of preparing the compound 2, the impurity is directly and continuously added, and the byproduct 2- (1- (1H-pyrazole-3-carbonyl) -1H-pyrazole-3-carbonyl) dimethyl malonate is correspondingly generated in the step of preparing the compound 3, so that the impurities are increased in the reaction, the product is difficult to purify, and the reaction yield is low; in the step of preparing the compound 3, pyridine base is added, so that a byproduct 1- (1H-pyrazole-3-carbonyl) -1H-pyrazole-3-carbonyl chloride can be decomposed in a reaction liquid, reacts with dimethyl malonate to generate a target intermediate 2- (1H-pyrazole-3-carbonyl) dimethyl malonate, and can be further converted into a final product 3-acetylpyrazole, and the yield and the purity of the final product are improved.
And simultaneously, because the decarboxylation is carried out in the third step, a strong alkaline aqueous solution is adopted, impurities such as salts and the like generated in the continuous feeding process can be completely dissolved, after the intermediate conversion is finished, a target product does not need to be purified, and the target product can be directly extracted by an organic solvent, so that the pure product 3-acetylpyrazole can be obtained and is easy to carry out industrial expanded production of the 3-acetylpyrazole.
Drawings
Figure 1 is a nuclear magnetic spectrum of compound 4.
Detailed Description
The technical solutions in 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 of the specification, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
A method for synthesizing 3-acetyl pyrazole:
(1) dissolving compound 1(600g, 5.36mol, 1eq) in 6L of dichloromethane, adding 60mL of anhydrous N, N-dimethylformamide dropwise at 2mL/min, adding oxalyl chloride (1.7kg, 13.39mol, 2.5eq) dropwise at 9.5mL/min at 15 ℃, reacting for 10h at 15 ℃, and distilling under reduced pressure to remove the solvent to obtain 700g of crude compound 2;
(2) dissolving anhydrous magnesium chloride (567g, 5.97mol, 1.11eq), dimethyl malonate (1.16kg, 7.24mol, 1.35eq) and triethylamine (1.63kg, 16.11mol, 3eq) in 5L of acetonitrile at 0 ℃, reacting for 0.5h at 15 ℃, adding 4-pyrrolidinyl pyridine (200g, 1.35mol, 0.25eq) and stirring uniformly to obtain a reaction solution 1, and dissolving a crude compound 2(700g) in 2L of acetonitrile to obtain a reaction solution 2; dropwise adding the reaction solution 2 into the reaction solution 1 at a rate of 15mL/min, reacting at 15 ℃ for 1h, filtering, concentrating the filtrate under reduced pressure, and drying by an oil pump to obtain 1.21kg of a compound 3;
(3) sodium hydroxide (1.1kg, 27.5mmol, 5eq) was dissolved in 9L of water, compound 3(1.21kg) was added, the reaction was heated at 100 ℃ for 10h, cooled to room temperature, and the pH was adjusted to 10 with hydrochloric acid, extracted with ethyl acetate 3 times, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, and petroleum ether was added and slurried to give 506g of compound 4.
Example 2
A method for synthesizing 3-acetyl pyrazole:
(1) dissolving the compound 1(60g, 0.54mol, 1eq) in 600mL of dichloromethane, dropwise adding 6mL of anhydrous N-N, dimethylformamide at 3mL/min, dropwise adding thionyl chloride (162.5g, 1.37mol, 2.5eq) at 4mL/min at 20 ℃, reacting for 11h under heat preservation, and distilling under reduced pressure to remove the solvent to obtain 75g of a crude compound 2;
(2) dissolving anhydrous magnesium chloride (57.0g, 0.60mol, 1.1eq), dimethyl malonate (116.80g, 7.24mol, 1.35eq) and triethylamine (160g, 1.6mol, 3eq) in 500mL of acetonitrile at 0 ℃, reacting for 0.5h at 20 ℃, adding 4-pyrrolidinylpyridine (8g, 54mmol, 0.10eq) and uniformly stirring to obtain a reaction solution 1, and dissolving a crude compound 2(75g) in 200mL of acetonitrile to obtain a reaction solution 2; dropwise adding the reaction solution 2 into the reaction solution 1 at a rate of 8mL/min, reacting at 20 ℃ for 1h, filtering, concentrating the filtrate under reduced pressure, and drying by an oil pump to obtain 130g of a compound 3;
(3) dissolving sodium hydroxide (110g,2.75mol, 5eq) in 900mL of water, adding compound 3(130g), heating to react at 90 ℃ for 11h, cooling to room temperature, adjusting pH to 11 with hydrochloric acid, extracting with ethyl acetate for 3 times, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove the solvent, adding petroleum ether, and pulping to obtain 41.2g of compound 4.
Example 3
A method for synthesizing 3-acetyl pyrazole:
(1) dissolving the compound 1(60.4g, 0.54mol, 1eq) in 600mL of dichloromethane, dropwise adding 6mL of anhydrous N-N, dimethylformamide at 3mL/min, dropwise adding thionyl chloride (139.6g,1.10mol, 2.0eq) at 4mL/min at 25 ℃, reacting for 12 hours under the condition of heat preservation, and distilling under reduced pressure to remove the solvent to obtain 68.8g of a crude compound 2;
(2) dissolving anhydrous magnesium chloride (57.0g, 0.60mol, 1.1eq), dimethyl malonate (117.0g, 7.30mol, 1.35eq) and triethylamine (160.3g, 1.6mol, 3eq) in 500mL of acetonitrile at 0 ℃, reacting for 0.5h at 25 ℃, adding 4-pyrrolidinylpyridine (40g, 27mmol, 0.50eq) and uniformly stirring to prepare a reaction solution 1, and dissolving a crude compound 2(68.8g) in 200mL of acetonitrile to prepare a reaction solution 2; dropwise adding the reaction solution 2 into the reaction solution 1 at a rate of 8mL/min, reacting at 25 ℃ for 1h, filtering, concentrating the filtrate under reduced pressure, and drying by an oil pump to obtain 125g of a compound 3;
(3) dissolving sodium hydroxide (110g,2.75mol, 5eq) in 900mL of water, adding compound 3(125g), heating at 100 ℃ for reaction for 12h, cooling to room temperature, adjusting the pH of the reaction solution to 11 with hydrochloric acid, extracting with ethyl acetate for 3 times, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove the solvent, adding petroleum ether, and pulping to obtain 47.45g of compound 4.
Comparative example 1
A method for synthesizing 3-acetyl pyrazole:
(1) dissolving 60.3g of compound 1(1eq) in 600mL of dichloromethane, dropwise adding 6mL of anhydrous N-N, dimethylformamide at 2mL/min, dropwise adding 169.5g of oxalyl chloride (2.5eq) at 3mL/min at 20 ℃, reacting for 11h under the condition of heat preservation, and distilling under reduced pressure to obtain 72g of crude compound 2;
(2) dissolving 57.3g of anhydrous magnesium chloride (1.11eq), 96.4g of dimethyl malonate (1.35eq) and 160g of triethylamine (3eq) in 500mL of acetonitrile at 0 ℃, reacting for 0.5h at 20 ℃ to obtain a reaction solution 1, dissolving 72g of a crude compound 2(1eq) 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 101g of a compound 3;
(3) 150.25g of potassium hydroxide (5eq) is dissolved in 100mL of water, 101g of crude compound 3(1 eq) is added, the mixture is heated and reacted at 100 ℃ for 11h, the reaction product is cooled to room temperature, the pH value is adjusted to 8 by hydrochloric acid, the mixture is extracted by ethyl acetate for 3 times, dried by anhydrous sodium sulfate, the solvent is removed by reduced pressure distillation, petroleum ether is added, and the mixture is pulped to obtain 25.83g of compound 4.
Examples of effects
Table 1 below gives the results of the analysis of the yield and purity of compound 4 using examples 1,2, 3 according to the invention and comparative example 1.
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 the experimental data of comparative example 1, it can be clearly found that in the method for synthesizing 3-acetylpyrazole in examples 1,2 and 3, pyrazole-3-formic acid with low price is used 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, is further decarboxylated to obtain a compound 4, and the acylated part is efficiently converted into a required intermediate by converting a reaction byproduct into a product by adding the pyridine base, so that the reaction yield is improved, the product purity is improved, and the complicated operations of protecting group loading and protecting group deprotection 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 attributes 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.
Claims (7)
1. The method for synthesizing the 3-acetylpyrazole is characterized by comprising the following steps of:
2. the method for synthesizing 3-acetylpyrazole according to claim 1, wherein the compound 1 is pyrazole-3-carboxylic acid; the compound 4 is 3-acetyl pyrazole.
3. The method for synthesizing 3-acetylpyrazole according to claim 2, wherein the method for synthesizing the 3-acetylpyrazole comprises the following specific steps:
(1) dissolving a compound 1 in a solvent 1, wherein the ratio of the solvent 1 to the compound 1 is 5-15 mL/g, dropwise adding N, N-dimethylformamide at a rate of 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 a rate of 3-10 mL/min at room temperature, and the molar ratio of the compound 1 to an 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 base to prepare a reaction solution 1, dissolving a crude product compound 2 in a solvent 3, wherein the ratio of the solvent 3 to the crude product compound 2 is 2-4 mL/g, and preparing a reaction solution 2; dropwise adding the reaction solution 2 into the reaction solution 1 at a rate 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 15-30 ℃ for 0.5-2 h to obtain a compound 3;
(3) and (3) blending 5-15% by mass of an alkali 2 aqueous solution with the compound 3, and reacting at 50-100 ℃ for 10-12 h to obtain a compound 4.
4. The process for synthesizing 3-acetylpyrazole according to claim 3, wherein in the step (1): the solvent 1 is one or more of dichloromethane, 1, 2-dichloroethane and toluene; the acyl chlorination reagent is one or more of thionyl chloride, phosgene and oxalyl chloride.
5. The process for synthesizing 3-acetylpyrazole according to claim 3, wherein 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-pyrrolidinylpyridine, 4-dimethylaminopyridine and 2, 6-dimethylpyridine.
6. The process for synthesizing 3-acetylpyrazole according to claim 3, wherein in the step (2): the molar ratio of the crude compound 2 to the anhydrous magnesium chloride, diethyl malonate, alkali 1 and pyridine base is 1: (1-1.3): (1.1-1.5): (2-5): (0.1-0.5).
7. The process for synthesizing 3-acetylpyrazole according to claim 3, wherein 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).
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