CN105218448B - A kind of synthetic method of the pyrazole carboxylic acid of 1 methyl, 3 difluoromethyl 4 - Google Patents
A kind of synthetic method of the pyrazole carboxylic acid of 1 methyl, 3 difluoromethyl 4 Download PDFInfo
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Abstract
The invention discloses a kind of synthetic method of the pyrazole carboxylic acid of 1 methyl, 3 difluoromethyl 4, it is related to a kind of synthetic method of fine-chemical intermediate, this method includes following four step：Step 1：Using dichloroacetyl ethyl acetate as raw material, obtained (IV) with Vilsmeier reagent reactings under alkali effect；Step 2：Intermediate (IV) carries out ring-closure reaction with methyl hydrazine and obtains the pyrazole carboxylic acid ethyl ester (V) of 1 methyl, 3 dichloromethyl 4；Step 3：Intermediate (V) carries out halogen exchange reaction with fluorination reagent and obtains the pyrazole carboxylic acid ethyl ester (VI) of 1 methyl, 3 difluoromethyl 4；Step 4：Intermediate (VI) that step 3 is obtained and sodium hydroxide solution hydrolysis, then obtain with acid neutralisation treatment the pyrazole carboxylic acid (I) of 1 methyl, 3 difluoromethyl 4 of high-purity.This method raw material is easily purchased, cheap, and preparation method is simple, and reaction condition is gentle, low for equipment requirements, suitable industrialized production.
Description
Technical field
The present invention relates to a kind of synthetic method of fine-chemical intermediate, specifically 1- methyl -3- difluoromethyls -4- pyrazoles
The synthetic method of formic acid.
Background technology
1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids (as shown in formula (I)), English name is 3-
(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid；Molecular weight is 176.12；CAS:
176969-34-9；Structural formula is shown in formula I：
The compound is bactericide fluorine azoles ring bacterium amine (sedaxane), isopyrazam (isopyrazam), benzo alkene fluorine
The active compounds such as bacterium azoles (benzovindiflupyr), biphenyl pyrrole bacterium amine (bixafen) and fluxapyroxad (fluxapyroxad)
Key intermediate.Fluorine-containing pyrazolecarboxamide series bactericidal agent is the class new type bactericide that developed recently gets up, swarm listing, gesture
It is powerful, have become the new focus of bactericide research and development.For example Sumitomo Chemical Co discloses in WO2013186325A1
It is a kind of it is new grinding bactericide, its structure is as follows：
So 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids have the very big market demand.Closed described in the disclosed invention
Have the advantages that cost is low, easy to operate, product purity is high into technique.
At present, the synthetic route of 1- methyl -3- difluoromethyls -4- pyrazole carboxylic acids mainly has following several：
1st, (BASF European Co., Ltd synthesizes the pyrazoles of 1,3,4- substitutions by CN201480000575.1 and CN102015654
The method of compound) and CN101959840 (BASF European Co., Ltd) patent in a kind of industrialized synthetic method for providing, with
Difluoro ethyl acetoacetate, acetic anhydride, triethyl orthoformate, methyl hydrazine are raw material, and three-step reaction synthesis obtains 1- methyl -3- two
Methyl fluoride -4- pyrazole carboxylic acids；The price for the raw material difluoro ethyl acetoacetate that the technique is used is very expensive, and cost is higher.Specifically
Route is described as follows：
2nd, CN103570623 (Hunan Chemical Research Institute), CN200880022057.4 (first just reaching) and US7358387 (are visitd
Ear) with N, N- dimethylaminos ethyl acrylate is raw material, first reacts with difluoroacetic acid chloride and generates 2- difluoro acetyl group -3- (diformazans
Amino) ethyl acrylate, then with methylated after hydrazine hydrate cyclization using dimethyl suflfate, finally hydrolysis obtain 1- methyl-
3- difluoromethyl -4- pyrazole carboxylic acids, overall yield of reaction is 54.6%, and route is longer, and industrialization cost is high.Specific route description is such as
Under：
3rd, the patent such as CN201410408225.02 and WO2008102678 (Mitsui Chemicals AGRO Co., Ltd) is with diformazan ammonia
Base acrylonitrile is raw material, first reacts with difluoroacetic acid chloride and generates 2- difluoro acetyl group -3- (dimethylamino) acrylonitrile, then and methyl
Hydrazine cyclization, finally hydrolysis obtains 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids, and overall yield of reaction is 65%.The shortcoming of the route
It is using the difluoroacetic acid chloride that toxicity is big, price is high.Specific route is described as follows：
The content of the invention
The present invention is directed to problems of the prior art, it is therefore an objective to provide a kind of reasonable technological design, high income, reaction
Mild condition, low in raw material price, are adapted to the synthetic method of industrialized 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids.
The technical scheme is that：
Using cheap dichloroacetyl ethyl acetate as raw material, first generated under alkali effect such as formula (II) dichloroacetyl
The salt of ethyl acetate, then in organic solvent with such as the Vilsmimer reagents of formula (III), reaction is obtained as shown in formula (IV)
2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate；
Toluene equal solvent is dissolved in again, at -80~40 DEG C, methyl hydrazine solution is added dropwise, reaction terminates post processing and obtained
Such as the 1- methyl -3- dichloromethyl -4- pyrazole carboxylic acid ethyl esters of formula (V)；
1- methyl -3- dichloromethyl -4- pyrazole carboxylic acids ethyl esters (V) and fluorination reagent are subjected to halogen exchange reaction and obtain 1-
Methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI)；
Reaction finally is hydrolyzed in intermediate (VI) and sodium hydroxide solution, then high-purity is obtained with sour neutralisation treatment
1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids (I)；
The route advantage is that the high difluoroacetic acid chloride of price is instead of with dichloroacetyl ethyl acetate, with high income, original
Material cost is low, the advantage that annulation regioselectivity is good and finished product purity is high.
Specific route is as follows：
Step 1：Synthesis on 2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate (IV) is described as follows：It is existing
Technology all be using dichloroacetyl chloride and N, N- dimethylamino ethyl acrylate reaction obtain, the patent of such as Bayer
US7358387 is described.We are dissolved in toluene using dichloroacetyl ethyl acetate cheap and easy to get, are generated under alkali effect such as formula
(II) salt of dichloroacetyl ethyl acetate, then obtained with the Vilsmeier reagent reactings such as formula (III) as shown in formula (IV)
2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate；
Compound (IV) is obtained, route is described as follows：
Wherein as formula (III) Vilsmeier reagents synthesis according to routine techniques by DMF and thionyl chloride, tri-chlorination
The reaction such as phosphorus, phosphorus pentachloride, phosgene, triphosgene, POCl3, oxalyl chloride is obtained.
Concretely comprise the following steps：
Dichloroacetyl ethyl acetate is dissolved in toluene, appropriate alkali is added, is cooled to 0-20 DEG C；Add 1 equivalent as
The Vilsmeier reagents of formula (III)；After reaction terminates, it is quenched with frozen water, stratification；Toluene is reclaimed in organic layer vacuum distillation,
Residue is directly used in next step reaction.
Wherein described alkali, can be sodium methoxide, caustic alcohol, sodium hydride, triethylamine etc., most preferably sodium hydride；Step
2：1- methyl -3- dichloromethyl -4- pyrazole carboxylic acids ethyl esters (V)
By step 1 obtain such as 2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate toluene solution of formula (IV), with
The reaction of methyl hydrazine solution reaction is obtained such as formula (V) 1- methyl -3- dichloromethyl -4- pyrazole carboxylic acid ethyl esters；Route is described as follows：
Wherein described solvent is non-protonic solvent, can select toluene, benzene, dichloromethane, petroleum ether, all kinds of alkane
Hydrocarbon, dimethylbenzene, hexamethylene, hexahydrotoluene etc., most preferred solvent are toluene；
Preferred range can be -80~40 DEG C, and preferred reaction temperature is -80~-40 DEG C.
Concretely comprise the following steps：
2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate (IV) is dissolved in toluene equal solvent, nitrogen protection declines
Methyl hydrazine solution is added dropwise at -60 DEG C in temperature, is reacted at -60 DEG C to terminating；It is warming up to room temperature and continues stirring reaction 2 hours, plus
Enter water stirring, stratification obtains the organic layer of product；Solvent is sloughed in organic layer decompression, obtains crude product；The crude product isopropyl ether
Crystallized, obtain isomers less than 1% such as the 1- methyl -3- dichloromethyl -4- pyrazole carboxylic acid ethyl esters of formula (V).
Step 3：1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI)
Tetrahedron Letters Volume 50 (2009), P3665-3668, which are disclosed, uses 1- methyl -3- dichloros
Methyl -4- pyrazole carboxylic acids ethyl ester (V) and TREAT-HF carry out the ins and outs of Finkelstein reactions.But used in document
TREAT-HF, price is very high, while finding that the product of hydrolysis is more, causes the yield of post processing there was only 69%.The present invention is used
Slightly excessive potassium fluoride and 1- methyl -3- dichloromethyl -4- pyrazole carboxylic acids ethyl esters (V) are in protonic solvent low-temp reaction, it is to avoid
The decomposition reactions such as open loop of the pyrazole ring under high temperature, strong acid and basic conditions, substantially increase product yield and quality.
The method that the present invention is used is the 1- methyl -3- dichloromethyl -4- pyrazoles as shown in formula (V) for obtaining step 2
Ethyl formate obtains the 1- methyl -3- difluoromethyl -4- pyrazoles as shown in formula (VI) with fluorination reagent progress halogen exchange reaction
Ethyl formate；
Route is described as follows：
Wherein described solvent is protonic solvent, can select DMF, formamide, acetamide, sulfolane, N, N- diformazans
Yl acetamide, DMSO etc., most preferred solvent are DMF；
Described reaction temperature can be 80-200 DEG C, more preferably 100-120 DEG C；
Wherein described fluorization agent is antimony fluoride, hydrogen fluoride, hydrogen fluoride/pyridine, triethylamine hydrogen fluoride, tri-n-butylamine fluorination
Hydrogen, most preferably potassium fluoride, triethylamine hydrogen fluoride.
Specific synthetic method is as follows：
1- methyl -3- dichloromethyl -4- pyrazole carboxylic acids ethyl esters (V) are dissolved in DMF equal solvents, the lower input fluorine of nitrogen protection
Change potassium, be warming up to 80-200 DEG C and react 3 hours；After reaction terminates, filtering, filtrate decompression sloughs solvent, obtained crude product 1- first
Base -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI)；Add water and toluene is post-processed, after toluene layer precipitation, residue is straight
Connect for next step hydrolysis.
Step 4：1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids (I)
1- methyl -3- difluoromethyls -4- pyrazole carboxylic acids the ethyl ester and sodium hydroxide as shown in formula (VI) that step 3 is obtained
Solution hydrolysis, then obtain with sour neutralisation treatment the 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids as shown in formula (I).
Route is described as follows：
Reaction dissolvent is a kind of in water, methanol, ethanol, propyl alcohol, butanol or wherein any two mixture；Reaction temperature
For 0-100 DEG C；The molar ratio of 1- methyl -3- difluoromethyls -4- pyrazole carboxylic acids ethyl ester and sodium hydroxide as shown in formula (VI)
1:1.0-1.5。
Preferably, described reaction temperature can be 0-100 DEG C, and preferred reaction temperature is 50-60 DEG C.
Concretely comprise the following steps：By 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI) and the molar ratio of sodium hydroxide
1:1.0-1.5, the amount of aqueous solvent is 3-5 times, and stirring is warming up to 50-70 DEG C of reaction to hydrolysis and terminated (typically about 2 hours)；Instead
It should terminate, hydrochloric acid regulation PH=1-2 is added dropwise at 40-50 DEG C, is stirred for 1 hour；Slowly it is cooled to 0-5 DEG C and filters consolidating for precipitation
Body, drying obtains the 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids (I) that purity is more than 99%.
Beneficial effect：
The high difluoroacetic acid chloride of price is instead of with dichloroacetyl ethyl acetate, with high income, cost of material be low, cyclization
The conversion zone selectively good and high advantage of finished product purity.
With cheap dichloroacetyl ethyl acetate, the Vilsmeier reagents such as formula (III), potassium fluoride, methyl hydrazine,
Sodium hydroxide, hydrochloric acid etc. are raw material, obtain the 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids (I) of high-purity.
Raw material of the present invention is simple and easy to get, and synthesis cost is low.
Synthetic operation of the present invention is easy, and high income, product isomers (1- methyl -5- difluoromethyl -4- pyrazole carboxylic acids) is small
In 1%, product quality is greatly improved.
Brief description of the drawings
Fig. 1 is the HPLC figures of the step 4 of embodiment 1
Fig. 2 is the H-NMR figures of the step 4 of embodiment 1
Embodiment
Scientific research personnel is will be helpful to by following examples of implementation and understands technical key point, but can not limit this hair
Bright content.
Embodiment 1
Step 1：The synthesis of 2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate (IV)
In 2L reaction bulb, input 100.12g dichloroacetyls ethyl acetate and 400g toluene are cooled to 0-10
DEG C, temperature in 20.56g 60% sodium hydride, control is added portionwise and is less than 50 DEG C, holding 1 hour is finished；It is cooled to 0-10 DEG C, plus
Enter the [(CH of 69.5g such as formulas (III)3)2N+=CHCl] Cl-
It is dissolved in 300g toluene solutions.At 15-25 DEG C, reaction 2 hours is kept.By reaction mass down to being quenched in frozen water
Go out, standing separates toluene layer.Toluene layer decompression is sloughed after the about 100g solvents of part, obtains 2- dichloro-acetyls -3- (diformazan ammonia
Base) ethyl acrylate (IV) toluene solution 800g (demarcation content be 13.40%, yield is 85%), to be directly used in next step.
[(CH3)2N+=CHCl] Cl-Prepared as follows：Put into 1L reaction bulb
26.50gDMF with 300g toluene；Stirring cools to 0-10 DEG C, and 43.02g thionyl chlorides about half an hour completion of dropping, control is added dropwise
0-5 DEG C of temperature, continues stirring half an hour standby.
Step 2：The synthesis of 1- methyl -3- dichloromethyl -4- pyrazole carboxylic acids ethyl esters (V)
In 2L reaction bulb, the toluene of input 2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate (IV)
Solution 798g (demarcation content is 13.40%)；, -60 DEG C are cooled under nitrogen protection, 18.60g methyl hydrazines are added dropwise and (are dissolved in
100g toluene)；Completion of dropwise addition, is kept for 2 hours at -60 DEG C.Then slowly return and warm to room temperature, and stir 2 hours.Reaction knot
Beam, adds 300g water, stirs 15min, and stratification, water layer is extracted once with 100g toluene；First is sloughed in combining methylbenzene layer, decompression
Benzene, obtained crude product is 88.45g, and yield is 82%.Crystallized by isopropyl ether, obtained product, isomers is less than 1%.
Step 3：The synthesis of 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI)
In 1L autoclave, input 23.75g 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI) and
Under the protection of solvent 200g DMF nitrogen, the potassium fluoride of 34.80g spray drying is added, it is small that stirring is warming up to 120-150 DEG C of reaction 6
When.Reaction end is cooled to room temperature, and desalination is removed in first filtering, and filtrate decompression sloughs solvent, and obtained residue adds toluene and water,
Stirring separates toluene layer；Toluene layer sloughs solvent, obtains 16.50g 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acid ethyl esters
(VI), yield is 79%.
Step 4：The synthesis of 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids (I)
20.41g 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI) are put into 500mL reaction bulb
With 5.00g sodium hydroxides and 150 milliliters of water, 60-70 DEG C, reaction to 1- methyl -3- difluoromethyl -4- pyrazoles are warming up under stirring
Ethyl formate (VI) is less than 0.5%；After reaction knot, at 40-50 DEG C, hydrochloric acid is added dropwise until pH=1-2, is stirred for more than 1 hour；
0-5 DEG C is slowly cooled to, white solid is filtered out, is dried under reduced pressure and obtains 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids (I)
15.30g, purity is 99.9%, and yield is 85%.
1H-NMR(DMSO,400MHz):3.88(3H,s,CH3),7.16(1H,t,CHF2),8.29(1H,s,pyrazole
H)。
The HPLC purity and H-NMR of product, are shown in accompanying drawing 1 and accompanying drawing 2.
The product of the present invention uses following HPLC testing conditions：
Attached condition of gradient elution：
| Time (min) | A% | B% |
| 0.01 | 80 | 20 |
| 2 | 80 | 20 |
| 10 | 60 | 40 |
| 12 | 60 | 40 |
| 28 | 25 | 75 |
| 35 | 25 | 75 |
| 36 | 80 | 20 |
| 45 | 80 | 20 |
Embodiment 2
Step 1：The synthesis of 2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate (IV)
In 2L reaction bulb, input 100g dichloroacetyls ethyl acetate and 400g dichloromethane are cooled to 0-10
DEG C, add [(CH3) 2N of 135g such as formulas (III)+=CHCl] [PO2Cl2]-It is dissolved in 300g dichloromethane solutions.At 15-25 DEG C
Under, keep reaction 2 small；80g triethylamines, about 1 hour are slowly added dropwise at 0-5 DEG C；Room temperature reaction 2 hours, adds water stirring,
Separate dichloromethane layer；Decompression precipitation obtains 2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate (IV) crude product 135g,
It is directly used in next step.
[(CH3)2N+=CHCl] [PO2Cl2]-Prepared as follows：Put into 1L reaction bulb
60.50g DMF and 300g dichloromethane；Stirring cools to 0-10 DEG C, and 85.55g phosphorus trichlorides about half an hour completion of dropping is added dropwise,
0-5 DEG C of temperature is controlled, continues stirring half an hour standby.
Step 2：The synthesis of 1- methyl -3- dichloromethyl -4- pyrazole carboxylic acids ethyl esters (V)
In 2L reaction bulb, add 2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate (IV) 135g and
400g toluene；, -80 DEG C are cooled under nitrogen protection, 18.62g methyl hydrazines (toluene for being dissolved in 100g) are added dropwise；Completion of dropwise addition,
Kept for 2 hours at -80 DEG C.Then slowly return and warm to room temperature, and stir 2 hours.Reaction terminates, and adds 300g water, stirring
15min, stratification, water layer is extracted once with 100g toluene；Toluene is sloughed in combining methylbenzene layer, decompression, and obtained crude product is
103.52g, yield is 82%.
Step 3：The synthesis of 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI)
In 1L reaction bulb, input 200g water and 62.53g potassium fluorides add 23.85g 1- methyl -3- two
Methyl fluoride -4- pyrazole carboxylic acids ethyl ester (VI), stirring is warming up to 120-130 DEG C and reacted 6 hours.Reaction end is cooled to room temperature, plus
Enter toluene and water, stirring separates toluene layer；Toluene layer sloughs solvent, obtains 14.50g 1- methyl -3- difluoromethyl -4- pyrazoles
The grease of Ethyl formate (VI), yield is 65%.
Step 4：The synthesis of 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids (I)
22.30g 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI) are put into 500mL reaction bulb
With 5.00g sodium hydroxides and 200 ml methanols, 50-60 DEG C, reaction to 1- methyl -3- difluoromethyl -4- pyrroles are warming up under stirring
Iminazole acid ethyl ester (VI) is less than 0.5%；After reaction knot, methanol is sloughed in decompression；Residue adds 100mL water, at 40-50 DEG C, drop
Plus sulfuric acid is until pH=1-2, is stirred for more than 1 hour；0-5 DEG C is slowly cooled to, white solid is filtered out, is dried under reduced pressure and obtains
1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids (I) 17.66g, purity is 99.5%, and yield is 91%.
Embodiment 3
Step 1：The synthesis of 2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate (IV)
In 2L reaction bulb, input 100g dichloroacetyls ethyl acetate and 400g dichloromethane are cooled to 0-10
DEG C, add the [(CH of 135g such as formulas (III)3)2N+=CHCl] [PO2Cl2]-It is dissolved in 300g toluene solutions；Slowly dripped at 0-5 DEG C
Plus 80g triethylamines, about 1 hour；Room temperature reaction 2 hours, adds water stirring, separates dichloromethane layer；Decompression precipitation obtains 2-
Dichloro-acetyl -3- (dimethylamino) ethyl acrylate (IV) crude product 150g, demarcation yield is 76%, is directly used in next
Step.
Step 2：The synthesis of 1- methyl -3- dichloromethyl -4- pyrazole carboxylic acids ethyl esters (V)
In 2L reaction bulb, 106.50g 2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate is put into
(IV) -60 DEG C and 400g toluene, are cooled under nitrogen protection, 19.62g methyl hydrazines (toluene for being dissolved in 100g) are added dropwise；It is added dropwise
Terminate, kept for 2 hours at -60 DEG C.Then slowly return and warm to room temperature, and stir 2 hours.Reaction terminates, and adds 300g water, stirs
15min is mixed, stratification, water layer is extracted once with 100g toluene；Toluene is sloughed in combining methylbenzene layer, decompression, and obtained crude product is
88.45g, yield is 82%.
Step 3：The synthesis of 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI)
In 1L autoclave, input 23.75g 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI) and
Under the protection of solvent 200g DMF nitrogen, the potassium fluoride of 52.25g spray drying is added, it is small that stirring is warming up to 120-130 DEG C of reaction 6
When.Reaction end is cooled to room temperature, and desalination is removed in first filtering, and filtrate decompression sloughs solvent, and obtained residue adds toluene and water,
Stirring separates toluene layer；Toluene layer sloughs solvent, obtains 17.50g 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acid ethyl esters
(VI), yield is 83%.
Step 4：The synthesis of 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids (I)
20.40g 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI) are put into 500mL reaction bulb
With 5.00g sodium hydroxides and 100 milliliters of water, 50-60 DEG C, reaction to 1- methyl -3- difluoromethyl -4- pyrazoles are warming up under stirring
Ethyl formate (VI) is less than 0.5%；After reaction knot, at 40-50 DEG C, hydrochloric acid is added dropwise until pH=1-2, is stirred for more than 1 hour；
0-5 DEG C is slowly cooled to, white solid is filtered out, is dried under reduced pressure and obtains 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids (I)
15.15g, purity is 99.5%, and yield is 85%.
Embodiment 4
Step 1：The synthesis of 2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate (IV)
In 2L reaction bulb, input 100g dichloroacetyls ethyl acetate and 400g toluene is cooled to 0-10 DEG C, plus
Enter the [(CH of 69.5g such as formulas (III)3)2N+=CHCl] Cl-It is dissolved in 300g toluene solutions；The second of 80g tri- is slowly added dropwise at 0-5 DEG C
Amine, about 1 hour；Room temperature reaction 2 hours, adds water stirring, separates toluene layer；Decompression precipitation obtains 2- dichloro-acetyls -3-
(dimethylamino) ethyl acrylate (IV) crude product 155g, yield is 78%, is directly used in next step.
Step 2：The synthesis of 1- methyl -3- dichloromethyl -4- pyrazole carboxylic acids ethyl esters (V)
In 2L reaction bulb, add 2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate (IV) 135g and
400g toluene；, -30 DEG C are cooled under nitrogen protection, 18.6g methyl hydrazines (toluene for being dissolved in 100g) are added dropwise；Completion of dropwise addition,
Kept for 2 hours at -30 DEG C.Then slowly return and warm to room temperature, and stir 2 hours.Reaction terminates, and adds 300g water, stirring
15min, stratification, water layer is extracted once with 100g toluene；Toluene is sloughed in combining methylbenzene layer, decompression, and obtained crude product is
105.63g, yield is 83%.
Step 3：The synthesis of 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI)
In 1L autoclave, input 23.50g 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI) and
Under the protection of solvent 150g DMF nitrogen, the potassium fluoride of 39.80g spray drying is added, it is small that stirring is warming up to 120-130 DEG C of reaction 15
When.Reaction end is cooled to room temperature, and desalination is removed in first filtering, and filtrate decompression sloughs solvent, and obtained residue adds toluene and water,
Stirring separates toluene layer；Toluene layer sloughs solvent, obtains 17.50g 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acid ethyl esters
(VI), yield is 83.7%；
Step 4：The synthesis of 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids (I)
22.30g 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI) are put into 500mL reaction bulb
With 5.00g sodium hydroxides and 200 milliliters of ethanol, 60 DEG C, reaction to 1- methyl -3- difluoromethyl -4- pyrazoles are warming up under stirring
Ethyl formate (VI) is less than 0.5%；After reaction knot, ethanol is sloughed in decompression；Residue adds 100mL water, at 40-50 DEG C, is added dropwise
Sulfuric acid is until pH=1-2, is stirred for more than 1 hour；0-5 DEG C is slowly cooled to, white solid is filtered out, is dried under reduced pressure and obtains 1-
Methyl -3- difluoromethyl -4- pyrazole carboxylic acids (I) 15.72g, purity is 99.4%, and yield is 88.2%.
Embodiment 5
Step 1：The synthesis of 2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate (IV)
In 2L reaction bulb, input 100g dichloroacetyls ethyl acetate and 400g dichloromethane are cooled to 0-10
DEG C, add the [(CH of 69.5g such as formulas (III)3)2N+=CHCl] Cl-It is dissolved in 300g dichloromethane solutions；Slowly dripped at 0-5 DEG C
Plus 90g triethylamines, about 1 hour；Room temperature reaction 2 hours, adds water stirring, separates dichloromethane layer；Decompression precipitation obtains 2-
Dichloro-acetyl -3- (dimethylamino) ethyl acrylate (IV) crude product 158g, yield is 79.5%, is directly used in next step.
Step 2：The synthesis of 1- methyl -3- dichloromethyl -4- pyrazole carboxylic acids ethyl esters (V)
In 2L reaction bulb, add 2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate (IV) 135g and
400g toluene；, 0 DEG C is cooled under nitrogen protection, 18.62g methyl hydrazines (toluene for being dissolved in 100g) are added dropwise；Completion of dropwise addition, 0
Kept for 2 hours at DEG C.Then slowly return and warm to room temperature, and stir 2 hours.Reaction terminates, and adds 300g water, stirs 15min, quiet
Layering is put, water layer is extracted once with 100g toluene；Toluene is sloughed in combining methylbenzene layer, decompression, and obtained crude product is 81.12g, yield
For 77%.
Step 3：The synthesis of 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI)
In 1L autoclave, input 37.91g 1- methyl -3- dichloromethyl -4- pyrazole carboxylic acids ethyl esters (VI) and
The hydrofluoric acid 150g of tri-n-butylamine three, stirring is warming up to 150 DEG C and reacted 10 hours.Reaction end is cooled to room temperature；Then by reactant
Diluted with 200g water, product is extracted with toluene, processing obtains 26.70g 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acid ethyl esters
(VI) solid, yield is 75%.
Step 4：The synthesis of 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids (I)
20.50g 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI) are put into 500mL reaction bulb
With 5.00g sodium hydroxides and 150 ml methanols, 50-60 DEG C, reaction to 1- methyl -3- difluoromethyl -4- pyrroles are warming up under stirring
Iminazole acid ethyl ester (VI) is less than 0.5%；After reaction knot, methanol is sloughed in decompression；Residue adds 100mL water, at 40-50 DEG C, drop
Plus hydrochloric acid is until pH=1-2, is stirred for more than 1 hour；0-5 DEG C is slowly cooled to, white solid is filtered out, is dried under reduced pressure and obtains
1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids (I) 14.25g, purity is 99.8%, and yield is 80.2%.
Embodiment 6
Step 1：The synthesis of 2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate (IV)
In 2L reaction bulb, input 100g dichloroacetyls ethyl acetate and 400g dichloromethane are cooled to 0-10
DEG C, add the [(CH of 69.5g such as formulas (III)3)2N+=CHCl] Cl-It is dissolved in 400g dichloromethane solutions；Slowly dripped at 0-5 DEG C
Plus 85g triethylamines, about 1 hour；Room temperature reaction 2 hours, adds water stirring, separates dichloromethane layer；Decompression precipitation obtains 2-
Dichloro-acetyl -3- (dimethylamino) ethyl acrylate (IV) crude product 164g, yield is 82.4%, is directly used in next step.
Step 2：The synthesis of 1- methyl -3- dichloromethyl -4- pyrazole carboxylic acids ethyl esters (V)
In 2L reaction bulb, add 2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate (IV) 135g and
400g toluene；, -60 DEG C are cooled under nitrogen protection, 18.65g methyl hydrazines (toluene for being dissolved in 100g) are added dropwise；Completion of dropwise addition,
Kept for 2 hours at -60 DEG C.Then slowly return and warm to room temperature, and stir 2 hours.Reaction terminates, and adds 300g water, stirring
15min, stratification, water layer is extracted once with 100g toluene；Toluene is sloughed in combining methylbenzene layer, decompression, and obtained crude product is
86.45g, yield is 82%.
Step 3：The synthesis of 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI)
In 1L autoclave, input 23.75g 1- methyl -3- dichloromethyl -4- pyrazole carboxylic acids ethyl esters (VI) and
Dimethyl sulfoxide (DMSO) 200g, the lower potassium fluoride for adding 36.85g spray drying of nitrogen protection, it is small that stirring is warming up to 120 DEG C of reactions 12
When.Reaction end is cooled to room temperature；Then reactant is diluted with 200g water, product is extracted with toluene, processing obtains 16.70g
1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI) solid, yield is 80.4%.
Step 4：The synthesis of 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids (I)
22.50g 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids ethyl esters (VI) are put into 500mL reaction bulb
With 5.00g sodium hydroxides and 150 ml methanols, 40-50 DEG C, reaction to 1- methyl -3- difluoromethyl -4- pyrroles are warming up under stirring
Iminazole acid ethyl ester (VI) is less than 0.5%；After reaction knot, methanol is sloughed in decompression；Residue adds 100mL water, at 40-50 DEG C, drop
Plus sulfuric acid is until pH=1-2, is stirred for more than 1 hour；0-5 DEG C is slowly cooled to, white solid is filtered out, is dried under reduced pressure and obtains
1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids (I) 17.27g, purity is 99.8%, and yield is 89.2%.
Claims (7)
1. a kind of synthetic method of 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids, its step is as follows：
Step 1：Dichloroacetyl ethyl acetate generates the salt of dichloroacetyl ethyl acetate such as formula (II) under alkali effect, then with such as
The Vilsmeier reagent reactings of formula (III) obtain 2- dichloro-acetyls -3- (dimethylamino) acrylic acid second as shown in formula (IV)
Ester, the alkali is sodium hydride, and the solvent used is toluene；
Step 2：By step 1 obtain such as 2- dichloro-acetyls -3- (dimethylamino) ethyl acrylate toluene solution of formula (IV),
Obtained with methyl hydrazine solution reaction such as formula (V) 1- methyl -3- dichloromethyl -4- pyrazole carboxylic acid ethyl esters；
Step 3：1- methyl -3- dichloromethyls -4- pyrazole carboxylic acids the ethyl ester as shown in formula (V) that step 2 is obtained is tried with fluorination
Agent progress halogen exchange reaction obtains the 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acid ethyl esters as shown in formula (VI)；
Step 4：1- methyl -3- difluoromethyls -4- pyrazole carboxylic acids the ethyl ester and hydroxide as shown in formula (VI) that step 3 is obtained
Sodium solution hydrolysis, then obtain with sour neutralisation treatment the 1- methyl -3- difluoromethyl -4- pyrazole carboxylic acids as shown in formula (I).
2. according to the method described in claim 1, it is characterized in that：In step 2, toluene, benzene, dichloromethane, petroleum ether, each is used
Class alkane, dimethylbenzene, hexamethylene, hexahydrotoluene make solvent, and the temperature for adding methyl hydrazine is -80~40 DEG C.
3. method according to claim 2, it is characterized in that：In step 2, using toluene as solvent, methyl hydrazine is added
Temperature is -80~-40 DEG C.
4. according to the method described in claim 1, it is characterized in that：In step 3, described fluorination reagent be antimony fluoride, potassium fluoride,
Hydrogen fluoride, hydrogen fluoride/pyridine, triethylamine hydrogen fluoride, tri-n-butylamine hydrogen fluoride；Reaction temperature is 80-200 DEG C；Solvent is N, N- bis-
NMF, formamide, acetamide, sulfolane, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide (DMSO).
5. method according to claim 4, it is characterized in that：In step 3, described fluorination reagent is potassium fluoride, triethylamine
Hydrogen fluoride；Described reaction temperature is 100-120 DEG C；Described solvent is N,N-dimethylformamide.
6. according to the method described in claim 1, it is characterized in that：In step 4, reaction dissolvent is water, methanol, ethanol, propyl alcohol, fourth
A kind of or wherein any two mixture in alcohol；Reaction temperature is 0-100 DEG C；1- methyl -3- difluoros as shown in formula (VI)
The molar ratio 1 of methyl -4- pyrazole carboxylic acids ethyl ester and sodium hydroxide:1.0-1.5.
7. method according to claim 6, it is characterized in that：In step 4, reaction dissolvent is water；Described reaction temperature is
50-60℃。
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| CN112480007B (en) * | 2020-12-08 | 2022-11-18 | 宿迁市科莱博生物化学有限公司 | Synthetic method of 1,3-dimethyl-1H-pyrazole-4-carboxylic acid |
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| CN114195715B (en) * | 2021-12-31 | 2024-05-10 | 福建永晶科技股份有限公司 | Process for preparing 1-methyl-3-difluoromethyl-4-pyrazole acid and 1-methyl-3-trifluoromethyl-4-pyrazole acid |
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Inventor after: Zhang Jiaqing Inventor after: Gao Dehua Inventor after: Li Anpai Inventor after: Liu Jianshu Inventor after: Sun Lei Inventor after: Wu Zhenghua Inventor after: Gu Xinghua Inventor after: Gu Aihong Inventor after: Shi Rongxian Inventor before: Gao Dehua Inventor before: Li Anpai Inventor before: Liu Jianshu Inventor before: Sun Lei Inventor before: Wu Zhenghua Inventor before: Gu Xinghua Inventor before: Gu Aihong Inventor before: Shi Rongxian |