CN105218448A - A kind of synthetic method of 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid - Google Patents
A kind of synthetic method of 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid Download PDFInfo
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- CN105218448A CN105218448A CN201510465959.7A CN201510465959A CN105218448A CN 105218448 A CN105218448 A CN 105218448A CN 201510465959 A CN201510465959 A CN 201510465959A CN 105218448 A CN105218448 A CN 105218448A
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- 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
- C07D231/14—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Abstract
The invention discloses a kind of synthetic method of 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid, relate to a kind of synthetic method of fine-chemical intermediate, the method comprises following four steps: step 1: with dichloroacetyl ethyl acetate for raw material, obtains (IV) under alkali effect with Vilsmeier reagent react; Step 2: intermediate (IV) and methyl hydrazine carry out ring-closure reaction and obtain 1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester (V); Step 3: intermediate (V) and fluorination reagent carry out halogen exchange reaction and obtain 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI); Step 4: the intermediate (VI) that step 3 is obtained and sodium hydroxide solution hydrolysis reaction, then obtain highly purified 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid (I) by sour neutralizing treatment.The method raw material is easily purchased, cheap, and preparation method is simple, and reaction conditions is gentle, low for equipment requirements, and suitability for industrialized is produced.
Description
Technical field
The present invention relates to a kind of synthetic method of fine-chemical intermediate, specifically the synthetic method of 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid.
Background technology
1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid (such as formula (I) Suo Shi), English name is 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylicacid; Molecular weight is 176.12; CAS:176969-34-9; Structural formula is such as formula shown in I:
This compound is the key intermediate of the former medicines such as sterilant fluorine azoles ring bacterium amine (sedaxane), isopyrazam (isopyrazam), benzo alkene fluorine bacterium azoles (benzovindiflupyr), biphenyl pyrrole bacterium amine (bixafen) and fluorine azoles bacterium acid amides (fluxapyroxad).Fluorine-containing pyrazolecarboxamide series bactericidal agent is the class new type bactericide that developed recently gets up, listing of swarming, and the impetus is powerful, has become the new focus of sterilant research and development.Such as Sumitomo Chemical Co WO2013186325A1 disclose a kind of newly grinding sterilant, its structure is as follows:
So 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid has the very large market requirement.The disclosure is invented described synthesis technique and is had that cost is low, easy and simple to handle, product purity advantages of higher.
At present, the synthetic route of 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid mainly contains following several:
1, CN201480000575.1 and CN102015654 (BASF European Co., Ltd's synthesis 1,3, the method of pyrazole compound that 4-replaces) and CN101959840 (BASF European Co., Ltd) patent in the industrialized synthetic method of one that provides, with difluoro methyl aceto acetate, diacetyl oxide, triethyl orthoformate, methyl hydrazine for raw material, three-step reaction synthesis obtains 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid; The price of the raw material difluoro methyl aceto acetate that this technique uses is very expensive, and cost is higher.Concrete route is described below:
2, CN103570623 (Hunan Chemical Research Institute), CN200880022057.4 (first just reaching) and US7358387 (Bayer) are with N; N-dimethylamino ethyl propenoate is raw material; first and difluoroacetic acid chloride reaction generates 2-difluoro ethanoyl-3-(dimethylamino) ethyl propenoate; methyl-sulfate is used to methylate again with after hydrazine hydrate cyclization; finally hydrolysis obtains 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid; overall yield of reaction is 54.6%; route is longer, and industrialization cost is high.Concrete route is described below:
3, the patent such as CN201410408225.02 and WO2008102678 (Mitsui Chemicals AGRO Co., Ltd) take dimethylaminopropionitrile as raw material; first and difluoroacetic acid chloride reaction generates 2-difluoro ethanoyl-3-(dimethylamino) vinyl cyanide; again with methyl hydrazine cyclization; finally hydrolysis obtains 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid, and overall yield of reaction is 65%.The shortcoming of this route uses the difluoroacetic acid chloride that toxicity is large, price is high.Concrete route is described below:
Summary of the invention
The present invention is directed to problems of the prior art, object is to provide that a kind of technological design is reasonable, yield is high, reaction conditions is gentle, low in raw material price, is applicable to the synthetic method of industrialized 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid.
Technical scheme of the present invention is:
With cheap dichloroacetyl ethyl acetate for raw material, under alkali effect, first generate the salt of the dichloroacetyl ethyl acetate such as formula (II), again in organic solvent with such as formula the Vilsmimer reagent of (III), be obtained by reacting such as formula 2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate shown in (IV);
Be dissolved in toluene equal solvent again, at-80 ~ 40 DEG C, drip methyl hydrazine solution, reaction end aftertreatment obtains the 1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester as formula V;
1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester (V) is carried out halogen exchange reaction with fluorination reagent and obtains 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI);
Finally intermediate (VI) and sodium hydroxide solution are hydrolyzed and react, then obtain highly purified 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid (I) by sour neutralizing treatment;
This route advantage instead of the high difluoroacetic acid chloride of price by dichloroacetyl ethyl acetate, has the advantage that yield is high, raw materials cost is low, annulation regioselectivity is good and finished product purity is high.
Concrete route is as follows:
Step 1: the synthesis about 2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV) is described below: existing technology is all use dichloroacetyl chloride and N; N-dimethylamino ethyl propenoate is obtained by reacting, and the patent US7358387 of such as Bayer describes.We adopt dichloroacetyl ethyl acetate cheap and easy to get to be dissolved in toluene, under alkali effect, generate the salt of the dichloroacetyl ethyl acetate such as formula (II), then obtain such as formula 2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate shown in (IV) with the Vilsmeier reagent react such as formula (III);
Obtain compound (IV), route is described below:
Wherein such as formula the Vilsmeier reagent of (III) synthesis conveniently technology be obtained by reacting by DMF and sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, phosgene, triphosgene, phosphorus oxychloride, oxalyl chloride etc.
Concrete steps are:
Dichloroacetyl ethyl acetate is dissolved in toluene, adds suitable alkali, be cooled to 0-20 DEG C; Add the Vilsmeier reagent such as formula (III) of 1 equivalent; After reaction terminates, use frozen water cancellation, stratification; Toluene is reclaimed in organic layer underpressure distillation, and residue is directly used in next step reaction.
Wherein said alkali, can be sodium methylate, sodium ethylate, sodium hydride, triethylamine etc., most preferably be sodium hydride; Step 2:1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester (V)
2-dichloro-acetyl-3-(dimethylamino) the ethyl propenoate toluene solution such as formula (IV) step 1 obtained, is obtained by reacting as formula V 1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester with methyl hydrazine solution reaction; Route is described below:
Wherein said solvent is non-protonic solvent, and can select toluene, benzene, methylene dichloride, sherwood oil, all kinds of alkane, dimethylbenzene, hexanaphthene, methylcyclohexane etc., most preferred solvent is toluene;
Preferred range can be-80 ~ 40 DEG C, and preferred temperature of reaction is-80 ~-40 DEG C.
Concrete steps are:
2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV) is dissolved in toluene equal solvent, and nitrogen protection borehole cooling, at-60 DEG C, dripping methyl hydrazine solution, reacting to terminating at-60 DEG C; Be warming up to room temperature and continue stirring reaction 2 hours, add water and stir, stratification obtains the organic layer of product; Solvent is sloughed in organic layer decompression, obtains crude product; This crude product isopropyl ether carries out crystallization, obtains the 1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester as formula V that isomer is less than 1%.
Step 3:1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI)
TetrahedronLettersVolume50 (2009), P3665-3668 disclose the ins and outs using 1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester (V) and TREAT-HF to carry out Finkelstein reaction.But use TREAT-HF in document, price is very high, finds that the product be hydrolyzed is more simultaneously, cause the yield of aftertreatment to only have 69%.The present invention adopt little over amount Potassium monofluoride and 1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester (V) at protic solvent low-temp reaction, avoid the decomposition reactions such as the open loop of pyrazole ring under high temperature, strong acid and basic conditions, substantially increase product yield and quality.
The method that the present invention adopts is that the 1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester as shown in formula V that step 2 obtained and fluorination reagent carry out halogen exchange reaction and obtain such as formula the 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester shown in (VI);
Route is described below:
Wherein said solvent is protic solvent, and can select DMF, methane amide, ethanamide, tetramethylene sulfone, N,N-dimethylacetamide, DMSO etc., most preferred solvent is DMF;
Described temperature of reaction can be 80-200 DEG C, is more preferably 100-120 DEG C;
Wherein said fluorizating agent is antimonic fluoride, hydrogen fluoride, hydrogen fluoride/pyridine, triethylamine hydrogen fluoride, Tributylamine hydrogen fluoride, is most preferably Potassium monofluoride, triethylamine hydrogen fluoride.
Concrete synthetic method is as follows:
1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester (V) is dissolved in DMF equal solvent, under nitrogen protection, drops into Potassium monofluoride, be warming up to 80-200 DEG C of reaction 3 hours; After reaction terminates, filter, filtrate decompression sloughs solvent, the crude product 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) obtained; Add water and toluene carries out aftertreatment, after toluene layer precipitation, residue is directly used in next step hydrolysis reaction.
Step 4:1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid (I)
Step 3 is obtained such as formula the 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester shown in (VI) and sodium hydroxide solution hydrolysis reaction, then to obtain such as formula the 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid shown in (I) by sour neutralizing treatment.
Route is described below:
Reaction solvent is a kind of in water, methyl alcohol, ethanol, propyl alcohol, butanols or wherein any two mixture; Temperature of reaction is 0-100 DEG C; Such as formula the molar ratio 1:1.0-1.5 of the 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester shown in (VI) and sodium hydroxide.
Preferably, described temperature of reaction can be 0-100 DEG C, and preferred temperature of reaction is 50-60 DEG C.
Concrete steps are: by the molar ratio 1:1.0-1.5 of 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) with sodium hydroxide, the amount of aqueous solvent is 3-5 times, stirs and is warming up to 50-70 DEG C of reaction to being hydrolyzed end (generally about 2 hours); Reaction terminates, and drips hydrochloric acid and regulates PH=1-2, then stir 1 hour at 40-50 DEG C; Slowly be cooled to 0-5 DEG C and filter the solid of separating out, dry 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid (I) obtaining purity and be greater than 99%.
Beneficial effect:
Instead of the high difluoroacetic acid chloride of price by dichloroacetyl ethyl acetate, there is the advantage that yield is high, raw materials cost is low, annulation regioselectivity is good and finished product purity is high.
With cheap dichloroacetyl ethyl acetate, such as formula the Vilsmeier reagent, Potassium monofluoride, methyl hydrazine, sodium hydroxide, hydrochloric acid etc. of (III) for raw material, obtain highly purified 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid (I).
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 yield is high, and product isomer (1-methyl-5-difluoromethyl-4-pyrazole carboxylic acid) is less than 1%, greatly improves product quality.
Accompanying drawing explanation
Fig. 1 is the HPLC figure of the step 4 of embodiment 1
Fig. 2 is the H-NMR figure of the step 4 of embodiment 1
Embodiment
Scientific research personnel will be contributed to by following examples of implementation and understand technical essential of the present invention, but content of the present invention can not be limited.
Embodiment 1
The synthesis of step 1:2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV)
In the reaction flask of a 2L, drop into 100.12g dichloroacetyl ethyl acetate and 400g toluene, be cooled to 0-10 DEG C, add the sodium hydride of 20.56g60% in batches, in controlling, temperature is less than 50 DEG C, finishes maintenance 1 hour; Be cooled to 0-10 DEG C, add the [(CH of 69.5g such as formula (III)
3)
2n
+=CHCl] Cl
-
Be dissolved in 300g toluene solution.At 15-25 DEG C, keep reaction 2 hours.Reaction mass is carried out cancellation down in frozen water, leaves standstill and separate toluene layer.The decompression of this toluene layer is sloughed after part is about 100g solvent; obtain 2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV) toluene solution 800g (demarcate content be 13.40%; yield is 85%), be directly used in next step.
[(CH
3)
2n
+=CHCl] Cl
-be prepared as follows: in the reaction flask of a 1L, drop into 26.50gDMF and 300g toluene; Stirring cools to 0-10 DEG C, and dropping 43.02g sulfur oxychloride is about and dropwises half an hour, and control temperature 0-5 DEG C, continues stirring for subsequent use for half an hour.
The synthesis of step 2:1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester (V)
In the reaction flask of a 2L, drop into the toluene solution 798g (demarcating content is 13.40%) of 2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV); , nitrogen protection borehole cooling, to-60 DEG C, drips 18.60g methyl hydrazine (being dissolved in the toluene of 100g); Drip and terminate, keep 2 hours at-60 DEG C.Then slowly rise again to room temperature, and stir 2 hours.Reaction terminates, and adds 300g water, stirs 15min, stratification, and water layer 100g toluene extracts once; Combining methylbenzene layer, toluene is sloughed in decompression, and the crude product obtained is 88.45g, and yield is 82%.Through isopropyl ether crystallization, the product obtained, isomer is less than 1%.
The synthesis of step 3:1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI)
In the autoclave of a 1L, under dropping into 23.75g1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) and solvent 200gDMF nitrogen protection, add the spray-dired Potassium monofluoride of 34.80g, stir and be warming up to 120-150 DEG C of reaction 6 hours.Reaction end is cooled to room temperature, and first filter and remove salt, filtrate decompression sloughs solvent, and the residue obtained adds toluene and water, stirs and separates toluene layer; Toluene layer sloughs solvent, and obtain 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) of 16.50g, yield is 79%.
The synthesis of step 4:1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid (I)
20.41g1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) and 5.00g sodium hydroxide and 150 ml waters are dropped in the reaction flask of a 500mL, be warming up to 60-70 DEG C under stirring, react to 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) and be less than 0.5%; After reaction knot, at 40-50 DEG C, drip hydrochloric acid until pH=1-2, then stir more than 1 hour; Slowly be cooled to 0-5 DEG C, filter out white solid, drying under reduced pressure obtains 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid (I) 15.30g, and 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,pyrazoleH)。
The HPLC purity of product and H-NMR, be shown in accompanying drawing 1 and accompanying drawing 2.
Product of the present invention adopts 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
The synthesis of step 1:2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV)
In the reaction flask of a 2L, drop into 100g dichloroacetyl ethyl acetate and 400g methylene dichloride, be cooled to 0-10 DEG C, add 135g [(CH3) 2N such as formula (III)
+=CHCl] [PO
2cl
2]
-be dissolved in 300g dichloromethane solution.At 15-25 DEG C, keep reaction 2 little; 80g triethylamine is slowly dripped, about 1 hour at 0-5 DEG C; Room temperature reaction 2 hours, adds water and stirs, separate dichloromethane layer; Decompression precipitation obtains the thick product 135g of 2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV), is directly used in next step.
[(CH
3)
2n
+=CHCl] [PO
2cl
2]
-be prepared as follows: in the reaction flask of a 1L, drop into 60.50gDMF and 300g methylene dichloride; Stirring cools to 0-10 DEG C, and dropping 85.55g phosphorus trichloride is about and dropwises half an hour, and control temperature 0-5 DEG C, continues stirring for subsequent use for half an hour.
The synthesis of step 2:1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester (V)
In the reaction flask of a 2L, add 2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV) 135g and 400g toluene; , nitrogen protection borehole cooling, to-80 DEG C, drips 18.62g methyl hydrazine (being dissolved in the toluene of 100g); Drip and terminate, keep 2 hours at-80 DEG C.Then slowly rise again to room temperature, and stir 2 hours.Reaction terminates, and adds 300g water, stirs 15min, stratification, and water layer 100g toluene extracts once; Combining methylbenzene layer, toluene is sloughed in decompression, and the crude product obtained is 103.52g, and yield is 82%.
The synthesis of step 3:1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI)
In the reaction flask of a 1L, drop into 200g water and 62.53g Potassium monofluoride, then add 23.85g1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI), stir and be warming up to 120-130 DEG C of reaction 6 hours.Reaction end is cooled to room temperature, adds toluene and water, stirs and separates toluene layer; Toluene layer sloughs solvent, and obtain the oily matter of 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) of 14.50g, yield is 65%.
The synthesis of step 4:1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid (I)
22.30g1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) and 5.00g sodium hydroxide and 200 ml methanol are dropped in the reaction flask of a 500mL, be warming up to 50-60 DEG C under stirring, react to 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) and be less than 0.5%; After reaction knot, methyl alcohol is sloughed in decompression; Residue adds 100mL water, at 40-50 DEG C, drips sulfuric acid until pH=1-2, then stirs more than 1 hour; Slowly be cooled to 0-5 DEG C, filter out white solid, drying under reduced pressure obtains 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid (I) 17.66g, and purity is 99.5%, and yield is 91%.
Embodiment 3
The synthesis of step 1:2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV)
In the reaction flask of a 2L, drop into 100g dichloroacetyl ethyl acetate and 400g methylene dichloride, be cooled to 0-10 DEG C, add the [(CH of 135g such as formula (III)
3)
2n
+=CHCl] [PO
2cl
2]
-be dissolved in 300g toluene solution; 80g triethylamine is slowly dripped, about 1 hour at 0-5 DEG C; Room temperature reaction 2 hours, adds water and stirs, separate dichloromethane layer; Decompression precipitation obtains the thick product 150g of 2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV), and demarcating yield is 76%, is directly used in next step.
The synthesis of step 2:1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester (V)
In the reaction flask of a 2L, drop into 2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV) and the 400g toluene of 106.50g, nitrogen protection borehole cooling, to-60 DEG C, drips 19.62g methyl hydrazine (being dissolved in the toluene of 100g); Drip and terminate, keep 2 hours at-60 DEG C.Then slowly rise again to room temperature, and stir 2 hours.Reaction terminates, and adds 300g water, stirs 15min, stratification, and water layer 100g toluene extracts once; Combining methylbenzene layer, toluene is sloughed in decompression, and the crude product obtained is 88.45g, and yield is 82%.
The synthesis of step 3:1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI)
In the autoclave of a 1L, under dropping into 23.75g1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) and solvent 200gDMF nitrogen protection, add the spray-dired Potassium monofluoride of 52.25g, stir and be warming up to 120-130 DEG C of reaction 6 hours.Reaction end is cooled to room temperature, and first filter and remove salt, filtrate decompression sloughs solvent, and the residue obtained adds toluene and water, stirs and separates toluene layer; Toluene layer sloughs solvent, and obtain 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) of 17.50g, yield is 83%.
The synthesis of step 4:1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid (I)
20.40g1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) and 5.00g sodium hydroxide and 100 ml waters are dropped in the reaction flask of a 500mL, be warming up to 50-60 DEG C under stirring, react to 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) and be less than 0.5%; After reaction knot, at 40-50 DEG C, drip hydrochloric acid until pH=1-2, then stir more than 1 hour; Slowly be cooled to 0-5 DEG C, filter out white solid, drying under reduced pressure obtains 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid (I) 15.15g, and purity is 99.5%, and yield is 85%.
Embodiment 4
The synthesis of step 1:2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV)
In the reaction flask of a 2L, drop into 100g dichloroacetyl ethyl acetate and 400g toluene, be cooled to 0-10 DEG C, add the [(CH of 69.5g such as formula (III)
3)
2n
+=CHCl] Cl
-be dissolved in 300g toluene solution; 80g triethylamine is slowly dripped, about 1 hour at 0-5 DEG C; Room temperature reaction 2 hours, adds water and stirs, separate toluene layer; Decompression precipitation obtains the thick product 155g of 2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV), and yield is 78%, is directly used in next step.
The synthesis of step 2:1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester (V)
In the reaction flask of a 2L, add 2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV) 135g and 400g toluene; , nitrogen protection borehole cooling, to-30 DEG C, drips 18.6g methyl hydrazine (being dissolved in the toluene of 100g); Drip and terminate, keep 2 hours at-30 DEG C.Then slowly rise again to room temperature, and stir 2 hours.Reaction terminates, and adds 300g water, stirs 15min, stratification, and water layer 100g toluene extracts once; Combining methylbenzene layer, toluene is sloughed in decompression, and the crude product obtained is 105.63g, and yield is 83%.
The synthesis of step 3:1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI)
In the autoclave of a 1L, under dropping into 23.50g1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) and solvent 150gDMF nitrogen protection, add the spray-dired Potassium monofluoride of 39.80g, stir and be warming up to 120-130 DEG C of reaction 15 hours.Reaction end is cooled to room temperature, and first filter and remove salt, filtrate decompression sloughs solvent, and the residue obtained adds toluene and water, stirs and separates toluene layer; Toluene layer sloughs solvent, and obtain 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) of 17.50g, yield is 83.7%;
The synthesis of step 4:1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid (I)
22.30g1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) and 5.00g sodium hydroxide and 200 milliliters of ethanol are dropped in the reaction flask of a 500mL, be warming up to 60 DEG C under stirring, react to 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) and be less than 0.5%; After reaction knot, ethanol is sloughed in decompression; Residue adds 100mL water, at 40-50 DEG C, drips sulfuric acid until pH=1-2, then stirs more than 1 hour; Slowly be cooled to 0-5 DEG C, filter out white solid, drying under reduced pressure obtains 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid (I) 15.72g, and purity is 99.4%, and yield is 88.2%.
Embodiment 5
The synthesis of step 1:2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV)
In the reaction flask of a 2L, drop into 100g dichloroacetyl ethyl acetate and 400g methylene dichloride, be cooled to 0-10 DEG C, add the [(CH of 69.5g such as formula (III)
3)
2n
+=CHCl] Cl
-be dissolved in 300g dichloromethane solution; 90g triethylamine is slowly dripped, about 1 hour at 0-5 DEG C; Room temperature reaction 2 hours, adds water and stirs, separate dichloromethane layer; Decompression precipitation obtains the thick product 158g of 2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV), and yield is 79.5%, is directly used in next step.
The synthesis of step 2:1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester (V)
In the reaction flask of a 2L, add 2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV) 135g and 400g toluene; , nitrogen protection borehole cooling to 0 DEG C, drips 18.62g methyl hydrazine (being dissolved in the toluene of 100g); Drip and terminate, keep 2 hours at 0 DEG C.Then slowly rise again to room temperature, and stir 2 hours.Reaction terminates, and adds 300g water, stirs 15min, stratification, and water layer 100g toluene extracts once; Combining methylbenzene layer, toluene is sloughed in decompression, and the crude product obtained is 81.12g, and yield is 77%.
The synthesis of step 3:1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI)
In the autoclave of a 1L, drop into 37.91g1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester (VI) and Tributylamine three hydrofluoric acid 150g, stir and be warming up to 150 DEG C of reactions 10 hours.Reaction end is cooled to room temperature; Then by reactant 200g water dilution, use toluene extraction product, process obtains the solid of 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) of 26.70g, and yield is 75%.
The synthesis of step 4:1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid (I)
20.50g1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) and 5.00g sodium hydroxide and 150 ml methanol are dropped in the reaction flask of a 500mL, be warming up to 50-60 DEG C under stirring, react to 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) and be less than 0.5%; After reaction knot, methyl alcohol is sloughed in decompression; Residue adds 100mL water, at 40-50 DEG C, drips hydrochloric acid until pH=1-2, then stirs more than 1 hour; Slowly be cooled to 0-5 DEG C, filter out white solid, drying under reduced pressure obtains 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid (I) 14.25g, and purity is 99.8%, and yield is 80.2%.
Embodiment 6
The synthesis of step 1:2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV)
In the reaction flask of a 2L, drop into 100g dichloroacetyl ethyl acetate and 400g methylene dichloride, be cooled to 0-10 DEG C, add the [(CH of 69.5g such as formula (III)
3)
2n
+=CHCl] Cl
-be dissolved in 400g dichloromethane solution; 85g triethylamine is slowly dripped, about 1 hour at 0-5 DEG C; Room temperature reaction 2 hours, adds water and stirs, separate dichloromethane layer; Decompression precipitation obtains the thick product 164g of 2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV), and yield is 82.4%, is directly used in next step.
The synthesis of step 2:1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester (V)
In the reaction flask of a 2L, add 2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate (IV) 135g and 400g toluene; , nitrogen protection borehole cooling, to-60 DEG C, drips 18.65g methyl hydrazine (being dissolved in the toluene of 100g); Drip and terminate, keep 2 hours at-60 DEG C.Then slowly rise again to room temperature, and stir 2 hours.Reaction terminates, and adds 300g water, stirs 15min, stratification, and water layer 100g toluene extracts once; Combining methylbenzene layer, toluene is sloughed in decompression, and the crude product obtained is 86.45g, and yield is 82%.
The synthesis of step 3:1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI)
In the autoclave of a 1L, drop into 23.75g1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester (VI) and dimethyl sulfoxide (DMSO) 200g, under nitrogen protection, add the spray-dired Potassium monofluoride of 36.85g, stir and be warming up to 120 DEG C of reactions 12 hours.Reaction end is cooled to room temperature; Then by reactant 200g water dilution, use toluene extraction product, process obtains the solid of 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) of 16.70g, and yield is 80.4%.
The synthesis of step 4:1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid (I)
22.50g1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) and 5.00g sodium hydroxide and 150 ml methanol are dropped in the reaction flask of a 500mL, be warming up to 40-50 DEG C under stirring, react to 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester (VI) and be less than 0.5%; After reaction knot, methyl alcohol is sloughed in decompression; Residue adds 100mL water, at 40-50 DEG C, drips sulfuric acid until pH=1-2, then stirs more than 1 hour; Slowly be cooled to 0-5 DEG C, filter out white solid, drying under reduced pressure obtains 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid (I) 17.27g, and purity is 99.8%, and yield is 89.2%.
Claims (9)
1. a synthetic method for 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid, its step is as follows:
Step 1: dichloroacetyl ethyl acetate generates the salt of the dichloroacetyl ethyl acetate such as formula (II) under alkali effect, then obtain such as formula 2-dichloro-acetyl-3-(dimethylamino) ethyl propenoate shown in (IV) with the Vilsmeier reagent react such as formula (III);
Step 2: 2-dichloro-acetyl-3-(dimethylamino) the ethyl propenoate toluene solution such as formula (IV) step 1 obtained, obtains as formula V 1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester with methyl hydrazine solution reaction;
Step 3: the 1-methyl-3-dichloromethyl-4-pyrazole carboxylic acid ethyl ester as shown in formula V step 2 obtained and fluorination reagent carry out halogen exchange reaction and obtain such as formula the 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester shown in (VI);
Step 4: step 3 is obtained such as formula the 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester shown in (VI) and sodium hydroxide solution hydrolysis reaction, then to obtain such as formula the 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid shown in (I) by sour neutralizing treatment.
2. method according to claim 1, is characterized in that: in step 1, and described alkali is sodium methylate, sodium ethylate, sodium hydride, triethylamine; The solvent toluene adopted or methylene dichloride.
3. method according to claim 1, is characterized in that: in step 1, and described alkali is sodium hydride.
4. method according to claim 1, is characterized in that: in step 2, and use toluene, benzene, methylene dichloride, sherwood oil, all kinds of alkane, dimethylbenzene, hexanaphthene, methylcyclohexane to make solvent, the temperature adding methyl hydrazine is-80 ~ 40 DEG C.
5. method according to claim 4, is characterized in that: in step 2, and use toluene as solvent, the temperature adding methyl hydrazine is-80 ~-40 DEG C.
6. method according to claim 1, is characterized in that: in step 3, and described fluorination reagent is antimonic fluoride, hydrogen fluoride, hydrogen fluoride/pyridine, triethylamine hydrogen fluoride, Tributylamine hydrogen fluoride; Temperature of reaction is 80-200 DEG C; Solvent is DMF, methane amide, ethanamide, tetramethylene sulfone, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO).
7. method according to claim 6, is characterized in that: in step 3, and described fluorination reagent is Potassium monofluoride, triethylamine hydrogen fluoride; Described temperature of reaction is 100-120 DEG C; Described solvent is DMF.
8. method according to claim 1, is characterized in that: in step 4, and reaction solvent is a kind of in water, methyl alcohol, ethanol, propyl alcohol, butanols or wherein any two mixture; Temperature of reaction is 0-100 DEG C; Such as formula the molar ratio 1:1.0-1.5 of the 1-methyl-3-difluoromethyl-4-pyrazole carboxylic acid ethyl ester shown in (VI) and sodium hydroxide.
9. method according to claim 8, is characterized in that: in step 4, and reaction solvent is water; Described temperature of reaction is 50-60 DEG C.
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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 |