CN106478508B - A kind of synthetic method of the 6-carbonitrile derivatives of pyrazoles containing halogen - Google Patents
A kind of synthetic method of the 6-carbonitrile derivatives of pyrazoles containing halogen Download PDFInfo
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Abstract
The invention discloses a kind of synthetic methods of 6-carbonitrile derivatives of pyrazoles containing halogen; carboxylic acid shown in dialkyl group acrylonitrile shown in formula (1) and formula (2) carries out acylation reaction in the presence of halogenating agent and organic base; obtain 2- acyl group -1- aminoacrylonitrile shown in formula (3); cyclization is carried out under alkaline condition with substitution hydrazine shown in formula (4) again, obtains pyrazoles 6-carbonitrile derivatives shown in formula (5)；The synthesis that this law is capable of high yield colours few 2- acyl group -1- aminoacrylonitrile, and synthesis highly selective in high yield colours few 1,3- disubstituted pyrazole -4- formonitrile HCN, and 1, the 5- disubstituted pyrazole -4- formonitrile HCN content of isomer in product is substantially reduced.
Description
Technical field
The present invention relates to a kind of synthesis sides as medicine/pesticide important intermediate 6-carbonitrile derivatives of pyrazoles containing halogen
Method.
Background technique
Pyrazol acid amide fungicide is novel SDHI class fungicide, and the mechanism of action of this kind of fungicide mainly inhibits disease
Opportunistic pathogen succinate dehydrogenase activity, to interfere its respiration, effect is special, and strong drug action, persistent, effect of increasing production are aobvious
, it is anti-for the fungi in various cultivated plants such as cotton, vegetables, barley, corn, rice, soybean, wheat and a large amount of seeds
It controls.1- alkyl -3- halogenated methyl -1H- pyrazoles -4- formonitrile HCN is the weight for synthesizing such agricultural or horticultural use pyrazol acid amide fungicide
Intermediate is wanted, therefore is a kind of highly useful to prepare intermediate.
It is less as the report of Material synthesis 1- alkyl -3- halogenated methyl -1H- pyrazoles -4- formonitrile HCN using aminoacrylonitrile.
US2010016612 is disclosed with 3- (dialkyl amido) acrylonitrile and trifluoro or difluoroacetic acid, chlorination reagent (phosgene or oxalyl
Chlorine) it is reacted to obtain the fluoro- 3- carbonyl butyronitrile of compound 2- ((dialkyl amido) methylene) -4,4,4- three under nitrogen atmosphere
Or after the fluoro- 3- carbonyl butyronitrile of 2- ((dialkyl amido) methylene) -4,4- bis-, then to methyl hydrazine carry out cyclization reaction obtain it is corresponding
Compound 1- methyl -3- difluoromethyl -1H- pyrazoles -4- formonitrile HCN or 1- methyl -3- difluoromethyl -1H- pyrazoles -4- formonitrile HCN.The method
In, the fluoro- 3- carbonyl butyronitrile of 2- ((dialkyl amido) methylene) -4,4,4- tri- is synthesized as chlorination reagent using phosgene or oxalyl chloride
Or the fluoro- 3- carbonyl butyronitrile compound of 2- ((dialkyl amido) methylene) -4,4- bis-, it needs after low polar solvent washs,
Obtained solid color be it is filbert, confirm coloring, coloration reason substance is indefinite, and the step yield is not high, only
83%.Cyclization reaction synthesizing pyrazole ring is carried out using methyl hydrazine, has nearly 10% by-product 1- methyl -5- difluoromethyl -
1H- pyrazoles -4- formonitrile HCN or 1- methyl -5- difluoromethyl -1H- pyrazoles -4- formonitrile HCN generate, although by rectification under vacuum or adding washing
The method washed can purify to obtain the target compound that purity is 99%, but yield is only respectively 63% and 71%.
Dou Qianqian et al. report, under nitrogen atmosphere, using 3- (dimethylamino) acrylonitrile as raw material, triethylamine is to tie up acid
Agent, selects trifluoro-acetyl chloride to replace hypertoxic gas phosgene as acylating agent, and synthesis obtains compound 2- ((dimethylamino) methylene
Base) after -4,4,4- tri- fluoro- 3- carbonyl butyronitrile, then carry out cyclization reaction with methyl hydrazine and obtain respective compound 1- methyl -3- difluoro
Methyl-1 H- pyrazoles -4- formonitrile HCN.In the method, the fluoro- 3- carbonyl butyronitrile of compound 2- ((dimethylamino) methylene) -4,4,4- tri-
Color it is deeper, it is yellowish-brown, and yield is lower that obtained solid color is also relatively deep after recrystallization, only 78.6%.With
Methyl hydrazine carries out cyclization reaction, and the purity and yield of obtained compound is not high, purity 93.6%, yield 74.3%
(synthesis [J] advanced chemical engineering journal of 1- methyl-3- trifluoromethyl-4- pyrazole carboxylic acid, 2012,26 (3): 470-474).
So existing synthesize 1- alkyl -3- halogenated methyl -1H- pyrazoles -4- formonitrile HCN with 3- (dialkyl amido) acrylonitrile
Technique the problem of being primarily present be: product color depth；Purity is low；Low yield；Process conditions are harsh, industry's enlarging production difficulty
Greatly；It is at high cost.
Summary of the invention
The purpose of the present invention is for solve the prior art defect, provide it is a kind of coloring less, purity is high, yield it is high and low at
Originally, the method for easy-operating synthesis 1- alkyl -3- halogenated methyl -1H- pyrazoles -4- formonitrile HCN.
The purpose of the present invention can be achieved by the following measures:
A kind of synthetic method of the 6-carbonitrile derivatives of pyrazoles containing halogen, shown in dialkyl group acrylonitrile and formula (2) shown in formula (1)
Carboxylic acid acylation reaction is carried out in the presence of halogenating agent and organic base, obtain 2- acyl group -1- amino propylene shown in formula (3)
Nitrile, then cyclization is carried out under alkaline condition with substitution hydrazine shown in formula (4), it is derivative to obtain pyrazoles formonitrile HCN shown in formula (5)
Object；
Wherein, R1、R2、R3It is separately C1~10Alkyl or C1-10Halogenated alkyl, R4For C1-10Alkyl, C1-10Alkyl halide
Base, C1-4The C that alkoxy replaces1-10Alkyl, C1-4The C that halogenated alkoxy replaces1-10Alkyl, C1-4The C that alkylthio group replaces1-10Alkane
Base, C3-8Naphthenic base, C3-8Halogenated cycloalkyl or aryl.
After obtaining 2- acyl group -1- aminoacrylonitrile shown in formula (3), carried out after which being post-processed and purified
Reaction solution after acylation reaction can also be directly cyclized by next step cyclization without post-processing
Reaction.
The inventors of the present invention's discovery, in manufacture 2- ((dimethylamino) methylene) -4,4,4- tri- fluoro- 3- carbonyl butyronitrile,
Hypertoxic gas phosgene or oxalyl chloride are replaced with triphosgene, not only reacts relatively milder, temperature will not steeply rise, and reaction solution
Color is faint yellow, hence it is evident that reduces the coloring of product, and yield and purity all improve.Step reaction can generate three second
Amine hydrochlorate is found through experiments that the presence of the hydrochloride can impact next step cyclization, isomers 1- alkyl-
The content of 5- halogenated methyl -1H- pyrazoles -4- formonitrile HCN will increase；If by washing etc. means of purification by triethylamine hydrochloride from
It is removed in the reaction solution that acylation reaction obtains, the ratio of isomers can be reduced.But purification process not only increases operation
Process, but also step yield reduction can be made.Then we have found that only being reacted without post-processing after acylation reaction
The inorganic bases such as metal hydroxides are added in liquid, directly progress cyclization, it can be to obtain the few 1- of content of isomer in high yield
Alkyl -3- halogenated methyl -1H- pyrazoles -4- formonitrile HCN.
In the present specification, 1,3- disubstituted pyrazole -4- formonitrile HCN is known as 1,3- isomers sometimes, 1,5- bis- is replaced into pyrrole
Azoles -4- formonitrile HCN is known as 1,5- isomers, but these expression ways are not meant to specific pyrazole compound.In addition, in this theory
In bright book, alkyl refers to including straight-chain, branched and cricoid alkyl.Referring to alkyl or aryl is that respectively also can have
Substituent group.
The synthesis (acylation reaction) of one: 2- acyl-3-aminoacrylonitrile of stage, 2- acyl group -1- ammonia shown in general formula (3)
Base acrylonitrile can be carried out by carboxylic acid shown in dialkyl group acrylonitrile shown in general formula (1) and general formula (2) acylation reaction come
Synthesis.
R in general formula (1)~(3)1、R2、R3Separately indicate alkyl.Herein, as alkyl, preferably carbon number 1~10
Alkyl, more preferable carbon number 1~4 alkyl.Each hydrogen atom can also be substituted with halogen atoms.As halogen, can include fluorine,
Chlorine, bromine, iodine, preferably fluorine or chlorine.As alkyl, specifically, can include methyl, ethyl, n-propyl, isopropyl, normal-butyl,
Group made of sec-butyl, tert-butyl, cyclohexyl, cyclopenta and their any hydrogen atom are substituted with halogen atoms.
In a kind of scheme, R1Or R2It is separately C1~4Alkyl or C3-6Naphthenic base, R3For C1-4Halogenated alkyl.
As R3, the preferably halogenated alkyl of carbon number 1~4, the fluoroalkyl of more preferable carbon number 1~4, chlorine alkyl or chlorofluoromethane
Base.Specifically, trifluoromethyl, difluoromethyl, a methyl fluoride, pentafluoroethyl group, 2 can be included, 2,2- trifluoroethyls, 2,2- bis-
Fluoro ethyl, tetra- fluoro ethyl of 1,1,2,2-, trichloromethyl, dichloromethyl, chloromethyl, five chloroethyls, 2,2,2- trichloroethyl, 2,
2- Dichloroethyl, tetra- chloroethyl of 1,1,2,2-, chlorodifluoramethyl-, dichlorofluoromethyl etc..In them, further preferred trifluoro
Methyl, difluoromethyl, dichloromethyl etc..
-NR1R2As leaving group, therefore R1、R2It is not particularly limited, can be the group of non-halogen substitution, aforementioned
In alkyl, preferably methyl or ethyl, particularly preferred R1、R2It is methyl.
Acylation reaction carries out in water-insoluble solvent.As the solvent, aliphatic or aromatic hydrocarbon can be included.
Petroleum ether, n-hexane, normal heptane, hexamethylene, benzene,toluene,xylene or naphthalane can be exemplified and by halogenated hydrocarbon by enumerating.
Such as chlorobenzene, dichloro-benzenes, methylene chloride, chloroform, carbon tetrachloride, dichloroethanes or trichloroethanes etc..It is preferable to use toluene, diformazan
Benzene, chlorobenzene, n-hexane or hexamethylene, more preferable toluene or dimethylbenzene.These solvents can be used in mixed way.
Acylation reaction usually carries out in the presence of base.Alkali can enumerate tertiary amine, pyridine or pyridine derivate etc..As
The alkali such as pyridine or pyridine derivate can enumerate pyridine, 2- picoline, 3- picoline or 4- picoline, 4- dimethyl
Aminopyridine etc., preferably pyridine.As tertiary amine, trimethylamine, triethylamine, Tri-n-Propylamine, tri-isopropyl amine, tri-n-butylamine can be enumerated
Etc. symmetrical tertiary amine；Asymmetric tertiary amines such as N- methyl di-n-butyl amine, N- methyl diisobutyl amine, N- methyl di-t-butyl amine etc.,
It is preferred that triethylamine.
Acylation reaction temperature is -20 DEG C~50 DEG C, preferably -10 DEG C~45 DEG C, further preferably 0 DEG C~40 DEG C.
Reaction time depends on reaction temperature, the ratio of reaction reagent, and usually 10min~10h or so, withs while following response
The reduction or disappearance of substrate are determined as benchmark.
In acylation reaction, dialkyl amido Bing Xi Jing ︰ halogen is for Suo Suan ︰ halogenating agent: organic base be 1 ︰, 0.5~3 ︰ 0.1~
0.5~1.5 ︰ of 3 ︰ 1~6, preferably 1 ︰ 0.1~1 ︰ 1~3,0.9~1.1 ︰ of more preferably 1 ︰, 0.3~0.6 ︰ 1.8~2.3.It is halogenated
Agent is solid light or surpalite.
Dialkyl amido acrylonitrile, halogenated carboxylic acid and organic base can be dissolved in solvent by acylation reaction, be kept on one side
Halogenating agent is added dropwise in reaction temperature on one side, and the solution of halogenating agent and halogenated carboxylic acid can also be instilled to dialkyl amido acrylonitrile and had
In the solvent of machine alkali.Alkali can also be with reaction by adding continuously or gradually.
Thus it obtains containing 2- acyl-3-aminoacrylonitrile and organic alkali salt in reaction solution.The reaction solution can be without
Further purifying, directly carries out lower step cyclization, but the presence of organic alkali salt can promote the generation of 1,5- isomers.?
Organic alkali salt of formation can be washed away with water, but since 2- acyl-3-aminoacrylonitrile has certain solubility in water,
Therefore benefit, which washes with water, can reduce yield.
Stage two: the synthesis (cyclization) of pyrazoles 6-carbonitrile derivatives, 2- acyl group -3- amino shown in above-mentioned general formula (3)
Hydrazine shown in acrylonitrile and general formula (4) carries out cyclization in the presence of base, can synthesize pyrazoles first shown in general formula (5)
Carbonitrile derivatives.
R in formula1、R2、R3It is as defined above.R in formula4Indicate alkyl or aryl, they also can have substitution
Base.Preferably, R4For the straight-chain of carbon number 1~10, branched or cricoid alkyl or alkoxyalkyl or aryl, alkyl
It can also be substituted with halogen atoms with any number of hydrogen atom of alkoxy, the oxygen atom of alkoxy can also be taken by sulphur atom
Generation.Halogen is fluorine, chlorine or bromine.
In a kind of scheme, R4For C1~4Alkyl, C1-4Halogenated alkyl, C3-6Naphthenic base or phenyl.
Specifically, R4Can enumerate methyl, ethyl, n-propyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl,
Hydroxymethyl, cyclopropyl or phenyl etc., preferably methyl, ethyl, isopropyl or tert-butyl, more preferable methyl.
Hydrazine shown in general formula (4), specifically, it is preferable that methyl hydrazine, ethyl hydrazine etc. replace hydrazine.Hydrazine can be it is anhydrous or
Have the hydrazine of water, preferably there is water hydrazine, be easier to obtain and it is easy to handle.
Cyclization carries out in the presence of base.Alkali is water-soluble inorganic base.As the more preferable alkaline-earth metal of inorganic base
Or hydroxide, carbonate or the bicarbonate of alkali metal, the hydroxide of particularly preferred alkali metal.Hydroxide can be enumerated
Sodium, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, saleratus or sodium bicarbonate etc..It is preferred that hydroxide
Sodium, potassium hydroxide.More preferable sodium hydroxide.Used alkali there is no particular requirement that high-purity product, preferably common industrialization
The alkali of the general purpose grades such as product, reagent.
The additive amount of alkali in cyclization relative to 1mol 2- acyl-3-aminoacrylonitrile, usually 0.05~
2mol, preferably 0.1~1mol, more preferably 0.1~0.5mol.When additive amount is less than 0.05mol, decolorizing effect is poor, is more than
When 2mol, raw material or product hydrolysis, the yield of target product can be reduced.The dosage of hydrazine is replaced to be equivalent to every mole of 2- acyl group -3-
Aminoacrylonitrile is 0.5~2mol, preferably 0.8~1.2mol.
Cyclization is preferably carried out in the presence of a solvent.As solvent, water outlet or aliphatic, ester ring type or virtue can be enumerated
Hydrocarbon of fragrant race, such as petroleum ether, n-hexane, normal heptane, hexamethylene, benzene,toluene,xylene or naphthalane etc.；By halogenated hydrocarbon, example
Such as chlorobenzene, dichloro-benzenes, methylene chloride, chloroform, carbon tetrachloride, dichloroethanes, trichloroethanes；Ethers, for example, it is diethyl ether, two different
Propyl ether, methyl tertiary butyl ether(MTBE), tert amyl methyl ether(TAME), dioxanes, tetrahydrofuran, 1,2- dimethoxy-ethane, 1,2- diethoxy
Ethane, phenyl ether etc.；Alcohols, such as acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), cyclohexanone etc.；Nitrile, for example, acetonitrile, propionitrile,
N-Butyronitrile or isobutyronitrile etc.；Amides, for example, n,N-Dimethylformamide, n,N-dimethylacetamide, N- methyl formyl aniline,
N-Methyl pyrrolidone etc.；Sulfoxide type, such as dimethyl sulfoxide etc.；Or sulfone class, such as sulfolane etc..Preferred hydrocarbons and halogenated
Hydrocarbon, more preferable aromatic hydrocarbon.Specifically, it is preferable that toluene, dimethylbenzene, chlorobenzene, n-hexane or hexamethylene, more preferable toluene or two
Toluene.Additionally, it is preferred that synthesizing identical solvent using with one 2- acyl-3-aminoacrylonitrile of stage.By one 2- acyl group -3- of stage
Reactant in aminoacrylonitrile synthesis is without isolation or purifying is used for stage Fused bicyclic reaction, especially preferentially selects identical molten
Agent.Solvent can also be used in mixed way with two or more solvent.
Cyclization preferably carries out under low temperature, carries out at -80 DEG C~30 DEG C, and preferably -20 DEG C~20 DEG C.Reaction temperature
It is higher to spend more low selectivity, but the lower cooling cost of temperature is higher, therefore the low temperature lower than -80 DEG C is undesirable.
When in addition more than 30 DEG C, side reaction occurs and selection rate reduces, therefore also not preferably.Reaction time according to the conditions such as temperature without
It together, is 10min~10h.
In cyclization, do not limit the sequence that related substrate and auxiliary material pour into reaction system will be reacted.Tool
For body, it is preferred that measured into any middle composition for put into reactor slowly through such as dropwise addition or utilization
The methods of injection of pump imports another composition.In above-mentioned preferred embodiment, it will be obtained by acylation reaction anti-
It answers device content, inorganic base and replaces hydrazine mixing, the reactor content and alkali that will preferably obtain comprising acylation reaction
Composition, inorganic base and replace hydrazine composition mixing.Preferably, whether the temperature of one side observing response device content
Rise, the variation of ingredient, is slowly added being no more than within the scope of previous reaction temperature upper limit on one side.Additionally, it is preferred that anti-
Device content is answered to be stirred.
The purifying of pyrazole compound can be carried out according to common purification process.For example, can wash with water in reactor
It is tolerant, solvent is removed from organic phase by distillation.The composition of reactor content according to be acylated process and magically change process it
Between purification process or be acylated process, whether different using solvent etc. in cyclisation process, reactor content is separated into
Include pyrazole compound in organic layer when this two layers of organic layer and water layer, furthermore has used in process comprising being acylated sometimes
Machine alkali and organic solvent etc..On the other hand, include the secondary amine such as the dimethylamine detached in water layer, furthermore sometimes also include chlorination
Potassium, sodium chloride, inorganic hydroxide, hydrazine etc..Flash distillation can be carried out to organic layer to obtain pyrazole compound, distillation removal
The solvent comprising alkali can be re-used for be acylated process.Alternatively, it is also possible to remove organic base washing with water organic layer
Distillation removal solvent is later to obtain pyrazole compound.The pyrazole compound purified using these methods can also be into one
Step is made it dry by heating or decompression.
1,5- isomers contained in 1,3- isomers can be recrystallized by using solvent to remove.It can also be pre-
First make 1,3- isomers and 1,5- isomers, which is hydrolyzed, is converted to corresponding carboxylic acid, is then recrystallized.Alternatively, it is also possible to
It is purified using further progresss such as adsorption columns.
1,3- isomers comprising 1,5- isomers can be made a return journey depolarization by being dissolved in organic solvent and with salt acid elution
Property substance or specific impurity.As organic solvent, preferably water-soluble low organic solvent can exemplify benzene, toluene, diformazan
Benzene, ethylbenzene, Di Iso Propyl Ether, methylene chloride, dichloroethanes.It is preferred that toluene, dimethylbenzene.Reactor content after cyclization
In when including organic solvent, preferably remain the state or carry out washing removal secondary amine etc..Contact Temperature is 0-80 DEG C, but not
Be heated or cooled etc. and carry out at normal temperature.Processing solution/hydrochloric acid volume ratio is not particularly limited, but preferably
9/1~1/1.The processing time depends on the content of polar substances or specific impurities etc., concentration of hydrochloric acid, processing solution/hydrochloric acid body
Ratio, admixture are accumulated, usually 30min~3h.Contact method can apply common stirred tank, static mixer, pump circulation
Etc. any means, the method for being stood, being separated after being mixed preferably by stirred tank.Treated, and organic liquor is separated with hydrochloric acid
Afterwards.Distillation removal solvent, i.e., recyclable pyrazoles.
Beneficial effects of the present invention:
According to the method for the present invention, the synthesis for capableing of high yield colours few 2- acyl group -1- aminoacrylonitrile, and high receipts
The highly selective synthesis of rate colours few 1,3- disubstituted pyrazole -4- formonitrile HCN, and 1, the 5- disubstituted pyrazole -4- formonitrile HCN in product is different
Structure body content is substantially reduced.In particular, being starting with dialkyl group acrylonitrile in the preferred embodiment of synthetic method of the present invention
Raw material carries out acylation reaction with solid light in the presence of organic base, without any post-processing, nothing is only added in reaction solution
Machine alkali carries out next step cyclization, and energy high yield synthesizes few 1, the 3- disubstituted pyrazole -4- of 1,5- content of isomer
Formonitrile HCN.
Specific embodiment
The present invention is specifically described below by embodiment, following embodiment is served only for carrying out the present invention further
Illustrate, should not be understood as limiting the scope of the invention.
Comparative example 1
Acylation reaction: compound 2 is synthesized with trifluoroacetic acid and phosgene
By 26.82g (0.279mol) compound N, the triethylamine of N- dimethylaminopropionitrile (1), 62.2g (0.615mol)
It is added in the four-hole boiling flask of 1000ml with 95.2g toluene, the trifluoroacetic acid of 31.85g (0.279mol), 30min is added dropwise at 5 DEG C
Drop finishes；After persistently stirring 30min at 5 DEG C again, the 120g toluene solution that will contain 41.40g (0.4185mol) phosgene is slow
It instills in above-mentioned reaction solution, drips temperature after finishing and be maintained at 5 DEG C of reaction 2h stirred below, HPLC monitors fully reacting.Then, it is added
It after water 66g carries out liquid separation, is washed with saturated aqueous sodium carbonate, dry, diisopropyl is added in removed under reduced pressure solvent in residue
Ether stirs, and filters, obtains 43.42g hazel-color solid, HPLC content 98.1%, yield 81.00%.
Toluene layer before precipitation is compared with JIS tinctorial pattern, what what as a result red degree was strong be closest to for reddish brown.
Embodiment 1
Acylation reaction: with trifluoroacetic acid and solid photosynthesis compound 2
In addition to the toluene solution of the 120g of 28.44g (0.0958mol) solid light is replaced 41.40g (0.4185mol) carbon
Except the 120ml toluene solution of acyl chlorides, similarly feed intake reaction process with comparative example 1, be added after reaction water 66g into
It after row liquid separation, is washed with saturated aqueous sodium carbonate, dry, removed under reduced pressure solvent obtains 49.38g bright yellow solid, and HPLC contains
Amount 99.2%, yield 92.12%.
Toluene layer before precipitation is compared with JIS tinctorial pattern, and as a result weak faint yellow of red degree is closest to.
The result of comparative example 1 and embodiment 1 is shown in table 1
Table 1
As shown in table 1, few 2- acyl group -3- amino propylene is coloured with the synthesis that solid light replaces phosgene to be capable of high yield
Nitrile.
Comparative example 2
Cyclization: compound 3 is converted by compound 2
By the fluoro- 3- carbonyl butyronitrile (embodiment 1 of 2- ((dimethylamino) methylene) -4,4,4- three of 13.0g (67.7mmol)
Obtained product) and the toluene of 25ml be added into the four-hole boiling flask of 100ml, at -10 DEG C, 7.8g is added dropwise while stirring
The 40% methyl hydrazine aqueous solution of (67.7mmol), has exothermic phenomenon, 5min is added dropwise.Continue after stirring 2h at -10 DEG C, rises
It is layered after to room temperature, collects toluene layer, water layer is extracted with 10ml toluene, combining methylbenzene layer, toluene layer 15% salt pickling of 5ml
It washs, pH value is modulated to neutral, layering, collection toluene layer, precipitation obtains 11.00g depth salmon pink crystal, and yield 92.81%, 1,3- is different
Gou Ti ︰ 1,5- isomers (HPLC analysis, λ=224nm)=91.40 ︰ 8.60.
Toluene layer before precipitation is compared with JIS tinctorial pattern, and as a result the strong Radix Curcumae color of red degree is closest to.
Embodiment 2
Cyclization: compound 3 is converted by compound 2
In addition in the fluoro- 3- carbonyl butyronitrile (product that embodiment 1 obtains) of 2- ((dimethylamino) methylene) -4,4,4- three and
It is added in 25ml toluene solution except the sodium hydroxide of 1.3g (0.033mol), similarly test with comparative example 2, precipitation obtains
11.15g light yellow crystal, yield 94.02%, 1,3- Yi Gou Ti ︰ 1,5- isomers (HPLC analysis, λ=224nm)=99.5 ︰
0.5。
Toluene layer before precipitation is compared with JIS tinctorial pattern, and as a result the weak Radix Curcumae color of red degree is closest to.
The result of comparative example 2 and embodiment 2 is shown in table 2
Table 2
1,3- isomers: 3- Trifluoromethyl-1-methyl-1 H- pyrazoles-4- formonitrile HCN, 1,5- isomers: 5- Trifluoromethyl-1-
Methyl-1 H- pyrazoles -4- formonitrile HCN.
As shown in table 2,2- acyl-3-aminoacrylonitrile and hydrazine carry out cyclization in the presence of base, high can receive
The highly selective synthesis of rate colours few 1,3- disubstituted pyrazole -4- formonitrile HCN.
Comparative example 3
The operation for first repeating embodiment 1, only without any post-processing, then by the 2- containing triethylamine hydrochloride
The toluene reaction solution of ((dimethylamino) methylene) -4,4,4- tri- fluoro- 3- carbonyl butyronitrile is down to -15 DEG C, is being no more than -10 DEG C
Under, the 40% methyl hydrazine aqueous solution of 32.13g (0.279mol) is instilled while stirring, has exothermic phenomenon, 30min is added dropwise.
Continuing after stirring 2h at -10 DEG C, 80g water is added dropwise, is layered after being warmed to room temperature, collects toluene layer, water layer is extracted with 20ml toluene,
PH value is modulated neutral, layering, collects toluene layer by combining methylbenzene layer, the salt acid elution of toluene layer 10ml 15%, and precipitation obtains
The thick pyrazoles of 45.48g brownish red, crude yield 93.10%, total pyrazoles (1,3- isomers and 1, the pyrazoles that 5- isomers merges
Close object) purity is 98.8 area %, 1,3- Yi Gou Ti ︰ 1,5- isomers (HPLC analysis, λ=224nm)=31.46 ︰ 68.54.
For by 1 synthesizing pyrazole of compound, total pyrazoles yield is 91.98%, 1,3- isomers yield is 28.93%.
Embodiment 3
In addition in the fluoro- 3- carbonyl butyronitrile of 2- ((dimethylamino) methylene) -4,4,4- three containing triethylamine hydrochloride
It is added in toluene reaction solution except the sodium hydroxide of 11.16g (0.279mol), is similarly tested with comparative example 3.It is tied
Fruit, obtains the thick pyrazoles of 45.34g glassy yellow, crude yield 92.81%, and total pyrazoles purity is 99.5 area %, 1,3- isomery
Ti ︰ 1,5- isomers (HPLC analysis, λ=224nm)=99.1 ︰ 0.9.For by 1 synthesizing pyrazole of compound, total pyrazoles yield is
92.34%, 1,3- isomers yield is 91.51%.
Embodiment 4
In addition in the fluoro- 3- carbonyl butyronitrile of 2- ((dimethylamino) methylene) -4,4,4- three containing triethylamine hydrochloride
It is added in toluene reaction solution except the potassium hydroxide of 15.65g (0.279mol), is similarly tested with comparative example 3.It is tied
Fruit, obtains the thick pyrazoles of 44.46g glassy yellow, crude yield 91.01%, and total pyrazoles purity is 96.81 area %, 1,3- isomery
Ti ︰ 1,5- isomers (HPLC analysis, λ=224nm)=99.3 ︰ 0.7.For by 1 synthesizing pyrazole of compound,
Total pyrazoles yield is 88.10%, and 1,3- isomers yield is 87.49%.
The result of embodiment 1, comparative example 2, embodiment 2, comparative example 3, embodiment 3 and embodiment 4 is shown in table 3.
Table 3
As shown in table 2, by desalination is removed in the washing not from the reaction solution that acylation reaction obtains add inorganic base come into
Row cyclization highly selective in high yield can obtain 1,3- disubstituted pyrazole -4- formonitrile HCN.
Derive according to the present invention, as described above, it is possible to which the synthesis of high yield colours few 2- acyl group -1- aminoacrylonitrile
Object, and synthesis highly selective in high yield colour few 1,3- disubstituted pyrazole -4- formonitrile HCN, 1,5- bis- can be replaced pyrrole
The content of azoles -4- formonitrile HCN is controlled to 0.4%.Therefore the present invention can be used as medicine/pesticide useful intermediates pyrazol derivative produce
The method of industry.
Claims (25)
1. a kind of synthetic method of the 6-carbonitrile derivatives of pyrazoles containing halogen, it is characterised in that dialkyl group acrylonitrile shown in formula (1) with
Carboxylic acid shown in formula (2) carries out acylation reaction in the presence of halogenating agent and organic base, obtains 2- acyl group-shown in formula (3)
1- aminoacrylonitrile, then cyclization is carried out under alkaline condition with substitution hydrazine shown in formula (4), obtain pyrrole shown in formula (5)
Azoles 6-carbonitrile derivatives；
Wherein, R1、R2、R3It is separately C1~10Alkyl or C1-10Halogenated alkyl, R4For C1-10Alkyl, C1-10Halogenated alkyl,
C1-4The C that alkoxy replaces1-10Alkyl, C1-4The C that halogenated alkoxy replaces1-10Alkyl, C1-4The C that alkylthio group replaces1-10Alkyl,
C3-8Naphthenic base, C3-8Halogenated cycloalkyl or aryl；Described halogenated dose is solid light or surpalite.
2. according to the method described in claim 1, it is characterized in that R1Or R2It is separately C1~4Alkyl or C3-6Naphthenic base,
R3For C1-4Halogenated alkyl, R4For C1~4Alkyl, C1-4Halogenated alkyl, C3-6Naphthenic base or phenyl.
3. according to the method described in claim 2, it is characterized in that R1Or R2It is separately methyl, ethyl, n-propyl, different
Propyl, normal-butyl, sec-butyl, tert-butyl, cyclohexyl or cyclopenta；R3For C1-4Fluoro-alkyl, C1-4Chloro alkyl or C1-4Chlorine fluorine
Substituted alkyl；R4For C1~4Alkyl, C1-4Fluoro-alkyl, C3-6Naphthenic base or phenyl.
4. according to the method described in claim 3, it is characterized in that R3For trifluoromethyl, difluoromethyl, a methyl fluoride, five fluorine second
Base, 2,2,2- trifluoroethyl, 2,2- bis-fluoro ethyls, tetra- fluoro ethyl of 1,1,2,2-, trichloromethyl, dichloromethyl, chloromethyl, five
Chloroethyl, 2,2,2- trichloroethyl, 2,2- Dichloroethyl, tetra- chloroethyl of 1,1,2,2-, chlorodifluoramethyl- or dichlorofluoromethyl.
5. according to the method described in claim 3, it is characterized in that R4For methyl, ethyl, n-propyl, isopropyl, tert-butyl, two
Methyl fluoride, trifluoromethyl, hydroxymethyl, cyclopropyl or phenyl.
6. according to the method described in claim 1, it is characterized in that the organic base is selected from tertiary amine, pyrrole in acylation reaction
Pyridine or pyridine derivate；The reaction dissolvent is nonaqueous solvents.
7. according to the method described in claim 6, it is characterized in that the organic base is selected from pyridine, 2- in acylation reaction
Picoline, 3- picoline, 4- picoline, 4-dimethylaminopyridine, trimethylamine, triethylamine, Tri-n-Propylamine, three isopropyls
Amine, tri-n-butylamine, N- methyl di-n-butyl amine, N- methyl diisobutyl amine or N- methyl di-t-butyl amine.
8. according to the method described in claim 6, it is characterized in that in acylation reaction, the reaction dissolvent be petroleum ether,
N-hexane, normal heptane, hexamethylene, benzene,toluene,xylene, naphthalane, chlorobenzene, dichloro-benzenes, methylene chloride, chloroform, carbon tetrachloride,
One or more of dichloroethanes, trichloroethanes.
9. according to the method described in claim 1, it is characterized in that acylation reaction temperature is -20 DEG C in acylation reaction
~50 DEG C；Reaction time is 10min~10h.
10. according to the method described in claim 9, it is characterized in that acylation reaction temperature is -10 DEG C in acylation reaction
~45 DEG C.
11. according to the method described in claim 10, it is characterized in that acylation reaction temperature is 0 DEG C in acylation reaction
~40 DEG C.
12. according to the method described in claim 1, it is characterized in that in acylation reaction, dialkyl amido Bing Xi Jing ︰ carboxylic
Suan ︰ halogenating agent: the molar ratio of organic base is 1 ︰, 0.5~3 ︰, 0.1~3 ︰ 1~6.
13. according to the method for claim 12, it is characterised in that in acylation reaction, dialkyl amido Bing Xi Jing ︰ carboxylic
Suan ︰ halogenating agent: the molar ratio of organic base is 1 ︰, 0.5~1.5 ︰, 0.1~1 ︰ 1~3.
14. according to the method for claim 13, it is characterised in that in acylation reaction, dialkyl amido Bing Xi Jing ︰ carboxylic
Suan ︰ halogenating agent: the molar ratio of organic base is 1 ︰, 0.9~1.1 ︰, 0.3~0.6 ︰ 1.8~2.3.
15. according to the method described in claim 1, it is characterized in that the substitution hydrazine is methyl hydrazine or second in cyclization
Base hydrazine；The alkali is hydroxide, carbonate or the bicarbonate of alkaline-earth metal or alkali metal.
16. according to the method for claim 15, it is characterised in that in cyclization, the alkali is sodium hydroxide, hydrogen-oxygen
Change potassium, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, saleratus or sodium bicarbonate.
17. according to claim 1 or method described in 15, it is characterised in that in cyclization, the dosage of alkali is relative to often rubbing
That 2- acyl-3-aminoacrylonitrile is 0.05~2mol；The dosage of hydrazine is replaced to be equivalent to every mole of 2- acyl group -3- amino propylene
Nitrile is 0.5~2mol.
18. according to the method for claim 17, it is characterised in that in cyclization, the dosage of alkali is relative to every mole of 2-
Acyl-3-aminoacrylonitrile is 0.1~1mol.
19. according to the method for claim 17, it is characterised in that in cyclization, the dosage of alkali is relative to every mole of 2-
Acyl-3-aminoacrylonitrile is 0.1~0.5mol.
20. according to the method for claim 17, it is characterised in that in cyclization, replace the dosage of hydrazine to be equivalent to and often rub
Your 2- acyl-3-aminoacrylonitrile is 0.8~1.2mol.
21. according to the method described in claim 1, it is characterized in that in cyclization, reaction dissolvent be petroleum ether, just oneself
Alkane, normal heptane, hexamethylene, benzene,toluene,xylene, naphthalane, chlorobenzene, dichloro-benzenes, methylene chloride, chloroform, carbon tetrachloride, dichloro
Ethane, trichloroethanes, diethyl ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), tert amyl methyl ether(TAME), dioxanes, tetrahydrofuran, 1,2-
Dimethoxy-ethane, 1,2- diethoxyethane, phenyl ether, acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), cyclohexanone, acetonitrile, third
Nitrile, n-Butyronitrile, isobutyronitrile, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N- methyl formyl aniline, N- methylpyrrole
Alkanone, dimethyl sulfoxide or sulfolane.
22. according to the method for claim 21, it is characterised in that in cyclization, reaction dissolvent be toluene, dimethylbenzene,
Chlorobenzene, n-hexane or hexamethylene.
23. according to the method described in claim 1, it is characterized in that reaction temperature is -80 DEG C~30 DEG C in cyclization.
24. according to the method for claim 23, it is characterised in that in cyclization, reaction temperature is -20 DEG C~20 DEG C.
25. according to the method for claim 24, it is characterised in that in cyclization, reaction temperature is 10min~10h.
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