JP2008504361A - Method for producing synthetic intermediate useful for production of pyrazole compound - Google Patents

Abstract

The present invention provides compounds of formula (I) wherein R ⁹ is C _1-8 alkyl, C _3-8 cycloalkyl, (CH ₂ ) _n Ph, and (CH ₂ ) _n heteroaryl {where n = 0 Each group is optionally halogen, hydroxy, cyano, nitro, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkanoyl, C ₁ Independent from _-4 haloalkanoyl, C _1-4 alkylsulfinyl, C _1-4 haloalkylsulfinyl, C _1-4 alkylsulfonyl, C _1-4 haloalkylsulfonyl, C _3-8 cycloalkyl, and C _3-8 halocycloalkyl Wherein R ⁹ can be hydrogen, wherein the method is 20 in a polar solvent, and is substituted on any carbon atom by one or more groups selected as formula (II) [wherein in the not exceeding temperature ° C., R ⁹ is above The cyanoacetate represented by as in a 'defined, which method comprises reacting with formaldehyde cyanohydrin and an inorganic base.

Description

  The present invention relates to a process for preparing certain cyanomethylpropane derivatives (eg 2,3-dicyanopropionate) and the use of these compounds in the synthesis of insecticides and insecticide intermediates. In particular, the present invention relates to the production of ethyl-2,3-dicyanopropionate.

  Ethyl-2,3-dicyanopropionate is an intermediate used in the production of arylpyrazole rings, and many of the arylpyrazole rings are lethal to a wide range of ectoparasites. In particular, 2,3-dicyanopropionate derivatives are particularly useful for the preparation of 1-phenyl pyrazole and 1-pyridyl pyrazole compounds.

Initially, alkylation of ethyl cyanoacetate was performed using DMF / K ₂ CO ₃ (DAWhite, Synth. Commun., 7 (8), 559, 1977), and DBU / toluene (N. Cho et al., Bull. Chem. Soc Jpn., 156, 1716-19, 1979) using chloroacetonitrile. Both methods are said to give only monoalkylation, but in practice both only dialkylation is observed.

Thorpe and Higson's method (JFThorpe, A. Higson, JCS, 89, 1455, 1906) is based on formaldehyde cyanohydrin (known as glycolonitrile) at temperatures above room temperature, as described below. It relates to alkylating ethyl cyanoacetate using ethanol solution and NaOMe.

で表される不飽和生成物を与えるという点である。 Unfortunately, glycolonitrile is only available as an aqueous solution that must be Soxhlet extracted with ether before solvent displacement with ethanol. The process has the disadvantage that only low yields can be obtained and typically yields yields varying from 20 to 50% and often on the low side of this range. One problem with this specific reaction is that many of the ethyl cyanoacetates are self-aggregating, as identified by H. Junek, W. Wilfinger, Monatsch. Chem., 1970 (101), 1208. ,below:

The unsaturated product represented by this is given.

Another literature method (DAWhite, JCS Perkin I 1926, 1976) is described below and the use of acrylonitrile with CO ₂ and tetraethylammonium cyanide is the desired 2,3-dicyanopropionate product. Gave some. However, this method has the disadvantage of producing many by-products.

  The preparation of 2,3-dicyanopropionate reported by Thorpe and Higson by reacting formaldehyde cyanohydrin with ethyl cyanoacetate sodium salt isolates the formaldehyde cyanohydrin intermediate described above. Suffers from a serious drawback that is needed first. EP 888291 attempts to overcome the disadvantages associated with using formaldehyde cyanohydrins by providing a method for preparing cyanomethyl propane derivatives. The method completely avoids the use of formaldehyde cyanohydrin and consequently avoids the dimerization side reaction involving formaldehyde cyanohydrin. Unfortunately, the process requires the use of cyanide salts, so careful handling is always required and the reaction conditions must always be maintained at a basic pH so that hydrogen cyanide is not liberated. Has the problem. The reaction also requires a supply of formaldehyde or paraformaldehyde that is more difficult to handle.

  It is an object of the present invention to provide a process for the preparation of 2,3-dicyanopropionate derivatives that overcomes the problems that arise in prior art processes. One or more of the following objectives: to avoid the use of formaldehyde and cyanide salts, to avoid dimerization side reactions reported in the literature, and to provide the desired product directly in high yield and purity, It is also an object of the present invention to provide a method that satisfies

  It is also an object of the present invention to provide a route to 2,3-dicyanopropionate derivatives that provide improved yields over existing routes. It is also an object of the method of the invention to avoid the use of unnecessary synthesis steps or reagents and / or purification steps. An important objective for that is to provide a method that minimizes the number of synthesis steps required and avoids the problem of competing reactions and / or disposal of hazardous substances. It is also an object of the present invention to provide a quick and thus economical route to 2,3-dicyanopropionate derivatives.

  It is also an object of the present invention to provide a convenient route to aryl-pyrazole derivatives, preferably in reactions that can be completed within a relatively short time. Thus, it is an object of the present invention to provide an efficient synthetic method for producing arylpyrazole derivatives that make available new compounds.

  Despite all the literature reports and problems observed in EP 888291, we have discovered a new process that can produce 2,3-dicyanopropionate derivatives in excellent yields using formaldehyde cyanohydrin.

  It has been discovered that in the reaction between cyanoacetate and formaldehyde cyanohydrin, carefully controlling the temperature gave a fairly clean and complete reaction. Furthermore, it has been discovered that the reaction can be carried out using glyconitrile without the need to purify it before use.

In particular, the reaction between ethyl cyanoacetate and aqueous glyconitrile is carried out in a polar solvent such as DMF and in the presence of an inorganic base such as K ₂ CO ₃ under the condition that the temperature is carefully controlled. I discovered that I could break. In practice, this method of guaranteeing temperature does not raise the temperature above 20 ° C. The reaction of the present invention is successful and provides the desired product in fairly good yields with yields of up to 95%.

  There is a further advantage that the process of the present invention uses aqueous glyconitrile and avoids the need for Sockley extraction of aqueous glyconitrile. This fact allows for significant time and cost savings. This is because to date, it has always been necessary to purify glycolonitrile before use. Purification is usually accomplished by continuous extraction of aqueous glycolonitrile with diethyl ether in a Sockley extractor. However, there is a problem that in this process glyconitrile can be heated and consequently decomposed to hydrogen cyanide and formaldehyde. This is a serious problem. In addition, aqueous glyconitriles usually contain a stabilizer that is lost when the material is refluxed in a Sockley extractor. This also leads to the degradation of glyconitrile.

  A further disadvantage of the prior art methods is that the purification process is time consuming. This thus adds complexity to the method and makes it less economical to implement. The method of the present invention can surprisingly be carried out without the need for the purification step under the condition that the reaction conditions are carefully controlled. This saves considerable time and money.

  While prior art methods require solid reagents, the method of the present invention has advantages over prior art methods in that the reagents are in liquid form. In particular, the handling of solid or gaseous reagents is much more problematic than the handling of liquids if the contained material is toxic or harmful. There is also the advantage that the addition of liquid reagents is much easier to control than the addition of solids or gases.

  Increasing the temperature above 20 ° C. results in a significant decrease in yield and produces a major impurity; this impurity is assumed to be the impurity reported by Thorpe and Higson.

[式中、
Ｒ⁹は、Ｃ_1-8アルキル、Ｃ_3-8シクロアルキル、（ＣＨ₂）_nＰｈ、及び（ＣＨ₂）_nヘテロアリール｛ここで、ｎ＝０、１、又は２である｝から選ばれ、これらの基の各々は、任意の炭素原子上で以下の：ハロゲン、ヒドロキシ、シアノ、ニトロ、Ｃ_1-4アルコキシ、Ｃ_1-4ハロアルコキシ、Ｃ_1-4アルカノイル、Ｃ_1-4ハロアルカノイル、Ｃ_1-4アルキルスルフィニル、Ｃ_1-4ハロアルキルスルフィニル、Ｃ_1-4アルキルスルフォニル、Ｃ_1-4ハロアルキルスルフォニル、Ｃ_3-8シクロアルキル、及びＣ_3-8ハロシクロアルキルから独立して選ばれる１以上の基により場合により置換されてもよく、
そしてＲ⁹は水素でありうる]
で表される化合物を製造するための方法であって、当該方法が以下の式（II）：

[式中、Ｒ⁹は上で定義される通りである]
で表されるシアノアセタートを、２０℃を超えない室温で極性溶媒中においてホルムアルデヒド・シアノヒドリン及び無機塩基と反応させることを含む、前記方法が提供される。 According to one embodiment of the present invention, the following formula (I):

[Where
R ⁹ is selected from C _1-8 alkyl, C _3-8 cycloalkyl, (CH ₂ ) _n Ph, and (CH ₂ ) _n heteroaryl {where n = 0, 1, or 2}. Each of these groups on any carbon atom: halogen, hydroxy, cyano, nitro, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkanoyl, C _1-4 haloalkanoyl , C _1-4 alkylsulfinyl, C _1-4 haloalkylsulfinyl, C _1-4 alkylsulfonyl, C _1-4 haloalkylsulfonyl, C _3-8 cycloalkyl, and C _3-8 halocycloalkyl. Optionally substituted by one or more groups,
And R ⁹ can be hydrogen]
In which the method is represented by the following formula (II):

[Wherein R ⁹ is as defined above]
Wherein the cyanoacetate is reacted with formaldehyde cyanohydrin and an inorganic base in a polar solvent at room temperature not exceeding 20 ° C.

Preferably, R ⁹ is H; C _1-8 alkyl, CH ₂ Ph, or Ph, each independently from the following: halogen, hydroxy, C _1-4 alkoxy, and C _1-4 haloalkoxy Optionally substituted by one or more selected groups. Here, the halogen atoms may be the same or different.
Most preferably R ⁹ is methyl or ethyl.

  In the above definition, halo means fluoro, chloro, bromo or iodo. The alkyl and alkoxy groups containing the essential number of carbon atoms can be unbranched or branched chains, except where indicated. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

  Suitable inorganic bases include alkali metal carbonates and hydroxides.

  The product is conveniently isolated, for example, by acidifying the reaction mixture with a mineral acid such as sulfuric acid or hydrochloric acid to give the compound of formula (I) in high yield. In one embodiment, high yields can be obtained when the reaction mixture is acidified without the addition of water.

  The reaction is generally carried out using about 1 molar equivalent of a compound of formula (II); about 0.95 to 1.0 molar equivalent of an inorganic base, and about 1 molar equivalent of formaldehyde cyanohydrin.

This reaction may be performed in the presence of a solvent. Preferably the reaction is carried out in a polar solvent. The solvent should be water miscible in a preferred embodiment. The solvent is usually an alcohol such as methanol, ethanol, or propanol; or dimethylformamide (DMF); DMSO (dimethylsulfoxide); DMAC (dimethylacetamide); MeCN; N-methyl pyrrolidone (NMP); Tetrahydrofuran (THF); or dimethoxyethane. Particularly preferred solvents are C ₁ -C ₈ alcohols such as methanol or ethanol.

  The reaction temperature is critical and the reaction must be carried out at a temperature not exceeding 20 ° C. In general, the best results are obtained by introducing the inorganic base after mixing the other reactants.

  The compounds of formula (I) are useful in the preparation of compounds that are active as insecticides, as described, for example, in European Patent Publication Nos. 0295117 and 0234119, and WO 93/06089.

[式中、
Ｒ¹は、水素；ハロ；Ｃ_1-6アルキル及びＣ_1-6アルコキシ（ここでこれらの各々は、場合により、１以上の独立して選ばれるハロ原子で置換される）；−Ｓ（Ｏ）_nＣ_1-6アルキル；及びペンタフルオロチオ；シアノ；Ｃ_1-6アルカノイル（ここで、Ｃ_1-6アルカノイルは、場合により１以上の独立して選ばれるハロ原子で置換されうる）から独立して選ばれる１以上の基により場合により置換されるアリール又はヘテロアリールであり、
Ｒ²は、水素；ハロ；Ｃ_1-6アルキル；−Ｓ（Ｏ）_nＣ_1-6アルキル；−（ＣＨ₂）_mＣ_3-8シクロアルキル（ここで、−（ＣＨ₂）_mＣ_3-8シクロアルキルは、ハロ及びＣ_1-6アルキルから独立して選ばれる１以上の置換基で場合により置換されうる）；シアノ；ニトロ；−（ＣＨ₂）_mＮＲ^aＲ^b；Ｃ_1-6アルカノイル（ここでＣ_1-6アルカノイルは、ハロ及びＣ_1-4アルコキシから独立して選ばれる１以上の基により場合により置換されうる）；フェニル；オキサジアゾール；−Ｃ（Ｏ）ＮＲ^aＲ^b；−ＮＲ^aＣ（Ｏ）Ｒ^b；Ｃ_2-6アルケニル；及びＣ_2-6アルキニルから選ばれ；
Ｒ⁵は、水素；ヒドロキシ；Ｃ_1-6アルキル；ＮＲ^aＲ^b；ハロ及びＣ_1-6アルコキシから選ばれ；
各ｎは、独立して０、１、又は２であり；
各ｍは、独立して０、１、２、又は３であり；
そしてここで、
ｈｅｔは、４〜７員環の複素環基を表し、当該基は、芳香族又は非芳香族であり、そして、窒素、酸素、硫黄、及びその混合物から選ばれる１以上のヘテロ原子を含み、そしてここで、当該複素環は、結合価が許容する場合、以下の：ハロ、シアノ、ニトロ、Ｃ_1-6アルキル、Ｃ_1-6ハロアルキル、Ｃ_1-6アルコキシ、ＯＣ（Ｏ）Ｃ_1-6アルキル、Ｃ（Ｏ）Ｃ_1-6アルキル、Ｃ（Ｏ）ＯＣ_1-6アルキル、及びＮＲ^aＲ^bから選ばれる１以上の置換基で場合により置換及び/又は末端化され（terminated)、
各Ｃ_1-6アルキル基は、分枝状であるか又は非分枝状であり、そして場合により、シアノ；ハロ；ヒドロキシ；ニトロ；Ｃ_1-6アルコキシ；ＮＲ^aＲ^b；Ｓ（Ｏ）_nＣ_1-6アルキル；Ｓ（Ｏ）_nＣ_3-8シクロアルキル；Ｓ（Ｏ）_nＣ_1-6アルキルｈｅｔ；Ｃ_3-8シクロアルキル；及びフェニルから独立して選ばれる１以上の基により場合により置換されうる；
各フェニルは、場合により、シアノ；ハロ；ヒドロキシ；ニトロ；Ｃ_1-6アルキル；Ｃ_1-6ハロアルキル；及びＣ_1-6アルコキシから独立して選ばれる１以上の置換基により置換されてもよく；そして
各Ｒ^a及びＲ^bは、水素；Ｃ_1-6アルキル；及びＣ_3-8シクロアルキル（ここでＣ_3-8シクロアルキルは、ハロ及びＣ_1-6アルキルから独立して選ばれる１以上の置換基で場合により置換されてもよい）から独立して選ばれ；或いは
Ｒ^a及びＲ^bは、それらが結合する窒素原子と一緒になって、４〜７員環を形成してもよい]
で表される化合物の製造方法であって、当該方法が以下の：
（ａ） 上で定義される式（ＩＩ）のシアノアセタートを、シアニド塩及びホルムアルデヒド若しくはその元化合物（source）と反応させて、上で定義される式（Ｉ）の化合物を与え；そして
（ｂ） こうして得られた式（Ｉ）の化合物を、以下の式（ＩＶ）：

[式中、Ｒ¹は上で定義されるとおりである]
で表される化合物のジアゾニウム塩と反応させて、以下の式（Ｖ）：

[式中、Ｒ、Ｒ¹、及びＲ²は上で定義されるとおりである]
で表される化合物を与えて、次に上記式（Ｖ）の化合物の環化を行う
を含む、前記製造方法を提供する。 In particular, the method of the invention may form part of the in situ production of another insecticide intermediate. Thus, in a further aspect, the present invention provides the following formula (III):

[Where
R ¹ is hydrogen; halo; C _1-6 alkyl and C _1-6 alkoxy, each of which is optionally substituted with one or more independently selected halo atoms; ) _N C _1-6 alkyl; and pentafluorothio; cyano; C _1-6 alkanoyl, wherein C _1-6 alkanoyl may be optionally substituted with one or more independently selected halo atoms. Aryl or heteroaryl optionally substituted with one or more groups selected as
R ² is hydrogen; halo; C _1-6 alkyl; -S (O) _n C _1-6 alkyl ;-( CH _{2) m} C _3-8 cycloalkyl _{(wherein, - (CH 2) m C} 3 _-8 cycloalkyl may be optionally substituted with one or more substituents independently selected from halo and C _1-6 alkyl); cyano; nitro; — (CH ₂ ) _m NR ^a R ^b ; C _{1- 6} alkanoyl (wherein C _1-6 alkanoyl may be optionally substituted by one or more groups independently selected from halo and C _1-4 alkoxy); phenyl; oxadiazole; —C (O) NR ^a R ^b ; selected from —NR ^a C (O) R ^b ; C _2-6 alkenyl; and C _2-6 alkynyl;
R ⁵ is selected from hydrogen; hydroxy; C _1-6 alkyl; NR ^a R ^b ; halo and C _1-6 alkoxy;
Each n is independently 0, 1, or 2;
Each m is independently 0, 1, 2, or 3;
And here
het represents a 4- to 7-membered heterocyclic group, which group is aromatic or non-aromatic and contains one or more heteroatoms selected from nitrogen, oxygen, sulfur, and mixtures thereof; And where the heterocycle is, if allowed by valence, the following: halo, cyano, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, OC (O) C _1- Optionally substituted and / or terminated with one or more substituents selected from ₆ alkyl, C (O) C _1-6 alkyl, C (O) OC _1-6 alkyl, and NR ^a R ^b ,
Each C _1-6 alkyl group is branched or unbranched, and optionally cyano; halo; hydroxy; nitro; C _1-6 alkoxy; NR ^a R ^b ; S (O) one or more groups independently selected from: _n C _1-6 alkyl; S (O) _n C _3-8 cycloalkyl; S (O) _n C _1-6 alkyl het; C _3-8 cycloalkyl; Can be optionally substituted by;
Each phenyl is optionally substituted with one or more substituents independently selected from cyano; halo; hydroxy; nitro; C _1-6 alkyl; C _1-6 haloalkyl; and C _1-6 alkoxy. And each R ^a and R ^b is hydrogen; C _1-6 alkyl; and C _3-8 cycloalkyl, wherein C _3-8 cycloalkyl is independently selected from halo and C _1-6 alkyl; R ^a and R ^b may be taken together with the nitrogen atom to which they are attached to form a 4 to 7 membered ring. Good]
Wherein the method is the following:
(A) reacting a cyanoacetate of formula (II) as defined above with a cyanide salt and formaldehyde or its source compound to give a compound of formula (I) as defined above; and (b) The compound of formula (I) thus obtained is converted into the following formula (IV):

[Wherein R ¹ is as defined above]
Is reacted with a diazonium salt of a compound represented by the following formula (V):

[Wherein R, R ¹ and R ² are as defined above]
Wherein the compound of formula (V) is cyclized.

In one embodiment, R ¹ is preferably phenyl or pyridyl, and more preferably R ¹ is phenyl.

Preferably, when the R ¹ group is phenyl, the R ¹ group is substituted at 3 positions, and more preferably at the 2-, 4-, and 6-positions, halogen, C _1-6 alkyl, C Substituted with any substituent selected from the group comprising _1-6 alkoxy, C _1-6 alkylthio, SF ₅ , and —COOC _1-8 alkyl, wherein the optional substituent is itself a chemical group. Where possible, they may be substituted by one or more independently selected halogen atoms.

More preferably, R ¹ is 2,4,6-trisubstituted phenyl, wherein the 2- and 6-position substituents are each independently selected from hydrogen and halo; and the 4-position A substituent of C _1-4 alkyl optionally substituted with one or more independently selected halo atoms; C _1-4 alkoxy optionally substituted with one or more independently selected halo atoms; 1 S (O) _n C _1-4 alkyl optionally substituted with the above independently selected halo atoms; selected from halo and pentafluorothio.

More preferably, R ¹ is a phenyl group having substituents at the 2-, 4-, and 6-positions, and the substituents at these positions are chloro, trifluoromethyl, trifluoromethoxy, and pentafluorothio Selected independently from

Even more preferably, R ¹ is a phenyl group wherein the 2- and 6-position substituents are chloro and the 4-position substituent is selected from trifluoromethyl, trifluoromethoxy, and pentafluorothio It is.

When R ¹ is 3,5-disubstituted pyridin-2-yl and the 3-position substituent is selected from hydrogen and halo; and the 5-position substituent is as defined above C _1-6 alkyl substituted by: C _1-6 alkoxy optionally substituted with one or more independently selected halo atoms; S (O) _n C _1-6 alkyl; halo, and pentafluorothio It is preferably 3,5-disubstituted pyridin-2-yl selected from

  Preferably, het contains 1, 2 or 3 heteroatoms and is independently selected from one N atom, one or two O atoms and one or two S atoms. Represents a 6-membered heterocyclic group.

More preferably, het is preferably selected from pyrazolyl, imidazolylyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, thiophenyl, pyrrolyl, and pyridyl, where the group is optionally C _1-6 It can be substituted by one or more groups independently selected from alkyl and halogen.

More preferably, het is selected from pyridyl, pyrazolyl, oxazolyl and isoxazolyl.
More preferably, het is selected from pyridyl and oxazolyl.

Preferably, R ² is cyano; C _1-6 alkyl; and C _3-8 cycloalkyl optionally substituted with one or more substituents independently selected from halo and C _1-6 alkyl; halo and C C _1-6 alkanoyl optionally substituted with one or more groups independently selected from _1-4 alkoxy; and halo.

More preferably R ² is selected from C _1-6 alkyl and cyano.
Even more preferably R ² is selected from trifluoromethyl and cyano.
Most preferably R ² is cyano.

Preferably R ⁵ is — (CH ₂ ) _m NR ^a R ^b , where R ^a and R ^b are as defined above, more preferably m = 0, and most preferably R ⁵ is amino.

  The compounds of formula (V) above have asymmetric centers giving rise to different enantiomers and may exist as different geometric isomers or mixtures thereof. All such forms are encompassed by the present invention.

  In this process, the product of reaction step (a) is generally acidified with an alcoholic solution of mineral acid, preferably an ethanolic solution of hydrogen chloride. This ensures that all acid by-products of step (a) (leading to the corresponding compound of formula (I) where R is replaced by hydrogen) are reesterified.

  Reaction step (b) is generally carried out in the presence of an inert solvent such as water, acetonitrile, dichloromethane or DMF, or more preferably an alcohol solvent (eg methanol or ethanol) and optionally (eg acetic acid). Buffered with sodium).

  The diazonium salt of the compound of formula (IV) may be prepared using diazotizing reagents known in the literature and with a molar equivalent of sodium nitrite and mineral acid (eg hydrochloric acid or sulfuric acid) of about −10 It is conveniently prepared at a temperature of from about 0C to about 50C, more preferably from about 0C to about 5C. The diazonium salt of the compound of formula (IV) was generally produced in situ as a solvent such as an alcohol to quickly reduce the diazonium salt. In this reaction, the reaction of the diazonium salt of the compound of formula (IV) to give the compound of formula (V) generally occurs faster than the reduction of the diazonium salt.

  Preferably subsequent hydrolysis using mild conditions with a base such as sodium hydroxide, sodium carbonate or aqueous ammonia to cyclize the compound of formula (V) to the compound of formula (III). May be necessary.

The molar ratio of the compound of formula (II) :( IV) is generally about 1.5: 1 to about 1: 4, preferably about 1.3: 1 to about 1: 1, more preferably Is about 1.1: 1.
The following non-limiting examples illustrate the invention.

Example 1
Preparation of ethyl-αβ-dicyanopropionate Ethyl cyanoacetate was stirred in 5 ml / g DMF and 1 equivalent of glycolonitrile was added dropwise maintaining the temperature below 20 ° C. Next, since a slight exotherm was observed when the base was added, the temperature was adjusted and K ₂ CO ₃ was added little by little. The reaction was allowed to stir overnight at room temperature. Excess K ₂ CO ₃ was filtered off and the filtrate was acidified to pH 4 with 4N HCl. The solvent was removed under moderate suction and the residue was dissolved in CH ₂ Cl ₂ , dried over MgSO ₄ and stripped to give an orange / red oil in 95% yield. The superiority of the method of the present invention is clear compared to the prior art.

Example 2
Ethyl cyanoacetate (511.7 g; 4.52 mol) was dissolved in DMF (1.81 L) and the solution was stirred at room temperature. Glycolonitrile was added to the above solution over 5 minutes using ice / water cooling while maintaining the reaction temperature so as not to exceed 20 ° C. Potassium carbonate (625.3 g, 4.52 mol) is then added in portions to the reaction mixture over 30 minutes with ice / water cooling to maintain the reaction temperature between 15-25 ° C. The reaction was allowed to stir for 16 hours. The reaction mixture was filtered to remove inorganic components, and the pH of the reaction mixture was adjusted to pH 4 using concentrated HCl. The resulting orange / yellow slurry was evaporated at 80 ° C. under reduced pressure to remove DMF. Ethyl acetate (4.25 ml / g) was added and the reaction mixture was stirred for 10 minutes, after which the reaction mixture was filtered. The resulting filter cake is washed with ethyl acetate (0.21 ml / g) and the filtrate is washed with dilute salt solution (3.2 ml / g) followed by saturated salt solution (2.1 ml / g). Washed twice. The final filtrate was then evaporated under reduced pressure to give 527.7 g of product representing a 77% yield of dark brown / black oil. NMR (CDCl ₃ ) data was consistent with the structure.

  The method exemplified above is applied to produce other αβ-dicyanopropionate derivatives.

Example 3
Preparation of 5-amino-3-cyano-1- (2,6-dichloro-4-trifluoromethyl-phenyl) pyrazole As described in Reference Example 2 of EP0295117, 5-amino-3-cyano- 1- (2,6-Dichloro-4-trifluoromethyl-phenyl) pyrazole can be prepared from 2,6-dichloro-4-trifluoromethyl aniline and ethyl-2,3 dicyanopropionate. The compounds are useful starting materials for the synthesis of 4-substituted-1-aryl pyrazoles, which can be obtained from the materials described for example in EP 0946515 by conventional synthetic methods.

Claims (1)

The following formula (I):

[Where
R ⁹ is selected from C _1-8 alkyl, C _3-8 cycloalkyl, (CH ₂ ) _n Ph, and (CH ₂ ) _n heteroaryl {where n = 0, 1, or 2}. Each of the groups is halogen, hydroxy, cyano, nitro, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 alkanoyl, C _1-4 haloalkanoyl, C _1-4 alkylsulfinyl, C ₁ Any carbon atom by one or more groups independently selected from _-4 haloalkylsulfinyl, C _1-4 alkylsulfonyl, C _1-4 haloalkylsulfonyl, C _3-8 cycloalkyl, and C _3-8 halocycloalkyl Optionally substituted above; and R ⁹ can be hydrogen]
Wherein the method comprises the following formula (II):

[Wherein R ⁹ is as defined above]
And reacting formaldehyde cyanohydrin and an inorganic base in a polar solvent at a temperature not exceeding 20 ° C.