JPH069499A - Production of halogenocyclopropanecarboxylic acid derivative - Google Patents

Abstract

PURPOSE:To industrially and advantageously obtain the compound useful as a raw material, etc., for new quinolone-based synthetic antimicrobial agents by reacting a 1,1-dihalogenoethylene with a diazoacetic acid derivative in the presence of a catalyst composed of a specific metal and an organic ligand, etc. CONSTITUTION:A 1,1-dihalogenoethylene expressed by formula I (X<1> and X<2> are halogen) (e.g. 1,1-difluoroethylene) is made to react with a diazoacetic acid derivative expressed by the formula N2CHCOR [R is (substituted) 1-6C alkyloxy, (substituted)aralkyloxy, (substituted)1-6C alkylthio, (substituted)aryloxy, etc.] (e.g. ethyl diazoacetate) in the presence of a catalyst composed of a metallic atom such as a group VIII metallic atom, molybdenum, copper and iron and one or more organic ligands such as carboxylic acid-based, amide-based, halogen- based and phosphine-based ligands and carbon monoxide (e.g. rhodium pivalate) to afford the objective 2,2-dihalogenocyclopropanecarboxylic acid derivative expressed by formula II.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a compound useful as an intermediate for producing a new quinolone derivative having excellent activity and safety.

[0002]

2. Description of the Related Art Among new quinolone type synthetic antibacterial agents having excellent properties as synthetic antibacterial agents, quinolone derivatives having 1,2-cis-2-fluorocyclopropyl group as the 1-position substituent have strong antibacterial activity. It has both high safety and is expected as an excellent synthetic antibacterial drug (Japanese Patent Laid-Open No. HEI-2)
(See Japanese Patent Publication No. 231475).

2-Fluorocyclopropanecarboxylic acid as a raw material for synthesizing a quinolone derivative having a 1,2-cis-2-fluorocyclopropyl group as a substituent at the 1-position, especially 1,
2-cis-2-fluorocyclopropanecarboxylic acid is important. Conventionally, the carboxylic acid ester, which is a raw material for synthesizing the 2-fluorocyclopropanecarboxylic acid, has been obtained by synthesizing by a four-step reaction using butadiene as a raw material and then separating and purifying by distillation.

[0004]

[Chemical 7]

Further, vinyl halogenides are reacted with ethyl diazoacetate in the presence of rhodium pivalate to give 1
A method of obtaining a 2-chloro- or 2-bromocyclopropanecarboxylic acid derivative in a step is also known (Journal of Org
anometallic Chemistry, 262 (1984), 85-88).

[0006]

In the conventional method for synthesizing a 2-fluorocyclopropanecarboxylic acid derivative, there is a step of using a trialkyltin hydride, for example, tributyltin hydride, in the step. However, this trialkyltin hydride is industrially difficult to use due to its toxicity and price.

Therefore, the present inventor has conducted earnest research to find out a method for easily obtaining a 2-fluorocyclopropanecarboxylic acid derivative. As a result, they found that the desired 2-fluorocyclopropanecarboxylic acid derivative can be synthesized in a high yield in one step by reacting vinyl fluoride with a diazoacetic acid derivative in the presence of a metal catalyst, and this reaction is used. It was found that 1,2-cis-2-fluorocyclopropanecarboxylic acid derivative was selectively produced by proceeding stereoselectively depending on the metal catalyst and diazoacetic acid derivative. In addition, this method produces 2,2-dihalogenocyclopropanecarboxylic acid derivatives in good yield,
Moreover, they have completed the present invention by discovering that they can be easily synthesized.

[0008]

[Means for Solving the Problems] That is, the present invention provides a metal atom selected from the group consisting of a Group 8 metal atom, molybdenum, copper and iron, a carboxylic acid system, an amide system, a halogen system,
Formula in the presence of a catalyst composed of a phosphine system and one or more ligands selected from the group consisting of carbon monoxide

[0009]

[Chemical 8] (In the formula, X ¹ and X ² each independently represent a halogen atom.)
The formula of 1,1-dihalogenoethylene represented by

[0010]

Embedded image N ₂ CHCOR (wherein R is a halogen atom or an alkyloxy group having 1 to 6 carbon atoms may be present, an alkyloxy group having 1 to 6 carbon atoms, a halogen atom, or 1 to 6 carbon atoms) 6 alkyl groups, halogenoalkyl groups having 1 to 6 carbon atoms, 1 to 6 carbon atoms
An aralkyloxy group composed of an aromatic ring which may have an alkyloxy group, a carbamoyl group, a cyano group or an amino group and an alkyl group having 1 to 6 carbon atoms, and a carbon number which may have a halogen atom. 1-6 alkylthio group, halogen atom, alkyl group having 1-6 carbon atoms, halogenoalkyl group having 1-6 carbon atoms, 1-6 carbon atoms
An aralkylthio group composed of an aromatic ring which may have an alkyloxy group, a carbamoyl group, a cyano group or an amino group, and an alkyl group having 1 to 6 carbon atoms, a halogen atom, a 1 to 6 carbon atom Alkyl group, halogenoalkyl group having 1 to 6 carbon atoms, 1 to 6 carbon atoms
Alkyloxy group, carbamoyl group, cyano group or aryloxy group having an aromatic ring which may have an amino group, amino group, mono- or dialkylamino group having an alkyl group having 1 to 6 carbon atoms, halogen atom, carbon An alkyl group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, and 1 to 6 carbon atoms
1 or 2 of a phenyl group which may have an alkyloxy group, a carbamoyl group, a cyano group or an amino group of
Having a phenyl-substituted amino group, or a halogen atom, an alkyl group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, or 1 to 6 carbon atoms
Aralkyl-substituted amino group having 1 or 2 aralkyl groups composed of an aromatic ring which may have an alkyloxy group, a carbamoyl group, a cyano group or an amino group, and an alkyl group having 1 to 6 carbon atoms. To do. )
A formula characterized by reacting a diazoacetic acid derivative represented by

[0011]

[Chemical 10] (In the formula, X ¹ , X ² and R are as defined above.) The present invention relates to a process for producing a 2,2-dihalogenocyclopropanecarboxylic acid derivative.

And the above-mentioned process wherein the metal atom of the catalyst is cobalt, rhodium, iridium, ruthenium, palladium, molybdenum, copper or iron.

The present invention also relates to the above-mentioned production method in which the metal atom of the catalyst is rhodium.

Further, the present invention relates to the above-mentioned production method in which the carboxylic acid type ligand among the catalyst ligands is an aliphatic carboxylic acid, aromatic carboxylic acid or aralkylcarboxylic acid residue.
The carboxylic acid-based ligand is formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myristic acid, palmitic acid, stearic acid, phenylacetic acid, diphenylacetic acid, Triphenylacetic acid, phenylpropionic acid, diphenylpropionic acid, triphenylmethylacetic acid, benzoic acid, hydroxybenzoic acid, trifluoromethylbenzoic acid, methylbenzoic acid, dimethylbenzoic acid, trimethylbenzoic acid, fluorobenzoic acid, difluorobenzoic acid, Trifluorobenzoic acid, pentafluorobenzoic acid, benzoylbenzoic acid, naphthoic acid, α-methoxy-α-trifluoromethylphenylacetic acid, 2-phenylpropionic acid, 2-phenylbutyric acid,
3-phenyllactic acid, 2-chloro-3-phenylpropionic acid,
The present invention relates to the above-mentioned production method which is a residue of mentoxyacetic acid, camphoric acid, tetrahydro-5-oxo-2-furancarboxylic acid, 2-methylbutyric acid or 2-chlorobutyric acid.

Among the catalyst ligands, the amide type ligands are formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myristic acid, palmitic acid, Stearic acid, phenylacetic acid, diphenylacetic acid, triphenylacetic acid, phenylpropionic acid, diphenylpropionic acid, triphenylmethylacetic acid, benzoic acid, hydroxybenzoic acid, trifluoromethylbenzoic acid, methylbenzoic acid, dimethylbenzoic acid, trimethylbenzoic acid , Fluorobenzoic acid, difluorobenzoic acid, trifluorobenzoic acid, pentafluorobenzoic acid,
Benzoylbenzoic acid, naphthoic acid, α-methoxy-α-
Trifluoromethylphenylacetic acid, 2-phenylbutyric acid, 3-
Phenyllactic acid, 2-chloro-3-phenylpropionic acid, mentoxyacetic acid, camphoric acid, tetrahydro
-5-oxo-2-furancarboxylic acid, 2-methylbutyric acid or
It relates to the above process, which is an amide or pyroglutamic acid ester derived from 2-chlorobutyric acid.

Further, among the catalyst ligands, the phosphine-based ligand is triphenylphosphine, and the carbon number is 1 to 6
And a trialkoxyphosphine having an alkyl group having 1 to 6 carbon atoms.

The catalyst is rhodium pivalate ([Rh
_{[OOCC (CH 3) 3]} 2] 2), rhodium benzoyl benzoate _{([Rh [OOC (C 6} H 4) COC 6 H 5] 2] 2), rhodium tri phenylacetate _{([Rh [OOCC (C 6} H ₅ ) ₃ ] ₂ ] ₂ ) and rhodium triphenylpropionate ([Rh [OOCCH ₂ C (C ₆ H ₅ ) ₃ ] ₂ ]
₂ ) The above process, wherein the catalyst is a catalyst selected from the group of catalysts.

Further, the 2,2-dihalogenocyclopropanecarboxylic acid derivative is 2,2-difluorocyclopropanecarboxylic acid derivative, 2-chloro-2-fluorocyclopropanecarboxylic acid derivative or 2-bromo-2-fluorocyclopropane. It relates to the above-mentioned production method which is a carboxylic acid derivative.

The details of the present invention will be described below.

The 2,2-dihalogenocyclopropanecarboxylic acid derivative synthesized in the present invention has halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferred as the 2,2-dihalogenocyclopropanecarboxylic acid derivative are 2,2-difluorocyclopropanecarboxylic acid derivative, 2-fluoro-2-chlorocyclopropanecarboxylic acid derivative, 2-fluoro-2-bromocyclopropanecarboxylic acid derivative. An acid derivative or the like in which one halogen atom is a fluorine atom. Further, when the kind of the halogen atom substituted at the 2-position is different, it is in the same plane as the substituent —COR of the cyclopropane ring, that is,
The halogen atom in the cis configuration with the substituent —COR is preferably a fluorine atom.

Examples of the diazoacetic acid derivative which is one of the starting materials in the production method of the present invention include esters, amides and thioesters.

Of these, examples of the esters include alkyl esters, aralkyl esters and aromatic esters.

As the alkyl ester, an alkyl ester having 1 to 6 carbon atoms, for example, methyl ester, ethyl ester, propyl ester such as normal propyl or isopropyl, normal butyl, isobutyl, secondary butyl or tertiary Examples thereof include butyl esters such as grade butyl, pentyl esters, and hexyl esters. In addition to the alkyl ester, for example, 1-menthyl ester and the like can be mentioned as the optically active ester.

Further, examples of the aralkyl ester include an aralkyl ester composed of an aralkyl group composed of an aryl group and an alkyl group having 1 to 6 carbon atoms. The aryl group is a halogen atom, an alkyl group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, an alkyloxy group having 1 to 6 carbon atoms,
It may be substituted with plural or plural kinds of substituents selected from a substituent group consisting of a carbamoyl group, a cyano group, a hydroxyl group, a nitro group, a cyano group and an amino group. Examples of the aryl group of the aralkyl group include a phenyl group and a naphthyl group. A typical example of the aralkyl group is a benzyl group, which may be further substituted with the substituents described above.

On the other hand, examples of the aromatic ester include phenyl ester and naphthyl ester, and these aromatic rings include a halogen atom, an alkyl group having 1 to 6 carbon atoms, and a halogenoalkyl group having 1 to 6 carbon atoms. A plurality of kinds of substituents selected from a substituent group consisting of an alkyloxy group having 1 to 6 carbon atoms, a carbamoyl group, a cyano group, a hydroxyl group, a nitro group, a cyano group and an amino group, Good.

When the diazoacetic acid derivative is an amide derivative, its nitrogen atom may have a substituent, and for example, an alkyl group, an aralkyl group, an aromatic substituent group, an acyl group, etc. may be substituted with 1 or 2 substituents. You may have.

In this case, the alkyl group has a carbon number of 1 to 6, for example, propyl groups such as methyl group, ethyl group, normal propyl group, isopropyl group, cyclopropyl group, normal butyl group, isobutyl group and secondary group. Examples thereof include butyl groups such as butyl group and tertiary butyl group, and pentyl groups and hexyl groups.

As the aralkyl group, an aralkyl group composed of an aryl group and an alkyl group having 1 to 6 carbon atoms can be mentioned. This aryl group is
Halogen atom, alkyl group having 1 to 6 carbon atoms, halogenoalkyl group having 1 to 6 carbon atoms, alkyloxy group having 1 to 6 carbon atoms, carbamoyl group, cyano group, hydroxyl group, nitro group, cyano group and amino It may be substituted with a plurality of or a plurality of types of substituents selected from the group consisting of substituents. Examples of the aryl group of the aralkyl group include a phenyl group and a naphthyl group. A typical example of the aralkyl group is a benzyl group, which may be further substituted with the substituents described above.

Examples of the aromatic group include a phenyl group and a naphthyl group, and these aromatic rings include a halogen atom, an alkyl group having 1 to 6 carbon atoms, and 1 to 6 carbon atoms.
Substituted with plural or plural kinds of substituents selected from the group consisting of halogenoalkyl group, alkyloxy group having 1 to 6 carbon atoms, carbamoyl group, cyano group, hydroxyl group, nitro group, cyano group and amino group. It may have been done.

The acyl group may be an aliphatic or aromatic acyl group, and various substituted acetyl groups, various substituted benzoyl groups and the like.

The catalysts that can be used in the production method of the present invention are composed of organic or inorganic ligands and metal atoms, which may be used alone or in combination, and will be described below.

First, regarding the metal atom, a Group 8 transition metal, molybdenum, copper, nickel or iron is preferable.
Examples of the Group 8 transition metal include rhodium (Rh), palladium (Pd), cobalt (Co), and ruthenium (Ru). Regarding the valence of these metal atoms, a metal that is in a divalent state when the catalyst is formed is usually used. However, a monovalent state such as copper may be used.

Next, the ligands coordinated to the metal atom are roughly classified into carboxylic acid type, amide type, halogen type, phosphine type, oxime type, sulfonic acid type, 1,3-diketone type, and Schiff base. System, and carbon monoxide (CO).

Examples of the carboxylic acid type ligand include formic acid,
It is a residue of an aliphatic carboxylic acid, an aromatic carboxylic acid, or an aralkylcarboxylic acid.

Examples of the aliphatic carboxylic acid include acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myristic acid, palmitic acid, stearic acid, 2-methylbutyric acid or 2-chloro. Butyric acid and the like, which may be not only a monocarboxylic acid but also a polycarboxylic acid. Further, it may have a branched or cyclic structure as well as a linear structure. Examples of aromatic carboxylic acids include benzoic acid, and the aromatic ring is further substituted with an alkyl group, a hydroxyl group, a halogen atom, a nitro group, a cyano group, an alkyloxy group, an acyl group or the like. May be. Examples of aromatic carboxylic acids include benzoic acid, hydroxybenzoic acid, trifluoromethylbenzoic acid, methylbenzoic acid, dimethylbenzoic acid, trimethylbenzoic acid, fluorobenzoic acid, difluorobenzoic acid, trifluorobenzoic acid, pentafluorobenzoic acid, Examples thereof include benzoylbenzoic acid and naphthoic acid.

The aralkylcarboxylic acid has an alkyl chain having about 1 to 6 carbon atoms, and the other constituent component, the aryl group, is a halogen atom, an alkyl group having 1 to 6 carbon atoms, It may be substituted with plural or plural kinds of substituents selected from a substituent group consisting of a halogenoalkyl group having 1 to 6 carbon atoms and an amino group having 1 to 6 carbon atoms.

When the aryl group (aromatic ring) is substituted on the terminal carbon atom of the alkyl chain, the number of aromatic rings may be from 1 to 3. On the other hand, the position where the aromatic ring is bonded need not be the carbon atom at the end of the alkyl chain, and may be, for example, a form in which carbon atoms adjacent to the alkyl chain are substituted.

Examples of the aralkylcarboxylic acid include phenylacetic acid, diphenylacetic acid, triphenylacetic acid, phenylpropionic acid, diphenylpropionic acid, triphenylmethylacetic acid, α-methoxy-α-trifluoromethylphenylacetic acid, 2-phenylpropione. Acid, 2-phenylbutyric acid, 3-phenyllactic acid, 2-chloro-3-phenylpropionic acid and the like can be mentioned.

Other carboxylic acids such as mentoxyacetic acid, camphoric acid, tetrahydro-5
-Oxo-2-furancarboxylic acid and the like can be mentioned.

The amide-based ligand includes aliphatic amides, aromatic amides, aralkylcarboxylic acid amides and the like. The carboxylic acid moieties of the various amides may be the carboxylic acids mentioned above. In addition, examples of amide-based ligands other than these include pyroglutamic acid esters.

The carboxylic acid may be an optically active one containing an asymmetric carbon. For example, (S)-(-)-α-methoxy-α-trifluoromethylphenylacetic acid, (S)-(+)-2-phenylpropionic acid, (S) -2-phenylbutyric acid, L-(-) -3-Phenyllactic acid, (S)-(+)-2-chloro-3-phenylpropionic acid, (-)-
Menthoxyacetic acid, (S)-(-)-1-camphenic acid, (S)-(+)-tetrahydro-5-oxo-2-furancarboxylic acid, (R) -2-methylbutyric acid or (S) -2 -Chlorobutyric acid is an example.
Further, various α-amino acids can also be used, and specific examples thereof include N-substituted prolines such as N-tosylproline.

Examples of the phosphine-based ligand include trialkylphosphines, trialkoxyphosphines and triphenylphosphines. In the trialkylphosphines and trialkoxyphosphines, the alkyl group may have 1 to 6 carbon atoms, and the same alkyl group substituted is usually used, but it does not have to be the same. In the triphenylphosphines, this phenyl group may be substituted with an alkyl group, a hydroxyl group, a halogen atom, a nitro group, a cyano group, an alkyloxy group or the like.

On the other hand, the catalyst may contain a solvent such as acetonitrile as a ligand or may contain phenylacetonitrile, for example. In addition, a compound having an imine structure may serve as a ligand, but in this case, the compound may have an imine structure as a part of the structure of the heterocyclic compound. Further, the ligand may be a ligand composed of a heterocyclic compound, and examples thereof include porphins.

When the above-mentioned ligand is coordinated with a metal atom to form a catalyst, only one kind of ligand may be coordinated to form a catalyst, and a plurality of kinds of coordinations are also possible. The child may coordinate with the metal atom to form a catalyst.

An example of a catalyst composed of a combination of a ligand and a metal atom is shown below. For example, as a compound containing divalent rhodium as a metal atom, there is a compound containing a carboxylic acid-based ligand of the following general formula.

[0046]

Embedded image [Rh (OOCR ¹ ) ₂ ] ₂ (wherein R ¹ is a linear, branched, or cyclic alkyl group having 1 to 30 carbon atoms, which may be substituted with a halogen atom, hydrogen Atom or an alkyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a cyano group, a hydroxyl group, an amino group, a carbamoyl group, an acyl group, or a phenyl group which may have an alkyloxy group having 1 to 6 carbon atoms Or the aromatic ring has an alkyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a cyano group, a hydroxyl group, an amino group, a carbamoyl group, an acyl group, or an alkoxyl group having 1 to 6 carbon atoms Well, the alkyl chain represents a mono-, di-, tri-, bis-, or tris-aryl-alkyl group having 1 to 6 carbon atoms.) Specific examples include the following compounds.

[0047]

Embedded image [Rh (OOCH) ₂ ] ₂ , [Rh (OOCCH ₃ ) ₂ ] ₂ , [Rh (OOCC ₂ H
₅ ) ₂ ] ₂ , [Rh (OOCC ₃ H ₇ ) ₂ ] ₂ , [Rh (OOCCH (CH ₃ ) ₂ ] ₂ , [Rh (OOCC ₄ H ₉ ) ₂ ] ₂ , [Rh [OOCC (C
_{H 3) 3] 2] 2} , [Rh [OOCC 6 H 13] 2] 2, [Rh (OOCC 17 H 35) 2] 2, [Rh (OOCCF 3) 2]
₂ , [Rh (OOCCH ₂ CCl ₃ ) ₂ ] ₂ , [Rh [OOCCH ₂ C ₆ H ₅ ] ₂ ] ₂ , [Rh (OOCCH _{2
CH 2 C 6 H 5) 2} ] 2, [Rh [OOCC (C 6 H 5) 3] 2] 2, [Rh (OOCC 6 H 5) 2] 2, [Rh [OOC (C
_{6 H 4) CO (C 6} H 5)] 2] 2, [Rh [OOCCH 2 C (C 6 H 5) 3] 2] 2,

Further, examples of the catalyst having an amide type ligand include those having the following structures.

[0049]

Embedded image Rh ₂ (OOCR ¹ ) _m (R ³ NCOR ² ) _n (in the formula, R ¹ , R ² and R ³ each independently have 1 to 30 carbon atoms which may be substituted with a halogen atom) Linear, branched, or cyclic alkyl group, hydrogen atom, or alkyl group having 1 to 6 carbon atoms, halogen atom, nitro group, cyano group, hydroxyl group, amino group, carbamoyl group, acyl group, or carbon number A phenyl group optionally having 1 to 6 alkyloxy group, or an aromatic ring having an alkyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a cyano group, a hydroxyl group, an amino group, a carbamoyl group, an acyl group, Alternatively, it may have an alkoxyl group having 1 to 6 carbon atoms, and the alkyl chain represents a mono, di, tri, bis, or tris-aryl-alkyl group having 1 to 6 carbon atoms, m
And n are integers from 0 to 4, respectively, and m + n = 4. ) Further, the catalyst having the following structure can be exemplified as the catalyst having an amide-based ligand.

[0050]

[Chemical 14]

The catalysts containing rhodium other than those exemplified above include the following halogen type, amide type, phosphine type and carbon monoxide type catalysts.

[0052]

Embedded image RhCl ₃ , RhCl (P (C ₆ H ₅ ) ₃ ) ₃ , Rh ₆ (CO) ₁₆ ,

Examples of the catalyst containing a metal other than rhodium include the following containing copper, palladium, manganese, ruthenium and cobalt.

[0054]

[Chemical 16] CuOSO ₂ CF ₃ , Cu (OSO ₂ CF ₃ ) ₂ , Copper bronze, CuCl ・ P [O
CH (CH ₃ ) ₂ ] ₃ , Cu (acac) ₂ , Pd (OOCCH ₃ ) ₂ , PdCl ₂・ 2 (C ₆ H ₅ CN) _, Pd [P (C
₆ H ₅ ) ₃ ] ₄ , Mo ₂ (OOCCH ₃ ) ₂ , Ru ₂ (OOCCH ₃ ) ₄ Cl, (acac means acetylacetonate).

As an example of a catalyst containing iron as a metal atom,
A catalyst having porphyrin as a ligand can be mentioned, but a catalyst having a heterocyclic compound as a ligand can also be used in the method of the present invention.

The above catalysts can be prepared by methods known in the art.

The method of the present invention may be specifically carried out as follows.

A diazoacetic acid derivative is necessary for the reaction. For example, in the case of diazoacetic acid esters, it may be prepared from aminoacetic acid esters, and this may be carried out by a usual method. Further, diazoacetic acid amides may be similarly processed.

The reaction with 1,1-dihalogenoethylene may be carried out as follows. That is, since 1,1-dihalogenoethylene is usually a low-boiling substance, in order to carry out the reaction at room temperature or in a heated state, it may be carried out using a sealed container such as an autoclave, while it is carried out under cooling. If so, the sealed container may not be used. When the sealed container is not used, a condenser filled with liquid nitrogen or the like may be used. The required amount of 1,1-dihalogenoethylene can be collected by introducing it into an organic solvent while cooling and dissolving it.
When using an autoclave, 1,1-dihalogenoethylene can be directly introduced into the container under pressure of gas.

When the reaction is carried out in a sealed vessel, for example, the solution of diazoacetic ester is first placed in the vessel, then the solution of 1,1-dihalogenoethylene in solution is added, and the catalyst is added. After the addition, the container is sealed and warmed to react if necessary.

On the other hand, the method of the present invention is carried out by adding a solution of diazoacetic acid derivative little by little to a mixture of a solution of 1,1-dihalogenoethylene and a catalyst, while cooling the product. The inventors have found that the rate is improved. That is, it was found that the target product can be obtained in a higher yield by carrying out the reaction under cooling in this reaction.
Moreover, in this case, it became clear that the reaction was completed in a relatively short time. To carry out the reaction in this way, it is not necessary to use a sealed vessel, and the cooling temperature is about zero.
1,1-Dihalogenoethylene will not be volatilized at a temperature below ℃.

Further, the production method of the present invention can be carried out by cooling a mixture obtained by adding a catalyst to a solvent and adding a solution of a diazoacetic acid derivative at the same time while introducing 1,1-dihalogenoethylene gas into the mixture.

The solvent that can be used in the reaction is not particularly limited as long as it is inert to the reaction. Usually non-polar solvents are preferred,
For example, aliphatic hydrocarbons and halogenated hydrocarbons are preferable. Specifically, normal hexane and cyclohexane,
Examples include dichloromethane and 1,2-dichloroethane. Of these, dichloromethane is most commonly used. In addition to these, ethers may be sufficient.

The amount of the catalyst used in the reaction may be a so-called catalytic amount, but as a guide, it may be about 10% or less of the number of moles of the diazoacetic acid ester, and more preferably 0.05 to 1%. A quantity in the range of a number is sufficient.

The reaction temperature may range from about -100 ° C to about 100 ° C, but preferably ranges from about -50 ° C to about 50 ° C.

The reaction time may be about 30 minutes to about 48 hours, but it is usually about 1 hour to 24 hours.

In the 2,2-dihalogenocyclopropanecarboxylic acid derivative obtained by the method of the present invention, if the type of the halogen atom substituted at the 2-position is the same, an enantiomer-related isomer is present. This means that there are two types of stereoisomers. On the other hand, when the type of halogen atom substituted at the 2-position is different, a stereoisomeric pair having a diastereomeric relationship exists, and four types of stereoisomers exist. When the halogen atom at the 2-position is different, especially when one of them is a fluorine atom, the other halogen atom is bulkier, and therefore the substituent —COR on the cyclopropane ring and this fluorine atom have a cis configuration. It is considered advantageous for such a reaction to proceed. Further, when the method of the present invention is carried out using a catalyst having a ligand having an asymmetric source as a catalyst, a reaction in which the substituent —COR on the cyclopropane ring and the fluorine atom are in a cis configuration is more advantageous. It is supposed to be.

The isomers of the 2,2-dihalogenocyclopropanecarboxylic acid derivative thus produced can be separated by a commonly used method such as distillation, chromatography, or a method of separating the derivative after conversion to another derivative. can do.

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

[0070]

【Example】

[Example 1] Synthesis of ethyl 2,2-difluorocyclopropanecarboxylate 155 mg of tetrakis (triphenylpropionato) dirhodium (II) was dissolved in 200 ml of methylene chloride, and about 10 g of molecular sieves 4A was added. The internal temperature of the mixture was set to -25 ° C, and 1,1-difluoroethylene was passed through the mixture little by little, and ethyl diazoacetate 220 mmo
A solution prepared by dissolving 1 l in 220 ml of methylene chloride was added dropwise over 3 hours. At this time, 39 g of 1,1-difluoroethylene was conducted. After completion of the dropwise addition, the reaction solution was returned to room temperature and the insoluble matter was filtered off, and the filtered insoluble matter was washed with a small amount of methylene chloride,
The filtrate and washings were combined. The combined organic layers were concentrated under reduced pressure to obtain 33 g of the title compound. The obtained compound was analyzed by gas chromatography and was found to be a mixture of enantiomers.

¹ H-NMR (CDCl ₃ ) δ: 1.29 (t, 3H), 1.69-
1.78 (m, 1H), 2.01-2.10 (m, 1H), 2.39-2.47 (m, 1
H), 4.23 (q, 2H)

Reference Example 1 Tetrakis (triphenylpropionato) dirhodium (II) (also referred to as rhodium triphenylpropionate in the present specification)
Dissolve 600 mg of rhodium (II) chloride trihydrate in 90 ml of 95% ethanol, add 3.44 g of 3,3,3-triphenylpropionic acid and 765 mg of sodium hydrogencarbonate, and add 2 under a nitrogen gas stream. After heating under reflux for an hour, the mixture was stirred overnight at room temperature. The reaction solution was filtered to remove the insoluble matter, and the filtered insoluble matter was washed with 50 ml of dichloromethane. The washing solution and the filtrate were combined and the solvent was distilled off under reduced pressure. 100 ml of the residue is dichloromethane
Was dissolved in, the insoluble matter was filtered off, the insoluble matter collected by filtration was washed with 10 ml of dichloromethane, and the filtrate and the washing solution were combined and dried over anhydrous sodium sulfate. After distilling off dichloromethane under reduced pressure,
The residue was chromatographed on silica gel (silica gel:
30 g, elution solvent; normal hexane: dichloromethane =
Purification by 1: 1), fractions of the target compound were collected, the solvent was distilled off under reduced pressure, and the residue was dried under reduced pressure at 60 ° C. overnight to obtain 2.19 g of the title complex as a blue-green powder.

Example 2 Synthesis of ethyl 2-chloro-2-fluorocyclopropanecarboxylate After dissolving 17.6 mg of tetrakis (triphenylpropionato) dirhodium (II) in 16 ml of dry dichloromethane,
Molecular Sieves 4A (750 mg) was added, and the mixture was cooled to -70 ° C. Conduct 1-chloro-1-fluoroethylene to this
2.01 g was dissolved and the internal temperature was set to -20 ° C. To this, add 8 ml of a solution of 5 mmol of ethyl diazoacetate in dichloromethane.
Dropped in 15 minutes. The result of gas chromatography analysis of the product showed that the desired product was produced in a yield of 90%, and the production ratio of its stereoisomer was 1.00: 1.33.

Gas chromatographic analysis conditions; Column: SHIMADZU CBP1-M25-025 (OV-1, SE-30) Column temperature: 100 ° C Injector temperature: 200 ° C Detector temperature: 250 ° C (FID) Retention time; Product 2.70 minutes (1.00) 2.83 minutes (1.33)

Reference Example 2 128.0 g of 1-bromo-1-fluoroethylene 1,2-dibromofluoroethane was heated at 50 to 60 ° C. and stirred to give 1,8-diazabicyclo [5.4.0] undec-7. -
93 ml of ene was gradually added dropwise over 4 hours. The product was collected by cooling with a dry ice-acetone bath through a distillation apparatus,
52.3 g of a colorless liquid containing the desired product was obtained. ¹ H- of product
As a result of NMR and gas chromatography analysis, the desired 1-bromo-1-fluoroethylene 24.35% and a by-product
It was a mixture of (Z) -1-bromo-2-fluoroethylene 53.44%, (E) -1-bromo-2-fluoroethylene 21.33%, and the raw material 0.88%. Used in next step reaction).

Gas chromatography analysis conditions; Column: SHIMADZU CBP1-M25-025 (OV-1, SE-30) Column temperature: 50 ° C Injector temperature: 200 ° C Detector temperature: 250 ° C (FID) Retention time; 1- Bromo-1-fluoroethylene: 1.38 minutes (E) -1-Bromo-2-fluoroethylene: 1.35 minutes (Z) -1-Bromo-2-fluoroethylene: 1.43 minutes

Example 3 Ethyl 2-bromo-2-fluorocyclopropanecarboxylate Tetrakis (triphenylpropionato) dirhodium (I
I) 17.6 mg was dissolved in 8 ml of dry dichloromethane, 370 mg of Molecular Sieves 4A was added, and the mixture was cooled to -40 ° C. 12.5 mmol of 1-bromo-1-fluoroethylene with a purity of 24.35% prepared in the above Reference Example (6.41% in 100% conversion amount)
g) was added and the internal temperature was adjusted to -25 ° C, then ethyl diazoacetate was added.
4 ml of a 2.5 mmol dichloromethane solution was added dropwise over 15 minutes. Gas chromatographic analysis of reaction products and ¹⁹ F
-From the NMR results, the yield of the target compound was 74%, and the formation ratio of stereoisomers (the ester part and the cis isomer of fluorine being the isomer in which the fluorine is on the same plane of the cyclopropane ring) The body ratio) was 1.43: 1.00.

Gas chromatography analysis conditions; Column: SHIMADZU CBP1-M25-025 (OV-1, SE-30) Column temperature: 100 ° C Injector temperature: 200 ° C Detector temperature: 250 ° C (FID) Retention time; Trans form : 3.64 minutes, cis: 3.89 minutes

Example 4 Tertiary butyl 2-bromo-2-fluorocyclopropanecarboxylic acid tetrakis (triphenylpropionato) dirhodium (I
I) 17.6 mg was dissolved in 10 ml of dry dichloromethane, 370 mg of Molecular Sieves 4A was added, and the mixture was cooled to -40 ° C. In addition to this, 12.5 mmol of 1-bromo-1-fluoroethylene with a purity of 24.35% prepared in the previous reference example (100% calculated as 6.41
g) was added and the internal temperature was set to -25 ° C, and then 4.8 ml of a dichloromethane solution of tertiary butyl diazoacetate 2.5 mmol was added dropwise over 15 minutes. From the results of gas chromatography analysis of the reaction product, ¹ H-NMR and ¹⁹ F-NMR, the yield of the desired product was 8
At 0%, the production ratio of stereoisomers (ratio of cis and trans isomers of ester moiety and fluorine) was 1.97: 1.00.

Gas chromatographic analysis conditions; retention time similar to that of the ethyl ester form of the previous example; trans form: 5.33 minutes, cis form: 5.58 minutes

Example 5 Reductive debromination of ethyl 2-bromo-2-fluorocyclopropanecarboxylate with sodium borohydride in the presence of Zr (acac) ₄ catalyst 2-in a 50 ml eggplant-shaped flask Ethyl bromo-2-fluorocyclopropanecarboxylate (trans / cis = 1.16, where cis is the isomer in which the ester moiety and fluorine are on the same plane of the cyclopropane ring) 422 mg, tetrakis (2,4-pentadionato) zirconium 10 mg And absolute ethanol 1
After adding 0 ml and adding 757 mg of sodium borohydride to this, the mixture was heated with stirring at 60 to 70 ° C. for 1 hour.

After cooling the reaction mixture, water was added to the mixture, and 10 ml of ether was added.
And the ether layer was dried over anhydrous sodium sulfate. Analysis of the ether solution by gas chromatography revealed that the reaction conversion rate was 100% and the product isomer ratio of ethyl 2-fluorocyclopropanecarboxylate was trans / cis = 1.01.

Gas chromatography analysis conditions; Column: SHIMADZU CBP1-M25-025 (OV-1, SE-30) Column temperature: 60 ° C Injector temperature: 200 ° C Detector temperature: 250 ° C (FID) Retention time; Product Trans form: 3.64 min, cis form: 5.57 min Raw material 12.17 min, 13.73 min

Example A: 2,2-difluoro-1-cyclo
Ethyl propanecarboxylate  Alumina column (Merck,
Dry jig through (filled with Aluminum Oxide 90)
Add 10 ml of loromethane and add tetrakis (triphenylamine).
Cetato) dirhodium (16.9 mg) was added and uniformly dissolved.
Then, 370 mg of powdered molecular sieves 4A was added.
Immerse the reaction vessel in dry ice-acetone bath and
800 mg of luoroethylene was dissolved. Zero the reaction temperature
Argon gas atmosphere while maintaining below 35 ℃ to below 40 ℃
Under ethyl diazoacetate 2.5 mmol dry dichloromethane
5.3 ml of the solution was added dropwise. At this time, the first half amount is 15 minutes,
The remaining half amount was added dropwise over 30 minutes. Reaction after the dropping
The liquid was slowly returned to room temperature. By gas chromatography
As a result, the reaction conversion rate is 100% and the yield is 87%.
It has been found.

Example B: 2-chloro-2-fluoro-1-
Alumina column (Merck,
10 ml of dry dichloromethane passed through (filled with Aluminum Oxide 90) was added, 16.9 mg of tetrakis (triphenylacetato) dirhodium was added, and after uniformly dissolving, powdered molecular sieves 4A, 370 mg was added.
Immerse the reaction vessel in a dry ice-acetone bath and
-1-Fluoroethylene 1.006 g was dissolved. While maintaining the temperature of the reaction solution at 35 ° C. below 40 ° C. below zero, 5.3 ml of a dry dichloromethane solution of 2.5 mmol of ethyl diazoacetate was added dropwise under an argon gas atmosphere. At this time, the first half amount was added dropwise over 15 minutes and the other half amount over 30 minutes. After the dropping was completed, the reaction solution was slowly returned to room temperature. As a result of analysis by gas chromatography, the reaction conversion rate was 100% and the yield was 9
It was found that 1%, cis: trans = 1.59: 1.0.

Example C: 2-Bromo-2-fluoro-1-
Alumina column (Merck,
10 ml of dry dichloromethane passed through (filled with Aluminum Oxide 90) was added, 16.9 mg of tetrakis (triphenylacetato) dirhodium was added, and after uniformly dissolving, powdered molecular sieves 4A, 370 mg was added.
Immerse the reaction vessel in a dry ice-acetone bath and
-1- Fluoroethylene 1.562 g was dissolved. While maintaining the temperature of the reaction solution at 35 ° C. below 40 ° C. below zero, 5.3 ml of a dry dichloromethane solution of 2.5 mmol of ethyl diazoacetate was added dropwise under an argon gas atmosphere. At this time, the first half amount was added dropwise over 15 minutes and the other half amount over 30 minutes. After the dropping was completed, the reaction solution was slowly returned to room temperature. As a result of analysis by gas chromatography, the reaction conversion rate was 100% and the yield was 90.
%, Cis: trans = 1.70: 1.0.

Example D: Ethyl 2,2-difluoro-1-cyclopropanecarboxylate An alumina column (manufactured by Merck & Co., Inc.) was placed in a 50 ml three-necked flask.
Add 9.0 ml of dry dichloromethane through (filled with Aluminum Oxide 90) and mix with powdered molecular sieves.
4A, 370 mg was added. The reaction vessel was immersed in a dry ice-acetone bath to dissolve 800 mg of 1,1-difluoroethylene. To this was added a solution prepared by dissolving 1.69 mg of tetrakis (triphenylacetato) dirhodium in 1 ml of dry dichloromethane. While maintaining the temperature of the reaction solution from 35 ° C below 40 ° C to 40 ° C below zero, use ethyl diazoacetate under an argon gas atmosphere.
5.3 ml of a 2.5 mmol dry dichloromethane solution was added dropwise. At this time, the first half amount was added dropwise over 120 minutes and the other half amount over 300 minutes. After the dropping was completed, the reaction solution was slowly returned to room temperature. As a result of analysis by gas chromatography, it was found that the reaction conversion rate was 100% and the yield was 89%.

Example E: 2-chloro-2-fluoro-1-
Alumina column (Merck,
Add 9.0 ml of dry dichloromethane through (filled with Aluminum Oxide 90) and mix with powdered molecular sieves.
4A, 370 mg was added. Dip the reaction vessel in a dry ice-acetone bath and add 1.01 g of 1-chloro-1-fluoroethylene.
Was dissolved. To this was added a solution prepared by dissolving 1.69 mg of tetrakis (triphenylacetato) dirhodium in 1 ml of dry dichloromethane. While maintaining the temperature of the reaction solution from 35 ° C below 40 ° C to 40 ° C below zero, 5.3 ml of a dry dichloromethane solution of 2.5 mmol of ethyl diazoacetate under an argon gas atmosphere.
Was dripped. At this time, the first half amount was added dropwise over 120 minutes and the other half amount over 300 minutes. After the dropping was completed, the reaction solution was slowly returned to room temperature. As a result of analysis by gas chromatography, it was found that the reaction conversion rate was 100%, the yield was 90%, and cis: trans = 1.58: 1.0.

Example F: 2-Bromo-2-fluoro-1-
Alumina column (Merck,
Add 9.0 ml of dry dichloromethane through (filled with Aluminum Oxide 90) and mix with powdered molecular sieves.
4A, 370 mg was added. Immerse the reaction vessel in a dry ice-acetone bath, and then 1.56 g of 1-bromo-1-fluoroethylene
Was dissolved. To this was added a solution prepared by dissolving 1.69 mg of tetrakis (triphenylacetato) dirhodium in 1 ml of dry dichloromethane. While maintaining the temperature of the reaction solution from 35 ° C below 40 ° C to 40 ° C below zero, 5.3 ml of a dry dichloromethane solution of 2.5 mmol of ethyl diazoacetate under an argon gas atmosphere.
Was dripped. At this time, the first half amount was added dropwise over 120 minutes and the other half amount over 300 minutes. After the dropping was completed, the reaction solution was slowly returned to room temperature. As a result of analysis by gas chromatography, it was found that the reaction conversion rate was 100%, the yield was 90%, and cis: trans = 1.71: 1.0.

Example G: 2-chloro-2-fluoro-1-
Alumina column (Merck,
Add 9.0 ml of dry dichloromethane through (filled with Aluminum Oxide 90) and mix with powdered molecular sieves.
4A, 370 mg was added. Dip the reaction vessel in a dry ice-acetone bath and add 10.06 g of 1-chloro-1-fluoroethylene.
Was dissolved. A solution prepared by dissolving 0.68 mg of tetrakis (triphenylacetato) dirhodium in 1 ml of dry dichloromethane was added thereto. While maintaining the temperature of the reaction solution at 15 ° C below zero, add ethyl diazoacetate 2.5 under argon atmosphere.
5.3 ml of a dry dichloromethane solution of mmol was added dropwise over 50 minutes. After completion of dropping, slowly return the reaction solution to room temperature, and
After stirring for an hour, it was analyzed by gas chromatography. As a result, it was found that the reaction conversion rate was 100%, the yield was 86%, and cis: trans = 1.59: 1.0.

Example H: 2-Chloro-2-fluoro-1-
Alumina column (Merck,
Add 9.0 ml of dry dichloromethane through (filled with Aluminum Oxide 90) and mix with powdered molecular sieves.
4A, 370 mg was added. 0.34 mg of tetrakis (triphenylacetato) dirhodium in dry dichloromethane
A solution dissolved in 1 ml was added. At room temperature (approximately 22 ° C)
1-Chloro-1-fluoroethylene was conducted little by little, and 5.3 ml of a dry dichloromethane solution of ethyl diazoacetate 2.5 mmol was added dropwise over 12 minutes while conducting. After the dropping was completed, the conduction was stopped, the mixture was stirred at room temperature for 10 minutes, and then analyzed by gas chromatography. As a result, the reaction conversion rate was 100% and the yield
76%, cis: trans = 1.68: 1.0.

The analytical conditions for gas chromatography used in Examples A to H above are shown below.・ Column: Shimadzu CBP1-M25-025 (OV-1, SE-30) ・ Column temperature: 100 ℃ ・ Injector temperature: 200 ℃ ・ Detector temperature: 250 ℃ ・ Carrier gas: Helium ・ Retention time; a) 2 Ethyl 2-difluoro-1-cyclopropanecarboxylate: 1.90 minutes. b) Ethyl 2-chloro-2-fluoro-1-cyclopropanecarboxylate: cis form: 2.72 min, trans form: 2.60 min. c) Ethyl 2-bromo-2-fluoro-1-cyclopropanecarboxylate: cis form: 3.89 min, trans form: 3.64 min. (For ethyl 2-chloro-2-fluoro-1-cyclopropanecarboxylate and ethyl 2-bromo-2-fluoro-1-cyclopropanecarboxylate, the fluorine atom and the carboxylic acid ester moiety are on the same plane of the cyclopropane ring. Some are called cis isomers, and those with chlorine or bromine atom and carboxylic acid ester moiety on the same plane of the cyclopropane ring are called trans isomers.)

The yield was calculated based on ethyl diazoacetate.

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Claims (16)

[Claims] 1. A metal atom selected from the group consisting of a Group 8 metal atom, molybdenum, copper and iron, and a carboxylic acid group,
In the presence of a catalyst composed of one or more ligands selected from the group consisting of amide-based, halogen-based, phosphine-based, and carbon monoxide (In the formula, X ¹ and X ² each independently represent a halogen atom.)
1,1-dihalogenoethylene represented by the formula: N ₂ CHCOR (In the formula, R is a halogen atom or an alkyloxy group having 1 to 6 carbon atoms and may have 1 to 6 carbon atoms. Alkyloxy group, halogen atom, alkyl group having 1 to 6 carbon atoms, halogenoalkyl group having 1 to 6 carbon atoms, 1 to 6 carbon atoms
An aralkyloxy group composed of an aromatic ring which may have an alkyloxy group, a carbamoyl group, a cyano group or an amino group and an alkyl group having 1 to 6 carbon atoms, and a carbon number which may have a halogen atom. 1-6 alkylthio group, halogen atom, alkyl group having 1-6 carbon atoms, halogenoalkyl group having 1-6 carbon atoms, 1-6 carbon atoms
An aralkylthio group composed of an aromatic ring which may have an alkyloxy group, a carbamoyl group, a cyano group or an amino group, and an alkyl group having 1 to 6 carbon atoms, a halogen atom, a 1 to 6 carbon atom Alkyl group, halogenoalkyl group having 1 to 6 carbon atoms, 1 to 6 carbon atoms
Alkyloxy group, carbamoyl group, cyano group or aryloxy group having an aromatic ring which may have an amino group, amino group, mono- or dialkylamino group having an alkyl group having 1 to 6 carbon atoms, halogen atom, carbon An alkyl group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, and 1 to 6 carbon atoms
1 or 2 of a phenyl group which may have an alkyloxy group, a carbamoyl group, a cyano group or an amino group of
Having a phenyl-substituted amino group, or a halogen atom, an alkyl group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, or 1 to 6 carbon atoms
Aralkyl-substituted amino group having 1 or 2 aralkyl groups composed of an aromatic ring which may have an alkyloxy group, a carbamoyl group, a cyano group or an amino group, and an alkyl group having 1 to 6 carbon atoms. To do. )
A diazoacetic acid derivative represented by the formula: (In the formula, X ¹ , X ² and R are as defined above.) A method for producing a 2,2-dihalogenocyclopropanecarboxylic acid derivative 2. The metal atom of the catalyst is cobalt, rhodium,
The method according to claim 1, which is iridium, ruthenium, palladium, molybdenum, copper or iron. 3. The method according to claim 1, wherein the metal atom of the catalyst is rhodium. 4. The method according to claim 1, 2 or 3, wherein the carboxylic acid ligand is an aliphatic carboxylic acid, aromatic carboxylic acid or aralkylcarboxylic acid residue. 5. The carboxylic acid type ligand is formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myristic acid, palmitic acid, stearic acid, phenylacetic acid, Diphenylacetic acid, triphenylacetic acid, phenylpropionic acid, diphenylpropionic acid, triphenylmethylacetic acid, benzoic acid, hydroxybenzoic acid, trifluoromethylbenzoic acid, methylbenzoic acid, dimethylbenzoic acid, trimethylbenzoic acid, fluorobenzoic acid, difluoro Benzoic acid, trifluorobenzoic acid, pentafluorobenzoic acid, benzoylbenzoic acid, naphthoic acid, α-methoxy-α-trifluoromethylphenylacetic acid, 2-phenylpropionic acid, 2-phenylbutyric acid,
3-phenyllactic acid, 2-chloro-3-phenylpropionic acid,
The method according to claim 4, which is a residue of mentoxyacetic acid, camphoric acid, tetrahydro-5-oxo-2-furancarboxylic acid, 2-methylbutyric acid or 2-chlorobutyric acid. 6. The amide-based ligand is formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myristic acid, palmitic acid, stearic acid, phenylacetic acid, diphenyl. Acetic acid, triphenylacetic acid, phenylpropionic acid, diphenylpropionic acid, triphenylmethylacetic acid, benzoic acid, hydroxybenzoic acid, trifluoromethylbenzoic acid, methylbenzoic acid, dimethylbenzoic acid, trimethylbenzoic acid, fluorobenzoic acid, difluorobenzoic acid Acid, trifluorobenzoic acid, pentafluorobenzoic acid, benzoylbenzoic acid, naphthoic acid, α-methoxy-α-trifluoromethylphenylacetic acid, 2-phenylbutyric acid, 3-phenyllactic acid, 2-chloro
3. An amide or a pyroglutamic acid ester derived from -3-phenylpropionic acid, mentoxyacetic acid, camphoric acid, tetrahydro-5-oxo-2-furancarboxylic acid, 2-methylbutyric acid or 2-chlorobutyric acid. Manufacturing method according to 2 or 3 7. The phosphine-based ligand is triphenylphosphine, trialkylphosphine having an alkyl group having 1 to 6 carbon atoms or trialkoxyphosphine having an alkyl group having 1 to 6 carbon atoms. Manufacturing method according to 1, 2, or 3 8. Rhodium pivalate ([Rh [OOCC (C
_{H 3) 3] 2] 2} ), rhodium benzoyl benzoate ([Rh [OO
_{C (C 6 H 4) COC} 6 H 5] 2] 2), rhodium tri phenylacetate _{([Rh [OOCC (C 6} H 5) 3] 2] 2) and rhodium tri-phenylpropionate ([Rh [OOCCH ₂ In the presence of a catalyst selected from the group of catalysts consisting of C (C ₆ H ₅ ) ₃ ] ₂ ] ₂ ) (In the formula, X ¹ and X ² each independently represent a halogen atom.)
1,1-dihalogenoethylene represented by the formula: N ₂ CHCOR (In the formula, R is a halogen atom or an alkyloxy group having 1 to 6 carbon atoms and may have 1 to 6 carbon atoms. Alkyloxy group, halogen atom, alkyl group having 1 to 6 carbon atoms, halogenoalkyl group having 1 to 6 carbon atoms, 1 to 6 carbon atoms
An aralkyloxy group composed of an aromatic ring which may have an alkyloxy group, a carbamoyl group, a cyano group or an amino group and an alkyl group having 1 to 6 carbon atoms, and a carbon number which may have a halogen atom. 1-6 alkylthio group, halogen atom, alkyl group having 1-6 carbon atoms, halogenoalkyl group having 1-6 carbon atoms, 1-6 carbon atoms
An aralkylthio group composed of an aromatic ring which may have an alkyloxy group, a carbamoyl group, a cyano group or an amino group, and an alkyl group having 1 to 6 carbon atoms, a halogen atom, a 1 to 6 carbon atom Alkyl group, halogenoalkyl group having 1 to 6 carbon atoms, 1 to 6 carbon atoms
Alkyloxy group, carbamoyl group, cyano group or aryloxy group having an aromatic ring which may have an amino group, amino group, mono- or dialkylamino group having an alkyl group having 1 to 6 carbon atoms, halogen atom, carbon An alkyl group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, and 1 to 6 carbon atoms
1 or 2 of a phenyl group which may have an alkyloxy group, a carbamoyl group, a cyano group or an amino group of
Having a phenyl-substituted amino group, or a halogen atom, an alkyl group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, or 1 to 6 carbon atoms
Aralkyl-substituted amino group having 1 or 2 aralkyl groups composed of an aromatic ring which may have an alkyloxy group, a carbamoyl group, a cyano group or an amino group, and an alkyl group having 1 to 6 carbon atoms. To do. )
Wherein the diazoacetic acid derivative represented by the formula is reacted. (In the formula, X ¹ , X ² and R are as defined above.) A method for producing a 2,2-dihalogenocyclopropanecarboxylic acid derivative 9. The catalyst is rhodium pivalate ([Rh [OOCC (C
Preparation of _{H 3) 3] 2] 2} ) a is claim 8, wherein 10. The method according to claim 8, wherein the catalyst is rhodium benzoylbenzoate ([Rh [OOC (C ₆ H ₄ ) COC ₆ H ₅ ] ₂ ] ₂ ). 11. The method according to claim 10, wherein the catalyst is rhodium (2-benzoyl) benzoate. 12. The method according to claim 8, wherein the catalyst is rhodium triphenylacetate ([Rh [OOCC (C ₆ H ₅ ) ₃ ] ₂ ] ₂ ). 13. The method according to claim 8, wherein the catalyst is rhodium triphenylacetate ([Rh [OOCCH ₂ C (C ₆ H ₅ ) ₃ ] ₂ ] ₂ ). 14. The method according to claim 8, 9, 10, 11, 12, or 13, wherein X ¹ and X ² are fluorine atoms. 15. The method according to claim 8, wherein X ¹ is a fluorine atom and X ² is a chlorine atom. 16. The method according to claim 8, wherein X ¹ is a fluorine atom and X ² is a bromine atom.