JP2516617B2 - Process for producing 1,1-difluoroethylene derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel method for producing a 1,1-difluoroethylene derivative.

2. Description of the Related Art As a method for producing an analog of a 1,1-difluoroethylene derivative represented by the general formula (I), a method using a Grignard reagent [J. Fluorine Chem., 3 , 247] has hitherto been known.
(1973/74), Synthesis, 1975 , 122] or a method using zinc in a stoichiometric amount or more [Tetrahedron Lett., 27 , 3655 (198
6)] etc. are known. However, in the former method, the reaction conditions are very severe, and care must be taken in handling the reaction reagent. Further, the latter method requires a heavy metal in a stoichiometric amount or more, and thus involves a serious problem in terms of pollution, and there is a problem in implementing it on an industrial scale.

OBJECT OF THE INVENTION It is an object of the present invention to provide a novel method for producing a 1,1-difluoroethylene derivative from a carbinol derivative by a safe and simple operation without the above-mentioned problems.

SUMMARY OF THE INVENTION [Wherein R is hydrogen, a C _{1 to} C ₂₀ linear or branched alkyl group, a C _{3 to} C ₁₆ alicyclic group, and a C _{1 to} C ₂₀ side chain of at least 1
C _{3 to} C ₁₆ alicyclic group, C _{2 to} C ₂₀ linear or branched unsaturated hydrocarbon group, aryl group, heterocyclic group, aralkyl group or aryloxy group, which are the same, May be different from each other, and may form a ring with a carbon chain or a carbon chain containing a hetero atom. Further, these may have a substituent. As a substituent, a hydroxyl group, a protected hydroxyl group,
Acyl group, acyloxy group, halogen, C _{1 to} C ₅ linear or branched alkyl group, C _{2 to} C ₆ linear or branched unsaturated hydrocarbon group, aralkyl group, amino group, C _{1 to} C ₅ An amino group substituted with a linear or branched alkyl group, a protected amino group, a nitro group, a protected thiol group, a carboxyl group, a protected carboxyl group, a formyl group,
It is a protected formyl group, sulfonic acid group, protected sulfonic acid group or cyano group, and the number of the substituents is 1 to 5, and these may be the same or different. ]
The carbinol derivative represented by is reacted with a lead compound in a polar solvent in the presence of a metal having a greater ionization tendency than lead, [Wherein R is as defined above. ] It is a method for producing a 1,1-difluoroethylene derivative represented by the following.

The 1,1-difluoroethylene derivative represented by the general formula (II) obtained in the present invention is a highly reactive olefin containing a fluorine atom and is very important as an intermediate for synthesizing pharmaceuticals, agricultural chemicals and the like. It is a compound.

As a result of intensive studies on the reduction of the carbinol derivative represented by the above general formula (I), the present inventors have found that lead is an excellent reducing agent in a unique reaction system using a lead compound and a metal having a greater ionization tendency than lead. They found that it worked, and completed the present invention. That is, according to the present invention, the 1,1-difluoroethylene derivative represented by the general formula (II) is the carbinol derivative represented by the general formula (I) in a polar solvent,
By reacting with a catalytic amount of a lead compound in the presence of a metal having an ionization tendency higher than that of lead, a high yield and a simple operation can be produced without accompanying byproducts.

In the present invention, R is hydrogen, a C _{1 to} C ₂₀ linear or branched alkyl group, a C _{3 to} C ₁₆ alicyclic group, or a C _{3 to} C ₁₆ having at least one C _{1 to} C ₂₀ side chain. An alicyclic group, a C _{2 to} C ₂₀ linear or branched unsaturated hydrocarbon group, an aryl group, a heterocyclic group, an aralkyl group or an aryloxy group, which may be the same or different, A ring may be formed by a carbon chain or a carbon chain containing a hetero atom. Further, these may have a substituent.

Specific examples of the C _{1 to} C ₂₀ linear or branched alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, isoamyl, hexyl, octyl, decyl and dodecyl groups. be able to.

Specific examples of the C _{3 to} C ₁₆ alicyclic group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Cyclooctyl, cyclodecyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclooctenyl,
Examples thereof include a cyclooctadienyl group.

Specific examples of the C _{3 to} C ₁₆ alicyclic group having at least one C _{1 to} C ₂₀ side chain include 1-methylcyclopropyl and 2,2
-Dimethylcyclopropyl, 3-methylcyclobutyl,
Examples thereof include 1-methylcyclopentyl, 3-ethylcyclopentyl, 3-t-butylcyclopentyl, 4-isopropylcyclohexyl and 4-t-butylcyclohexyl groups.

Specific examples of the C _{2 to} C ₂₀ linear or branched unsaturated hydrocarbon group include vinyl, ethynyl, 1-propenyl, 2-
Methyl-1-propenyl, propynyl, 3-butenyl,
Butynyl, pentenyl, pentadienyl, pentynyl,
Examples include hexenyl, hexynyl, heptenyl, heptynyl, octenyl, octynyl, 9-decenyl, prenyl, geranyl groups and the like.

The aryl group is a phenyl group or a polynuclear aromatic hydrocarbon group, and specific examples of the polynuclear aromatic hydrocarbon group include α
Examples thereof include -naphthyl, β-naphthyl, anthranyl and pyrenyl groups.

Examples of the heterocyclic group include oxygen, nitrogen, and cyclic groups containing a sulfur atom, and specific examples thereof include tetrahydrofuryl, furyl, tetrahydropyranyl, pyranyl,
Pyrrolyl, piperidinyl, pyridyl, oxazolyl, morpholinyl, tetrahydrothienyl, thienyl, thiadiazolyl, triazolyl, thiazolyl, triazolyl,
A tetrazolyl group etc. can be mentioned.

Specific examples of the aralkyl group include benzyl, phenethyl, phenylbutyl, diphenylmethyl, triphenylmethyl, naphthylmethyl and naphthylethyl groups.

Specific examples of the aryloxy group include phenoxy and α-
Examples thereof include naphthyloxy, β-naphthyloxy, anthranyloxy and pyrenyloxy groups.

In the case of forming a ring with carbon chain containing a carbon chain or heteroatom [- (CH ₂₎ k -] a (k is 2 to 13) -CH ₂ -
A heteroatom such as oxygen, nitrogen, or sulfur may enter in place of the group.

As the substituent of R, a hydroxyl group, a protected hydroxyl group, an acyl group, an acyloxy group, a halogen, a C _{1 to} C ₅ linear or branched alkyl group, and a C _{2 to} C ₆ linear or branched unsaturated group. A hydrocarbon group, an aralkyl group, an amino group, an amino group substituted with a C _{1 to} C ₅ linear or branched alkyl group, a protected amino group, a nitro group, a protected thiol group,
A carboxyl group, a protected carboxyl group, a formyl group, a protected formyl group, a sulfonic acid group, a protected sulfonic acid group, and a cyano group, and the number of the substituents is 1 to
5, which may be the same or different. Examples of the hydroxyl-protecting group include methyl, ethyl,
Lower alkyl groups such as propyl, isopropyl and butyl, or “Prote” by Greene (Theodora W. Greene)
ctive Groups in Organic Synthesis "(A. Weiley-Inter
Mention may be made of the hydroxyl-protecting groups described in Chapter 2 of Science Publication, 1981). As the acyl group, formyl, acetyl, propionyl, valeryl, benzoyl,
Examples thereof include toluoyl and furoyl groups. Specific examples of the acyloxy group include formyloxy, acetyloxy, propionyloxy, valeryloxy, benzoyloxy, toluoyloxy and furoyloxy groups. Examples of halogen include fluorine, chlorine, bromine and iodine. Examples of the C _{1 to} C ₅ linear or branched alkyl group include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, amyl and isoamyl groups. Examples of the C _{2 to} C ₆ linear or branched unsaturated hydrocarbon group include vinyl, ethynyl, propenyl,
Examples of the aralkyl group include butenyl and hexenyl groups, and examples of the aralkyl group include benzyl, phenethyl, phenylpropyl, phenylbutyl, and diphenylmethyl groups. Examples of the C _{1 to} C ₅ linear or branched alkyl group substituted with an amino group include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, amyl, isoamyl groups and the like. Examples of the amino-protecting group include the amino-protecting groups described in Chapter 7 of the same book.
Examples of the protecting group for the thiol group include C _{1 to} C ₅ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, amyl and isoamyl groups, phenyl, benzyl, phenethyl group and formyl, acetyl, trichloroacetyl, Examples thereof include acyl groups such as propionyl, benzoyl, toluoyl and furoyl groups. Examples of the carboxyl protecting group include carboxyl protecting groups described in Chapter 5 of the above book. Examples of the formyl protecting group include formyl protecting groups described in Chapter 4 of the same book. Methyl, ethyl, propyl, isopropyl, as a protecting group for the sulfonic acid group,
Examples thereof include alkyl groups such as butyl, t-butyl, amyl and isoamyl groups, and aralkyl groups such as phenyl, benzyl and phenethyl groups.

Further, specific examples of the above-mentioned substituents substituted with these groups include general formulas [In the formula, R 'is hydrogen or the above-mentioned carboxylic acid-protecting group].

The carbinol derivative represented by the general formula (I), which is the starting material of the present invention, is, for example, J. Fluorine Chem., 26 , 467 (1
984), Tetrahedron Lett., 27 , 2135 (1986), Chem.Let
It can be produced by the method described in T., 1986 , 2043 or the like.

In order to carry out the present invention, the carbinol derivative represented by the general formula (I) is reacted with a catalytic amount of a lead compound in a polar solvent in the presence of a metal having a greater ionization tendency than that of the general formula (II). ), The 1,1-difluoroethylene derivative represented by

The lead compound used in this reaction has a lead valence of 0 and 2
It may be monovalent or tetravalent, and these compounds may be in the form of hydrates. As the lead compound used, conventionally known compounds can be widely used. For example, lead halide such as fluoride, lead chloride, lead bromide, lead iodide, etc., lead nitrate, lead sulfate, lead perchlorate, lead borate, lead carbonate, lead phosphate, etc., inorganic acid lead, lead acetate. Examples thereof include fatty acid lead such as lead oxalate and lead stearate, lead oxide, and lead hydroxide. These lead compounds can be used alone or in combination of two or more. Among these lead compounds, lead halides such as lead fluoride, chloride, lead bromide and lead iodide are particularly preferable. The amount of these lead compounds used is preferably in the range of 0.001 to 0.5 equivalent relative to 1 equivalent of the carbinol derivative represented by the general formula (I) usually used as a starting material.

Aluminum, iron, nickel, tin, cobalt and magnesium are used as the metal having a greater ionization tendency than lead used in this reaction. These metals can be used alone or in combination of two or more. Aluminum is particularly preferred. The shape of these metals used is not particularly limited, and various shapes such as powder, plate, foil, lump or needle can be used. The amount of the metal having a greater ionization tendency than that of lead is preferably in the range of 0.3 to 4 equivalents relative to 1 equivalent of the carbinol derivative of the general formula (I).

The solvent used in this reaction is preferably a polar solvent, such as alcohols, ethers, nitriles,
Amides and the like, specifically, methanol, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2
It can be selected from a wide range as long as it dissolves the compound of the general formula (I) such as imidazolidinone and dimethyl sulfoxide and is not reduced under the reaction conditions. These solvents may be used in combination of two or more. Water may be contained as needed. Particularly preferred is dimethylformamide, and its use amount is not particularly limited, but is preferably at least an amount in which the raw material is completely dissolved.

The reaction temperature in this reaction varies depending on the raw material, solvent, etc., but it is usually preferably in the range of about 0 to 100 ° C.

As described above, the method of the present invention is industrially extremely advantageous.
This is a method for producing a 1-difluoroethylene derivative.

EXAMPLES The present invention will be described in more detail below with reference to Examples.

Example 1 In a round-bottomed flask, take 184 mg (0.5 mmol) of lead bromide and 162 mg (6.0 mmol) of finely chopped aluminum foil, add 10 ml of dimethylformamide and 1.52 g (5 mmol) of compound (1), and incubate at room temperature. The reaction was carried out with stirring for 20 hours. After completion of the reaction, 10 ml of water was added to the reaction solution and extracted with ether. The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 1.30 g of a pale yellow liquid. By refining this using a silica gel column, 1.23 g (yield 99%) of compound (2) was obtained as a colorless liquid. ¹ H-NMR [CDCl ₃ ; compound (2)] δ2.70 (br s, 1H, OH),
5.45~5.75 (m, 1H, CH- O), 5.90 (s, 2H, O-CH 2 -O),
6.70 to 6.95 (m, 3H, Ph).

Example 2 In a round-bottomed flask, take 139 mg (0.5 mmol) of lead chloride and 162 mg (6.0 mmol) of finely chopped aluminum foil, add 10 ml of dimethylformamide and 1.19 g (5 mmol) of compound (3), and add 10 mg at room temperature. The reaction was stirred for a while. After completion of the reaction, ice water (10 ml) was added to the reaction solution and the mixture was extracted with ether. The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 800 mg of a pale yellow liquid. By refining this using a silica gel column, 740 mg (yield 81%) of compound (4) was obtained as a colorless liquid. ¹ H-NMR [CDCl ₃ ; compound (4)] δ 1.75 (s, 6H, CH ₃ ), 2.
10 (br s, 1H, OH), 5.08 to 5.55 (m, 2H, CH-O, C = CH
-).

Examples 3 to 7 The reaction was carried out under the same conditions as in Example 1 except for the conditions shown in Table 1, and the products shown in Table 1 were obtained in high yield and high selectivity.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location C07D 317/54 C07D 317/54

Claims (2)

(57) [Claims] 1. A general formula [Wherein R is hydrogen, a C _{1 to} C ₂₀ linear or branched alkyl group, a C _{3 to} C ₁₆ alicyclic group, and a C _{1 to} C ₂₀ side chain of at least 1
C _{3 to} C ₁₆ alicyclic group, C _{2 to} C ₂₀ linear or branched unsaturated hydrocarbon group, aryl group, heterocyclic group, aralkyl group or aryloxy group, which are the same, May be different from each other, and may form a ring with a carbon chain or a carbon chain containing a hetero atom. Further, these may have a substituent. As a substituent, a hydroxyl group, a protected hydroxyl group,
Acyl group, acyloxy group, halogen, C _{1 to} C ₅ linear or branched alkyl group, C _{2 to} C ₆ linear or branched unsaturated hydrocarbon group, aralkyl group, amino group, C _{1 to} C ₅ An amino group substituted with a linear or branched alkyl group, a protected amino group, a nitro group, a protected thiol group, a carboxyl group, a protected carboxyl group, a formyl group,
It is a protected formyl group, sulfonic acid group, protected sulfonic acid group, or cyano group, and the number of the substituents is 1 to 5, and these may be the same or different. ] The general formula characterized by reacting a carbinol derivative represented by the formula with a lead compound in a polar solvent in the presence of a metal having a greater ionization tendency than lead. [Wherein R is as defined above. ] The manufacturing method of the 1,1- difluoro ethylene derivative represented by these. 2. The method according to claim 1, wherein the metal having a higher ionization tendency than lead is any one of aluminum, iron, nickel, tin, cobalt, magnesium, or a mixture thereof.