JP2516618B2 - 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 and an acyl fluoride 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. In addition, the latter method requires a heavy metal in a stoichiometric amount or more, and thus involves a serious problem of pollution. There is a problem in implementing the method on an industrial scale, and the yield is not always satisfactory.

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 an aldehyde by a safe and simple operation without the above-mentioned problems of the conventional method.

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, which may be the same or different Alternatively, a carbon chain or a carbon chain containing a hetero atom may form a ring.
Further, these may have a substituent. As a substituent, a hydrogen group, a protected hydroxyl group, an acyloxy group, a halogen, a C _{1 to} C ₅ linear or branched alkyl group, a C _{2 to} C ₆ linear or branched unsaturated hydrocarbon group, an aralkyl group , Amino group, amino group substituted with C _{1 to} C ₅ linear or branched alkyl group, protected amino group, nitro group, protected thiol group, carboxyl group, protected carboxyl group, sulfonic acid A group, a protected sulfonic acid group and a cyano group, the number of the substituents is 1 to 5, and these may be the same or different. The aldehyde represented by the general formula is reacted with 1,1,1-trichloro-2,2,2-trifluoroethane in a polar solvent in the presence of a lead compound and a metal having a greater ionization tendency than lead, to give a compound represented by the general formula [Wherein R is as defined above. ] The method for producing a 1,1-difluoroethylene derivative represented by

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 diligent studies on the method for producing a 1,1-difluoroethylene derivative, the present inventors have found that a unique reaction system using a lead compound and a metal having a greater ionization tendency than lead is used to react with aldehyde and 1,1,1-trichloro-2. The inventors have found that a 1,1-difluoroethylene derivative can be produced in a good yield in one step by reacting 2,2,2-trifluoroethane, and completed the present invention. That is, according to the present invention, the general formula (II)
The 1,1-difluoroethylene derivative represented by the formula (1) is an aldehyde represented by the general formula (I) and 1,1,1-trichloro-
By reacting 2,2,2-trifluoroethane in a polar solvent in the presence of a lead compound and a metal having an ionization tendency higher than that of lead, it is produced in a high yield and by a simple operation.

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, and a C _{3 to} C having at least one C _{1 to} C ₂₀ side chain. ₁₆ alicyclic groups, C _{2 to} C ₂₀ linear or branched unsaturated hydrocarbon groups, aryl groups, heterocyclic groups, aralkyl groups, which may be the same or different, carbon chain or A carbon chain containing a hetero atom may form a ring. 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.

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.

The substituent of R is a hydroxyl group, a protected hydroxyl group, an acyloxy group, a halogen, a C _{1 to} C ₅ linear or branched alkyl group, or a C _{2 to} C ₆ linear or branched unsaturated 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 sulfonic acid group, a protected sulfonic acid group, and a cyano group, and the number of the substituents is 1 to 5, and these may be the same or different. Examples of the hydroxyl-protecting group include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, and butyl groups, or “Prod” by Greene (Theodora W. Greene).
tective Groups in Organic Synthesis "(A Weiley Int
erscience Publication, 1981) and the protecting group for the hydroxyl group described in Chapter 2. 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, butenyl, and hexenyl groups, and aralkyl groups such as benzyl.
Examples thereof include 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,
Examples thereof include t-butyl, amyl and isoamyl groups. Examples of the amino-protecting group include the amino-protecting groups described in Chapter 7 of the same book. Methyl, ethyl, propyl, isopropyl, as a protecting group for the thiol group,
Butyl, C ₁ -C _5, such as t- butyl, amyl, isoamyl group
Examples of the alkyl group, phenyl, benzyl, and phenethyl group. Examples of the carboxyl protecting group include carboxyl protecting groups described in Chapter 5 of the above book. Examples of the protective group for the sulfonic acid group include alkyl groups such as methyl, ethyl, propyl, isopropyl, 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 A group represented by the formula [wherein R ¹ is hydrogen or the above-mentioned carboxylic acid protecting group] can be mentioned as an example.

In order to carry out the present invention, an aldehyde represented by the above general formula (I) is used in a polar solvent in the presence of a catalytic amount of a lead compound and a metal having a greater ionization tendency than that of lead, 1,1,1-trichloro-2. The 11-difluoroethylene derivative represented by the general formula (II) is produced by reacting with 2,2,2-trifluoroethane.

The 1,1,1-trichloro-2,2,2-trifluoroethane used in this reaction may be used in an equivalent amount with respect to the aldehyde represented by the general formula (I). Good results are obtained, and the preferred range of use is 1 to 4 equivalents.

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 halides such as lead fluoride, lead chloride, lead bromide, and lead iodide, lead oxides such as lead nitrate, lead sulfate, lead perchlorate, lead borate, lead carbonate, lead phosphate, etc .; , Lead oxalate, fatty acid lead such as lead stearate, lead oxide, lead hydroxide and the like can be used. These lead compounds can be used alone or in combination of two or more. Particularly preferred among these lead compounds are lead halides such as lead fluoride, lead chloride, lead bromide and lead iodide. 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 aldehyde represented by the general formula (II) 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 0.5 to 10 with respect to 1 equivalent of the aldehyde represented by the general formula (I).
It is preferably within the equivalent range.

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, the amount of the lead compound and the metal having a greater ionization tendency than lead, the solvent, etc.
It is preferable to carry out within the range.

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 405 mg (15 mmol) of finely cut aluminum foil, and add 10 ml of dimethylformamide and benzaldehyde (1) 53 to it.
0 mg (5 mmol) and 1.87 g (10 mmol) of 1,1,1-trichloro-2,2,2-trifluoroethane (2) were added, and the reaction was carried out by stirring at room temperature for 20 hours. After the reaction was completed, 10 ml of ice water 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 then concentrated to give a pale yellow liquid of about 1.
0 g was obtained. This product was purified by using a silica gel column to give Compound (3) as a colorless liquid, 920 mg.
(Yield 90%) was obtained. ¹ H-NMR [CDCl ₃ ; compound (3)] δ 2.76 (s, 1H, OH), 5.5
7-5.73 (m, 1H, CH-O), 7.06-7.44 (m, 5H, Ph).

Example 2 In a round bottom flask, take 139 mg (0.5 mmol) of lead chloride and 405 mg (15 mmol) of finely cut aluminum foil, and add 10 ml of dimethylformamide, 421 mg (5 mmol) of 3-methyl-2-butenal (4), 1 , 1,1-trichloro-2,
1,2-Trifluoroethane (2) (1.87 g, 10 mmol) was added, and the mixture was stirred at room temperature for 20 hours for reaction. After the reaction was completed, 10 ml of ice water 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 about 700 mg of a pale yellow liquid. By refining this using a silica gel column, 640 mg (yield 70%) of compound (5) was obtained as a colorless liquid. ¹ H-NMR [CDCl ₃ ; compound (5)] 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 code Internal reference number FI Technical display location C07C 69/743 C07C 69/743 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, which may be the same or different Alternatively, a carbon chain or a carbon chain containing a hetero atom may form a ring.
Further, these may have a substituent. As a substituent, a hydrogen group, a protected hydroxyl group, an acyloxy group, a halogen, a C _{1 to} C ₅ linear or branched alkyl group, a C _{2 to} C ₆ linear or branched unsaturated hydrocarbon group, an aralkyl group , Amino group, amino group substituted with C _{1 to} C ₅ linear or branched alkyl group, protected amino group, nitro group, protected thiol group, carboxyl group, protected carboxyl group, sulfonic acid A group, a protected sulfonic acid group and a cyano group, the number of the substituents is 1 to 5, and these may be the same or different. ] The aldehyde represented by the formula [1] is reacted with 1,1,1-trichloro-2,2,2-trifluoroethane in a polar solvent in the presence of a lead compound and a metal having a higher ionization tendency than lead. formula [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.