JPH09110729A - Production of difluoro compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently obtain a difluoro compound useful as a medicine, agrochemical, etc., from a readily available raw material under mild conditions in a short time by fluorinating a specific compound with an electrophilic fluorinating agent in the presence of a reacting agent of a metal compound under basic conditions. SOLUTION: (A) A compound (preferably a carboxylic ester such as methyl phenyl acetate) of the formula RCH2 Z (R is H, a <=30C monovalent chain hydrocarbon, etc.; Z is an electro-attractive substituent group) is fluorinated with (C) an electrophilic fluorinating agent (preferably N-fluorobenzene sulfonimide) in the presence of (B) a reacting agent of a metal compound (preferably a halide of transition metal such as vanadium chloride) under basic conditions to provide the objective compound of the formula RCF2 Z. Lithium amide, etc., is exemplified as the base. The reaction is preferably carried out in a inert organic solvent at -80 deg.C to 40 deg.C. The components B, C and the base are each used in amounts of 0.1-10 pts.wt., 2-10 pts.wt. and 2-10 pts.wt. based on 1 pt.wt. component A.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a difluoro compound which is useful as a medical and agricultural chemical or an intermediate thereof.

[0002]

BACKGROUND OF THE INVENTION Difluoro compounds are important compounds as medicines and agricultural chemicals or their intermediates. For example, an intermediate of an antitumor agent (LW Hertel et al., J. Org. Chem., 53, 2406 (1988).
), An intermediate of difluoroprostaglandins (Table 56-501319), difluoropeptides (S.Th
aisrivongs et al., J. Med. Chem., 29, 2080 (1986)) are known.

[0003]

However, in any of the methods for producing these compounds, it is difficult to obtain the raw materials,
Since reaction control is difficult because of using harsh reaction conditions or it is a non-general method, development of a practical production method of difluoro compounds has been strongly desired.

As the electrophilic fluorinating agent, fluorine gas, xenon fluoride, perchloryl fluoride and the like have been known for a long time, and in recent years, N-fluorosulfonimide, N-fluorosulfonamide and the like have been known. Electrophilic fluorinating agents have also been used. Electrophilic fluorinating agents such as N-fluorosulfonimide and N-fluorosulfonamide are described by DHR Barton et al. (USP 3,917,688, J. Ch.
em. Soc. Perkin I, 732 (1974)), WEBarnette et al. (US
P 4,479,901), E. Differding et al. (EP 0,311,086),
E. Differding et al. (Synlett, 187 (1991)), B. Wilkes et al. (DE 3,623,184A1), DDDes Marteau et al. (JP 62-26).
264), FA Davis et al. (Tetrahedron Lett., 32, 1631
(1991)) and the like.

Examples of direct difluorination of the α-position of an electron-withdrawing group using these fluorinating agents include direct difluorination of the α-position of carbonyl groups such as ketones and esters using N-fluorosaccharin sultam. Example (E.Differding
Et al., Tetrahedron Lett., 32,1779 (1991)), an example of fluorinating each α-position of a phosphonate ester in two steps using N-fluorobenzenesulfonimide (E. Diff
erding et al., Synlett, 395 (1991)), and there were problems in yield, selectivity, practicability and versatility. The former also had problems such as difficulty in handling and manufacturing the fluorinating agent. An example of direct difluorination of a lactone was not known at all except the example of the present inventors (EP0669329).

[0006]

The present inventor has been made to solve the above-mentioned drawbacks and problems. The present inventors have found a practical production method for efficiently producing a difluoro compound. The present invention is the following invention relating to a method for producing a difluoro compound useful as a medical or agricultural chemical or an intermediate thereof.

A difluoro compound represented by the following formula (2), characterized in that a compound represented by the following formula (1) is fluorinated by causing an electrophilic fluorinating agent to act under basic conditions in the presence of a metal catalyst. Manufacturing method.

[0008]

[Image Omitted] RCH ₂ Z (1)

[0009]

[Image Omitted] RCF ₂ Z (2)

(Wherein R is a hydrogen atom, a monovalent chain hydrocarbon group having 30 or less carbon atoms which may have a substituent,
It represents a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted heterocyclic group, and Z represents an electron-withdrawing substituent. )

[0011]

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the following description of the present specification,
The term "lower" organic group means 1 to 6 carbon atoms. More preferred lower organic groups are organic groups having 1 to 4 carbon atoms. The "alkyl group" may be linear or branched, and a lower alkyl group is preferable unless otherwise specified. Suitable examples thereof include methyl group, ethyl group, n-
Examples thereof include propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group and n-hexyl group. Unless otherwise specified, the "alkenyl group" is preferably a lower alkenyl group, more preferably a linear or branched alkenyl group having 2 to 6 carbon atoms and one unsaturated group, and suitable examples thereof. Examples thereof include a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 3-butenyl group, a 3-pentenyl group and a 4-hexenyl group. Unless otherwise specified, the "alkynyl group" is preferably a lower alkynyl group,
More preferably, it is a linear or branched alkynyl group having 2 to 6 carbon atoms and one unsaturated group, and suitable examples thereof include 1-propynyl group, 2-propynyl group, 3-butynyl group and 3 Examples include -pentynyl group and 4-hexynyl group.

As the "alkoxy group", a wide variety of general alkoxy groups can be used, but a lower alkoxy group is preferable, and a linear or branched alkoxy group having 1 to 4 carbon atoms is more preferable. Examples include methoxy, ethoxy, propoxy, butoxy and the like.

Further, the "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The "aryl group" refers to a monovalent aromatic hydrocarbon group, which may have a substituent (eg, lower alkyl group, halogen atom, lower alkoxy group, lower alkylamino group, etc.), and is preferably phenyl. And a derivative thereof, such as a phenyl group, a tolyl group, a p-halophenyl group (eg, p-chlorophenyl group, p-bromophenyl group, etc.), an alkoxyphenyl group (eg, p-methoxyphenyl group, p-ethoxyphenyl group). Group) and the like. The "aralkyl group" refers to an aryl group-substituted alkyl group, and examples of the aryl group as the substituent include those described above. The alkyl group preferably has 1 to 4 carbon atoms. Suitable examples thereof include a benzyl group, a benzhydryl group, a trityl group, a phenethyl group and the like.

The monovalent chain hydrocarbon group having 30 or less carbon atoms in the present invention may be linear or branched, and may be a saturated hydrocarbon group or one or more unsaturated groups. It may be an unsaturated hydrocarbon group containing. Examples of these monovalent chain hydrocarbon groups include an alkyl group, an alkenyl group, and an alkynyl group, which may have a substituent bonded thereto. The monovalent chain hydrocarbon group preferably has 16 or less carbon atoms, and more preferably a lower chain hydrocarbon group as described above. Specific examples of these chain hydrocarbon groups include the following chain hydrocarbon groups in addition to those described above.

N-heptyl group, n-octyl group, n-nonyl group, n-decyl group, n-undecyl group, n-dodecyl group, n-tetradecyl group, n-hexadecyl group, n-
Linear alkyl groups such as octadecyl group and n-eicosyl group. Neopentyl group, 1-methylpentyl group, 1,1
-Dimethylpentyl group, 1-methyl-3-hexyl group,
A branched alkyl group such as a 2-methylpentyl group or a 2-methylhexyl group. 1-methyl-3-pentenyl group,
1,1-dimethyl-hexenyl group, octenyl group, 1-
A linear or branched alkenyl group or alkynyl group such as a methyl-3-hexynyl group, a 1,1-dimethyl-3-pentynyl group or a 1,1-dimethyl-3-hexynyl group.

Examples of the substituent of the above monovalent chain hydrocarbon group include a cycloalkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aryl group (excluding those which will be an aralkyl group described later), halogen. Atom, protected hydroxyl group, protected amino group, protected carboxy group, nitro group,
Substituents such as a cyano group, an oxime group, an alkoxyme group and the like can be mentioned. As the cycloalkyl group having 3 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms is preferable. Further, a lower alkyl group as a substituent may be bonded to this cycloalkyl group.

The aryl group in the present invention means a monovalent aromatic hydrocarbon group as described above, and may or may not have a substituent. Preferably a phenyl group, a naphthyl group,
And derivatives thereof, and those having a substituent such as a lower alkyl group, a halogen atom, a lower alkoxyl group, a lower alkylamino group and a nitro group are preferable as the derivative. Specifically, for example, in addition to the above, p-fluorophenyl group, p-nitrophenyl group, o-chlorophenyl group, o-bromophenyl group, o-methoxyphenyl group, o-ethoxyphenyl group, o-nitro. A phenyl group and the like are preferable.

As the protected hydroxyl group, a hydroxyl group protected by a known or known protecting group used as a hydroxyl protecting group can be adopted. As the protecting group, for example,
A triorganosilyl group, an acyl group, a cyclic ether group, an optionally substituted alkyl group or an aralkyl group is used.

The triorganosilyl group is a group in which three organic groups such as an alkyl group, an aryl group, an aralkyl group and an alkoxy group are bonded to a silicon atom, and at least one kind selected from a lower alkyl group and an aryl group is particularly preferable. A triorganosilyl group having 3 groups is preferable. Specifically, for example, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, triethylsilyl group, triphenylsilyl group, triisopropylsilyl group and the like are preferable. The acyl group is preferably an acetyl group, a benzoyl group or a p-phenylbenzoyl group. As the cyclic ether group, a tetrahydropyranyl group or a tetrahydrofuranyl group is preferable. Further, the alkyl group and aralkyl group which may have a substituent include a methoxymethyl group, 1
-Alkoxyalkyl groups such as -ethoxyethyl group and 2-methoxyethoxymethyl group, and benzyl group, methoxybenzyl group and trityl group.

As the protected amino group, an amino group protected by a known or well-known protecting group used as a protecting group for an amino group can be adopted. Examples of the protecting group include an acyl group, an alkoxycarbonyl group, an alkyl group, an alkenyl group, an aralkyl group, a triorganosilyl group and a sulfonyl group, and examples of the acyl group include an acetyl group, a benzoyl group and a trifluoroacetyl group. Is preferred. The alkoxycarbonyl group is preferably a t-butoxycarbonyl group, a benzyloxycarbonyl group or the like, and the alkyl group, the alkenyl group or the alkynyl group is a methoxymethyl group, an allyl group, a benzyl group, a trityl group or a methoxybenzyl group. preferable. As the triorganosilyl group, t-butyldimethylsilyl group, t
-Butyldiphenylsilyl group, triethylsilyl group, triphenylsilyl group, triisopropylsilyl group and the like are preferable. As the sulfonyl group, a p-toluenesulfonyl group, a benzenesulfonyl group, a p-chlorobenzenesulfonyl group, a p-nitrobenzenesulfonyl group, a methanesulfonyl group and the like are preferable.

As the protected carboxy group, a carboxyl group protected by a known or known protecting group used as a protecting group or equivalent of the carboxy group can be adopted. As the protecting group, an orthoester group, a tetrazole group and the like are preferable.

As the aralkyl group, widely-used general aralkyl groups as described above are used, and suitable examples thereof include the above-mentioned benzyl group, benzhydryl group, trityl group and phenethyl group. As the substituted aralkyl group, an aralkyl group having a substituent described as the substituent of the aryl group as the substituent of the aryl moiety and a substituent described as the substituent of the alkyl group as the substituent of the alkyl moiety There is.

The heterocyclic group includes an oxygen atom, a nitrogen atom,
A monovalent group derived from a ring of a heterocyclic compound containing one or more hetero atoms such as a sulfur atom and a phosphorus atom by removing a hydrogen atom is widely used. The heterocyclic compound may be a monocyclic compound or a condensed ring compound. Various substituents as described above may be bonded to this heterocyclic group. Specific examples of the heterocyclic compound include the following compounds.

Furan, thiophene, pyrrole, 2H-pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, furazan, pyran, pyridine, pyridazine, pyrimidine, pyrazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, Pyrazolidine, piperidine, piperazine, morpholine, indole, isoindole,
1H-indazole, 4H-chromene, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, purine, pteridine, xanthene, carbazole, phenanthridine, acridine, phenazine, phenanthroline, indoline, isoindoline, clomanthienofuran, imidazothiazole, Phosphanaphthalene, dithianaphthalene aziridine, thiolane, silolene, azepine, dioxolane, triazine, oxathiane, dithiazine.

Examples of the substituent of the heterocyclic group include a linear or branched saturated or unsaturated hydrocarbon group having 30 or less carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, and a substituted or unsubstituted aryl group. , Halogen atom, protected hydroxyl group, alkoxy group, protected amino group, protected carboxy group, nitro group, cyano group, alkoxyme group,
Thiocarboxy group, dithiocarboxy group, alkoxycarboxy group, alkylsulfonyl group, arylsulfonyl group, aralkylsulfonyl group, alkylsulfinyl group, arylsulfinyl group, aralkylsulfinyl group, alkylsulfenyl group, arylsulfenyl group, aralkyl Sulfenyl group, carbamoyl group,
Examples of the substituent include an isocyano group, an oxo group, a thioformyl group, a thioxo group and a phosphoryl group.

In the present invention, the electron-withdrawing substituent represented by Z is a carboxy group, a thiocarboxy group,
Dithiocarboxy group, alkoxycarboxy group, alkylsulfonyl group, arylsulfonyl group, aralkylsulfonyl group, alkylsulfinyl group, arylsulfinyl group, aralkylsulfinyl group, alkylsulfenyl group, arylsulfenyl group, aralkylsulfenyl group, A carbamoyl group, a hydrazinocarbonyl group, an amidino group, a cyano group, an isocyano group, an oxo group, a thioformyl group, a thioxo group, a nitro group, an oxime group, an alkoxyme group, an imino group, a phosphoryl group and the like are preferable.

Particularly preferred Z is --COX (provided that X
Is a hydrogen atom, a monovalent chain hydrocarbon group having 30 or less carbon atoms which may have a substituent, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted A heterocyclic group, a hydroxyl group, an alkoxy group, a protected hydroxyl group, an amino group, a protected amino group, an alkylthio group, an arylthio group, or a mercapto group). Here, a monovalent chain hydrocarbon group having 30 or less carbon atoms which may have a substituent, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heterocycle As the group, alkoxy group, protected hydroxyl group, and protected amino group, those mentioned above are suitable.

The alkylthio group is preferably an alkylthio group containing the above-mentioned alkyl group (more preferably a lower alkyl group). Specific examples include a methylthio group, an ethylthio group, a propylthio group, a butylthio group and the like. The arylthio group is preferably an arylthio group including the above aryl group. Specifically, a phenylthio group, a naphthylthio group, a methoxyphenylthio group, a chlorophenylthio group, a nitrophenylthio group and the like are preferable. Preferred X is a lower alkyl group, a lower alkoxy group, a phenyl group, and those groups having an inert substituent such as a halogen atom.

Preferred X is a hydrogen atom, a monovalent chain hydrocarbon group having 30 or less carbon atoms which may have a substituent, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, And an alkoxy group.

The most preferable compound represented by the general formula (1) is an ester of a carboxylic acid represented by RCH ₂ COOH (especially one in which X is an alkoxy group), and an RCH ₂ CO- structure. It is a ketone that has. More preferred are carboxylic acid esters and ketones containing an aryl group or a heterocyclic group in the R portion or X portion.

The difluoro compound represented by the general formula (2) can be produced by difluorinating the compound represented by the general formula (1). As a method for producing a difluoro compound represented by the general formula (2) by difluorinating the compound represented by the general formula (1), in the present invention, an electrophilic fluorine is present in the presence of a metal compound reactant. A method of reacting with an agent is adopted. It is believed that the metal compound reactant activates the active substance generated in the intermediate stage of the reaction with respect to the fluorination reaction. When fluorination is carried out in the absence of a metal compound reactant, a difluoride is scarcely produced even if a monofluoride is produced.

Examples of the metal compound reactant include organic metal compounds and metal salts. The metal species in this metal compound include B, Mg, Al, Ca, Ti, V, and M.
n, Fe, Co, Ni, Cu, Zn, Zr, Sn, B
Metal species such as a, Hf, W, La, Ce and Sm can be mentioned.

The metal compound reactant is preferably a metal halide, an organic metal halide, (particularly an alkyl metal halide), a metallocene halide, a trifluoromethanesulfonic acid metal salt and the like. A transition metal is preferable as the metal species. Specific metal catalysts include, for example, the following metal compounds.

Boron trifluoride etherate, magnesium chloride, magnesium bromide, magnesium iodide, magnesium trifluoromethanesulfonate, aluminum chloride, dialkyl aluminum chloride, alkyl aluminum dichloride, calcium chloride, titanium tetrachloride,
Titanium trichloride isopropoxide, titanium dichloride diisopropoxide, titanium chloride triisopropoxide, titanium tetrabromide, titanium tribromide isopropoxide, dibromotitanium chloride diisopropoxide, titanium bromide triisopropoxy Dehydrate, titanocene dichloride, vanadium chloride, manganese dichloride, manganese dibromide, iron trichloride, iron tribromide, iron triiodide, cobalt chloride, nickel chloride, nickel bromide, copper chloride, copper bromide, iodide Copper, zinc chloride, zinc bromide, zinc iodide, zinc trifluoromethanesulfonate, zirconium chloride, zirconium bromide, zirconocene dichloride,
Zirconocene chloride hydride, tin tetrachloride, tin dichloride, tin trifluoromethanesulfonate, barium chloride, barium bromide, barium iodide, hafnium chloride,
Hafnocene dichloride, tungsten chloride, lanthanum chloride, cerium chloride, samarium iodide.

The amount of the metal compound used is usually 0.1% by weight per 1 part by weight of the compound represented by the formula (1).
The amount is about 01 to 20 parts by weight, preferably about 0.1 to 10 parts by weight.

The electrophilic fluorinating agent is not particularly limited, and a known or well-known electrophilic fluorinating agent can be adopted. For example, the electrophilic fluorinating agent described in the authors such as Tomoya Kitazume, Takashi Ishihara, Takeo Taguchi "Chemistry of Fluorine" (Kodansha Scientific) can be used. Specific examples thereof include fluorine gas, xenon fluoride, perchloryl fluoride, acetyl hypofluorite, N-fluorosulfonamides and N-fluorosulfonimides. N-fluorosulfonimides are preferable, N-fluorobenzenesulfonimide, N-fluoro-p-fluorobenzenesulfonimide, N-fluoro-o-benzenedisulfonimide, N-fluoro-
Particularly preferred is p-toluenesulfonimide.

The amount of the electrophilic fluorinating agent is usually
It is used in an amount more than the amount that provides the necessary fluorine atoms for the intended difluorination. In a usual reaction, the amount is about 0.5 to 20 parts by weight, preferably about 2 to 10 parts by weight, relative to 1 part by weight of the compound represented by the general formula (1) as a substrate.

The above difluorination reaction is preferably carried out under basic conditions in an inert solvent. As a base, an alkali metal such as lithium, sodium or potassium,
Amides of ammonia and secondary amines, alkali metal hydrides, alkali metal alkoxides, alkali metal organic compounds and the like are used. Specifically, lithium amide, sodium amide, potassium amide, lithium diisopropylamide, lithium diethylamide, lithium dicyclohexylamide, lithium isopropylcyclohexylamide, lithium-2,2,6,6-tetramethylpiperidine, lithium hexamethyldisilazide, Sodium diethylamide, sodium hexamethyldisilazide, potassium-3-aminopropylamide, potassium hexamethyldisilazide, lithium hydride, sodium hydride, potassium hydride, potassium t-butoxide,
Examples thereof include n-butyllithium, s-butyllithium, t-butyllithium, lithium naphthalenide, lithium biphenylide and the like.

The amount of the base is usually 0.5 to 20 parts by weight, preferably 2 to 10 parts by weight, based on 1 part by weight of the compound which is the substrate.

The inert solvent is preferably an ether solvent, a hydrocarbon solvent, a polar solvent or a mixed solvent thereof. As the ether solvent, diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diglyme, t-butyl methyl ether, etc., and as the hydrocarbon solvent, hexane, toluene, benzene, pentane, xylene, petroleum ether, etc. As the polar solvent, dimethyl sulfoxide, hexamethylphosphoramide (HMPA), 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU),
1,3-dimethyl-2-imidazolidinone (DMI),
N, N, N ', N'-tetramethylethylenediamine (TMEDA) and the like are preferable. The amount of the inert solvent is usually about 5 to 1000 parts by weight, preferably 10 parts by weight, relative to 1 part by weight of the compound represented by the general formula (1).
-100 parts by weight is preferable.

The reaction temperature of the above fluorination reaction is usually about -150 to + 100 ° C, and -80 to +4.
0 ° C. is preferred.

The compound represented by the general formula (2) of the present invention is an important intermediate which can be derived into a medical and agricultural chemicals containing various difluoro units.

The compound which is the starting material for the compound of the present invention is an easily available compound. The synthesis methods of the present invention are excellent methods that do not require severe reaction conditions or long-term reactions, and do not require special reaction reagents or reaction equipment. Therefore, the production method of the present invention is versatile and is an extremely excellent method applicable to the synthesis of many derivatives.

The present invention will be specifically described below with reference to examples and reference examples. However, the present invention is not limited to these examples.

[0045]

【Example】

(Example 1: Synthesis of methyl 2,2-difluorophenylacetate) Manganese bromide anhydrous 185 mg (1.5 mmol)
Anhydrous tetrahydrofuran (3 ml) was added to N, and then N-
Fluorobenzenesulfonimide 473 mg (1.5 m
Anhydrous tetrahydrofuran solution (3 ml) of (mol) was added at room temperature and stirred for 1 hour. Next, a solution of methyl phenylacetate (150 mg) in THF (3 ml) was added at -78 ° C at -78 ° C.
Add at 60 ° C and add potassium hexamethyldisilazide (0.5M
Of toluene solution) was added, and the temperature was -78 ° C for 1 hour at 0 ° C.
For 1 hour. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, and purified by silica gel column chromatography to obtain 101 mg of the title compound. The structural formula of the title compound is shown below. ¹ H-NMR (CDCl ₃ ) δ (ppm): 3.8 (s, 3H), 7.3-7.8 (m, 5H). ¹⁹ F-NMR (CDCl ₃ , ppm): -114 (s).

(Example 2: Synthesis of methyl 2,2-difluorophenylpropionate) In the same manner as in Example 1 except that 164 mg of methyl phenylpropionate was used, 96 mg of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 3.4 (t, J = 7.5Hz, 2H), 3.8 (s, 3
H), 7.3 (m, 5H). ¹⁹ F-NMR (CDCl ₃ , ppm): -106 (t, J = 17Hz).

(Example 3: Synthesis of methyl 2,2-difluoro (2-pyridyl) acetate) Methyl 2-pyridylacetate 1
The title compound 87 was prepared in the same manner as in Example 1 except that 50 mg was used.
mg was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 3.9 (s, 3H), 7.3-8.6 (m, 4H). ¹⁹ F-NMR (CDCl ₃ , ppm): -115 (s).

(Example 4: Synthesis of methyl 2,2-difluoro-5-benzyloxypentanoate) Using 222 mg of methyl 5-benzyloxypentanoate, the title compound 87 mg was obtained in the same manner as in Example 1. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.5-2.6 (m, 4H), 3.5 (t, J = 7,2
H), 3.8 (s, 3H), 4.6 (s, 2H), 7.3-7.6 (m, 5H). ¹⁹ F-NMR (CDCl ₃ , ppm): -106 (t, J = 17Hz).

(Example 5: Synthesis of 2,2-difluorobutyrophenone) In the same manner as in Example 1 except that 148 mg of butyrophenone was used, 117 mg of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.2 (t, J = 7Hz, 3H), 2.3 (s, 3H),
7.3-8.0 (m, 5H). ¹⁹ F-NMR (CDCl ₃ , ppm): -100 (t, J = 17Hz).

[0050]

INDUSTRIAL APPLICABILITY The fluorination method of the present invention is an excellent method that does not require severe reaction conditions or long-term reaction, and does not require a special reaction reagent or reaction apparatus.
Further, the compound as a raw material is a compound that is easily available.
Therefore, the production method of the present invention is also excellent in versatility and can be applied to the synthesis of many other derivatives.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07C 67/307 C07C 67/307 69/65 69/65 69/734 69/734 Z 327/04 7106-4H 327 / 04 327/20 7106-4H 327/20 C07D 213/55 C07D 213/55 213/79 213/79 // C07B 61/00 300 C07B 61/00 300

Claims (6)

[Claims] 1. A compound represented by the following formula (1), characterized by fluorinating a compound represented by the following formula (1) by reacting an electrophilic fluorinating agent in the presence of a metal compound reactant under basic conditions. Of producing a difluoro compound. Embedded image RCH ₂ Z (1) embedded image RCF ₂ Z (2) (wherein R is a hydrogen atom or a monovalent chain hydrocarbon having 30 or less carbon atoms which may have a substituent) Represents a group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted heterocyclic group, Z
Represents an electron-withdrawing substituent. ) 2. Z is --COX (where X is a hydrogen atom, a monovalent chain hydrocarbon group having 30 or less carbon atoms which may have a substituent, a substituted or unsubstituted aryl group, A substituted or unsubstituted aralkyl group, a substituted or unsubstituted heterocyclic group, a hydroxyl group, an alkoxy group, a protected hydroxyl group, an amino group, a protected amino group, an alkylthio group,
It represents an arylthio group or a mercapto group). 3. The method according to claim 2, wherein X is an alkoxy group. 4. X is a hydrogen atom, a monovalent chain hydrocarbon group having 30 or less carbon atoms which may have a substituent, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aralkyl. The method according to claim 2, which is a base. 5. A metal compound reactant is B, Mg, Al, C.
a, Ti, V, Mn, Fe, Co, Ni, Cu, Zn,
Zr, Sn, Ba, Hf, W, La, Ce, and Sm
The method according to claim 1, 2, 3, or 4, which is a metal compound containing a metal species selected from the group consisting of: 6. The method according to claim 1, 2, 3, 4, or 5, wherein the electrophilic fluorinating agent is an N-fluorosulfonimide.