JP2008266242A - Method for producing difluoromethyl heterocyclic compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing an α-difluoromethyl heterocyclic compound. <P>SOLUTION: The method for producing the α-difluoromethyl heterocyclic compound represented by general formula (3) (wherein, R<SP>1</SP>represents a triorganosilyl group or a hydrogen; R<SP>2</SP>, R<SP>3</SP>, R<SP>4</SP>and R<SP>5</SP>may each be the same or different and represent each a hydrogen or a monovalent organic group; and any of R<SP>2</SP>, R<SP>3</SP>, R<SP>4</SP>and R<SP>5</SP>may mutually be bonded to form a bivalent or higher-valent organic group) is carried out as follows: a trifluoromethyl compound represented by general formula (1) äwherein, R<SP>2</SP>, R<SP>3</SP>, R<SP>4</SP>and R<SP>5</SP>are each as described in the general formula (3)} is reacted with a halogenated triorganosilane represented by general formula (2): (R<SP>6</SP>)<SB>3</SB>SiX (wherein, R<SP>6</SP>s represent each independently a methyl group, an ethyl group, a propyl group, an isopropyl group or a phenyl group; and X represents chlorine, bromine or iodine) in the presence of a low-valent metal and a solvent. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method for producing an α-difluoromethyl heterocyclic compound, and more particularly to a method for producing an α-difluoro (hydrogen) methyl heterocyclic compound and an α-difluoro (silyl) methyl heterocyclic compound. The α-difluoromethyl heterocyclic compound is useful as a reaction reagent for introducing a difluoromethyl group into an organic compound or as an intermediate for producing organic compounds such as pharmaceuticals and agricultural chemicals.

  In recent years, since a compound having a difluoromethylene group has a specific biological activity, its synthesis method has attracted attention. Until now, the carbonyl group, thiocarbonyl group or thiocetal group is frequently converted to a difluoromethylene group by reacting with DAST (dimethylaminosulfur trifluoride) or an oxidative fluorinating agent having the same action. A method of dehalogenating a halodifluoromethyl group to form a difluoromethylene group is also well known. However, little is known about selective demonofluorination from trifluoromethyl groups.

Although the above method is an excellent method with a good yield, an expensive fluorinating agent is a method that is difficult to say industrially general, and therefore, the appearance of an alternative synthetic method is desirable.
Therefore, the present invention provides a method for producing an α-difluoromethyl heterocyclic compound that can constitute an industrial process by applying operations conventionally performed in many reactions.

When the present inventors reacted a trifluoromethyl heterocyclic compound and a halogenated trialkylsilane in the presence of a low-valent metal and a solvent, α-difluoro (R) represented by the following general formulas (4) and (5) The inventors have found that hydrogen) methyl heterocyclic compounds and α-difluoro (silyl) methyl heterocyclic compounds are formed, and have reached the present invention.
That is, the present invention provides the following.

  [1] General formula (1):

(In the formula, R ² , R ³ , R ⁴ and R ⁵ may be the same or different and each represents hydrogen or a monovalent organic group, and any one of R ² , R ³ , R ⁴ and R ⁵ is bonded to each other. A divalent or higher valent organic group) may be represented by the general formula (2):
(R ⁶ ) ₃ SiX (2)
(Wherein R ⁶ independently represents a methyl group, an ethyl group, a propyl group, an isopropyl group or a phenyl group, and X represents chlorine, bromine or iodine) and a low atom General formula (3) characterized by reacting with a valent metal in the presence of a solvent:

(Wherein, R ¹ represents a triorganosilyl group or hydrogen, and R ² , R ³ , R ⁴ , and R ⁵ are as described above).
[2] The α-difluoromethyl heterocyclic compound is represented by the general formula (4):

^{(Wherein, R 2, R 3, R} 4, R R 2 ⁵ each formula ^{(1), R 3, R} 4, represents the same substituent as ^{R 5.)} Represented by α- difluoro (hydrogen ) Methyl heterocyclic compounds and general formula (5):

(Wherein, ^{R 6} represents the same substituent as ^{R 6} in formula ^{(2), R 2, R} 3, R 4, R 2 of the ^{R 5} each formula ^{(1), R 3, R} 4, R 5 And the same substituent as above.), Which is obtained as a mixture of α-difluoro (silyl) methyl heterocyclic compounds represented by formula (1).

  The present invention is characterized in that the trifluoromethyl compound represented by the general formula (1) is reacted in the presence of a halogenated triorganosilane represented by the general formula (2), a low-valent metal, and a solvent. This is a method for producing an α-difluoromethyl heterocyclic compound represented by the general formula (3).

The α-trifluoromethyl heterocyclic compound represented by the general formula (1) according to the present invention is not particularly limited, and R ² , R ³ , R ⁴ , and R ⁵ are not hydrogen atoms or non-reactive under the conditions of the present invention. Any active monovalent organic group may be used, and any of R ² , R ³ , R ⁴ , and R ⁵ may be bonded to each other to form a divalent or higher valent organic group. Examples of such an organic group include various aromatic heterocycles (including quinoline derivatives and the like), alkyl groups, alkenyl groups, or alkynyl groups that may have 1 to 20 carbon atoms, and 1 to 1 carbon atoms. A cycloalkyl group that may have 20 substituents, an aryl group that may have a substituent of 1 to 20 carbon atoms, a secondary to tertiary amino group, a general formula (6):
_{- (CH 2) n -R 3} (6)
(In the formula, R ³ represents a cycloalkyl group having 1 to 10 carbon atoms, an aryl group, an alkoxyl group, a thioalkoxyl group, a tertiary amino group, an acyl group, an alkoxycarbonyl group, or a heteroaromatic group, and n is 0 or And an organic group represented by 1). Specific examples of the α-trifluoromethyl heterocyclic compound represented by the general formula (1) include α-trifluoromethylpyridine, α-trifluoromethyl-β-phenylmethylpyridine, α-trifluoromethyl-β. -Phenethylmethylpyridine, α-trifluoromethyl-β-n-hexylpyridine, α-trifluoromethyl-β-c-hexylpyridine, α-trifluoromethyl-β-ethoxycarbonylmethylpyridine, α-trifluoromethyl- β-2-furylpyridine, α-trifluoromethyl-β-2-thienylpyridine, α-trifluoromethyl-β-ethoxypyridine, α-trifluoromethyl-β-t-butoxypyridine, α-trifluoromethyl- β-hexoxypyridine, α-trifluoromethyl-β-St-butylpyridine, α-trif Oromethyl-β-S-phenylpyridine, α-trifluoromethyl-β-methoxyethylpyridine, α-trifluoromethyl-β-methoxyphenylpyridine, α-trifluoromethyl-β-trifluoromethylphenylpyridine, α-trimethyl Fluoromethyl-β-chlorophenylpyridine, α-trifluoromethyl-β-thiomethoxyethylpyridine, α-trifluoromethyl-β-dimethylaminoethylpyridine, α-trifluoromethyl-β-N, N-diphenylaminopyridine, Pyridine derivatives such as α-trifluoromethyl-β-N, N-dibutylaminopyridine; α-trifluoromethylquinoline, α-trifluoromethyl-β-phenylmethylquinoline, α-trifluoromethyl-β-phenethylmethylquinoline , Α-trifluoromethyl-β- n-hexylquinoline, α-trifluoromethyl-β-c-hexylquinoline, α-trifluoromethyl-β-ethoxycarbonylmethylquinoline, α-trifluoromethyl-β-2-furylquinoline, α-trifluoromethyl- β-2-thienylquinoline, α-trifluoromethyl-β-ethoxyquinoline, α-trifluoromethyl-β-t-butoxyquinoline, α-trifluoromethyl-β-hexyloxyquinoline, α-trifluoromethyl-β -St-butylquinoline, α-trifluoromethyl-β-S-phenylquinoline, α-trifluoromethyl-β-methoxyethylquinoline, α-trifluoromethyl-β-methoxyphenylquinoline, α-trifluoromethyl -Β-trifluoromethylphenylquinoline, α-trifluoromethyl-β-chloro Rophenylquinoline, α-trifluoromethyl-β-thiomethoxyethylquinoline, α-trifluoromethyl-β-dimethylaminoethylquinoline, α-trifluoromethyl-β-N, N-diphenylaminoquinoline, α-trifluoro And quinoline derivatives such as methyl-β-N, N-dibutylaminoquinoline. In addition to the β-position substituents as described above, compounds having substituents at the γ-position, δ-position, and ε-position can also be used in the present invention. Furthermore, compounds having substituents in any combination at one or more positions can also be used in the present invention.

The α-difluoro (hydrogen) methyl heterocyclic compound represented by the general formula (4) and the α-difluoro (silyl) methyl heterocyclic compound represented by the general formula (5) according to the present invention are each represented by the general formula (1). ) R ² , R ³ , R ⁴ , R ⁵ and a corresponding α-difluoro (hydrogen) methyl heterocyclic compound or α-difluoro (silyl) methyl having the same substituents R ² , R ³ , R ⁴ , R ⁵ It is a heterocyclic compound.

The halogenated triorganosilane used in the present invention has the general formula (2):
(R ⁶ ) ₃ SiX (2)
It is represented by In this general formula, each R ⁶ independently represents a methyl group, an ethyl group, a propyl group, an isopropyl group or a phenyl group, and X represents chlorine, bromine or iodine. Preferred halogenated triorganosilanes include halogenated trialkylsilanes such as trimethylsilane chloride, triethylsilane chloride, and triethylsilane bromide; halogenated arylsilanes such as phenyldimethylsilane chloride and diphenylmethylsilane chloride. it can. Of these, trimethylsilane chloride is most preferred because it is readily available.

The amount of the halogenated triorganosilane of the general formula (2) is preferably used in an amount of about 2 to 50 mol with respect to 1 mol of the trifluoromethyl compound of the general formula (1).
The solvent used in the method of the present invention may be inert under the reaction conditions of the present invention, and aliphatic hydrocarbon solvents such as pentane, hexane, heptane, etc., aromatic hydrocarbons such as benzene, toluene, etc. , Xylene, etc., nitriles such as acetonitrile, propionitrile, phenylacetonitrile, isobutyronitrile, benzonitrile, etc., acid amides such as dimethylformamide, dimethylacetamide, methylformamide, formamide, hexamethylphosphoric triamide, etc. Lower ethers such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, 1,2-epoxyethane, 1,4-dioxane, dibutyl ether, t-butyl methyl ether, substituted tetrahydrofuran, etc. ,Such Can be used, dimethylformamide, tetrahydrofuran is preferred. A combination of these solvents can also be used.

  The amount of the solvent is about 1 to 100 parts by weight, preferably 1 to 10 parts by weight with respect to 1 part by weight of the trifluoromethyl compound of the general formula (1). It is preferable to remove the water as much as possible, but it is not always necessary to remove it completely. The amount of water that is usually mixed in industrially available solvents is not particularly problematic in the practice of this production method, and can therefore be used as it is without removing the water.

  The low-valent metal used in the present invention is not particularly limited, but as a simple metal, for example, magnesium, zinc, copper, iron, cadmium, tin, titanium, sodium, or an alloy containing these metals as a main component Examples thereof include zinc-copper alloy, Raney nickel, silver-zinc alloy, copper-magnesium alloy and the like. In addition, low-valent ions of metal elements having multiple oxidation states, such as titanium trichloride, samarium diiodide, chromium dichloride, metal complexes such as sodium naphthalenide, sodium benzophenone ketyl complex, tetrakis (triphenyl) Phosphine) palladium and the like. Furthermore, these metal simple substances or alloys and mixed systems of metal ions or metal complexes, for example, titanium tetrachloride-metal zinc system, titanocene dichloride-metal zinc system, samarium diiodide-metal samarium system, samarium diiodide-metal magnesium The system etc. are mentioned. Among these, a system using magnesium, for example, metal magnesium, samarium diiodide-metal magnesium system, and the like are particularly preferable. When used alone, the low-valent metal may be in any shape such as powder, granule, lump, porous, cutting waste, and wire. For example, as the magnesium metal, a known shape magnesium usually used in the Grignard reaction can be used as it is.

The amount of the low-valent metal is preferably about 1 to 20 mol relative to 1 mol of the trifluoromethyl compound of the general formula (1).
The reaction temperature is about −78 to 120 ° C., and the reaction time varies depending on the reaction reagent, but it is usually convenient to carry out in about 10 minutes to 20 hours. The reaction pressure may be close to normal pressure, and other reaction conditions may be those known to those skilled in the art using organic magnesium compounds.

  In the method of the present invention, various reaction promotion methods generally used in the Grignard reaction can be applied for the purpose of promoting the reaction. Examples of such means include halogens such as bromine or iodine, Grignard reagents, organic halides such as ethyl bromide, methyl iodide, methylene iodide, ethyl iodide, β-bromoethyl ether, or ethyl orthosilicate. And the like, and a method of stirring or irradiating with ultrasonic waves.

  When the α-trifluoromethyl heterocyclic compound represented by the general formula (1) is reduced by the method of the present invention, the site other than the trifluoromethyl group does not change, and the α- represented by the corresponding general formula (5) A difluoro (silyl) methyl heterocyclic compound is produced, and the α-difluoromethyl heterocyclic ring represented by the general formula (4) is prepared by adjusting the reaction reagent and / or reaction conditions from the compound of the general formula (5). Further compounds can be obtained. For example, when α-trifluoromethylpyridine is used as the α-trifluoromethyl heterocyclic compound represented by the general formula (1), first, α-difluoro (silyl) methylpyridine is formed. Difluoro (silyl) methylpyridine can be converted to α-difluoromethylpyridine by, for example, desilylation at a temperature of about 0 to 100 ° C. in the presence of an acid. On the other hand, the presence of a basic compound such as triethylamine in the reaction system can increase the ratio of α-difluoro (silyl) methylpyridine in the product. The amount of the basic compound used in this case is usually about 1 to 4 mol, preferably about 2 mol, per 1 mol of the trifluoromethyl compound of the general formula (1). Thus, by adjusting the reaction conditions, the α-difluoromethyl heterocyclic compound represented by the general formula (4) and the α-difluoro (5) represented by the general formula (5) in the final product are obtained. The ratio with the silyl) methyl heterocyclic compound can be adjusted.

  The crude product containing the products represented by the general formulas (4) and (5) obtained by the method of the present invention is preferably subjected to a purification treatment according to the purpose and application. The means for the purification treatment is not particularly limited, and it is preferable to carry out a normal extraction operation or column chromatography.

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to the embodiments of these examples.
The product yield was determined by the following method.

That is, benzotrifluoride (0.0365 g, 0.25 mmol) was added to the reaction system as an internal standard substance, and the integrated value ratio of the target compound and benzotrifluoride was calculated by ¹⁹ F NMR analysis. The ¹⁹ F NMR data of the product is a value obtained by setting the chemical shift of benzotrifluoride to 99 ppm.

[Example 1]
Magnesium (powder) (0.0243 g, 1 mmol) was weighed into a 20 ml branched reactor, dried under reduced pressure with a vacuum pump, and purged with argon. Thereto were added dry dimethylformamide (DMF) (5 ml) and trimethylsilane chloride (TMSCl) (0.25 ml, 2 mmol), and the reactor was placed in a sonicator for 20 minutes. Thereafter, dry triethylamine (0.15 ml, 1 mmol) and α-trifluoromethylpyridine (0.0738 g, 0.5 mmol) were added, and the mixture was stirred at normal pressure and room temperature for 30 minutes. The reaction mixture was filtered through celite using hexane, and the filtrate was washed 3 times with 10 ml of water to remove DMF. Hexane was distilled off and distilled under reduced pressure at 1 mmHg to obtain α-difluoromethylpyridine (4% in ¹⁹ F-NMR yield) and α-difluoro (trimethylsilyl) methylpyridine (53% in ¹⁹ F-NMR yield). It was.

[NMR and MS data of α-difluoro (trimethylsilyl) methylpyridine]
¹ H NMR δ (300 MHz, ppm):
0.21 (s, 9H), 7.29 (dd, J = 4.8, 7.2 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1 H), 8.64 (d, J = 5.4 Hz, 1 H)
¹⁹ F NMR δ (ppm):
47.4 (s, 2F)
MS (intensity):
201 (2), 110 (100), 73 (85), 45 (23)
[NMR data of α-difluoromethylpyridine]
¹⁹ F NMR δ (ppm):
45.9 (d, J = 56Hz, 2F)
[Example 2]
Magnesium (powder) (0.0243 g, 1 mmol) was weighed into a 20 ml branched reactor, dried under reduced pressure with a vacuum pump, and purged with argon. Thereto were added dry acetonitrile (5 ml) and TMSCl (0.25 ml, 2 mmol), and the reactor was placed in a sonicator for 20 minutes. Thereafter, dry triethylamine (0.15 ml, 1 mmol) and α-trifluoromethylquinoline (0.0983 g, 0.5 mmol) were added, and the mixture was stirred at normal pressure and room temperature for 30 minutes. The reaction mixture was filtered through celite with hexane, and the filtrate was washed 3 times with 10 ml of water to remove acetonitrile. Hexane was distilled off and distilled under reduced pressure at 1 mmHg to obtain α-difluoromethylquinoline (14% in ¹⁹ F-NMR yield) and α-difluoro (trimethylsilyl) methylquinoline (20% in ¹⁹ F-NMR yield). It was.

[NMR and MS data of α-difluoro (trimethylsilyl) methylquinoline]
¹ H NMR δ (300 MHz, ppm):
0.29 (s, 9H), 7.59 (t, J = 7.2 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.74 (dt, J = 7.8 Hz) , J = 1.8 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.26 (d, J = 8. (7Hz, 1H)
¹⁹ F NMR δ (ppm):
49.4 (s, 2F)
MS (intensity):
251 (33), 250 (100), 220 (21), 159 (36), 128 (26), 73 (58)
[NMR and MS data of α-difluoromethylquinoline]
¹⁹ F NMR δ (ppm):
47.5 (d, J = 56Hz, 2F)
MS (intensity):
179 (100), 129 (30), 128 (63), 101 (33)
Example 3
Magnesium (powder) (0.097 g, 4 mmol) was weighed into a 20 ml branched reactor, dried under reduced pressure with a vacuum pump, and purged with argon. Thereto were added dry DMF (5 ml) and TMSCl (1 ml, 8 mmol), and the reactor was placed in a sonicator for 20 minutes. Thereafter, dry triethylamine (0.15 ml, 1 mmol) and α-trifluoromethylpyridine (0.0738 g, 0.5 mmol) were added, and the mixture was stirred at normal pressure and room temperature for 30 minutes. The reaction mixture was filtered through celite using hexane, and the filtrate was washed 3 times with 10 ml of water to remove DMF. Hexane was distilled off and distilled under reduced pressure at 1 mmHg to obtain α-difluoromethylpyridine (2% in ¹⁹ F-NMR yield) and α-difluoro (trimethylsilyl) methylpyridine (56% in ¹⁹ F-NMR yield). It was.

Example 4
Magnesium (powder) (0.097 g, 4 mmol) was weighed into a 20 ml branched reactor, dried under reduced pressure with a vacuum pump, and purged with argon. Thereto were added dry N-methylpyrrolidinone (NMP) (5 ml) and TMSCl (1 ml, 8 mmol), and the reactor was placed in a sonicator for 20 minutes. Thereafter, dry triethylamine (0.15 ml, 1 mmol) and α-trifluoromethylpyridine (0.0738 g, 0.5 mmol) were added, and the mixture was stirred at normal pressure and room temperature for 30 minutes. The reaction mixture was filtered through celite using hexane, and the filtrate was washed 3 times with 10 ml of water to remove NMP. Hexane was distilled off and distilled under reduced pressure at 1 mmHg to obtain α-difluoromethylpyridine (4% in ¹⁹ F-NMR yield) and α-difluoro (trimethylsilyl) methylpyridine (46% in ¹⁹ F-NMR yield). It was.

Example 5
Magnesium (powder) (0.097 g, 4 mmol) was weighed into a 20 ml branched reactor, dried under reduced pressure with a vacuum pump, and purged with argon. Thereto were added dry DMF (5 ml) and TMSCl (1 ml, 8 mmol), and the reactor was placed in a sonicator for 20 minutes. Thereafter, dry triethylamine (0.15 ml, 1 mmol) and α-trifluoromethylpyridine (0.0738 g, 0.5 mmol) were added and stirred at normal pressure and 55 ° C. for 30 minutes. The reaction mixture was filtered through celite using hexane, and the filtrate was washed 3 times with 10 ml of water to remove DMF. Hexane was distilled off and distilled under reduced pressure at 1 mmHg to obtain α-difluoromethylpyridine (4% in ¹⁹ F-NMR yield) and α-difluoro (silyl) methylpyridine (53% in ¹⁹ F-NMR yield). It was.

Claims (2)

General formula (1):

(In the formula, R ² , R ³ , R ⁴ and R ⁵ may be the same or different and each represents hydrogen or a monovalent organic group, and any one of R ² , R ³ , R ⁴ and R ⁵ is bonded to each other. A divalent or higher valent organic group) may be represented by the general formula (2):
(R ⁶ ) ₃ SiX (2)
(Wherein R ⁶ independently represents a methyl group, an ethyl group, a propyl group, an isopropyl group or a phenyl group, and X represents chlorine, bromine or iodine) and a low atom General formula (3) characterized by reacting with a valent metal in the presence of a solvent:

(Wherein, R ¹ represents a triorganosilyl group or hydrogen, and R ² , R ³ , R ⁴ , and R ⁵ are as described above). The α-difluoromethyl heterocyclic compound has the general formula (4):

^{(Wherein, R 2, R 3, R} 4, R R 2 ⁵ each formula ^{(1), R 3, R} 4, represents the same substituent as ^{R 5.)} Represented by α- difluoro (hydrogen ) Methyl heterocyclic compounds and general formula (5):

(Wherein, ^{R 6} represents the same substituent as ^{R 6} in formula ^{(2), R 2, R} 3, R 4, R 2 of the ^{R 5} each formula ^{(1), R 3, R} 4, R 5 The production method according to claim 1, which is obtained as a mixture of α-difluoro (silyl) methyl heterocyclic compounds represented by: