KR20170066310A - Method for producing geminal difluoro compound - Google Patents

Abstract

To provide a novel process for the preparation of geminal difluoro compounds. A novel process for producing a geminal difluoro compound represented by the formula (2) at a high yield by reacting a compound represented by the formula (1) with a fluorinating agent in the presence of an N-chloroimide compound. (Wherein R ¹ represents C _1-4 alkyl and X represents a halogen atom.)

Description

METHOD FOR PRODUCING GEMINAL DIFLUORO COMPOUND FIELD OF THE INVENTION [0001]

The present invention relates to a novel process for producing a geminated difluoro compound using an oxime compound as a starting material.

A geminal difluoro compound having a group in which two fluorine atoms are substituted for one carbon atom as a partial structure is a compound useful as medicines, pesticides, or intermediates thereof (Patent Document 1) Is being developed. Representative examples include a di-fluorination reaction of an oxime compound (Non-Patent Documents 1 to 3).

As a difluorination reaction using an oxime compound as a starting material, a method using iodine monofluoride (Non-Patent Document 2) has been reported. However, iodine used can only exist at a low temperature. In addition, in order to generate iodine monofluoride in the system, pulverized iodine is added to the reaction solution, and fluorine / nitrogen gas is blown at -78 ° C It is necessary to perform an operation of inserting. Therefore, there is a problem that special reaction conditions and reaction apparatus are used for the use of iodine fluoride (Non-Patent Documents 2 and 4).

A method of using nitroxyl tetrafluoroborate and hydrogen fluoride-pyridine complex (Non-Patent Document 3) has also been reported. However, in the examples applied to the synthesis of the 1-phenyl-1,1-difluoroethane derivative, only the desired compound was obtained in a low yield (Patent Document 2). Since nitroxyl tetrafluoroborate has strong hygroscopicity, it is necessary to treat it under a dry inert gas when carrying out the difluorination reaction, and there is a problem that it is expensive and the like (Non-Patent Documents 5 and 6).

Therefore, a new process for producing geminal difluoro compounds has been demanded, which does not use these reagents, is useful as a high yield and industrial production method.

International Publication No. 2011/154298 International Publication No. 2012/139775

 Science of Synthesis, 2007, Vol. 29, pp. 13-61  Journal of Organic Chemistry, 1991, vol. 56, pp. 4695-4700  Synlett, 1994, pages 425-426  Chemische Berichte, 1970, 103, 590-593, 880-884  Inorganic Synthesis, 2004, Vol. 33, pp. 75-82  Encyclopedia of Reagents for Organic Synthesis, 1995, Vol. 6, pp. 3768-3770

An object of the present invention is to provide a process for producing a high yield of a geminal difluoro compound which does not require a special reaction apparatus or a reaction condition.

The present inventors have intensively studied and, as a result, have found out a novel production process for producing a geminal difluoro compound at a high yield by reacting a fluorinating agent with an oxime compound in the presence of an N-chloromide compound, It came to the following. That is, the present invention is characterized by the following.

[1] A process for producing a geminal difluoro compound represented by the formula (2), which comprises reacting an oxime compound represented by the formula (1) with a fluorinating agent in the presence of an N-chloroimide compound.

[Chemical Formula 1]

_Wherein R ¹ represents C _1-4 alkyl and X represents a halogen atom.

(2)

Wherein R ¹ and X have the same meanings as defined above.

[2] The process according to [1], wherein the N-chloroimide compound is at least one selected from the group consisting of N-chlorosuccinimide, N-chlorophthalimide, 1,3-dichloro-5,5-dimethylhydantoin, sodium dichloroisocyanurate or trichloroisocyanuric acid , A process for producing a geminal difluoro compound according to the above [1].

[3] The process for producing a geminal difluoro compound according to [2], wherein the N-chloroimide compound is N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin or trichloroisocyanuric acid Gt;

The geminal difluoro compound according to any one of the above [1] to [3], wherein the amount of the N-chloroimide compound present is 0.1 to 100 equivalents based on 1 equivalent of the oxime compound of the formula (1) ≪ / RTI >

[5] The process for producing a geminal difluoro compound according to any one of [1] to [4], wherein the fluorinating agent is used in an amount of 2 to 1000 equivalents based on 1 equivalent of the oxime compound of the formula (1).

[6] The process for producing a geminal difluoro compound according to any one of [1] to [5], wherein the fluorinating agent is a hydrogen fluoride-pyridine complex or poly [4-vinylpyridinium poly (hydrogen fluoride)].

[7] The process for producing a geminal difluoro compound according to the above [6], wherein the fluorinating agent is a hydrogen fluoride-pyridine complex.

[8] The process for producing a geminal difluoro compound according to the above [7], wherein the weight ratio of hydrogen fluoride and pyridine in the hydrogen fluoride-pyridine complex is from 70:30 to 20:80.

[9] The process for producing a geminated difluoro compound according to any one of [1] to [5], wherein the fluorinating agent is hydrogen fluoride.

[10] The process for producing a geminal difluoro compound according to any one of [1] to [9], wherein R ¹ is methyl.

[11] The process for producing a geminal difluoro compound according to any one of [1] to [10], wherein X is a chlorine atom or a bromine atom.

[12] The process for producing a geminal difluoro compound according to [11], wherein X is a bromine atom.

[13] A process for producing a geminal difluoro compound according to any one of [1] to [12], wherein the geminal difluoro compound is reacted in the presence of a solvent.

[14] The process for producing a geminal difluoro compound according to [13], wherein the solvent is a halohydrogen hydrocarbon.

The present invention provides a novel process for producing a geminal difluoro compound useful as a pesticide intermediate or the like in a high yield.

Hereinafter, the present invention will be described in detail.

In the present specification, "n-" means normal, "s-" means secondary, and "t-" means tertiary.

In addition, "(E)" used for the base material of chemical structure means E-form, and "(Z)" means Z-form.

The term " C _1-4 alkyl " means a straight chain or branched chain alkyl having 1 to 4 carbon atoms. Specifically, it means methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl or t-butyl.

The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

(Method for producing geminal difluoro compound)

(3)

The geminal difluoro compound (compound (2)) represented by the formula (2) is prepared by reacting the oxime compound (compound (1)) represented by the formula (1) with a fluorinating agent in the presence of an N- .

The N-chloroimide compound in the present specification means an imide compound in which a nitrogen atom is chlorinated. Examples of the N-chloroimide compound used in the present invention include N-chlorosuccinimide, N-chlorophthalimide, 1,3-dichloro-5,5-dimethylhydantoin, dichloroisocyanuric acid Sodium, trichloroisocyanuric acid, and the like. A preferred N-chloroimide compound is N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin or trichloroisocyanuric acid, and the more preferred N-chloroimide compound is trichloroisocyanuric acid .

These N-chloroimide compounds may be used alone or in combination of two or more.

Of the N-chloroimide compounds used in the present invention, trichloroisocyanuric acid is known as a bactericide and deodorant for swimming pools. It is also known that trichloroisocyanuric acid is a highly stable and inexpensive reagent (Organic Process Research and Development, 2002, Vol. 6, pp. 384-393).

The amount of the N-chloroimide compound to be used is preferably 0.1 equivalents to 100 equivalents, more preferably 0.5 equivalents to 30 equivalents, and still more preferably 1 equivalents to 15 equivalents to the compound (1).

Examples of the fluorinating agent used in the present invention include a hydrogen fluoride-pyridine complex and poly [4-vinylpyridinium poly (hydrogen fluoride)]. A preferred fluorinating agent is a hydrogen fluoride-pyridine complex.

As the fluorinating agent, hydrogen fluoride may be used.

The hydrogen fluoride-pyridine complex in a weight ratio of hydrogen fluoride: pyridine = 70: 30 is known as an Olah reagent (Encyclopedia of Reagents for Organic Synthesis, vol. 6, pp. 4373-4375). It is known that the reagent is stabilized and acts as hydrogen fluoride having a small volatility, and is preferable for industrial use.

Poly [4-vinylpyridinium poly (hydrogen fluoride)] is a compound composed of a polymer of pyridine derivatives and hydrogen fluoride (Synlett, 1990, pp. 267-269).

With respect to the hydrogen fluoride-pyridine complex used in the present invention, the upflow reagent having a weight ratio of hydrogen fluoride: pyridine = 70: 30 can be obtained from, for example, Aldrich, Fluorochem, and the like. The composition of hydrogen fluoride: pyridine = 60:40, 50:50, 40:60 and 20:80 in terms of weight ratio can be obtained from, for example, Manchester Organics and hydrogen fluoride: pyridine = 55 : 45 is, for example, available from Apollo Scientific Corporation.

The weight ratio of the hydrogen fluoride-pyridine complex used in the present invention is preferably hydrogen fluoride: pyridine = 70:30 to 20:80. A more preferable weight ratio is hydrogen fluoride: pyridine = 70:30 to 50:50, and a more preferable weight ratio is hydrogen fluoride: pyridine = 68: 32 to 63: 37.

The amount of the fluorinating agent to be used in the present invention may be from 2 equivalents to 1000 equivalents per equivalent of the oxime compound represented by the formula (1), preferably from 2 equivalents to 500 equivalents, more preferably, 5 to 200 equivalents.

The compound (1) used in the present invention means any one of the oxime compounds represented by the formula (1a) or (1b), or a mixture of the formula (1a) and the formula (1b).

[Chemical Formula 4]

According to the ordering rule, the oxime compound represented by the formula (1a) is the stereochemical structure of (E), and the oxime compound represented by the formula (1b) is the stereochemical structure of (Z).

The compounds which are the stereochemistry of (E) and the stereochemistry of (Z) are geometric isomers with respect to each other, and in many cases they are isolatable. In order to obtain one isomer, isomerization to a thermodynamically stable isomer may be carried out by fractional recrystallization, hydrochloric acid treatment or the like. In the present invention, only one isomer of the oxime compound can be used, and it is also possible to use a mixture of the oxime compounds (E) and (Z).

As a general method for preparing an oxime compound, for example, a condensation reaction of a carbonyl compound and a hydroxylamine can be mentioned, and an oxime compound can be prepared according to a method described in a known document (Comprehensive Organic Functional Group Transformations II, 2005, vol. 3, pp. 451-467).

The solvent used in the present invention is not particularly limited as long as it does not disturb the reaction, and examples thereof include the following. (E.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-trichloroethane, trichloroethane and the like) in an alcohol solvent (for example, methanol, ethanol or 2-propanol) (E.g., ethylene, tetrachlorethylene), aromatic halogenated hydrocarbon solvents (e.g., chlorobenzene, dichlorobenzene), aromatic hydrocarbon solvents (e.g., benzene, toluene, xylene), aliphatic hydrocarbon solvents , Heptane), an amine-based solvent (e.g., triethylamine, N, N-dibutylbutan-1 -amine, 2-methyl- , N-dimethylaniline), pyridine-based solvents (for example, pyridine, picoline), ether solvents (for example, dimethyl ether, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4 -Dioxane, cyclopentyl methyl ether, 1-methoxy-2- (2-methoxyethoxy) ethane) and the like.

Preferably, it is a halogenated hydrocarbon solvent, an amine-based solvent, a pyridine-based solvent or an ether solvent, more preferably a halogenated hydrocarbon solvent, more preferably dichloromethane or chloroform.

These solvents may be used alone or in combination of two or more.

The amount of the solvent that can be used in the production method of the present invention is preferably from 0 to 1000 times by weight, more preferably from 1 to 100 times by weight, more preferably from 1 to 100 times by weight, based on the oxime compound represented by formula (1) Is from 5 times by weight to 50 times by weight.

The reaction temperature is not particularly limited, but is preferably from -78 deg. C to the reflux temperature of the reaction mixture, more preferably from -60 deg. C to 50 deg. C, and still more preferably from -40 deg. C to 30 deg. Another mode of the preferable reaction is 0 占 폚 for about 7 hours from the start of the reaction, and then 3 to 21 hours at 20 占 폚 to 30 占 폚.

The total reaction time is within about 28 hours, preferably from 3 to 21 hours. Further, when hydrogen fluoride is used as the fluorinating agent, it is within about 20 hours, preferably from 1 to 5 hours.

Example

The following Reference Synthesis Examples and Synthesis Examples are given to illustrate the present invention in more detail, but the present invention is not limited to these Examples.

Proton nuclear magnetic resonance ( ¹ H NMR) in the Example (Synthesis Example) was carried out by using JNM-ECP300 manufactured by JEOL Corporation or JNM-ECX300 manufactured by JEOL Corporation, And the chemical shift was represented by a value (ppm) when tetramethylsilane was used as an internal standard (0.0 ppm).

The fluorine nuclear magnetic resonance ( ¹⁹ F NMR) of the example was measured in a medium chloroform solvent using JNM-ECX300 manufactured by JEOL, and the chemical shift was performed using hexafluorobenzene as an internal standard (-162.2 ppm) (Ppm) in the case where the value is expressed in terms of ppm.

In the description of the NMR spectrum, "s" is singlet, "d" is doublet, "t" is triplet, "q" is quartet, "m" coupling constants, "㎐" is Hertz, "CDCl _3" means deuterated chloroform.

Synthesis Example 1

Preparation of 1- (1,1-difluoroethyl) -4-bromobenzene

[Chemical Formula 5]

The inside of the reaction vessel made of a resin of tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer (hereinafter abbreviated as PFA) was replaced with nitrogen gas, and then hydrogen fluoride-pyridine complex (10.0 g, [63.8% (hydrogen fluoride ): 36.2% (pyridine)], 318.8 mmol of hydrogen fluoride, manufactured by Aldrich) was added to the reaction vessel and cooled to 0 ° C. Subsequently, a dichloromethane (30.0 g) solution of trichloroisocyanuric acid (2.70 g, 11.62 mmol) and 1- (4-bromophenyl) ethanone oxime (1.00 g, 4.67 mmol) , And the reaction mixture was stirred at 0 ° C for 7 hours. Further, the reaction temperature was raised to 20 ° C and then stirred at the same temperature for 3 hours. The reaction was then stopped by adding water to the reaction mixture. Next, chloroform was added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (eluent: n-hexane) to obtain the title compound (0.93 g, yield 90%) as a colorless liquid.

Synthesis Example 2

Preparation of 1- (1,1-difluoroethyl) -4-bromobenzene

The inside of the reaction vessel made of PFA resin was replaced with nitrogen gas, and then a hydrogen fluoride-pyridine complex (10.0 g, [63.8% (hydrogen fluoride): 36.2% (pyridine)] in a weight ratio, 318.8 mmol as hydrogen fluoride, Ltd.) was added to the reaction vessel and cooled to 0 占 폚. Subsequently, a dichloromethane (30.0 g) solution of N-chlorosuccinimide (5.01 g, 37.52 mmol) and 1- (4-bromophenyl) ethanone oxime (1.00 g, 4.67 mmol) And the reaction mixture was stirred at 0 ° C for 3 hours. Further, the reaction temperature was raised to 25 ° C to 30 ° C and then stirred at the same temperature for 21 hours. The reaction was then stopped by adding water to the reaction mixture. Next, chloroform was added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (eluent: n-hexane) to obtain the title compound (0.94 g, yield 88%) as a colorless liquid.

Synthesis Example 3

Preparation of 1- (1,1-difluoroethyl) -4-bromobenzene

(10.0 g, [63.8% (hydrogen fluoride): 36.2% (pyridine)]] as hydrogen fluoride, 318.8 mmol as hydrogen fluoride], and the inside of the reaction vessel made of PFA resin was replaced with nitrogen gas. Manufactured by Aldrich) was added to the reaction vessel and cooled to 0 占 폚. Subsequently, to a reaction vessel was added a solution of 1,3-dichloro-5,5-dimethylhydantoin (4.60 g, 23.35 mmol) and 1- (4-bromophenyl) ethanone oxime (1.00 g, (30.0 g) were successively added thereto, and the reaction mixture was stirred at 0 ° C for 7 hours. Further, the reaction temperature was raised to 20 ° C and then stirred at the same temperature for 3 hours. The reaction was then stopped by adding water to the reaction mixture. Next, chloroform was added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, and then the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (eluent: n-hexane) to obtain the title compound (0.96 g, yield 93%) as a colorless liquid.

In Synthesis Examples 4 to 6 below, 1- (1,1-difluoroethyl) -4-bromobenzene isolated and purified was used as a standard substance and methyl 4-hydroxybenzoate was used as an internal standard material , And quantitative analysis using ultrafast liquid chromatography.

Ultra-fast liquid chromatography: ACQUITY UPLC H-Class manufactured by Waters

Column: Waters Acquity UPLC BEH C18 (1.7 탆, 2.1 x 50 mm) column

Column oven temperature: 40 ° C

Eluent: acetonitrile: 10 mM aqueous ammonium acetate solution / acetonitrile = 100/5 (v / v), 30:70 (0-1 min), 30: 70-95: 5 (1-3 min) (3-5 min), (v / v)

Eluent speed: 0.5 ml / min

Detection wavelength: 230 nm

Synthesis Example 4

Preparation of 1- (1,1-difluoroethyl) -4-bromobenzene

The inside of the reaction vessel made of PFA resin was replaced with nitrogen gas, and then a hydrogen fluoride-pyridine complex (1.00 g, [weight ratio of 63.8% (hydrogen fluoride): 36.2% (pyridine)] and hydrogen fluoride 31.9 mmol] Manufactured by Aldrich) was added to the reaction vessel and cooled to 0 占 폚. Then, trichloroisocyanuric acid (0.24 g, 1.03 mmol) was added to the reaction vessel and then chloroform (2.01 g) of 1- (4-bromophenyl) ethanone oxime (103.5 mg, 0.484 mmol) Was added and the reaction mixture was stirred at 0 < 0 > C for 3 hours. Then, the reaction was stopped by adding chloroform and water to the reaction mixture, and the organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution. As a result of quantifying the obtained organic layer, the quantitative yield of 1- (1,1-difluoroethyl) -4-bromobenzene (target compound) was 97%.

Synthesis Example 5

Preparation of 1- (1,1-difluoroethyl) -4-bromobenzene

The inside of the reaction vessel made of PFA resin was replaced with nitrogen gas, and then a hydrogen fluoride-pyridine complex (1.00 g, [weight ratio of 63.8% (hydrogen fluoride): 36.2% (pyridine)] and hydrogen fluoride 31.9 mmol] Manufactured by Aldrich) was added to the reaction vessel and cooled to 0 占 폚. Subsequently, trichloroisocyanuric acid (0.23 g, 0.99 mmol) was added to the reaction vessel, and then 1- (4-bromophenyl) ethanone oxime (104.3 mg, 0.487 mmol) Was stirred at 0 占 폚 for 3 hours and 30 minutes. Then, the reaction was stopped by adding chloroform and water to the reaction mixture, and the organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution. The quantitative yield of 1- (1,1-difluoroethyl) -4-bromobenzene (target compound) was 94%.

Synthesis Example 6

1- (4-bromophenyl) ethanone oxime (1.00 g, 4.67 mmol) and trichloroisocyanuric acid (2.40 g, 10.33 mmol) were successively added to a reaction vessel made of resin of trifluoroethylene chloride copolymer . Next, the reaction vessel was cooled in a dry ice-methanol bath and hydrogen fluoride (11 ml, 551 mmol) was introduced under reduced pressure. Subsequently, the external temperature of the reaction vessel was maintained at -38 to -35 占 폚 and stirred for 3 hours. Subsequently, the reaction vessel was cooled in a dry ice-methanol-water bath and hydrogen fluoride was distilled off under reduced pressure. Then, chloroform and water were added to the reaction vessel, followed by stirring, followed by liquid separation. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate. The quantitative yield of 1- (1,1-difluoroethyl) -4-bromobenzene (target compound) was 51%.

Reference Example 1

Preparation of 1- (4-bromophenyl) ethanone oxime

[Chemical Formula 6]

After the inside of the glass reaction vessel was replaced with nitrogen gas, 4'-bromoacetophenone (50.0 g, 251.31 mmol), ethanol (100 g) and hydroxyamine hydrochloride (19.6 g, 282.05 mmol) The reaction mixture was heated to 72 < 0 > C. Next, the reaction mixture was stirred at 72 ° C to 80 ° C for 3 hours. Subsequently, the reaction was stopped by cooling the reaction mixture to 5 占 폚. Next, water (100 g) was added to the reaction mixture to precipitate a solid. After filtration, the resulting solid was washed with a mixed solution of ethanol (50 g) and water (100 g). Further, the obtained solid and ethanol (100 g) were added to the reaction vessel, and the mixture was heated to 65 DEG C, then the reaction mixture was cooled to 4 DEG C and again a solid was precipitated and filtered. The obtained solid was washed with ethanol (50 g) cooled to 0 占 폚 and dried under reduced pressure at 50 占 폚 for 3 hours to obtain the aimed compound (26.15 g, yield 49%) as a white solid.

Industrial availability

The geminal difluoro compound obtained by the present invention is used in a wide range of fields as an intermediate for production of pesticides and the like.

Also, the entire contents of the specification, claims and abstract of Japanese Patent Application No. 2014-199055 filed on September 29, 2014 are incorporated herein by reference and are hereby incorporated by reference.

Claims (14)

A process for producing a geminal difluoro compound represented by the formula (2), which comprises reacting an oxime compound represented by the formula (1) with a fluorinating agent in the presence of an N-chloroimide compound.
[Chemical Formula 1]

_Wherein R ¹ represents C _1-4 alkyl and X represents a halogen atom.
(2)

Wherein R ¹ and X have the same meanings as defined above. The method according to claim 1,
Wherein the N-chloroimide compound is selected from the group consisting of N-chlorosuccinimide, N-chlorophthalimide, 1,3-dichloro-5,5-dimethylhydantoin, sodium dichloro isocyanurate or trichloroisocyanuric acid, (2), < / RTI > 3. The method of claim 2,
Wherein the N-chloroimide compound is N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin or trichloroisocyanuric acid, and a geminal difluoro compound. 4. The method according to any one of claims 1 to 3,
Wherein the amount of the N-chloroimide compound present is 0.1 to 100 equivalents based on 1 equivalent of the oxime compound of the formula (1). 5. The method according to any one of claims 1 to 4,
Wherein the amount of the fluorinating agent to be used is 2 to 1000 equivalents based on 1 equivalent of the oxime compound of the formula (1). 6. The method according to any one of claims 1 to 5,
Wherein the fluorinating agent is a hydrogen fluoride-pyridine complex or poly [4-vinylpyridinium poly (hydrogen fluoride)]. The method according to claim 6,
Wherein the fluorinating agent is a hydrogen fluoride-pyridine complex. 8. The method of claim 7,
Wherein the weight ratio of hydrogen fluoride to pyridine in the hydrogen fluoride-pyridine complex is from 70:30 to 20:80. 6. The method according to any one of claims 1 to 5,
Wherein the fluorinating agent is hydrogen fluoride. 10. The method according to any one of claims 1 to 9,
And R < ¹ > is methyl. 11. The method according to any one of claims 1 to 10,
And X is a chlorine atom or a bromine atom. 12. The method of claim 11,
And X is a bromine atom. 13. The method according to any one of claims 1 to 12,
A process for producing a geminal difluoro compound, wherein the geminal difluoro compound is reacted in the presence of a solvent. 14. The method of claim 13,
Wherein the solvent is a halohydrogen-hydrocarbon.