Method for producing cycloalkyl bromide

Abstract

The purpose of the present invention is to provide a method for producing cycloalkyl bromide without using heavy metals, etc.　The present invention provides a method for producing a compound represented by formula (2) [in the formula, R represents an optionally substituted C3-C4 cycloalkyl group] by reacting a compound represented by formula (1) [in the formula, R represents the same meaning as indicated above, and M represents an alkali metal] and bromine in the presence of a radical initiator or under irradiation with light.

Description

Method for producing cycloalkyl bromides

[0001] The present invention relates to a method for producing cycloalkyl bromides.

[0002] Cycloalkyl bromides are useful compounds that can be converted into various compounds, including cycloalkyl magnesium bromides and cycloalkyl boronic acid compounds, which are used as intermediates for active ingredient compounds in the agricultural and pharmaceutical fields. For example, Patent Documents 1 and 2 describe examples of the synthesis of pharmaceuticals using cyclopropyl magnesium bromide and cyclopropyl boronic acid. A method using a stoichiometric amount of heavy metal is known as a method for synthesizing cycloalkyl bromides. For example, Patent Document 3 and Non-Patent Document 1.

[0003] WO2006 / 26356WO2011 / 042918CN107915689

[0004] Journal of the American Chemical Society, 1951, p. 3176

[0005] An object of the present invention is to provide a method for producing a cycloalkyl bromide without using heavy metals or the like.

[0006] The present inventors have investigated methods for producing cycloalkyl bromides and found that the use of a potassium salt of a cycloalkyl carboxylic acid makes it possible to produce the desired cycloalkyl bromide without using heavy metals, etc. That is, the present invention is as follows. [1] A compound represented by the formula (1) [wherein R represents an optionally substituted C3-C4 cycloalkyl group, and M represents an alkali metal] with bromine in the presence of a radical initiator or under light irradiation to produce a compound represented by formula (2): [wherein R has the same meaning as defined above.] [2] The production method according to [1], wherein in the compound represented by formula (1), R is a cyclopropyl group or a cyclobutyl group. [3] The production method according to [1] or [2], wherein in the compound represented by formula (1), M is potassium or cesium. [4] The production method according to any one of [1] to [3], wherein the radical initiator is an azo compound. [5] The production method according to any one of [1] to [4], which is carried out in the presence of a solvent. [6] The production method according to [5], wherein a halogenated hydrocarbon, a nitrile, or an ester is used as the solvent. [7] The production method according to [5] or [6], wherein an aryl chloride, a C1-C3 alkylnitrile, a benzonitrile, or a C1-C6 alkyl ester of acetate is used as the solvent.

[0007] According to the present invention, cycloalkyl bromides can be synthesized without using heavy metals or the like.

[0008] The substituents used in the present invention will be explained below. In this specification, the notation "CY-CZ" means that the number of carbon atoms is Y to Z. For example, the notation "C1-C6" means that the number of carbon atoms is 1 to 6. Examples of C1-C6 alkyl groups include methyl, ethyl, propyl, isopropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, butyl, sec-butyl, tert-butyl, pentyl, and hexyl groups. Examples of C1-C6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy groups. Examples of C2-C7 alkylcarbonyl groups include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, hexanoyl, and heptanoyl groups. Examples of C2-C7 alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropyloxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl groups. Examples of C1-C6 alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, and hexylthio groups. Examples of C1-C6 alkylsulfinyl groups include methanesulfinyl, ethanesulfinyl, propanesulfinyl, propane-2-ylsulfinyl, butanesulfinyl, pentanesulfinyl, and hexanesulfinyl groups. Examples of C1-C6 alkylsulfonyl groups include methanesulfonyl, ethanesulfonyl, propanesulfonyl, propan-2-ylsulfonyl, butanesulfonyl, pentanesulfonyl, and hexanesulfonyl groups. Examples of di(C1-C6 alkyl)aminocarbonyl groups include dimethylaminocarbonyl, ethylmethylaminocarbonyl, diisopropylcarbonyl, and dihexylaminocarbonyl groups.Examples of (C2-C7 alkylcarbonyl)(C1-C6 alkyl)amino groups optionally substituted with one or more halogen atoms include N-methylacetamino, N-methyl-2,2,2-trifluoroacetamino, and N-hexylheptanoylamino. A halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Examples of aryl groups include a phenyl group, a naphthyl group, an indanyl group, and a tetrahydronaphthyl group. Examples of heteroaryl groups include a pyrrolyl group, a furyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an oxadiazolyl group, a thiadiazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group, and a tetrazinyl group. When a substituent is substituted with two or more halogen atoms or substituents, these halogen atoms or substituents may be the same or different. In formula (1), examples of the substituent that the C3-C4 cycloalkyl group represented by R may have include one or more substituents selected from Group A. Group A: a C1-C6 alkyl group optionally substituted with one or more substituents selected from Group B, a C3-C7 cycloalkyl group optionally substituted with one or more substituents selected from Group C, an aryl group optionally substituted with one or more substituents selected from Group D, a heteroaryl group optionally substituted with one or more substituents selected from Group D, and OR. 1 , OS(O) m R 1 , O.C.(O.)R 1 , N.R. 1 R 2 , N.R. 1 NR 2 R 3 , N.R. 2 OR 1 , N.R. 2 C(O)R 1 , N.R. 2 NR 3 C(O)R 1 , N.R. 2 C(O)OR 1 , N.R. 2 NR 3C(O)OR 1 , N.R. 1 C(O)NR 2 R 3 , N.R. 2 S(O)2R 1 , C(O)R 1 , C(O)OR 1 , C(O)NR 1 R 2 , C(O)NR 2 S(O)2R 1 , C.R. 2 = NOR 1 , S(O) m R 1 , a cyano group, a nitro group, a formyl group, or a halogen atom. 1 , R 2 , and R 3are the same or different and represent a C1-C6 alkyl group optionally substituted with one or more substituents selected from Group B, a C3-C7 cycloalkyl group optionally substituted with one or more substituents selected from Group C, or an aryl group optionally substituted with one or more substituents selected from Group D, and m represents 0, 1, or 2. Group B: a group consisting of a C3-C7 cycloalkyl group optionally substituted by one or more substituents selected from Group C, a C1-C6 alkoxy group optionally substituted by one or more halogen atoms, a C2-C7 alkylcarbonyl group optionally substituted by one or more halogen atoms, a C2-C7 alkoxycarbonyl group optionally substituted by one or more halogen atoms, a C1-C6 alkylthio group optionally substituted by one or more halogen atoms, a C1-C6 alkylsulfinyl group optionally substituted by one or more halogen atoms, a C1-C6 alkylsulfonyl group optionally substituted by one or more halogen atoms, a di(C1-C6 alkyl)aminocarbonyl group, a (C2-C7 alkylcarbonyl)(C1-C6 alkyl)amino group, an aryl group optionally substituted by one or more substituents selected from Group E, an aryloxy group optionally substituted by one or more substituents selected from Group E, a cyano group, a nitro group, a formyl group, and a halogen atom. Group C: the group consisting of a C1-C6 alkyl group optionally substituted with one or more halogen atoms, a C1-C6 alkoxy group optionally substituted with one or more halogen atoms, a C2-C7 alkylcarbonyl group optionally substituted with one or more halogen atoms, a C2-C7 alkoxycarbonyl group optionally substituted with one or more halogen atoms, a C1-C6 alkylthio group optionally substituted with one or more halogen atoms, a C1-C6 alkylsulfinyl group optionally substituted with one or more halogen atoms, a C1-C6 alkylsulfonyl group optionally substituted with one or more halogen atoms, a di(C1-C6 alkyl)aminocarbonyl group, a (C2-C7 alkylcarbonyl optionally substituted with one or more halogen atoms)(C1-C6 alkyl)amino group, an aryl group optionally substituted with one or more substituents selected from Group E, an aryloxy group optionally substituted with one or more substituents selected from Group E, a cyano group, a nitro group, a formyl group, and a halogen atom.Group D: a group consisting of a C3-C7 cycloalkyl group optionally substituted by one or more substituents selected from Group E, a C1-C6 alkyl group optionally substituted by one or more halogen atoms, a C1-C6 alkoxy group optionally substituted by one or more halogen atoms, a C2-C7 alkylcarbonyl group optionally substituted by one or more halogen atoms, a C2-C7 alkoxycarbonyl group optionally substituted by one or more halogen atoms, a C1-C6 alkylthio group optionally substituted by one or more halogen atoms, a C1-C6 alkylsulfinyl group optionally substituted by one or more halogen atoms, a C1-C6 alkylsulfonyl group optionally substituted by one or more halogen atoms, a di(C1-C6 alkyl)aminocarbonyl group, a (C2-C7 alkylcarbonyl)(C1-C6 alkyl)amino group, an aryl group optionally substituted by one or more substituents selected from Group E, an aryloxy group optionally substituted by one or more substituents selected from Group E, a cyano group, a nitro group, a formyl group, and a halogen atom. Group E: a group consisting of a C1-C6 alkyl group optionally substituted with one or more halogen atoms, a C1-C6 alkoxy group optionally substituted with one or more halogen atoms, a C2-C7 alkylcarbonyl group optionally substituted with one or more halogen atoms, a C2-C7 alkoxycarbonyl group optionally substituted with one or more halogen atoms, a C1-C6 alkylthio group optionally substituted with one or more halogen atoms, a C1-C6 alkylsulfinyl group optionally substituted with one or more halogen atoms, a C1-C6 alkylsulfonyl group optionally substituted with one or more halogen atoms, a cyano group, a nitro group, and a halogen atom. Preferably, the substituent that the C3-C4 cycloalkyl group represented by R may have is one or more substituents selected from Group F. Group F: a C1-C6 alkyl group optionally substituted with one or more substituents selected from Group G, a C3-C7 cycloalkyl group optionally substituted with one or more substituents selected from Group H, an aryl group optionally substituted with one or more substituents selected from Group H, and OR. 1 , S(O) m R 1and halogen atoms. Group G: a group consisting of a C3-C7 cycloalkyl group optionally substituted with one or more halogen atoms, a C1-C6 alkoxy group optionally substituted with one or more halogen atoms, an aryl group, an aryloxy group (the aryl group and the aryloxy group are optionally substituted with one or more substituents selected from the group consisting of a C1-C6 alkyl group optionally substituted with one or more halogen atoms, and a halogen atom), and a halogen atom. Group H: a group consisting of a C1-C6 alkyl group optionally substituted with one or more halogen atoms, a C3-C7 cycloalkyl group optionally substituted with one or more halogen atoms, a C1-C6 alkoxy group optionally substituted with one or more halogen atoms, an aryl group, an aryloxy group (the aryl group and the aryloxy group are optionally substituted with one or more substituents selected from the group consisting of a C1-C6 alkyl group optionally substituted with one or more halogen atoms, and a halogen atom), and a halogen atom. More preferably, the substituent that the C3-C4 cycloalkyl group represented by R may have includes a C1-C6 alkyl group optionally substituted with one or more halogen atoms, an aryl group optionally substituted with one or more halogen atoms, a C3-C7 cycloalkyl group optionally substituted with one or more halogen atoms, a C1-C6 alkoxy group optionally substituted with one or more halogen atoms, and a C3-C4 cycloalkyl group optionally substituted with one or more substituents selected from the group consisting of halogen atoms, and even more preferably, R is a C3-C4 cycloalkyl group.

[0009] Examples of the alkali metal represented by M in formula (1) include lithium, sodium, potassium, rubidium, and cesium, with potassium and cesium being preferred, and potassium being more preferred.

[0010] This reaction will be explained below.

[0011] When this reaction is carried out in the presence of a solvent, examples of the solvent include halogenated hydrocarbons such as alkyl chlorides, aryl chlorides, alkyl bromides, and aryl bromides; nitriles such as C1-C3 alkylnitriles and aromatic nitriles; esters such as C1-C6 alkyl acetates and C1-C6 alkyl benzoates; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, diethyl ether, and polyethylene glycol; and carbonates such as dimethyl carbonate, diethyl carbonate, ethylene carbonate, and propylene carbonate. Examples of alkyl chlorides include dichloromethane and chloroform, examples of aryl chlorides include monochlorobenzene, o-dichlorobenzene, and p-dichlorobenzene, examples of alkyl bromides include bromomethane, examples of aryl bromides include bromobenzene, examples of C1-C3 alkylnitriles include acetonitrile and propionitrile, examples of aromatic nitriles include benzonitrile, examples of C1-C6 alkyl acetates include ethyl acetate, isopropyl acetate, and butyl acetate, and examples of C1-C6 alkyl benzoate esters include methyl benzoate, ethyl benzoate, and butyl benzoate. Preferred solvents are halogenated hydrocarbons, nitriles, and esters, more preferably aryl chlorides, C1-C3 alkylnitriles, benzonitrile, and C1-C6 alkyl acetates, and even more preferably monochlorobenzene, acetonitrile, benzonitrile, and butyl acetate. A single solvent may be used, or multiple solvents may be used in combination.

[0012] The amount of the solvent used is 0.1 to 100 parts by weight, preferably 0.5 to 10 parts by weight, per part by weight of the compound represented by formula (1) (hereinafter referred to as compound (1)).

[0013] The amount of bromine used is usually 0.5 to 10 moles, preferably 0.8 to 2.0 moles, per mole of compound (1).

[0014] The amount of the radical initiator used is usually 0.001 to 1.0 mol, preferably 0.01 to 0.1 mol, per mol of compound (1). Examples of the radical initiator include azo compounds such as azobisisobutyronitrile (AIBN), 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile (V-70), 2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride (VA-044), and 2,2'-azobis(2-methylpropionamidine)dihydrochloride (V-50); and peroxides such as tert-butyl hydroperoxide and benzoyl peroxide, with azo compounds being preferred, and azobisisobutyronitrile being more preferred.

[0015] When the reaction is carried out under light irradiation, examples of the light source include a high-pressure mercury lamp, a low-pressure mercury lamp, and an incandescent lamp, and a high-pressure mercury lamp is preferred. A radical initiator and light irradiation can also be used in combination.

[0016] The reaction temperature is usually in the range of 0°C to 200°C, preferably 30°C to 100°C, more preferably 60°C to 80°C.

[0017] The reaction time is usually 0.1 to 100 hours, preferably 0.5 to 10 hours.

[0018] Methods for mixing raw materials in this reaction include, for example, a batch system in which all raw materials are added to a single container, and a flow system using a flow reactor. Examples of batch-type mixing methods include adding a radical initiator to a mixed solution of compound (1) and a solvent, followed by dropwise addition of bromine, or simultaneously adding a mixed solution of compound (1) and a solvent and bromine dropwise to a mixed solution of a solvent and a radical initiator. If necessary, the mixed solution of compound (1) and a solvent may be treated by concentration or by adding a dehydrating agent to remove moisture. When the radical initiator is irradiated with light, a method in which bromine is added dropwise to a mixed solution of compound (1) and a solvent while irradiating the solution with light is included. In either case, bromine may be added as is, or may be diluted with a solvent and then added. The dropwise addition time for bromine is typically 0.1 to 100 hours, preferably 0.1 to 24 hours. In the case of a flow system, a method in which compound (1), a mixed solution of a radical initiator and a solvent, and bromine are passed through a flow reactor is included. When the radical initiator is irradiated with light, a method in which a mixed solution of compound (1) and a solvent and bromine are passed through a flow reactor irradiated with light can be mentioned.

[0019] After the reaction is complete, compound (2) can be isolated by post-treatment such as distilling the reaction mixture, mixing the reaction mixture with neutral or weakly basic water, extracting the mixture with an organic solvent, and drying or distilling the resulting organic layer, etc. The isolated compound (2) can also be further purified by distillation, recrystallization, chromatography, or other methods.

[0020] Compound (1) may be a commercially available compound or may be synthesized by a known method. Compound (1) can be synthesized, for example, by neutralizing the corresponding carboxylic acid with a base such as an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); an alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, etc.); an alkali metal carbonate (e.g., sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, etc.); an alkali metal phosphate (e.g., trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, etc.); an alkali metal hydride (e.g., sodium hydride, potassium hydride, etc.); an alkali metal amide (e.g., sodium amide, potassium amide, etc.); sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc.); and a carboxylic acid (e.g., in which M in formula (1) is a hydrogen atom).

[0021] Because this reaction is affected by moisture, the water content of the reaction system is preferably 1.0 wt% or less, more preferably 0.2 wt% or less, relative to compound (1). Therefore, it is preferable to remove moisture from compound (1). The water concentration of compound (1) is preferably 1.0 wt% or less, more preferably 0.2 wt% or less. Methods for removing moisture from compound (1) include treating it with a dehydrating agent such as anhydrous sodium sulfate, anhydrous magnesium sulfate, or molecular sieves; or removing it by concentration. For example, moisture can be removed from (1) synthesized from the corresponding carboxylic acid and an alkali metal hydroxide by azeotropic dehydration after the neutralization reaction. When an alkali metal alkoxide is used, compound (1) suitable for the reaction can be obtained by concentrating the alcohol generated by the neutralization reaction. When an alkali metal carbonate, alkali metal phosphate, alkali metal hydride, or alkali metal amide is used as the base, the solution after the neutralization reaction can be used directly in this reaction without isolating compound (1).

[0022] The present invention will be described below with reference to the following examples. The contents of Compound (1) and Compound (2) were determined by the internal standard method using gas chromatography with commercially available products as standards.

[0023] Reference example 1 Under a nitrogen atmosphere, 26.07 g of potassium tert-butoxide was added to a mixture of 20 g of cyclopropanecarboxylic acid and 200 g of ethanol at 20° C., and the mixture was stirred for 1 hour at 50° C. The resulting mixture was concentrated to obtain 27.26 g of potassium cyclopropanecarboxylate with a water concentration of 0.0064 wt %.

[0024] Example 1 Under a nitrogen atmosphere, a mixture of 9.65 g of bromine and 15 g of monochlorobenzene was added dropwise over 2 hours to a mixture of 7.5 g of potassium cyclopropanecarboxylate obtained in Reference Example 1, 0.496 g of AIBN, and 22.5 g of monochlorobenzene at 70° C. The resulting mixture was analyzed by gas chromatography internal standard method and was confirmed to contain 4.90 g of cyclopropyl bromide (yield: 67.6%).

[0025] Example 2 Under a nitrogen atmosphere, a mixture of 7.5 g of potassium cyclopropanecarboxylate obtained in Reference Example 1 and 45 g of acetonitrile was added dropwise to a mixture of 9.65 g of bromine and 30 g of acetonitrile over a period of 2 hours at 70° C. under irradiation with light (light source: 400 W high-pressure mercury lamp). After stirring for 2 hours, the resulting mixture was analyzed by gas chromatography internal standard method and was confirmed to contain 4.82 g of cyclopropyl bromide (yield: 65.9%).

[0026] Example 3 The same procedure as in Example 1 was carried out except that acetonitrile was used as the solvent instead of monochlorobenzene, and cyclopropyl bromide was obtained in a yield of 54.5%.

[0027] Example 4 The same procedure as in Example 1 was carried out except that benzonitrile was used as the solvent instead of monochlorobenzene, and cyclopropyl bromide was obtained in a yield of 52.1%.

[0028] Example 5 The same procedure as in Example 1 was carried out except that butyl acetate was used as the solvent instead of monochlorobenzene, and cyclopropyl bromide was obtained in a yield of 50.3%.

[0029] Reference example 2 Under a nitrogen atmosphere, 2.24 g of potassium tert-butoxide was added to a mixture of 2 g of cyclobutanecarboxylic acid and 20 g of ethanol at 20° C., and the mixture was stirred for 1 hour at 50° C. The resulting mixture was concentrated to obtain 2.54 g of potassium cyclobutanecarboxylate with a water concentration of 0.20 wt %.

[0030] Example 6 Under a nitrogen atmosphere, a mixture of 0.5 g of potassium cyclobutanecarboxylate obtained in Reference Example 2, 0.03 g of AIBN, and 3.0 g of monochlorobenzene was added dropwise to a mixture of 0.58 g of bromine and 2.0 g of monochlorobenzene at 70° C. over 2 hours. The resulting mixture was analyzed by gas chromatography internal standard method and was confirmed to contain 0.36 g of cyclobutyl bromide (yield 75.0%).

[0031] Example 7 Under a nitrogen atmosphere, 5.0 g of cyclopropanecarboxylic acid, 0.477 g of AIBN, 6.16 g of tripotassium phosphate, and 30 g of acetonitrile were mixed at room temperature to obtain a mixture containing potassium cyclopropanecarboxylate. Next, a mixture of 9.28 g of bromine and 20 g of acetonitrile was added dropwise to the mixture at 70°C over 2 hours. After stirring for 3 hours, the resulting mixture was analyzed by gas chromatography internal standard method and was confirmed to contain 3.82 g of cyclopropyl bromide (yield: 54.3%).

[0032] Example 8 Under a nitrogen atmosphere, 5.0 g of cyclopropanecarboxylic acid, 6.16 g of tripotassium phosphate, and 30 g of acetonitrile were mixed at room temperature to obtain a mixture containing potassium cyclopropanecarboxylate. Next, a mixture of 9.28 g of bromine and 20 g of acetonitrile was added dropwise to the mixture over 2 hours at 70°C under irradiation with light (light source: 400 W high-pressure mercury lamp). After stirring for 4 hours, the resulting solution was analyzed by gas chromatography internal standard method and confirmed to contain 4.61 g of cyclopropyl bromide (yield: 65.7%).

[0033] Reference example 3 Under a nitrogen atmosphere, 11.2 g of sodium methoxide was added to a mixture of 5 g of cyclopropanecarboxylic acid and 50 g of methanol at 20° C., and the mixture was stirred for 1 hour at 50° C. The resulting mixture was concentrated to obtain 6.97 g of sodium cyclopropanecarboxylate with a water concentration of 0.29 wt %.

[0034] Example 9 Under a nitrogen atmosphere, a mixture of 0.5 g of sodium cyclopropanecarboxylate, 0.038 g of AIBN, and 3.0 g of acetonitrile was added dropwise to a mixture of 0.74 g of bromine and 2.0 g of acetonitrile at 70°C over 2 hours. After stirring at the same temperature for 4 hours, the resulting mixture was analyzed by gas chromatography internal standard method and was confirmed to contain 0.14 g of cyclopropyl bromide (yield 24.1%).

[0035] Reference example 4 Under a nitrogen atmosphere, a mixture of 0.5 g of potassium cyclopentanecarboxylate, 0.03 g of AIBN, and 3.0 g of monochlorobenzene was added dropwise to a mixture of 0.52 g of bromine and 2.0 g of monochlorobenzene at 70° C. over 2 hours. The resulting mixture was analyzed by gas chromatography internal standard method and was confirmed to contain 0.1 g of cyclopentyl bromide (yield: 20.7%).

[0036] Example 10 Cyclopropyl bromide was obtained in a yield of 31.3% in the same manner as in Example 1, except that potassium cyclopropanecarboxylate having a water concentration of 0.99 wt % was used.

[0037] Example 11 Cyclopropyl bromide was obtained in a yield of 56.3% in the same manner as in Example 1, except that potassium cyclopropylcarboxylate having a water concentration of 0.010 wt % was used.

[0038] Reference example 5 Under a nitrogen atmosphere, 18.9 g of cesium carbonate was added to a mixture of 10 g of cyclopropanecarboxylic acid and 50 g of ethanol at 20°C, and the mixture was stirred at 50°C for 1 hour. The solvent was distilled off from the resulting mixture under reduced pressure. The resulting cesium cyclopropanecarboxylate was refluxed and dehydrated in chlorobenzene, and the solvent was then distilled off under reduced pressure to obtain 23.88 g of cesium cyclopropanecarboxylate with a water concentration of 0.009 wt%.

[0039] Example 12 Under a nitrogen atmosphere, a mixture of 10 g of cesium cyclopropanecarboxylate, 0.377 g of AIBN, and 40 g of chlorobenzene was added dropwise at 70°C over 2 hours to a mixture of 7.33 g of bromine and 10 g of chlorobenzene. After stirring at the same temperature for 4 hours, the resulting mixture was analyzed by gas chromatography internal standard method and was confirmed to contain 3.77 g of cyclopropyl bromide (yield 68.0%). [GC analysis conditions]

[0040] Column: DB-WAX (0.25 μm × 0.25 mm Φ × 30 m) Injection port temperature: 250°C Detector: FID, 250°C Control mode: Linear velocity Pressure: 188.2 kPa Linear velocity: 55.7 cm / sec Carrier gas: Helium Flow rate: 3.23 mL / min Injection volume: 1.0 μL (Split ratio 50:1) Oven temperature: 40°C (20 min) → 20°C / min → 250°C (20 min)

[0041] According to the present invention, cycloalkyl bromides, which are useful compounds as raw materials for producing active ingredient compounds in the agricultural and pharmaceutical fields, can be synthesized without using heavy metals or the like.

Claims

1. Formula (1) [In the formula, R represents an optionally substituted C3-C4 cycloalkyl group, and M represents an alkali metal.] with bromine in the presence of a radical initiator or under light irradiation to obtain a compound represented by formula (2): (In the formula, R has the same meaning as above.) A method for producing a compound represented by the formula:

2. The method according to claim 1, wherein in the compound represented by formula (1), R is a cyclopropyl group or a cyclobutyl group.

3. 2. The method according to claim 1, wherein in the compound represented by formula (1), M is potassium or cesium.

4. 2. The process according to claim 1, wherein the radical initiator is an azo compound.

5. A method for producing a compound according to any one of claims 1 to 4, which is carried out in the presence of a solvent.

6. The process according to claim 5, wherein the solvent is a halogenated hydrocarbon, a nitrile, or an ester.

7. The method of claim 5, wherein an aryl chloride, a C1-C3 alkyl nitrile, benzonitrile, or a C1-C6 alkyl ester of acetate is used as the solvent.

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