Process for producing cycloalkyl bromides

Abstract

Provided is a method for producing a cycloalkyl bromide without using a heavy metal or the like. Provided is a method for producing a compound represented by formula (2) (in the formula, R represents the same meaning as in formula (1)), which is performed by reacting a compound represented by formula (1) (in the formula, R represents a C3-C4 cycloalkyl group which can be substituted, and M represents an alkali metal) with bromine in the presence of a radical initiator or under light irradiation. R-Br (2).

Description

Technical Field

[0001] This invention relates to a method for manufacturing cycloalkyl bromides. Background Technology

[0002] Cycloalkyl bromides are useful compounds that can be converted into various compounds, such as cycloalkyl magnesium bromide and cycloalkyl borate compounds, which are intermediates of compounds used as active ingredients in the fields of agro-pharmaceuticals.

[0003] For example, Patent Documents 1 and 2 describe examples of the synthesis of pharmaceuticals using cyclopropylmagnesium bromide and cyclopropylboronic acid.

[0004] Methods for synthesizing cycloalkyl bromides that use stoichiometric amounts of heavy metals are known. For example, Patent Document 3 and Non-Patent Document 1.

[0005] Existing technical documents

[0006] Patent documents

[0007] Patent Document 1: WO2006 / 26356

[0008] Patent Document 2: WO2011 / 042918

[0009] Patent Document 3: CN107915689

[0010] Non-patent literature

[0011] Non-patent literature 1: Journal of the American Chemical Society, 1951, 3176 pages Summary of the Invention

[0012] The problem that the invention aims to solve

[0013] The object of this invention is to provide a method for manufacturing cycloalkyl bromides without using heavy metals or the like.

[0014] Methods for solving problems

[0015] The inventors of this application have studied methods for manufacturing cycloalkyl bromides and discovered that, by using potassium salts of cycloalkyl carboxylic acids, the target cycloalkyl bromides can be manufactured without the use of heavy metals or the like. That is, the present invention is as follows.

[0016] [1] The method for producing the compound shown in formula (2) is carried out by reacting the compound shown in formula (1) with bromine in the presence of a free radical initiator or under light irradiation.

[0017]

[0018] [In the formula, R represents a substituted C3-C4 cycloalkyl group, and M represents an alkali metal.]

[0019] R-Br (2)

[0020] [In the formula, R represents the same meaning as above.]

[0021] [2] The manufacturing method as described in [1], wherein R in the compound shown in formula (1) is cyclopropyl or cyclobutyl.

[0022] [3] The manufacturing method as described in [1] or [2], wherein M is potassium or cesium in the compound represented by formula (1).

[0023] [4] The manufacturing method as described in any one of [1] to [3], wherein the free radical initiator is an azo compound.

[0024] [5] The manufacturing method as described in any one of [1] to [4] is carried out in the presence of a solvent.

[0025] [6] The manufacturing method as described in [5], wherein a halogenated hydrocarbon, nitrile or ester is used as a solvent.

[0026] [7] The manufacturing method as described in [5] or [6], wherein an aryl chloride, a C1-C3 alkyl nitrile, a benzonitrile or a C1-C6 alkyl acetate is used as a solvent.

[0027] Invention Effects

[0028] According to the present invention, cycloalkyl bromides can be synthesized without the use of heavy metals or the like. Detailed Implementation

[0029] The substituents in this invention will be explained.

[0030] In this specification, expressions such as "CY-CZ" refer to carbon atoms ranging from Y to Z. For example, expressions such as "C1-C6" refer to carbon atoms ranging from 1 to 6.

[0031] 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.

[0032] Examples of C1-C6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, and hexyloxy.

[0033] Examples of C2-C7 alkyl carbonyl groups include acetyl, propionyl, butyryl, 2-methylpropionyl, valeryl, hexanoyl, and heptanoyl.

[0034] Examples of C2-C7 alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropyloxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl.

[0035] Examples of C1-C6 alkyl thio groups include methyl thio, ethyl thio, propyl thio, isopropyl thio, butyl thio, pentyl thio, and hexyl thio.

[0036] Examples of C1-C6 alkyl sulfinyl groups include methane sulfinyl, ethane sulfinyl, propane sulfinyl, propane-2-yl sulfinyl, butane sulfinyl, pentane sulfinyl, and hexane sulfinyl.

[0037] Examples of C1-C6 alkyl sulfonyl groups include methanesulfonyl, ethanesulfonyl, propanesulfonyl, propane-2-ylsulfonyl, butanesulfonyl, pentanesulfonyl, and hexanesulfonyl.

[0038] Examples of di(C1-C6 alkyl)aminocarbonyl groups include dimethylaminocarbonyl, ethylmethylaminocarbonyl, diisopropylcarbonyl, and dihexylaminocarbonyl.

[0039] Examples of (C2-C7 alkyl carbonyl groups that may be substituted with one or more halogen atoms) (C1-C6 alkyl)amino groups include, for example, N-methylacetamitamido, N-methyl-2,2,2-trifluoroacetamitamido and N-hexylheptamido.

[0040] Halogen atoms refer to fluorine, chlorine, bromine, or iodine atoms.

[0041] Examples of aryl groups include phenyl, naphthyl, indanthyl, and tetrahydronaphthyl.

[0042] Examples of heteroaryl groups include pyrroleyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetraazinyl.

[0043] When a substituent is replaced by two or more halogen atoms or substituents, these halogen atoms or substituents may be the same or different.

[0044] As a substituent that can be present in the C3-C4 cycloalkyl group represented by R in formula (1), one or more substituents selected from group A can be cited.

[0045] Group A: C1-C6 alkyl groups that can be substituted by one or more substituents selected from Group B; C3-C7 cycloalkyl groups that can be substituted by one or more substituents selected from Group C; aryl groups that can be substituted by one or more substituents selected from Group D; heteroaryl groups that can be substituted by one or more substituents selected from Group D; OR 1 OS(O) m R 1 OC(O)R 1 NR 1 R 2 NR 1 NR 2 R 3 NR 2 OR 1 NR 2 C(O)R 1 NR 2 NR 3 C(O)R 1 NR 2 C(O)OR 1 NR 2 NR 3 C(O)OR 1 NR 1 C(O)NR 2 R 3 NR 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 CR 2 =NOR 1 S(O) m R 1 A group consisting of cyano, nitro, formyl, or halogen atoms.

[0046] R 1 R 2 and R 3 "Same" or "different from each other" indicates a C1-C6 alkyl group that can be substituted by one or more substituents selected from group B, a C3-C7 cycloalkyl group that can be substituted by one or more substituents selected from group C, or an aryl group that can be substituted by one or more substituents selected from group D.

[0047] m represents 0, 1, or 2.

[0048] Group B: The group consisting of C3-C7 cycloalkyl groups that can be substituted by one or more substituents selected from Group C, C1-C6 alkoxy groups that can be substituted by one or more halogen atoms, C2-C7 alkyl carbonyl groups that can be substituted by one or more halogen atoms, C2-C7 alkoxy carbonyl groups that can be substituted by one or more halogen atoms, C1-C6 alkyl thio groups that can be substituted by one or more halogen atoms, C1-C6 alkyl sulfinyl groups that can be substituted by one or more halogen atoms, bis(C1-C6 alkyl)amino carbonyl groups, (C2-C7 alkyl carbonyl groups that can be substituted by one or more halogen atoms) (C1-C6 alkyl)amino groups, aryl groups that can be substituted by one or more substituents selected from Group E, aryloxy groups that can be substituted by one or more substituents selected from Group E, cyano groups, nitro groups, formyl groups, and halogen atoms.

[0049] Group C: The group consisting of C1-C6 alkyl groups that can be substituted with one or more halogen atoms, C1-C6 alkoxy groups that can be substituted with one or more halogen atoms, C2-C7 alkyl carbonyl groups that can be substituted with one or more halogen atoms, C2-C7 alkoxy carbonyl groups that can be substituted with one or more halogen atoms, C1-C6 alkyl thio groups that can be substituted with one or more halogen atoms, C1-C6 alkyl sulfinyl groups that can be substituted with one or more halogen atoms, bis(C1-C6 alkyl)amino carbonyl groups, (C2-C7 alkyl carbonyl groups that can be substituted with one or more halogen atoms) (C1-C6 alkyl)amino groups, aryl groups that can be substituted with one or more substituents selected from Group E, aryloxy groups that can be substituted with one or more substituents selected from Group E, cyano groups, nitro groups, formyl groups, and halogen atoms.

[0050] Group D: Composed of C3-C7 cycloalkyl groups substituted with one or more substituents selected from Group E; C1-C6 alkyl groups substituted with one or more halogen atoms; C1-C6 alkoxy groups substituted with one or more halogen atoms; C2-C7 alkyl carbonyl groups substituted with one or more halogen atoms; C2-C7 alkoxy carbonyl groups substituted with one or more halogen atoms; C1-C6 alkyl thio groups substituted with one or more halogen atoms; or C2-C7 alkyl carbonyl groups substituted with one or more halogen atoms. The group consisting of C1-C6 alkyl sulfinyl groups with atomic substitution, C1-C6 alkyl sulfonyl groups with substitution by one or more halogen atoms, di(C1-C6 alkyl)amino carbonyl groups, (C2-C7 alkyl carbonyl groups with substitution by one or more halogen atoms) (C1-C6 alkyl)amino groups, aryl groups with substitution by one or more substituents selected from group E, aryloxy groups with substitution by one or more substituents selected from group E, cyano groups, nitro groups, formyl groups, and halogen atoms.

[0051] Group E: The group consisting of C1-C6 alkyl groups that can be substituted with one or more halogen atoms, C1-C6 alkoxy groups that can be substituted with one or more halogen atoms, C2-C7 alkyl carbonyl groups that can be substituted with one or more halogen atoms, C2-C7 alkoxy carbonyl groups that can be substituted with one or more halogen atoms, C1-C6 alkyl thio groups that can be substituted with one or more halogen atoms, C1-C6 alkyl sulfinyl groups that can be substituted with one or more halogen atoms, C1-C6 alkyl sulfonyl groups that can be substituted with one or more halogen atoms, cyano groups, nitro groups, and halogen atoms.

[0052] Preferably, the substituents that the C3-C4 cycloalkyl group represented by R may have include one or more substituents selected from group F.

[0053] Group F: C1-C6 alkyl groups that can be substituted by one or more substituents selected from Group G, C3-C7 cycloalkyl groups that can be substituted by one or more substituents selected from Group H, aryl groups that can be substituted by one or more substituents selected from Group H, OR 1 S(O) m R 1 Or a group composed of halogen atoms.

[0054] Group G: The group consisting of C3-C7 cycloalkyl groups that can be substituted by one or more halogen atoms, C1-C6 alkoxy groups that can be substituted by one or more halogen atoms, aryl groups, aryloxy groups {the aryl group and the aryloxy group can be substituted by one or more substituents selected from the group consisting of C1-C6 alkyl groups that can be substituted by one or more halogen atoms and halogen atoms}, and halogen atoms.

[0055] Group H: The group consisting of C1-C6 alkyl groups that can be substituted by one or more halogen atoms, C3-C7 cycloalkyl groups that can be substituted by one or more halogen atoms, C1-C6 alkoxy groups that can be substituted by one or more halogen atoms, aryl groups, aryloxy groups {the aryl group and the aryloxy group can be substituted by one or more substituents selected from the group consisting of C1-C6 alkyl groups that can be substituted by one or more halogen atoms and halogen atoms}, and halogen atoms.

[0056] More preferably, examples of substituents that the C3-C4 cycloalkyl group represented by R may include C3-C4 cycloalkyl groups that can be substituted with one or more halogen atoms, aryl groups that can be substituted with one or more halogen atoms, C3-C7 cycloalkyl groups that can be substituted with one or more halogen atoms, C1-C6 alkoxy groups that can be substituted with one or more halogen atoms, and C3-C4 cycloalkyl groups that can be substituted with one or more halogen atoms.

[0057] Further preferred R is a C3-C4 cycloalkyl group.

[0058] Examples of alkali metals represented by M in formula (1) include lithium, sodium, potassium, rubidium, and cesium, with potassium and cesium being preferred, and potassium being more preferred.

[0059] This reaction will be explained.

[0060] When this reaction is carried out in the presence of a solvent, examples of such solvents include halogenated hydrocarbons such as alkyl chlorides, aryl chlorides, alkyl bromides, and aryl bromides; nitriles such as C1-C3 alkyl nitriles and aromatic nitriles; esters such as C1-C6 alkyl esters of acetate and C1-C6 alkyl esters of benzoic acid; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl 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 alkyl nitriles include acetonitrile and propionitrile; examples of aromatic nitriles include benzonitrile; examples of C1-C6 alkyl acetates include ethyl acetate, isopropyl acetate, and butyl acetate; examples of C1-C6 alkyl benzoates include methyl benzoate, ethyl benzoate, and butyl benzoate.

[0061] The preferred solvents are halogenated hydrocarbons, nitriles and esters, more preferably aryl chlorides, C1-C3 alkyl nitriles, benzonitrile and C1-C6 alkyl acetates, and even more preferably monochlorobenzene, acetonitrile, benzonitrile and butyl acetate.

[0062] Solvents can be a single type or a combination of multiple solvents.

[0063] The amount of solvent used is 0.1 to 100 parts by weight relative to 1 part by weight of the compound shown in formula (1) (hereinafter referred to as compound (1)), preferably 0.5 to 10 parts by weight.

[0064] Regarding the amount of bromine used, it is usually 0.5 to 10 moles relative to 1 mole of compound (1), preferably 0.8 to 2.0 moles.

[0065] Regarding the amount of free radical initiator used, it is usually 0.001 to 1.0 moles relative to 1 mole of compound (1), and preferably 0.01 to 0.1 moles.

[0066] Examples of free radical initiators include azobisisobutyronitrile (AIBN), 2,2'-azobis(4-methoxy-2,4-dimethylpentanonitrile (V-70), 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (VA-044), and 2,2'-azobis(2-methylpropanediamine) dihydrochloride (V-50); peroxides such as tert-butyl hydroperoxide and benzoyl peroxide are preferred, and azo compounds are even more preferred.

[0067] When this reaction is carried out under light irradiation, the light source can be, for example, a high-pressure mercury lamp, a low-pressure mercury lamp, or an incandescent lamp, with a high-pressure mercury lamp being preferred.

[0068] It can also be used in combination with free radical initiators and light irradiation.

[0069] The reaction temperature is typically in the range of 0℃ to 200℃, preferably 30℃ to 100℃, and more preferably 60℃ to 80℃.

[0070] The reaction time is typically 0.1 to 100 hours, preferably 0.5 to 10 hours.

[0071] Examples of methods for mixing the raw materials in this reaction include batch mixing, where all raw materials are added to a single container, and flow mixing using a flow reaction apparatus.

[0072] As a batch mixing method, examples include adding bromine dropwise after adding a free radical initiator to a mixed solution of compound (1) and solvent; or simultaneously adding a mixed solution of compound (1) and solvent and bromine dropwise to a mixed solution of solvent and free radical initiator. If necessary, the mixed solution of compound (1) and solvent may be pretreated by removing water based on the addition of a concentrator or dehydrating agent. When the action of the free radical initiator is carried out by light irradiation, a method of adding bromine dropwise while irradiating the mixed solution of compound (1) and solvent with light can be used. In any case, bromine can be added directly or diluted with a solvent before addition. The dropwise addition time of bromine is typically 0.1 to 100 hours, preferably 0.1 to 24 hours. In the case of a flow reaction, a method of passing a mixed solution of free radical initiator and solvent, compound (1), and bromine into a flow reaction apparatus can be used. When the action of a free radical initiator is carried out by light irradiation, an example is the method of passing a mixture of compound (1) and solvent and bromine into a light-irradiated flow reaction apparatus.

[0073] After the reaction is complete, compound (2) can be separated by performing the following post-treatment operations: distilling the reaction mixture; mixing the reaction mixture with neutral or weakly alkaline water and extracting it with an organic solvent; drying or distilling the resulting organic layer; etc.

[0074] Alternatively, the isolated compound (2) can be further purified by methods such as distillation, recrystallization or chromatography.

[0075] Compound (1) can be a commercially available compound or a compound synthesized by known methods. For example, compound (1) can be obtained by neutralizing the corresponding carboxylic acid, a base, and a carboxylic acid in formula (1) where M is a hydrogen atom. The base can be: alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, and potassium tert-butoxide; alkali metal carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and cesium carbonate; alkali metal phosphates such as trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate; alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal amines such as sodium amino and potassium amino; sodium hexamethyldisilamide and potassium hexamethyldisilamide; and so on.

[0076] This reaction is affected by water content; therefore, the water content of the reaction system is preferably 1.0% by weight or less, more preferably 0.2% by weight or less, relative to compound (1). Therefore, compound (1) is more preferably free of water. The water concentration of compound (1) is preferably 1.0% by weight or less, more preferably 0.2% by weight or less. Methods for removing water from compound (1) include, for example, reacting it with a dehydrating agent such as anhydrous sodium sulfate, anhydrous magnesium sulfate, or a molecular sieve; or removing it by concentration. For example, (1) synthesized using the corresponding carboxylic acid and alkali metal hydroxide can be subjected to azeotropic dehydration after neutralization reaction, thereby removing its water content. In the case of using an alkali metal alkoxide, the alcohol produced by the neutralization reaction can be concentrated to obtain the compound (1) corresponding to the reaction. In the case of using an alkali metal carbonate, alkali metal phosphate, alkali metal hydride, or alkali metal amino compound as a base, the solution after neutralization reaction can be used directly in this reaction without separating compound (1).

[0077] Example

[0078] The present invention will now be described based on examples. It should be noted that, regarding the content of compounds (1) and (2), commercially available products were used as standards, and the content was determined by gas chromatography using the internal standard method.

[0079] Reference Example 1

[0080]

[0081] Under a nitrogen atmosphere, 26.07 g of potassium tert-butoxide was added to a mixture of 20 g of cyclopropaneformic acid and 200 g of ethanol at 20 °C, and the mixture was stirred at 50 °C for 1 hour. The resulting mixture was then concentrated to obtain 27.26 g of potassium cyclopropaneformate with a water concentration of 0.0064 wt%.

[0082] Example 1

[0083]

[0084] Under a nitrogen atmosphere, at 70°C, a mixture of 9.65 g of bromine and 15 g of monochlorobenzene was added dropwise to a mixture of 7.5 g of potassium cyclopropaneformate, 0.496 g of AIBN, and 22.5 g of monochlorobenzene obtained in Reference Example 1 over 2 hours. Analysis of the resulting mixture using gas chromatography with internal standard method confirmed the presence of 4.90 g of cyclopropyl bromide (yield 67.6%).

[0085] Example 2

[0086]

[0087] Under a nitrogen atmosphere and at 70°C, under light (source: 400W high-pressure mercury lamp), a mixture of 9.65 g of bromine and 30 g of acetonitrile was added dropwise to a mixture of 7.5 g of potassium cyclopropaneformate and 45 g of acetonitrile obtained in Reference Example 1 after 2 hours of stirring. After stirring for 2 hours, the resulting mixture was analyzed by gas chromatography with internal standard method, confirming the presence of 4.82 g of cyclopropyl bromide (yield 65.9%).

[0088] Example 3

[0089] Acetonitrile was used instead of monochlorobenzene as a solvent, and otherwise the procedure was carried out in the same manner as in Example 1, yielding cyclopropyl bromide in 54.5% yield.

[0090] Example 4

[0091] Benzonitrile was used instead of monochlorobenzene as a solvent, and otherwise the procedure was carried out in the same manner as in Example 1, yielding cyclopropyl bromide in 52.1% yield.

[0092] Example 5

[0093] Butyl acetate was used as a solvent instead of monochlorobenzene, and otherwise the procedure was carried out in the same manner as in Example 1, yielding cyclopropyl bromide in 50.3% yield.

[0094] See Example 2

[0095]

[0096] 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 at 50 °C for 1 hour. The resulting mixture was then concentrated to obtain 2.54 g of potassium cyclobutanecarboxylate with a water concentration of 0.20 wt%.

[0097] Example 6

[0098]

[0099] Under a nitrogen atmosphere, at 70°C, a mixture of 0.58 g of bromine and 2.0 g of monochlorobenzene was added dropwise to a mixture of 0.5 g of potassium cyclobutaneformate, 0.03 g of AIBN, and 3.0 g of monochlorobenzene obtained in Reference Example 2 over 2 hours. Analysis of the resulting mixture using gas chromatography with internal standard method confirmed the presence of 0.36 g of cyclobutyl bromide (yield 75.0%).

[0100] Example 7

[0101]

[0102] Under a nitrogen atmosphere, 5.0 g of cyclopropaneformic 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 cyclopropaneformate. Then, at 70°C, a mixture of 9.28 g of bromine and 20 g of acetonitrile was added dropwise to this mixture over 2 hours. After stirring for 3 hours, the mixture was analyzed by gas chromatography with internal standard method, confirming the presence of 3.82 g of cyclopropyl bromide (yield 54.3%).

[0103] Example 8

[0104]

[0105] Under a nitrogen atmosphere, 5.0 g of cyclopropaneformic acid, 6.16 g of tripotassium phosphate, and 30 g of acetonitrile were mixed at room temperature to obtain a mixture containing potassium cyclopropaneformate. Then, at 70°C and under light (source: 400W high-pressure mercury lamp), a mixture of 9.28 g of bromine and 20 g of acetonitrile was added dropwise to this mixture over 2 hours. After stirring for 4 hours, the resulting solution was analyzed by gas chromatography with internal standard method, confirming the presence of 4.61 g of cyclopropyl bromide (yield 65.7%).

[0106] See Example 3

[0107]

[0108] Under a nitrogen atmosphere, 11.2 g of sodium methoxide was added to a mixture of 5 g of cyclopropaneformic acid and 50 g of methanol at 20 °C, and the mixture was stirred at 50 °C for 1 hour. The resulting mixture was then concentrated to obtain 6.97 g of sodium cyclopropaneformate with a water concentration of 0.29 wt%.

[0109] Example 9

[0110]

[0111] Under a nitrogen atmosphere, at 70°C, a mixture of 0.74 g bromine and 2.0 g acetonitrile was added dropwise over 2 hours to a mixture of 0.5 g sodium cyclopropaneformate, 0.038 g AIBN, and 3.0 g acetonitrile. After stirring at the same temperature for 4 hours, the resulting mixture was analyzed by gas chromatography with internal standard method, confirming the presence of 0.14 g cyclopropyl bromide (yield 24.1%).

[0112] See Example 4

[0113]

[0114] Under a nitrogen atmosphere, at 70°C, a mixture of 0.52 g bromine and 2.0 g monochlorobenzene was added dropwise over 2 hours to a mixture of 0.5 g potassium cyclopentaneformate, 0.03 g AIBN, and 3.0 g monochlorobenzene. Gas chromatography with internal standard analysis confirmed the presence of 0.1 g cyclopentyl bromide (yield 20.7%).

[0115] Example 10

[0116]

[0117] Potassium cyclopropaneformate with a water concentration of 0.99 wt% was used, and otherwise the procedure was carried out in the same manner as in Example 1, yielding cyclopropyl bromide in a yield of 31.3%.

[0118] Example 11

[0119]

[0120] Potassium cyclopropaneformate with a water concentration of 0.010 wt% was used, and otherwise the procedure was carried out in the same manner as in Example 1, yielding cyclopropyl bromide in a yield of 56.3%.

[0121] See Example 5

[0122]

[0123] Under a nitrogen atmosphere, 18.9 g of cesium carbonate was added to a mixture of 10 g of cyclopropaneformic acid and 50 g of ethanol at 20 °C, and the mixture was stirred at 50 °C for 1 hour. The solvent was removed by distillation under reduced pressure from the resulting mixture. The obtained cesium cyclopropaneformate was then dehydrated by reflux in chlorobenzene, and the solvent was removed by distillation under reduced pressure, yielding 23.88 g of cesium cyclopropaneformate with a water concentration of 0.009 wt%.

[0124] Example 12

[0125]

[0126] Under a nitrogen atmosphere, at 70°C, a mixture of 7.33 g of bromine and 10 g of chlorobenzene was added dropwise over 2 hours. After stirring at the same temperature for 4 hours, the resulting mixture was analyzed by gas chromatography with internal standard method, confirming the presence of 3.77 g of cyclopropyl bromide (yield 68.0%).

[0127] [GC Analysis Conditions]

[0128] Column: DB-WAX (0.25μm×0.25mmΦ×30m)

[0129] Inlet temperature: 250℃

[0130] Detector: FID, 250℃

[0131] Control mode: Linear velocity; Pressure: 188.2 kPa; Linear velocity: 55.7 cm / sec

[0132] Carrier gas: Helium

[0133] Flow rate: 3.23 mL / min

[0134] Injection volume: 1.0 μL (split ratio 50:1)

[0135] Column oven temperature: 40℃ (20 min) → 20℃ / min → 250℃ (20 min)

[0136] Industrial availability

[0137] According to the present invention, cycloalkyl bromides (which are useful raw materials for manufacturing active ingredient compounds in the fields of agro-pharmaceuticals) can be synthesized without the use of heavy metals or the like.

Claims

1. A method for producing the compound shown in formula (2), said method being carried out by reacting the compound shown in formula (1) with bromine in the presence of a free radical initiator or under light irradiation, In formula (1), R represents a substituted C3-C4 cycloalkyl group, and M represents an alkali metal. In equation (2), R represents the same meaning as above.

2. The manufacturing method as described in claim 1, wherein, In the compound shown in formula (1), R is cyclopropyl or cyclobutyl.

3. The manufacturing method as described in claim 1 or claim 2, wherein, In the compound shown in formula (1), M is potassium or cesium.

4. The manufacturing method as described in claim 1 or claim 2, wherein, The free radical initiator is an azo compound.

5. The manufacturing method according to claim 1 or claim 2, wherein the manufacturing method is carried out in the presence of a solvent.

6. The manufacturing method as described in claim 5, wherein, As a solvent, halogenated hydrocarbons, nitriles, or esters are used.

7. The manufacturing method as described in claim 5, wherein, As solvents, aryl chlorides, C1-C3 alkyl nitriles, benzonitriles, or C1-C6 alkyl esters of acetate are used.

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