JP2006111595A - Method for halogenation of active methylene compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for safely halogenating an active methylene compound with a simple operation, using an inexpensive raw material, generating little impurities such as by-products in high reactivity without producing harmful acidic gases such as hydrogen chloride, hydrogen bromide and sulfur dioxide. <P>SOLUTION: An active methylene compound is halogenated by using a metal halide or ammonium halide in water or an organic solvent in the presence of hydrogen peroxide. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a novel method for halogenating active methylene compounds.

  A compound having an active methylene group in the structure, a so-called active methylene compound, is extremely useful as an intermediate compound for pharmaceuticals, agricultural chemicals, photographic materials, dyes, pigments, and others. Further, halides of these active methylene compounds are also important as reaction intermediates for various substitution reactions. Halogenating agents such as chlorine, bromine, and sulfuryl chloride have been used for halogenation of active methylene compounds (including active methine compounds, the same shall apply hereinafter) and have been known (Non-patent Documents 1, 2, and 3). .

  Further, as a specific example of brominating an active methylene compound, a method is disclosed in which an active methylene compound is dissolved in a halogen-based solvent or an ester-based solvent, and bromine diluted with the same solvent is added to brominate (Patent Document 1). ).

  Also disclosed is a method of brominating or chlorinating an active methylene compound using 1,3-dihalogeno-5,5-dimethylhydantoin or N-halogenosuccinimide (Patent Documents 2 and 3).

  Further, a method is disclosed in which an active methylene compound is dissolved in an organic solvent and hydrochloric acid or hydrobromic acid is mixed, and hydrogen peroxide is added to form bromide or chlorinate (Patent Document 4).

  Also disclosed is a method of brominating an active methylene compound in diethyl ether, tetrahydrofuran, or a mixed solvent of diethyl ether and tetrahydrofuran using a diethyl ether complex of hydrogen peroxide and magnesium bromide (non- Patent Document 4).

  However, although these methods are useful, there are problems (defects) specific to each of them, and attention to these problems becomes more necessary as the production scale increases.

  For example, the methods of Non-Patent Documents 1, 2, 3 and Patent Document 1 have a drawback that toxic acidic gases such as hydrogen chloride, hydrogen bromide, sulfur disulfide and the like are by-produced simultaneously with halogenation. In addition, when an active methylene compound has an aromatic ring or a hetero ring, there is a problem that not only the active methylene but also protons on the ring are partially halogen-substituted. Therefore, these methods are disadvantageous when it is intended to obtain a halide of an active methylene compound that is originally intended with high purity.

  Halogenating agents such as 1,3-dihalogeno-5,5-dimethylhydantoin and N-halogenosuccinimide in Patent Documents 2 and 3 are industrially easy to handle as compared with chlorine and bromine as described in Patent Document 1, There is little by-product of acid gas. In addition, there is an advantage that halogen substitution to an aromatic ring or the like hardly occurs. However, these halogenating agents are disadvantageous in that they are more expensive than chlorine, bromine, sulfuryl chloride, and the like, and because the reaction activity is low, it takes a long time to complete the reaction. Further, after the reaction is completed, there is a problem in the post-treatment in which equimolar amounts of 5,5-dimethylhydantoin and succinimide are by-produced with the halogenating agent used, and a load is imposed on the organic waste treatment.

  In Patent Document 4, hydrochloric acid or hydrobromic acid is used as the halogenating agent. Advantages of this method include that there is no generation of acid gas, and the raw material is inexpensive and easy to handle. However, there is a problem that the halogenation of active methylene is not completed and the reaction rate is low. Furthermore, when a carboxylic acid amide, a carboxylic acid ester, or the like is present in the same molecule of the active methylene compound, these sites are caused by the action of hydrogen halides such as hydrochloric acid and hydrobromic acid which are halogenating agents and water. There was a fatal drawback of acid hydrolysis. When it is intended to obtain a target active methylene compound halide with high purity, it is not preferred that the active methylene compound as a raw material remains. In addition, it is very disadvantageous that carboxylic acids, amines, and alcohols are by-produced by hydrolysis. In addition to a decrease in the yield of the target halide, a complicated purification operation is required to separate the halide from these impurities. Therefore, this method is not a method that can be applied to all active methylene compounds, and a problem remains in terms of versatility.

  In Non-Patent Document 4, magnesium bromide diethyl ether complex is used as a halogenating agent, hydrogen peroxide, MCBP (m-chlorobenzoic acid peroxide), DBP (dibenzoyl peroxide), etc. are used as reaction solvents. Diethyl ether, tetrahydrofuran, or a mixture of diethyl ether and tetrahydrofuran is used.

  According to this method, there is an advantage that there is no generation of acid gas. However, there is a problem that the preparation of the reaction reagent used is complicated and difficult to handle. Furthermore, there was a fatal defect that an ether solvent had to be used for the reaction. In this method, there is a high possibility that the reaction solvent is oxidized by the action of a peroxide as a reaction reagent, and a peroxide of ether is generated. Ether peroxides are known for their high risk of explosive decomposition and explosion when they reach a certain concentration. Therefore, this method has a problem in terms of safety and cannot be carried out at an industrial level with a large scale.

Org. Synht. , I, 128 (1941) Org. Synht. , III, 132 (1955) Org. Synht. , III, 267 (1955) Japanese Patent Laid-Open No. 8-60010 JP-A-8-301830 JP-A-9-189987 Japanese Patent Laid-Open No. 2002-37148 Chem. Pharm. Bull. , 24 (4), 820 (1976)

  Therefore, the problem to be solved by the present invention is to solve the disadvantages of the above-mentioned conventional techniques, that is, there is no acid gas by-product, simple, safe, inexpensive and high reaction rate of active methylene compounds. It is to provide a method for realizing the above.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that one or both of a metal halide and an ammonium halide are halogenated in the presence of hydrogen peroxide in water or an organic solvent. As a result, it was found that the active methylene compound can be halogenated at a high reaction rate, and the present invention has been completed. Furthermore, in this invention, it discovered simultaneously that reaction was promoted by making an acid coexist in a reaction system. That is, the present invention has been found to be achieved by the following means.

(Claim 1)
A method for halogenating an active methylene compound, comprising halogenating an active methylene compound with a metal halide or ammonium halide in the presence of hydrogen peroxide in water or an organic solvent.

(Claim 2)
The method for halogenating an active methylene compound according to claim 1, wherein an acid is allowed to coexist.

(Claim 3)
The metal halide or ammonium halide is sodium bromide, potassium bromide, magnesium bromide, calcium bromide, ammonium bromide, sodium iodide, potassium iodide, magnesium iodide, calcium iodide, ammonium iodide. The method for halogenating an active methylene compound according to claim 1 or 2, which is selected from the group consisting of:

  According to the method of the present invention, it is possible to halogenate an active methylene compound safely, inexpensively and easily without by-product of toxic acid gas. can get.

  Hereinafter, the best mode for carrying out the present invention will be described in detail, but the present invention is not limited thereto.

  The halogenated method of the active methylene compound in the present invention is characterized by using a metal halide or ammonium halide as a halogenating agent in the presence of hydrogen peroxide in water or an organic solvent.

  The active methylene compound in the present invention refers to a compound having a saturated hydrocarbon bonded to an unsaturated functional group such as a nitro group, a carbonyl group, a sulfone group, a cyano group, a sulfinyl group, an imino group and a phenyl group. The acidity so-called pKa is preferably 4 to 17. The pKa value of the active methylene compound is Herbert O.D. HOUSE MODERN SYNTHETIC REACTIONS Second Edition 428 (Hirokawa Shoten), JP 50-13041, JP 56-151937, and the like.

  Specific active methylene compounds include aliphatic nitro compounds such as dinitromethane, nitroethane and nitromethane, cyanoacetic acid compounds such as methyl cyanoacetate, ethyl cyanoacetate, cyanoacetate anilide and cyanoacetylcoumarone, and aliphatic dicyano such as malononitrile. Compounds, β-diketone compounds such as acetylacetone and benzoylacetone, methyl acetoacetate, ethyl pivaloyl acetate, methyl benzoylacetate, acetoacetanilide, pivaloylacetate anilide, β-ketoacetate compounds such as benzoylacetate anilide, diethyl malonate, malonic acid Examples thereof include dicarboxylic acid compounds such as diphenyl and malonic acid dianilide, and nitrogen-containing heterocyclic compounds such as pyrazol-5-one and pyrazoloazole.

  Hereinafter, although the active methylene compound which can be used in this invention is illustrated concretely, this invention is not limited at all by these.

  Although the reaction solvent used in the present invention is not particularly limited, it is preferable not to use ethers and carboxylic acids that easily generate peroxides from the viewpoint of safety. Preferred solvents include aliphatic hydrocarbons, aromatic hydrocarbons, alcohols, esters, ketones, nitriles, halogen solvents, amide solvents, water, and the like. However, the solvent used is preferably inert to the active methylene compound. The exemplified organic solvent can also be used in a mixed system of any combination. Further, a two-component system of an organic solvent and water, or a three-component system or more can also be used.

  Specific solvents for aliphatic hydrocarbons include n-pentane, n-hexane, n-heptane, n-octane, isooctane, n-nonane, n-decane, n-undecane, n-dodecane, n-tridecane, Examples thereof include n-tetradecane, n-pentadecane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like. Specific solvents for aromatic hydrocarbons include benzene, toluene, xylene and the like. Specific examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, t-butanol, pentanol, hexanol, octanol and the like. Specific examples of the esters include ethyl acetate, methyl acetate, butyl acetate, methyl propionate, and ethyl propionate. Specific examples of ketones include acetone, methyl ethyl ketone, methyl isopropyl ketone, and methyl isobutyl ketone. Specific examples of nitrile solvents include acetonitrile and propionitrile. Specific examples of the halogen solvent include methylene chloride, chloroform, carbon tetrachloride, dichloroethylene, dichloroethane, trichloroethane, trichloroethylene, dibromoethane, chlorobenzene and the like. Specific examples of the amide solvent include N, N-dimethylformamide, N, N-dimethylacetamide and the like.

  In the present invention, among the organic solvents described above, n-heptane, toluene, xylene, methanol, ethanol, isopronol, ethyl acetate, acetone, acetonitrile, methylene chloride, chloroform, N, N-dimethylformamide are particularly preferable. Results in a reaction.

  In the present invention, the active methylene compound can be carried out in either a completely dissolved state or a partially dissolved suspension state in the solvent used. Although the usage-amount of a solvent is not specifically limited, 1-200 mass parts is preferable with respect to an active methylene compound, More preferably, it is 2-30 mass parts.

  In the present invention, the halogenating agent used is one or both of a metal halide and an ammonium halide.

  In the present invention, the halogen atom of the halogenating agent is any one of chlorine, bromine and iodine.

  In the present invention, any metal halide can be used. Specific examples (element symbols) of the metal element include Li, Be, Na, Mg, Al, K, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ga, Ge, As, Se, Rb, Sr, Y, Zr, Nb, Mo, Ru, Rh, Pd, Ag, Cd, In, Sn, Sb, Te, Cs, Ba, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg, Tl, Pb, Bi, etc. can be mentioned.

  In the present invention, among the above metal halides, alkali metal halides and alkaline earth metal halides are preferable.

  Specific examples of the alkali metal halide include lithium chloride, sodium chloride, potassium chloride, rubidium chloride, cesium chloride, lithium bromide, sodium bromide, potassium bromide, rubidium bromide, cesium bromide, lithium iodide, iodine Examples thereof include sodium iodide, potassium iodide, rubidium iodide, cesium iodide and the like.

  Specific examples of alkaline earth metal halide salts include beryllium chloride, magnesium chloride, calcium chloride, strontium chloride, barium chloride, beryllium bromide, magnesium bromide, calcium bromide, strontium bromide, barium bromide, iodide. Examples thereof include beryllium, magnesium iodide, calcium iodide, strontium iodide, and barium iodide.

  Specific examples of the ammonium halide salt include ammonium chloride, ammonium bromide, ammonium iodide and the like.

  In the present invention, among the aforementioned halogenating agents, particularly preferred metal halides and ammonium halides are sodium bromide, potassium bromide, magnesium bromide, calcium bromide, ammonium bromide, sodium iodide, and iodide. Potassium, magnesium iodide, calcium iodide, and ammonium iodide.

  In the present invention, the amount of the halogenating agent to be used is not particularly limited, but is preferably in the range of 0.5 to 3.5 equivalents and in the range of 0.8 to 1.5 equivalents with respect to 1 mol of the active methylene compound used. It is particularly preferred to use in

  The reaction of the present invention is carried out in the presence of hydrogen peroxide. The amount of hydrogen peroxide used is not particularly limited, but the preferred amount used is in the range of 0.5 to 7.0 equivalents, particularly preferably 0.8 to 2.0 equivalents per mole of active methylene compound. . Hydrogen peroxide is preferably used as an aqueous solution, and hydrogen peroxide water having a concentration of 1 to 50% by weight is preferably used.

  The reaction of the present invention proceeds by dissolving or suspending an active methylene compound in a solvent and adding hydrogen peroxide and a halogenating agent thereto. In particular, the reaction of the present invention facilitates ion dissociation of the halogenating agent to be used. Therefore, when a two-component system of an organic solvent and water is used as a reaction solvent, a favorable reaction result is obtained.

With such a reaction system, a halide of an active methylene compound can be obtained without any problem on a production scale with a simple and safe reagent and with a high yield and a high purity.

  In the present invention, the reaction temperature for halogenation is not particularly limited, but is preferably in the range of −50 to 150 ° C., particularly preferably in the range of −10 to 100 ° C.

  In the present invention, it is preferable to add an acid into the reaction system in order to cause the reaction to proceed rapidly. In the present invention, as the halogenation reaction proceeds, a metal hydroxide or ammonia corresponding to the halogenating agent used is by-produced. If the alkalinity in the reaction system becomes strong due to the by-product of these bases, the progress of the halogenation reaction may be inhibited. Therefore, it is effective to add an acid for the purpose of adjusting the pH in the system.

  In the present invention, the acid added to the reaction system may be any acid that can neutralize by-produced alkali. Specific examples of the acid to be added include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, benzoic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like. The present invention is not limited to these acid types.

  The amount of the acid used in the present invention is not particularly limited, but is preferably in the range of 0.1 to 5.0 equivalents, particularly in the range of 0.5 to 3.0 equivalents, based on the active methylene compound used. preferable.

  Since the halide of the active methylene compound obtained by the present invention has few impurities such as by-products, it can be used for the next reaction in the state of the reaction mixture. Further, after removing the remaining hydrogen peroxide, halogenating agent, acid and salts by washing with water, it can be used for the next reaction without being taken out. It can also be cooled as it is in the solvent used for crystallization and taken out by a solid-liquid separation method. It is also possible to distill off the solvent used in the reaction and then recrystallize it with an appropriate organic solvent or water. However, the present invention is not limited to the above-described presence / absence of water washing, presence / absence of recrystallization, type of solid-liquid separation solvent, apparatus used for solid-liquid separation, and the like.

EXAMPLES Hereinafter, although this invention is demonstrated in detail based on an Example, this invention is not limited at all by the following example. The progress of the reaction in the examples was measured by high performance liquid chromatography under the following conditions.
Apparatus: LC-9A series (Shimadzu Corporation)
Column: Inertsil ODS-2 (4.6φ × 250 mm) (GL Science Inc.)
Mobile phase: acetonitrile / distilled water / 99% acetic acid = 90/10/1
Mobile phase flow rate: 1.0 ml / min
Detection wavelength: 254 nm

Example 1
5'-Chloro-2'-dodecyloxy-3-phenyl-3-oxopropionic acid anilide (Exemplary Compound 18) brominated stirrer, 500 ml flask equipped with thermometer, 250 ml of toluene, 5'-chloro-2'- 10.00 g (21.8 mmol) of dodecyloxy-3-phenyl-3-oxopropionic acid anilide (Exemplary Compound 18) was charged and dissolved at room temperature, and 2.59 g (21.8 mmol) of potassium bromide was added thereto, 35% Hydrogen peroxide water (2.54 g, 26.16 mmol) and 35% hydrochloric acid (2.72 g, 26.16 mmol) were added, and the reaction was allowed to stir within a range of 20-25 ° C. After 6 hours, the organic layer was collected, and the reaction rate was measured under the high performance liquid chromatography measurement conditions. In addition, the numerical value shown below is a simple area percentage after removing the peak derived from toluene.
Active methylene compound monobromide of Exemplified Compound 18: 99.6%
Active methylene compound dibromide of Exemplified Compound 18: 0.2%
Exemplary compound 18: 0.2%
Bromination was carried out without generation of acid gas, and a high purity active methylene compound monobromide was produced.
The reaction mixture obtained above was allowed to stand, and the aqueous layer separated into the lower layer was removed. The organic layer was washed with 100 ml of distilled water, 100 ml of 5% sodium thiosulfate aqueous solution, and 100 ml of distilled water in this order. Thereafter, toluene is distilled off under reduced pressure using a rotary evaporator, and the organic layer concentrate is recrystallized with n-heptane, and 5'-chloro-2'-dodecyloxy-2-bromo-3-phenyl-3- 10.32 g of pale yellowish white crystals of oxopropionic acid anilide were obtained. The yield based on 5'-chloro-2'-dodecyloxy-3-phenyl-3-oxopropionic acid anilide was 88.0%.
¹ H-NMR (CDCL ₃ ) δ (ppm): 0.7 (3H, t), 1.2-1.4 (18H, m), 1.9 (2H, m), 4.0-4. 1 (2H, t), 5.7 (1H, s), 6.8 (1H, d), 7.0 (1H, q), 7.5 (2H, t), 7.7 (1H, t ), 8.1 (2H, d), 8.3 (1 H, d), 9.5 (1 H, s-br)
m. p. : 97-98 ° C

Example 2
5'-Chloro-2'-dodecyloxy-3-phenyl-3-oxopropionic acid anilide (Exemplary Compound 18) brominated stirrer, 500 ml flask equipped with thermometer, 250 ml of toluene, 5'-chloro-2'- 10.00 g (21.8 mmol) of dodecyloxy-3-phenyl-3-oxopropionic acid anilide (Exemplary Compound 18) was added and dissolved at room temperature, and 2.14 g (21.8 mmol) of ammonium bromide was added to the solution. Hydrogen peroxide water (2.54 g, 26.16 mmol) and 35% hydrochloric acid (2.72 g, 26.16 mmol) were added, and the reaction was allowed to stir within a range of 20-25 ° C. After 6 hours, the organic layer was collected, and the reaction rate was measured under the high performance liquid chromatography measurement conditions. In addition, the numerical value shown below is a simple area percentage after removing the peak derived from toluene.
Active methylene compound monobromide of Exemplified Compound 18: 98.2%
Active methylene compound dibromide of Exemplified Compound 18: 0.7%
Illustrative compound 18: undetected The reaction mixture obtained was allowed to stand, and the aqueous layer separated into the lower layer was removed. The organic layer was washed with 100 ml of distilled water, 100 ml of 5% sodium thiosulfate aqueous solution, and 100 ml of distilled water in this order. Thereafter, toluene is distilled off under reduced pressure using a rotary evaporator, and the organic layer concentrate is recrystallized with n-heptane, and 5'-chloro-2'-dodecyloxy-2-bromo-3-phenyl-3- 10.25 g of pale yellowish white crystals of oxopropionic acid anilide was obtained. The yield based on 5'-chloro-2'-dodecyloxy-3-phenyl-3-oxopropionic acid anilide was 87.4%. ¹ H-NMR (CDCL ₃ ) measurement results and melting point measurement results were the same as in Example 1.

Example 3
200 ml of toluene and 1,3-diphenylpropane-1,3-dione (Exemplary Compound 11) in a 500 ml flask equipped with a brominated stirrer and thermometer of 1,3-diphenylpropane-1,3-dione (Exemplary Compound 11) 20.00 g (89.20 mmol) was added and dissolved at room temperature, and the total amount of an aqueous solution in which 10.61 g (89.20 mmol) of potassium bromide was dissolved in 50 ml of water, 11.15 g (107.04 mmol) of 35% hydrochloric acid, Then, 12.13 g (107.00 mmol) of 30% aqueous hydrogen peroxide was added and stirred for 8 hours. After 8 hours, the organic layer was collected and the reaction rate was measured under the above-mentioned high performance liquid chromatography measurement conditions. In addition, the numerical value shown below is a simple area percentage after removing the peak derived from toluene.
Active methylene compound monobromide of Exemplified Compound 11: 100.0%
Active methylene compound dibromide of Exemplified Compound 11: Undetected Exemplified Compound 11: Undetected The obtained reaction mixture was allowed to stand, and the aqueous layer separated into the lower layer was removed. The organic layer was washed with 100 ml of distilled water, 100 ml of 5% sodium thiosulfate aqueous solution and 100 ml of distilled water in this order. Thereafter, toluene was removed under reduced pressure using a rotary evaporator to obtain 26.77 g of slightly yellowish white crystals of 2-bromo-1,3-diphenylpropane-1,3-dione. The yield based on 1,3-diphenylpropane-1,3-dione was 99.0%.
¹ H-NMR (CDCL ₃ ) δ (ppm): 6.54 (1H, s), 7.47 (4H, t-like, J = 7.6 Hz), 7.60 (2H, t-like, j = 7.6 Hz), 7.98 (4H, dd, J = 8.3 Hz, 1.3 Hz)
IR (neat) cm-1: 1674, 1448, 1205, 1149, 686, 638, 503
MS m / z 304 (M ⁺ for 81Br), 302 (M ⁺ for 79Br)
m. p. : 72-73 ° C

Example 4
N- {3- (4,4-dimethyl-3-oxo-pentanoylamino) -4-methoxyphenyl} octadecanamide (Exemplary Compound 21) brominated stirrer, 500 ml flask equipped with thermometer, 116 ml toluene, N -{3- (4,4-dimethyl-3-oxo-pentanoylamino) -4-methoxyphenyl} octadecanamide (Exemplary Compound 21) 11.57 g (21.8 mmol) was added and suspended at room temperature. 2.59 g (21.8 mmol) of potassium hexabromide, 2.54 g (26.16 mmol) of 35% aqueous hydrogen peroxide and 2.72 g (26.16 mmol) of 35% hydrochloric acid were added, and the temperature was in the range of 20 to 25 ° C. And stirred. After 3 hours, the organic layer was collected and the reaction rate was measured under the high performance liquid chromatography measurement conditions. In addition, the numerical value shown below is a simple area percentage after removing the peak derived from toluene.
Active methylene compound monobromide of exemplary compound 21: 96.6%
Active methylene compound dibromide of exemplary compound 21: 2.3%
Illustrative compound 21: undetected The reaction mixture obtained was allowed to stand, and the aqueous layer separated into the lower layer was removed. The organic layer was washed with 100 ml of distilled water, 100 ml of 5% sodium thiosulfate aqueous solution, and 100 ml of distilled water in this order. Thereafter, toluene was distilled off under reduced pressure using a rotary evaporator to give a slightly yellow color of N- {3- (2-bromo-4,4-dimethyl-3-oxo-pentanoylamino) -4-methoxyphenyl} octadecanamide. 13.20 g of white crystals were obtained. Yield 99.3% from N- {3- (4,4-dimethyl-3-oxopentanoylamino) -4-methoxyphenyl} octadecanamide.
¹ H-NMR (CDCL ₃ ) δ (ppm): 0.9 (3H, t), 1.2 (28H, m), 1.3 (9H, s), 1.6-1.7 (2H, m), 2.3 (2H, t), 3.9 (3H, s), 5.2 (1H, s), 6.8 (1H, d), 7.1 (1H, s-br), 7.7 (1H, q), 8.1 (1H, d), 9.2 (1H, s-br)
m. p. : 88-90 ° C

Example 5
A 500 ml flask equipped with a brominated stirrer and thermometer of N- {3- (4,4-dimethyl-3-oxopentanoylamino) -4-methoxyphenyl} octadecanamide (Exemplary Compound 21) was charged with N, N-dimethyl. 116 ml of formamide and 11.57 g (21.8 mmol) of N- {3- (4,4-dimethyl-3-oxo-pentanoylamino) -4-methoxyphenyl} octadecanamide (Exemplary Compound 21) were added at room temperature. Then, 2.13 g (20.7 mmol) of sodium bromide, 2.54 g (26.16 mmol) of 35% aqueous hydrogen peroxide and 2.72 g (26.16 mmol) of 35% hydrochloric acid were added thereto, and 20-25 The reaction was allowed to stir within the range of ° C. After 1 hour, the organic layer was collected and the reaction rate was measured under the high performance liquid chromatography measurement conditions. In addition, the numerical value shown below is a simple area percentage after removing the peak derived from N, N-dimethylformamide.
Active methylene compound monobromide of Exemplary Compound 21: 97.4%
Active methylene compound dibromide of exemplary compound 21: 0.1%
Exemplary compound 21: 1.2%
To the resultant reaction mixture, 150 m of toluene and 80 ml of distilled water were added, and after stirring and mixing, the mixture was allowed to stand, and the aqueous layer separated into the lower layer was removed. The organic layer was washed with 100 ml of distilled water twice, once with 100 ml of 5% aqueous sodium thiosulfate solution, and twice with 100 ml of distilled water. Thereafter, toluene is distilled off under reduced pressure using a rotary evaporator, and the organic layer concentrate is recrystallized with n-heptane, and N- {3- (2-bromo-4,4-dimethyl-3-oxopentanoylamino) is obtained. ) -4-methoxyphenyl} octadecanamide pale yellowish white crystal 11.96g was obtained. Yield 90.0% from N- {3- (4,4-dimethyl-3-oxopentanoylamino) -4-methoxyphenyl} octadecanamide. ¹ H-NMR (CDCL ₃ ) measurement results and melting point measurement results were the same as in Example 4.

  As described above, the method of the present invention does not generate any harmful acidic gas, and easily uses a simple reagent such as a halogen salt and hydrogen peroxide to produce a by-product easily and with little activity. It can be seen that a halide of a methylene compound can be produced in a high yield, and that the operability and safety are excellent.

Claims (3)

A method for halogenating an active methylene compound, comprising halogenating an active methylene compound with a metal halide or ammonium halide in the presence of hydrogen peroxide in water or an organic solvent. The method for halogenating an active methylene compound according to claim 1, wherein an acid is allowed to coexist. The metal halide or ammonium halide is sodium bromide, potassium bromide, magnesium bromide, calcium bromide, ammonium bromide, sodium iodide, potassium iodide, magnesium iodide, calcium iodide, ammonium iodide. The method for halogenating an active methylene compound according to claim 1 or 2, which is selected from the group consisting of: