JP2010047551A - Method of preparing haloalkane carboxylate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method of easily and efficiently preparing a haloalkane carboxylate with a high yield in one step using a hydroxyalkane carboxylate as a starting material. <P>SOLUTION: According to the method, a haloalkane carboxylate is prepared by halogenating a hydroxyalkane carboxylate using a halogenation agent in the presence of an N,N-dialkylformamide. N,N-dimethylformamide may be used as an N,N-dialkylformamide, 3-hydroxy-2,2-dimethylpropionate may be used as a hydroxyalkane carboxylate, and thionyl chloride may be used as a halogenation agent. The halogenation reaction may further be caused to proceed at a temperature not lower than the boiling point of the halogenation agent, subsequent to causing it to proceed at a temperature not higher than the boiling point of the halogenation agent. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing a haloalkane carboxylic acid ester useful as an intermediate for fine chemicals such as pharmaceuticals, agricultural chemicals and fragrances.

  A method for producing a haloalkanecarboxylic acid ester (such as 3-chloro-2,2-dimethylpropionic acid ester) via a haloalkanecarboxylic acid halide (such as 3-chloro-2,2-dimethylpropionic acid chloride). It has been known.

  For example, Yanbian Daxue Xuebao, Ziran Kexueban, 2004, 30, 270-273 (Non-patent Document 1), 3-hydroxy-2,2-dimethylpropionic acid is catalyzed by pyridine and N, N-dimethylformamide. Describes a method for obtaining 3-chloro-2,2-dimethylpropionic acid chloride by chlorination with thionyl chloride. However, in order to obtain 3-chloro-2,2-dimethylpropionic acid ester by this method, further esterification must be performed. Pyridine is also used as a catalyst.

  Also, Huaxue Yu Shengwu Gongcheng, 2005, 22, 52-54 (Non-patent Document 2), Huaxue Shijie 2003, 44, 651-652, 655 (Non-patent Document 3), Faming Zhuanli Shenqing Gongkai Shuomingshu 2004, 1491932 (Non-patent document 4), Zhongguo Yiyao Gongye Zazhi 2003, 34, 373-374 (Non-patent document 5), 2,2-dimethylpropionic acid chloride was chlorinated using chlorine gas. A process for obtaining 3-chloro-2,2-dimethylpropionic acid chloride is described. However, these methods use chlorine, which is a toxic gas, and thus impede industrial implementation. Further, in order to obtain 3-chloro-2,2-dimethylpropionic acid ester, further esterification must be performed.

  In Non-Patent Document 4, 2,2-dimethylpropionic acid is led to 2,2-dimethylpropionic acid chloride with phosphorus trichloride, and then 3-chloro-2,2-dimethylpropionic acid chloride is converted with chlorine gas. The method of obtaining is described. On the other hand, Huaxue Shiji 2003, Vol. 25, pp. 91-92 (Non-patent Document 6) introduces 2,2-dimethylpropionic acid to 3-chloro-2,2-dimethylpropionic acid with chlorine gas, Describes a method for obtaining 3-chloro-2,2-dimethylpropionic acid chloride by chlorination with thionyl chloride. However, even in these methods, chlorine, which is a toxic gas, is an obstacle to industrial implementation. Further, in order to obtain 3-chloro-2,2-dimethylpropionic acid ester, further esterification must be performed.

Thus, the method for producing a hydroxyalkanecarboxylic acid ester (such as 3-hydroxy-2,2-dimethylpropionic acid ester) via an acid halide requires a two-step reaction. In addition, it is necessary to remove a halogen-containing gas such as hydrogen chloride produced as a by-product with esterification, and the process is complicated.
Yanbian Daxue Xuebao, Ziran Kexueban, 2004, 30, 270-273 Huaxue Yu Shengwu Gongcheng, 2005, 22, 52-54 Huaxue Shijie 2003, 44, 651-652, 655 Faming Zhuanli Shenqing Gongkai Shuomingshu 2004, 1491932 Zhongguo Yiyao Gongye Zazhi 2003, 34, 373-374 Huaxue Shiji 2003, 25, 91-92

  Accordingly, an object of the present invention is to provide a method capable of producing a haloalkanecarboxylic acid ester in a high yield in one step simply and efficiently even on an industrial scale.

  As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that N, N-dimethylformamide acts as a catalyst and uses hydroxyalkanecarboxylic acid in the form of an ester rather than in the form of a free acid. It was found that when halogenated with an agent, a high-purity haloalkanecarboxylic acid ester can be produced in a high yield in one step, the present invention was completed. In addition, when the reaction temperature is set to be lower than the boiling point of the halogenating agent to generate a reaction intermediate, and the reaction temperature is set to be higher than the boiling point of the halogenating agent to convert the reaction intermediate to a haloalkanecarboxylic acid ester. The present inventors have found that haloalkanecarboxylic acid esters can be produced easily and efficiently without stopping the reaction at the reaction intermediate.

  That is, in the method of the present invention, a hydroxyalkanecarboxylic acid ester is halogenated using a halogenating agent in the presence of N, N-dialkylformamide to produce a haloalkanecarboxylic acid ester.

  In this method, the N, N-dialkylformamide is N, N-dimethylformamide, the hydroxyalkanecarboxylic acid ester is 3-hydroxy-2,2-dimethylpropionic acid ester, and the halogenating agent is thionyl chloride. It may be.

  A method of allowing the halogenation reaction to proceed at a temperature lower than the boiling point of the halogenating agent and then proceeding at a temperature equal to or higher than the boiling point of the halogenating agent may be used. For example, in a solvent inert to the reaction, thionyl chloride is used as a halogenating agent, and the halogenation reaction is allowed to proceed at 50 to 75 ° C., and further proceeds at a temperature of 80 ° C. or higher and below the boiling point of the reaction system. It is also possible to use a method.

  The proportion of each component is, for example, 1 to 2 mol of the halogenating agent and 1 to 0.2 mol of N, N-dialkylformamide with respect to 1 mol of the hydroxyalkanecarboxylic acid ester. It may be.

  The production method includes a reaction step of halogenating in an aromatic hydrocarbon solvent inert to the reaction, and a step of adding water to the reaction mixture and extracting the haloalkanecarboxylic acid ester to the organic phase after this reaction step. And a step of isolating the extracted haloalkanecarboxylic acid ester by distillation under reduced pressure.

  In the above production method, 3-hydroxy-2,2-dimethylpropionic acid ester is halogenated with an aromatic agent in an aromatic hydrocarbon solvent in the presence of N, N-dimethylformamide, and the reaction mixture is neutralized. Then, water may be mixed to extract 3-halo-2,2-dimethylpropionic acid ester into the organic phase, and the extract may be concentrated and distilled under reduced pressure.

  In the present invention, a hydroxyalkanecarboxylic acid is subjected to a halogenation reaction with a halogenating agent in the form of a carboxylic acid ester in the presence of N, N-dialkylformamide, so that a haloalkane carboxylic acid ester can be produced in a single step with a high yield. . Moreover, even if it is an industrial scale, it can manufacture with haloalkane carboxylic acid ester simply and efficiently.

  In the present invention, a hydroxyalkanecarboxylic acid is used in the form of a carboxylic acid ester in the presence of N, N-dialkylformamide and halogenated using a halogenating agent to produce a haloalkane carboxylic acid ester.

  The hydroxyalkanecarboxylic acid ester is not particularly limited, and examples thereof include compounds represented by the following formula (I).

In formula (I), R ¹ and R ² are the same or different and each represents a hydrogen atom or an alkyl group. R ³ represents an alkyl group, a cycloalkyl group, an aryl group or an aralkyl group. m and n are the same or different and represent an integer of 0 to 2;

Examples of the alkyl group represented by R ¹ and R ² include C _1-4 alkyl groups such as a methyl group and an ethyl group. Preferred R ¹ and R ² are a hydrogen atom or a C _1-2 alkyl group (particularly a methyl group).

Examples of the alkyl group for R ³ include linear or branched C ₁ such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, and pentyl group. _-20 alkyl group (preferably C _1-10 alkyl group, more preferably C _1-6 alkyl group) and the like. Examples of the cycloalkyl group represented by R ³ include a C _4-10 cycloalkyl group (preferably a C _4-8 cycloalkyl group) such as a cyclopentyl group and a cyclohexyl group. Examples of the aryl group for R ³ include C _6-12 aryl groups such as a phenyl group and a naphthyl group. Examples of the aralkyl group for R ³ include C _6-12 aryl-C _1-4 alkyl groups such as a benzyl group and a phenethyl group. Among R ³ , a linear or branched C _1-6 alkyl group, particularly a linear or branched C _1-4 alkyl group (for example, an isobutyl group) is preferable. When used in the form of an ester, the formation of by-products can be suppressed, the target compound can be advantageously separated industrially, and a useful intermediate haloalkanecarboxylic acid ester can be produced in a high yield.

  In addition, in the case of preparing an alkoxyalkanecarboxylic acid ester by further reacting a metal alkoxide with the haloalkanealkanecarboxylic acid ester obtained in the present invention, the alkyl group of the alkoxy part and the alkyl group of the ester part are made the same group. Then, generation of by-products that are difficult to separate can be prevented. For example, when methyl haloalkanecarboxylate is produced using methyl hydroxyalkanecarboxylate, when this methyl haloalkanecarboxylate is reacted with sodium isobutoxide, methyl isobutoxyalkanecarboxylate, isobutyloxyalkanecarboxylate, methoxy Methyl alkanecarboxylate and isobutyl methoxyalkanecarboxylate are obtained, making it difficult to separate both compounds. On the other hand, when isobutyl hydroxyalkanecarboxylate is used to produce isobutyl haloalkanecarboxylate, only isobutyl isobutoxyalkanecarboxylate can be prepared by reacting isobutyl haloalkanecarboxylate with sodium isobutoxide.

  m and n are the same or different and represent an integer of 0 to 2. Among them, m is preferably 1, and n is preferably 0.

  Examples of the hydroxyalkanecarboxylic acid ester represented by the above formula (I) include 2-hydroxy-2,2-dimethylacetic acid ester, 3-hydroxy-2,2-dimethylpropionic acid ester, 4-hydroxy-3, Examples thereof include 3-dimethylbutyric acid ester and 4-hydroxy-2,2-dimethylbutyric acid ester. Specifically, 2-hydroxy-2,2-dimethylisobutyl acetate, 3-hydroxy-2,2-dimethylpropionate isobutyl, 4-hydroxy-3,3-dimethylbutyrate isobutyl, 4-hydroxy-2,2- Examples include isobutyl dimethyl butyrate. Hydroxyalkanecarboxylic acid esters can be used alone or in combination of two or more. Of these, 3-hydroxy-2,2-dimethylpropionic acid ester (particularly isobutyl 3-hydroxy-2,2-dimethylpropionic acid) is preferable. In this case, the reaction proceeds smoothly and a haloalkanecarboxylic acid ester can be produced in high yield.

  Examples of the halogenating agent include chlorinating agents such as thionyl chloride, phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride, oxalyl dichloride, brominating agents such as thionyl bromide, phosphorus tribromide, oxalyl bromide, and the like. A fluorinating agent such as dialkylamino sulfur fluoride can be used. A halogenating agent can be used individually or in combination of 2 or more types. Of these halogenating agents, chlorinating agents (for example, thionyl chloride) are frequently used. When thionyl chloride is used, the yield of the target compound can be increased.

  The ratio (amount used) of the halogenating agent is 1 to 2 mol, preferably 1.1 to 1.5 mol, more preferably 1.05 to 1.45 mol (for example, per mol of hydroxyalkanecarboxylic acid ester). 1.05 to 1.2 mol). If the proportion of the halogenating agent is too large, it may contribute to the formation of by-products.

  N, N-dialkylformamide functions as a catalyst. Therefore, a basic compound such as pyridine is not always necessary. As N, N-dialkylformamide, for example, N, N-dimethylformamide is often used. N, N-dialkylformamide can be used alone or in combination of two or more.

  In the reaction, the ratio (amount used) of N, N-dialkylformamide is not particularly limited and may be used as a reaction solvent. From the viewpoint of yield, reaction efficiency, etc., for example, 1 mol of hydroxyalkanecarboxylic acid ester is used. On the other hand, it may be about 0.01 to 0.3 mol (for example, 0.01 to 0.2 mol), preferably about 0.05 to 0.2 mol, and about 0.07 to 0.15 mol.

  The halogenation reaction may be performed in a solvent inert to the reaction. As a solvent, it can select suitably in the range which does not impair reaction, for example, hydrocarbons [aliphatic hydrocarbons (hexane, heptane, etc.), alicyclic hydrocarbons (cyclohexane, etc.), aromatic hydrocarbons (toluene, xylene, etc.) Etc.], ketones (alkyl ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, cyclohexanone etc.), esters (such as ethyl acetate), ethers (dialkyl ethers such as diethyl ether and diisopropyl ether) and the like. These solvents may be used alone or in combination of two or more. Of these solvents, aromatic hydrocarbons such as toluene are preferred in view of reaction temperature, reaction efficiency, and post-treatment after reaction.

  The ratio (amount used) of the solvent is 0 to 5 parts by weight, preferably 0.5 to 2.5 parts by weight (for example, 1.5 to 2.5 parts by weight) based on 1 part by weight of the hydroxyalkanecarboxylic acid ester. Part), more preferably about 1.0 to 2.2 parts by weight (for example, 1.8 to 2.2 parts by weight).

  As described above, in the present invention, the reaction system may be substantially free of pyridine (the amount of pyridine used is, for example, 0 to 0.01 part by weight relative to 1 part by weight of hydroxyalkanecarboxylic acid ester). Preferably about 0 to 0.001 parts by weight). That is, in the present invention, the hydroxyalkanecarboxylic acid ester may be halogenated using a halogenating agent in the presence of N, N-dialkylformamide, and the reaction can proceed smoothly without using pyridine.

  The reaction is usually performed by stirring in a liquid phase system at a predetermined temperature. The halogenation temperature can be appropriately selected depending on the type of halogenating agent. For example, halogenation taking into account the boiling point of the halogenating agent and the fact that unreacted halogenating agent is discharged together with the halogen-containing gas (hydrogen chloride gas, etc.) generated by the reaction of the halogenating agent. The temperature may be set.

  The reaction temperature may be about 0 to 120 ° C. (for example, 10 to 110 ° C., preferably 20 to 100 ° C., more preferably 25 to 95 ° C.) depending on the kind of the halogenating agent and the solvent.

  In the halogenation reaction, each component may be supplied to the reaction system all at once or sequentially or continuously. Usually, the halogenating agent is often added to the reaction system sequentially or intermittently or continuously. For example, a halogenating agent is often added dropwise to a mixture of a hydroxyalkane carboxylic acid ester, N, N-dialkylformamide and a reaction inert solvent at a predetermined temperature.

  The temperature at which the halogenating agent is dropped (mixing temperature) may be set to a temperature lower than the boiling point of the halogenating agent. For example, when thionyl chloride is used as the halogenating agent, the temperature at which the halogenating agent is dropped (mixing temperature) is 0 ° C. or higher and lower than the boiling point of thionyl chloride (for example, 0 to 78 ° C.), preferably 10 to 75 ° C. (For example, 25-75 degreeC), More preferably, about 10-40 degreeC (for example, 25-30 degreeC) may be sufficient. With such a dropping temperature (mixing temperature), the heat of reaction can be controlled, and the reaction proceeds efficiently.

  The reaction temperature may be raised continuously or stepwise according to the type of halogenating agent. In particular, the reaction temperature is often raised stepwise.

  As the halogenation method, the first reaction temperature (low temperature) is set to generate a reaction intermediate, and the reaction temperature is further changed to the second reaction temperature (high temperature) for converting the reaction intermediate to the haloalkanecarboxylic acid ester. The haloalkane carboxylic acid ester can be prepared by setting. In this case, the reaction can proceed smoothly and the target compound can be obtained in high yield.

  In the above method, the first reaction temperature at which the reaction intermediate is generated may be a temperature lower than the boiling point of the halogenating agent. For example, when thionyl chloride is used as the halogenating agent, the first reaction temperature is 0 ° C. or higher and lower than the boiling point of thionyl chloride (eg, 0 to 78 ° C.), preferably 50 to 75 ° C., more preferably 55 to 75 ° C. It may be about 0 ° C. (for example, 60 to 75 ° C.). The reaction intermediate is an intermediate produced by the reaction of a hydroxyl group of a hydroxyalkanecarboxylic acid ester with a halogenating agent, for example, -O- produced by dehydrochlorination when thionyl chloride is used as the halogenating agent. It may be an intermediate having S (= O) Cl [halosulfino group].

  In the above method, the second reaction temperature for converting the reaction intermediate to the haloalkanecarboxylic acid ester may be a temperature equal to or higher than the boiling point of the halogenating agent. For example, when thionyl chloride is used as the halogenating agent, the second reaction temperature is preferably 79 ° C. or higher and lower than the boiling point of the reaction system (for example, 79 to 120 ° C.), more preferably 80 ° C. or higher. Further, the temperature may be about the boiling point of the reaction system (for example, 80 to 100 ° C.), more preferably about 85 to 95 ° C.

  The reaction time is not particularly limited, but may be, for example, 3 to 30 hours, preferably 4 to 10 hours, and more preferably about 5 to 6 hours. The reaction can be carried out in a batch system, semi-batch system, continuous system or the like using a conventionally known apparatus equipped with a stirring device.

  By the reaction, a haloalkanecarboxylic acid ester in which the hydroxyl group of the hydroxyalkanecarboxylic acid ester is substituted with the halogen atom of the halogenating agent can be produced. For example, by reacting a hydroxyalkanecarboxylic acid ester represented by the above formula (I) with a halogenating agent, the hydroxyl group is substituted with a halogen atom (X), and the haloalkanecarboxylic acid represented by the following formula (II) Esters (such as 3-chloro-2,2-dimethylpropionic acid ester) are synthesized.

  The reaction time is not particularly limited, but may be, for example, 3 to 30 hours, preferably 4 to 10 hours, and more preferably about 5 to 6 hours. The reaction can be carried out in a batch system, semi-batch system, continuous system or the like using a conventionally known apparatus equipped with a stirring device.

  By the reaction, a haloalkanecarboxylic acid ester in which the hydroxyl group of the hydroxyalkanecarboxylic acid ester is substituted with the halogen atom of the halogenating agent can be produced. For example, by reacting a hydroxyalkanecarboxylic acid ester represented by the above formula (I) with a halogenating agent, the hydroxyl group is substituted with a halogen atom (X), and the haloalkanecarboxylic acid represented by the following formula (II) Esters (such as 3-chloro-2,2-dimethylpropionic acid ester) are synthesized.

R ^{1 to} R ³ , m and n in the formula are the same as described above.

  X represents a halogen atom corresponding to the halogenating agent, and examples thereof include fluorine, chlorine, bromine atom (preferably chlorine or bromine atom, particularly chlorine atom) and the like.

  The reaction mixture may be subjected to the isolation step as it is, but it is often isolated and purified after neutralization of the reaction mixture after completion of the reaction. For neutralization, strong alkali or weak alkali can be used. For example, alkali metal compounds (alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, etc. Alkali metal hydrogen carbonates, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal acetates such as sodium acetate and potassium acetate), alkaline earth metal compounds (alkaline earth metal hydroxides such as magnesium hydroxide) And alkaline earth metal carbonates such as magnesium carbonate). Of these alkalis, alkali metal carbonates such as potassium carbonate and alkali metal hydroxides are particularly preferable.

  After the halogenation reaction, the haloalkanecarboxylic acid ester can be isolated using a conventional isolation method such as concentration, extraction, distillation, crystallization, or a combination thereof. Isolation is usually performed by extraction in many cases. Specifically, the separation is performed using water and an organic solvent separable from water. As the water, an aqueous alkali solution (such as an aqueous alkali metal carbonate solution) used for neutralization may be used.

  Organic solvents that can be separated from water include hydrocarbons [aliphatic hydrocarbons (hexane, heptane, etc.), alicyclic hydrocarbons (cyclohexane, etc.), aromatic hydrocarbons (toluene, xylene, mesitylene, etc.), Halogen hydrocarbons (methylene chloride, chloroform, etc.)], ketones (alkyl ketones such as methyl ethyl ketone and methyl isobutyl ketone), esters (such as ethyl acetate), ethers (dialkyl ethers such as diethyl ether and diisopropyl ether) Etc. can be exemplified. These organic solvents may be used alone or in combination of two or more. Of these organic solvents, aromatic hydrocarbons (such as toluene) are preferred. In particular, when an organic solvent that can be separated from water as a reaction solvent, for example, an aromatic hydrocarbon inert to the reaction, such as toluene, the operation of adding the extraction solvent can be omitted, and only by washing several times with water, N, N-dialkylformamide can be removed to the aqueous phase.

  When the halogenation reaction is carried out in an aromatic hydrocarbon solvent inert to the reaction, water is added to the reaction mixture after the halogenation to extract the haloalkanecarboxylic acid ester into the organic phase, followed by distillation under reduced pressure. The haloalkanecarboxylic acid ester thus extracted may be isolated.

  For example, when an aromatic hydrocarbon inert to the reaction, such as toluene, is used as a reaction solvent, water is added to the reaction mixture to extract the target compound into the organic phase, and the organic phase is concentrated and aromatic carbonized. Hydrogen is distilled off at 30 to 60 ° C. (for example, 45 ° C.) under a reduced pressure of 10 to 100 hPa (for example, 30 hPa), and then vacuum distillation is performed to isolate the haloalkanecarboxylic acid ester. The reduced pressure in the vacuum distillation may be 5-100 hPa, preferably 10-80 hPa, more preferably 20-60 hPa (especially 45-55 hPa). Moreover, the temperature in vacuum distillation is 30-130 degreeC normally, Preferably it is 60-120 degreeC, More preferably, about 100-115 degreeC may be sufficient.

  In the present invention, a highly pure haloalkane carboxylic acid ester can be produced in high yield, and the obtained haloalkane carboxylic acid ester can be used as an intermediate for fine chemicals of pharmaceuticals, agricultural chemicals, and fragrances.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

  The properties of the products obtained in the examples were measured by the following method.

⁽¹ H-NMR spectrum)
¹ H-NMR spectrum was measured using tetramethylsilane as an internal standard and CDCl ₃ as a solvent.

Example 1
(Synthesis of isobutyl 3-chloro-2,2-dimethylpropionate)
To the reactor was isobutyl 3-hydroxy-2,2-dimethylpropionate (149.0 g, 0.86 mol), N, N-dimethylformamide (6.3 g, 0.085 mol), and toluene (187 g, 2.03 mol). After thionyl chloride (139.1 g, 1.11 mol) was added dropwise at 25 ± 10 ° C. over 0.5 hours, the mixture was stirred at 60 ° C. for 1 hour. The reaction was traced by GC, and after confirming disappearance of isobutyl 3-hydroxy-2,2-dimethylpropionate, the mixture was further heated to 90 ° C. and stirred for 3 hours. Then, it stood to cool to room temperature (about 25 degreeC). Next, 10% aqueous potassium carbonate solution was added to neutralize. Subsequently, the separated toluene layer was washed with water and concentrated to distill off toluene at 45 ° C. under reduced pressure of 30 hPa, and then distilled under reduced pressure at 105 ° C. and 50 hPa to give isobutyl 3-chloro-2,2-dimethylpropionate. Was obtained in 75% yield.

Example 2
(Synthesis of isobutyl 3-chloro-2,2-dimethylpropionate)
To the reactor was isobutyl 3-hydroxy-2,2-dimethylpropionate (152.1 g, 1.06 mol), N, N-dimethylformamide (7.8 g, 0.106 mol), and toluene (187 g, 2.03 mol). Then, thionyl chloride (158.5 g, 1.27 mol) was added dropwise at 25 ± 10 ° C. over 0.5 hours, followed by stirring at 60 ° C. for 1 hour. The reaction was traced by GC, and after confirming disappearance of isobutyl 3-hydroxy-2,2-dimethylpropionate, the mixture was further heated to 90 ° C. and stirred for 3 hours. Then, it stood to cool to room temperature (about 25 degreeC). Next, 10% aqueous potassium carbonate solution was added to neutralize. Subsequently, the separated toluene layer was washed with water and concentrated to distill off toluene at 45 ° C. under reduced pressure of 30 hPa, and then distilled under reduced pressure at 105 ° C. and 50 hPa to give isobutyl 3-chloro-2,2-dimethylpropionate. Was obtained in 79% yield.

Example 3
(Synthesis of isobutyl 3-chloro-2,2-dimethylpropionate)
To the reactor was added isobutyl 3-hydroxy-2,2-dimethylpropionate (9.0 g, 0.052 mol) and N, N-dimethylformamide (0.4 g, 0.005 mol), and thionyl chloride at 25 ± 10 ° C. (8.4 g, 0.07 mol) was added dropwise over 0.5 hours, followed by stirring at 60 ° C. for 2 hours. The reaction was traced by GC, and after confirming disappearance of isobutyl 3-hydroxy-2,2-dimethylpropionate, the mixture was further heated to 90 ° C. and stirred for 4 hours. Then, it stood to cool to room temperature (about 25 degreeC). The reaction yield by GC was 95%.

The ¹ H-NMR spectral data of isobutyl 3-chloro-2,2-dimethylpropionate obtained in the examples are shown below.

¹ H-NMR (CDCl ₃ ): 0.95 (d, 6H, j = 6.7 Hz), 1.30 (s, 6H), 1.96 (m, 1H), 3.62 (s, 2H) , 3.9 (d, 2H, J = 6.7 Hz)
Comparative Example 1
(Synthesis of isobutyl 3-chloro-2,2-dimethylpropionate)
To the reactor was added isobutyl 3-hydroxy-2,2-dimethylpropionate (4.5 g, 0.026 mol) and toluene (18.7 g, 0.20 mol), and thionyl chloride (4.2 g, 0.034 mol) was added dropwise over 0.5 hours, followed by stirring at 60 ° C. for 1 hour. The reaction was traced by GC to confirm the disappearance of isobutyl 3-hydroxy-2,2-dimethylpropionate, and further heated to 90 ° C. and stirred for 7 hours. Many peaks of (= O) Cl-containing intermediate) remained. Then, it stood to cool to room temperature (about 25 degreeC). The reaction yield by GC of isobutyl 3-chloro-2,2-dimethylpropionate was 51%.

As is apparent from the results of the above ¹ H-NMR spectral data, the reaction of 3-hydroxy-2,2-dimethylpropionic acid ester with thionyl chloride in the presence of N, N-dimethylformamide in a toluene solvent is performed. After setting the reaction temperature to 60 ° C. (below the boiling point of the reaction system) and setting to 90 ° C. (above the boiling point of the reaction system), the 3-chloro-2,2-dimethylpropionic acid ester is formed in one step. It can be easily and efficiently produced at a high yield. Even when a toluene solvent is not used, the target compound can be similarly produced.

Claims (7)

  A method for producing a haloalkane carboxylic acid ester, wherein a hydroxyalkane carboxylic acid ester is halogenated using a halogenating agent in the presence of N, N-dialkylformamide.   The N, N-dialkylformamide is N, N-dimethylformamide, the hydroxyalkanecarboxylic acid ester is 3-hydroxy-2,2-dimethylpropionic acid ester, and the halogenating agent is thionyl chloride. Production method.   The production method according to claim 1 or 2, wherein the halogenation reaction is allowed to proceed at a temperature lower than the boiling point of the halogenating agent, and is further allowed to proceed at a temperature equal to or higher than the boiling point of the halogenating agent.   Claim: Using thionyl chloride as a halogenating agent in a solvent inert to the reaction and allowing the halogenation reaction to proceed at a temperature of 50 to 75 ° C. and then proceeding at a temperature of 80 ° C. or higher and lower than the boiling point of the reaction system. Item 4. The production method according to any one of Items 1 to 3.   The ratio of the halogenating agent is 1 to 2 moles and the ratio of N, N-dialkylformamide is 0.01 to 0.2 moles with respect to 1 mole of the hydroxyalkanecarboxylic acid ester. The manufacturing method of crab.   A reaction step of halogenating in an aromatic hydrocarbon solvent inert to the reaction; a step of adding water to the reaction mixture after the reaction step to extract the haloalkanecarboxylic acid ester into the organic phase; and an extracted haloalkane. And a step of isolating the carboxylic acid ester by distillation under reduced pressure.   In the presence of N, N-dialkylformamide, 3-hydroxy-2,2-dimethylpropionic acid ester is halogenated with a halogenating agent in an aromatic hydrocarbon solvent to neutralize the reaction mixture, and then water is added. The production method according to any one of claims 1 to 6, wherein the mixture is mixed to extract 3-halo-2,2-dimethylpropionate to an organic phase, the extract is concentrated, and distilled under reduced pressure.