JP2010047550A - Method of preparing alkoxyalkane carboxylate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method of easily and efficiently preparing an alkoxyalkane carboxylate of high purity with a high yield even in an industrial scale, which is capable of allowing the reaction to smoothly proceed even under a mild condition. <P>SOLUTION: According to the method, an alkoxyalkane carboxylate is prepared by causing a haloalkane carboxylate and a metal alkoxide to react with each other in a nonprotonic polar solvent. N,N-dimethylformamide may be used as a nonprotonic polar solvent, and 3-chloro-2,2-dimethylpropionate may be used as a haloalkane carboxylate. Subsequent to neutralizing or acidifying the liquid reaction mixture and extracting the resulting alkoxyalkane carboxylate by mixing the reaction liquid with water and a 5-10C alkane, into the organic phase, the extracted liquid may be concentrated and distilled under vacuum. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

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

  Various methods are conventionally known as a method for producing an alkoxyalkanecarboxylic acid ester (such as 3-alkoxy-2,2-dimethylpropionic acid ester) useful as an intermediate for fine chemicals.

  For example, in JP-A-1-249778 (Patent Document 1), ethyl 3-hydroxy-2,2-dimethylpropionate is treated with sodium hydride and then reacted with various alkyl iodides in dimethylformamide. A method for obtaining ethyl alkoxy-2,2-dimethylpropionate is disclosed. Bioorganic & Medicinal Chemistry Letters. 2007, Vol. 17, 2452-2455 (Non-patent Document 1), methyl 3-hydroxy-2,2-dimethylpropionate was treated with sodium hydride, and then propyl iodide. A method is disclosed in which methyl 3-propyloxy-2,2-dimethylpropionate is obtained by reacting with. However, in these methods, 3-alkoxy-2,2-dimethylpropionic acid ester is obtained in a yield of about 60%, and it is difficult to obtain the target compound in a high yield.

  On the other hand, in Japanese translation of PCT publication No. 2007-521314 (Patent Document 2), methyl 2,2-dimethyl-3-tosyloxypropionate and 3,5-dimethylphenol are reacted in dimethylacetamide in the presence of potassium carbonate. And obtaining methyl 3- (3,5-dimethylphenyloxy) -2,2-dimethylpropionate. In addition, Liebigs Ann. Chem. 1969, 725, 106-115 (Non-patent Document 2) includes dimethyl sulfoxide in methyl 2,2-dimethyl-3-tosyloxypropionate or 2,2-dimethyl- A method is described in which ethyl 3-tosyloxypropionate and sodium methoxide are reacted to obtain methyl 3-methoxy-2,2-dimethylpropionate or ethyl 3-methoxy-2,2-dimethylpropionate. However, these methods have problems such as a low yield of about 60%, a large amount of by-products, and difficulty in separation from the target compound.

Japanese Patent Application Laid-Open No. 7-25826 (Patent Document 3) discloses that a hydroxycarboxylic acid ester and an alcohol are reacted at high temperature in the presence of zeolite or a phosphate obtained by hydrothermal action. A method for obtaining an acid ester is described. Although this method has an advantage that an alkoxycarboxylic acid can be obtained from hydroxycarboxylic acid in one step, the reaction requires a high temperature of 240 ° C. or more, which is an obstacle to industrial implementation.
JP-A-1-249778 (page 7, lower right column, line 18 to page 8, upper right column, line 13) JP-T-2007-521314 (paragraph number [0032]) Japanese Unexamined Patent Publication No. 7-25826 (Claims, paragraph number [0028]) Bioorganic & Medicinal Chemistry Letters. 2007, 17, 2452-2455 Liebigs Ann. Chem. 1969, 725, 106-115

  Accordingly, an object of the present invention is to provide a method capable of producing a high purity alkoxyalkanecarboxylic acid ester in a high yield.

  Another object of the present invention is to provide a method capable of producing an alkoxyalkanecarboxylic acid ester easily and efficiently even on an industrial scale, allowing the reaction to proceed smoothly even under mild conditions.

  As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that when a haloalkanecarboxylic acid ester and a metal alkoxide are reacted in a liquid phase reaction system in an aprotic polar solvent, a high-purity alkoxyalkanecarboxylic acid. The present inventors have found that an ester can be easily and efficiently produced in high yield.

  That is, in the method of the present invention, a haloalkanecarboxylic acid ester and a metal alkoxide are reacted in an aprotic polar solvent to produce an alkoxyalkanecarboxylic acid ester.

  In this method, the aprotic polar solvent may be an amide solvent, and the haloalkanecarboxylic acid ester may be a 3-halo-2,2-dimethylpropionic acid ester. Also, for example, the aprotic polar solvent may be N, N-dimethylformamide, the haloalkanecarboxylic acid ester may be 3-chloro-2,2-dimethylpropionic acid ester, and the metal alkoxide may be an alkali metal alkoxide. Good.

  For example, the proportion of each component is such that the proportion of the metal alkoxide is about 1 to 2.5 mol per 1 mol of the haloalkanecarboxylic acid ester, and the amount of the aprotic polar solvent is 1 part by weight of the haloalkanecarboxylic acid ester. The ratio may be about 4 to 12.5 parts by weight.

In the production method, after the reaction step of reacting at 60 to 120 ° C., water and C _5-10 alkane are added to the reaction mixture to extract the alkoxyalkanecarboxylic acid ester into the C _5-10 alkane phase; And a step of isolating the extracted alkoxyalkanecarboxylic acid ester by vacuum distillation.

The above production method comprises reacting 3-halo-2,2-dimethylpropionic acid ester with a metal alkoxide in N, N-dialkyl-C _1-2 acylamine to neutralize or acidify the reaction mixture. _{Alternatively} , water and C _5-10 alkane may be mixed to extract 3-alkoxy-2,2-dimethylpropionic acid ester into the organic phase, and the extract may be concentrated and distilled under reduced pressure.

  In the present invention, since the haloalkanecarboxylic acid ester and the metal alkoxide are reacted in a liquid phase reaction system in an aprotic polar solvent, a highly pure alkoxyalkanecarboxylic acid ester can be produced in a high yield. Furthermore, the reaction can proceed smoothly even under mild conditions, and an alkoxyalkanecarboxylic acid ester can be produced easily and efficiently even on an industrial scale.

  In the present invention, an alkoxyalkanecarboxylic acid ester is produced by reacting a haloalkanecarboxylic acid ester with a metal alkoxide in an aprotic polar solvent.

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

In formula (I), X represents a halogen atom. 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 X include halogen atoms such as fluorine, chlorine, bromine and iodine atoms. Preferred halogen atoms are bromine and iodine atoms from the viewpoint of reactivity, and chlorine atoms from the viewpoint of low cost. In the case of a chlorine atom, the reactivity generally decreases, but the reaction system of the present invention is excellent in that the target compound can be obtained in a high yield.

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. In this case, the reaction proceeds smoothly and an alkoxyalkanecarboxylic acid ester can be produced in a high yield.

  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 haloalkanecarboxylic acid ester represented by the above formula (I) include 3-halo-2,2-dimethylpropionic acid ester. Specific examples include isobutyl 3-chloro-2,2-dimethylpropionate. Haloalkanecarboxylic acid esters can be used alone or in combination of two or more. Of these, 3-halo-2,2-dimethylpropionic acid ester (particularly isobutyl 3-chloro-2,2-dimethylpropionate) is preferred.

  The metal alkoxide is not particularly limited, and examples thereof include a compound represented by the following formula (II).

M (OR ⁴ ) _k (II)
In the formula, M represents a metal, R ⁴ represents an alkyl group, and k represents the valence of M.

  Examples of the metal (M) of the metal alkoxide include alkali metals (M: Li, Na, K, etc.), alkaline earth metals (M: Be, Mg, Ca, Sr, Ba, etc.), transition metals (periodic table). And Ib, IIb, IIIb, IVb, Vb, VIb, VIIb, and Group 8 metals (M: Ti, Zr, V, Mn, Co, Cu, etc.).

There is no particular limitation on the alkyl groups of the metal alkoxide (R ^4), for example, linear, may be either branched or cyclic. Examples of the alkyl group include C _1-6 such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, and hexyl group. Examples thereof include a linear or branched alkyl group, a C _4-10 cycloalkyl group such as a cyclopentyl group and a cyclohexyl group. The alkyl group may be, for example, a linear or branched C _1-6 alkyl group such as an ethyl group, an n-propyl group, or an isobutyl group (for example, a linear or branched C _{3-6 group). 5} alkyl groups and linear or branched C ₄ alkyl groups).

  Examples of the metal alkoxide include alkali metal alkoxide, alkaline earth metal alkoxide, and transition metal alkoxide.

Specific examples of the alkali metal alkoxide include, for example, lithium alkoxide (lithium C _1-5 alkoxide such as lithium methoxide, lithium ethoxide, lithium propoxide, lithium isopropoxide and lithium butoxide), sodium alkoxide (sodium methoxide). Sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium butoxide, sodium _C1-5 alkoxide such as sodium isobutoxide, etc., potassium alkoxide (potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide) And potassium C _1-5 alkoxide such as potassium butoxide).

Specific examples of the alkaline earth metal alkoxide include, for example, magnesium alkoxide (magnesium dimethoxide, magnesium diethoxide, magnesium di n-propoxide, magnesium diisopropoxide, magnesium di n-butoxide, magnesium di sec-butoxide, Magnesium di C _1-5 alkoxide such as magnesium di-tert-butoxide), calcium alkoxide corresponding to magnesium alkoxide, strontium alkoxide, barium alkoxide and the like.

Specific examples of transition metal alkoxides include titanium alkoxides (titanium C _1-5 alkoxides such as titanium methoxide, titanium ethoxide, titanium n-propoxide, titanium isopropoxide, titanium n-butoxide, titanium isobutoxide, etc.) ) And the like. Further, zirconium alkoxide, vanadium alkoxide, manganese alkoxide, cobalt alkoxide, copper alkoxide and the like corresponding to titanium alkoxide are also included.

A metal alkoxide can be used individually or in combination of 2 or more types. Of the metal alkoxides, alkali metal C _1-5 alkoxides (eg, sodium C _1-4 alkoxides such as sodium isobutoxide) are preferred.

  In the reaction, the ratio (amount used) of the metal alkoxide is usually 1 to 2.5 mol, preferably 1 to 2 mol, more preferably 1.1 to 1.8 mol (especially with respect to 1 mol of the haloalkanecarboxylic ester). It may be about 1.2 to 1.7 mol). If the proportion of metal alkoxide is too high, the conversion rate is improved, but the proportion of by-products may increase.

Regarding the haloalkane carboxylic acid ester and the metal alkoxide, R ^{3 of the} haloalkane carboxylic acid ester represented by the above formula (I) and R ^{4 of the} metal alkoxide represented by the above formula (II) are the same alkyl group (for example, isobutyl A linear or branched C _1-6 alkyl group such as a group). In this case, generation of by-products can be prevented.

  Regarding the reaction solvent, generally, the alcohol used in the preparation of the metal alkoxide is often used as the solvent for the Williamson ether synthesis method. However, alcohols (methanol, ethanol, n-propanol, 2-propanol, n- When a protic polar solvent such as butanol, isobutanol, monohydric alcohols such as sec-butanol and t-butanol, and polyhydric alcohols such as ethylene glycol and diethylene glycol is used alone, the reaction rate may be slow. . Even in the production method of the present invention, the alcohols are not suitable because the reaction is slow or the metal alkoxide is not sufficiently dissolved. Therefore, an aprotic polar solvent is used in the reaction in the present invention.

  Examples of the aprotic polar solvent include amide solvents (chain amides such as N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, and cyclic amides such as N-methylpyrrolidone). ), Nitrile solvents (aliphatic nitriles such as acetonitrile and propionitrile, aromatic nitriles such as benzonitrile, etc.), sulfoxide solvents (dimethyl sulfoxide and the like), and the like. These solvents may be used alone or in combination of two or more, and may be combined with the alcohols.

Among these solvents, amide solvents, for example, N, N-dialkyl-C _1-2 acylamine (particularly N, N-dimethyl-C _1-2 acylamine) such as N, N-dimethylformamide may be used. Many. In addition, aprotic polar solvents (for example, amide solvents such as chain amides) are often used alone, and for example, N, N-dimethylformamide may be used alone.

  In the reaction, the proportion (amount of use) of the aprotic polar solvent is not particularly limited, but from the viewpoint of the isolation efficiency of the target compound, for example, about 1 to 20 parts by weight with respect to 1 part by weight of the haloalkanecarboxylic acid ester. 2 to 15 parts by weight (for example, 4 to 12.5 parts by weight), preferably 3 to 10 parts by weight (for example, 5 to 7 parts by weight), and more preferably 4 to 8 parts by weight (for example, 5.5 to 6.5 parts by weight).

  In the reaction, iodine compounds such as iodine alkali metal salts (potassium iodide, sodium iodide, etc.) may be added from the viewpoint that improvement in reactivity can be expected when the substrate is at a low concentration.

  The reaction can be performed, for example, by stirring in a liquid phase system at a predetermined temperature. The reaction temperature can usually be selected from 60 ° C. or higher (for example, 60 to 120 ° C.), preferably 70 to 100 ° C. (for example, 70 to 90 ° C.), and more preferably about 75 to 85 ° C. If it is less than 60 degreeC, progress of reaction may become slow.

  The reaction time is not particularly limited, but for example, 5 to 40 hours (for example, 5 to 30 hours), preferably 10 to 35 hours (for example, 10 to 28 hours), more preferably 20 to 30 hours (for example, 20 to 20 hours). 27 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.

  The reaction can be carried out by introducing each component all at once or sequentially into a reaction system. For example, a solution in which a metal alkoxide is dissolved in an aprotic polar solvent is prepared in advance, and the prepared solution and a haloalkanecarboxylic acid ester are prepared. Can be mixed with stirring to proceed. In this case, the reaction can proceed smoothly and the target compound can be obtained in high yield.

By the reaction, an alkoxyalkanecarboxylic acid ester in which the halogen atom of the haloalkanecarboxylic acid ester is substituted with the alkoxy group of the metal alkoxide can be produced. For example, by reacting the haloalkanecarboxylic acid ester represented by the above formula (I) with the metal alkoxide represented by the above formula (II), the halogen atom (X) is substituted with an alkoxy group (OR ⁴ ), An alkoxyalkanecarboxylic acid ester (3-alkoxy-2,2-dimethylpropionic acid ester or the like) represented by the following formula (III) is synthesized.

R ^{1 to} R ⁴ , m and n in the formula are the same as described above.

  The reaction mixture may be subjected to an isolation and purification step as it is, but after the reaction is completed, the reaction mixture is often neutralized or acidified and then isolated and purified. For neutralization or acidification, an organic acid (such as acetic acid) may be used in addition to an inorganic acid (such as hydrochloric acid or sulfuric acid). Neutralization or acidification can be performed by adding an acid until the pH is 7 or less (for example, 3 to 7), preferably 6 or less (4 to 6).

  After the reaction, the alkoxyalkanecarboxylic 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 acid aqueous solution (such as hydrochloric acid) used for neutralization or acidification 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, aliphatic hydrocarbons (for example, heptane), aromatic hydrocarbons (for example, toluene), and aliphatic chain ethers (for example, diisopropyl ether) are often used. Preferred organic solvents are C _5-10 alkanes such as heptane, especially C _6-8 alkanes.

For example, water and C _5-10 alkane (such as heptane) are added to the reaction mixture to extract the target compound into the organic phase, the organic phase is concentrated, and C _5-10 alkane (such as heptane) is converted to 10 to 10 After distilling off at 30 to 45 ° C. under reduced pressure of 100 hPa (for example, 50 hPa), the alkoxyalkanecarboxylic acid ester can be isolated by distillation under reduced pressure. The reduced pressure in the vacuum distillation may be 1-100 hPa, preferably 10-80 hPa (eg, 20-70 hPa), more preferably 30-60 hPa (particularly 40-50 hPa). Moreover, the temperature in vacuum distillation is 30-150 degreeC normally, Preferably it is 80-140 degreeC, More preferably, about 110-130 degreeC may be sufficient.

  In the present invention, a high-purity alkoxyalkanecarboxylic acid ester can be produced in a high yield, and the resulting alkoxyalkanecarboxylic acid ester is used for pharmaceuticals (for example, cephalosporin antibiotics, proton pump inhibitors, etc.), agricultural chemicals, It can be used as an intermediate for fine chemicals such as 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 3-isobutoxy-2,2-dimethylpropionate isobutyl)
Sodium isobutoxide (39.6 g, 0.412 mol), N, N-dimethylformamide (816.2 g, 11.2 mol), potassium iodide (68.5 g, 0.412 mol) were added to the reactor, and 80 ± 5 The mixture was heated to 0 ° C. to completely dissolve sodium isobutoxide. Subsequently, isobutyl 3-chloro-2,2-dimethylpropionate (66.2 g, 0.344 mol) was added dropwise, and the mixture was stirred at 80 ° C. for 11 hours. The reaction was traced by gas chromatography (GC) (GC-14A, column CBP-10, manufactured by Shimadzu Corporation), and after confirming disappearance of isobutyl 3-chloro-2,2-dimethylpropionate, heating was stopped. And allowed to cool to 25 ° C. Subsequently, the mixture was acidified with 1N hydrochloric acid (500.0 g, 0.10 mol) until the pH became 2 or less, and then heptane (340.0 g, 3.40 mol) was added for extraction. The separated heptane layer was washed with water and concentrated to distill off heptane at 30 to 45 ° C. under reduced pressure of 50 hPa, and then distilled under reduced pressure at 125 ° C. and 50 hPa to give isobutyl 3-isobutoxy-2,2-dimethylpropionate. Obtained in a yield of 37.4%.

Example 2
(Synthesis of 3-isobutoxy-2,2-dimethylpropionate isobutyl)
Sodium isobutoxide (84.6 g, 0.880 mol), N, N-dimethylformamide (614.4 g, 8.41 mol), potassium iodide (103.1 g, 0.621 mol) were added to the reactor, and 80 ± 5 The mixture was heated to 0 ° C. to completely dissolve sodium isobutoxide. Subsequently, isobutyl 3-chloro-2,2-dimethylpropionate (99.7 g, 0.517 mol) was added dropwise, followed by stirring at 80 ° C. for 27 hours. The reaction was traced by gas chromatography (GC) (GC-14A, column CBP-10, manufactured by Shimadzu Corporation), and after confirming disappearance of isobutyl 3-chloro-2,2-dimethylpropionate, heating was stopped. And allowed to cool to 25 ° C. Subsequently, the mixture was acidified with 1N hydrochloric acid (500.0 g, 0.10 mol) until the pH became 3 or less, and then heptane (250.0 g, 2.49 mol) was added for extraction. The separated heptane layer was washed with water and concentrated to distill off heptane at 30 to 45 ° C. under a reduced pressure of 50 hPa, and then distilled under reduced pressure at 125 ° C. and 50 hPa to give isobutyl 3-isobutoxy-2,2-dimethylpropionate. Obtained in a yield of 65.1%.

Example 3
(Synthesis of 3-isobutoxy-2,2-dimethylpropionate isobutyl)
Sodium isobutoxide (167.9 g, 1.75 mol) and N, N-dimethylformamide (1220.2 g, 16.7 mol) were added to the reactor and heated to 80 ± 5 ° C. to completely dissolve sodium isobutoxide. . Subsequently, isobutyl 3-chloro-2,2-dimethylpropionate (198.0 g, 1.028 mol) was added dropwise, followed by stirring at 80 ° C. for 14 hours. The reaction was traced by gas chromatography (GC) (GC-14A, column CBP-10, manufactured by Shimadzu Corporation), and after confirming disappearance of isobutyl 3-chloro-2,2-dimethylpropionate, heating was stopped. And allowed to cool to 25 ° C. Subsequently, the mixture was acidified with 1N hydrochloric acid (900.0 g, 0.90 mol) until the pH became 4 or less, and then heptane (500.0 g, 4.99 mol) was added for extraction. The separated heptane layer was washed with water and concentrated to distill off heptane at 30 to 45 ° C. under a reduced pressure of 50 hPa, and then distilled under reduced pressure at 125 ° C. and 50 hPa to give isobutyl 3-isobutoxy-2,2-dimethylpropionate. Obtained in a yield of 77.8%.

Comparative Example 1
(Synthesis of 3-isobutoxy-2,2-dimethylpropionate isobutyl)
Sodium isobutoxide (0.60 g, 0.006 mol) and toluene (11.2 g, 0.12 mol) were added to the reactor, and the mixture was heated to 80 ± 5 ° C. to completely dissolve sodium isobutoxide. Subsequently, isobutyl 3-chloro-2,2-dimethylpropionate (1.0 g, 0.005 mol) was added dropwise, followed by stirring at 80 ° C. for 6 hours. Only trace amounts of isobutyl 3-isobutoxy-2,2-dimethylpropionate, which was subjected to gas chromatography (GC) tracking, were obtained.

Comparative Example 2
(Synthesis of 3-isobutoxy-2,2-dimethylpropionate isobutyl)
Sodium isobutoxide (0.60 g, 0.006 mol) and pyridine (12.7 g, 0.16 mol) were added to the reactor and heated to 80 ± 5 ° C. to completely dissolve sodium isobutoxide. Subsequently, isobutyl 3-chloro-2,2-dimethylpropionate (1.0 g, 0.005 mol) was added dropwise, followed by stirring at 80 ° C. for 6 hours. Only trace amounts of isobutyl 3-isobutoxy-2,2-dimethylpropionate, which was subjected to gas chromatography (GC) tracking, were obtained.

Comparative Example 3
(Synthesis of 3-isobutoxy-2,2-dimethylpropionate isobutyl)
Sodium isobutoxide (0.60 g, 0.006 mol) and tetrahydrofuran (11.03 g, 0.15 mol) were added to the reactor and heated to 80 ± 5 ° C. to completely dissolve the sodium isobutoxide. Subsequently, isobutyl 3-chloro-2,2-dimethylpropionate (1.0 g, 0.005 mol) was added dropwise, followed by stirring at 80 ° C. for 6 hours. Only trace amounts of isobutyl 3-isobutoxy-2,2-dimethylpropionate, which was subjected to gas chromatography (GC) tracking, were obtained.

Comparative Example 4
(Synthesis of 3-isobutoxy-2,2-dimethylpropionate isobutyl)
Sodium isobutoxide (0.60 g, 0.006 mol) and isobutanol (10.38 g, 0.14 mol) were added to the reactor and heated to 80 ± 5 ° C. to completely dissolve sodium isobutoxide. Subsequently, isobutyl 3-chloro-2,2-dimethylpropionate (1.0 g, 0.005 mol) was added dropwise, followed by stirring at 80 ° C. for 6 hours. Only trace amounts of isobutyl 3-isobutoxy-2,2-dimethylpropionate, which was subjected to gas chromatography (GC) tracking, were obtained.

Claims (6)

  A method for producing an alkoxyalkanecarboxylic acid ester, comprising reacting a haloalkanecarboxylic acid ester with a metal alkoxide in an aprotic polar solvent.   The method according to claim 1, wherein the aprotic polar solvent is an amide solvent, and the haloalkanecarboxylic acid ester is 3-halo-2,2-dimethylpropionic acid ester.   The aprotic polar solvent is N, N-dimethylformamide, the haloalkanecarboxylic acid ester is 3-chloro-2,2-dimethylpropionic acid ester, and the metal alkoxide is an alkali metal alkoxide. Production method.   The ratio of the metal alkoxide is 1 to 2.5 moles with respect to 1 mole of the haloalkanecarboxylic acid ester, and the ratio of the aprotic polar solvent is 4 to 12.5 parts by weight with respect to 1 part by weight of the haloalkanecarboxylic acid ester. The manufacturing method in any one of Claims 1-3. After the reaction step of reacting at a reaction temperature of 60 to 120 ° C., water and C _5-10 alkane are added to the reaction mixture to extract the alkoxyalkanecarboxylic acid ester into the C _5-10 alkane phase, and the extracted alkoxy The process according to any one of claims 1 to 4, comprising a step of isolating the alkanecarboxylic acid ester by distillation under reduced pressure. In N, N-dialkyl-C _1-2 acylamine, 3-halo-2,2-dimethylpropionic acid ester and metal alkoxide are reacted to neutralize or acidify the reaction mixture, and then water and C _5. The production method according to any one of claims 1 to 5, wherein _-10 alkane is mixed to extract 3-alkoxy-2,2-dimethylpropionic acid ester into an organic phase, the extract is concentrated and distilled under reduced pressure.