JP2007302591A - Method for producing 1,2-propanediol acetal derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method capable of producing a desired 1,2-propanediol acetal derivative by few steps. <P>SOLUTION: (1) The method for producing a compound of formula (1) [wherein R<SP>1</SP>and R<SP>2</SP>are independently H, a linear or branched chain 1-6C alkyl or phenyl, or R<SP>1</SP>and R<SP>2</SP>are combined to be a 4-7C methylene; and R<SP>3</SP>is H or methyl] comprises acetalization of a 3-halogeno-1,2-propanediol compound in the presence of an acid catalyst, azidation and catalytic hydrogenation. (2) The method for producing a compound of formula (6) [wherein R<SP>1</SP>and R<SP>2</SP>are same as those mentioned above] comprises acetalization of a 3-halogeno-2-methyl-1,2-propanediol in the presence of an acid catalyst, and, reaction with a metal carboxylate and deacylation, or reaction with an alkoxide and catalytic hydrogenation. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a method for producing a 3-amino-1,2-propanediol acetal compound, particularly an optically active substance thereof, which can be an important synthetic intermediate for pharmaceuticals, agricultural chemicals and the like. The present invention also relates to 3-amino-2-methyl-1,2-propanediol acetonide, which is one of 3-amino-1,2-propanediol acetal compounds.

  The present invention also relates to a method for producing 1,3-dioxolane-4-methyl-4-methanol derivatives useful as synthetic intermediates for pharmaceuticals, agricultural chemicals and the like, particularly optically active substances thereof.

  Conventionally, the following general formula (1)

[Wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a phenyl group, or R ¹ and R ² are terminals thereof. Represents a methylene group having 4 to 7 carbon atoms formed by bonding, and R ³ represents a hydrogen atom or a methyl group. ]
As a method for producing an optically active 3-amino-1,2-propanediol acetal represented by the following formula:

The following four examples have been reported in the production method of optically active 3-amino-1,2-propanediol acetonide represented by:
(a) After ring opening of 3-hydroxy-γ-butyrolactone with ammonia, the diol of 3,4-dihydroxybutyric acid amide thus obtained is acetonated, and the reaction product is reacted with hypohalite in the presence of a base. And obtaining 3-amino-1,2-propanediol acetonide by Hoffman rearrangement (Patent Document 1).
(b) A method of obtaining 3-amino-1,2-propanediol acetonide by mesylation, azidation, and hydrogenolysis of glycerol acetonide (Non-patent Document 1).
(c) Method for obtaining 3-amino-1,2-propanediol acetonide obtained by reduction, tosylation, azidation, and hydrogenolysis of glyceraldehyde obtained by oxidative cleavage of L-ascorbic acid (Non-patent document 2).
(d) A method in which 3-amino-1,2-propanediol acetonide is obtained by oximation of glyceraldehyde obtained by oxidative cleavage of D-mannitol followed by hydride reduction (Non-patent Document 2).
Etc. are known.

  However, these production methods have the following industrial problems. That is, the method (a) was obtained by treating maltose monohydrate with hydrogen peroxide in an aqueous sodium hydroxide solution to obtain 3-hydroxy-γ-butyrolactone as a starting material (S). -3,4-Dihydroxybutanoic acid must be acid-treated under heating, or alternatively, malic acid must be esterified, then converted to a monoester with sodium borohydride in the presence of lithium chloride, and then acid-treated. Thus, there is a problem that a dangerous peroxide is used or the process is long.

  In the method (b), it is necessary to react glycerin with an acetonating agent in order to obtain glycerol acetonide. In this case, a product acetalized with hydroxyl groups at the 1st and 2nd positions of glycerin; Since a mixture with the product acetalized with the hydroxyl groups at the 1-position and the 3-position is obtained, it is very difficult to separate them. In this method, only racemates can be synthesized.

  In the methods (c) and (d), it is necessary to oxidatively cleave L-ascorbic acid or D-mannitol with a stoichiometric amount of lead tetraacetate or sodium periodate, which is problematic in terms of safety and cost. is there.

  Furthermore, in the methods (a), (c) and (d), although a carbohydrate raw material obtained from a natural resource can be used, the desired optically active substance is a stereoisomer opposite to the optically active substance obtained from a natural product. In this case, it is difficult to obtain raw materials.

  For these reasons, conversion to a larger production scale is made difficult, and improvement has been desired.

  Optically active 1,3-dioxolane-4-methyl-4-methanol derivatives are used as synthetic intermediates for pharmaceuticals, agricultural chemicals and the like. In particular, the carbon at the 4-position is a quaternary carbon. In recent years, its usefulness as a pharmaceutical has been pointed out because of its unique physiological activity derived from its structure, and has attracted attention. As for the production method, a method of optical resolution using an enzyme, a method of utilizing an asymmetric catalytic reaction, a method of using an asymmetric auxiliary group, and a method of obtaining from commercially available optically active 2-methylglycidol are known.

The following methods are known as optical resolution methods using enzymes.
(A) A method in which a racemic ester of 1,3-dioxolane-4-methyl-4-methanol is asymmetrically hydrolyzed in the presence of an enzyme (Patent Document 2, Non-Patent Document 3). (B) After epoxidizing diacetate of 2-methylene-1,3-propanediol, it is asymmetrically hydrolyzed in the presence of the enzyme, silylation of the released hydroxyl group, hydrogenation reaction of the epoxy group, and acetal And obtained by further desilylation (Non-patent Document 4).
(C) A method in which racemic 2-methylglycidyl benzyl ether is asymmetrically hydrated in the presence of an enzyme to obtain an optically active diol derivative, acetalized and then debenzylated by hydrogenation (non-patented) Reference 5).

The following methods are known as methods utilizing asymmetric catalysis.
(D) A method obtained by subjecting 2-benzyloxymethylallyl alcohol to an asymmetric epoxidation reaction in the presence of a Sharpless catalyst, reducing the epoxy group, acetalizing, and debenzylating by hydrogenation (Non-patent Document 6) .
(E) A method obtained by converting a amide group into an ester group after a Sharpless asymmetric diol-forming reaction of methacrylic acid amide, acetalizing, and ester reduction (Non-patent Document 7).

The following methods are known as methods using an asymmetric auxiliary group.
(F) A method in which a racemic form of 1,3-dioxolane-4-methyl-4-methanol is reacted with camphanyl chloride, fractionated by HPLC, and obtained by hydrolysis (Non-patent Document 8).
(G) Reacting 1-menthone with 1,3-dihydroxyacetone, reacting the resulting acetal with a methyl Grignard reagent in a stereoselective manner, silylating the hydroxyl group, opening the acetal ring, and releasing the diol A method of removing l-menton unit by acetonide and treating with potassium t-butoxide (Non-patent Document 9).

  As a method of obtaining from commercially available optically active 2-methylglycidol, (h) Commercially available (S) -2-methylglycidol is converted into benzyl ether, diol-ized by hydration reaction, acetonide-ized, and debenzylated by hydrogenation. The method to obtain is known (nonpatent literature 10).

However, these synthesis methods have the following problems industrially. That is,
The methods (a), (b), and (c) for optical resolution using an enzyme require an aqueous medium, and it is necessary to isolate water-soluble 1,3-dioxolane-4-methyl-4-methanol. Generally, it is difficult, and even if the reaction is carried out most efficiently, the yield is up to 50%.

  The methods (d) and (e) using an asymmetric catalyst have a problem that the total yield is low because a multi-stage is required, the catalyst is difficult to obtain, and is expensive.

  The methods (f) and (g) using an asymmetric auxiliary group are multi-step, complicated in process, and are hardly industrially practical.

The method (h) using commercially available optically active 2-methylglycidol has a large number of steps, and is still not practical in view of industrialization.
Special table 2002-516893 J. Org. Chem., 59, 7503 (1994). Tetrahedron Asymmetry, 6, 1181 (1995). Japanese Patent No. 3012273 J. et al. Org. Chem. 58, 3980 (1993). Tetrahedron Lett. 33, 7015 (1992). Synlett, 2001, 111. Tetrahedron, 42, 5985 (1986). Tetrahedron: Asymmetry, 12, 1383 (2001. J. et al. Org. Chem. 48, 3592 (1983). J. et al. Org. Chem. 57, 720 (1992). J. et al. Am. Chem. Soc. 121, 2071 (1999).

  The first object of the present invention is to provide a method capable of producing a desired 3-amino-1,2-propanediol acetal with a small number of steps using readily available starting materials.

  It is a second object of the present invention to provide a method capable of producing a desired 1,3-dioxolane-4-methyl-4-methanol derivative with a small number of steps using readily available starting materials. And

In order to solve the above-mentioned problems, the present inventor repeated research and obtained the following knowledge.
(i) The following general formula (1)

[Wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a phenyl group, or R ¹ and R ² are terminals thereof. Represents a methylene group having 4 to 7 carbon atoms formed by bonding, and R ³ represents a hydrogen atom or a methyl group. ]
In the production of a 3-amino-1,2-propanediol acetal compound represented by the following general formula (2)

[Wherein, X represents a halogen atom, and R ³ represents a hydrogen atom or a methyl group. The compound is acetalized in the presence of an acid catalyst, further azidized, and further subjected to a catalytic hydrogenation reaction in the presence of the catalyst. A compound of the general formula (1) can be produced.
(ii) If an optically active form of the compound of the general formula (2) is used as a starting material, an optically active form of the compound of the general formula (1) can be easily obtained.
(iii) The following general formula (6)

[Wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a phenyl group, or R ¹ and R ² are terminals thereof. Represents a methylene group having 4 to 7 carbon atoms formed by bonding. ]
In producing a 1,3-dioxolane-4-methyl-4-methanol derivative represented by
The following general formula (7)

[Wherein X represents a halogen atom. ]
And a compound of the general formula (7) is reacted with an acetalizing agent in the presence of an acid catalyst in the presence of an acid catalyst. 8)

[Wherein, R ¹ , R ² and X are the same as above. ]
4-halogenomethyl-4-methyl-1,3-dioxolane derivative represented by
Next, the compound of the above formula (8) and the following general formula (9)

ROH (9)

[Wherein, R represents a linear or branched aliphatic acyl group having 2 to 5 carbon atoms, an aromatic ring, an alkyl group having 1 to 4 carbon atoms, a nitro group, a cyano group, a halogen atom, or a carbon number An aromatic acyl group, an aralkyl group having 7 to 12 carbon atoms, or an allyl group which may have 1 to 5 substituents selected from the group consisting of 1 to 4 alkoxy groups. ]
Is reacted with an alkali metal salt or alkaline earth metal salt of a carboxylic acid represented by the formula (9), or an alkali metal or alkaline earth metal alkoxide of an alcohol represented by the general formula (9). )

[Wherein, R, R ¹ and R ² are the same as above. ]
To obtain a compound represented by
Next, in the compound of the general formula (10), when R is an acyl group, deacylation is performed in the presence of a base, and when R is an aralkyl group or an allyl group, hydrogenation is performed in the presence of a reduction catalyst. Thus, the compound of the general formula (6) is obtained.
(ii) If an optically active form of the compound of the general formula (7) is used as a starting material, an optically active form of the compound of the general formula (6) can be easily obtained.

  The present invention has been completed based on the above findings, and provides the following production method and the like.

  Item 1. The following general formula (1)

[Wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a phenyl group, or R ¹ and R ² are terminals thereof. Represents a methylene group having 4 to 7 carbon atoms formed by bonding, and R ³ represents a hydrogen atom or a methyl group. ]
A process for producing a 3-amino-1,2-propanediol acetal compound represented by:
The following general formula (2)

[Wherein, X represents a halogen atom, and R ³ represents a hydrogen atom or a methyl group. ]
Is reacted with an acetalizing agent in the presence of an acid catalyst to give the following general formula (3):

[Wherein R ¹ , R ² , R ³ , and X are the same as above. A first step of obtaining a 3-halogeno-1,2-propanediol acetal compound represented by the formula:
By reacting the compound of the general formula (3) with an azidating agent, the following general formula (4)

[Wherein R ¹ , R ² and R ³ are the same as above]
A second step of obtaining a 3-azido-1,2-propanediol acetal compound represented by:
And a third step of obtaining the compound of the general formula (1) by catalytic hydrogenation of the compound of the general formula (4) in the presence of a reduction catalyst.

  Item 2. Item 2. The method according to Item 1, wherein the halogen atom in General Formula (2) is a chlorine atom or a bromine atom.

Item 3. Item 3. The method according to Item 1 or 2, wherein a compound that gives a compound in which R ¹ and R ² are both a methyl group, an ethyl group, or a phenyl group in the general formula (3) is used as an acetalizing agent.

  Item 4. Item 4. The method according to Item 3, wherein at least one selected from the group consisting of acetone, 2,2-dimethoxypropane, and 2-methoxypropene is used as the acetalizing agent.

  Item 5. Item 5. The method according to any one of Items 1 to 4, wherein the azidating agent is at least one compound selected from the group consisting of a metal azide, a silicon azide compound, and a phosphoryl azide compound.

  Item 6. Item 6. The method according to Item 5, wherein the azidating agent is at least one compound selected from the group consisting of sodium azide, trimethylsilyl azide, and diphenylphosphoryl azide.

  Item 7. Item 7. The method according to any one of Items 1 to 6, wherein the reduction catalyst is a noble metal catalyst.

  Item 8. Item 8. The method according to Item 7, wherein the noble metal catalyst is a palladium-based catalyst.

  Item 9. Item 1-8, wherein an optically active 3-amino-1,2-propanediol acetal compound is obtained by using an optically active substance as the 3-halogeno-1,2-propanediol compound represented by the general formula (2) The method according to any one.

  Item 10. Following formula (5)

3-amino-2-methyl-1,2-propanediol acetonide represented by:

Item 11.
The following general formula (6)

[Wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a phenyl group, or R ¹ and R ² are terminals thereof. Represents a methylene group having 4 to 7 carbon atoms formed by bonding. ]
A process for producing a 1,3-dioxolane-4-methyl-4-methanol derivative represented by
The following general formula (7)

[Wherein X represents a halogen atom. ]
In the presence of an acid catalyst, 3-halogeno-2-methyl-1,2-propanediol represented by the following general formula (8) is reacted.

[Wherein, R ¹ , R ² and X are the same as above. ]
A first step of obtaining a 4-halogenomethyl-4-methyl-1,3-dioxolane derivative represented by:
The compound of the above formula (8) and the following general formula (9)

ROH (9)

[Wherein, R represents a linear or branched aliphatic acyl group having 2 to 5 carbon atoms, an aromatic ring, an alkyl group having 1 to 4 carbon atoms, a nitro group, a cyano group, a halogen atom, and a carbon number. An aromatic acyl group, an aralkyl group having 7 to 12 carbon atoms, or an allyl group which may have 1 to 5 substituents selected from the group consisting of 1 to 4 alkoxy groups. ]
By reacting with an alkali metal salt or alkaline earth metal salt of a carboxylic acid represented by the above, or an alkali metal or alkaline earth metal alkoxide of an alcohol represented by the general formula (9) above, 10)

[Wherein, R, R ¹ and R ² are the same as above. ]
A second step of obtaining a compound represented by:
In the compound of the above general formula (10), when R is an acyl group, deacylation is performed in the presence of a base, and when R is an aralkyl group or an allyl group, hydrogenation is performed in the presence of a reduction catalyst. And a third step of obtaining a compound of the above general formula (6).

  Item 12. Item 12. The method according to Item 11, wherein the halogen atom in General Formula (7) is a chlorine atom or a bromine atom.

Item 13. Item 13. The method according to Item 11 or 12, wherein a compound that gives a compound in which R ¹ and R ² are both a methyl group, an ethyl group, or a phenyl group in the general formula (8) is used as an acetalizing agent.

  Item 14. Item 14. The method according to Item 13, wherein the acetalizing agent is at least one selected from the group consisting of acetone, 2,2-dimethoxypropane, and 2-methoxypropene.

  Item 15. The compound of the general formula (9) is a carboxylic acid, and in the third step, at least selected from the group consisting of alkali metal or alkaline earth metal carbonates and alkali metal or alkaline earth metal hydroxides as a base Item 15. The method according to any one of Items 11 to 14, wherein one type is used.

  Item 16. Item 16. The method according to any one of Items 11 to 15, wherein the compound of the general formula (9) is acetic acid, propionic acid, or benzoic acid.

  Item 17. Item 15. The method according to any one of Items 11 to 14, wherein the compound of the general formula (9) is an alcohol, and a noble metal catalyst is used as a reduction catalyst in the third step.

  Item 18. Item 18. The method according to Item 17, wherein the noble metal catalyst is a palladium-based catalyst.

  Item 19. An optically active 1,3-dioxolane-4-methyl-4-methanol derivative is obtained by using an optically active substance as the 3-halogeno-2-methyl-1,2-propanediol represented by the general formula (7). Item 19. The method according to any one of Items 11 to 18.

  According to the first production method of the present invention, 3-amino-1,2-propanediol acetal compound that can be an important intermediate for pharmaceuticals and agricultural chemicals, particularly its optically active substance, can be obtained by using easily available starting materials. Can be obtained in numbers. Each process is easy to operate and does not require the use of dangerous raw materials. The present invention makes it possible to produce 3-amino-1,2-propanediol acetal compounds, particularly optically active substances, on an industrial scale.

  By the second production method of the present invention, 1,3-dioxolane-4-methyl-4-methanol derivatives useful as synthetic intermediates for pharmaceuticals having specific physiological activity, particularly optically active forms thereof, can be easily obtained. The starting material can be used with a small number of steps. Each process is easy to operate and does not require the use of dangerous raw materials. According to the present invention, 1,3-dioxolane-4-methyl-4-methanol derivatives, particularly optically active substances, can be produced on an industrial scale.

Hereinafter, the present invention will be described in detail.
(I) Method for Producing 3-Amino-1,2-propanediol Acetal The first method of the present invention is the production of a 3-amino-1,2-propanediol acetal compound represented by the above general formula (1). Is the method.
As the starting material of the first step , the following general formula (2)

[Wherein, X represents a halogen atom, and R ³ represents a hydrogen atom or a methyl group. ]
The 3-halogeno-1,2-propanediol compound represented by these is used.

  Specific examples of X in the general formula (2) include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. A chlorine atom or a bromine atom is preferable because it becomes an easily available compound. A chlorine atom is most preferred.

The method for producing the compound of the general formula (2) is well known. In the above general formula (2), the compound in which R ³ is a methyl group will be described by taking 3-chloro-2-methyl-1,2-propanediol in which X is a chlorine atom as an example. It can be easily prepared by a conventional method such as a method in which it is oxidized to 2-methylepichlorohydrin and hydrated and cleaved under acidic conditions.

Further, in the above general formula (2), the compound in which R ³ is a hydrogen atom will be described by taking 3-chloro-1,2-propanediol, in which X is a chlorine atom, as an example, by oxidizing allyl chloride with peracetic acid or the like. Epichlorohydrin can be easily prepared by a conventional method such as a method of hydration cleavage under acidic conditions.

  Moreover, the optically active substance of General formula (1) can be obtained by using the optically active substance of the compound of said Formula (2).

The optically active substance (S form) of the compound in which R ³ is a methyl group in the general formula (2) will be described with reference to 3-chloro-2-methyl-1,2-propanediol in which X is a chlorine atom. It can be synthesized by the method described in Japanese Patent No. 2567430 (Japanese Patent Laid-Open No. 63-150234).

  Further, taking 3-chloro-2-methyl-1,2-propanediol where X is a chlorine atom as an example, the R isomer is composed of a racemic mixture, Pseudomonas sp. DS-K-436-1 strain (FERM BP-7079) or Pseudomonas sp. It can be obtained by contacting with OS-K-29 strain (FERM BP-994). In addition, S-form is composed of racemic mixture and Pseudomonas sp. DS-SI-5 strain (FERM BP-7080), Pseudomonas nitroreducence DS-S-RP8 strain (FERM BP-7793), or Alkaligenes sp. It can be obtained by contacting with DS-S-7G strain (FERM BP-3098). Moreover, you may make the microbial cell crushed material of these microorganisms, the enzyme extracted from the microbial cell, etc. contact a racemic mixture. The optical resolution proceeds by contact.

An optically active form of the compound in which R ³ is a hydrogen atom in the general formula (2) is commercially available.

  In the first step, by carrying out an acetalization reaction in which 3-halogeno-1,2-propanediol represented by the general formula (2) is reacted with an acetalizing agent in the presence of an acid catalyst, the following general formula (3)

[Wherein R ¹ , R ² , R ³ and X are the same as above]
3-halogeno-1,2-propanediol acetal represented by

Examples of the acetalizing agent include aldehyde reagents, ketone reagents, ketone dialkyl acetal reagents, and ketone enol ether reagents. Any of them reacts with the diol of the general formula (2), and in the general formula (3), R ¹ and R ² are each independently a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, Or what is necessary is just a compound which has a functional group which gives the compound which is a phenyl group or the C4-C7 methylene group formed by the terminal of each other couple | bonding.

  Examples of the aldehyde reagent include formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, valeraldehyde, capronaldehyde, benzaldehyde and the like.

  Examples of the ketone reagent include acetone, methyl ethyl ketone, diethyl ketone, cyclobutanone, cyclohexanone, cyclopentanone, cycloheptanone, benzophenone, acetophenone, propiophenone, butyrophenone, isobutyrophenone, valerophenone, isovalerophenone, pivalerophenone, benzophenone ( Diphenyl ketone)) and the like.

  Examples of the dialkyl acetal reagent for ketones include 2,2-dimethoxypropane and 2,2-dimethoxypentane.

  Examples of the enol ether reagent for ketones include 2-methoxypropene.

Among them, it is preferable to use an acetalizing reagent that can obtain a compound in which R ¹ and R ² are the same in general formula (3). In general formula (3), R ¹ and R ² are both methyl groups, It is more preferable to use an acetalizing reagent that can obtain a compound that is an ethyl group or a phenyl group. In particular, it is preferable to use an acetalizing reagent that can obtain a compound in which both R ¹ and R ² are methyl groups.

For example, in order to synthesize a compound in which R ¹ and R ² are both hydrogen atoms in general formula (3), formaldehyde may be used. To synthesize a compound in which R ¹ and R ² are both methyl groups May use acetone, 2,2-dimethoxypropane, and / or 2-methoxypropene, and benzophenone may be used to synthesize a compound in which R ¹ and R ² are both phenyl groups, and R ¹ Cyclohexanone may be used to synthesize a compound in which R ² and R ² form a 6-membered ring with the adjacent carbon.

  The amount of the acetalizing agent used is preferably about 1 to 2 equivalents and more preferably about 1.1 to 1.5 equivalents with respect to the 3-halogeno-1,2-propanediol compound represented by the general formula (2). preferable. If it is the said range, acetalization reaction will fully advance. Further, the acetalizing agent may be used as a solvent, and the amount of the acetalizing agent used in that case is 5 to 5 with respect to the 3-halogeno-1,2-propanediol compound represented by the general formula (2). The amount is preferably about 30 times (v / w), more preferably about 10 to 20 times (v / w). In addition, 1 time amount (v / w) here means using 1mL of a solvent with respect to 1g of 3-halogeno-1, 2-propanediol compounds.

As the acid catalyst used in the acetalization reaction, a known acid catalyst usually used in the acetalization reaction can be used without limitation. Such known acid catalysts include mineral acids such as sulfuric acid, hydrochloric acid, phosphoric acid; organic acids such as camphorsulfonic acid (CSA), p-toluenesulfonic acid, pyridinium p-toluenesulfonic acid (PPTS); Examples include Lewis acids such as boron trifluoride. A hydrogen ion type (H ⁺ type) ion exchange resin can also be used. Of these, mineral acids and organic acids are preferable, and sulfuric acid, hydrochloric acid, phosphoric acid, and p-toluenesulfonic acid are more preferable. Hydrate may be sufficient as p-toluenesulfonic acid. An acid catalyst can be used individually by 1 type or in mixture of 2 or more types.

  The amount of the acid catalyst used for the acetalization reaction is not particularly limited, but is about 0.2 to 20 mol% with respect to the 3-halogeno-1,2-propanediol compound represented by the general formula (2). Preferably, about 1-10 mol% is more preferable.

  The acetalization reaction may be performed without a solvent, or a solvent may be used. It is preferable to carry out without a solvent because there is no fear of hindering the reaction site. However, a solvent may be used when the viscosity of the reaction solution is high and stirring is difficult. As the solvent, known solvents can be used without limitation except for those that react with the acetalizing agent, for example, glycols such as ethylene glycol. Such solvents include dichloromethane, 1,2-dichloroethane, n-hexane, n-heptane, toluene, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethyl. Examples include formamide, dimethyl sulfoxide, and acetone. A solvent can be used individually by 1 type or in mixture of 2 or more types.

  The acetalization reaction can be performed at 0 ° C. to the reflux temperature of the solvent. Moreover, reaction time should just be normally about 1 to 12 hours.

The compound of General formula (3) produces | generates in a reaction liquid by the said reaction. The compound of the general formula (3) may be isolated by distilling off the solvent or using partition chromatography or the like.
Second Step In the second step, the compound of the above general formula (3) is azidated using an azidating agent, whereby the following general formula (4)

[Wherein R ¹ , R ² and R ³ are the same as above]
A 3-azido-1,2-propanediol acetal compound represented by the formula:

  As the azidating agent, a known azidating agent can be used without limitation. Examples of such known azidating agents include metal azides such as lithium azide and sodium azide; silicon azide compounds such as trimethylsilyl azide; and azide phosphoryl compounds such as diphenylphosphoryl azide. be able to.

  In terms of versatility, sodium azide, trimethylsilyl azide, and diphenylphosphoryl azide are preferable, and sodium azide is more preferable. An azidating agent can be used alone or in combination of two or more.

  About 1-2 equivalent is preferable with respect to the 3-halogeno-1, 2-propanediol acetal compound represented by General formula (3), and the usage-amount of an azidating agent is about 1.1-1.3 equivalent. More preferred. If it is the said range, azidation reaction will fully advance.

  The azidation reaction may be usually performed in a solvent. The type of the solvent is not particularly limited, but an aprotic polar solvent is preferable. Examples of the aprotic polar solvent include organic solvents such as acetone, acetonitrile, N, N-dimethylformamide, and dimethyl sulfoxide, and water. Among these, N, N-dimethylformamide and dimethyl sulfoxide are preferable. A solvent can be used individually by 1 type or in mixture of 2 or more types.

  The amount of the solvent used is preferably about 1 to 10 times, more preferably about 3 to 5 times the 3-halogeno-1,2-propanediol acetal represented by the general formula (3). If it is the range of the usage-amount of the said solvent, azidation reaction will fully advance.

  The reaction temperature can be about 60 to 160 ° C., for example. In particular, about 80-150 degreeC is preferable. If it is the said temperature range, azidation reaction will fully advance. The reaction time may be about 5 to 24 hours.

  The azidation reaction proceeds smoothly even without any additives. For example, when a compound in which X is a chlorine atom in the general formula (2) is used as a starting material, sodium bromide, potassium bromide, bromide By adding an alkali metal halide such as bromide such as cesium, sodium iodide, potassium iodide, iodide such as cesium iodide, the chlorine atom in the compound of the general formula (3) is a bromine atom or Substitution with an iodine atom makes the compound of general formula (3) more reactive.

  The alkali metal halide can be used at a ratio of about 1 to 2 equivalents with respect to the 3-halogeno-1,2-propanediol acetal compound represented by the general formula (3). If it is the said range, azidation reaction can fully be accelerated | stimulated.

The compound of General formula (4) produces | generates in a reaction liquid by the said reaction. After completion of the reaction, for example, the inorganic salt by-produced during the reaction is filtered off, water is added, the mixture is extracted with an organic solvent such as ethyl acetate, and concentrated under reduced pressure to separate the compound of the general formula (4). can do. In the case of further purification, the compound of general formula (4) may be isolated and purified by subjecting the concentrated residue to silica gel chromatography.
Third Step In the third step, the 3-azido-1,2-propanediol acetal compound of the general formula (4) is catalytically hydrogenated in the presence of a reduction catalyst to thereby produce the 3-amino-1 of the general formula (1). , 2-propanediol acetal is obtained. By this catalytic hydrogenation, the azide group of the compound of the general formula (4) is hydrocracked to an amino group.

  As the reduction catalyst, a known reduction catalyst used for the catalytic hydrogenation reaction can be used without limitation. Typical examples of such a reduction catalyst include noble metal catalysts such as palladium carbon, palladium alumina, palladium silica, platinum carbon, ruthenium carbon, and rhodium carbon. In particular, a palladium-based catalyst such as palladium carbon is more preferable because of its versatility. A reduction catalyst can be used individually by 1 type or in combination of 2 or more types.

  When a noble metal catalyst is used as the reduction catalyst, the noble metal content in the catalyst is preferably about 0.5 to 10% by weight. In the case of the above-mentioned palladium carbon, the palladium content is preferably about 5 to 10% by weight. If it is the said range, a catalytic hydrogenation reaction will fully advance. The precious metal content may exceed 10% by weight, but it is not economical. As the noble metal catalyst, a water-containing product of about 50% by weight can be used in order to improve safety.

  The amount of the reduction catalyst used is preferably about 0.5 to 10% by weight and about 1 to 5% by weight with respect to the 3-azido-1,2-propanediol acetal compound represented by the general formula (4). More preferred. If it is the said range, a catalytic hydrogenation reaction will fully advance.

  The catalytic hydrogenation reaction can be performed under hydrogen pressure or normal pressure. At that time, a mixed gas with an inert gas such as nitrogen or a rare gas can be used. When the reaction is carried out under hydrogen pressure, the container internal pressure is preferably about 0.1 to 10 MPa, more preferably about 0.5 to 10 MPa. When the reaction is carried out under normal pressure in an open system, it is not particularly limited. For example, a solvent-resistant hose such as a Teflon (registered trademark) tube may be inserted into the system, and bubbling may be performed through hydrogen gas with stirring. .

  The catalytic hydrogenation reaction may be usually performed in a solvent. The kind of solvent is not specifically limited, A well-known organic solvent can be used. Examples of such known organic solvents include methanol, ethanol, 2-propanol, ethyl acetate, n-hexane, n-heptane, toluene, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1, 4 -Dioxane, N, N-dimethylformamide and the like. Of these, ethyl acetate and methanol are preferable, and ethyl acetate is more preferable. A solvent can be used individually by 1 type or in combination of 2 or more types.

  The amount of the solvent used is preferably about 2 to 10 times, more preferably about 3 to 5 times the amount of the 3-azido-1,2-propanediol acetal compound represented by the above formula (4). If it is the said range, a catalytic hydrogenation reaction will fully advance.

  The reaction temperature of the catalytic hydrogenation reaction is preferably about −10 to 50 ° C., more preferably about 20 to 40 ° C. If it is the said range, a catalytic hydrogenation reaction will fully advance. The reaction time can be appropriately determined in relation to temperature, pressure and the like.

The compound of General formula (1) produces | generates in a reaction liquid by the said reaction. After completion of the reaction, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to separate the compound of general formula (1). In the case of further purification, the concentrated residue may be isolated and purified by, for example, vacuum distillation or partition chromatography.
(II) 3-Amino-2-methyl-1,2-propanediol acetonide In the first production method described above, a compound in which R ³ is a methyl group is used as the compound of the general formula (2), and acetalization is performed. By using acetone, 2,2-dimethoxypropane, and / or 2-methoxypropene as the agent, the following formula (5)

3-amino-2-methyl-1,2-propanediol acetonide is obtained.

This compound has an amino group or an acetonide group in its structure, and the acetonide group can easily undergo a deacetonide reaction under acidic conditions to obtain a 1,2-diol form. Furthermore, the alcohol moiety can be easily derived into a leaving group and can be developed into various structures. The carbon at the 4-position is a quaternary carbon, and has recently attracted attention in terms of its usefulness as a pharmaceutical and agricultural chemical because of its unique physiological activity derived from its structure. It becomes possible to obtain a containing compound.
(III) Method for Producing 1,3-Dioxolane-4-methyl-4-methanol Derivative The second production method of the present invention comprises the following general formula (6):

[Wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a phenyl group, or R ¹ and R ² are terminals thereof. Represents a methylene group having 4 to 7 carbon atoms formed by bonding. ]
A process for producing a 1,3-dioxolane-4-methyl-4-methanol derivative represented by
The following general formula (7)

[Wherein X represents a halogen atom. ]
In the presence of an acid catalyst, 3-halogeno-2-methyl-1,2-propanediol represented by the following general formula (8) is reacted.

[Wherein, R ¹ , R ² and X are the same as above. ]
A first step of obtaining a 4-halogenomethyl-4-methyl-1,3-dioxolane derivative represented by:
The compound of the above formula (8) and the following general formula (9)

ROH (9)

[Wherein, R represents a linear or branched aliphatic acyl group having 2 to 5 carbon atoms, an aromatic ring, an alkyl group having 1 to 4 carbon atoms, a nitro group, a cyano group, a halogen atom, or a carbon number An aromatic acyl group, an aralkyl group having 7 to 12 carbon atoms, or an allyl group which may have 1 to 5 substituents selected from the group consisting of 1 to 4 alkoxy groups. ]
Is reacted with an alkali metal salt or alkaline earth metal salt of a carboxylic acid represented by the formula (9), or an alkali metal or alkaline earth metal alkoxide of an alcohol represented by the general formula (9). )

[Wherein, R, R ¹ and R ² are the same as above. ]
A second step of obtaining a compound represented by:
In the compound of the above general formula (10), when R is an acyl group, deacylation is performed in the presence of a base, and when R is an aralkyl group or an allyl group, hydrogenation is performed in the presence of a reduction catalyst. And a third step of obtaining a compound of the above general formula (6).

  The reaction process of the method for producing a 1,3-dioxolane-4-methyl-4-methanol derivative of the present invention is illustrated as follows.

(In the formula, X, R ¹ , R ² and R are the same as above.)
The method for producing 3-halogeno-2-methyl-1,2-propanediol of the general formula (7) used as the starting material for the first step is well known. For example, when 3-chloro-2-methyl-1,2-propanediol in which X is a chlorine atom is described, methallyl chloride is oxidized with peracetic acid to give 2-methylepichlorohydrin, which is subjected to acidic conditions. It can be easily prepared by a conventional method such as a hydration cleavage method.

  If an optically active form of 3-halogeno-2-methyl-1,2-propanediol of the general formula (7) is used, 1,3-dioxolane-4-methyl-4-methanol of the general formula (6) An optically active derivative is obtained.

  The optically active form (S form) of the compound of the general formula (7) will be described by taking 3-chloro-2-methyl-1,2-propanediol where X is a chlorine atom as an example. Can be synthesized by the method described in JP-A 63-150234.

  Further, taking 3-chloro-2-methyl-1,2-propanediol where X is a chlorine atom as an example, the R isomer is composed of a racemic mixture, Pseudomonas sp. DS-K-436-1 strain (FERM BP-7079) or Pseudomonas sp. It can be obtained by contacting with OS-K-29 strain (FERM BP-994). In addition, S-form is composed of racemic mixture and Pseudomonas sp. DS-SI-5 strain (FERM BP-7080), Pseudomonas nitroreducence DS-S-RP8 strain (FERM BP-7793), or Alkaligenes sp. It can be obtained by contacting with DS-S-7G strain (FERM BP-3098). Moreover, you may make the microbial cell crushed material of these microorganisms, the enzyme extracted from the microbial cell, etc. contact a racemic mixture. The optical resolution proceeds by contact.

  When 3-halogeno-2-methyl-1,2-propanediol with high optical purity is used, no significant racemization reaction occurs during the reaction, and 1,3-dioxolane-4-methyl-4-methanol derivative with high optical purity Can be manufactured.

  In the first step, 3-halogeno-2-methyl-1,2-propanediol of the general formula (7) is acetalized in the presence of an acid catalyst to give 4-halogenomethyl- of the general formula (8). A 4-methyl-1,3-dioxolane derivative is obtained.

  Specific examples of X in the general formula (7) include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. A chlorine atom or a bromine atom is preferable because it becomes an easily available compound. A chlorine atom is most preferred.

  Examples of the acetalizing agent include those described for the first method of the present invention.

Among them, it is preferable to use an acetalizing reagent that can obtain a compound in which R ¹ and R ² are the same in general formula (3). In general formula (3), R ¹ and R ² are both methyl groups, It is more preferable to use an acetalizing reagent that can obtain a compound that is an ethyl group or a phenyl group. In particular, it is preferable to use an acetalizing reagent that can obtain a compound in which both R ¹ and R ² are methyl groups.

In the general formula (8), formaldehyde may be used to synthesize a compound in which both R ¹ and R ² are hydrogen atoms, and acetone is used to synthesize a compound in which both R ¹ and R ² are methyl groups. 2,2-dimethoxypropane or / and 2-methoxypropene may be used, and benzophenone may be used to synthesize a compound in which R ¹ and R ² are both phenyl groups, and R ¹ is hydrogen. Benzaldehyde may be used to synthesize a compound in which R ² is a phenyl group, and cyclohexanone may be used to synthesize a compound in which R ¹ and R ² form a 6-membered ring with the adjacent carbon. .

  The amount of the acetalizing agent used is preferably about 1 to 2 equivalents relative to 3-halogeno-2-methyl-1,2-propanediol represented by the general formula (7), 1.1 to 1.5 equivalents The degree is more preferred. If it is the said range, acetalization reaction will fully advance. Moreover, you may use an acetalizing agent as a solvent, and the usage-amount of the acetalizing agent in that case is 5-30 with respect to 3-halogeno-1, 2-propanediol represented by General formula (7). About twice the amount (v / w) is preferable, and about 10 to 20 times the amount (v / w) is more preferable. The 1-fold amount (v / w) here also means that 1 mL of the solvent is used per 1 g of the 3-halogeno-1,2-propanediol compound.

As the acid catalyst used in the acetalization reaction, a known acid catalyst usually used in the acetalization reaction can be used without limitation. Such known acid catalysts include mineral acids such as sulfuric acid, hydrochloric acid, phosphoric acid; organic acids such as camphorsulfonic acid (CSA), p-toluenesulfonic acid, pyridinium p-toluenesulfonic acid (PPTS); Examples include Lewis acids such as boron trifluoride. A hydrogen ion type (H ⁺ type) ion exchange resin can also be used. Of these, mineral acids and organic acids are preferable, and sulfuric acid, hydrochloric acid, phosphoric acid, and p-toluenesulfonic acid are more preferable. Hydrate may be sufficient as p-toluenesulfonic acid. An acid catalyst can be used individually by 1 type or in mixture of 2 or more types.

  Although the usage-amount of the acid catalyst used for acetalization reaction is not specifically limited, It is 0.2-20 mol with respect to 3-halogeno-2-methyl-1, 2-propanediol represented by General formula (7). % Is preferable, and about 1 to 10 mol% is more preferable.

  The acetalization reaction may be performed without a solvent, or a solvent may be used. It is preferable to carry out without a solvent because there is no fear of hindering the reaction site. However, a solvent may be used when the viscosity of the reaction solution is high and stirring is difficult. As the solvent, known solvents can be used without limitation except for those that react with the acetalizing agent, for example, glycols such as ethylene glycol. Such solvents include dichloromethane, 1,2-dichloroethane, acetone, n-hexane, n-heptane, toluene, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, N, N -Dimethylformamide, dimethyl sulfoxide, etc. are mentioned. A solvent can be used individually by 1 type or in mixture of 2 or more types.

  The acetalization reaction can be performed, for example, in the range of 0 ° C. to the reflux temperature of the solvent. Moreover, reaction time should just be normally about 1 to 12 hours.

By the above reaction, a 4-halogenomethyl-4-methyl-1,3-dioxolane derivative of the general formula (8) is generated in the reaction solution. The compound of the general formula (8) may be isolated by evaporating the solvent or using partition chromatography or the like.
Second Step In the second step, the compound of the general formula (8) and the general formula (9)
ROH (9)
[Wherein, R represents a linear or branched aliphatic acyl group having 2 to 5 carbon atoms, an aromatic ring, an alkyl group having 1 to 4 carbon atoms, a nitro group, a cyano group, a halogen atom, or a carbon number An aromatic acyl group, an aralkyl group having 7 to 12 carbon atoms, or an allyl group which may have 1 to 5 substituents selected from the group consisting of 1 to 4 alkoxy groups. ]
Is reacted with an alkali metal salt or alkaline earth metal salt of a carboxylic acid represented by the formula (9), or an alkali metal or alkaline earth metal alkoxide of an alcohol represented by the general formula (9). To obtain a compound represented by:

  This reaction may be usually performed in a solvent. The type of the solvent is not particularly limited. For example, aprotic polar solvents such as acetone, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, water; ester solvents such as ethyl acetate and butyl acetate; tetrahydrofuran, 1 Ether solvents such as 1,4-dioxane, 1,2-dimethoxyethane, diglyme, triglyme and diethylene glycol monomethyl ether; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; nitrile solvents such as acetonitrile; dichloroethane, A halogen type solvent such as 1,2-dichloroethane may be mentioned. Among these, an aprotic polar solvent is preferable. A solvent can be used individually by 1 type or in combination of 2 or more types.

  When R is an acyl group in the general formula (9), that is, when the compound of the general formula (9) is a carboxylic acid, 4-acyloxymethyl-4-methyl-1,3-dioxolane of the general formula (10) A derivative (R = acyl group) is obtained.

  The carboxylic acid of the general formula (9) includes a linear or branched aliphatic carboxylic acid having 2 to 5 carbon atoms; An aromatic carboxylic acid which may have 1 to 5 substituents selected from the group consisting of an atom and an alkoxy group having 1 to 4 carbon atoms is included. Examples of the aromatic ring include a benzene ring and a naphthalene ring.

  Among them, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, benzoic acid, 3-chlorobenzoic acid, 4-chlorobenzoic acid, 4-nitrobenzoic acid, 1-naphthoic acid, 2-naphthoic acid Acetic acid, propionic acid, and benzoic acid are more preferable. That is, in the general formula (9), a carboxylic acid in which R is an acetyl group, a propionyl group or a benzoyl group is preferable.

  Examples of the salt include sodium salt, potassium salt, calcium salt, barium salt and the like.

  Preferable examples of the carboxylate of the general formula (9) include sodium benzoate, potassium benzoate, sodium acetate, potassium acetate, sodium propionate, potassium propionate, calcium benzoate and barium benzoate.

  The amount of the alkali metal or alkaline earth metal salt of the carboxylic acid is preferably about 1 to 3 equivalents relative to the 4-halogenomethyl-4-methyl-1,3-dioxolane derivative of the general formula (8). About 2 equivalents are more preferable. If it is the said range, reaction will fully advance.

  The reaction temperature can be from 0 ° C to the reflux temperature of the solvent. If it is the said temperature range, reaction will fully advance. The reaction time may be about 5 to 24 hours.

  When R is an aralkyl group or an allyl group in the general formula (9), that is, when the compound of the general formula (9) is an arylalkyl alcohol or allyl alcohol, 4-alkoxymethyl-4- of the general formula (10) A methyl-1,3-dioxolane derivative (R = aralkyl or allyl group) is obtained.

  The alcohol of the general formula (9) includes phenylalkyl alcohol having an alkyl group having 1 to 6 carbon atoms, naphthylalkyl alcohol having an alkyl group having 1 to 2 carbon atoms, and allyl alcohol.

  Of these, phenylalkyl alcohols and allyl alcohols having an alkyl group having 1 to 6 carbon atoms are preferred. That is, an alcohol in which R is a phenylalkyl group having an alkyl group having 1 to 6 carbon atoms or an allyl group in the general formula (9) is preferable. In particular, benzyl alcohol and allyl alcohol are preferable.

  Examples of the metal alkoxide include lithium alkoxide, sodium alkoxide, potassium alkoxide, calcium alkoxide, barium alkoxide and the like. Of these, sodium alkoxide is preferable. Alkoxides may be commercially available, but may be unstable, so carbonates such as sodium carbonate, potassium carbonate, calcium carbonate; sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide It can be synthesized by reacting a metal hydride such as sodium hydride, lithium hydride or calcium hydride with an alcohol. Particularly preferred are hydroxides and metal hydrides.

  The amount of alkoxide used is preferably about 1 to 4 equivalents, more preferably about 1 to 2 equivalents, relative to the 4-halogenomethyl-4-methyl-1,3-dioxolane derivative of the general formula (8).

  The reaction in the second step proceeds smoothly even without any additives. For example, when a compound in which X is a chlorine atom in the general formula (7) is used as a starting material, sodium bromide, potassium bromide, By adding an alkali metal halide such as bromide such as cesium bromide, sodium iodide, potassium iodide, iodide such as cesium iodide, the chlorine atom in the compound of the general formula (8) is bromine. Substitution with an atom or iodine atom makes the compound of general formula (8) more reactive. Of these, sodium bromide is preferable. An additive can be used individually by 1 type or in combination of 2 or more types.

The compound of General formula (10) produces | generates in a reaction liquid by the said reaction. After completion of the reaction, the inorganic salt produced as a by-product during the reaction was filtered off, the solvent was distilled off, water was added to the residue, extracted with an organic solvent such as toluene, and concentrated under reduced pressure to give Compounds can be separated. In the case of further purification, the compound of general formula (10) may be isolated and purified from the concentrated residue using silica gel chromatography or the like.
Third Step In the third step, when R is an acyl group in the compound of the general formula (10), the 4-acyloxy-4-methyl-1,3-dioxolane derivative is deacylated with a base, The desired 1,3-dioxolane-4-methyl-4-methanol derivative of formula (6) is obtained.

  This reaction may be usually performed in a solvent. The solvent is not particularly limited as long as it is a polar solvent. Examples of such a solvent include alcohol solvents such as methanol, ethanol, propanol and butanol, ether solvents such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, and water. A solvent can be used individually by 1 type or in mixture of 2 or more types.

  Examples of the base include alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate and calcium carbonate, water of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide and barium hydroxide. An oxide etc. are mentioned. Of these, alkali metal carbonates such as sodium carbonate and potassium carbonate are preferred.

  The amount of the base used is preferably about 1 to 3 equivalents, more preferably about 1 to 1.5 equivalents, relative to the 4-acyloxy-4-methyl-1,3-dioxolane derivative of the general formula (10). If it is the said range, a deacylation reaction will fully advance.

  The reaction temperature can be about 0 ° C. to the reflux temperature of the solvent. If it is the said range, a deacylation reaction will fully advance. The reaction time can be about 1 to 24 hours.

  In the third step, when R is an aralkyl group or an allyl group in the compound of the general formula (10), the 4-alkoxy-4-methyl-1,3-dioxolane derivative of the general formula (10) is added to a hydrogen atmosphere. Among them, the target 1,3-dioxolane-4-methyl-4-methanol derivative of the general formula (6) is obtained by catalytic reduction, that is, hydrogenation in the presence of a reduction catalyst.

  As the reduction catalyst, a known reduction catalyst used for the catalytic hydrogenation reaction can be used without limitation. Typical examples of such a reduction catalyst include noble metal catalysts such as palladium carbon, palladium alumina, palladium silica, platinum carbon, ruthenium carbon, and rhodium carbon. In particular, a palladium-based catalyst such as palladium carbon is more preferable because of its versatility. A reduction catalyst can be used individually by 1 type or in combination of 2 or more types.

  When a noble metal catalyst is used as the reduction catalyst, the noble metal content in the catalyst is preferably about 0.5 to 10% by weight. In the case of the above-mentioned palladium carbon, the palladium content is preferably about 5 to 10% by weight. If it is the said range, a catalytic hydrogenation reaction will fully advance. The precious metal content may exceed 10% by weight, but it is not economical. As the noble metal catalyst, a water-containing product of about 50% by weight can be used in order to improve safety.

  The amount of the reduction catalyst used is preferably about 0.5 to 50% by weight, preferably 1 to 30% by weight, based on the 4-alkoxy-4-methyl-1,3-dioxolane derivative represented by the general formula (10). The degree is more preferred. If it is the said range, a catalytic hydrogenation reaction will fully advance.

  The catalytic hydrogenation reaction can be performed under hydrogen pressure or normal pressure. At that time, a mixed gas with an inert gas such as nitrogen or a rare gas can be used. When the reaction is carried out under hydrogen pressure, the container internal pressure is preferably about 0.1 to 10 MPa, more preferably about 0.5 to 10 MPa. When the reaction is carried out under normal pressure in an open system, there is no particular limitation. For example, a solvent-resistant hose such as a Teflon (registered trademark) tube may be inserted into the system, and bubbling may be performed through hydrogen gas with stirring. .

  The catalytic hydrogenation reaction may be usually performed in a solvent. The kind of solvent is not specifically limited, A well-known organic solvent can be used. Examples of such known organic solvents include methanol, ethanol, 2-propanol, ethyl acetate, n-hexane, n-heptane, toluene, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1, 4 -Dioxane, N, N-dimethylformamide and the like. Of these, ethyl acetate and methanol are preferable, and ethyl acetate is more preferable. A solvent can be used individually by 1 type or in combination of 2 or more types.

  The amount of the solvent used is preferably about 2 to 10 times, more preferably about 3 to 5 times the amount of the 4-alkoxy-4-methyl-1,3-dioxolane derivative represented by the above formula (10). preferable. If it is the said range, reaction will fully advance.

  The reaction temperature of the catalytic hydrogenation reaction is preferably about −10 to 50 ° C., more preferably about 20 to 40 ° C. If it is the said range, reaction will fully advance. The reaction time can be appropriately determined in relation to temperature, pressure and the like.

  By the above reaction, a 1,3-dioxolane-4-methyl-4-methanol derivative of the general formula (6) is generated in the reaction solution. After completion of the reaction, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to separate the compound of general formula (6). In the case of further purification, the concentrated residue may be isolated and purified by, for example, vacuum distillation or partition chromatography.

EXAMPLES Examples are shown below, but the present invention is not limited to these examples.
(I) Production of 3-amino-1,2-propanediol acetal compound

Example 1-1 Synthesis of (S) -4-aminomethyl-2,2-dimethyl-1,3-dioxolane (c))
First step (synthesis of (R) -4-chloromethyl-2,2-dimethyl-1,3-dioxolane (a))
In a 1 L four-necked flask, 180.0 g (99.8% ee, 1.628 mol) of (R) -3-chloro-1,2-propanediol (commercial product) and 220.5 g of 2,2-dimethoxypropane (2. 117 mol) and 15.5 g (81 mmol) of p-toluenesulfonic acid monohydrate were added and stirred at an internal temperature of 30 ° C. for 1 hour. Thereafter, 8.4 g (100 mmol) of sodium bicarbonate was added for neutralization, and the inorganic salt was separated by filtration. When methanol was distilled off under reduced pressure, the target product (R) -4-chloromethyl-2,2-dimethyl-1,3-dioxolane (220.7 g, 1.466 mol, yield 90.0%) was obtained. .

By subjecting the product to ¹ H-NMR, it was confirmed to be a compound represented by the following formula (a).

¹ H-NMR (CDCl ₃ , 270 MHz): δ 1.37 (3H, s), 1.44 (3H, s), 3.47 (1H, dd, J = 10.8, 7.6 Hz); 58 (1H, dd, J = 10.8, 4.3 Hz), 3.88 (1H, dd, J = 8.6, 5.1 Hz), 4.11 (1H, dd, J = 9.5) 6.5 Hz), 4.27-4.34 (1 H, m).
Second step (synthesis of (S) -4-azidomethyl-2,2-dimethyl-1,3-dioxolane (b))
Into a 1 L four-necked flask, 150.6 g (1.000 mol) of (R) -4-chloromethyl-2,2-dimethyl-1,3-dioxolane and 452 mL of N, N-dimethylformamide were added, and 78.0 g of sodium azide. (1.200 mmol) was added, and the mixture was stirred at an internal temperature of 110 ° C. for 20 hours. After completion of the reaction, the inorganic salt in the reaction mixture was filtered off, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and the combined organic layers were washed with 10% aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure to obtain 118.0 g (0.751 mol, yield 75.1%) of the desired product (S) -4-azidomethyl-2,2-dimethyl-1,3-dioxolane.

By subjecting the product to ¹ H-NMR, it was confirmed to be a compound represented by the following formula (b).

¹ H-NMR (CDCl ₃ , 270 MHz): δ 1.37 (3H, s), 1.47 (3H, s), 3.30 (1H, dd, J = 12.4, 5.1 Hz), 3, 41 (1H, dd, J = 12.7, 4.6 Hz), 3.78 (1H, dd, J = 8.4, 5.9 Hz), 4.07 (1H, dd, J = 8.6, 6.2 Hz), 4.28 (1 H, m).
Step 3 (Synthesis of (S) -4-aminomethyl-2,2-dimethyl-1,3-dioxolane (c))
In a 1 L four-necked flask, 118.0 g (0.751 mmol) of (S) -4-azidomethyl-2,2-dimethyl-1,3-dioxolane, 470 mL of ethyl acetate, 5.9 g of 5% palladium-carbon (NE CHEMCAT, 55.43 wt% water-containing product) was added. While stirring, hydrogen gas was blown into the reaction for 5 hours. After filtration, the filtrate was concentrated. The concentrated residue was distilled at an internal temperature of 100 ° C. or less and 5 mmHg, and the target product (S) -4-aminomethyl-2,2-dimethyl-1,3-dioxolane 88.7 g (0.676 mol, yield 90). 0.0%). The chemical purity (GC) was 99.8%, and the optical purity (GC) was 99.8% ee.

By subjecting the product to ¹ H-NMR, it was confirmed to be a compound of the following formula (c).

¹ H-NMR (CDCl ₃ , 270 MHz): δ 1.36 (3H, s), 1.43 (3H, s), 2.74-2.89 (2H, m), 3.67 (1H, dd, J = 7.8, 6.2 Hz), 4.04 (1H, dd, J = 7.6, 6.3 Hz), 4.08-4.18 (1H, m).

Example 1-2 Synthesis of ((R) -4-aminomethyl-2,2,4-trimethyl-1,3-dioxolane (f)
Preparation of (S) -3-chloro-2-methyl-1,2-propanediol 500 mL of a medium of 100 mL (pH 7.0) having a composition comprising 10 g / L of peptone, 10 g / L of yeast extract, and 10 g / L of glycerin It put into the Erlenmeyer flask with a baffle, and autoclaved at 121 degreeC for 15 minutes. Next, Pseudomonas sp. DS-SI-5 strain (International Deposit Number: FERM BP-7080) was inoculated into one platinum loop and cultured aerobically at 30 ° C. for 24 hours. The obtained culture broth was centrifuged to collect the cells.

In the Erlenmeyer flask, 100 mL of bacterial cells are suspended in 20 mM potassium phosphate buffer (pH 7.0), and racemic 3-chloro-2-methyl-1,2-propanediol is added to the suspension in 2.5%. (V / v) and 3.6% calcium carbonate were added and reacted at 30 ° C. and 120 rpm for 48 hours. After completion of the reaction, the reaction solution was taken out and the cells were removed by centrifugation to obtain a supernatant. The supernatant was concentrated with an evaporator and extracted with ether. Subsequently, after dehydration with anhydrous magnesium sulfate, ether was removed under reduced pressure, and (S) -3-chloro-2-methyl-1,2-propanediol (racemic 3-chloro-2-methyl-1,2) was removed. A residual ratio of 40.9% from propanediol and an optical purity of 99% ee) was obtained.
Step 1 (Synthesis of (S) -4-chloromethyl-2,2,4-trimethyl-1,3-dioxolane (d))
In a 1 L four-necked flask, 22.9 g (99.8% ee, 0.184 mol) of (S) -3-chloro-2-methyl-1,2-propanediol, 24.9 g of 2,2-dimethoxypropane (0 .239 mol) and 1.8 g (9.2 mmol) of p-toluenesulfonic acid monohydrate were added and stirred at an internal temperature of 30 ° C. for 0.5 hour. Thereafter, 0.9 g (11 mmol) of sodium bicarbonate was added for neutralization, and inorganic salts were separated by filtration. Methanol was distilled off under reduced pressure to obtain 27.2 g (0.165 mol, yield 89.9%) of the desired product (S) -4-chloromethyl-2,2,4-trimethyl-1,3-dioxolane. It was.

By subjecting the product to ¹ H-NMR, it was confirmed to be a compound of the following formula (d).

¹ H-NMR (CDCl ₃ , 270 MHz): δ 1.39 (3H, s), 1.42 (3H, s), 1.43 (3H, s), 3.41 (1H, dd, J = 10. 5, 0.5 Hz), 3.52 (1 H, d, J = 10.8 Hz), 3.73 (1 H, dd, J = 8.9, 1.1 Hz), 4.09 (1 H, d, J = 8.9 Hz).
Step 2 (Synthesis of (R) -4-azidomethyl-2,2,4-trimethyl-1,3-dioxolane (e))
In a 1 L four-necked flask, 26.0 g (0.158 mol) of (S) -4-chloromethyl-2,2,4-trimethyl-1,3-dioxolane, 23.7 g (0.158 mmol) of sodium iodide, N, N-dimethylformamide (78 mL) was added, sodium azide (12.3 g, 0.190 mmol) was added, and the mixture was stirred at an internal temperature of 140 ° C. for 20 hours. After completion of the reaction, the inorganic salt in the reaction mixture was filtered off, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and the combined organic layers were washed with 10% aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure to obtain 19.7 g (0.115 mol, yield 72.8%) of the target product (R) -4-azidomethyl-2,2,4-trimethyl-1,3-dioxolane. .

By subjecting the product to ¹ H-NMR, it was confirmed to be a compound of the following formula (e).

¹ H-NMR (CDCl ₃ , 270 MHz): δ 1.34 (3H, s), 1.41 (3H, s), 1.45 (3H, s), 3.23 (1H, d, J = 12. 4 Hz), 3.28 (1 H, d, J = 12.2 Hz), 3.71 (1 H, d, J = 8.9 Hz), 3.94 (1 H, d, J = 8.9 Hz).
Step 3 (Synthesis of (R) -4-aminomethyl-2,2,4-trimethyl-1,3-dioxolane (f))
In a 1 L four-necked flask, 19.5 g (0.114 mmol) of (R) -4-azidomethyl-2,2,4-trimethyl-1,3-dioxolane, 96.8 mL of ethyl acetate, 0.98 g of 5% palladium-carbon ( NE CHEMCAT, 55.43 wt% water-containing product) was added. While stirring, hydrogen gas was blown into the reaction for 5 hours. After filtration, the filtrate was concentrated. The concentrated residue was distilled at an internal temperature of 100 ° C. or less and 5 mmHg, and 14.0 g (0.096 mol, yield) of the target product (R) -4-aminomethyl-2,2,4-trimethyl-1,3-dioxolane. 84.5%). The chemical purity (GC) was 99.7%, and the optical purity (GC) was 99.8% ee.

The product was confirmed to be a compound represented by the following formula (f) by subjecting the product to ¹ H-NMR, mass spectrometry, elemental analysis, and specific rotation measurement.

¹ H-NMR (CDCl ₃ , 270 MHz): δ 1.29 (3H, s), 1.41 (6H, s), 2.71 (2H, s), 3.73 (1H, d, J = 8. 6 Hz), 3.91 (1H, d, J = 8.6 Hz).
_{LRMS m / z: Calcd for C} 7 H 15 NO 2 (M +) 145.
Found 145.
Anal. _{Calcd for C 7 H 15 NO 2} : C, 57.90; H, 10.41; N, 9.65
Found: C, 55.32; H, 10.26; N, 9.01
[α] _D ²⁰ = + 2.51 (MeOH, c = 1).

Example 1-3 (Synthesis of (R) -4-aminomethyl-2,2-diethyl-4-methyl-1,3-dioxolane (i))
Step 1 (Synthesis of (S) -4-chloromethyl-2,2-diethyl-4-methyl-1,3-dioxolane (g))
In a 1 L 4-necked flask, 180.0 g (99.2% ee, 1.445 mol) of (S) -3-chloro-2-methyl-1,2-propanediol prepared as described in Example 1-3. ), 161.8 g (1.878 mol) of diethyl ketone and 13.7 g (72 mmol) of p-toluenesulfonic acid monohydrate were added and stirred at an internal temperature of 30 ° C. for 3 hours. Thereafter, 7.6 g (90 mmol) of sodium bicarbonate was added for neutralization, and the inorganic salt was separated by filtration. When diethylketone was distilled off under reduced pressure, 243.9 g (0.876 mmol, yield) of (S) -4-chloromethyl-2,2-diethyl-4-methyl-1,3-dioxolane represented by the following formula (g) was obtained. 87.6%) was obtained as a slightly yellow oil.

Step 2 (Synthesis of (R) -4-azidomethyl-2,2-diethyl-4-methyl-1,3-dioxolane (h))
Into a 1 L four-necked flask, 192.7 g (1.000 mol) of (S) -4-chloromethyl-2,2-diethyl-4-methyl-1,3-dioxolane and 450 mL of N, N-dimethylformamide were added, and azination was performed. Sodium 78.0g (1.200mmol) was added, and it stirred at the internal temperature of 110 degreeC for 20 hours. After completion of the reaction, the inorganic salt in the reaction mixture was filtered off, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and the combined organic layers were washed with 10% aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure, and 156.0 g (0.783 mol, yield 78) of (R) -4-azidomethyl-2,2-diethyl-4-methyl-1,3-dioxolane represented by the following formula (h). .3%) was obtained.

Step 3 (Synthesis of (R) -4-aminomethyl-2,2-diethyl-4-methyl-1,3-dioxolane (i))
In a 1 L four-necked flask, 156.0 g (0.783 mmol) of (R) -4-azidomethyl-2,2-diethyl-4-methyl-1,3-dioxolane, 500 mL of ethyl acetate, 5.9 g of 5% palladium-carbon ( NE CHEMCAT, 55.43 wt% water-containing product) was added. While stirring, hydrogen gas was blown into the reaction for 7 hours. After filtration, the filtrate was concentrated. The concentrated residue was distilled at an internal temperature of 100 ° C. or less and 5 mmHg, and 124.8 g (0.720 mol, yield 92) of (R) -4-aminomethyl-2,2-diethyl-4-methyl-1,3-dioxolane. 0.0%). The chemical purity (GC) was 99.6% and the optical purity (GC) was 99.2% ee.

By being subjected to ¹ H-NMR, it was confirmed that it was a compound represented by the following formula (i).

¹ H-NMR (CDCl ₃ , 270 MHz): δ 0.96 (3H, t, J = 4.5 Hz), 0.98 (3H, t, J = 4.5 Hz), 1.29 (3H, s), 1.41 (4H, s), 2.71 (2H, s), 3.72 (1H, d, J = 8.5 Hz), 3.90 (1H, d, J = 8.5 Hz).

(II) Method for producing 1,3-dioxolane-4-methyl-4-methanol derivative
Example 2-1
(S) -3-Chloro-2-methyl-1,2-propanediol (117.72 g, 0.945 mol, 99.2% ee), acetone (prepared as described in Example 1-2) P-Toluenesulfonic acid monohydrate (1.79 g, 9.4 mmol) was added to a mixture of 1500 ml), and the mixture was stirred at 25 ° C. for 12 hours. After completion of the reaction, acetone was distilled off under reduced pressure, and the crude product was distilled to obtain 136.91 g (yield) of (S) -4-chloromethyl-2,2,4-trimethyl-1,3-dioxolane. 88%, boiling point 48 ° C. (5 mmHg)).

  Subsequently, sodium bromide was added to the mixture of (S) -4-chloromethyl-2,2,4-trimethyl-1,3-dioxolane (64.21 g, 0.39 mol) and N, N-dimethylformamide (600 ml). (43.01 g, 0.42 mol) and sodium benzoate (60.24 g, 0.42 mol) were added and stirred at 150 ° C. for 15 hours. After allowing to cool, the salt was filtered, N, N-dimethylformamide was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with toluene. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 87.85 g of (S) -4-benzoyloxymethyl-2,2,4-trimethyl-1,3-dioxolane (yield). 90%) of crude product.

To a mixture of this crude (S) -4-benzoyloxymethyl-2,2,4-trimethyl-1,3-dioxolane (50.81 g, 0.203 mol) and water (100 ml) was added sodium carbonate (32.22 g, 0 .304 mol) was added and the mixture was stirred at 100 ° C. for 8 hours. The mixture was allowed to cool and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was distilled to obtain 24.33 g of (R) -2,2,4-trimethyl-1,3-dioxolane-4-methanol (yield 82%, boiling point 75 ° C. (8 mmHg), optical rotation [α ^{_{] D 20 -10.4 ° (c =}} 1, MeOH), was obtained ee 99.0%).

Example 2-2
(S) -4-chloromethyl-2,2,4-trimethyl-1,3-dioxolane was obtained in the same manner as in Example 2-1. That is, (S) -3-chloro-2-methyl-1,2-propanediol (117.72 g, 0.945 mol, 99.2% ee) and acetone (1500 ml) were mixed with p-toluenesulfonic acid monohydrate. The Japanese product (1.79 g, 9.4 mmol) was added and stirred at 25 ° C. for 12 hours. After completion of the reaction, acetone was distilled off under reduced pressure, and the crude product was distilled to obtain 136.91 g (yield) of (S) -4-chloromethyl-2,2,4-trimethyl-1,3-dioxolane. 88%, boiling point 48 ° C. (5 mmHg)).

  A mixture of 56.47 g (0.343 mol) of this (S) -4-chloromethyl-2,2,4-trimethyl-1,3-dioxolane and N, N-dimethylformamide (400 ml) was mixed with sodium bromide (37 0.04 g, 0.36 mol) and sodium acetate (29.53 g, 0.36 mol) were added, and the mixture was stirred at 150 ° C. for 15 hours. After cooling, the salt was filtered, and N, N-dimethylformamide was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with toluene. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This crude product was distilled to obtain 41.32 g (yield 64%, boiling point 83 ° C. (12 mmHg)) of (S) -4-acetoxymethyl-2,2,4-trimethyl-1,3-dioxolane. .

Subsequently, a mixture of (S) -4-acetoxymethyl-2,2,4-trimethyl-1,3-dioxolane (36.89 g, 0.196 mol) and methanol (200 ml) was added to potassium carbonate (40.63 g, 0.8. 294 mol) was added and the mixture was stirred at 25 ° C. for 8 hours. After completion of the reaction, the salt was filtered and the filtrate was concentrated under reduced pressure. The crude product was distilled to obtain 25.50 g of (R) -2,2,4-trimethyl-1,3-dioxolane-4-methanol (yield 89%, boiling point 75 ° C. (8 mmHg), optical rotation [α ^{_{] D 20 -10.3 ° (c =}} 1, MeOH), was obtained ee 99.1%).

  The 3-amino-1,2-propanediol acetal compound and 1,3-dioxolane-4-methyl-4-methanol derivative obtained by the method of the present invention can be used as starting materials for the production of pharmaceuticals and agricultural chemicals. An optically active substance is an important compound as an intermediate for producing pharmaceuticals.

Claims (19)

The following general formula (1)

[Wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a phenyl group, or R ¹ and R ² are terminals thereof. Represents a methylene group having 4 to 7 carbon atoms formed by bonding, and R ³ represents a hydrogen atom or a methyl group. ]
A process for producing a 3-amino-1,2-propanediol acetal compound represented by:
The following general formula (2)

[Wherein, X represents a halogen atom, and R ³ represents a hydrogen atom or a methyl group. ]
Is reacted with an acetalizing agent in the presence of an acid catalyst to give the following general formula (3):

[Wherein R ¹ , R ² , R ³ , and X are the same as above. A first step of obtaining a 3-halogeno-1,2-propanediol acetal compound represented by the formula:
By reacting the compound of the general formula (3) with an azidating agent, the following general formula (4)

[Wherein R ¹ , R ² and R ³ are the same as above]
A second step of obtaining a 3-azido-1,2-propanediol acetal compound represented by:
And a third step of obtaining the compound of the general formula (1) by catalytic hydrogenation of the compound of the general formula (4) in the presence of a reduction catalyst. The method according to claim 1, wherein the halogen atom in the general formula (2) is a chlorine atom or a bromine atom. The method according to claim 1 or 2, wherein a compound which gives a compound in which R ¹ and R ² are both a methyl group, an ethyl group or a phenyl group in the general formula (3) is used as an acetalizing agent. The method according to claim 3, wherein at least one selected from the group consisting of acetone, 2,2-dimethoxypropane, and 2-methoxypropene is used as the acetalizing agent. The method according to any one of claims 1 to 4, wherein the azidating agent is at least one compound selected from the group consisting of a metal azide, a silicon azide compound, and a phosphoryl azide compound. The method according to claim 5, wherein the azidating agent is at least one compound selected from the group consisting of sodium azide, trimethylsilyl azide, and diphenylphosphoryl azide. The method according to any one of claims 1 to 6, wherein the reduction catalyst is a noble metal catalyst. The method according to claim 7, wherein the noble metal catalyst is a palladium-based catalyst. 9. An optically active 3-amino-1,2-propanediol acetal compound is obtained by using an optically active substance as the 3-halogeno-1,2-propanediol compound represented by the general formula (2). The method in any one of. Following formula (5)

3-amino-2-methyl-1,2-propanediol acetonide represented by: The following general formula (6)

[Wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, or a phenyl group, or R ¹ and R ² are terminals thereof. Represents a methylene group having 4 to 7 carbon atoms formed by bonding. ]
A process for producing a 1,3-dioxolane-4-methyl-4-methanol derivative represented by
The following general formula (7)

[Wherein X represents a halogen atom. ]
In the presence of an acid catalyst, 3-halogeno-2-methyl-1,2-propanediol represented by the following general formula (8) is reacted.

[Wherein, R ¹ , R ² and X are the same as above. ]
A first step of obtaining a 4-halogenomethyl-4-methyl-1,3-dioxolane derivative represented by:
The compound of the above formula (8) and the following general formula (9)

ROH (9)

[Wherein, R represents a linear or branched aliphatic acyl group having 2 to 5 carbon atoms, an aromatic ring, an alkyl group having 1 to 4 carbon atoms, a nitro group, a cyano group, a halogen atom, and a carbon number. An aromatic acyl group, an aralkyl group having 7 to 12 carbon atoms, or an allyl group which may have 1 to 5 substituents selected from the group consisting of 1 to 4 alkoxy groups. ]
By reacting with an alkali metal salt or alkaline earth metal salt of a carboxylic acid represented by the above, or an alkali metal or alkaline earth metal alkoxide of an alcohol represented by the general formula (9) above, 10)

[Wherein, R, R ¹ and R ² are the same as above. ]
A second step of obtaining a compound represented by:
In the compound of the above general formula (10), when R is an acyl group, deacylation is performed in the presence of a base, and when R is an aralkyl group or an allyl group, hydrogenation is performed in the presence of a reduction catalyst. And a third step of obtaining a compound of the above general formula (6). The method according to claim 11, wherein the halogen atom in the general formula (7) is a chlorine atom or a bromine atom. The method according to claim 11 or 12, wherein a compound that gives a compound in which R ¹ and R ² are both a methyl group, an ethyl group, or a phenyl group in the general formula (8) is used as an acetalizing agent. The method according to claim 13, wherein the acetalizing agent is at least one selected from the group consisting of acetone, 2,2-dimethoxypropane, and 2-methoxypropene. The compound of the general formula (9) is a carboxylic acid, and in the third step, at least selected from the group consisting of alkali metal or alkaline earth metal carbonates and alkali metal or alkaline earth metal hydroxides as a base The method according to claim 11, wherein one kind is used. The method according to any one of claims 11 to 15, wherein the compound of the general formula (9) is acetic acid, propionic acid, or benzoic acid. The method according to any one of claims 11 to 14, wherein the compound of the general formula (9) is an alcohol, and a noble metal catalyst is used as a reduction catalyst in the third step. The method according to claim 17, wherein the noble metal catalyst is a palladium-based catalyst. By using an optically active form as 3-halogeno-2-methyl-1,2-propanediol represented by the general formula (7), an optically active 1,3-dioxolane-4-methyl-4-methanol derivative is obtained. The method according to claim 11.