JP6393396B2 - Method for producing glyceric acid ester - Google Patents

Description

  The present invention relates to a method for producing a glyceric acid ester.

Compounds having a glyceric acid skeleton in which the hydroxyl groups at the 2nd and 3rd positions are protected as cyclic acetal groups include, for example, synthetic intermediates such as glyceric acid and esters thereof used as raw materials for various pharmaceuticals, cosmetics, detergents, polymers, etc. Useful as a body.
As an example of a compound having a glyceric acid skeleton in which the hydroxyl groups at the 2-position and 3-position are protected as cyclic acetal groups, for example, Non-Patent Document 1 includes 4-hydroxymethyl-2,2-dimethyl-1,3-dioxolane. , 2,2,6,6-tetramethylpiperidine-1-oxyl (hereinafter also referred to as “TEMPO”), an oxidizing agent and pyridine, and oxidative dimerization (oxidative esterification). A preparation example of dimethyl-1,3-dioxolane-4-carboxylic acid (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester is described.

Synlett, Vol. 23, 2261-2265, 2012

Non-Patent Document 1 clearly shows the wide range of application range of raw alcohol for this reaction, based on the reaction results using a large number of alcohols. On the other hand, from the viewpoint of oxidative esterification yield, there is a description that only pyridine can be used as an essential base for the reaction. In order to industrialize this reaction method using a large excess of pyridine relative to the raw material alcohol, it is very important from the economic point of view to regenerate and reuse pyridine from pyridine salts produced as a by-product after reaction. .
The most common method of regenerating pyridine is to add a strong base aqueous solution such as sodium hydroxide to the pyridine salt to liberate pyridine. However, since pyridine is miscible with water, It is difficult to recover in high yield by organic solvent extraction. Although pyridine in the aqueous phase can be recovered by distillation, pyridine has physical properties that azeotrope with water. Therefore, in order to obtain anhydrous or near-water content pyridine necessary for reuse, it is This is disadvantageous from the viewpoint of economy.
The present invention relates to providing a method for producing a glyceric acid ester that is easy to produce and has a high yield, and that facilitates the reuse of pyridines used in the reaction.

  In the present invention, compound A represented by the following formula (I) is selected from an organic nitroxyl radical, an N-hydroxy form thereof, and a salt containing an oxoammonium cation in the presence of pyridine having an alkyl substituent. Compound B and a step of oxidative esterification using an oxidant, wherein the compound B is used in a molar ratio of 0.0001 or more and 0.1 or less with respect to Compound A. It relates to the manufacturing method of the compound represented by these.

(In formula (I), R ¹ and R ² each independently represent a hydrogen atom or a monovalent hydrocarbon group, or R ¹ and R ² are bonded to each other to form a ring structure. Represents a hydrocarbon group.)

(In formula (II), R ¹ and R ² each independently represent a hydrogen atom or a monovalent hydrocarbon group, or R ¹ and R ² are bonded to each other to form a ring structure. Represents a hydrocarbon group of

  According to the present invention, it is possible to provide a method for producing a glyceric acid ester that is easy to produce and has a high yield, and that allows easy reuse of pyridines used in the reaction.

GC chart of reaction solution obtained in Comparative Example 1-1

[Production Method of Compound Represented by Formula (II)]
The production method of the present invention of a compound represented by the following formula (II) (hereinafter, also referred to as “glyceric acid ester” or “ester dimer”) comprises a compound A represented by the following formula (I) (hereinafter, A compound B selected from an organic nitroxyl radical, an N-hydroxy form thereof and a salt containing an oxoammonium cation in the presence of pyridine having an alkyl substituent, and an oxidizing agent. A step of oxidative esterification (hereinafter also referred to as “step 2”). In step 2, the compound B is used in a molar ratio of 0.0001 to 0.1 with respect to the compound A.
In the following description, the compound represented by the formula (II) obtained by the production method of the present invention is also referred to as “the glycerate ester of the present invention” or “the ester dimer of the present invention”.
In the present invention, the production is easy and the ester dimer of the present invention can be obtained in high yield, and pyridine having an alkyl substituent can be easily recovered after the reaction. Furthermore, glyceric acid and an esterified product thereof can be produced from the obtained ester dimer of the present invention, and the compound represented by the following formula (II) is also useful as an intermediate for various useful substances.

(In formula (I), R ¹ and R ² each independently represent a hydrogen atom or a monovalent hydrocarbon group, or R ¹ and R ² are bonded to each other to form a ring structure. Represents a hydrocarbon group of

(In formula (II), R ¹ and R ² each independently represent a hydrogen atom or a monovalent hydrocarbon group, or R ¹ and R ² are bonded to each other to form a ring structure. Represents a hydrocarbon group of

In Formula (I) and Formula (II), R ¹ and R ² each independently represent a hydrogen atom or a monovalent hydrocarbon group, or R ¹ and R ² are bonded to each other to form a ring structure Represents a divalent hydrocarbon group.
In a preferred embodiment of R ¹ and R ² , R ¹ is a hydrogen atom, and R ² is a hydrogen atom or a monovalent hydrocarbon group. The monovalent hydrocarbon group preferably has 1 to 20 carbon atoms. The hydrocarbon group for R ² is preferably an alkyl group or an aryl group. The alkyl group preferably has 1 or more carbon atoms, preferably 20 or less, more preferably 18 or less, still more preferably 16 or less, still more preferably 14 or less, still more preferably 12 or less, and still more preferably. It is 10 or less, more preferably 8 or less, still more preferably 6 or less, still more preferably 4 or less, and still more preferably 2 or less. These alkyl groups may be linear or branched. The number of carbon atoms of the aryl group represented by R ² is preferably 6 or more, preferably 20 or less, more preferably 18 or less, still more preferably 16 or less, still more preferably 14 or less, still more preferably 12 or less, More preferably, it is 10 or less, still more preferably 8 or less, and still more preferably 6 or less. From the above viewpoint, R ² is preferably a hydrogen atom or a monovalent hydrocarbon group having 1 to 20 carbon atoms, more preferably a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, and 1 carbon atom. A branched alkyl group having 8 or less or an aryl group having 6 to 20 carbon atoms, more preferably a hydrogen atom, a methyl group or a phenyl group, still more preferably a hydrogen atom.
Other preferable embodiments of R ¹ and R ² include the availability and reactivity of raw materials, the stability of dioxolane and the ester dimer of the present invention, and the ease of recovery of ketones by-produced by the acetal decomposition of the ester dimer of the present invention. From the viewpoint, R ¹ and R ² are monovalent hydrocarbon groups. R ¹ is preferably a monovalent hydrocarbon group having 1 to 8 carbon atoms, and R ² is a monovalent hydrocarbon group having 2 to 8 carbon atoms, more preferably R ¹ is an alkyl having 1 to 8 carbon atoms. R ² is an alkyl group having 2 to 8 carbon atoms, more preferably R ¹ is an alkyl group having 1 or 2 carbon atoms, and R ² is an alkyl group having 2 to 6 carbon atoms, more preferably R ¹ is An alkyl group having 1 or 2 carbon atoms and R ² having 2 or more and 4 or less carbon atoms, more preferably R ¹ is a methyl group and R ² is an ethyl group.
As another preferred embodiment of R ¹ and R ^2, R ¹ and R ² is a divalent hydrocarbon group that forms a ring structure with each other, from the point of view, preferably 2 or more carbon atoms 7 The following divalent hydrocarbon group, more preferably a divalent hydrocarbon group having 3 to 6 carbon atoms, more preferably a divalent hydrocarbon group having 4 to 5 carbon atoms, still more preferably 5 carbon atoms. These are divalent hydrocarbon groups. That is, the ring structure containing R ¹ and R ² is preferably a 3- to 8-membered ring, more preferably a 4- to 7-membered ring, still more preferably a 5- to 6-membered ring, and even more preferably a 6-membered ring. The ring structure containing R ¹ and R ² is preferably a cycloalkane structure, more preferably a ring structure having 5 or 6 carbon atoms (cyclopentane ring or cyclohexane ring), and a cyclohexane ring. More preferably it is.

In formula (I), when R ¹ and R ² are bonded to each other to form a ring structure, formula (I) becomes formula (I ′). Similarly, in the formula (II), when R ¹ and R ² are bonded to each other to form a ring structure, the formula (II) becomes the formula (II ′).

(In formula (I ′) and formula (II ′), R ^A represents a divalent hydrocarbon group forming a ring structure.)

In formula (I ′) and formula (II ′), the ring structure containing ^RA is preferably a 3- to 8-membered ring, more preferably a 4- to 7-membered ring, still more preferably a 5- to 6-membered ring, and even more preferably. Is a 6-membered ring. The ring structure containing R ^A is preferably a cycloalkane structure, more preferably a cyclopentane ring or a cyclohexane ring as described above, and a cyclohexane ring formed. Is more preferable.
That is, ^RA preferably represents an ethylene group (— (CH ₂ ) ₂ —), a trimethylene group (— (CH ₂ ) ₃ —), a tetramethylene group (— (CH ₂ ) ₄ —), a pentamethylene group (— (CH ₂ ) ₅ —), hexamethylene group (— (CH ₂ ) ₆ —) or heptamethylene group (— (CH ₂ ) ₇ —), more preferably trimethylene group, tetramethylene group, pentamethylene group or hexamethylene More preferably a tetramethylene group or a pentamethylene group, still more preferably a pentamethylene group.

In the compound represented by the formula (I), one or more asymmetric carbons are present. Therefore, unless enantioselective reaction or stereoisomer separation is performed, the compound represented by the formula (I) exists as a racemate or a stereoisomer mixture.
In the present invention, the stereoisomer ratio of the compound represented by the formula (I) is not particularly limited.

  Since dioxolane of formula (I) contains one or more asymmetric carbons, the ester dimer of formula (II) can be obtained as a stereoisomer mixture unless dioxolane with an enantiomeric excess of 100% is used. It is done.

  In the present invention, the compound represented by the above formula (I) may be a commercially available product or may be produced and used, and is not particularly limited. From this viewpoint, it is preferable to produce dioxolane by the following method.

<Step 1: Dioxolane production method>
The method for producing a compound represented by formula (II) of the present invention is a step for producing a compound (dioxolane) represented by the above formula (I) prior to step 2 (hereinafter also referred to as “step 1”). It is preferable to have.
The production method of dioxolane (compound represented by the formula (I)) used in the present invention is not particularly limited, and glycerol and a compound represented by the following formula (III) are generally well-known methods. Is acetalized in the presence of an acid catalyst (method 1), or a method of acetal exchange of glycerol and a compound represented by the following formula (IV) in the presence of an acid catalyst (method 2) is It is preferable from the viewpoints of availability, yield, and ease of reaction operation.
That is, it is preferable that the manufacturing method of the glycerol ester of this invention includes the following process 1 and process 2.
Step 1: Acetalization of glycerol and a compound represented by the following formula (III) or a multimer thereof in the presence of an acid catalyst (step 1-1), or glycerol and a compound represented by the following formula (IV) For acetal exchange in the presence of an acid catalyst (step 1-2)
Step 2: Oxidative esterification of a mixture of a compound represented by the following formula (I) and a compound represented by the following formula (V)

(In the formula (III) and formula (IV), ^{R 1} and ^{R 2} are each ^{R 1} and ^{R 2} synonymous in Formula (II), wherein (IV), ^{R 3} is independently a monovalent Represents a hydrocarbon group of

R ³ in formula (IV) is each independently a monovalent hydrocarbon group, preferably from 1 to 8 carbon atoms, from the viewpoint of availability of raw materials, and by-produced by an acetal exchange reaction. From the viewpoint of accelerating the reaction by distilling alcohol out of the reaction system, more preferably a monovalent hydrocarbon group having 1 to 3 carbon atoms, still more preferably a monovalent alkyl group having 1 to 3 carbon atoms, Even more preferred is a methyl group.
Method 1 and method 2 (step 1-1 and step 1-2) are shown below.

The dioxolane obtained by the acetalization or acetal exchange method is an isomer mixture with the compound represented by the above formula (V) (hereinafter also referred to as “dioxane”) as shown in the above reaction formula. can get. The isomer ratio between dioxolane and dioxane is not limited, but from the viewpoint of productivity and economy, the higher the isomerization ratio of dioxolane, the better.
Dioxolane isomers obtained by a general production method from a compound in which at least one of R ¹ and R ^{2 in} the above formulas (III) and (IV) is a hydrogen atom (hereinafter also referred to as “aldehydes”) The conversion ratio is 40% or more and 60% or less. Further, it can be obtained from a compound (hereinafter also referred to as “ketones”) in which both of R ¹ and R ^{2 in} the above formulas (III) and (IV) are not hydrogen atoms by the above general production method. The isomerization ratio of dioxolane is 95% or more. Therefore, ketones are preferred from the viewpoint of high isomerization ratio of dioxolane.
On the other hand, when dioxolane obtained from aldehydes is oxidatively esterified, the yield of the ester dimer of the present invention tends to be significantly higher than that obtained using ketones as a raw material. Aldehydes are preferred from the viewpoint that the reaction proceeds easily and has aspects such as stability of the acetal group and the viewpoint of obtaining the ester dimer of the present invention in high yield.

The mixture of dioxolane (compound represented by formula (I)) and dioxane (compound represented by formula (V)) obtained by the above method 1 or method 2 is used as a raw material for the next step as it is or after purification. Although it can be used, it is preferable to purify the mixture and remove unreacted raw materials from the viewpoint of the yield in the next step, and it is more preferable to purify by distillation from the viewpoint of ease of purification.
In addition, since it is difficult to separate dioxolane and dioxane by purification, it is preferable to use as a raw material for the next step in the state of a mixture of dioxolane and dioxane.

<Step 2: Oxidative esterification>
The glyceric acid ester (compound represented by formula (II)) of the present invention can be obtained by oxidative esterification of the dioxolane (compound represented by formula (I)).
Oxidative esterification is a kind of oxidation reaction for obtaining an ester from a primary alcohol and an alcohol in a broad sense, and more generally a reaction for obtaining one molecule of an ester dimer from two molecules of the same primary alcohol. There are also other names such as quantification. In the present invention, oxidative esterification means carrying out a reaction for obtaining the ester dimer (compound represented by formula (II)) of the present invention from dioxolane (compound represented by formula (I)).
In addition, when the mixture of the said dioxolane (compound represented by Formula (I)) and dioxane (compound represented by Formula (V)) is oxidatively esterified, the following reactions typically occur.

(Wherein R ¹ and R ² are as described above.)

  The present invention is characterized by oxidative esterification in the presence of pyridine having an alkyl substituent. Step 2 includes at least one selected from an organic nitroxyl radical, an N-hydroxy form thereof, and a salt containing an oxoammonium cation thereof (hereinafter also referred to as “nitroxyl radical species”), an oxidizing agent, and an alkyl substituent. It is an oxidative esterification method using pyridine having

  As described above, the dioxolane used in the present invention is usually a mixture with dioxane, but in the oxidative esterification step, formyl dioxolane (a compound represented by the formula (VII)) is by-produced from dioxolane depending on the reaction conditions. There is. Although there is no limitation on the amount of by-produced formyldioxolane, from the viewpoint of obtaining the ester dimer of the present invention in a high yield, the yield of formyldioxolane produced from dioxolane is preferably 20% or less, more preferably 10% or less. More preferably, it is 5% or less, still more preferably substantially 0%, and still more preferably 0%. In order to reduce the amount of by-produced formyldioxolane, a preferable production method described later may be followed.

  Similarly, in the step of oxidative esterification of a mixture of dioxolane and dioxane, a compound represented by the above formula (VI) from dioxane (hereinafter also referred to as “dioxanone”) in which dioxane does not react depending on the reaction conditions. May be produced, or a compound other than dioxanone may be produced, or a mixture of these compounds may be obtained. However, as long as it does not adversely affect the purification process of the ester dimer of the present invention, the production amount and production ratio of these compounds are affected. There is no limit.

[Pyridine having an alkyl substituent]
In this reaction, pyridine having an alkyl substituent is used for the purpose of neutralizing an acid generated as a by-product due to consumption of the oxidizing agent. The pyridine having the alkyl substituent only needs to have at least one alkyl substituent, and the number of the alkyl substituents is 1 to 5 substitutions, preferably 1 to 4 substitutions, more preferably 1 to 4 substitutions. Trisubstituted, more preferably monosubstituted or disubstituted. The number of carbon atoms of the alkyl substituent is independently preferably 1 or more, preferably 12 or less, more preferably 10 or less, still more preferably 8 or less, still more preferably 6 or less, and still more preferably. 4 or less, more preferably 2 or less. The alkyl group may be linear, branched or cyclic, but is preferably linear or branched, more preferably linear.
Examples of pyridine having an alkyl substituent include 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2-ethylpyridine, 3-ethylpyridine, 4-ethylpyridine, 2-propylpyridine, 3-propylpyridine, 4 -Propylpyridine, 3-n-butylpyridine, 4-tert-butylpyridine, 2-amylpyridine, 4-amylpyridine, 2- (3-pentyl) pyridine, 4- (3-pentyl) pyridine, 2,3- Lutidine (alias: 2,3-dimethylpyridine), 2,4-lutidine (alias: 2,4-dimethylpyridine), 2,5-lutidine (alias: 2,5-dimethylpyridine), 2,6-lutidine ( Alias: 2,6-dimethylpyridine), 3,4-lutidine (alias: 3,4-dimethylpyridine), 3,5-lutidine (alias: 3) 5-dimethylpyridine), 5-ethyl-2-methylpyridine, 2,6-di-tert-butylpyridine, 2,3,5-collidine (also known as 2,3,5-trimethylpyridine), 2,4, Preferable examples include 6-collidine (alias: 2,4,6-trimethylpyridine) and the like.

The pyridine having an alkyl substituent is preferably a pyridine having an alkyl substituent at at least one position selected from the 3-position, 4-position and 5-position from the viewpoint of availability and water-insolubility. Moreover, it is preferable that it is a pyridine which does not have an alkyl substituent in 2nd-position and 6-position from a viewpoint of obtaining the ester dimer of this invention with a higher yield. That is, pyridine having an alkyl substituent only at 1 to 3 positions selected from the 3rd, 4th and 5th positions among the 1st to 6th positions of pyridine is preferable. From the viewpoint of equipment load at the time of distillation purification, pyridine having an alkyl substituent in which the carbon number of the alkyl substituent is 1 or more and 4 or less is more preferable.
Examples of pyridine having an alkyl substituent include 5-ethyl-2-methylpyridine, 3,5-lutidine, 2,6-lutidine, 2,6 from the viewpoints of availability, water-insolubility, and ease of recovery. -At least 1 chosen from tertiary butyl lutidine, 3-ethylpyridine, 4-methylpyridine, and 4-ethylpyridine is illustrated preferably. Further, from the viewpoint of obtaining the ester dimer of the present invention in a higher yield, it is more preferably at least one selected from 3,5-lutidine, 3-ethylpyridine, 4-methylpyridine and 4-ethylpyridine.

  From the viewpoint of completely neutralizing the acid derived from the oxidizing agent and suppressing the decomposition of the acetal group of dioxolane and the ester dimer of the present invention, the molar ratio of pyridine having an alkyl substituent to dioxolane or a mixture of dioxolane and dioxane is preferably Is 1.0 or more, more preferably 1.1 or more, still more preferably 1.2 or more, and still more preferably 1.3 or more. In addition, from the viewpoints of economy and ease of recovery of excess base, the molar ratio is preferably 2.5 or less, more preferably 2.0 or less, and even more preferably 1.7 or less.

[Nitroxyl radical species]
In this reaction, the nitroxyl radical species is selected from any organic nitroxyl radical that has an oxidative esterification activity for dioxolane in combination with an oxidizing agent, its N-hydroxy form, and salts containing their oxoammonium cations. Use compounds.
That is, as the nitroxyl radical species, at least one compound B selected from a salt containing an organic nitroxyl radical, an N-hydroxy form thereof, and an oxoammonium cation thereof is used.
From the viewpoint of obtaining high oxidative esterification activity, compound B is preferably a compound selected from organic nitroxy radicals and salts containing oxoammonium cations thereof, and is an N-hydroxy form of organic nitroxy radicals. Is more preferable.
From the viewpoint of obtaining high oxidative esterification activity, the organic nitroxyl radical is a compound represented by the following formula (VIII), a compound represented by the following formula (IX) or a compound represented by the following formula (X). It is preferable that That is, the nitroxyl radical species includes a compound represented by the following formula (VIII), a compound represented by the following formula (IX) or a compound represented by the following formula (X), an N-hydroxy form thereof, and It is preferable that it is a compound chosen from the salt containing the oxoammonium cation.

(In the formula (VIII), R ⁴ is a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, an amino group, an acylamino group, a sulfonyloxy group, an N-alkylcarbamoyloxy group, a carboxy group, a cyano group. Represents an isocyanato group, an isothiocyanato group, or an oxo group, and in formula (IX), R ⁵ and R ⁶ each independently represents a hydrogen atom or a methyl group, and in formula (X), R ⁷ and R ⁸ represent Each independently represents a hydrogen atom or a methyl group.)

In the formula (VIII), R ⁴ is a hydrogen atom, a halogen atom, a hydroxyl group (—OH), an alkoxy group, an acyloxy group, an alkoxycarbonyl group, an amino group, an acylamino group, a sulfonyloxy group, an N-alkylcarbamoyloxy group, or a carboxy group. (—C (═O) —OH), cyano group (—C≡N), isocyanato group (—N═C═O), isothiocyanato group (—N═C═S), or oxo (═O) group. Represent. In formula (VIII), R ⁴ is preferably an alkoxy group, an acyloxy group, or an acylamino group from the viewpoint of availability and high yield of the ester dimer of the present invention.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a fluorine atom, a chlorine atom, or a bromine atom is preferable from the viewpoint of easy acquisition or preparation and low molecular weight.
The alkoxy group is represented by —OR ⁹ , R ⁹ represents a monovalent hydrocarbon group, and is preferably an alkyl group having 1 to 12 carbon atoms or a carbon number from the viewpoint of easy acquisition or preparation and low molecular weight. An alkenyl group having 2 to 12 carbon atoms, an alkynyl group having 2 to 12 carbon atoms, or an aryl group having 6 to 20 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, and 2 carbon atoms. -6 alkynyl group, or aryl group having 6 to 14 carbon atoms, more preferably alkyl group having 1 to 4 carbon atoms, alkenyl group having 2 to 4 carbon atoms, alkynyl group having 2 to 4 carbon atoms, or 6 carbon atoms. Is an aryl group of from 10 to 10, more preferably a methyl group. In R ⁹ , part of the hydrogen atoms may be substituted with a halogen atom.

The acyloxy group is represented by —O (C═O) —R ¹⁰ , and R ¹⁰ is preferably a hydrogen atom, an alkyl group having 1 to 12 carbon atoms from the viewpoint of easy acquisition or preparation and low molecular weight. C1-C12 alkenyl group, or C6-C20 aryl group, More preferably, a hydrogen atom, C1-C8 alkyl group, or C6-C14 aryl group, More preferably, a hydrogen atom , An alkyl group having 1 to 4 carbon atoms, or an aryl group having 6 to 10 carbon atoms, more preferably a methyl group, an ethyl group, or a phenyl group, and still more preferably a phenyl group.
The acylamino group is represented by —NH (C═O) —R ¹¹ , and R ¹¹ is preferably a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, from the viewpoint of easy acquisition or preparation and low molecular weight. Or an aryl group having 6 to 20 carbon atoms, more preferably a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an aryl group having 6 to 14 carbon atoms, still more preferably a hydrogen atom, an alkyl group having 1 to 4 carbon atoms. Or an aryl group having 6 to 10 carbon atoms, more preferably a methyl group, an ethyl group, or a phenyl group, and still more preferably a methyl group.
The sulfonyloxy group is represented by —O (O═S═O) —R ¹² , and R ¹² is preferably an alkyl group having 1 to 12 carbon atoms from the viewpoint of easy acquisition or preparation and low molecular weight. Or an aryl group having 6 to 20 carbon atoms, more preferably an alkyl group having 1 to 8 carbon atoms, or an aryl group having 6 to 14 carbon atoms, still more preferably an alkyl group having 1 to 4 carbon atoms, or 6 to 6 carbon atoms. 10 aryl groups, more preferably a methyl group, an ethyl group, or a paratolyl group, still more preferably a methyl group or a paratolyl group.

Specific examples of the nitroxyl radical species include TEMPO, 4-hydroxy TEMPO, 4-amino-TEMPO, 4-methoxy-TEMPO (hereinafter also referred to as “4-OMe-TEMPO”), 4-ethoxy-TEMPO. 4-phenoxy-TEMPO, 4-acetoxy-TEMPO, 4-benzoyloxy-TEMPO (hereinafter also referred to as “4-OBz-TEMPO”), 4-methacrylate-TEMPO, 4-acetamido-TEMPO (hereinafter referred to as “4”). -NHAc-TEMPO "), 4-methylsulfonyloxy-TEMPO (hereinafter also referred to as" 4-OMs-TEMPO "), 4-paratoluenesulfonyloxy-TEMPO, 4-oxo-TEMPO, 2-aza Adamantane-N-hydroxyl (hereinafter referred to as “AZADOL (Also referred to as Nissan Chemical Industries, Ltd., trademark)), 2-azaadamantane-N-oxyl (hereinafter also referred to as “AZADO”), 1-methyl-2-azaadamantane-N-oxyl (hereinafter referred to as “trademark”). 1-Me-AZADO ”), 9-azanoradamantane-N-oxyl (hereinafter also referred to as“ nor-AZADO ”), 1,5-dimethyl-9-azanoradamantane-N-oxyl (hereinafter referred to as“ nor-AZADO ”). , Also referred to as “DMM-AZADO”).
From the viewpoint of availability and high yield of the ester dimer of the present invention, nitroxyl radical species include 4-methoxy-TEMPO, 4-benzoyloxy-TEMPO, 4-acetamido-TEMPO, 4-methylsulfonyloxy-TEMPO. And a compound selected from AZADOL, and a compound selected from 4-benzoyloxy-TEMPO, 4-acetamido-TEMPO, 4-methylsulfonyloxy-TEMPO, and AZADOL is more preferable.
Preferred compounds are exemplified below, but in the present invention, the nitroxyl radical species is not limited to these compounds.

  From the viewpoint of ensuring sufficient oxidative esterification activity, the amount of compound B selected from organic nitroxyl radicals, N-hydroxy forms thereof and salts containing oxoammonium cations thereof is dioxolane (that is, formula (I) The molar ratio is 0.0001 or more, preferably 0.0002 or more, more preferably 0.0005 or more, relative to the compound A) represented by From the viewpoint of economy, the molar ratio is 0.1 or less, preferably 0.05 or less, more preferably 0.02 or less.

〔Oxidant〕
In this reaction, an oxidizing agent is preferably used together with the above-described nitroxyl radical species from the viewpoint of reactivity. As the oxidizing agent, any oxidizing agent capable of oxidizing an organic nitroxyl radical or an N-hydroxy form thereof to an oxoammonium cation can be used. However, the yield reduction due to hydration or hydrolysis of the ester dimer of the present invention can be used. From the viewpoint of suppression, an oxidizing agent composed of a halogen-containing compound that can be used in an organic solvent (hereinafter also referred to as “halogen-containing oxidizing agent”) is preferable. Examples of the halogen-containing oxidizing agent include sodium hypochlorite pentahydrate, metachloroperbenzoic acid, trichloroisocyanuric acid (hereinafter, also referred to as “TCCA”), tertiary butyl hypochlorite (hereinafter, “ ^t BuOCl”). ), An oxidizing agent comprising a chlorine-containing compound such as N-chlorosuccinimide (hereinafter also referred to as “chlorine-containing oxidizing agent”), and an oxidizing agent comprising a bromine-containing compound such as N-bromosuccinimide ( Hereinafter, the halogen-containing oxidizing agent having a plurality of halogen elements such as “bromine-containing oxidizing agent” and (dichloroiodo) benzene is exemplified. Halogen-containing oxidizing agent, oxidizing the viewpoint of obtaining an ester dimers of the present invention in high yield, stability of the oxidizing agent, from the viewpoint of safety and ease of handling, the chlorine-containing oxidizing agent is preferably selected from TCCA and ^t BuOCl An agent is more preferable, and TCCA is more preferable from the viewpoint of availability.
The oxidizing agent of the present invention includes a compound represented by the formula (VIII), a compound represented by the formula (IX), or an oxoammonium cation obtained by one-electron oxidation of the compound represented by the formula (X). The organic nitroxyl radical or its N-hydroxy oxoammonium cation is excluded.
From the viewpoint of achieving both a high reaction conversion rate of dioxolane or a mixture of dioxolane and dioxane and a reduction in the amount of formyl dioxolane produced, the molar ratio of the oxidizing active species to dioxolane or a mixture of dioxolane and dioxane is preferably 1.0 or more, more preferably. Is 1.1 or more. Further, from the viewpoint of economy and reduction of waste amount, the molar ratio is preferably 2.0 or less, more preferably 1.5 or less.
The oxidation active species means a chlorine atom in the case of a chlorine-containing oxidant, and in the case of TCCA, there are 3 mol of oxidation active species in 1 mol of the molecule.

〔solvent〕
In this reaction, it can be carried out either in the absence of a solvent or under the conditions of use of a solvent. However, when the oxidant to be used or the reduced product or salt derived from the oxidant by-produced during the reaction is solid, the viewpoint of dissolving them, and the reaction solution From the viewpoint of lowering the viscosity of the resin and facilitating stirring, solvent use conditions are preferred. Any solvent can be used as long as it is inert to dioxolane or a mixture of dioxolane and dioxane, an oxidizing agent, and a base. For example, when TCCA is used as an oxidizing agent, TCCA solubility and availability are considered. To preferably a solvent selected from acetone, 2-butanone, cyclopentanone, acetonitrile and dichloromethane, more preferably a solvent selected from acetone, 2-butanone, acetonitrile and dichloromethane, still more preferably selected from acetone and 2-butanone. It is a solvent. Moreover, acetonitrile is more preferable from the viewpoint of the productivity of the ester dimer of the present invention.

A solvent may be used individually by 1 type and may use 2 or more types together.
The amount of solvent used is not particularly limited, but from the viewpoint of operability, the amount of solvent used with respect to the entire reaction system is preferably 20% by mass or more, more preferably 30% by mass or more, and further preferably 40% by mass or more. More preferably, it is 50% by mass or more, and still more preferably 60% by mass or more. From the viewpoint of productivity, the amount of the solvent used for the entire reaction system is preferably 90% by mass or less, more preferably 85% by mass or less, More preferably, it is 80 mass% or less.

[Reaction procedure]
In this reaction, there is no limitation on the order of charging the raw materials, but since the oxidative esterification reaction is an exothermic reaction, raw materials other than the oxidizing agent are used from the viewpoint of ease of temperature control of the reaction solution and safety. The method of dripping an oxidizing agent or an oxidizing agent solution in a mixture or a mixed solution is preferable.
The temperature of the reaction solution during dropping of the oxidant or oxidant solution is preferably −15 ° C. or higher, more preferably −10 ° C. or higher, from the viewpoint of equipment load and suppression of viscosity increase of the reaction solution. Moreover, from the viewpoint of suppressing side reactions such as decomposition at high temperature and obtaining the ester dimer of the present invention in a high yield, it is preferably 25 ° C. or less, more preferably 10 ° C. or less. After the addition of the oxidizing agent or oxidizing agent solution, the reaction is continued until the total amount of dioxolane reacts or the decrease in the residual amount stops. The temperature of the reaction solution is preferably −10 from the viewpoint of promoting the reaction of dioxolane. From the viewpoint of suppressing side reactions, it is preferably 50 ° C. or lower, more preferably 30 ° C. or lower.

At the end of the reaction, from the viewpoint of side reaction suppression and safety, it is preferable to add a reaction terminator that completely consumes the residual oxidizing agent. As the reaction terminator, any compound can be used as long as it does not easily react with the reaction product such as the ester dimer of the present invention and reacts with the oxidizing agent. However, the availability and the purification of the ester dimer of the present invention are easy. From the viewpoint of making it, alcohol is preferable. The alcohol is preferably a primary or secondary alcohol, and more preferably a secondary alcohol from the viewpoint of suppressing transesterification with the ester dimer of the present invention. Moreover, C1-C12 alcohol is preferable.
The addition amount of the reaction terminator is not particularly limited.

[Separation of compound represented by formula (II) and recovery of pyridine having alkyl substituent]
In the present invention, it is preferable to have a step of separating the ester dimer (the compound represented by the formula (II)) of the present invention after the step of oxidative esterification of dioxolane or preferably a mixture of dioxolane and dioxane.
In the step of separating the ester dimer of the present invention, from the viewpoint of efficiency, solids such as salts and reduced products of oxidants are separated by filtration or oil-water extraction, and dioxanone, formyldioxolane and residual base are distilled or column chromatography. It is preferable to separate by.
In the separation of dioxanone and the ester dimer of the present invention, separation by distillation is more preferable from the viewpoint of easy separation utilizing a large boiling point difference. Separation by distillation can be carried out under either simple distillation conditions or rectification conditions, but it is preferable to carry out under rectification conditions from the viewpoint of obtaining a high-purity ester dimer of the present invention with a high distillation yield. As the rectification conditions, from the viewpoint of increasing the purity of the ester dimer of the present invention, the number of theoretical columns of the rectification column is preferably 2 or more, more preferably 5 or more, and the reflux ratio is preferably 0.1 or more. More preferably, it is 0.5 or more. Further, from the viewpoint of productivity of the ester dimer purification of the present invention, the theoretical plate of the rectifying column is preferably 20 plates or less, more preferably 10 plates or less, and the reflux ratio is preferably 20 or less, more preferably 10 or less. It is.

  In the production method of the present invention, pyridine having an alkyl substituent can be easily recovered after the reaction by organic solvent extraction or the like.

  The novel glyceric acid ester obtained by the present invention (the ester dimer of the present invention) is a glyceric acid ester in which the hydroxyl groups at the 2nd and 3rd positions are protected as a cyclic acetal group. Various pharmaceuticals, cosmetics, detergents, polymers It is useful as a synthetic intermediate for glyceric acid, glycerate and deprotected glyceric acid ester used as raw materials.

[Method for producing glyceric acid, glycerate or deprotected glyceric acid ester]
Glyceric acid, glycerate, or deprotected glyceric acid ester can be produced by hydrolysis or alcoholysis of the acetal group and ester group of the ester dimer of the present invention obtained as described above. The method of hydrolysis or alcoholysis is not particularly limited, but the method of decomposing using an excess amount of water or alcohol in the presence of an acid catalyst is the simplest and preferred.
The alcohol used for the alcoholysis is preferably a primary alcohol from the viewpoint of reactivity (particularly the decomposition of the acetal group), and more preferably from the viewpoint that the deprotected glyceric acid ester has a low boiling point and can be easily purified by distillation. It is a primary alcohol having 1 to 3 carbon atoms.
Further, from the viewpoint of easily reducing the polarity of the deprotected glyceric acid ester and separating and purifying the deprotected glyceric acid ester and glycerin by an oil-water extraction method, more preferably a straight chain having 4 to 8 carbon atoms. It is a chain or branched primary alcohol.

  The obtained glyceric acid, glycerate, or deprotected glyceric acid ester is preferably separated from a by-product (glycerin, aldehyde or acetal thereof) by distillation or column chromatography.

The present invention discloses the following [1] to [39].
[1] Compound A represented by the following formula (I) is selected from a salt containing an organic nitroxyl radical, an N-hydroxy form thereof and an oxoammonium cation in the presence of pyridine having an alkyl substituent. B and an oxidative esterification step using an oxidizing agent, wherein the compound B is used in an amount of 0.0001 or more and 0.1 or less with respect to the compound A in the following formula (II): A method for producing the represented compound.

(In formula (I), R ¹ and R ² each independently represent a hydrogen atom or a monovalent hydrocarbon group, or R ¹ and R ² are bonded to each other to form a ring structure. Represents a hydrocarbon group.)

(In formula (II), R ¹ and R ² each independently represent a hydrogen atom or a monovalent hydrocarbon group, or R ¹ and R ² are bonded to each other to form a ring structure. Represents a hydrocarbon group.)

[2] The number of alkyl substituents in the pyridine having the alkyl substituent is preferably 1 to 4 substitutions, more preferably 1 to 3 substitutions, and even more preferably 1 substitution or 2 substitutions. Production method.
[3] The carbon number of the alkyl substituent of the pyridine having the alkyl substituent is preferably independently 1 or more, preferably 12 or less, more preferably 10 or less, and still more preferably 8 or less. More preferably, it is 6 or less, More preferably, it is 4 or less, More preferably, it is 2 or less, The manufacturing method as described in [1] or [2].
[4] The alkyl substituent of the pyridine having the alkyl substituent may be linear, branched or cyclic, but is preferably linear or branched, more preferably linear.
[5] The pyridine having an alkyl substituent is a pyridine having an alkyl substituent at at least one position selected from the 3-position, 4-position, and 5-position, preferably from the 3-position, 4-position, and 5-position. The production method according to any one of [1] to [4], which is pyridine having an alkyl substituent at at least one selected position and having no alkyl substituent at the 2-position and the 6-position.
[6] The pyridine having the alkyl substituent is preferably 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2-ethylpyridine, 3-ethylpyridine, 4-ethylpyridine, 2-propylpyridine, 3 -Propylpyridine, 4-propylpyridine, 3-n-butylpyridine, 4-tert-butylpyridine, 2-amylpyridine, 4-amylpyridine, 2- (3-pentyl) pyridine, 4- (3-pentyl) pyridine 2,3-lutidine (alias: 2,3-dimethylpyridine), 2,4-lutidine (alias: 2,4-dimethylpyridine), 2,5-lutidine (alias: 2,5-dimethylpyridine), 2 , 6-lutidine (alias: 2,6-dimethylpyridine), 3,4-lutidine (alias: 3,4-dimethylpyridine), 3,5-lutizi Gin (alias: 3,5-dimethylpyridine), 5-ethyl-2-methylpyridine, 2,6-di-tert-butylpyridine, 2,3,5-collidine (alias: 2,3,5-trimethylpyridine) ), Or 2,4,6-collidine (also known as 2,4,6-trimethylpyridine), more preferably 5-ethyl-2-methylpyridine, 3,5-lutidine, 2,6-lutidine, 3-ethyl At least one selected from pyridine, 4-methylpyridine and 4-ethylpyridine, more preferably at least one selected from 3,5-lutidine, 3-ethylpyridine, 4-methylpyridine and 4-ethylpyridine. [1] The production method according to any one of [5].
[7] The molar ratio of pyridine having an alkyl substituent to dioxolane or a mixture of dioxolane and dioxane is preferably 1.0 or more, more preferably 1.1 or more, still more preferably 1.2 or more, and still more preferably 1. 3. The production method according to [1] to [6], wherein the molar ratio is 2.5 or less, preferably 2.5 or less, more preferably 2.0 or less, and even more preferably 1.7 or less.

[8] In the above formulas (I) and (II), preferably R ¹ is a hydrogen atom, R ² is a hydrogen atom or a monovalent hydrocarbon group, more preferably R ¹ is a hydrogen atom. , R ² is a hydrogen atom or a monovalent hydrocarbon group having 1 to 20 carbon atoms, and the hydrocarbon group for R ² is preferably an alkyl group or an aryl group, and the carbon number of the alkyl group is Preferably it is 1 or more, preferably 20 or less, more preferably 18 or less, still more preferably 16 or less, even more preferably 14 or less, still more preferably 12 or less, still more preferably 10 or less, and still more preferably 8 Or less, more preferably 6 or less, even more preferably 4 or less, and still more preferably 2 or less. These alkyl groups may be linear or branched, and the aryl group of R ² The number of carbon atoms is preferably 6 or more, preferably 20 or less, more preferably 18 or less, still more preferably 16 or less, still more preferably 14 or less, still more preferably 12 or less, still more preferably 10 or less, More preferably, it is 8 or less, more preferably 6 or less, and R ² is more preferably a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group having 1 to 8 carbon atoms, or carbon. The production method according to [1] to [7], which is an aryl group having a number of 6 or more and 14 or less, more preferably a hydrogen atom, a methyl group or a phenyl group, and still more preferably a hydrogen atom.
[9] In the above formulas (I) and (II), preferably R ¹ and R ² are monovalent hydrocarbon groups, and R ¹ is more preferably a monovalent hydrocarbon having 1 to 8 carbon atoms. R ² is a monovalent hydrocarbon group having 2 to 8 carbon atoms, more preferably R ¹ is an alkyl group having 1 to 8 carbon atoms, and R ² is an alkyl group having 2 to 8 carbon atoms, and more Preferably R ¹ is an alkyl group having 1 or 2 carbon atoms and R ² is an alkyl group having 2 to 6 carbon atoms, more preferably R ¹ is an alkyl group having 1 or 2 carbon atoms and R ² is 2 or more carbon atoms. An alkyl group of 4 or less, more preferably R ¹ is a methyl group and R ² is an ethyl group, and R ¹ and R ² are divalent hydrocarbon groups which are bonded to each other to form a ring structure, preferably A divalent hydrocarbon group having 2 to 7 carbon atoms, more preferably 3 carbon atoms Above 6 following divalent hydrocarbon group, more preferably a divalent hydrocarbon group having 4 to 5 carbon atoms, even more preferably a divalent hydrocarbon group having 5 carbon atoms, R ¹ and R ² The ring structure containing is preferably a 3- to 8-membered ring, more preferably a 4- to 7-membered ring, still more preferably a 5- to 6-membered ring, still more preferably a 6-membered ring, and a ring containing R ¹ and R ² The structure is preferably a cycloalkane structure, more preferably a ring structure having 5 or 6 carbon atoms (cyclopentane ring or cyclohexane ring), and still more preferably a cyclohexane ring, [1] to [ [7] The production method according to any one of [7].

  [10] The production according to any one of [1] to [9], comprising a step of oxidative esterification of a mixture of the compound represented by the following formula (I) and the compound represented by the following formula (V). Method.

(In Formula (I) and Formula (V), R ¹ and R ² each independently represent a hydrogen atom or a monovalent hydrocarbon group, or R ¹ and R ² are bonded to each other to form a ring structure. Represents a divalent hydrocarbon group.)

  [11] A method in which the compound represented by the formula (I) acetalizes glycerol and a compound represented by the following formula (III) in the presence of an acid catalyst (Method 1), or glycerol and the following formula (IV) The production method according to any one of [1] to [10], which is produced by a method (Method 2) in which the compound represented is acetal exchanged in the presence of an acid catalyst.

(In Formula (III) and Formula (IV), R ¹ and R ² each independently represent a hydrogen atom or a monovalent hydrocarbon group, or R ¹ and R ² are bonded to each other to form a ring structure. In formula (IV), each R ³ independently represents a monovalent hydrocarbon group, preferably a group selected from hydrocarbon groups having 1 to 8 carbon atoms, It preferably represents a monovalent hydrocarbon group having 1 to 3 carbon atoms, more preferably a monovalent alkyl group having 1 to 3 carbon atoms, and still more preferably a methyl group.

[12] The production method according to [1] to [11], including the following step 1 and step 2.
Step 1: Acetalization of glycerol and a compound represented by the following formula (III) or a multimer thereof in the presence of an acid catalyst (step 1-1), or glycerol and a compound represented by the following formula (IV) For acetal exchange in the presence of an acid catalyst (step 1-2)
Step 2: Oxidative esterification of a mixture of a compound represented by the following formula (I) and a compound represented by the following formula (V)

(Wherein R ¹ and R ² each independently represents a hydrogen atom or a monovalent hydrocarbon group, or R ¹ and R ² are bonded to each other to form a ring structure) Except that R ¹ and R ² are simultaneously methyl groups, and R ³ is independently a monovalent hydrocarbon group, preferably a hydrocarbon group having 1 to 8 carbon atoms, More preferably, it represents a monovalent hydrocarbon group having 1 to 3 carbon atoms, more preferably a monovalent alkyl group having 1 to 3 carbon atoms, and still more preferably a methyl group.

[13] In formulas (III) and (IV), R ¹ and R ² are preferably groups in which R ¹ and R ² are selected from a hydrogen atom and a monovalent hydrocarbon group having 1 to 20 carbon atoms, or R ¹ and R ² are bonded to a divalent hydrocarbon radical which forms a number 5 to 8 ring structure carbon manufacturing method according to [11] or [12].
[14] In formula (III) and formula (IV), preferably R ¹ is a hydrogen atom, R ² is a hydrogen atom or a monovalent hydrocarbon group, more preferably R ¹ is a hydrogen atom, R ² is a hydrogen atom or a monovalent hydrocarbon group having 1 to 20 carbon atoms, and the hydrocarbon group of R ² is preferably an alkyl group or an aryl group, and the carbon number of the alkyl group is preferably Is 1 or more, preferably 20 or less, more preferably 18 or less, still more preferably 16 or less, still more preferably 14 or less, still more preferably 12 or less, still more preferably 10 or less, and still more preferably 8 or less. , even more preferably 6 or less, still more preferably 4 or less, still more preferably 2 or less, the alkyl group may be branched be straight, also, an aryl group of R ² The number of carbon atoms is preferably 6 or more, preferably 20 or less, more preferably 18 or less, still more preferably 16 or less, still more preferably 14 or less, still more preferably 12 or less, even more preferably 10 or less, and more. More preferably, it is 8 or less, more preferably 6 or less, and R ² is more preferably a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group having 1 to 8 carbon atoms, or a carbon number. The production method according to any one of [11] to [13], which is an aryl group having 6 or more and 14 or less, more preferably a hydrogen atom, a methyl group or a phenyl group, and still more preferably a hydrogen atom.
[15] In formula (III) and formula (IV), R ¹ is preferably a monovalent hydrocarbon group having 1 to 8 carbon atoms and R ² is a monovalent hydrocarbon group having 2 to 8 carbon atoms, More preferably, R ¹ is an alkyl group having 1 to 8 carbon atoms and R ² is an alkyl group having 2 to 8 carbon atoms, more preferably R ¹ is an alkyl group having 1 or 2 carbon atoms and R ² is ² carbon atoms. An alkyl group having 6 or less, more preferably R ¹ is an alkyl group having 1 or 2 carbon atoms and R ² is an alkyl group having 2 to 4 carbon atoms, and even more preferably, R ¹ is a methyl group and R ² is an ethyl group. And R ¹ and R ² are divalent hydrocarbon groups that are bonded to each other to form a ring structure, preferably a divalent hydrocarbon group having 2 to 7 carbon atoms, more preferably 3 or more carbon atoms. 6 or less divalent hydrocarbon group, more preferably 4 to 5 carbon atoms Divalent hydrocarbon radical, even more preferably a divalent hydrocarbon group having 5 carbon atoms, the ring structure comprising R ¹ and R ^2, preferably 3 to 8-membered ring, more preferably 4-7 membered A ring, more preferably a 5- to 6-membered ring, still more preferably a 6-membered ring, and the ring structure containing R ¹ and R ² is preferably a cycloalkane structure, more preferably a ring having 5 or 6 carbon atoms. The production method according to any one of [11] to [13], which has a structure (cyclopentane ring or cyclohexane ring), and more preferably a cyclohexane ring.

[16] The production method according to [1] to [15], wherein the compound B is a compound selected from a salt containing an organic nitroxy radical and an oxoammonium cation thereof.
[17] The organic nitroxyl radical is a compound represented by the following formula (VIII), a compound represented by the following formula (IX), or a compound represented by the following formula (X): [16] The production method according to any one of [16].

(In the formula (VIII), R ⁴ is a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, an amino group, an acylamino group, a sulfonyloxy group, an N-alkylcarbamoyloxy group, a carboxy group, a cyano group. Represents an isocyanato group, an isothiocyanato group, or an oxo group, preferably an alkoxy group, an acyloxy group, or an acylamino group, wherein R ⁵ and R ⁶ each independently represent a hydrogen atom or a methyl group; In formula (X), R ⁷ and R ⁸ each independently represents a hydrogen atom or a methyl group.)

  [18] The production method according to any one of [1] to [15], wherein the compound B is an N-hydroxy form of an organic nitroxyl radical.

[19] One or more compounds selected from the organic nitroxyl radical, its N-hydroxy form, and a salt containing an oxoammonium cation thereof are preferably TEMPO, 4-hydroxy TEMPO, 4-amino-TEMPO, 4 -Methoxy-TEMPO (hereinafter also referred to as "4-OMe-TEMPO"), 4-ethoxy-TEMPO, 4-phenoxy-TEMPO, 4-acetoxy-TEMPO, 4-benzoyloxy-TEMPO (hereinafter referred to as "4-OBz"). -TEMPO "), 4-methacrylate-TEMPO, 4-acetamido-TEMPO (hereinafter also referred to as" 4-NHAc-TEMPO "), 4-methylsulfonyloxy-TEMPO (hereinafter" 4-OMs-TEMPO "). And 4-paratoluenesulfonyl. Oxy-TEMPO, 4-oxo-TEMPO, 2-azaadamantane-N-hydroxyl (hereinafter also referred to as “AZADOL”), 2-azaadamantane-N-oxyl (hereinafter also referred to as “AZADO”), 1- Methyl-2-azaadamantane-N-oxyl (hereinafter also referred to as “1-Me-AZADO”), 9-azanoradamantane-N-oxyl (hereinafter also referred to as “nor-AZADO”), 1,5 -Dimethyl-9-azanoradamantane-N-oxyl (hereinafter also referred to as "DMM-AZADO"), more preferably 4-methoxy-TEMPO, 4-benzoyloxy-TEMPO, 4-acetamido-TEMPO, 4-methyl Compounds selected from sulfonyloxy-TEMPO and AZADOL, more preferably 4-benzo Yloxy -TEMPO, 4-acetamido -TEMPO, is a compound selected from 4-methylsulfonyloxy -TEMPO and AZADOL, The process according to any one of [1] to [18].
[20] The amount of the compound B selected from the salt containing the organic nitroxyl radical, its N-hydroxy isomer, and their oxoammonium cation is the compound represented by the formula (I) or the formula (I). With respect to the compound A represented, the molar ratio is 0.0001 or more, preferably the molar ratio is 0.0002 or more, more preferably the molar ratio is 0.0005 or more, and the molar ratio is 0.1 or less, preferably The manufacturing method in any one of [1]-[19] whose molar ratio is 0.05 or less, More preferably, molar ratio is 0.02 or less.

[21] The oxidizing agent is preferably an oxidizing agent (halogen-containing oxidizing agent) made of a halogen-containing compound, more preferably an oxidizing agent (chlorine-containing oxidizing agent) made of a compound containing chlorine, more preferably trichloroisocyanuric. The manufacturing method according to any one of [1] to [20], wherein the oxidizing agent is selected from an acid and tertiary butyl hypochlorite, more preferably trichloroisocyanuric acid.
[22] The molar ratio of the oxidizing active species of the oxidizing agent to the compound represented by the formula (I) or the mixture of the compound represented by the formula (I) and the compound represented by the formula (V) However, Preferably it is 1.0 or more, More preferably, it is 1.1 or more, Preferably it is 2.0 or less, More preferably, it is 1.5 or less, The manufacture in any one of [1]-[21] Method.
[23] The molar ratio of the pyridine having an alkyl substituent to the compound represented by the formula (I) or the mixture of the compound represented by the formula (I) and the compound represented by the formula (V) is: Preferably it is 1.0 or more, more preferably 1.1 or more, still more preferably 1.2 or more, still more preferably 1.3 or more, and the molar ratio is preferably 2.5 or less, more preferably 2 The production method according to any one of [1] to [22], which is 0.0 or less, more preferably 1.7 or less.

[24] In the step of oxidative esterification of the compound represented by the formula (I), a solvent is preferably used, and the solvent is preferably selected from acetone, 2-butanone, cyclopentanone, acetonitrile and dichloromethane. [1] to [23], more preferably a solvent selected from acetone, 2-butanone, acetonitrile and dichloromethane, more preferably a solvent selected from acetone and 2-butanone, and further preferably acetonitrile. The manufacturing method in any one of.
[25] The amount of the solvent used relative to the entire reaction system is preferably 20% by mass or more, more preferably 30% by mass or more, still more preferably 40% by mass or more, still more preferably 50% by mass or more, and still more preferably 60%. The production method according to [24], wherein the content is 90% by mass or less, preferably 90% by mass or less, more preferably 85% by mass or less, and still more preferably 80% by mass or less.

[26] In the step of oxidative esterification of the compound represented by the formula (I) or the mixture of the compound represented by the formula (I) and the compound represented by the formula (V), preferably an oxidizing agent The manufacturing method according to [1] to [25], wherein an oxidizing agent or an oxidizing agent solution is dropped into a mixture or mixed solution of raw materials other than the above.
[27] The temperature of the reaction solution during dropping of the oxidizing agent or oxidizing agent solution is preferably −15 ° C. or higher, more preferably −10 ° C. or higher, preferably 25 ° C. or lower, more preferably 10 ° C. or lower. The manufacturing method according to [26].
[28] The production method according to [26] or [27], wherein the reaction is continued until the total amount of dioxolane reacts or the decrease in the residual amount stops after the addition of the oxidizing agent or the oxidizing agent solution.
[29] The production method according to [28], wherein the temperature of the reaction solution is preferably −10 ° C. or higher, more preferably −5 ° C. or higher, preferably 50 ° C. or lower, more preferably 30 ° C. or lower. .

[30] The production method according to any one of [1] to [29], preferably using alcohol as a reaction terminator.
[31] The production method according to [30], wherein the reaction terminator is preferably a primary or secondary alcohol, and more preferably a secondary alcohol.
[32] The production method according to [30] or [31], wherein the reaction terminator is preferably an alcohol having 1 to 12 carbon atoms.

[33] After the step of oxidative esterification of the compound represented by the formula (I), or preferably the mixture of the compound represented by the formula (I) and the compound represented by the formula (V), The manufacturing method in any one of [1]-[32] which has the process (process 3) which isolate | separates the compound represented by Formula (II).
[34] The production method according to [33], wherein the separation in the step 3 is separation by distillation.
[35] The production method according to [34], wherein the separation by distillation is preferably performed under rectification conditions.
[36] The rectification conditions are such that the theoretical plate number of the rectification column is preferably 2 or more, more preferably 5 or more, and the reflux ratio is preferably 0.1 or more, more preferably 0.5 or more. The production method according to [35], wherein the theoretical plate of the rectification column is preferably 20 plates or less, more preferably 10 plates or less, and the reflux ratio is preferably 20 or less, more preferably 10 or less.
[37] Glyceric acid, glycerate, or deprotected glyceric acid ester, which hydrolyzes or alcoholates the compound represented by formula (II) separated in any of [33] to [36] Manufacturing method.
[38] The production method according to [37], wherein the alcohol used for the alcoholysis is preferably a primary alcohol, more preferably a primary alcohol having 1 to 3 carbon atoms.
[39] The production method according to [37], wherein the alcohol used for the alcoholysis is more preferably a linear or branched primary alcohol having 4 to 8 carbon atoms.

[Identification of compounds]
Each compound obtained in the following Production Examples, Examples or Comparative Examples (hereinafter also referred to as “Examples”) is a nuclear magnetic resonance apparatus (NMR, manufactured by Agilent Technologies, Inc., Model: Agilent 400-MR). DD2), spectrum using an infrared spectrophotometer (IR, manufactured by Horiba, Ltd., model: FT-710), gas chromatograph mass spectrometer (GC-MS, manufactured by Agilent Technologies, model: Agilent 5975C) Identified by analysis.

[Purity of manufactured or purified compound]
In the following Examples and the like, the purity of the produced or purified compound was determined by analysis (GC analysis) using a gas chromatograph (manufactured by Agilent Technologies, Inc., model: Agilent 6850). Note that “%” relating to purity means “GC%”, and this value was used when converting the raw material of the reaction raw material or the high-purity sample into a pure amount.

[Units, conversion and yield]
The conversion rates of reaction raw materials and product yields shown in the following examples and the like were determined by internal standard method quantitative GC analysis. A calibration curve necessary for quantitative analysis was prepared using a high-purity sample purified from a commercially available sample or reaction mixture by distillation or silica gel column chromatography. However, the yield of formyldioxolane was calculated by substituting the corresponding calibration curve of dioxanone.

[Measurement conditions for GC and GC-MS]
The measurement conditions for GC and GC-MS are as follows.
Column: Ultra ALLOY-1 (MS / HT) (Frontier Labs, trademark, inner diameter 0.25 mm, film thickness 0.15 μm, length 30 m)
Carrier gas: helium, 1.0 mL / min
Injection conditions: 250 ° C., split ratio 1/50
Detection condition: FID method, 220 ° C
Column temperature condition: held at 40 ° C. for 5 minutes, then raised to 350 ° C. at 10 ° C./min.
Ion source temperature: 230 ° C
Interface temperature: 350 ° C

Production Example: Production of 2,2-dialkyl-4-hydroxymethyl-2-methyl-1,3-dioxolane as a raw material The reaction carried out in the production example is as follows.

Production Example 1: Production of 2-ethyl-4-hydroxymethyl-2-methyl-1,3-dioxolane (R ¹ = Me, R ² = Et) as a raw material To a 1 L flask equipped with a Dean-Stark apparatus, glycerol 184 g (purity 100%, 2.00 mol), 2-butanone 162 g (purity 98.0%, 2.20 mol), methanesulfonic acid 981 mg (purity 98.0%, 10.0 mmol), n-hexane 50 g And refluxed for 5 hours while removing water produced as a by-product in the reaction. After cooling, the solution was neutralized with 3.50 g of a 20% ethanol solution of sodium ethoxide (700 mg as sodium ethoxide, 10.3 mmol). As a result of GC analysis of the reaction solution, the reaction yield of a mixture of cis and trans isomers of 2-ethyl-4-hydroxymethyl-2-methyl-1,3-dioxolane was 74%.
Subsequently, the reaction solution was transferred to a 500 mL flask equipped with a Claisen head, heated to 50 ° C. and then gradually reduced in pressure to distill off n-hexane and ethanol, and then further reduced under a reduced pressure of 0.13 kPa (absolute pressure). Distillation was performed to obtain 220 g of an isomer mixture distilled as a colorless liquid at a fraction temperature of 91 to 94 ° C. The purity was 95.3% and the distillation yield was 97%.
<Spectral data of isomer mixture>
IR (neat, cm ⁻¹ ): 3465 (br), 2993, 2935, 2883, 1466, 1375, 1190, 1078, 1041, 876.
MS (m / z): 131, 117, 57, 43.

Production Example 2: Production of 2-hydroxymethyl-1,4-dioxaspiro [4.5] decane (R ¹ , R ² = — (CH ₂ ) ₅ —) as a raw material 218 g of cyclohexanone (purity 99.0%, 2 .20 mol) was used as a reaction raw material, and the same operation as in Production Example 1 was performed to obtain 2-hydroxymethyl-1,4-dioxaspiro [4.5] decane in a reaction yield of 80%.
Furthermore, simple distillation was performed under reduced pressure of 0.13 kPa (absolute pressure) to obtain 297 g of a colorless liquid distilled at a fraction temperature of 123 to 126 ° C. The purity was 97.0% and the distillation yield was 95%.
<Spectral data>
¹ H-NMR (400 MHz, CDCl ₃ , δ _ppm ): 1.37-1.42 (2H, m), 1.54-1.63 (8H, m), 2.30 (1H, s), 3.56-3.61 (1H, m), 3.70-3.80 (2H, m), 4.02-4.05 (1H, m), 4.21-4.25 (1H, m ).
^{· 13 C-NMR (100MHz,} CDCl 3, δ ppm): 23.7,24.0,25.1,34.7,36.3,63.1,65.3,75.7,110.0 .
IR (neat, cm ⁻¹ ): 3423 (br), 2933, 2860, 1448, 1365, 1281, 1163, 1097, 1039, 926.
MS (m / z): 172 (M ^<+> ), 143, 129, 116, 81, 73, 55, 41, 31.

Example 1 and Comparative Example 1: Production of 1,3-dioxolane-4-carboxylic acid (1,3-dioxolan-4-yl) methyl ester The reaction carried out in Example 1 and Comparative Example 1 was as follows. is there.

Example 1-1
In a 50 mL flask equipped with a 20 mL dropping funnel, 3.19 g of a mixture of 1,3-dioxane-5-ol and 4-hydroxymethyl-1,3-dioxolane (product of Tokyo Chemical Industry Co., Ltd., trade name glycerol formal, purity 98) 0.0%, 30.0 mmol, Reference 1 (Journal of Catalysis, Vol. 245, pp. 428-435, 2007) contains the protons at the 2-position of the two isomers. ¹ H-NMR signal assignments are described, and the isomer ratio of 1,3-dioxane-5-ol and 4-hydroxymethyl-1,3-dioxolane determined from this information and ¹ H-NMR analysis is 58. 42), 2-hydroxy-2-azaadamantane 4.7 mg (AZADOL, Nissan Chemical Industries Ltd.) Company, trademark, purity 98.0%, 30 micromole), 3,5-lutidine 4.92 g (purity 98.0%, 45.0 mmol) and 2-butanone 10 g were charged under cooling in a nitrogen atmosphere. Stir. A solution prepared by dissolving 2.94 g of TCCA (purity 95.0%, 12.0 mmol) in 10 g of 2-butanone was charged into a dropping funnel so that the temperature of the reaction solution in the flask was within a range of −10 ° C. to 10 ° C. It dropped over 1 hour, adjusting a dropping speed. Stirring was continued for 2 hours while cooling was stopped and the temperature of the reaction solution was raised to about 25 ° C. Finally, 0.20 g of 2-propanol (purity 99.7%, 3.3 mmol) was added, and further 10 The reaction was completed by stirring for a minute. GC analysis of the filtrate after filtering off the by-product powdered solid revealed that the conversion rate of 4-hydroxymethyl-1,3-dioxolane was 100% and 1,3-dioxolane-4-carboxylic acid (1,3-dioxolane) The yield of -4-yl) methyl ester was 91%, and the recovery rate relative to the amount of unreacted 3,5-lutidine charged was 18%.
When a mixed solution of 50 g of tert-butyl methyl ether in which the entire amount of the filtrate was dispersed and 25 g of ion-exchanged water was stirred, a 2 mol / L sodium hydroxide aqueous solution was added dropwise until the pH of the aqueous layer became 12 or more. At the end of dropping, all of the filtrate was dissolved in oil water. As a result of GC analysis of the tert-butyl methyl ether solution from which the aqueous layer was removed by oil-water separation, the recovery rate with respect to the charged amount of 3,5-lutidine was 76%, and the total recovery rate was 94%.

Example 1-2
The same operation as in Example 1-1 was performed except that the types of base and solvent were changed. The reaction conditions and results of Example 1-2 are shown in the table.

Comparative Example 1-1
In a 1 L flask equipped with a 100 mL dropping funnel, glycerol formal 63.7 g (purity 98.0%, 600 mmol), AZADOL 93.8 mg (AZADOL, degree 98.0%, 0.60 mmol), pyridine 71.5 g ( (Purity 99.5%, 900 mmol) and 150 g of acetonitrile were charged and stirred under cooling in a nitrogen atmosphere. A solution prepared by dissolving 58.7 g of trichloroisocyanuric acid (TCCA, purity 95.0%, 240 mmol) in 150 g of acetonitrile was charged in three portions into a dropping funnel, and the reaction solution temperature in the flask was −2 ° C. to 2 ° C. It dripped over 3.5 hours, adjusting dripping speed | rate so that it might be settled in the range. Stirring was continued for 4 hours while cooling was stopped and the temperature of the reaction solution was raised to around 20 ° C. Finally, 7.23 g of 2-propanol (purity 99.7%, 120 mmol) was added and stirred for another 20 minutes. To complete the reaction. 100 g of tert-butyl methyl ether was added to the reaction solution in which acetonitrile was distilled off after filtering off the powdery solid produced as a by-product, and the filtered powdered solid and solvent distillation were repeated twice to obtain an orange oily crude 70.5 g of product was obtained. As a result of GC analysis of the crude product, the conversion rate of 4-hydroxymethyl-1,3-dioxolane was 100% and 1,3-dioxolane-4-carboxylic acid (1,3-dioxolan-4-yl) methyl ester was The yield was 95%, and the recovery rate relative to the amount of unreacted pyridine charged was 24%.
When a mixed solution of 500 g of tert-butyl methyl ether and 250 g of ion-exchanged water in which the entire amount of the filtrate had been dispersed was stirred, an 8 mol / L aqueous sodium hydroxide solution was added dropwise until the pH of the aqueous layer became 12 or more. At the end of dropping, all of the filtrate was dissolved in oil water. As a result of GC analysis of the tert-butyl methyl ether solution from which the aqueous layer was removed by oil-water separation, the recovery rate relative to the charged amount of 3,5-lutidine was 41%, and the total recovery rate was 65%.
Into a 200 mL pear-type flask equipped with a 6-stage packed distillation column (packing: Helipac Packing No. 2), 65.0 g of the crude product was charged, 0.13 kPa (absolute pressure), reflux ratio 0.1 Then, 21.9 g of 1,3-dioxolane-4-carboxylic acid (1,3-dioxolan-4-yl) methyl ester distilled out as a pale yellow liquid at a fraction temperature of 89 to 91 ° C. was obtained. The purity was 98.8% and the distillation yield was 96%. ¹³ C-NMR analysis suggested that this ester dimer was a stereoisomer mixture consisting of two racemates. For the other two sets of racemates, it is presumed that the peaks overlapped and could not be detected.
<Spectral data of 1,3-dioxolane-4-carboxylic acid (1,3-dioxolan-4-yl) methyl ester (stereoisomer mixture)>
IR (neat, cm ⁻¹ ): 2956, 2856, 1751, 1284, 1151, 1082, 1016, 916.
MS (m / z): 204 (M ^<+> ), 159, 129, 86, 73, 57, 45.
FIG. 1 shows a GC chart of the reaction solution.

Comparative Examples 1-2 and 1-3
The same operation as in Example 1-1 was performed except that the type of base and solvent was changed. The reaction conditions and results of Comparative Examples 1-2 and 1-3 are shown in the table.

Examples 2, 3, 4 and Comparative Examples 2, 3, 4: 2,2-dialkyl-1,3-dioxolane-4-carboxylic acid (2,2-dialkyl-1,3-dioxolan-4-yl) methyl Production of ester The reaction carried out in the examples is as follows.

Example 2 and Comparative Example 2: 2,2-Dimethyl-1,3-dioxolan-4-carboxylic acid (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester (R ¹ , R ² = Production Example 2-1 of Me)
4.05-g of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane (Tokyo Chemical Industry Co., Ltd., trade name: 2,2-dimethyl-1,3-dioxolane-4-methanol, purity: 98.0% 30.0 mmol) was used as a reaction raw material, and the same operation as in Example 1-1 was performed except that the reaction conditions were changed as described in the table. As a result of GC analysis of the filtrate, the conversion rate of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane was 100%, and 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (2,2 The yield of -dimethyl-1,3-dioxolan-4-yl) methyl ester was 69%.
The recovery rate relative to the amount of unreacted 2,6-lutidine charged in the filtrate was 15%, the recovery rate of 2,6-lutidine regenerated by alkali treatment of the filtrate was 76%, and the total recovery rate was 91%.

Comparative Example 2-1
In a 300 mL flask equipped with a 100 mL dropping funnel, 20.2 g of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane (purity 98.0%, 150 mmol), 2-hydroxy-2-azaadamantane 23. 4 mg (AZADOL, Nissan Chemical Industries, Ltd., trademark, purity 98.0%, 150 μmol), 17.9 g of pyridine (purity 99.5%, 225 mmol), and 50 g of acetonitrile were charged under a nitrogen atmosphere while cooling. Stir. A solution prepared by dissolving 14.7 g of trichloroisocyanuric acid (TCCA, purity 95.0%, 60.0 mmol) in 50 g of acetonitrile was charged into a dropping funnel, and the reaction liquid temperature in the flask was kept in the range of −2 ° C. to 10 ° C. The dropwise addition was performed over 2 hours while adjusting the dropping rate. Stirring was continued for 3 hours while cooling was stopped and the temperature of the reaction solution was raised to about 20 ° C. Finally, 1.81 g of 2-propanol (purity 99.7%, 30.0 mmol) was added, and further 20 The reaction was completed by stirring for a minute. As a result of GC analysis of the filtrate after filtering off the powdery solid produced as a by-product, 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (2,2-dimethyl-1,3-dioxolan-4-yl) was obtained. The yield of methyl ester was 70%, and the recovery rate relative to the amount of unreacted pyridine charged was 19%.
When a mixed solution of 300 g of tert-butyl methyl ether in which the entire amount of the filtrate was dispersed and 150 g of ion-exchanged water was stirred, an 8 mol / L aqueous sodium hydroxide solution was added dropwise until the pH of the aqueous layer became 12 or more. At the end of dropping, all of the filtrate was dissolved in oil water. As a result of GC analysis of the tert-butyl methyl ether solution from which the aqueous layer was removed by oil-water separation, the recovery rate relative to the charged amount of pyridine was 38%, and the total recovery rate was 57%.
In order to remove the powdered solid precipitated after distilling off acetonitrile from the filtrate, 100 g of tert-butyl methyl ether and 50 g of ion-exchanged water were added for extraction. Lower layer water was extracted after the stationary separation, and 50 g of ion exchange water was added again to repeat extraction to extraction of the lower layer water. The obtained organic layer was dried over 20 g of anhydrous sodium sulfate, and after filtration, tert-butyl methyl ether was distilled off to obtain 15.1 g of a dark orange oily crude product. As a result of GC analysis of the crude product, the yield of 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester was 59%. Met.
Subsequently, 14.1 g of the crude product was transferred to a 50 mL flask equipped with a Claisen head, subjected to simple distillation under a reduced pressure of 0.13 kPa (absolute pressure), and distilled as a colorless liquid at a fraction temperature of 103 to 106 ° C. There were obtained 8.20 g of 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester. The purity was 98.7% and the distillation yield was 97%. ^{From 13} C-NMR analysis, this ester dimer was found to be a stereoisomer mixture composed of two racemates.
<Spectral data of stereoisomer mixture>
IR (neat, cm ⁻¹ ): 2987, 2939, 1759, 1734, 1371, 1192, 1153, 1099, 1066, 837.
MS (m / z): 259, 245, 186, 130, 115, 101, 73, 59, 43.

Comparative Example 2-2
The same operation as in Example 2 was performed except that the type of base was changed. The reaction conditions and results of Comparative Example 2-2 are shown in the table.

Example 3 and Comparative Example 3: 2-ethyl-2-methyl-1,3-dioxolane-4-carboxylic acid (2-ethyl-2-methyl-1,3-dioxolan-4-yl) methyl ester (R ¹ = Me, R ² = Et) Production Example 3
Example 1 Using 4.60 g (purity 95.3%, 30.0 mmol) of 2-ethyl-4-hydroxymethyl-2-methyl-1,3-dioxolane obtained in Production Example 1 as a reaction raw material, Example 1 The same operation as -1 was performed. As a result of GC analysis of the filtrate, conversion of 2-ethyl-4-hydroxymethyl-2-methyl-1,3-dioxolane was 100% and 2-ethyl-2-methyl-1,3-dioxolane-4-carboxylic acid The yield of (2-ethyl-2-methyl-1,3-dioxolan-4-yl) methyl ester was 73%.
The recovery rate relative to the amount of unreacted 3,5-lutidine charged in the filtrate was 15%, the recovery rate of 3,5-lutidine regenerated by alkali treatment of the filtrate was 66%, and the total recovery rate was 81%.

Comparative Example 3-1
Comparative Example 2-1 using 23.0 g (purity 95.3%, 150 mmol) of 2-ethyl-4-hydroxymethyl-2-methyl-1,3-dioxolane obtained in Production Example 1 as a reaction raw material The same operation was performed. As a result of GC analysis of the filtrate, conversion of 2-ethyl-4-hydroxymethyl-2-methyl-1,3-dioxolane was 100% and 2-ethyl-2-methyl-1,3-dioxolane-4-carboxylic acid The yield of (2-ethyl-2-methyl-1,3-dioxolan-4-yl) methyl ester was 74%.
The recovery rate with respect to the charged amount of unreacted pyridine in the filtrate was 21%, the recovery rate of regenerated pyridine by alkali treatment of the filtrate was 29%, and the total recovery rate was 50%.
2-ethyl-2-methyl-1,3-dioxolane-4-carboxylic acid (2-ethyl-2-methyl-) obtained by GC analysis of 19.8 g of a red oily crude product obtained after washing with water of the filtrate The yield of 1,3-dioxolan-4-yl) methyl ester was 72%.
Subsequently, 17.0 g of the crude product is subjected to simple distillation under a reduced pressure of 40 Pa (absolute pressure), and 2-ethyl-2-methyl-1,3-distilled as a pale yellow liquid at a fraction temperature of 119 to 122 ° C. 11.6 g of dioxolane-4-carboxylic acid (2-ethyl-2-methyl-1,3-dioxolan-4-yl) methyl ester was obtained. The purity was 98.1% and the distillation yield was 80%. GC-MS analysis suggested that this ester dimer was a stereoisomer mixture consisting of at least three racemates. For other racemates, it is presumed that peaks were overlapped and could not be detected.
<Spectral data of stereoisomer mixture>
IR (neat, cm ⁻¹ ): 2979, 2939, 2883, 1761, 1736, 1377, 1186, 1072, 874.
MS (m / z, common to 3 peaks on GC): 287, 273, 259, 115, 57, 43.

Comparative Example 3-2
The same operation as in Example 3 was performed except that the type of base was changed. The table shows the reaction conditions and results of Comparative Example 3-2.

Example 4 and Comparative Example 4: 1,4-Dioxaspiro [4.5] decane-2-carboxylic acid (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester (R ¹ , R ² = Production Example 4 of — (CH ₂ ) ₅ —)
Example 1-1 was used using 5.32 g (purity 97.0%, 30.0 mmol) of 2-hydroxymethyl-1,4-dioxaspiro [4.5] decane obtained in Production Example 2 as a reaction raw material. The same operation was performed. As a result of GC analysis of the filtrate, the conversion of 2-hydroxymethyl-1,4-dioxaspiro [4.5] decane was 100%, and 1,4-dioxaspiro [4.5] decane-2-carboxylic acid (1,4 The yield of -dioxaspiro [4.5] decan-2-yl) methyl ester was 70%.
The recovery rate of the unreacted 3,5-lutidine in the filtrate with respect to the charged amount was 32%, the recovery rate of 3,5-lutidine regenerated by alkali treatment of the filtrate was 55%, and the total recovery rate was 87%.

Comparative Example 4-1
As in Comparative Example 2-1, 26.6 g (purity 97.0%, 150 mmol) of 2-hydroxymethyl-1,4-dioxaspiro [4.5] decane obtained in Production Example 2 was used as a reaction raw material. Was performed. As a result of GC analysis of the filtrate, the conversion of 2-hydroxymethyl-1,4-dioxaspiro [4.5] decane was 100%, and 1,4-dioxaspiro [4.5] decane-2-carboxylic acid (1,4 The yield of -dioxaspiro [4.5] decan-2-yl) methyl ester was 66%.
The recovery rate relative to the amount of unreacted pyridine charged was 18%, the recovery rate of regenerated pyridine by alkali treatment of the filtrate was 34%, and the total recovery rate was 52%.
1,4-dioxaspiro [4.5] decane-2-carboxylic acid (1,4-dioxaspiro [4.4]) obtained by GC analysis of 23.5 g of a dark orange oily crude product obtained after washing with water of the filtrate 5] The yield of decan-2-yl) methyl ester was 66%.
Subsequently, 6.50 g of the crude product is distilled under a reduced pressure of 40 Pa (absolute pressure) using a Kugelrohr distillation apparatus, and 1,4-dioxaspiro [4] distilled as an orange liquid at an apparatus temperature of 225 to 240 ° C. .5] 2.89 g of decane-2-carboxylic acid (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester was obtained. The purity was 95.6% and the distillation yield was 60%. ^{From 13} C-NMR analysis, this ester dimer was found to be a mixture of four stereoisomers consisting of two racemates.
<Spectral data of stereoisomer mixture>
IR (neat, cm ⁻¹ ): 2933, 2862, 1761, 1738, 1448, 1367, 1161, 1097, 922.
MS (m / z): 340 (M ^<+> ), 311, 297, 242, 199, 141, 127, 55.

Comparative Example 4-2
The same operation as in Example 4 was performed except that the type of base was changed. The table shows the reaction conditions and results of Comparative Example 4-2.
The following table shows the reaction conditions and results of the above examples and comparative examples.

  In Example 1 and Example 2, Example 1 and Example 2 except that the conditions such as Compound A, Compound B (catalyst), oxidizing agent, base, solvent, etc. used were changed as shown in Table 2 below. As well as. The results are shown in Table 2 below.

Example 5: Production of ethyl glycerate The reaction carried out in Example 5 is as follows.

2-ethyl-2-methyl-1,3-dioxolane-4-carboxylic acid (2-ethyl-2-methyl-1,3-dioxolan-4-yl) methyl ester 5.00 g obtained in Comparative Example 3 ( Purity 98.1%, 17.0 mmol), methanesulfonic acid 83 mg (purity 98.0%, 0.85 mmol), ethanol 39.4 g (purity 99.5%, 850 mmol) were charged into a 100 mL flask, Refluxed for 2 hours. After cooling, the mixture was neutralized with 290 mg of a 20% ethanol solution of sodium ethoxide (58 mg as sodium ethoxide, 0.85 mmol), and ethanol was distilled off. Subsequently, 8.75 g of the obtained orange oily crude product was purified with a Kugelrohr distillation apparatus. Under conditions of 0.13 kPa (absolute pressure) and an apparatus temperature of 150 to 155 ° C., 1.53 g of ethyl glycerate distilled as a colorless liquid was obtained. The purity was 93.5% and the yield was 63%.
<Spectral data of ethyl glycerate>
^{· 1 H-NMR (400MHz,} CDCl 3, δ ppm): 1.31 (3H, t, J = 6.8Hz), 3.82-3.92 (2H, m), 4.24-4.30 (3H, m) The ¹ H peak of the hydroxyl group was broad and could not be detected.
^{· 13 C-NMR (100MHz,} CDCl 3, δ ppm): 14.1,62.0,64.1,71.8,173.0.
IR (neat, cm ⁻¹ ): 3425 (br), 2974, 2935, 1728, 1201, 1111, 1063, 1020.
MS (m / z): 134 (M ^<+> ), 104, 76, 61, 43, 31.

  According to the production method of the present invention, the ester dimer of the present invention (a glycerate ester in which the hydroxyl groups at the 2nd and 3rd positions are protected as cyclic acetal groups) can be obtained easily and in high yield, and further used for the reaction. Reuse of pyridines is easy. The ester dimer obtained by the present invention is useful as a synthetic intermediate such as glyceric acid and deprotected glyceric acid ester used as raw materials for various pharmaceuticals, cosmetics, detergents, polymers and the like.

Claims (11)

Compound A represented by the following formula (I) is oxidized in the presence of pyridine having an alkyl substituent from a compound B containing an organic nitroxyl radical, an N-hydroxy form thereof, and a salt containing an oxoammonium cation thereof, and oxidation. And the amount of the compound B used is represented by the following formula (II), wherein the molar ratio of the compound B to the compound A is 0.0001 or more and 0.1 or less. Compound production method.

(In formula (I), R ¹ is a hydrogen atom, and R ² is a hydrogen atom or a monovalent hydrocarbon group.)

(In formula (II), R ¹ is a hydrogen atom, and R ² is a hydrogen atom or a monovalent hydrocarbon group.) Compound A represented by the following formula (I) is oxidized in the presence of pyridine having an alkyl substituent from a compound B containing an organic nitroxyl radical, an N-hydroxy form thereof, and a salt containing an oxoammonium cation thereof, and oxidation. A step of oxidative esterification using an agent, wherein the amount of the compound B used relative to the compound A is 0.0001 or more and 0.1 or less, and the pyridine having the alkyl substituent is A pyridine having an alkyl substituent at at least one position selected from the 3-position, the 4-position, and the 5-position and having no alkyl substituent at the 2-position and the 6-position, and the compound B is an organic nitroxyl radical and And a method for producing a compound represented by the following formula (II), which is a compound selected from salts containing the oxoammonium cation.

(In formula (I), R ¹ and R ² each independently represent a hydrogen atom or a monovalent hydrocarbon group, or R ¹ and R ² are bonded to each other to form a ring structure. Represents a hydrocarbon group.)

(In formula (II), R ¹ and R ² each independently represent a hydrogen atom or a monovalent hydrocarbon group, or R ¹ and R ² are bonded to each other to form a ring structure. Represents a hydrocarbon group.) A mixture of the compound A represented by the following formula (I) and the compound represented by the following formula (V) in the presence of a pyridine having an alkyl substituent, an organic nitroxyl radical, its N-hydroxy form, and their A compound B selected from a salt containing an oxoammonium cation and an oxidative esterification step using an oxidizing agent, wherein the amount of the compound B used relative to the compound A is 0.0001 or more and 0.1. The manufacturing method of the compound represented by following formula (II) which is the following.

(In Formula (I) and Formula (V), R ¹ and R ² each independently represent a hydrogen atom or a monovalent hydrocarbon group, or R ¹ and R ² are bonded to each other to form a ring structure. Represents a divalent hydrocarbon group to be formed.)

(In formula (II), R ¹ and R ² each independently represent a hydrogen atom or a monovalent hydrocarbon group, or R ¹ and R ² are bonded to each other to form a ring structure. Represents a hydrocarbon group.) In the compounds A, R ¹ is hydrogen atom, R ² is a hydrocarbon group of a hydrogen atom or a monovalent method according to claim 2 or 3. The production method according to claim 2 or 3 , wherein, in the compound A, R ¹ and R ² are monovalent hydrocarbon groups. Said compound B is a N- hydroxy of organic nitroxyl radical, The process according to any one of claims 1-5. The number of carbon atoms of the alkyl substituents is 1 to 4 independently, the manufacturing method according to any one of claims 1-6. The organic nitroxyl radical is a compound represented by the following formula (VIII), a compound represented by the compound represented by the following formula (IX), or the following formula (X), one of the claim 1-7 The manufacturing method of crab.

(In the formula (VIII), R ⁴ is a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group, an acyloxy group, an alkoxycarbonyl group, an amino group, an acylamino group, a sulfonyloxy group, an N-alkylcarbamoyloxy group, a carboxy group, a cyano group. Represents an isocyanato group, an isothiocyanato group, or an oxo group, and in formula (IX), R ⁵ and R ⁶ each independently represents a hydrogen atom or a methyl group, and in formula (X), R ⁷ and R ⁸ represent Each independently represents a hydrogen atom or a methyl group.) The manufacturing method according to any one of claims 1 to 8 , wherein the oxidizing agent is an oxidizing agent comprising a compound containing chlorine. After the step of oxidative esterification of the compound of formula (I), a step of separating the compound represented by Formula (II), The process according to any one of claims 1-9. The production method according to claim 10 , wherein the step of separating the compound represented by the formula (II) is separation by distillation.