JP6402239B2 - Method for producing glyceric acid ester - Google Patents

Description

  The present invention relates to a method for producing a novel 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 examples of compounds 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 Documents 1 to 4 include 4-hydroxymethyl-2,2 that can be produced from glycerol and acetone. -2,2-dimethyl-1,3-dioxolane-4-carboxylic acid by dimerization reaction of dimethyl-1,3-dioxolane or its oxidized 4-formyl-2,2-dimethyl-1,3-dioxolane A preparation example of acid (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester is described.

Synlett, Vol. 10, pp. 1565-1566, 2001 The Journal of Organic Chemistry, Vol. 69, p. 5116-5119, 2004. The Journal of Organic Chemistry (The Journal of Organic Chemistry), Vol. Tetrahedron, 63, 11325-11340, 2007 Synlett, Vol. 23, 2261-2265, 2012

  The method for producing 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester described in Non-Patent Documents 1 to 4 is as follows. Is as follows.

However, the compounds having a glyceric acid skeleton in which the hydroxyl groups at positions 2 and 3 described in Non-Patent Documents 1 to 4 are protected as cyclic acetal groups are only compounds derived from acetone. Moreover, this compound was not obtained in a sufficiently high yield.
The present invention relates to providing a novel glyceric acid ester that can be produced in high yield and expected to be applied as a synthetic intermediate, and a method for producing the same.

The present invention relates to the following <1> and <2>.
<1> A method for producing a compound represented by the following formula (I), comprising a step of oxidative esterification of the compound represented by the following formula (II).

(In formula (II), R1 represents a hydrogen atom or a monovalent hydrocarbon group.)

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

<2> A compound represented by the following formula (I).

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

  ADVANTAGE OF THE INVENTION According to this invention, the novel glycerol ester which can be manufactured with a high yield and the application as a synthetic intermediate is anticipated, and its manufacturing method can be provided.

GC chart of reaction liquid obtained in Example 1-1 GC chart of reaction liquid obtained in Example 2-1 GC chart of reaction liquid obtained in Example 3-3 GC chart of reaction liquid obtained in Example 4

[Compound represented by formula (I)]
The compound represented by the following formula (I) of the present invention is a novel glyceric acid ester (hereinafter also referred to as “the glyceric acid ester of the present invention” or “the ester dimer of the present invention”).
The glyceric acid ester of the present invention can be produced in a high yield by the method described below. Moreover, glyceric acid and its ester body can be manufactured from the glyceric acid ester of this invention. In addition, the glyceric acid ester of the present invention has high acetal group stability while acetalization proceeds rapidly in each step up to its production and use as an intermediate.

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

In formula (I), R ¹ represents a hydrogen atom or a monovalent hydrocarbon group, and the availability and reactivity of aldehyde raw materials, the stability of dioxolane and the ester dimer of the present invention, and the acetal decomposition of the ester dimer of the present invention From the viewpoint of easy recovery of aldehyde produced as a by-product, a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms is preferred. The hydrocarbon group is preferably an alkyl group or an aryl group. The number of carbon atoms of the alkyl group is preferably 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, and still more preferably 10 In the following, it is 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 carbon number of the aryl group 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, and even more preferably. Is 10 or less, more preferably 8 or less, and still more preferably 6 or less.
From the above viewpoint, R ¹ 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, or 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, and still more preferably a hydrogen atom.

In addition, since the compound represented by the formula (I) (the ester dimer of the present invention) has two or more asymmetric carbon atoms, when the number of asymmetric carbon atoms is n, the maximum is 2 ⁿ (2 to the nth power). ) Species stereoisomer mixture. In the present invention, the compound represented by the formula (I) may be a stereoisomer mixture and is not particularly limited.

<Method for Producing Compound Represented by Formula (I)>
The method for producing the ester dimer of the present invention is not particularly limited, but from the viewpoint of inexpensive production, the compound represented by the following formula (II) (hereinafter also referred to as “dioxolane”) is produced by oxidative esterification reaction. It is preferable to do.

(In formula (II), R ¹ represents a hydrogen atom or a monovalent hydrocarbon group.)

  In the present invention, as dioxolane, the compound represented by the above formula (II) may be used alone, and the compound represented by formula (II) and the compound represented by formula (V) described below (hereinafter, A mixture with “dioxane”) may also be used. In addition, the mixture of the compound represented by the formula (II) and the compound represented by the formula (V) may be a commercially available product, or, as described later, in the formula (II) A mixture of the compound represented by formula (V) and the compound represented by formula (V) may be produced and used, but is not particularly limited. From the viewpoint of producing at a low cost, a mixture of dioxolane and dioxane is produced (synthesized). , Preferably used.

[Method for producing dioxolane]
The production method of dioxolane (a compound represented by the formula (II)) 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. (Hereinafter also referred to as “aldehyde”) or a method of acetalizing a multimer thereof in the presence of an acid catalyst (Method 1), or acetal exchange between glycerol and a compound represented by the following formula (IV) in the presence of an acid catalyst Is preferably produced from the viewpoint of availability of raw materials, 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 (II) and a compound represented by the following formula (V)

(In Formula (III) and Formula (IV), R ¹ has the same meaning as R ¹ in Formula (I). In Formula (IV), R ² independently represents a monovalent hydrocarbon group. )

R ² in formula (IV) is each independently a monovalent hydrocarbon group, and 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.

  As a multimer of the compound represented by the above formula (III), paraformaldehyde which is a formaldehyde multimer, paraaldehyde which is a cyclic trimer of acetaldehyde (also known as 2,4,6-trimethyl-1,3,3) 5-trioxane). In consideration of ease of handling, etc., the compound represented by formula (III) or a multimer thereof may be appropriately selected and used.

  Usually, the dioxolane obtained by the acetalization or acetal exchange method is obtained as a mixture with a compound (dioxane) represented by the following formula (V) as shown in the following reaction formula. Although there is no restriction | limiting in the isomer ratio of the dioxolane and dioxane used for this invention, From a viewpoint of productivity and economical efficiency, the isomer ratio of dioxolane is so preferable that it is high. The isomer ratio of dioxolane obtained by the above general production method is preferably 40% or more and 60% or less.

A mixture of dioxolane (compound represented by formula (II)) and dioxane (compound represented by formula (V)) obtained by the above method 1 (step 1-1) or method 2 (step 1-2) is It can be used as a raw material for the next step as it is or after purification, but it is preferable to purify the mixture and remove unreacted raw materials from the viewpoint of the yield in the next step, and distillation purification from the viewpoint of ease of purification. More preferably.
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.

[Oxidative esterification]
The glyceric acid ester of the present invention can be obtained by oxidative esterification of the above dioxolane (compound represented by the formula (II)).
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 (I)) of the present invention from dioxolane (compound represented by formula (II)).
Examples of the oxidative esterification method include a method using a homogeneous or heterogeneous metal catalyst, and 4-acetamido-2,2,6,6-tetramethyl-1-oxopiperidinium described in Non-Patent Document 2. A method using tetrafluoroborate and pyridine, a catalytic amount of 2,2,6,6-tetramethylpiperidine-1-oxyl (hereinafter also referred to as “TEMPO”), an oxidizing agent and pyridine described in Non-Patent Document 4. There is a method of using.

  In addition, when the mixture of the said dioxolane (compound represented by Formula (II)) and dioxane (compound represented by Formula (V)) is oxidatively esterified, the following reactions typically occur.

(Wherein R ¹ is as described above.)

  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.

  In the present invention, any oxidative esterification method can be used as long as the compound represented by the formula (I) is obtained. From the viewpoint of obtaining high reaction activity, an organic compound as described in Non-Patent Document 2 is used. From the oxidative esterification method using a nitroxyl radical-containing salt containing an oxoammonium cation and a base, as well as the organic nitroxyl radical, its N-hydroxy form, and salts containing those oxoammonium cations as in Non-Patent Document 4. An oxidative esterification method selected from oxidative esterification methods (hereinafter also referred to as “nitroxyl radical methods”) using a selected compound, an oxidizing agent, and a base is preferable, and the yield of the ester dimer of the present invention is The nitroxyl radical method is preferable from the viewpoint of high yield and low yield of formyldioxolane. An oxidative esterification method using a radical and / or its N-hydroxy form, an oxidizing agent, and a base is more preferred.

(Nitroxyl radical method)
[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. Compounds can be used.
That is, as the nitroxyl radical species, it is preferable to use at least one compound selected from organic nitroxyl radicals, N-hydroxy isomers thereof, and salts containing oxoammonium cations thereof.
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 formula (IX) or a compound represented by the formula (X), an N-hydroxy form thereof, and an oxo thereof. A compound selected from salts containing an ammonium cation is preferred.

(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 the compound selected from the organic nitroxyl radical, its N-hydroxy form, and salts containing their oxoammonium cations is used with respect to dioxolane or a mixture of dioxolane and dioxane. The molar ratio is preferably 0.0001 or more, more preferably the molar ratio is 0.0002 or more, and still more preferably the molar ratio is 0.0005 or more. From the viewpoint of economy, the molar ratio is preferably 0.1 or less, more preferably the molar ratio is 0.05 or less, and still more preferably the molar ratio is 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 its N-hydroxy form to an oxoammonium cation can be used, but a decrease in yield due to hydration or hydrolysis of dioxanone or ester dimer is suppressed. Therefore, 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 dioxane and dioxolane 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.

〔base〕
In this reaction, a base is used for the purpose of neutralizing an acid produced as a by-product due to consumption of the oxidizing agent. Any base can be used as long as it does not interfere with the desired oxidation reaction, but it is weakly basic and side reactions are suppressed as it causes a direct side reaction with dioxolane or a mixture of dioxolane and dioxane, a catalyst or an oxidizing agent. From the viewpoint, a heterocyclic aromatic amine having a pyridine skeleton is preferable. The heterocyclic aromatic amine having a pyridine skeleton may be used in combination with an inorganic base in order to suppress the amount used, but has a pyridine skeleton from the viewpoint of obtaining the ester dimer of the present invention in a high yield. More preferably, the heterocyclic aromatic amine is used alone.
Examples of the heterocyclic aromatic amine having a pyridine skeleton include pyridine, alkyl-substituted pyridines, polycyclic quinolines, bipyridyls that are pyridine dimers, and the like. Specifically, pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2-ethylpyridine, 3-ethylpyridine, 4-ethylpyridine, 2,6-lutidine, 3,5-lutidine, 2 , 3,5-collidine, 2,4,6-collidine, 5-ethyl-2-methylpyridine, 3,5-diethylpyridine, 2,2′-bipyridyl, 2,4′-bipyridyl, 4,4′- Bipyridyl, quinoline and the like can be mentioned.
Among the heterocyclic aromatic amines having a pyridine skeleton, it is preferable to select and use a heterocyclic aromatic amine having a pyridine skeleton that has a large boiling point difference from dioxanone and the ester dimer of the present invention and is easily separated by distillation. From the viewpoint of availability, an amine selected from pyridine and 5-ethyl-2-methylpyridine is preferable. From the viewpoint of easy recovery when the amine is regenerated from the amine salt after the reaction is completed, a water-insoluble pyridine skeleton is formed. Preferred is a heterocyclic aromatic amine having, from the viewpoint of yield, selected from pyridine, 3,5-lutidine, 2,6-lutidine, 3-ethylpyridine, 4-ethylpyridine and 5-ethyl-2-methylpyridine. Preferred amines are pyridine, 3,5-lutidine, 3-ethylpyridine, 4-ethylpyridine and 5-ethyl-2. Amines selected from methyl pyridine is more preferred.

  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 the base to dioxolane or a mixture of dioxolane and dioxane is preferably 1.0 or more. More preferably, it is 1.1 or more, More preferably, it is 1.2 or more, More preferably, it is 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.

〔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 (I)]
In the present invention, it is preferable to have a step of separating the ester dimer of the present invention (compound represented by the formula (I)) 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.

  The novel glyceric acid ester of 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 cyclic acetal groups, and is a raw material for various pharmaceuticals, cosmetics, detergents, polymers, etc. It is useful as a synthetic intermediate for glyceric acid, glycerate and deprotected glyceric acid esters used as

[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 further discloses the following [1] to [36].
[1] A process for producing a compound represented by the following formula (I), comprising a step of oxidative esterification of the compound represented by the following formula (II).

(In formula (II), R ¹ represents a hydrogen atom or a monovalent hydrocarbon group.)

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

  [2] The production method according to [1], including a step of oxidative esterification of a mixture of a compound represented by the following formula (II) and a compound represented by the following formula (V).

(In Formula (II) and Formula (V), R ¹ represents a hydrogen atom or a monovalent hydrocarbon group.)

  [3] A mixture of a compound represented by the formula (II) and a compound represented by the formula (V) is obtained by converting glycerol and a compound represented by the following formula (III) or a multimer thereof in the presence of an acid catalyst into an acetal. The production method according to [2], which is produced by a method (Method 1) or a method (Method 2) in which glycerol and a compound represented by the following formula (IV) are acetal exchanged in the presence of an acid catalyst.

(In the formula, R ¹ represents a hydrogen atom or a monovalent hydrocarbon group. In Formula (IV), each R ² is independently a monovalent hydrocarbon group, preferably having 1 to 8 carbon atoms. And more preferably a monovalent hydrocarbon group having 1 to 3 carbon atoms, more preferably a monovalent alkyl group having 1 to 3 carbon atoms, still more preferably a methyl group.)

[4] The production method according to [2] or [3], 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 (II) and a compound represented by the following formula (V)

(In the formula, R ¹ represents a hydrogen atom or a monovalent hydrocarbon group. In Formula (IV), each R ² is independently a monovalent hydrocarbon group, preferably having 1 to 8 carbon atoms. And more preferably a monovalent hydrocarbon group having 1 to 3 carbon atoms, more preferably a monovalent alkyl group having 1 to 3 carbon atoms, still more preferably a methyl group.)

[5] R ¹ is preferably a hydrogen atom or a monovalent hydrocarbon group having 1 to 20 carbon atoms, and the hydrocarbon group is preferably an alkyl group or an aryl group, and the carbon number of the alkyl group is , Preferably 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 even 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 carbon of the aryl group. The number 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, and even more. Mashiku 12 or less, even more preferably 10 or less, even more preferably 8 or less, even more preferably 6 or less, the production method according to any one of [1] to [4].
[6] R ¹ 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, or 1 to 8 carbon atoms. The following branched alkyl group or aryl group having 6 to 20 carbon atoms, more preferably a hydrogen atom, a methyl group or a phenyl group, and still more preferably a hydrogen atom, according to any one of [1] to [4]. Production method.
[7] The yield of the formula formyldioxolane produced from the compound represented by the formula (II) is preferably 20% or less, more preferably 10% or less, still more preferably 5% or less, and still more preferably substantially The production method according to any one of [1] to [6], which is 0%, more preferably 0%.
[8] In the oxidative esterification step, preferably, an oxidative esterification method using a salt containing an oxoammonium cation of an organic nitroxyl radical and a base, an organic nitroxyl radical, an N-hydroxy form thereof, and the like Using an oxidative esterification method selected from an oxidative esterification method (hereinafter also referred to as “nitroxyl radical method”) using a compound selected from salts containing an oxoammonium cation, an oxidizing agent, and a base; [1] The production method according to any one of [7].

  [9] In the above [8], 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). The manufacturing method as described.

(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.)

[10] 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 Compound selected from sulfonyloxy-TEMPO and AZADOL, more preferably 4-ben Yloxy-TEMPO, 4-acetamido-TEMPO, a compound selected 4-methylsulfonyloxy-TEMPO, and the AZADOL, production method according to [8] or [9].
[11] The amount of the compound selected from the organic nitroxyl radical, its N-hydroxy form, and a salt containing the oxoammonium cation is represented by the compound represented by the formula (II) or the formula (II). Preferably, the molar ratio is 0.0001 or more, more preferably the molar ratio is 0.0002 or more, and still more preferably the molar ratio is 0.0005 with respect to the mixture of the compound represented by formula (V). The molar ratio is 0.1 or less, more preferably the molar ratio is 0.05 or less, and still more preferably the molar ratio is 0.02 or less. Manufacturing method.
[12] The oxidizing agent is preferably an oxidizing agent (halogen-containing oxidizing agent) composed of a halogen-containing compound, more preferably an oxidizing agent (chlorine-containing oxidizing agent) composed of a chlorine-containing compound, more preferably trichloroisocyanuric. The manufacturing method according to any one of [8] to [11], wherein the oxidizing agent is selected from an acid and tertiary butyl hypochlorite, more preferably trichloroisocyanuric acid.
[13] The molar ratio of the oxidizing active species of the oxidizing agent to the compound represented by the formula (II) or the mixture of the compound represented by the formula (II) 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 [8]-[12] Method.
[14] The production method according to any one of [8] to [13], wherein the base is a heterocyclic aromatic amine having a pyridine skeleton.
[15] The heterocyclic aromatic amine having a pyridine skeleton is preferably pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2-ethylpyridine, 3-ethylpyridine, 4-ethylpyridine, 2,6-lutidine, 3,5-lutidine, 2,3,5-collidine, 2,4,6-collidine, 5-ethyl-2-methylpyridine, 3,5-diethylpyridine, 2,2'-bipyridyl , 2,4′-bipyridyl, 4,4′-bipyridyl, and quinoline, more preferably pyridine, 3,5-lutidine, 2,6-lutidine, 3-ethylpyridine, 4- At least one selected from ethylpyridine and 5-ethyl-2-methylpyridine, more preferably pyridine, 3,5-lutidine, 3-ethylpyridine, 4- The production method according to [14], which is at least one selected from ethylpyridine and 5-ethyl-2-methylpyridine.
[16] The molar ratio of the base to the compound represented by the formula (II) or the mixture of the compound represented by the formula (II) and the compound represented by the formula (V) is preferably 1.0 or more, more preferably 1.1 or more, still more preferably 1.2 or more, still more preferably 1.3 or more, preferably 2.5 or less, more preferably 2.0 or less, still more preferably The production method according to any one of [8] to [15], which is 1.7 or less.

[17] Preferably, a solvent is used in the oxidative esterification step, and the solvent is preferably a solvent selected from acetone, 2-butanone, cyclopentanone, acetonitrile, and dichloromethane, more preferably acetone, 2-butanone. The method according to any one of [1] to [16], which is a solvent selected from acetonitrile and dichloromethane, more preferably a solvent selected from acetone and 2-butanone.
[18] 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. The production method according to [17], which is 60% by mass or more, preferably 90% by mass or less, more preferably 85% by mass or less, and still more preferably 80% by mass or less.
[19] The production according to any one of [1] to [18], wherein in the oxidative esterification step, the oxidant or the oxidant solution is preferably added dropwise to a mixture or mixed solution of raw materials other than the oxidant. Method.
[20] 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. [19] The production method described in [19].
[21] The production method according to [19] or [20], wherein the reaction is continued until the total amount of dioxolane reacts or the decrease in the residual amount stops after the oxidant or oxidant solution is dropped.
[22] The production method according to [21], 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. .
[23] The production method according to any one of [1] to [22], wherein alcohol is preferably used as a reaction terminator.
[24] The production method according to [23], wherein the reaction terminator is preferably a primary or secondary alcohol, and more preferably a secondary alcohol.
[25] The production method according to [23] or [24], wherein the reaction terminator is preferably an alcohol having 1 to 12 carbon atoms.
[26] After the step of oxidative esterification of the compound represented by the formula (II) or preferably the mixture of the compound represented by the formula (II) and the compound represented by the formula (V) The manufacturing method in any one of [1]-[25] which has the process of isolate | separating the compound represented by (I).
[27] The production method according to [26], wherein the separation in the step of separating the compound represented by the formula (I) is separation by distillation.
[28] The production method according to [27], wherein the separation by distillation is preferably performed under rectification conditions.
[29] 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 [28], wherein the number of theoretical plates of the rectification column is preferably 20 or less, more preferably 10 or less, and the reflux ratio is preferably 20 or less, more preferably 10 or less.
[30] Glyceric acid, glycerate, or deprotected glyceric acid ester, which hydrolyzes or alcoholates the compound represented by the formula (I) separated in any one of [26] to [29] Production method.
[31] A process for producing a compound represented by the formula (I) by the production method according to any one of [1] to [29], and represented by the formula (I) produced in the process The manufacturing method of the glycerol acid, glycerol salt, or deprotected glycerol ester which has the process of hydrolyzing or alcohololyzing the compound which carries out.
[32] The production method according to [30] or [31], wherein the alcohol used for the alcoholysis is preferably a primary alcohol, more preferably a primary alcohol having 1 to 3 carbon atoms.
[33] The production method according to [30] or [31], wherein the alcohol used for the alcoholysis is more preferably a linear or branched primary alcohol having 4 to 8 carbon atoms.

  [34] A compound represented by the following formula (I).

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

[35] R ¹ is preferably a hydrogen atom or a monovalent hydrocarbon group having 1 to 20 carbon atoms, and the hydrocarbon group is preferably an alkyl group or an aryl group, and the carbon number of the alkyl group is , Preferably 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 even 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 carbon of the aryl group. The number 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, and even more. Preferably 12 or less, even more preferably 10 or less, even more preferably 8 or less, even more preferably 6 or less, compounds described in [34].
[36] R ¹ 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, or 1 to 8 carbon atoms. The compound according to [34], which is a branched alkyl group or an aryl group having 6 to 20 carbon atoms, more preferably a hydrogen atom, a methyl group or a phenyl group, and still more preferably a hydrogen atom.

[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]
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 1: Production of a mixture of raw materials 2-phenyl-1,3-dioxane-5-ol and 4-hydroxymethyl-2-phenyl-1,3-dioxolane The reaction carried out in Production Example 1 was carried out as follows. Street.

In a 1 L flask equipped with a Dean Stark apparatus, 184 g of glycerol (purity 100%, 2.00 mol), 238 g of benzaldehyde (purity 98.0%, 2.20 mol), 18 g of Amberlyst 15DRY (strongly acidic cation exchange resin) , Dow Chemical Co., Ltd.) and 50 g of n-hexane were added and refluxed for 6 hours while removing water produced as a by-product in the reaction. After cooling, the ion exchange resin was filtered off, and the filtrate was analyzed by GC. As a result, cis and trans-2-phenyl-1,3-dioxan-5-ol and cis and trans-4-hydroxymethyl-2-phenyl-1, The reaction yield of a mixture of four isomers consisting of 3-dioxolane was 91%.
Subsequently, the filtrate was transferred to a 500 mL flask equipped with a Claisen head, heated to 50 ° C. and gradually reduced in pressure to distill off n-hexane, and further subjected to simple distillation under reduced pressure of 0.13 kPa (absolute pressure). Then, 317 g of an isomer mixture distilled as a colorless liquid at a fraction temperature of 110 to 120 ° C. was obtained. The purity was 100% and the distillation yield was 97%.
Reference 1 (Journal of Catalysis, Vol. 245, pp. 428-435, 2007) describes the ¹ H-NMR signal assignment of protons at the 2-position of each isomer. . The isomer ratio of 2-phenyl-1,3-dioxane-5-ol and 4-hydroxymethyl-2-phenyl-1,3-dioxolane determined from this information and ¹ H-NMR analysis was 49:51. It was.

<Spectral data of isomer mixture>
IR (neat, cm ⁻¹ ): 3429 (br), 2991, 937, 2856, 1408,
1151, 1082, 1039.

Production Example 2: Production of a mixture of 2-phenyl-1,3-dioxane-5-ol and 4-hydroxymethyl-2-phenyl-1,3-dioxolane as raw materials The reaction carried out in Production Example 2 was carried out as follows. Street.

In a 100 mL flask, 9.21 g of glycerol (purity 100%, 100 mmol), 17.1 g of benzaldehyde dimethyl acetal (purity 98.0%, 110 mmol), 0.50 g of Amberlyst 36 (strongly acidic cation exchange resin, Dow Chemical Co., Ltd.) and 23 g of dichloromethane were charged and stirred at 25 ° C. for 6 hours under a nitrogen atmosphere. After the ion exchange resin was filtered off and dichloromethane was distilled off from the filtrate, GC analysis showed that cis and trans-2-phenyl-1,3-dioxane-5-ol and cis and trans-4-hydroxymethyl-2- The reaction yield of a mixture of four isomers consisting of phenyl-1,3-dioxolane was 77%. Moreover, the isomer ratio of 2-phenyl-1,3-dioxane-5-ol and 4-hydroxymethyl-2-phenyl-1,3-dioxolane obtained from the information in Reference 1 and ¹ H-NMR analysis is as follows: 55 vs 45.

Production Example 3: Production of a mixture of raw materials 2-methyl-1,3-dioxane-5-ol and 4-hydroxymethyl-2-methyl-1,3-dioxolane The reaction carried out in Production Example 3 was carried out as follows. Street.

In a 500 mL flask equipped with a Dean-Stark apparatus, 184 g of glycerol (purity 100%, 2.00 mol), 117 g of paraaldehyde (purity 98.0%, 868 mmol), 981 mg of methanesulfonic acid (purity 98.0%, 10% 0.0 mmol) and 40 g of n-hexane were charged 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 analysis of the reaction solution, four isomers consisting of cis and trans-2-methyl-1,3-dioxan-5-ol and cis and trans-4-hydroxymethyl-2-methyl-1,3-dioxolane were obtained. The reaction yield of the mixture was 71%.
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 0.67 kPa (absolute pressure). Distillation was performed to obtain 160 g of an isomer mixture distilled as a colorless liquid at a fraction temperature of 62 to 70 ° C. The purity was 100% and the distillation yield was 96%.
Reference 2 (Tetrahedron, Vol. 71, No. 20, pp. 3032-3038, 2015) describes the ¹ H-NMR signal assignment of protons at the 2-position of each isomer. . The isomer ratio of 2-methyl-1,3-dioxane-5-ol and 4-hydroxymethyl-2-methyl-1,3-dioxolane determined from this information and ¹ H-NMR analysis was 70:30. It was.

<Spectral data of isomer mixture>
IR (neat, cm ⁻¹ ): 3415 (br), 2856, 1456, 1394, 1149, 1086.

Production Example 4: Production of a mixture of 2-n-heptyl-1,3-dioxan-5-ol and 4-hydroxymethyl-2-n-heptyl-1,3-dioxolane as raw materials Reaction performed in Production Example 4 Is as follows.

In a 300 mL flask equipped with a Dean-Stark apparatus, 69.1 g of glycerol (purity 100%, 750 mmol), 98.1 g of n-octanal (purity 98.0%, 750 mmol), 368 mg of methanesulfonic acid (purity 98.0) %, 3.75 mmol) and 18 g of n-hexane were added and refluxed for 3 hours while removing water produced as a by-product in the reaction. After cooling, the solution was neutralized with 1.30 g of a 20% ethanol solution of sodium ethoxide (260 mg as sodium ethoxide, 3.82 mmol). As a result of analysis of the reaction solution, 4 consisting of cis and trans-2-n-heptyl-1,3-dioxane-5-ol and cis and trans-4-hydroxymethyl-2-n-heptyl-1,3-dioxolane was obtained. The reaction yield of the seed isomer mixture was 100%.
Subsequently, the reaction solution was transferred to a 200 mL flask equipped with a Claisen head, heated to 50 ° C. and gradually reduced in pressure to distill off n-hexane and ethanol, and further subjected to simple distillation under reduced pressure of 67 Pa (absolute pressure). Cis and trans-2-n-heptyl-1,3-dioxan-5-ol and cis and trans-4-hydroxymethyl-2-n-heptyl distilled at a distillation temperature of 95 to 102 ° C. 135 g of a mixture of four isomers consisting of -1,3-dioxolane was obtained. The purity was 99% and the distillation yield was 89%.
Reference 3 (Green Chemistry, Vol. 12, pages 2225-2231, 2010) describes the ¹ H-NMR signal assignment of the proton at the 2-position of each isomer. The isomer ratio of 2-heptyl-1,3-dioxane-5-ol and 4-hydroxymethyl-2-heptyl-1,3-dioxolane determined from this information and ¹ H-NMR analysis was 57:43. It was.

<Spectral data of isomer mixture>
IR (neat, cm ⁻¹ ): 3479 (br), 2954, 2854, 1462, 1394, 1146, 1043.

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

Example 1-1
In a 1 L flask equipped with a 100 mL dropping funnel, 63.7 g of a mixture of 1,3-dioxane-5-ol and 4-hydroxymethyl-1,3-dioxolane (Tokyo Chemical Industry Co., Ltd., trade name: glycerol formal, purity: 98) 1.0%, 600 mmol, isomer ratio 58:42) of 1,3-dioxane-5-ol and 4-hydroxymethyl-1,3-dioxolane determined from the information in Reference 1 and ¹ H-NMR analysis, 93.8 mg of 2-hydroxy-2-azaadamantane (AZADOL, Nissan Chemical Industries, Ltd., trademark, purity 98.0%, 0.60 mmol), 71.5 g of pyridine (purity 99.5%, 900 mmol), acetonitrile 150 g was charged and stirred in a nitrogen atmosphere while cooling. 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%.
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 mixture of four stereoisomers consisting of two racemates.
FIG. 1 shows a GC chart of the reaction solution obtained in Example 1-1.

<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.

Example 1-2
In a 50 mL flask equipped with a 20 mL dropping funnel, the same glycerol formal 3.19 g (purity 98.0%, 30.0 mmol) as in Example 1-1, AZADOL 4.7 mg (purity 98.0%, 30 μmol) , 4.77 g of pyridine (purity 99.5%, 60.0 mmol) and 10 g of acetonitrile were charged and stirred under a nitrogen atmosphere while cooling. A solution prepared by dissolving 2.94 g of TCCA (purity 95.0%, 12.0 mmol) in 10 g of acetonitrile was charged into a dropping funnel, and the dropping speed was adjusted so that the temperature of the reaction solution in the flask was within a range of −10 ° C. to 10 ° C. The solution was added dropwise over 1 hour while adjusting. 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 99%.

Examples 1-3 to 1-11
The same operation as in Example 1-2 was performed except that the type and amount of catalyst used, the type and amount of base used, or the solvent type were changed. Table 1 shows the reaction conditions and results of Examples 1-2 to 1-11.

Example 2: Preparation of 2-phenyl-1,3-dioxolane-4-carboxylic acid (2-phenyl-1,3-dioxolan-4-yl) methyl ester The reaction carried out in Example 2 is as follows. is there.

Examples 2-1 and 2-2
Mixture of 2-phenyl-1,3-dioxan-5-ol and 4-hydroxymethyl-2-phenyl-1,3-dioxolane obtained in Production Example 1 3.60 g (100% purity, 20.0 mmol) As a reaction raw material, the same operation as in Example 1-2 was carried out to give 2-phenyl-1,3-dioxolan-4-carboxylic acid (2-phenyl-1,3-dioxolan-4-yl) methyl ester A reaction solution containing was obtained. Table 2 shows the reaction conditions and results of Examples 2-1 and 2-2.
The reaction solutions obtained in Examples 2-1 and 2-2 were mixed, and subjected to simple distillation under reduced pressure of 0.13 kPa (absolute pressure), such as 2-phenyl-1,3-dioxane-5-one. Low boiling components were distilled off. Subsequently, a component having an Rf value of 0.24 was separated by silica gel column chromatography (developing solvent n-hexane / ethyl acetate = 3) of a dark brown oily simple distillation residue, and after removing the solvent and vacuum drying, an orange liquid was obtained. 2.58 g of 2-phenyl-1,3-dioxolane-4-carboxylic acid (2-phenyl-1,3-dioxolan-4-yl) methyl ester was obtained. The purity was 90.6% and the purification yield was 78%. GC-MS analysis confirmed that the ester dimer was a stereoisomer mixture consisting of at least 6 racemates. For the other two racemates, it is presumed that the peaks overlapped and could not be detected.
FIG. 2 shows a GC chart of the reaction solution obtained in Example 2-1.

<Spectral data of 2-phenyl-1,3-dioxolane-4-carboxylic acid (2-phenyl-1,3-dioxolan-4-yl) methyl ester (stereoisomer mixture)>
IR (neat, cm ⁻¹ ): 2881, 1751, 1734, 1458, 1394, 1200, 1080, 648.
MS (m / z, common to 6 peaks on GC): 356 (M ⁺ ), 250, 233, 149, 129, 105, 91, 77, 55.

Example 3: Preparation of 2-methyl-1,3-dioxolan-4-carboxylic acid (2-methyl-1,3-dioxolan-4-yl) methyl ester The reaction performed in Example 3 is as follows. is there.

Example 3-1
Reaction of 70.9 g (purity 100%, 600 mmol) of the mixture of 2-methyl-1,3-dioxane-5-ol and 4-hydroxymethyl-2-methyl-1,3-dioxolane obtained in Production Example 3 Using as a raw material, the same operation as in Example 1-1 was performed to obtain 66.2 g of a yellow oily crude product. As a result of GC analysis of the crude product, the conversion of 2-methyl-4-hydroxymethyl-1,3-dioxolane was 100%, and 2-methyl-1,3-dioxolane-4-carboxylic acid (2-methyl-1 , 3-Dioxolan-4-yl) methyl ester was 88%.
60.0 g of a crude product was charged in a 100 mL pear-type flask equipped with a 6-stage packed distillation column (packing: Helipac Packing No. 2), 0.13 kPa (absolute pressure), reflux ratio 0.5 2-Methyl-1,3-dioxolan-4-carboxylic acid (2-methyl-1,3-dioxolan-4-yl) methyl distilled as a pale yellow liquid at a fraction temperature of 110 to 113 ° C. under the conditions of 16.1 g of ester was obtained. The purity was 98.6% and the distillation yield was 95%. ¹³ C-NMR and GC-MS analysis suggested that this ester dimer was a mixture of four stereoisomers consisting of two racemates. For the other two racemates, it is presumed that the peaks overlapped and could not be detected.

<Spectral data of 2-methyl-1,3-dioxolane-4-carboxylic acid (2-methyl-1,3-dioxolan-4-yl) methyl ester (stereoisomer mixture)>
IR (neat, cm ⁻¹ ): 2991, 2864, 1751, 1408, 1201, 1146, 1088, 1076, 858.
MS (m / z, common to 2 peaks on GC): 232 (M ⁺ ), 217, 173, 129, 101, 87, 59, 43.

Examples 3-2 to 3-4
A mixture of 2-methyl-1,3-dioxan-5-ol and 4-hydroxymethyl-2-methyl-1,3-dioxolane obtained in Production Example 3 as a reaction raw material 3.54 g (purity 100%, 30. 0 mmol), and the same operation as in Example 1-2 was carried out to give 2-methyl-1,3-dioxolan-4-carboxylic acid (2-methyl-1,3-dioxolan-4-yl) methyl ester. A reaction solution containing was obtained. Table 3 shows the reaction conditions and results of Examples 3-2 to 3-4.
FIG. 3 shows a GC chart of the reaction solution obtained in Example 3-3.

Example 4: Preparation of 2-n-heptyl-1,3-dioxolane-4-carboxylic acid (2-n-heptyl-1,3-dioxolan-4-yl) methyl ester The reaction carried out in Example 4 was It is as follows.

A mixture of 2-n-heptyl-1,3-dioxane-5-ol and 4-hydroxymethyl-2-n-heptyl-1,3-dioxolane obtained in Production Example 4 (4.34 g, purity 99.2%) 21.3 mmol) was used as a reaction raw material, and the same reaction operation as in Example 1-1 was performed. In order to remove the powdered solid that re-precipitated after filtration of the powdered solid and evaporation of acetonitrile, 20 g of tert-butyl methyl ether and 10 g of ion-exchanged water were added, and saturated sodium bicarbonate until the pH of the aqueous layer reached 8. Extraction was carried out after adding an aqueous solution. The lower layer water was extracted after the stationary separation, and 20 g of saturated aqueous sodium chloride solution was added to repeat the extraction to the extraction of the lower layer water. The obtained organic layer was dried over 10 g of anhydrous sodium sulfate, and after filtration, tert-butyl methyl ether was distilled off to obtain 5.40 g of a pale yellow oily crude product. As a result of GC analysis of the crude product, the conversion of 2-n-heptyl-1,3-dioxane-5-ol was 93%, and the yield of 2-n-heptyl-1,3-dioxane-5-one was 74%, conversion of 2-n-heptyl-4-hydroxymethyl-1,3-dioxolane is 100%, 2-n-heptyl-1,3-dioxolane-4-carboxylic acid (2-n-heptyl-1 , 3-Dioxolan-4-yl) methyl ester was 98%, and 4-formyl-n-heptyl-1,3-dioxolane was 2%.
Subsequently, 2.00 g of the crude product is distilled under a reduced pressure of 40 Pa (absolute pressure) using a Kugelrohr distillation apparatus, and 2-n-heptyl-1, which is distilled as a colorless liquid at an apparatus temperature of 140 to 160 ° C., 1.35 g of 3-dioxane-5-one was obtained. The purity was 97% and the distillation yield was 78%. In addition, the purity of 2-n-heptyl-1,3-dioxolane-4-carboxylic acid (2-n-heptyl-1,3-dioxolan-4-yl) methyl ester in the yellow gel-like distillation residue 1.86 is The distillation recovery rate was 87%. ¹³ C-NMR and GC-MS analysis confirmed that this ester dimer was a mixture of 16 stereoisomers consisting of 8 racemates.

<Spectral data of 2-n-heptyl-1,3-dioxane-5-one>
¹ H-NMR (400 MHz, CDCl ₃ , δ _ppm ): 0.88 (3H, t, J = 6.8 Hz), 1.23-1.37 (8H, m), 1.40-1.47 (2H, m), 1.69-1.74 (2H, m), 4.28 (2H, d, J = 18.2 Hz) 4.40 (2H, d, J = 18.2 Hz), 4. 86 (1H, t, J = 5.0 Hz).
^{· 13 C-NMR (100MHz,} CDCl 3, δ ppm): 14.0,22.6,24.0,29.1,29.3,31.7,34.0,72.2,100.4 204.5.
IR (neat, cm ⁻¹ ): 2956, 2858, 1741, 1134, 1053, 957.
MS (m / z): 200 (M ^<+> ), 101, 71, 55, 43.
<Spectral data of 2-n-heptyl-1,3-dioxolane-4-carboxylic acid (2-n-heptyl-1,3-dioxolan-4-yl) methyl ester (stereoisomer mixture)>
IR (neat, cm ⁻¹ ): 2925, 2854, 1747, 1458, 1198, 1147, 949.
MS (m / z, common to 8 peaks on GC): 400 (M ⁺ ), 301, 173, 157, 101, 69, 57, 43.
<Spectral data of 4-formyl-n-heptyl-1,3-dioxolane (stereoisomer mixture)>
MS (m / z, common to two peaks on GC): 200 (M ⁺ ), 171, 101, 69, 55, 41.
FIG. 4 shows a GC chart of the reaction solution obtained in Example 4.

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

  2.00 g (purity 90) of 2-phenyl-1,3-dioxolan-4-carboxylic acid (2-phenyl-1,3-dioxolan-4-yl) methyl ester obtained in Examples 2-1 and 2-2 .6%, 5.08 mmol), 100 mg of methanesulfonic acid (purity 98.0%, 1.02 mmol), and 10.0 g of ethanol (purity 99.5%, 216 mmol) were charged into a 30 mL flask for 3 hours. Refluxed. After cooling, the mixture was neutralized with 1 mol / L sodium hydroxide solution, and ethanol was distilled off. 20 mL of ion-exchanged water was added to the residue, and the mixture was extracted twice with 50 mL of tert-butyl methyl ether to remove the water-insoluble product, and then water was distilled off. Subsequently, 827 mg of the obtained dark orange oily crude product was purified with a Kugelrohr distillation apparatus. Under the conditions of 0.13 kPa (absolute pressure) and apparatus set temperature of 150 to 155 ° C., 548 mg of ethyl glycerate distilled out as a colorless liquid was obtained. The purity was 97.0% and the yield was 78%.

<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.

  The ester dimer of the present invention (glyceric acid ester in which the hydroxyl groups at the 2-position and 3-position are protected as a cyclic acetal group) can be produced in high yield, for example, used as a raw material for various pharmaceuticals, cosmetics, detergents, polymers, etc. It is useful as a synthetic intermediate for glyceric acid and its esters.

Claims (12)

The manufacturing method of the compound represented by a following formula (I) which has the process of oxidatively esterifying the compound represented by a following formula (II).

(In formula (II), R ¹ represents a hydrogen atom or a monovalent hydrocarbon group.)

(In formula (I), R ¹ represents a hydrogen atom or a monovalent hydrocarbon group.) The oxidative esterification step uses one or more compounds selected from salts containing an organic nitroxyl radical, an N-hydroxy form thereof, and an oxoammonium cation thereof, an oxidizing agent, and a base. 2. The production method according to 1 . The production according to claim 2 , wherein 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). Method.

(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 of Claim 2 or 3 which is an oxidizing agent which the said oxidizing agent consists of a compound containing chlorine. The production method according to any one of claims 2 to 4 , wherein the base is a heterocyclic aromatic amine having a pyridine skeleton. The manufacturing method in any one of Claims 1-5 which has the process of isolate | separating the compound represented by Formula (I) after the process of oxidative esterification. The production method according to claim 6 , wherein the separation in the step of separating the compound represented by the formula (I) is separation by distillation. In manufacturing method according to any of claims 1 to 7, to produce a compound represented by the formula (I), and, a compound of the formula prepared in about該工(I), hydrolysis Alternatively, a method for producing glyceric acid, glycerate, or deprotected glyceric acid ester, which comprises a step of alcoholysis. A compound represented by the following formula (I).

(In formula (I), R ¹ represents a hydrogen atom or a monovalent hydrocarbon group having 1 to 20 carbon atoms.)   R ¹ Is a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group having 2 to 8 carbon atoms, or an aryl group having 6 to 20 carbon atoms. The compound according to claim 9 or 10 , wherein R ¹ is a hydrogen atom, a methyl group, or a phenyl group. A method for producing a compound represented by the following formula (I) , comprising a step of oxidative esterification of a mixture of the compound represented by the following formula (II) and the compound represented by the following formula (V) .

(In Formula (II) and Formula (V), R ¹ represents a hydrogen atom or a monovalent hydrocarbon group.)

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