JP6405443B2 - Process for producing 1,3-dioxane-5-ones - Google Patents

Description

  The present invention relates to a method for producing 1,3-dioxane-5-ones.

1,3-Dioxane-5-ones are useful as synthetic intermediates for various useful compounds.
For example, Non-Patent Document 1 discloses a method for producing dihydroxyacetone (hereinafter also referred to as “DHA”) by a deprotection reaction (deacetalization reaction) of 2-phenyl-1,3-dioxane-5-one. Is disclosed.
Non-Patent Document 2 discloses 2-amino-1,3-propanediol (hereinafter referred to as “serinol”), which is useful as a raw material for an X-ray contrast agent, from 2-phenyl-1,3-dioxane-5-one. The method for producing the acetal body of the above-mentioned is disclosed. Patent Document 1 also discloses various carbon skeleton construction examples by asymmetric aldol reaction between 1,3-dioxane-5-ones and aldehydes.

As a method for producing 1,3-dioxane-5-ones, for example, Non-Patent Document 3 uses trishydroxymethylnitromethane or trishydroxymethylaminomethane that can be derived from nitromethane that can be procured on an industrial scale as a raw material. A manufacturing method is disclosed.
Further, Non-Patent Document 1 includes four kinds of cis and trans-2-phenyl-1,3-dioxan-5-ol and cis and trans-4-hydroxymethyl-2-phenyl-1,3-dioxolane. Disclosed is a process for producing 2-phenyl-1,3-dioxane-5-one that oxidizes high-purity 2-phenyl-1,3-dioxan-5-ol obtained by low-temperature recrystallization of an isomer mixture. .
Patent Document 2 discloses 1,3-dioxane-5-one and 1,3-dioxolane-4-carbohydrate obtained by oxidizing glycerol formal that can be produced from glycerol (glycerin) and formaldehyde that can be procured at low cost. A method for producing 1,3-dioxane-5-one is disclosed in which a mixture of aldehydes (4-formyl-1,3-dioxolane) is separated by precision distillation.

US Pat. No. 7,851,639 German Patent Application No. 3900479

Industrial & Engineering Chemistry Research, 51, 3715-3721, 2012 Synthetic Communications, 27, 16, 2813-2816, 1997 Journal of the American Chemical Society, 111, 5902-5915, 1989

As described above, 1,3-dioxane-5-ones are useful as intermediates for synthesizing various useful compounds, but high-quality 1,3-dioxane-5-ones are commercially available from easily available raw materials. No technology has been established for producing a particularly advantageous method.
For example, the production method of Non-Patent Document 3 is a multi-stage synthesis method from an explosive or expensive starting material, and it is necessary to use an expensive oxidizing agent in a stoichiometric amount or more in the oxidative cleavage step. It is not suitable for industrial scale manufacturing.
In the production method of Non-Patent Document 1, the yield of 2-phenyl-1,3-dioxane-5-ol after recrystallization is as low as 25%, and the recrystallized mother liquor is used for the next acetalization reaction. Although measures to reduce the loss of raw materials by recycling are presented, the problem of extremely low productivity from reaction to purification has not been solved, and it is difficult to say that it is suitable for industrial scale production.
In the production method of Patent Document 2, 1,3-dioxane-5-one and 4-formyl-1,3-dioxolane as the main components are obtained from an oxidation mixture having the same molecular weight and very low boiling points. In order to separate 3-dioxane-5-one, precise distillation using a multi-stage rectification column corresponding to 60 theoretical plates is required, and it is difficult to say that it is suitable for production on an industrial scale.
The present invention easily uses 1,3-dioxane (a compound represented by the following formula (I)) which is a mixture with 1,3-dioxolane (a compound represented by the following formula (II)) as a raw material. In addition, the present invention relates to a method for producing 1,3-dioxane-5-ones from raw materials that can be procured at low cost by a short process and a simple method. Further, DHA and serinol can be produced. Relates to providing a method.

The present inventor has found that the above problem can be solved by a manufacturing method having a specific process.
That is, the present invention is a method for producing 1,3-dioxane-5-ones using a mixture of a compound represented by the following formula (I) and a compound represented by the following formula (II) as a raw material, The present invention relates to a method for producing 1,3-dioxan-5-ones having a step (step 2) of oxidizing the mixture under oxidative esterification conditions. Here, step 2 is a step of oxidizing the compound represented by formula (I) with respect to the mixture under the condition that the compound represented by formula (II) is oxidatively esterified.
Furthermore, the present invention relates to a method for producing 1,3-dihydroxyxyacetone, in which the obtained 1,3-dioxane-5-ones are deacetalized. The present invention also relates to a method for producing 2-amino-1,3-propanediol, wherein the obtained 1,3-dioxane-5-one is reductively aminated and further deacetalized.

(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 that forms

  According to the present invention, 1,3-dioxane can be obtained from 1,3-dioxane, which is a mixture with 1,3-dioxolanes, from a raw material that can be procured easily and inexpensively by a short process and a simple method. 5-ones can be produced. In addition, DHA and serinol can be produced from the obtained 1,3-dioxane-5-ones.

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

[material]
The method for producing 1,3-dioxane-5-ones of the present invention uses a mixture of a compound represented by the following formula (I) and a compound represented by the following formula (II) as a raw material.

(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 that forms

R ¹ and R ^{2 in} formula (I) and formula (II) are each independently a hydrogen atom or a monovalent hydrocarbon group, or R ¹ and R ² are bonded to each other to form a ring structure A divalent hydrocarbon group.
As a preferred embodiment of R ¹ and R ² , R ¹ is preferably a hydrogen atom from the viewpoint of a high isomer ratio of dioxane, and from the viewpoint of availability of raw materials, stability of dioxanone, and ease of separation. , R ² is preferably a hydrogen atom or a monovalent hydrocarbon group having 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.
As another preferred embodiment of R ¹ and R ² , R ¹ is preferably a monovalent hydrocarbon group having 1 to 8 carbon atoms and R ² is 1 carbon from the viewpoint of availability and reactivity of the raw materials. to 8 monovalent hydrocarbon group, more preferably R ¹ is an alkyl group is an alkyl group and R ² of 1 to 8 carbon atoms 1 to 8 carbon atoms, more preferably R ¹ is or 1 carbon atoms 2 alkyl group, R ² is an alkyl group having 1 to 6 carbon atoms, more preferably R ¹ is an alkyl group having 1 or 2 carbon atoms, and R ² is an alkyl group having 1 to 4 carbon atoms, and more Preferably, R ¹ is a methyl group and R ² is a methyl group or an ethyl group, more preferably R ¹ is a methyl group and R ² is a methyl 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 viewpoint of reactivity with the availability of raw materials, preferably Is a divalent hydrocarbon group having 2 to 7 carbon atoms, more preferably a divalent hydrocarbon group having 3 to 6 carbon atoms, more preferably a divalent hydrocarbon group having 4 to 5 carbon atoms, More preferably, it is a C5 divalent hydrocarbon group. 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 the formula (I), when R ¹ and R ² are bonded to each other to form a ring structure, the formula (I) becomes the following 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 following formula (II ′).

(In the formulas (I ′) and (II ′), R ^A represents a divalent hydrocarbon group that forms 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, and as described above, preferably forms a cyclopentane ring or a cyclohexane ring, and forms a cyclohexane ring. Further preferred.
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 addition, the cis-trans isomer exists in the compound represented by the formula (I) when R ¹ and R ² are not the same.
In addition, one or more asymmetric carbons are present in the compound represented by the formula (II). Therefore, unless enantioselective reaction or stereoisomer separation is performed, the compound represented by the formula (II) exists as a racemate or a stereoisomer mixture.
In addition, as a raw material of this invention, the stereoisomer ratio of the compound represented by Formula (I) and the stereoisomer ratio of the compound represented by Formula (II) are not specifically limited.

As the mixture of the compound represented by the above formula (I) and the compound represented by the above formula (II), a commercially available product may be used. As described later, in the formula (I) A mixture of the compound represented by the formula (dioxane) and the compound represented by the formula (II) (dioxolane) may be used, and is not particularly limited. It is preferable to have a step (Step 1) for producing a mixture of dioxolanes.
<Step 1: Production of a mixture of dioxane and dioxolane>
Although there is no restriction | limiting in the manufacturing method of the compound (dioxane) represented by the formula (I) used by this invention, and the compound (dioxolane) represented by the following formula (II), It is generally known widely A method, a method of acetalizing glycerol and a compound represented by the following formula (V), or a multimer thereof in the presence of an acid catalyst (method 1), or glycerol and a compound represented by the following formula (VI) Production by a method of exchanging acetals in the presence of an acid catalyst (Method 2) is preferable from the viewpoint of availability of raw materials, yield, and ease of reaction operation. The obtained mixture can be used as it is as a raw material in the next step 2 as it is or after purification, but it is preferable to purify the mixture to remove unreacted raw materials from the viewpoint of the yield in step 2 and facilitate purification. It is more preferable to carry out distillation purification from the viewpoint of properties.
Glycerol, a compound represented by the following formula (V), and a compound represented by the following formula (VI) can be easily and inexpensively obtained. By using Method 1 or Method 2, the raw material of the present invention can be easily obtained. In addition, it can be manufactured at low cost.
The reaction formulas of Method 1 and Method 2 are shown below.

(In the formula (V) and formula (VI), ^{R 1} and ^{R 2} are the same as ^{R 1} and ^{R 2} in formula (I) or Formula (II), wherein (VI), ^{R 3} are each independently Represents a monovalent hydrocarbon group.)

  As the mixture of dioxane and dioxolane used in the present invention, any mixture in which the isomer ratio of dioxane is 20% or more can be used, but from the viewpoint of productivity and economy, the higher the isomer ratio of dioxane, the better. . The isomer ratio of dioxane is preferably 30% or more, more preferably 40% or more, and still more preferably 50% or more.

R ³ in the formula (VI) is a monovalent hydrocarbon group, and from the viewpoint of availability of raw materials, preferably a hydrocarbon group having 1 to 8 carbon atoms and an alcohol by-produced by an acetal exchange reaction are used as a reaction system. From the viewpoint of promoting the reaction by distilling out, 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, still more preferably It is a methyl group.

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

[Production method of 1,3-dioxane-5-ones]
The method for producing 1,3-dioxane-5-ones of the present invention comprises 1,3-dioxane starting from a mixture of a compound represented by the above formula (I) and a compound represented by the above formula (II). It is a manufacturing method of -5-one, Comprising: It has the process (process 2) which oxidizes the said mixture on oxidative esterification conditions.

  By the step 2, the compound represented by the above formula (I) is oxidized to 1,3-dioxane-5-ones represented by the following formula (III) (hereinafter also referred to as “dioxanone”). In addition, the compound represented by the above formula (II) is oxidatively esterified into a compound represented by the following formula (IV) (hereinafter also referred to as “ester dimer”).

(In the formula (III) and formula (IV), ^{R 1} and ^{R 2} have the same meanings as ^{R 1} and ^{R 2} in formula (I) or Formula (II).)

  Since dioxolane of formula (II) has one or more asymmetric carbons, the ester dimer of formula (IV) is a stereoisomer mixture unless dioxolane with an enantiomeric excess of 100% is used. As obtained.

6-membered dioxane (compound represented by the above formula (I)) and 5-membered ring dioxolane (compound represented by the above formula (II)) in glycerin acetal are close to each other in physical properties such as boiling point and solubility. Is very difficult. Moreover, the oxidation mixture and the deprotection mixture have the same problem. In the present invention, oxidative esterification is adopted as the oxidation condition of the glycerin acetal mixture, and an oxidation mixture (compound (dioxanone) represented by the above formula (III) and the above formula (IV) having a large difference in physical properties such as boiling point and solubility is used. ), A dimerone having a molecular weight approximately twice as large as that of dioxanone becomes a by-product to be separated, so that dioxanone can be easily obtained by separating the ester dimer. Can be. For example, high-purity dioxanone can be easily obtained by distillation purification utilizing a large difference in boiling points.
That is, in the present invention, the step 2 comprises dioxolane (formula (II) above) with respect to a mixture of glycerin acetals (a mixture of the compound represented by the formula (I) and the compound represented by the formula (II)). Dioxanone (compound represented by the above formula (III)) having a large difference in physical properties by oxidizing dioxane (compound represented by the formula (I)) under the condition that the compound represented by ) And an ester dimer (compound represented by the above formula (IV)).

<Step 2: Oxidation reaction under oxidative esterification conditions>
In the present invention, step 2 is a step of oxidizing a mixture of a compound represented by the following formula (I) and a compound represented by the following formula (II) under oxidative esterification conditions.
In Step 2, when a mixture of the compound represented by the following formula (I) and the compound represented by the following formula (II) is oxidized under oxidative esterification conditions, the following reaction occurs.

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

Oxidative esterification is a kind of oxidation reaction for obtaining an ester from a primary alcohol and an alcohol in a broad sense. More generally, it is 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 dimerization. In the present invention, it means a reaction for obtaining an ester dimer (compound represented by formula (IV)) from dioxolane (compound represented by formula (II)).
Examples of the oxidative esterification method include a method using a homogeneous or heterogeneous metal catalyst, Reference 1 (The Journal of Organic Chemistry, Vol. 69, 5116-). 5119, 2004), a method using 4-acetamido-2,2,6,6-tetramethyl-1-oxopiperidinium tetrafluoroborate and pyridine, Reference 2 (Synlett, No. 1). 23, 2261-2265, 2012), a method using a catalytic amount of 2,2,6,6-tetramethylpiperidine-1-oxyl (hereinafter also referred to as “TEMPO”), an oxidizing agent and pyridine. and so on.

The object of the present invention is to oxidize dioxane (a compound represented by formula (I)) to obtain dioxanone (a compound represented by formula (III)). In addition, in order to easily separate dioxanone produced by the reaction from other components, a compound represented by the above formula (VII) that can be produced by oxidation of dioxolane (compound represented by formula (II)) , Also referred to as “formyldioxolane”).
Therefore, in the present invention, oxidation under oxidative esterification conditions is defined as an oxidation method that satisfies the following three conditions.
Condition 1: Dioxanone is produced from dioxane Condition 2: Ester dimer is produced from dioxolane Condition 3: The yield of formyldioxolane produced from dioxolane is 10% or less and 0% or more.

  In the present invention, any oxidation method satisfying the above definition can be used. From the viewpoint of obtaining high reaction activity, a salt containing an oxoammonium cation of an organic nitroxyl radical as in Reference 1 and a base are used. And an oxidation method using an organic nitroxyl radical, an N-hydroxy form thereof, and a salt containing an oxoammonium cation thereof, an oxidant, and a base (hereinafter referred to as “Reference 2”). The nitroxyl radical method is also preferred. From the viewpoint of high yields of dioxanone and ester dimer and low yields of formyldioxolane, the nitroxyl radical method is preferred, and among these, organic nitroxyls are preferred. Acid using radical and / or N-hydroxy form thereof, oxidizing agent and base The law is more preferable.

(Nitroxyl radical method)
[Nitroxyl radical species]
In this reaction, as the nitroxyl radical species, a compound selected from any organic nitroxyl radical, an N-hydroxy form thereof, and a salt containing an oxoammonium cation having an oxidative activity for dioxane and dioxolane when combined with an oxidizing agent. 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 a high oxidation 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). Is preferred. 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 viewpoints of availability and high yield of dioxanone.

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 standpoint of availability and high yields of dioxanone, the nitroxyl radical species include 4-methoxy-TEMPO, 4-benzoyloxy-TEMPO, 4-acetamido-TEMPO, 4-methylsulfonyloxy-TEMPO, and AZADOL. The compound selected is preferable, and the 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.

  The amount of the compound selected from the organic nitroxyl radical, its N-hydroxy form and a salt containing their oxoammonium cation is preferably molar relative to the mixture of dioxane and dioxolane from the viewpoint of securing sufficient oxidation activity. The 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 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 the mixture of dioxane and dioxolane and suppression of the production amount of formyldioxolane, the molar ratio of the oxidizing active species to the mixture of dioxane and dioxolane is preferably 1.0 or more, more preferably 1.1. That's it. 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 causes a side reaction directly with a mixture of dioxane and dioxolane, a catalyst or an oxidizing agent, and does not inhibit the target oxidation reaction. A heterocyclic aromatic amine having a pyridine skeleton is preferred. The heterocyclic aromatic amine having a pyridine skeleton may be used in combination with an inorganic base in order to suppress the amount used. From the viewpoint of obtaining dioxanone in high yield, the heterocyclic aromatic amine having a pyridine skeleton is used. More preferably, the group 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 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 difference in boiling point from dioxanone and can be easily separated by distillation, from the viewpoint of availability. An amine selected from pyridine and 5-ethyl-2-methylpyridine is preferred, and a heterocyclic aromatic having a water-insoluble pyridine skeleton from the viewpoint of easy recovery when the amine is regenerated from the amine salt after completion of the reaction. An amine is preferable, and from the viewpoint of yield, an amine selected from pyridine, 3,5-lutidine, 2,6-lutidine, 3-ethylpyridine, 4-ethylpyridine and 5-ethyl-2-methylpyridine is preferable. , 3,5-lutidine, 3-ethylpyridine, 4-ethylpyridine and 5-ethyl-2-methylpyridine That the amine is more preferable.

  From the viewpoint of completely neutralizing the acid derived from the oxidizing agent and suppressing the decomposition of the acetal group of dioxane and dioxolane, the molar ratio of the base to the mixture of dioxane and dioxolane is preferably 1.0 or more, more preferably 1. 1 or more, 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.

〔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 the mixture of dioxane and dioxolane, the oxidizing agent and the base. For example, when TCCA is used as the oxidizing agent, from the viewpoint of the solubility and availability of TCCA, Preferably a solvent selected from acetone, 2-butanone, cyclopentanone, acetonitrile and dichloromethane, more preferably a solvent selected from acetone, 2-butanone, acetonitrile and dichloromethane, and still more preferably a solvent selected from acetone and 2-butanone. is there. In addition, acetonitrile is more preferable from the viewpoint of the productivity of the dioxanenone of the present invention.

A solvent may be used individually by 1 type and may use the above together.
The amount of solvent used is not particularly limited, but from the viewpoint of operability and from the viewpoint of obtaining dioxanone in a high yield, 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, More preferably, it is 40% by mass or more, more preferably 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, it is 85 mass% or less, More preferably, it is 80 mass% or less.

[Reaction procedure]
In this reaction, there is no restriction on the order of charging the raw materials, but since it is an exothermic oxidation reaction, from the viewpoint of ease of temperature control and safety of the reaction liquid, a mixture or mixed solution of raw materials other than the oxidizing agent A method in which an oxidant or an oxidant solution is added dropwise 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 dioxanone in a high yield, it is preferably 25 ° C. or less, more preferably 10 ° C. or less. After completion of the addition of the oxidizing agent or oxidizing agent solution, the reaction is continued until the total amount of dioxane and dioxolane reacts or the decrease in the residual amount stops, but the temperature of the reaction solution is preferably from the viewpoint of promoting the reaction of dioxane. Is −10 ° C. or higher, more preferably −5 ° C. or higher, and preferably 50 ° C. or lower, more preferably 30 ° C. or lower, from the viewpoint of suppressing side reactions.

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 an oxidation product such as dioxanone and reacts with the oxidant, but alcohol is preferred from the viewpoint of availability and easy purification of dioxanone. . The alcohol is preferably a primary or secondary alcohol, and more preferably a secondary alcohol from the viewpoint of suppressing transesterification with an ester dimer. Moreover, C1-C12 alcohol is preferable.
The addition amount of the reaction terminator is not particularly limited.

<Step 3: Separation and purification of dioxanone>
In this invention, it is preferable to have after the process 2 the process (process 3) which isolate | separates 1, 3- dioxane-5-one (dioxanone, the compound represented by Formula (III)). According to step 3, dioxanone is purified.
In step 3, from the viewpoint of efficiency, solids such as salts and reduced products of oxidants may be separated by filtration or oil-water extraction, and ester dimer, formyldioxolane and residual base may be separated by distillation or column chromatography. preferable.
In the separation of dioxanone and ester dimer, separation by distillation is more preferable from the viewpoint of easy separation using a large difference in boiling points.
Separation by distillation can be carried out under simple distillation conditions or rectification conditions, but it is preferable to carry out under rectification conditions from the viewpoint of obtaining high-purity dioxanone with a high distillation yield. As the rectification conditions, from the viewpoint of high purity dioxanone, 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 It is 0.5 or more. Further, from the viewpoint of dioxanone refining productivity, the theoretical plate number 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.

[Method for producing dihydroxyacetone]
The dioxanone obtained as described above is important as an intermediate for synthesizing various useful compounds. For example, dihydroxyacetone can be produced by deacetalizing the dioxanone separated in Step 3.
In addition, deacetalization of dioxanone can be performed by hydrolysis. Specifically, Non-Patent Document 1 and Reference Document 3 (Chemical Engineering Journal, Vol. 229, pages 234-238). 2013), a method of hydrolyzing dioxanone in the presence of water and an acid (for example, hydrochloric acid or a strong acidic cation exchange resin) is exemplified.
Dihydroxyacetone may be used without being purified or may be used after being purified. When purified and used, it may be purified according to a conventional method, for example, a method described in Non-Patent Document 1, such as a method of recrystallization from a water-ethanol mixed solution after removing aldehyde or ketone by organic solvent extraction or the like. Illustrated.

[Method for Producing 5-Amino-1,3-Dioxane (Protected Serolinol)]
By reductive amination of the dioxanone obtained as described above, 5-amino-1,3-dioxanes (serinol protector) represented by the following formula (XI) can be produced.

(In the formula (XI), ^{R 1} and ^{R 2} have the same meanings as ^{R 1} and ^{R 2} in formula (I) or Formula (II).)

  As a method for reductive amination of dioxanone, for example, the method described in Non-Patent Document 2 is exemplified. Specifically, dioxanone is added to an anhydrous ammonia-ethanol solution, palladium-supported carbon is added as a catalyst, hydrogen atmosphere The method of making it react under is illustrated. Further, examples include a method using ammonium formate as a hydrogen source and an ammonia source, and a method of removing a benzyl group after reductive amination using benzylamine as an amine.

  When the dioxanone obtained in the above step 2 is reductively aminated without separating dioxanone and the ester dimer to produce a serinol protected body, the serolinol protected body is separated and purified by the same method as in the above step 3. can do.

[Method for producing 2-amino-1,3-propanediol (serinol)]
Serinol can be produced by reductive amination of the dioxanone obtained as described above to produce 5-amino-1,3-dioxanes and further deacetalization.
Examples of the method for reductive amination of dioxanone include the methods described above.
In addition, deacetalization is performed in the presence of water and an acid (for example, hydrochloric acid) as described in Reference 4 (European Patent No. 0643055), for example. The method of hydrolyzing dioxane is illustrated.
When 2-amino-1,3-propanediol is purified and used, it may be carried out according to a conventional method. For example, as described in Reference 4, water is distilled off after hydrolysis, and the residue is converted from acetone. The method of obtaining the hydrochloride of 2-amino-1,3-propanediol by recrystallization is exemplified.

  The 1,3-dioxane-5-ones obtained by the present invention are important as intermediates for synthesizing various useful compounds, and are suitably used for the production of pharmaceuticals, chemicals and the like.

The present invention further discloses the following [1] to [39].
[1] A method for producing 1,3-dioxane-5-ones using a mixture of a compound represented by the following formula (I) and a compound represented by the following formula (II) as a raw material, A method for producing 1,3-dioxane-5-ones having a step of oxidizing under oxidative esterification conditions (Step 2).

(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 that forms

[2] The method for producing 1,3-dioxan-5-ones according to [1], wherein R ¹ is a hydrogen atom in formula (I) and formula (II).
[3] In formula (I) and formula (II), R ¹ is preferably a hydrogen atom, R ² is preferably a hydrogen atom or a monovalent hydrocarbon group having 1 to 20 carbon atoms, The hydrocarbon group for R ² is preferably an alkyl group or an aryl group, and the carbon number of this alkyl group is preferably 1 or more, preferably 20 or less, more preferably 18 or less, still more preferably 16 or less. 14 or less, still more preferably 12 or less, even more preferably 10 or less, still more preferably 8 or less, still more preferably 6 or less, still more preferably 4 or less, and still more preferably 2 or less. There, the alkyl group may be branched may be linear, the number of carbon atoms of the aryl group R ² is preferably 6 or more, preferably 20 or less, more preferably 18 or less, more preferably 16 or less, even more preferably 14 or less, even more preferably 12 or less, even more preferably 10 or less, even more preferably 8 or less, even more preferably 6 or less, wherein 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, a branched alkyl group having 1 to 8 carbon atoms, or a carbon atom. The method for producing 1,3-dioxane-5-ones according to [1], which is an aryl group having a number of 6 or more and 20 or less, more preferably a hydrogen atom, a methyl group or a phenyl group, and still more preferably a hydrogen atom.
[4] In formula (I) and formula (II), preferably R ¹ is a monovalent hydrocarbon group having 1 to 8 carbon atoms and R ² is a monovalent hydrocarbon group having 1 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 1 to 8 carbon atoms, more preferably R ¹ is an alkyl group having 1 or 2 carbon atoms and R ² is 1 carbon atom. 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 1 to 4 carbon atoms, and even more preferably, R ¹ is a methyl group and R ² is methyl. The method for producing 1,3-dioxane-5-ones according to [1], wherein R ¹ is a methyl group and R ² is a methyl group, more preferably a group or an ethyl group.
[5] In the formula (I) and the formula (II), 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. A hydrocarbon group, more preferably a divalent hydrocarbon group having 3 to 6 carbon atoms, still more preferably a divalent hydrocarbon group having 4 to 5 carbon atoms, still more preferably a divalent carbon group having 5 carbon atoms. The ring structure that is a hydrogen group and includes 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 cyclohexane. The 1,3-dioxa as described in [1], which is more preferably a ring. Process for producing N-5-ones.
[6] A mixture of a compound represented by the formula (I) and a compound represented by the following formula (II) is prepared by mixing glycerol and a compound represented by the following formula (V), or a multimer thereof in the presence of an acid catalyst. Any one of [1] to [5] produced by a method for acetalization (method 1) or a method for acetal exchange between glycerol and a compound represented by the following formula (VI) in the presence of an acid catalyst (method 2) A process for producing the 1,3-dioxane-5-one according to claim 1.

(In Formula (V) and Formula (VI), 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 the formula (VI), each R ³ is independently a monovalent hydrocarbon group, preferably a group selected from hydrocarbon groups 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.)

[7] The process for producing 1,3-dioxan-5-ones according to [6], wherein in formula (V) and formula (VI), R ¹ is a hydrogen atom.
[8] In Formula (V) and Formula (VI), R ¹ is preferably a hydrogen atom, R ² is preferably a hydrogen atom or a monovalent hydrocarbon group having 1 to 20 carbon atoms, The hydrocarbon group for R ² is preferably an alkyl group or an aryl group, and the carbon number of this alkyl group is preferably 1 or more, preferably 20 or less, more preferably 18 or less, still more preferably 16 or less. 14 or less, still more preferably 12 or less, even more preferably 10 or less, still more preferably 8 or less, still more preferably 6 or less, still more preferably 4 or less, and still more preferably 2 or less. There, the alkyl group may be branched may be linear, the number of carbon atoms of the aryl group R ² is preferably 6 or more, preferably 20 or less, more preferably 18 or less, more preferably 16 or less, even more preferably 14 or less, even more preferably 12 or less, even more preferably 10 or less, even more preferably 8 or less, even more preferably 6 or less, wherein 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, a branched alkyl group having 1 to 8 carbon atoms, or a carbon atom. The method for producing 1,3-dioxane-5-ones according to [6], which is an aryl group having a number of 6 or more and 20 or less, more preferably a hydrogen atom, a methyl group or a phenyl group, and still more preferably a hydrogen atom.
[9] In formula (V) and formula (VI), preferably R ¹ is a monovalent hydrocarbon group having 1 to 8 carbon atoms and R ² is a monovalent hydrocarbon group having 1 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 1 to 8 carbon atoms, more preferably R ¹ is an alkyl group having 1 or 2 carbon atoms and R ² is 1 carbon atom. 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 1 to 4 carbon atoms, and even more preferably, R ¹ is a methyl group and R ² is methyl. The method for producing 1,3-dioxane-5-ones according to [6], wherein R ¹ is a methyl group and R ² is a methyl group, more preferably a group or an ethyl group.
[10] In the formula (V) and the formula (VI), 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. A hydrocarbon group, more preferably a divalent hydrocarbon group having 3 to 6 carbon atoms, still more preferably a divalent hydrocarbon group having 4 to 5 carbon atoms, still more preferably a divalent carbon group having 5 carbon atoms. The ring structure that is a hydrogen group and includes 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 cyclohexane. The 1,3-dioxy group according to [6], which is more preferably a ring. A method for producing sun-5-ones.

[11] In step 2, an oxidation method using an organic nitroxyl radical containing an oxoammonium cation and a base, and an organic nitroxyl radical, an N-hydroxy form thereof, and a salt containing an oxoammonium cation thereof are selected. The 1,3-dioxane according to [1] to [10], wherein an oxidation method selected from an oxidation method using a compound, an oxidizing agent, and a base (hereinafter also referred to as “nitroxyl radical method”) is preferably used. -5-one production method.
[12] In step 2, an oxidation method (nitroxyl) using one or more compounds selected from an organic nitroxyl radical, an N-hydroxy form thereof, and a salt containing an oxoammonium cation, an oxidizing agent, and a base. The method for producing 1,3-dioxane-5-ones according to [1] to [11], using a radical method.
[13] 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), [11] or [12] The process for producing a 1,3-dioxane-5-one according to [12].

(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.)

[14] One or more compounds selected from the organic nitroxyl radical, its N-hydroxy form, and salts containing their oxoammonium cations 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 1,3-Dioxane-5-one according to any one of [11] to [13], which is a compound selected from yloxy-TEMPO, 4-acetamido-TEMPO, 4-methylsulfonyloxy-TEMPO, and AZADOL Manufacturing method.
[15] The amount of the compound selected from the organic nitroxyl radical, its N-hydroxy form, and a salt containing an oxoammonium cation thereof is represented by the compound represented by the formula (I) and the following formula (II). Preferably, the molar ratio is 0.0001 or more, more preferably the molar ratio is 0.0002 or more, still more preferably the molar ratio is 0.0005 or more, and preferably the molar ratio is 0.1. The 1,3-dioxane-5-ones according to any one of [12] to [14], wherein the molar ratio is 0.05 or less, more preferably 0.02 or less. Production method.
[16] 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. Production of 1,3-dioxane-5-ones according to any one of [11] to [15], which is an oxidizing agent selected from an acid and tertiary butyl hypochlorite, and more preferably trichloroisocyanuric acid Method.
[17] The molar ratio of the oxidizing active species of the oxidizing agent to the mixture of the compound represented by the formula (I) and the compound represented by the formula (II) is preferably 1.0 or more, more preferably Is 1.1 or more, preferably 2.0 or less, more preferably 1.5 or less, production of 1,3-dioxane-5-ones according to any one of [11] to [16] Method.
[18] The process for producing 1,3-dioxane-5-ones according to any one of [11] to [17], wherein the base is preferably a heterocyclic aromatic amine having a pyridine skeleton.
[19] The heterocyclic aromatic amine having a pyridine skeleton is preferably pyridine, 3,5-lutidine, 2,6-lutidine, 3-ethylpyridine, 4-ethylpyridine and 5-ethyl-2-methylpyridine. [18], wherein at least one selected from pyridine, 3,5-lutidine, 3-ethylpyridine, 4-ethylpyridine and 5-ethyl-2-methylpyridine is more preferable. Of the method for producing 1,3-dioxane-5-ones.
[20] The molar ratio of the base to the mixture of the compound represented by the formula (I) and the compound represented by the formula (II) is preferably 1.0 or more, more preferably 1.1. Or more, 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 1.7 or less, [11] to [19] The method for producing a 1,3-dioxane-5-one according to any one of [19].

[21] In the step 2, a solvent is preferably used, and the solvent is preferably a solvent selected from acetone, 2-butanone, cyclopentanone, acetonitrile and dichloromethane, more preferably acetone, 2-butanone and acetonitrile. The method for producing 1,3-dioxane-5-ones according to any one of [1] to [20], which is a solvent selected, more preferably a solvent selected from acetone and 2-butanone.
[22] 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 of 1,3-dioxane-5-ones according to [21], 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. Method.
[23] The 1,3-dioxane according to any one of [1] to [22], wherein in the step 2, the oxidant or the oxidant solution is preferably added dropwise to a mixture or mixed solution of raw materials other than the oxidant. A method for producing 5-ones.
[24] 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. , [23] The method for producing 1,3-dioxane-5-ones according to [23].
[25] After completion of dropwise addition of the oxidizing agent or oxidizing agent solution, the reaction is continued until the total amount of dioxane and dioxolane reacts or the decrease in the residual amount stops, 1,3- according to [23] or [24] A method for producing dioxane-5-ones.
[26] 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. A method for producing 3-dioxane-5-ones.

[27] The process for producing 1,3-dioxane-5-ones according to any one of [1] to [26], preferably using an alcohol as the reaction terminator in Step 2.
[28] The process for producing 1,3-dioxane-5-ones according to [27], wherein the reaction terminator is preferably a primary or secondary alcohol, more preferably a secondary alcohol.
[29] The method for producing 1,3-dioxane-5-ones according to [27] or [28], wherein the reaction terminator is preferably an alcohol having 1 to 12 carbon atoms.
[30] The 1,3-dioxane-5-one according to any one of [1] to [29], wherein the step of oxidizing under the oxidative esterification conditions (step 2) satisfies the following conditions 1 to 3. Manufacturing method.
Condition 1: Dioxanone is produced from dioxane Condition 2: An ester dimer is produced from dioxolane Condition 3: The yield of formyldioxolane produced from dioxolane is 10% or less and 0% or more. [31] The method for producing 1,3-dioxane-5-ones according to any one of [1] to [30], comprising a step of separating 3-dioxane-5-ones (Step 3).
[32] The method for producing 1,3-dioxane-5-ones according to [31], wherein the separation in the step 3 is separation by distillation.
[33] The method for producing 1,3-dioxane-5-ones according to [32], wherein the separation by distillation is preferably performed under rectification conditions.
[34] The rectification condition is 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 1,3-dioxane according to [33], wherein 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. A method for producing 5-ones.

[35] A method for producing dihydroxyxyacetone, wherein the 1,3-dioxane-5-one separated in any of [31] to [34] is deacetalized.
[36] Production of 2-amino-1,3-propanediol, wherein the 1,3-dioxane-5-one separated in any of [31] to [34] is reductively aminated and further deacetalized. Method.
[37] A step of producing 1,3-dioxane-5-one by the production method of any one of [1] to [34], and 1,3-dioxane-5-one produced in the step A method for producing dihydroxyxyacetone, comprising a step of deacetalizing.
[38] A step of producing 1,3-dioxane-5-one by the production method of any one of [1] to [34], and 1,3-dioxane-5-one produced in the step A method for producing 2-amino-1,3-propanediol, comprising a step of reductive amination and further deacetalization.
[39] A step of producing 1,3-dioxane-5-one by the production method according to any one of [1] to [34], and the 1,3-dioxane-5-one produced in the step A method for producing 5-amino-1,3-dioxane, which comprises a step of reductive amination.

[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 analysis using an infrared spectrophotometer (IR, manufactured by Horiba, Ltd., model: FT-710), gas chromatograph mass spectrometer (GC-MS, manufactured by Agilent Technologies, Inc., model: Agilent 5975C) Identified.
[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 5 (Journal of Catalysis, Vol. 245, pp. 428-435, 2007) describes the ¹ H-NMR signal attribution of the proton 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, 2937, 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%. Further, 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 5 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). Cis and trans-2-methyl-1,3-dioxan-5-ol and cis and trans-4-hydroxymethyl-2-methyl-1 are distilled and distilled as a colorless liquid at a fraction temperature of 62-70 ° C. Thus, 160 g of a mixture of four isomers consisting of 3-dioxolane was obtained. The purity was 100% and the distillation yield was 96%.
Reference 6 (Tetrahedron, Vol. 71, No. 20, pp. 3032-3038, 2015) describes the ¹ H-NMR signal assignment of the proton 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 7 (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-dioxane-5-one 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-dioxan-5-ol and 4-hydroxymethyl-1,3-dioxolane determined from information in Reference 5 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 of 1,3-dioxan-5-ol was 100%, the yield of 1,3-dioxan-5-one was 90%, 4-hydroxymethyl-1,3- Conversion of dioxolane was 100%, yield of 1,3-dioxolane-4-carboxylic acid (1,3-dioxolan-4-yl) methyl ester was 95%, yield of 4-formyl-1,3-dioxolane Was 1%.
Into a 200 mL pear-type flask equipped with a 6-stage packed distillation column (packing: Helipac Packing No. 2) was charged 65.0 g of the crude product, and 0.67 kPa ( After the pressure was reduced to (absolute pressure), the reflux ratio was set to 3 to obtain 27.4 g of 1,3-dioxane-5-one distilling as a colorless liquid at a fraction temperature of 42 to 43 ° C. The purity was 99.2% and the distillation yield was 92%. Further, the pressure was changed to 0.13 kPa (absolute pressure), the reflux ratio was changed to 0.1, and 1,3-dioxolane-4-carboxylic acid (1) distilled as a pale yellow liquid at a fraction temperature of 89 to 91 ° C. , 3-Dioxolan-4-yl) methyl ester 21.9 g 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-dioxan-5-one>
^{· 1 H-NMR (400MHz,} CDCl 3, δ ppm): 4.36 (4H, s), 5.02 (2H, s).
^{· 13 C-NMR (100MHz,} CDCl 3, δ ppm): 73.4,91.4,203.7.
IR (neat, cm ⁻¹ ): 2864, 1736, 1425, 1240, 1178, 1122, 1043, 930.
MS (m / z): 102 (M ^<+> ), 73, 44.
<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.
<Spectral data of 4-formyl-1,3-dioxolane>
MS (m / z): 102 (M ^<+> ), 73, 56, 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. As a result of GC analysis of the filtrate after filtering off the powdery solid produced as a by-product, the conversion of 1,3-dioxane-5-ol was 100%, and the yield of 1,3-dioxane-5-one was 98%. The conversion of -hydroxymethyl-1,3-dioxolane is 100%, the yield of 1,3-dioxolane-4-carboxylic acid (1,3-dioxolan-4-yl) methyl ester is 99%, 4-formyl- The yield of 1,3-dioxolane was 1%.

Examples 1-3 to 1-15
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 1-15.

Example 2: Production of 2-phenyl-1,3-dioxane-5-one The reaction carried out in Example 2 is as follows.

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) Was used as a reaction raw material in the same manner as in Example 1-2 to give 2-phenyl-1,3-dioxane-5-one and 2-phenyl-1,3-dioxolane-4-carboxylic acid (2- A reaction solution containing phenyl-1,3-dioxolan-4-yl) methyl ester as a main product was obtained. Table 2 shows the reaction conditions and results of Examples 2-1 and 2-2.
The reaction liquids obtained in Examples 2-1 and 2-2 were mixed and subjected to simple distillation under reduced pressure of 0.13 kPa (absolute pressure). A pale yellow liquid distilled at a fraction temperature of 94 to 96 ° C. was recrystallized from tert-butyl methyl ether to obtain 1.28 g of colorless thin plate crystals of 2-phenyl-1,3-dioxane-5-one. The purity was 100% and the purification yield was 43%. Further, 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 simple brown residue in the form of a dark brown oil. 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-dioxan-5-one>
^{· 1 H-NMR (400MHz,} CDCl 3, δ ppm): 4.46 (2H, d, J = 17.2Hz), 4.52 (2H, d, J = 17.2Hz), 5.89 (1H , S), 7.25-7.55 (5H, m).
^{· 13 C-NMR (100MHz,} CDCl 3, δ ppm): 72.4,99.0,126.1,128.5,129.4,133.8,204.4.
IR (neat, cm ⁻¹ ): 3070, 2860, 1718, 1394, 1094, 975.
MS (m / z): 178 (M ^<+> ), 148, 119, 105, 91, 77, 51.
<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.
<Spectral data of 4-formyl-2-phenyl-1,3-dioxolane (stereoisomer mixture)>
MS (m / z, common to two peaks on GC): 178 (M ⁺ ), 177, 149, 105, 91, 77, 51.

Example 2-3
A mixture of 2-phenyl-1,3-dioxan-5-ol and 4-hydroxymethyl-2-phenyl-1,3-dioxolane obtained in Production Example 1 451 mg (purity 100%, 2.50 mmol), 4 -Acetamide-2,2,6,6-tetramethyl-1-oxopiperidinium tetrafluoroborate 1.98 g (purity 95.0%, 6.26 mmol), molecular dried in advance under vacuum heating conditions Sieve 4A (1.0 g) and dichloromethane (10 g) were charged into a 50 mL flask equipped with a dropping funnel and stirred at room temperature under a nitrogen atmosphere. A solution consisting of 0.457 g of pyridine (purity 99.5%, 5.75 mmol) and 5 g of dichloromethane was placed in a 20 mL dropping funnel and added dropwise over 10 minutes. Stirring was further continued at room temperature for 2 hours, and finally, 0.10 g of methanol (purity 99.8%, 3.1 mmol) was added and stirred for another 10 minutes to complete the reaction. As a result of GC analysis of the filtrate after filtering the molecular sieve 4A and by-product powdery solid, the conversion rate of 2-phenyl-1,3-dioxane-5-ol was 56%, and 2-phenyl-1,3-dioxane. The yield of -5-one was 13%, the conversion of 4-hydroxymethyl-2-phenyl-1,3-dioxolane was 60%, 2-phenyl-1,3-dioxolane-4-carboxylic acid (2-phenyl The yield of -1,3-dioxolan-4-yl) methyl ester was 51%, and the yield of 4-formyl-2-phenyl-1,3-dioxolane was 4%.

Example 3 Production of 2-methyl-1,3-dioxane-5-one The reaction performed in Example 3 is as follows.

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 rate of 2-methyl-1,3-dioxane-5-ol was 100%, the yield of 2-methyl-1,3-dioxane-5-one was 74%, Conversion of methyl-4-hydroxymethyl-1,3-dioxolane is 100%, 2-methyl-1,3-dioxolan-4-carboxylic acid (2-methyl-1,3-dioxolan-4-yl) methyl The yield of ester was 88%, and the yield of 4-formyl-1,3-dioxolane was 0%.
60.0 g of the crude product was charged into a 100 mL pear-type flask equipped with a 6-stage theoretical distillation column (packing: Helipac Packing No. 2), and 1.3 kPa ( After the pressure was reduced to (absolute pressure), the reflux ratio was set to 3 to obtain 31.4 g of 2-methyl-1,3-dioxane-5-one distilling as a colorless liquid at a fraction temperature of 52 to 53 ° C. The purity was 100% and the distillation yield was 96%. Further, the pressure is reduced to 0.13 kPa (absolute pressure), the reflux ratio is set to 0.5, and 2-methyl-1,3-dioxolane-4-distilled as a pale yellow liquid at a fraction temperature of 110 to 113 ° C. 16.1 g of carboxylic acid (2-methyl-1,3-dioxolan-4-yl) methyl ester was obtained. The purity was 98.6% and the distillation yield was 95%. ¹³ C-NMR and GC-MS analysis confirmed that this ester dimer was a mixture of four stereoisomers consisting of at least two racemates. In addition, about another 6 sets of racemic bodies, a peak overlaps and it is estimated that it was not able to be detected.

<Spectral data of 2-methyl-1,3-dioxan-5-one>
¹ H-NMR (400 MHz, CDCl ₃ , δ _ppm ): 1.44 (3H, d, J = 5.2 Hz), 4.29 (2H, d, J = 17.6 Hz), 4.39 (2H , D, J = 17.6 Hz), 5.06 (1H, q, J = 5.2 Hz).
^{· 13 C-NMR (100MHz,} CDCl 3, δ ppm): 20.2,72.6,97.4,204.4.
IR (neat, cm ⁻¹ ): 2994, 2875, 1739, 1408, 1130, 1097, 1051, 872.
MS (m / z): 116 (M ^<+> ), 101, 86, 58, 43.
<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 3.54 g (purity 100%, 30.0 mmol) As a reaction raw material, the same operation as in Example 1-2 was performed to give 2-methyl-1,3-dioxane-5-one and 2-methyl-1,3-dioxolane-4-carboxylic acid (2- A reaction solution having methyl-1,3-dioxolan-4-yl) methyl ester as a main product was obtained. Table 3 shows the reaction conditions and results of Examples 3-2 to 3-4.

<Spectral data of 2-methyl-4-formyl-1,3-dioxolane (stereoisomer mixture)>
MS (m / z, common to two peaks on GC): 115, 101, 87, 71, 59, 43.
FIG. 3 shows a GC chart of the reaction solution obtained in Example 3-3.

Example 4: Production of 2-n-heptyl-1,3-dioxane-5-one The reaction carried out in Example 4 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 dihydroxyacetone The reaction carried out in Example 5 is as follows.

1.00 g (purity 100%, 5.61 mmol) of 2-phenyl-1,3-dioxane-5-one obtained in Examples 2-1 and 2-2, 1.0 g of Dowex 50Wx8 (strongly acidic positive) 40 mg of ion exchange resin, Dow Chemical Co., Ltd., and 10 g of ion exchange water were charged into a 20 mL flask and stirred at 40 ° C. for 2 hours. After cooling, the reaction solution from which the ion exchange resin had been filtered was extracted three times with 10 g of tert-butyl methyl ether to remove benzaldehyde. 100 g of acetonitrile was added to the aqueous solution, and the solvent was distilled off at 40 ° C., followed by vacuum drying. As a result of GC analysis after 500 mg of the obtained pale yellow resinous crude product was converted to trimethylsilyl (TMS), the main product was a cyclic hemiacetal dimer of DHA and DHA. Reference 8 (Journal of Catalysis, Vol. 245, pages 428-435, 2007) describes ¹ H-NMR signal attribution of DHA in heavy water. As a result of ¹ H-NMR analysis of the crude product under the same conditions, DHA and DHA hydrate (molar ratio 1.0 to 0.26) were the main constituents as in the literature, and a small amount of other hemiacetal dimer was found. Existed. As a result of ¹ H-NMR analysis of the crude product to which dimethylsulfone was added as an internal standard substance, the purity of the DHA skeleton in the crude product obtained by quantifying the hydrates of DHA and DHA was 63.3%. The rate was 63%.

Example 6: Production of 2-amino-1,3-propanediol (serinol) The reaction carried out in Example 6 is as follows.

In a 200 mL flask equipped with a 20 mL dropping funnel, ammonium formate 14.2 g (purity 100%, 224 mmol), 10% -palladium carbon 0.50 g (manufactured by Kawaken Fine Chemical Co., Ltd., MA type, 52% water-containing product), 60 g of methanol was charged and stirring was started. Immediately thereafter, 4.00 g (purity 100%, 22.4 mmol) of 2-phenyl-1,3-dioxan-5-one obtained in the same manner as described in Examples 2-1 and 2-2 was added. A solution dissolved in 15 g of methanol was dropped from the dropping funnel over 30 minutes (during this time, the temperature of the liquid in the flask rose from 17 ° C. to 20 ° C.), and the mixture was further stirred for 2 hours. After the palladium carbon was filtered off and the methanol was distilled off, a 2 mol / L sodium hydroxide solution was added until the pH was 12, followed by extraction three times with 50 g of tert-butyl methyl ether. After distilling off tert-butyl methyl ether from the combined organic layers, 5-amino-2 is distilled as a colorless liquid at a device temperature of 170 to 180 ° C. under a reduced pressure of 130 Pa (absolute pressure) using a Kugelrohr distillation apparatus. -2.04 g of phenyl-1,3-dioxane was obtained. 40 mL of 2 mol / L hydrochloric acid was added to this 5-amino-2-phenyl-1,3-dioxane, and the mixture was stirred at around 20 ° C. for 2 hours. After extraction with 50 mL of tert-butyl methyl ether three times to remove benzaldehyde, 1 mol / L sodium hydroxide solution was added until the pH reached 10. After distilling off water, 10 mL of 2-propanol was added and insoluble matters were filtered off. Further, 2-propanol was distilled off and vacuum-dried to obtain 1.10 g of a colorless oily crude product. As a result of ¹ H-NMR analysis of a crude product in which dimethyl sulfone was added as an internal standard substance in heavy water, the purity of serinol was 90.8% and the yield was 49%.

  According to the method for producing 1,3-dioxane-5-ones of the present invention, 1,3-dioxane-5-ones are produced from raw materials that can be procured easily and inexpensively by a short process and a simple method. A method is provided. The 1,3-dioxane-5-ones obtained by the present invention are important as intermediates for various useful compounds, are also useful as raw materials for the synthesis of DHA and serinol, and are suitably used as raw materials for pharmaceuticals and chemicals. Is done.

Claims (11)

A method for producing 1,3-dioxan-5-ones using a mixture of a compound represented by the following formula (I) and a compound represented by the following formula (II) as a raw material, wherein the mixture is an oxidative ester A process for producing 1,3-dioxan-5-ones, which comprises a step of oxidizing under oxidizing conditions (step 2).

(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 that forms The method for producing 1,3-dioxane-5-ones according to claim 1, wherein R ¹ is a hydrogen atom in formula (I) and formula (II).   3. The process 2 according to claim 1, wherein at least one compound selected from an organic nitroxyl radical, an N-hydroxy form thereof, and a salt containing an oxoammonium cation thereof, an oxidizing agent, and a base are used in Step 2. Of the method for producing 1,3-dioxane-5-ones. 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). , 3-Dioxane-5-one production 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 method for producing 1,3-dioxane-5-ones according to claim 3 or 4, wherein the oxidant is an oxidant composed of a compound containing chlorine.   The method for producing 1,3-dioxane-5-ones according to any one of claims 3 to 5, wherein the base is a heterocyclic aromatic amine having a pyridine skeleton.   The method for producing 1,3-dioxane-5-ones according to any one of claims 1 to 6, further comprising a step (step 3) of separating 1,3-dioxane-5-ones after step 2.   The method for producing 1,3-dioxane-5-ones according to claim 7, wherein the separation in Step 3 is separation by distillation.   A process for producing 1,3-dioxane-5-ones by the production method according to claim 1, and deacetalization of the 1,3-dioxane-5-ones produced in the process A process for producing 1,3-dihydroxyxyacetone, comprising the step of:   A process for producing 1,3-dioxane-5-ones by the production method according to any one of claims 1 to 8, and a 1,3-dioxane-5-one produced in the process is reduced to a reductive amino acid. And a method for producing 2-amino-1,3-propanediol, further comprising a step of deacetalization.   A process for producing 1,3-dioxane-5-ones by the production method according to any one of claims 1 to 8, and a 1,3-dioxane-5-one produced in the process is reduced to a reductive amino acid. A process for producing 5-amino-1,3-dioxane, which comprises the step of: