WO2013035899A1 - Method for preparing 5-hydroxy-1,3-dioxane and method for preparing branched glycerol trimers using 5-hydroxy-1,3-dioxane as a raw material - Google Patents

Abstract

The present invention relates to a method for preparing 5-hydroxy-1,3-dioxane (α, α'-isomer of glycerol formal) which is very suitable as a raw material for branched glycerol, and more particularly, to a method for preparing 5-hydroxy-1,3-dioxane, comprising the steps of: using, as a starting material, a mixture of 5-hydroxy-1,3-dioxane and 4-hydroxymethyl-1,3-dioxolane, preferably adding glycerol, and then heating the mixture at 40-100°C in the presence of a concentrated sulfuric acid as an acid catalyst to obtain a mixture in which the proportion of 5-hydroxy-1,3-dioxane is higher than that in the starting material; and allowing pivaloyl chloride and trityl chloride to react with the mixture having the increased proportion of 5-hydroxy-1,3-dioxane, thereby performing separation and purification of unreacted 5-hydroxy-1,3-dioxane through distillation or extraction.

Description

Method for producing 5-hydroxy-1,3-dioxane and method for producing branched glycerol trimer using the same

The present invention is a glycerol form which is a mixture of 5-hydroxy-1, 3-dioxane (α, α-isomer) and 4-hydroxymethyl-1, 3-dioxolane (α, β-isomer) A method of producing 5-hydroxy-1,3-dioxane with high purity by using horses as a raw material, and preferably adding glycerol, and using 5-hydroxy-1,3-dioxane as raw materials A method for producing a branched glycerol trimer.

The present inventors have previously conducted a series of studies on glycerol derivatives, and are referred to as branched oligo glycerol (hereinafter referred to as "branched glycerol" or "BGL") for improving the stability and water solubility of physiologically active polypeptides. Has been developed (Patent Document 1). In addition, the present inventors have also developed a technique in which the branched glycerol is bound to an amphiphilic substance or a hydrophobic substance and used as a drug carrier (Patent Document 2), which improves the water solubility of the fibrate-based antihyperlipidemic compound and makes it easier to use as a medicine. Technology has also been developed (Patent Document 3).

In order to produce the branched glycerol described in Patent Documents 1 to 3, first, an alcohol compound such as epichlorohydrin or the like or a protecting compound such as glycerol is reacted to produce a compound in which two hydroxyl groups are protected. You need to start with.

Compounds in which the two hydroxyl groups are protected include 5-hydroxy-1 and 3-dioxane, which are α, α-isomers of glycerol formal represented by the following formula (1) having a formal protecting group.

[Formula 1]

It is known that the (alpha), (alpha)-isomer of the said glycerol formal can be manufactured with glycerol and formaldehyde (nonpatent literature 1, 2).

The glycerol formal obtained from the glycerol and formaldehyde is a mixture of the α, α-isomer and 4-hydroxymethyl-1, 3-dioxolane which is the α, β-isomer represented by the following formula (2). .

[Formula 2]

The α and β-isomers cannot be used as raw materials for branched glycerol derivatives. For example, glycerol formal available from Tokyo Chemical Industry Co., Ltd. is a mixture of α, α-isomers and α, β-isomers. Because the properties of the two isomers are similar, it is very difficult to separate and purify them.

[Preceding technical literature]

[Patent Documents]

Patent Document 1: International Publication No. 2004/029018

Patent Document 2: International Publication No. 2005/023844

Patent Document 3: International Publication No. 2008/093655

[Non-Patent Documents]

[Non-Patent Document 1] Jean-Louis Gras, Robert Nouguier, Mohammed Mchich, Tetrahedron Letters 28 (52), 1987, P6601-6604

Non-Patent Document 2: Merck Index (14) 4485

Glycerol formal obtained from glycerol and formaldehyde is suitable as a raw material for branched glycerol because of its low cost, but α and β-isomers contained in glycerol formal cannot be used as raw materials for branched glycerol.

Therefore, in the present invention, a mixture of α, α＇-isomers and α, β-isomers of glycerol formal is used as a raw material to produce α, α＇-isomers of high purity, and α, α＇-isomers of the high purity are used as raw materials. It was mentioned as a subject to manufacture branched glycerol trimer as a subject.

In order to solve the above problems, in the present invention, using a mixture of 5-hydroxy-1, 3-dioxane and 4-hydroxymethyl-1, 3-dioxolane as starting materials, concentrated sulfuric acid as an acid catalyst is added Heating at 40 to 100 ° C. to obtain a mixture having a higher proportion of 5-hydroxy-1,3-dioxane than starting materials; And reacting the mixture with pivaloyl chloride and trityl chloride, and separating and purifying unreacted 5-hydroxy-1,3-dioxane by distillation or extraction. It provides a method for producing 1, 3-dioxane.

In one embodiment of the present invention, the step of obtaining a mixture having a higher ratio of 5-hydroxy-1,3-dioxane than the starting material is characterized in that the addition of 0.1 to 5 moles of glycerol per 1 mole of the starting material mixture do.

In another aspect, the present invention provides a method for producing a formal group-protected branched glycerol trimer represented by the formula (3), characterized in that the 5-hydroxy-1, 3-dioxane as a raw material.

[Formula 3]

[Correction under Article 91 of the Rule 10.11.2011]

In addition, the present invention provides a formal group-protected branched glycerol trimer [Formula 3] prepared using the 5-hydroxy-1, 3-dioxane as a raw material.

In addition, the present invention provides a method for producing a branched glycerol trimer protected with acetonide group, characterized in that the formally protected branched glycerol trimer is used as a raw material.

[Formula 4]

[Correction under Article 91 of the Rule 10.11.2011]

According to the manufacturing method of this invention, the (alpha), (beta) -isomer contained in glycerol formal can be converted into the (alpha), (alpha)-isomer. In particular, when isomerization reaction is carried out by adding glycerol, it is possible to obtain high concentrations of the α and α＇-isomers in high yield while suppressing the formation of by-products. In addition, by selectively pivalylating and tritylating only unisomerized α, β-isomers, the α, α＇-isomer, pivaloyl and trityl bodies can be separated by distillation or extraction. Therefore, it is possible to manufacture high purity α, α-isomers easily and inexpensively with high efficiency. It is also possible to produce branched glycerol trimers using the above high-purity α and α-isomers as raw materials.

1 is a schematic diagram briefly showing a pibylation method.

2 is a schematic diagram briefly showing a tritylation method.

FIG. 3 is a diagram showing ¹ H-NMR results of a mixture of (a) a ratio of 1,3-mG and 1,2-mG of 99.8: 0.2, and (b) a trityl mixture.

As confirmed by the inventors, available glycerol formals include 5-hydroxy-1, 3-dioxane (α, α＇-isomer) and 4-hydroxymethyl-1, 3-dioxolane (α, β -Isomer) is contained at 55: 45-60: 40 (mass ratio). However, the α, α-isomer and the α, β-isomer have a boiling point difference of 0.3 ° C. at normal pressure, for example, and it is difficult to separate them by distillation. Therefore, the present inventors performed some treatment operation | movement to the said mixture and tested in order to raise the ratio of the (alpha), (alpha) '-isomer. As a result, it was confirmed that the conversion from the α, β-isomer to the α, α＇-isomer occurred only by heating with addition of concentrated sulfuric acid as the acid catalyst.

Therefore, in the present invention, a mixture of 5-hydroxy-1, 3-dioxane, 4-hydroxymethyl-1, 3-dioxolane is used as a starting material, and concentrated sulfuric acid is added as an acid catalyst at 40 to 100 ° C. The process of heating is performed.

Isomerization takes place in this simple way because of the presence of water. That is, since concentrated sulfuric acid has strong hygroscopicity, it is thought that isomerization advanced because the addition of concentrated sulfuric acid made the amount of water in a raw material mixture very small. Glycerol and formaldehyde, which are starting materials for glycerol formal, are hygroscopic, and when one equivalent of water is produced in the manufacturing process, the presence of water is 5-hydroxymethyl-1, 3-dioxolane, and 5-hydroxyl-1. It can be surmised that it interferes with the isomerization to hydroxy-1,3-dioxane (details will be described later).

In the isomerization reaction, it takes a long time when the heating temperature is less than 40 ° C. Moreover, when it exceeds 1000 degreeC, an isomerization efficiency will gradually fall. 50-95 degreeC is preferable, as for heating temperature, 50-75 degreeC is more preferable, and its 60-75 degreeC is still more preferable.

Although heating time is not specifically limited, Usually, they are several hours-about several ten hours. In the Example mentioned later, since the isomerization rate improved in order of 3 hours, 6 hours, and 18 hours, it is preferable to heat for 6 hours or more.

Concentrated sulfuric acid, which is an acid catalyst, can be used in a concentration of 90% or more (mass). However, as described above, water may inhibit isomerization, and therefore, 98% of concentrated sulfuric acid having the highest concentration among the concentrated sulfuric acid on the market. Preference is given to using. The amount of concentrated sulfuric acid is preferably about 0.01% to 8% of the raw material mass, and more preferably about 0.2% to 5%. After completion | finish of reaction, it is preferable to neutralize concentrated sulfuric acid with alkali, such as sodium carbonate.

In the present invention, it is preferable to use commercially available glycerol formal, i.e., a mixture of 5-hydroxy-1, 3-dioxane and 4-hydroxymethyl-1, 3-dioxolane as starting materials. You may use a mixture with commercially available glycerol formal.

In addition, since 5-hydroxy-1, 3-dioxane or 4-hydroxymethyl-1, 3-dioxolane are all liquid at room temperature, the isomerization reaction can be carried out without solvent. Moreover, you may carry out in presence of a solvent, As a preferable solvent, ethers, such as 1, 4- dioxane, cyclopentyl methyl ether, and tetrahydrofuran, are mentioned, 1, 4- dioxane is most preferable from a viewpoint of solubility. desirable. Isomerization occurs in other ethers, but the yield is low, and toluene is not preferable because isomerization is unlikely to occur. 1,4-dioxane is hygroscopic, but in the reaction of the present invention, the presence of water is not preferable, and it was also confirmed in the experimental example described later that the dioxane dried was higher than the wet one, and therefore, the dioxane was dried. It is preferable to use oxane.

In the isomerization reaction of this invention, it is preferable to add glycerol. When glycerol is added, it is because the present inventors discovered that the effect of raising the ratio of alpha, alpha -isomer is large and the yield is further improved. The reason for this is as follows.

Isomerization between the α, α＇-isomers and α, β-isomers in the presence of an acid catalyst, concentrated sulfuric acid, can draw various reaction mechanisms including an equilibrium process, but a typical case is shown by Scheme 1 below.

Scheme 1

[Correction under Article 91 of the Rule 10.11.2011]

When water is present in the reaction system in the reaction scheme 1, formaldehyde and glycerol are by-produced by deprotection of the methylene acetal moiety.

The by-produced formaldehyde causes a new side reaction, as shown in Scheme 2 below.

Scheme 2

[Correction under Article 91 of the Rule 10.11.2011]

Since side reactions such as dimerization and multimerization of the starting raw materials shown in Scheme 2 further promote the generation of water molecules, as a result, formaldehyde continues to increase, and the side reactions proceed gradually. and negative chain reaction in a direction different from that of high concentration of the α＇-isomer. If isomerization is carried out under highly diluted conditions, the side reaction may be suppressed. However, highly dilute and reacted small molecular weight compounds are industrially uneconomical measures and are not suitable for mass synthesis.

In the past, a large number of chemical reaction processes such as "protection, deprotection and crosslinking of acetal" have been reported, but in most cases, compounds having a relatively high molecular weight are subject to a dimerization reaction as shown in Scheme 2 above. Since further multimerization reactions are unlikely to occur and may return to the desired compound in the equilibrium reaction, there has been no historical context in which such side reactions are problematic. That is, the problem that the dimerization and multimerization of a target compound advance with the compound derived from the protecting group removed, As a result, the problem that the yield of a target compound will be greatly reduced was not recognized at all until now.

In this invention, the said problem was solved by adding an glycerol and performing an isomerization reaction, and succeeded in raising the yield of the (alpha), (alpha) '-isomer.

First, in order to carry out the desired reaction in the present invention, it is preferable to operate the acid while removing water as much as possible. However, since most of the inexpensive acids have a nucleophilicity, X ⁻ , which is a pair of ions, frequently causes side reactions such as introduction of an X group into the target compound (for example, when hydrochloric acid is used, Cl is introduced into the molecule of the target compound). It becomes). On the other hand, sulfuric acid (X- = HSO _4- ) has a very low nucleophilicity of X in an inexpensive acid, so the worry of such side reactions is very low. However, it is well known that sulfuric acid (concentrated sulfuric acid) excluding water as much as possible deteriorates the function as a dehydrating agent causing the dehydration reaction and the resulting carbonization reaction, and the function as an acid is already weakened. Therefore, the attack of the α, α＇-isomer and α, β-isomer of oxygen on the lone electron pair shown in Scheme 1 is very unlikely to occur.

On the other hand, dilute sulfuric acid functions well as an acid, but as mentioned above, since the presence of water encourages unwanted side reactions, it cannot be said to be an acid suitable for the isomerization reaction in the present invention. If dilute sulfuric acid does not contain water, it can be said to be an acid suitable for the isomerization reaction in the present invention, but it does not exist in the world.

Therefore, in the present invention, the isomerization reaction was performed in high yield in a novel concept of adding glycerol to the reaction system instead of water, rather than a chemical species of dilute sulfuric acid containing no water. As a result, as shown in Scheme 3 below, hydrogen atoms capable of acid = H ⁺ can be present in a large amount in the reaction system, thereby greatly increasing the speed of the reaction for promoting isomerization.

Scheme 3

[Correction under Article 91 of the Rule 10.11.2011]

In addition, since almost no water is present in the reaction system, by-products of formaldehyde and glycerol do not occur theoretically, and the yield of α, α＇-isomers, α, β-isomers can be suppressed since the side reactions can be suppressed. As a result of being able to increase the holding ratio and increasing the isomerization rate by the presence of the glycerol, it is considered that it is possible to obtain high concentrations of the α and α-isomers in high yield. In addition, since an excess of glycerol is added, the effect that the rightmost equilibrium of Scheme 3 is shifted to the left is also combined, and even in the case where it is difficult to completely remove water from the reaction system at the industrial level, the above-mentioned multimer byproducts The negative chain reaction of can be thoroughly suppressed. Glycerol added as a substitute for water should be the same compound as the polyhydric alcohol moiety (glycerol) constituting the α, α-isomer or α, β-isomer, but glycerol is inexpensive and can be recycled. In addition to the above-mentioned chemical reasons, in terms of cost, use is recommended in the present invention.

Chemistry of vast acetals in the past (e.g. Roush, WR; Coe, JWJ Org. Chem. 1989, 54, 915, Mukai, C .; Miyakawa, M .; Hanaoka, MJ Chem. Soc., Perkin Trans. 1 In 1997 and 913, dimerization and multimerization were not observed, and it is considered that the suppression of such side reactions was not attracted attention as a study subject. For this reason, in the companies producing glycerol formal, the reaction is stopped at a stage where the total chemical yield of the α, α-isomer and the α, β-isomer is optimal. Therefore, commercially available glycerol formal is α , α＇-isomer and α, β-isomer can be assumed to be a mixture of 55:45 to 60:40 (mass ratio). In other words, if the reaction time is short, a large amount of formaldehyde and glycerin remain, and the long-term reaction can be expected to decrease the total chemical yield as a result of the side reaction. However, in the present invention, after finding that the mixing ratio of the α and α-isomers cannot be increased is a side reaction called multimerization, in order to suppress the side reactions, the polyhydric alcohols constituting the α and α-isomers and What is necessary is just to add the same alcohol, and came to this invention. This technical idea is a technical idea which was not seen before.

From the above reasons, in the present invention, the following production method is recommended as the most suitable method.

(1) From glycerol and formaldehyde, the reaction is carried out so that the total chemical yield of the α, α-isomer and the α, β-isomer is greatest, and water and formaldehyde are removed from these mixtures to form α, α-- The mixture of isomers and α, β-isomers is separated and purified. This mixture is commercially available as mentioned above and can be obtained, and this reaction can be skipped.

(2) To the mixture of α, α-isomers and α, β-isomers, add glycerol of high purity dried (excluding water) as much as possible, add catalytic amount of concentrated sulfuric acid, and heat in the above-described temperature range. Stir. It is preferable to add 0.01-5 mol of glycerol with respect to 1 mol of raw material mixtures, 0.5-2 mol is more preferable, and 0.5-1 mol is more preferable. As the solvent, dioxane is most preferred from the viewpoint of solubility as described above.

(3) When the reaction between the α, α-isomer and the α, β-isomer reaches equilibrium, a solid base (sodium carbonate) or the like is added to stop the equilibrium reaction.

(4) The obtained mixture of α, α-isomers and α, β-isomers undergoes selective pivaloylation and tritylation reactions with α, β-isomers, and the α, α-isomer and By forming a boiling point difference between the pivaloylated body and the tritylated body of the α and β-isomers, high-purity α and α-isomers can be easily obtained by distillation.

By the above method, a mixture of α, α-isomers and α, β-isomers of glycerol formal as starting materials can be obtained in high yield with a mixture having a higher ratio of α, α-isomers than the starting materials. .

Next, in order to obtain α, α-isomer from the mixture with high purity, it is difficult to react with the α, α-isomer and react with the mixture a compound having a group that selectively binds to the hydroxyl group of the α, β-isomer. do. At this time, the boiling point of the reaction product produced by the selective binding of the compound to the hydroxyl groups of the α and β-isomers is considerably higher than the α and α＇-isomers, so that only the α and α-isomers can be separated and purified by distillation. . Alternatively, the pivaloylated or tritylated α, β-isomer becomes insoluble in water due to the high fat solubility of pivaloyl group or trityl group, so that only the α, α-isomer is transferred to the aqueous layer by an extraction operation. Monolithic or tritylated α, β-isomers are separated and purified by transition to an organic solvent (e.g., hexane, ether, and the like, more preferably a lower polar solvent, hexane, benzene, toluene, preferably hexane). It is also possible.

As such a compound, in this invention, the compound which can be pivalylated and tritylation (all two places), for example, pivaloyl chloride and trityl chloride (all three places) is used. Pivaloyl chloride or trityl chloride (all two places) hardly reacts with the α and α-isomers and binds only to the hydroxyl groups of the α and β-isomers. However, since the product reacted with the α and α-isomers is not zero, pivaloyl chloride or trityl chloride is added to a mixture of the α and α-isomers of the glycerol formal with the α and β-isomers. When it reacts, (alpha), (alpha)-isomer of glycerol formal (unreactant), (beta) -pivaloyl- (alpha)-(alpha)-isomer of glycerol formal, (alpha)-(pivaloyl-alpha) of glycerol formal, Mixtures with β-isomers are obtained as reaction products. Here, the α, α＇-isomers have a boiling point of about 65 ° C., for example, at 8 mmHg (10.7 hPa), whereas the β-pivaloyl-α, α＇-isomers and α＇-P obtained after pivaloylation. The baloyl-α and β-isomers have a boiling point of about 110 ° C. at 8 mmHg (10.7 hPa). Therefore, by performing vacuum distillation after pivaloylation and tritylation, it becomes possible to isolate (alpha), (alpha)-isomer from a reaction product. In addition, the pressure reduction degree at the time of vacuum distillation is not limited to the above, There is no restriction as long as it can isolate | separate (alpha), (alpha) '-isomer. In addition to distillation, an extraction operation using water and an organic solvent described above may be used.

Pivaloylation is halogenated, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, and dichlorobenzene, in the presence of organic bases such as N-methylpiperidine, pyridine, 4-pyrrolidinopyridine and the like. Hydrocarbons can be performed as a solvent. As for reaction temperature, about -10 degreeC-about 30 degreeC are preferable, and reaction time is not specifically limited. After the reaction, it is preferable to neutralize the reaction product as appropriate. Tritylation is necessary in the presence of an organic base such as N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, 2, 4, 6-collidine, or an inorganic base such as sodium hydrogencarbonate in addition to these. Therefore, halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, and dichlorobenzene, can be performed as a solvent. As for reaction temperature, about -10 degreeC-about 30 degreeC are preferable, and reaction time is not specifically limited. After the reaction, it is preferable to neutralize the reaction product as appropriate.

Thereafter, the solvent is distilled off as necessary, followed by distillation under reduced pressure as described above, and the α and α＇-isomers are separated from the reaction product.

The (alpha), (alpha)-isomer of this glycerol formal can be said to be a compound which protected glycerol with a formal group. Therefore, by using α and α-isomers of glycerol formal as raw materials and appropriately reacting with epihalohydrin such as epichlorohydrin, a branched glycerol trimer protected by a formal group can be produced. This trimerization reaction can be performed, for example in presence of a base, such as potassium hydroxide, and a correlation transfer catalyst, such as tetrabutylammonium bromide. The product is preferably purified by silica gel column chromatography or the like.

Moreover, the branched glycerol trimer protected with the acetonide group can also be manufactured using the said branched glycerol trimer protected by the said formal group. Acetonide by removing a formal protecting group of the branched glycerol trimer with, for example, an acid such as hydrochloric acid, and then neutralizing and reacting a known compound such as 2,2-dimethoxypropane for acetonitrile after neutralization. Branched glycerol trimers protected with groups can be obtained. Although acetonitrile may use a general acid catalyst, it is more preferable to carry out in presence of solid acid catalysts, such as "Amberlyst (R) 15" (made by Rohm and Haas). Of course, other protecting groups may be attached.

The said patent document 1-3 describes the synthesis method of BGL in detail, and the (alpha), (alpha) '-isomer of the said glycerol formal is suitable as a raw material of these BGL.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.

EXAMPLE

Example 1 Isomerization of Glycerol Formal

A mixture of 520 mg (5 mmol) and 2.5 mmol of glycerol obtained by mixing the α, α-isomer and α, β-isomer of glycerol formal obtained from Tokyo Chemical Co., Ltd. at 57:43 (mass ratio: ^1H- NMR) Concentrated sulfuric acid (98%) was added to 2.5 mL of the dissolved dioxane solution, and it heated at 60 degreeC for 3 hours, stirring. The obtained reaction solution was left to cool to room temperature, and an appropriate amount of sodium carbonate solution was added to neutralize concentrated sulfuric acid. After filtration through celite, dioxane was removed by distillation under reduced pressure. About the obtained product, the ratio (mass ratio, below) and recovery (mol%, below) of the (alpha), (alpha)-isomer, and (alpha), (beta) -isomer were calculated | required using <^1> H-NMR. The results are shown in Table 1.

The isomerization reaction was performed by the same method as the above except having changed the mixing ratio of a solvent, glycerol amount, heating temperature, reaction time, and a raw material mixture as shown in Table 1. The results are shown in Table 1.

TABLE 1

[Correction under Article 91 of the Rule 10.11.2011]

No. From the contrast of 1-3, it turns out that the ratio of isomerization becomes high and the yield also increases, so that reaction time is long. Moreover, since it reached nearly equilibrium in 18 hours, No. In 4-15, reaction time was made constant at 18 hours.

No. From the contrast of 4-6, isomerization is occurring also in any of 50-95 degreeC, and the isomerization rate in 60-75 degreeC was especially high.

No. From the contrast of 3 and 7-9, the isomerization reaction occurs even if glycerol is not added (No. 7), but high isomerization rate was obtained by adding 2.10-10 mmol of glycerol. However, no. Compared to 8, No. 10 mmol added In 9, the isomerization rate and the yield fell slightly.

No. From the contrast of 3, 10, and 11, when there was no dioxane as a solvent, it turned out that although yield is low, it shows very high isomerization rate. In addition, No. using wet dioxane In 11, since isomerization hardly proceeded even in reaction of 18 hours, it is suitable to use dried dioxane.

No. In 12-15, the 30:70 mixture of the (alpha), (alpha)-isomer, and (alpha), (beta) -isomer was used as raw material mixture. No. The same result as in the case of 3, 7, 10, and 11 was shown, and even if there were many amounts of the (alpha), (beta) -isomer, it turned out that isomerization to (alpha), (alpha)-isomer is advanced. In addition, the said 30:70 mixture is experiment No. mentioned later. The ratios of β-pivaloyl-α, α＇-isomers and α＇-pivaloyl-α, β-isomers obtained in 17 were obtained by depivaloylation from a 9:91 mixture. , β-isomer ratio was prepared by mixing a 9:91 mixture and the commercially available 57:43 mixture.

Example 2. Isomerization of Glycerol Formal

No. of Example 1 Under the same reaction conditions, 10.4 g (100 mmol) and 9.2 g (100 mmol) of glycerol were mixed in a mixture of α, α-isomer and α, β-isomer of glycerol formal at 30:70 (mass ratio). One drop of concentrated sulfuric acid (98%) was added to 20 mL of the dissolved dioxane solution, and the mixture was heated with stirring at 60 ° C. for 18 hours in an oil bath. The obtained reaction solution was left to cool to room temperature, an appropriate amount of sodium carbonate solution was added, and concentrated sulfuric acid was neutralized. After filtration through celite, dioxane was removed by distillation under reduced pressure, and the obtained product was further purified by distillation under reduced pressure (8 mmHg (10.7 hPa), 65 ° C). Yield of a colorless oil. The reaction product was 8.85g, and the yield was 85.0%, and the ratio of α, α'- isomer and α, β- isomers obtained by using a ¹ H-NMR was 70:30. The added glycerol was recovered by distillation under reduced pressure (8 mmHg (10.7 hPa), 150 ° C). The recovery amount of glycerol was 8.70 g and the recovery rate was 94.6%.

Example 3. Isomerization of Glycerol Formal

At room temperature, glycerol formal (1 equivalent), glycerol (1 equivalent), and 1,4-dioxane (3-6 M) are added to the reaction vessel and installed in a mantle heater, equipped with a mechanical stirrer and a thermometer, and argon ( Ar) was replaced with gas and stirred at 200 rpm. Thereafter, the mixture was added dropwise with H ₂ SO ₄ (1-0.355 mol%), and the temperature was slowly increased until the internal temperature became 60 ° C, and the ratio of 1,3-mG and 1,2-mG was> 70: Stir at 500 rpm until <30 (see Scheme 4 below). When the desired ratio was reached, the speed was lowered to 200 rpm and cooled to room temperature. After cooling, 10 equivalents of Na ₂ CO ₃ in H ₂ SO ₄ was added and stirred well to stop the reaction. Mixed solution was filtered through a Celiteⓡ, and the residue was washed with CH ₂ Cl ₂ and the filtrate 1,4-dioxane and CH ₂ Cl ₂ was removed by distillation under reduced pressure. The residue was separated by distillation under reduced pressure into glycerol formal (66 ° C./8 mmHg) and glycerol (108 ° C./1.0 mmHg). The final product was analyzed using ¹ H-NMR. The result is as follows.

1, 3-mG

¹ H NMR (400 MHz, CDCl 3) δ 3.01 (d, J = 10 Hz, 1 H), 3.63 (dquin, J = 10, 3 Hz, 1 H), 3.88 (dd, J = 11, 3 Hz, 2 H), 3.93 (dd, J = 11, 3 Hz, 2 H), 4.77 (d, J = 6 Hz, 1 H), 4.94 (d, J = 6 Hz, 1 H), 13 C NMR (75 MHz, CDCl 3) 64.2 (CH-OH), 71.7 (CH 2 x 2), 94.1 (-O-CH 2 -O-). IR (neat) v 3424, 2976, 2921, 2859, 1479, 1459, 1183, 1153, 1066, 1039, 1013, 980, 957, 914, 809.ESI-HRMS: m / z ([M + Na] ⁺ ) Calcd for C 4 H 8 O 3 Na: 127.0366, Found: 127.0338.

Scheme 4

[Correction under Article 91 of the Rule 10.11.2011]

Example 4. Pivaloylation Reaction

Pyridine at 0 ° C. in 333 mL of a dichloromethane solution in which 104 g (1.00 mol) of a mixture of α, α-isomers and α, β-isomers of glycerol formal and commercially available α, β-isomers were mixed in a mass ratio of 57:43 under argon conditions. 54.5 mL (0.675 mol) and 67.7 mL (0.550 mol) of pivaloyl chloride were added sequentially, followed by stirring at 0 ° C. for 30 minutes and then at room temperature for 4 hours to react.

An appropriate amount of sodium carbonate was added to the obtained reaction solution at room temperature, neutralized, and filtered through celite, and then dichloromethane was removed by distillation under reduced pressure. The obtained product is a mixture of unreacted α, α-isomer, β-pivaloyl-α, α′-isomer, and α′-pivaloyl-α, β-isomer (see Scheme 5 below). This product was purified by distillation under reduced pressure (8 mmHg (10.7 hPa), 65 ° C). The (alpha), (alpha)-isomer of the glycerol formal obtained by vacuum distillation was colorless and oily, and the yield was 52.2g and yield 50.1%. In addition, a mixture (colorless oily) in which the ratio of β-pivaloyl α, α＇-isomer, α＇-pivaloyl-α, β-isomer of glycerol formal is 9:91 was yielded in 85.1 g (yield 45.2%). Was obtained.

Scheme 5

[Correction under Article 91 of the Rule 10.11.2011]

Example 5. Pivaloylation Reaction

70:30 glycerol formal (1,2-mG = 1 equivalent) was added to the reaction vessel at room temperature, and a dropping funnel and a thermometer were installed, and substituted with argon gas, followed by dichloromethane and pyridine (1.33 equivalents). It was. When the reaction vessel was installed in an ice bath and the internal temperature fell to 5-10 degreeC, pivaloyl chloride (1.22 equivalent) was dripped for 5 hours using the dropping funnel. After completion of the dropwise addition, the mixture was slowly returned to room temperature, stirred at room temperature for 6 hours, and stirred until the ratio of 1,3-mG and 1,2-mG became 92: 8 or more. Thereafter, 10 equivalents of NaHCO ₃ equivalent of pivaloyl chloride was slowly added until the carbon dioxide gas was not generated and stirred well to stop the reaction. The mixed solution was filtered through Celite®, the residue on Celite® was washed with CH ₂ Cl ₂ , and CH ₂ Cl ₂ of the filtrate was removed by distillation under reduced pressure. Pyridine in the residue was distilled off with a diaphragm pump. And the product was replaced with 1 wt% NaHCO ₃ aq _. The mixture was poured into a mixed solution of hexane and separated into a hexane layer and an aqueous layer with a separating funnel, and the hexane layer was removed. The aqueous layer was once more added hexane, separated into an aqueous layer and a hexane layer, and the hexane layer was combined with the hexane layer. The combined hexane layer was dried over anhydrous MgSO ₄ , filtered, and distilled under reduced pressure, and the remaining product was a mixture of Piv-1, 3-mG, Piv-1, 2-mG. The water in the aqueous layer was added with ethanol and distilled under reduced pressure to obtain a residue. The residue was diluted with dichloromethane, dried over anhydrous MgSO ₄ , filtered, and the solvent was distilled off. The water and ethanol recovered by distillation under reduced pressure were distilled under reduced pressure again to obtain an additional residue. The residue was combined, and simple distillation (66 ° C./8 mmHg) was performed to obtain a mixture having 1,3-mG as a main component (see Scheme 6 below). A schematic diagram of the experiment is shown in FIG. 1.

Scheme 6

[Correction under Article 91 of the Rule 10.11.2011]

Example 6. Tritylation Reaction

Add 1,3-mG and 1,2-mG mixture (1 equiv), 2,4,6-collidine (0.12 equiv) and dichloromethane (1 M) to the reaction vessel at room temperature A curler and a dropping funnel were attached, replaced with argon (Ar) gas, and stirred at 500 rpm. Thereafter, a dichloromethane solution of TrCl (0.08 equiv) was added dropwise for 6 hours using a dropping funnel, and stirred at a rotational speed of 500 rpm at room temperature. When the desired ratio was reached, the rotational speed was lowered to 200 rpm, and 1 wt% NaHCO ₃ aq. Of 10 equivalents of TrCl was added to the reaction, and the reaction was stopped by stirring until no CO ₂ gas was generated. The mixed solution was separated into an aqueous layer and a dichloromethane layer. CH ₂ Cl ₂ of the organic layer was distilled off under reduced pressure, and the residue was added to the aqueous layer. The aqueous layer was extracted by adding hexane, and separated into an aqueous layer and an organic layer A. The aqueous layer is extracted once more with hexane and separated into aqueous layer and organic layer B. Ethanol for azeotropic addition to the aqueous layer was added, and the residue was distilled under reduced pressure to obtain a residue. The crude product was diluted with dichloromethane, dried over anhydrous MgSO ₄ , filtered, and solvent distilled off to obtain residue A. The water and ethanol recovered by the above-mentioned pressure distillation were distilled under reduced pressure again to obtain a residue B. The residue A and the residue B were combined and subjected to simple distillation (66 ° C./8 mmHg) to obtain 1,3-mG having a purity> 99.5% or more. The organic layer A and the organic layer B were combined, dried over anhydrous MgSO ₄ , filtered, and distilled under reduced pressure, and the remaining product was a mixture of Tr-1, 3-mG, Tr-1, 2-mG (see Scheme 7 below). The final product was analyzed using ¹ H-NMR. The results are shown in FIG.

Scheme 7

[Correction under Article 91 of the Rule 10.11.2011]

Example 7 Synthesis of BGL

9:91 mixture of β-pivaloyl-α, α＇-isomers and α＇-pivaloyl-α, β-isomers of glycerol formal obtained by the method of Example 4 or 5, and 57:43 233 ml (233 mmol) of 1 M aqueous NaOH solution was added to 50 ml of an ethanol solution of 29.1 g (155 mmol) having a mixture ratio of 30:70 by mixing the mixture, followed by stirring at room temperature for 18 hours to react.

1 M hydrochloric acid was added to the obtained reaction solution at room temperature, the pH was adjusted to slightly exceed 7, and ethanol and water were distilled off under reduced pressure. The sodium pivalate salt was filtered through celite from the obtained residue, the celite pad was washed with ether, and ether was distilled off from the filtrate under reduced pressure. The obtained crude product was purified by distillation under reduced pressure (8 mmHg (10.7 hPa), 65 ° C). A mixture (colorless oil, yield 14.5 g, yield 89.8%) having α, α-isomer and α, β-isomer of glycerol formal at a ratio of 30:70 was obtained.

Example 8 Synthesis of BGL (fm)

0.5 ml of an aqueous solution containing 0.994 g (17.7 mmol) of potassium hydroxide in 2.21 g (21.3 mmol) of the α and α-isomers of glycerol formal obtained in the reaction of Example 4, and 0.457 g of tetra-n-butylammonium bromide After adding (1.42 mmol), 0.354 mL (7.09 mmol) of epichlorohydrin was gradually added so as not to generate too much heat, stirred at room temperature for 30 minutes, and then stirred at 60 ° C. for 48 hours in an oil bath to react.

To the reaction solution, 1 M hydrochloric acid was added at room temperature until the pH was 7, and the reaction solution was neutralized. After distilling off the water under reduced pressure, potassium chloride was separated from the obtained crude product by celite filtration. After washing a celite pad with dioxane, dioxane was distilled off from the filtrate under reduced pressure. The obtained residue was purified by silica gel chromatography (dichloromethane: acetone = 3: 1 (liquid ratio)) to obtain BGL003 (fm) (colorless oily phase, yield 14.5 g, yield 89.8%). The final product was analyzed using ¹ H-NMR. The result is as follows.

¹ H-NMR (400 MHz, CDCl ₃ )

δ / ppm 3. 41-3. 47 (m, 2H), 3. 50-3. 65 (m, 4H), 3. 71 (dd, J = 15, 8 Hz, 4H), 3. 85-3. 98 (m, 1H), 4. 03 (dd, J = 15, 4 Hz, 4H), 4. 73 (d, J = 1 Hz, 2H), 4. 83 (d, J = 1 Hz, 2H)

¹³ C-NMR (75 MHz, CDCl ₃ )

δ / ppm 69. 0, 69. 5, 70. 0, 70. 4, 93. 4

From this analysis, the product was identified as a branched glycerol trimer: BGL003 (fm) protected with a formal group represented by the following formula (3).

[Formula 3]

[Correction under Article 91 of the Rule 10.11.2011]

Example 9. BGL003 (mtl) ₂ Synthesis of

To the reaction vessel at room temperature, a mixture of 1,3-mG and 1,2-mG in a ratio of 96: 4 (1 equiv), 2,4,6-collidine (0.12 equiv) and dichloromethane (1 M) were added and stirred The ruler was put, the dropping funnel was attached, and it substituted by argon (Ar) gas. A dichloromethane solution of TrCl (0.08 equiv) was added dropwise for 6 hours using a dropping funnel and stirred at 500 rpm at room temperature. When the desired ratio was reached, the number of revolutions was lowered to 200 rpm, and 1 wt% NaHCO ₃ aq. Of 10 equivalents of TrCl was added to the reaction and stirred until no CO ₂ gas was generated. The mixed solution was separated into an aqueous layer and a dichloromethane layer. CH ₂ Cl ₂ of the organic layer was distilled off under reduced pressure, and the residue was added to the aqueous layer. The aqueous layer was extracted by adding hexane, and separated into an aqueous layer and an organic layer A. The aqueous layer was extracted once more with hexane, and separated into an aqueous layer and an organic layer B. Ethanol for azeotropic addition to the aqueous layer was added and distillation under reduced pressure was carried out to obtain a residue. The product was diluted with dichloromethane, dried over anhydrous MgSO ₄ , filtered, and solvent distilled off to obtain residue A. The water and ethanol recovered at reduced pressure were distilled off under reduced pressure again to obtain residue B. The residue A and the residue B were combined and subjected to simple distillation (66 ° C./8 mmHg) to obtain 1,3-mG of purity> 99.5% or more. The organic layer A and the organic layer B were combined, dried over anhydrous MgSO ₄ , filtered, and distilled under reduced pressure, and the remaining product was a mixture of Tr-1, 3-mG, Tr-1, and 2-mG (see Scheme 8 below).

Scheme 8

[Correction under Article 91 of the Rule 10.11.2011]

Example 10 Replacement of Protectors

BGL003 (fm) 528 mg (2.00 mmol) obtained in Example 8, 2 mL (2.00 mmol) of 1 M hydrochloric acid and 2 mL of a methanol solution containing 1 drop of concentrated sulfuric acid were stirred in an oil bath at 100 ° C. for 12 hours to react. The formal group was removed.

11 g (10 mmol) of solid base "Amberlite (R) IRA-96" (ion exchange resin manufactured by Rohm and Haas) was added to the obtained reaction solution, and the mixture was neutralized by stirring at room temperature for 1 hour, and the solid base was filtered. Separated by. After methanol and water were distilled off under reduced pressure, celite filtration was carried out to remove sodium chloride and sodium sulfate from the crude product obtained, and after washing the celite pad with dioxane, dioxane was distilled off under reduced pressure from the filtrate.

To 2 mL of N, N'-dimethylformaldehyde solution containing 0.738 ml (6.00 mmol) of the obtained residue and 2,2-dimethoxymethane (acetone dimethylacetal; acetonated compound) at room temperature, the solid acid catalyst "Amberlyst (registered trademark)" 39.5 mg (0.2 mmol) of 15 ”(the catalyst ion exchange resin manufactured by Rohm and Haas Co., Ltd.) were added, and it stirred for 24 hours and made it react.

The solid acid catalyst was separated from the obtained reaction solution by filtration. N, N'-dimethylformaldehyde was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane: acetone = 5: 1 (liquid ratio)) and protected with an acetonide group represented by the following formula (4). Branched glycerol trimer: BGL003 (Atn) (white solid, yield 487 mg, yield 76.0%) was obtained.

[Formula 4]

[Correction under Article 91 of the Rule 10.11.2011]

The above description of the present invention is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive.

The 5-hydroxy-1, 3-dioxane (α, α＇-isomer) of glycerol formal obtained in the present invention is bound to a stability or water solubility improvement technique such as a physiologically active polypeptide, a biphilic substance or a hydrophobic substance. It is useful as a raw material of branched glycerol applicable to the technique used as a drug carrier, the technique which improves the water solubility of a fibrate type antihyperlipidemic compound, and makes it easy to use as a medicine. In addition, it is also possible to synthesize the branched glycerol trimer protected by a formal group or the branched glycerol trimer protected by an acetonide group from the alpha and alpha -isomers of glycerol formal.

Claims (5)

1. (a) Using a mixture of 5-hydroxy-1, 3-dioxane and 4-hydroxymethyl-1, 3-dioxolane as starting materials, concentrated sulfuric acid as an acid catalyst is added and heated at 40-100 캜. Obtaining a mixture having a higher ratio of 5-hydroxy-1 and 3-dioxane than starting materials; And

   (b) reacting the mixture with pivaloyl chloride and trityl chloride, and separating and purifying the unreacted 5-hydroxy-1,3-dioxane by distillation or extraction. -1, 3-dioxane manufacturing method.
2. The method of claim 1,

   Obtaining a mixture having a higher ratio of 5-hydroxy-1 and 3-dioxane than the starting raw material is characterized in that the addition of 0.1 to 5 moles of glycerol per 1 mole of the starting raw material mixture.
3. [Correction under Article 91 of the Rule 10.11.2011]
   

   A method for producing a formal group-protected branched glycerol trimer represented by the formula (3), characterized by using the 5-hydroxy-1, 3-dioxane of claim 1 as a raw material.

   [Formula 3]

   
4. [Correction under Article 91 of the Rule 10.11.2011]
   

   A formal group-protected branched glycerol trimer prepared by using 5-hydroxy-1 and 3-dioxane according to claim 1 [Formula 3].

   [Formula 3]

   
5. [Correction under Article 91 of the Rule 10.11.2011]
   

   The method for producing a branched glycerol trimer protected with an acetonide group, wherein the branched glycerol trimer protected with the formal group of claim 4 is used as a raw material.

   [Formula 4]

   

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