JP6992976B2 - Method for Producing Trimethylene Carbonate Derivative - Google Patents

Description

The present invention relates to a method for producing a trimethylene carbonate derivative having functions such as heat sensitivity and biodegradability.

Since polylactic acid has biodegradability and is decomposed and absorbed in a living body, it is expected to be used for medical materials such as carriers for drug delivery systems (DDS) and medical adhesives. However, many macromolecular compounds having biodegradability, such as polylactic acid, have an ester bond in the polymer main chain and hydrolyze to produce an acidic organic compound, which may cause inflammation. ..

On the other hand, since polytrimethylene carbonate has a polymer backbone as a polymer main chain, carbon dioxide and diol are produced by hydrolysis, and no acidic organic compound is produced. Therefore, paying attention to such properties, a novel polymer material in which various substituents are introduced into polytrimethylene polycarbonate has been proposed (Patent Document 1). By introducing a predetermined substituent, a biodegradable derivative of polytrimethylene carbonate can be created. Furthermore, by selecting the type of substituent, it is possible to obtain a polytrimethylene carbonate derivative having functions suitable for medical materials such as biodegradability, heat sensitivity and antithrombotic properties.

Japanese Unexamined Patent Publication No. 2012-232909

For the introduction of a substituent, a method of ester-bonding the substituent with the main chain of the compound into which the substituent is introduced is often adopted. However, in this method, an ester bond is present in the trimethylene carbonate derivative obtained by introducing a substituent, and when this derivative is polymerized, the above-mentioned properties of polytrimethylene carbonate are exhibited. I will lose it. Therefore, in Patent Document 1, a method of introducing a substituent into trimethylene carbonate in a bond form different from that of an ester bond is adopted, but this method involves steps from a starting substance to a target substance (trimethylene carbonate derivative). Since there are many and the synthesis route is complicated, there is a problem that it takes time and labor to synthesize the trimethylene carbonate derivative.

An object to be solved by the present invention is to make it possible to easily synthesize a trimethylene carbonate derivative containing no ester bond in a small number of steps.

The method for producing a trimethylene carbonate derivative according to the present invention, which has been made to solve the above problems, is to protect two of the three hydroxyl groups of triol, which is a starting material, by benzylation, and the protected 2 After deprotection of only one of the sites, and carbonateization of a total of two hydroxyl groups, one of the deprotected sites and one of the three hydroxyl groups of the triol that was not protected by benzylation. , A method for obtaining a trimethylene carbonate derivative.

Specifically, the method for producing a trimethylene carbonate derivative according to the present invention is as follows.
A step of obtaining compound A represented by the following formula (2) by simultaneously protecting two hydroxyl groups of trimethylolpropane represented by the following formula (1) with a protective agent.
A step of reducing the compound A with a reducing agent and deprotecting only one of the two locations to obtain a compound B having two hydroxyl groups represented by the following formula (3).
It is characterized by comprising a step of obtaining a trimethylene carbonate derivative represented by the following formula (4) by carbonylating the two hydroxyl groups of the compound B.

In the formulas (1) to (4), R1 represents a hydrogen atom or an alkyl group, preferably a lower alkyl group having 1 to 5 carbon atoms, and more preferably a methyl group or an ethyl group.
Further, in the formulas (2) to (4), R represents an aryl group, preferably a phenyl group.

In the above production method, two hydroxyl groups of trimethylolpropane are simultaneously protected with an aldehyde group, and then only one is deprotected. As a result, a structure in which the aldehyde compound is bonded to trimethylolpropane by an ether bond (that is, the structure of compound B) is obtained. Next, a trimethylene carbonate derivative is formed by a cycloaddition reaction between the deprotected hydroxyl group and the originally unprotected hydroxyl group by carbonylation (carbonation). The formed trimethylene carbonate derivative can be made into a high molecular weight by a well-known method.

The above method focuses on the symmetry of the three hydroxyl groups of the starting material, trimethylolalkane, and protects the two hydroxyl groups of trimethylolalkane at the same time with a protective agent, and then deprotects and cleaves only one of them. It was possible to obtain a trimethylene carbonate derivative from trimethylolalkane in a smaller number of steps as compared with the conventional method.

The protective agent used to obtain compound A from the trimethylolpropane, that is, to protect the two hydroxyl groups of the trimethylolpropane, may be an aldehyde compound, and preferred protective agents include benzaldehyde and vanillin. .. R1 in the above formula (1) and R in the above formulas (2) and (3) (that is, related to the type of protective agent) depending on the type and degree of functionality required for the trimethylene carbonate derivative. Should be selected as appropriate.

The reducing agent used to obtain compound B from compound A, that is, to deprotect only one of the two protecting agent-protected hydroxyl groups in compound A, has a relatively weak reducing power. Preferably, examples of such reducing agents include diisobutylaluminum hydride or sodium borohydride. In particular, when R1 is a methyl group, it is preferable to use diisobutylaluminum hydride as a reducing agent. On the other hand, if a reducing agent having a strong reducing power such as lithium aluminum hydride (LiAlH ₄ ) is used, both of the two protected hydroxyl groups are deprotected and cannot be used.

According to the present invention, a trimethylene carbonate derivative having a side chain composed of only a polyether and not containing an ester bond can be easily produced with a small number of steps.

Ethyl (2-methoxy-4-(((5-methyl-2-oxo-1,3-dioxane-5-yl) methoxy) methyl) phenyl) obtained in Example 1 of the production method according to the present invention. ¹ H NMR spectrum of carbonate. FT-IR spectrum of ethyl (2-methoxy-4-(((5-methyl-2-oxo-1,3-dioxane-5-yl) methoxy) methyl) phenyl) carbonate. ¹ H NMR spectrum of a high molecular weight form of ethyl (2-methoxy-4-(((5-methyl-2-oxo-1,3-dioxane-5-yl) methoxy) methyl) phenyl) carbonate. ^{1 1} H NMR spectra of compound A2 and compound B2 obtained in Example 2 of the production method according to the present invention.

Hereinafter, specific examples of the production method according to the present invention will be described.

[Example 1]
A trimethylene carbonate derivative (monomer) was obtained by a three-step synthetic reaction shown below. The synthesis procedure at each stage will be described in detail below.

(1) Synthesis of 4- (5-hydroxymethyl-5-methyl-1,3-dioxane-2-yl) -2-methoxyphenol (protection of diol)
Add 60.0 g (500 mmol) of trimethylolethane, 0.860 g (5.0 mmol) of p-toluenesulfonic acid (TsOH) and 400 mL of tetrahydroxyfuran (THF) to a 500 mL two-necked flask under a nitrogen atmosphere, and add 1 at room temperature. Stir for hours to dissolve. Then, 15.2 g (100 mmol) of vanillin represented by the following formula (5) was added, and the mixture was stirred at 50 ° C. for 15 hours. The solvent was removed, and a liquid separation operation was performed using ultrapure water and dichloromethane (CH ₂ Cl ₂ ) to recover the organic layer. Sodium sulfate (Na ₂ SO ₄ ) was added to the recovered organic layer, and the solvent was removed after filtration. Then, it was purified by silica gel column chromatography (developing solvent ethyl acetate (EtOAc): hexane = 4: 1) to obtain compound A1 (8.58 g, 33.7 mmol, yield 34%).

(2) Synthesis of 2-(((4-hydroxy-3-methoxybenzyl) oxy) methyl) -2-methylpropane-1,3-diol (deprotection (cleavage))
Compound A1: 2.55 g (10.0 mmol) was dissolved in a small amount of THF and dried using a desiccant (trade name: Molecular Sieve (MS) 4A) in an anhydrous state. Added to the flask. Then, the mixture was cooled to 0 ° C. in an ice bath, 30.1 mL (30.1 mmol) of diisobutylaluminum hydride (DIBAL) was slowly added, and the mixture was stirred at room temperature for 10 hours. The following equation (6) shows the structure of DIBAL.

Next, the mixture was cooled to 0 ° C. in an ice bath, and 21 mL of methanol was slowly added dropwise. After confirming that the solution became jelly-like, a saturated aqueous solution of Rochelle salt was added, and the mixture was stirred at room temperature until it was separated into two layers. Then, a liquid separation operation was performed using diethyl ether, and the organic layer was recovered. Sodium sulfate was added to the recovered organic layer, and the solvent was removed after filtration. Then, it was purified by silica gel column chromatography (developing solvent ethyl acetate: hexane = 4: 1) to obtain compound B1 (1.31 g, 5.39 mmol, yield 54%).

Although not shown, the production of 4- (5-hydroxymethyl-5-methyl-1,3-dioxane-2-yl) -2-methoxyphenol and 2-methoxyphenol by ¹ H NMR and FT-IR The formation of (((4-hydroxy-3-methoxybenzyl) oxy) methyl) -2-methylpropane-1,3-diol was confirmed.

(3) Synthesis of ethyl (2-methoxy-4-(((5-methyl-2-oxo-1,3-dioxane-5-yl) methoxy) methyl) phenyl) carbonate Compound B1: 1.31 g (5. (39 mmol) was dissolved in a small amount of THF, dried with the desiccant MS4A, and added to a 300 mL two-mouthed flask under a nitrogen atmosphere. Ethyl chloroformate (1.55 mL (16.2 mmol)) was added, and the mixture was cooled to 0 ° C. in an ice bath. Subsequently, 2.23 mL (16.1 mmol) of triethylamine was slowly added dropwise, and the mixture was stirred for 6 hours. A liquid separation operation was performed using 1 M hydrochloric acid and dichloromethane, and the organic layer was recovered. Magnesium sulfate was added to the recovered organic layer, and the solvent was removed after filtration. Then, it was purified by silica gel column chromatography (developing solvent ethyl acetate) to obtain compound C1 (1.33 g, 3.75 mmol, yield 69.5%).

Compound C1 was identified by ¹ H NMR (400 MHz, room temperature, in CDCl ₃ ) and FT-IR and ethyl (2-methoxy-4-(((5-methyl-2-oxo-1,3-dioxane-5-)). It was confirmed that i) methoxy) methyl) phenyl) carbonate was produced. FIG. 1 shows the measurement results of ¹ H NMR, and FIG. 2 shows the measurement results of FT-IR.

(4) Confirmation of high molecular weight ethyl (2-methoxy-4-(((5-methyl-2-oxo-1,3-dioxane-5-yl) methoxy) methyl) phenyl) carbonate A small amount of compound C1 Those dissolved in a solvent and made anhydrous with the desiccant MS4A were added to a two-mouth test tube under a nitrogen atmosphere. The solvent was then dried using a vacuum pump (room temperature, 24 hours). Under nitrogen atmosphere again, 2,2-dimethyl-1-propanol was prepared to 1.0 M with a solvent, and 1,8-diazabicyclo [5.4.0] -7-undecene was prepared to 1.0 M with a solvent. I added something. Then, it was stirred a little with a test tube mixer and allowed to stand.
In this example, the standing time was 8 hours or 24 hours, and the solvent was THF or dichloromethane to increase the molecular weight.
After the reaction was completed, it was dissolved in a small amount of dichloromethane, methanol was used as a poor solvent, and reprecipitation was performed for purification.

The obtained product was identified by ¹ H NMR (400 MHz, room temperature, in CDCl ₃ ), and the molecular weight was confirmed. FIG. 3 shows the measurement results of ¹ H NMR of the high molecular weight body. In addition, the molecular weight distribution (PDI) of the product was measured by size exclusion chromatography, and the number average molecular weight (Mn), weight average molecular weight (Mw), and yield were determined. The results are shown in Table 1.

From the above results, it was presumed that a high molecular weight compound (polymer) of compound C1 was formed by the polymerization reaction represented by the following formula.

[Example 2]
In this example, an intermediate of the synthetic pathway of the trimethylene carbonate derivative was obtained by the following two-step synthetic reaction. The synthesis procedure at each stage will be described in detail below.

(1) Synthesis of 5-hydroxymethyl-5-methyl-2-phenyl- [1,3] -dioxane (protection of diol)
In a nitrogen atmosphere, 72.048 g (600 mmol) of trimethylolethane, 3.69 g (21.4 mmol) of p-toluenesulfonic acid and 1.5 L of THF were added to a 2.0 L two-necked flask, and the mixture was stirred at room temperature for 1 hour. Then, 64.2 mL (630 mmol) of benzaldehyde was added, and the mixture was stirred at room temperature for 15 hours. The solvent was removed, and a liquid separation operation was performed using ultrapure water and dichloromethane (CH ₂ Cl ₂ ) to recover the organic layer. Sodium sulfate (Na ₂ SO ₄ ) was added to the recovered organic layer, and the solvent was removed after filtration. Then, it was suspended in hexane, stirred for 15 minutes and removed by filtration to obtain Compound A2 (111 g, 534 mmol, yield 89%).

(2) Synthesis of 2-((benzyloxy) methyl) -2-methylpropane-1,3-diol (deprotection (cleavage))
Compound A2: 1.0 g (4.80 mmol) was dissolved in a small amount of dichloromethane (CH ₂ Cl ₂ ), dried with the desiccant MS4A, and added to a 300 mL two-necked flask under a nitrogen atmosphere. .. Then, the mixture was cooled to 0 ° C. in an ice bath, 14.4 mL (14.4 mmol) of diisobutylaluminum hydride (DIBAL) was slowly added, and the mixture was stirred at room temperature for 10 hours.

Next, the mixture was cooled to 0 ° C. in an ice bath, and 2.05 mL of ultrapure water was slowly added dropwise. Subsequently, 2.05 mL of a 5 M aqueous sodium hydroxide solution was slowly added dropwise. Finally, 6.15 mL of ultrapure water was slowly added dropwise. The mixture was stirred at room temperature for 1 hour, and the resulting precipitate was removed by suction filtration using Celite. Then, the filtered solution was subjected to a liquid separation operation using ultrapure water and dichloromethane (CH ₂ Cl ₂ ), and the organic layer was recovered. Sodium sulfate was added to the recovered organic layer, and the solvent was removed after filtration. Then, it was purified by silica gel column chromatography (developing solvent ethyl acetate: hexane = 1: 1) to obtain compound B2 (0.587 g, 2.79 mmol, yield 58%).

The results of identification of compounds A2 and B2 by ¹ H NMR (400 MHz, room temperature, in CDCl ₃ ) are shown in FIG. In FIG. 3, the lower side shows the ¹ H NMR spectrum of compound A2, and the upper side shows the ¹ H NMR spectrum of compound B2.

Claims (4)

A step of obtaining compound A represented by the following formula (2) by simultaneously protecting two hydroxyl groups of trimethylolpropane represented by the following formula (1) with a protective agent.
A step of reducing the compound A with a reducing agent and deprotecting only one of the two locations to obtain a compound B having two hydroxyl groups represented by the following formula (3).
The present invention comprises a step of obtaining a trimethylene carbonate derivative represented by the following formula (4) by carbonylating the two hydroxyl groups of the compound B.
A method for producing a trimethylene carbonate derivative , wherein the reducing agent is diisobutylaluminum hydride or sodium borohydride .

In the formulas (1) to (4), R1 represents a hydrogen atom or an alkyl group, and in the formulas (2) to (4), R represents an aryl group. The method for producing a trimethylene carbonate derivative according to claim 1, wherein R1 is a lower alkyl group having 1 to 5 carbon atoms. The method for producing a trimethylene carbonate derivative according to claim 1, wherein R1 is a methyl group. The method for producing a trimethylene carbonate derivative according to any one of claims 1 to 3, wherein R is a phenyl group.

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