KR100301218B1 - Method of resolving para-dioxanone - Google Patents

Abstract

The present invention relates to a process for purifying para-dioxanone.

That is, the method for purifying para-dioxanone of the present invention,

(a) dissolving the para-dioxanone mixture in a solvent to prepare a mixed solution;

(b) crystallizing para-dioxanone from the mixed solution;

(c) filtering to obtain para-dioxanone crystals of higher purity than the reaction mixture;

(d) recrystallizing the para-dioxanone filtered in step (c) by repeating steps (a) to (c); And

(e) removing the isopropanol under reduced pressure and distilling high purity para-dioxanone under reduced pressure, in particular using aliphatic alcohol as a solvent to dissolve the para-dioxanone mixture. It features.

Purification method according to the present invention, when the re-crystallization using an aliphatic alcohol solvent and distillation under reduced pressure can be purified para-dioxanone with a purity of 99.97% by weight or more, and also in terms of yield when using an existing aliphatic ester solvent Para-dioxanone can be obtained with a yield of 48% by weight, which is significantly higher than 30% by weight.

Description

Method of Purification of Para-Dioxanone

The present invention relates to a method for purifying para-dioxanone. More particularly, the present invention relates to a purification method capable of obtaining high purity para-dioxanone with high yield by using an aliphatic alcohol as a solvent for dissolving para-dioxanone.

The polymers synthesized with the para-dioxanone monomer are used as absorbent surgical products and also used to prepare surgical sutures. Dodi describes, among other things, that very high-purity para-dioxanone monomers are required to make strong poly (para-dioxanone) yarns, but US Patent No. 5,391,768 specifically mentions a high purity purification method. none.

There are also many patents for making polymers (e.g., U.S. Pat. There is no.

U.S. Patent No. 3,020,289 describes a continuous purification process by fractional distillation, while U.S. Patent No. 3,063,967 distills under nitrogen conditions, but this simple distillation purification yields only low-purity para-dioxanone which is unsuitable for polymerization. .

Thus, studies to improve the purity has been carried out, US Patent No. 5,391,707 in the reaction mixture of diethylene glycol reacted with benzyl bromide to make a high boiling point derivative than para-dioxanone to make diethylene glycol easily A distillation purification method is described.

However, it is impossible to obtain high-purity para-dioxanone because a myriad of impurities other than diethylene glycol are mixed in the reaction mixture and other impurities are not removed simply by distillation.

Thus, as a method of obtaining higher purity para-dioxanone, para-dioxanone purification method using a solvent has been proposed in US Pat. No. 5,391,768, in which para-dioxanone is dissolved in an aliphatic ester solvent and recrystallized. Relatively high purity para-dioxanone is obtained at a yield of 30% by weight.

However, in the case of the solvent ethyl acetate used in the above patent, the temperature must be lowered to -30 ° C, and since it cannot be filtered at room temperature, it is difficult to work at room temperature and has a low yield.

In addition, the reaction mixture is immediately cooled without using a solvent to crystallize the para-dioxanone, discard the remaining filtrate, and dissolve again to crystallize several times to obtain a purity of 99% by weight US Patent No. 5,675,022 Although described in the present invention, much higher purity of para-dioxanone is required to synthesize a polymer having a high molecular weight.

The process of the invention can also purify para-dioxanone made by any method. Para-dioxanone may be prepared by methods such as US Pat. Nos. 2,142,033, 2,900,395, 3,119,840, 4,070,375, 4,116,821, and the like.

The para-dioxanone can be obtained through dehydrogenation from diethylene glycol and used as various medical polymer raw materials. In order to obtain a higher molecular weight poly (para-dioxanone) polymer, high purity para-dioxanone is required. US Pat. No. 5,391,768 discloses a process for recrystallizing para-dioxanone using an ethyl acetate solvent. Distillation gave a relatively high purity of para-dioxanone at a yield of 30% by weight.

However, in the case of the solvent ethyl acetate used in the patent, all of the para-dioxanone is dissolved in the vicinity of -3 ° C (dissolution temperature, see Table 1), so it is difficult to operate at room temperature and has a low yield.

Accordingly, the inventors of the present invention have repeatedly studied tablets to solve the conventional problems, and when using an aliphatic alcohol as a solvent for dissolving the para-dioxanone mixture, high purity para-dioxanone of 99.97% by weight or more can be obtained. It has been found that the present invention has been achieved.

Purification method of the para-dioxanone of the present invention,

(a) dissolving the para-dioxanone mixture in a solvent to prepare a mixed solution;

(b) crystallizing para-dioxanone from the mixed solution;

(c) filtering to obtain para-dioxanone crystals of higher purity than the mixture;

(d) recrystallizing the para-dioxanone filtered in step (c) by repeating steps (a) to (c); And

(e) removing the isopropanol under reduced pressure and distilling the high-purity para-dioxanone from the final product obtained in the above step, using aliphatic alcohol as a solvent for dissolving the para-dioxanone mixture. It is done.

Hereinafter, the present invention will be described in more detail.

The present invention is characterized in that an aliphatic alcohol is used to recrystallize para-dioxanone without using an alkyl ester solvent such as ethyl acetate, and to obtain high-purity para-dioxanone at high yield by distilling the recrystallized solid. It is a way.

The aliphatic alcohol used in step (a) includes methanol, ethanol or isopropanol and the like, most preferably isopropanol.

The amount of para-dioxanone mixture dissolved in the solvent is mixed 400 to 1,800 g per liter of solvent depending on the reaction used to prepare the para-dioxanone. When diethylene glycol is used to prepare the para-dioxanone, it is preferable to mix 400 to 2,000 g per liter of solvent. The mixed solution is prepared at 18 ° C. to 50 ° C. and stirred to make a uniform solution.

Step (b) is a step of crystallizing para-dioxanone from the mixed solution, the temperature at which the crystals are dissolved in the aliphatic alcohol used is methanol -10 ℃, ethanol 3 ℃, as shown in Table 1 below It is seen that isopropanol is 18 ° C., and crystals are completely dissolved at this temperature, so that crystals are formed below the temperature described above.

In the crystallization step, the solution is prepared at room temperature, and the temperature is first lowered to about 17 ° C., and then 1 to 10 g of the para-dioxanone crystals are added per liter of the solution, or just stirred to form a crystal and the solution temperature is 7 to 24 Over time, the crystals form slowly, and finally the temperature is lowered to -20 ° C to form crystals.

To form the crystals, crystals were formed in all three solvents when the para-dioxanone nucleus was added, but when stirred at low temperature without addition of the para-dioxanone nucleus, in ethanol and methanol Crystals did not form, and isopropanol was shaken at low temperature without addition of nuclei to form crystals.

The step (c) is a step of filtering the formed para-dioxanone crystals, the result of the filtration test at room temperature, when isopropanol was used as a solvent, it was able to successfully filter, the para-dioxanone crystals It was not melted but kept in shape, so that it was easy to wash, so that high-purity para-dioxanone could be obtained at high yield. However, when methanol, ethanol and ethyl acetate were used as a solvent, many crystals were dissolved during filtration. Or crystalline forms were deformed so that cleaning was not possible to remove impurities.

The above results have a close relationship with the melting point of para-dioxanone according to the solvent shown in Table 1 below, and the possibility of filtration at room temperature is the easiest with isopropanol and also with para-dioxanone in isopropanol. Recrystallization can remove not only diethylene glycol but also other impurities.

The step (d) is a recrystallization step for increasing the purity of the para-dioxanone crystals, and the para-dioxanone crystals obtained by repeating steps (a) to (c) 1 to 10 times are isopropanol, para- Impurities, such as dioxanone, hydroxy acid, and diethylene glycol, are mixed.

Step (e) is to remove isopropanol under reduced pressure from the final product obtained in step (d) and to distill high-purity para-dioxanone, and the final product is a ratio of para-dioxanone to isopropanol. Is the highest, and when the resultant is distilled under reduced pressure as described above, para-dioxanone having a purity of 99.97% by weight can be obtained.

Hereinafter, the present invention will be described in more detail with reference to the following Examples, but the present invention is not limited by the following Examples.

EXAMPLE

The reaction mixture obtained by refluxing 3,900 mL of diethylene glycol and 60 g of copper-chromite for 6 hours was distilled to obtain a mixture of 70% by weight of para-dioxanone (28% by weight of diethylene glycol, other impurities). . All examples below were subjected to purification tests using this para-dioxanone mixture.

Example 1 Filtration Experiment of Para-Dioxanone

The solution prepared by dissolving 100 g of the prepared para-dioxanone mixture in 300 ml of solvents (acetone, ethyl acetate, methanol, ethanol, and isopropanol) was lowered to -14 ° C, and then pure para-dioxanone crystals were prepared. Table 1 shows the results obtained by only stirring the solution without adding 1 g each and adding para-dioxanone crystals. The amount of crystals produced was in the order of isopropanol> ethanol> methanol> ethyl acetate and no acetone produced crystals. In addition, it was found that when the solution was stirred without adding the para-dioxanone crystals, crystals were formed only in the solvent of isopropanol.

In addition, as a result of the filtration test, the remaining para-dioxanone: isopropanol (1: 1) crystals obtained by filtering the solvent are not dissolved at room temperature, but the crystals remain intact, and thus, they can be easily filtered at room temperature. In the case of ethanol, methanol and ethyl acetate solvents, the mixture was filtered at room temperature and dissolved by the remaining para-dioxanone. The filtration was not performed at room temperature.

As a result of the melting temperature in each solvent, as shown in Table 1, isopropanol was 18 ℃, while other solvents showed the phenomenon of para-dioxanone melting at low temperatures below 3 ℃.

Table 1

Para-dioxanone (PDO) recrystallization depending on the solvent (mixed solution 100 ml / solvent 300 ml)

Contents Isopropanol (IPA) Ethanol (EtOH) Ethyl Acetate (EtOAc) Methanol (MeOH) Acetone Para-dioxanone (PDO) -14 ℃ Crystal Formation Clear solution Clear solution Clear solution Clear solution crystal Seed addition Crystal Formation Crystal Formation Crystal Formation Crystal Formation Clear solution Crystal Formation Amount plenty plenty Small sheep Small sheep No decision Melting temperature 18 ℃ 3 ℃ -4 ℃ -10 ℃ 25 ℃ Room temperature filtration possible impossible impossible impossible Remove impurities Very good Good

Example 2 Purity and Yield of Para-Dioxanone

2,000 g of the prepared para-dioxanone mixture and 3 l of isopropanol were placed in an 8-l container, and the solution temperature was lowered to 17 ° C. and 1 g of para-dioxanone crystals were added. After the crystals were filtered at room temperature, the product was washed three times using 100 ml each of isopropanol solvent, which was precooled to -20 ° C. The product was 1,360 g, and the result of gas chromatography was 10% by weight (isopropanol): 88. % By weight (para-dioxanone): 0.15% by weight (diethylene glycol). After transferring 1,360 g of the first recrystallized product to an 8 L beaker and adding 3 L of isopropanol to dissolve para-dioxanone, the temperature of the resulting solution was lowered to 17 ° C., and then 1 g of the para-dioxanone crystal was added. The product was gradually crystallized while lowering the temperature to -20 ° C, and the crystals formed were filtered at room temperature, and then washed three times using 100 ml of isopropanol solvent, which was precooled to -20 ° C, respectively, to obtain 1,200 g of 9.3 weight. % (Isopropanol): 90% by weight (para-dioxanone): 0.05% by weight (diethylene glycol). 1,200 g obtained by the second recrystallization was added to a 3 liter three-necked flask equipped with a Vigrese column with boiling stone and distilled under reduced pressure. As a result, 1,000 g (50% yield) of para-dioxanone having a purity of 99.98% by weight was obtained. Could get

Example 3 Purity and Yield of Para-Dioxanone

2,000 g of the prepared para-dioxanone mixture and 3 l of isopropanol were placed in an 8 l container, and the solution temperature was lowered to 16 ° C. and stirred with a rod without adding para-dioxanone crystals, thereby producing a certain amount of the para-dioxanone crystals. Thereafter, the temperature was gradually lowered to −20 ° C. and further crystallized, and the formed crystals were filtered at room temperature, and then washed three times using 100 ml of isopropanol solvent, which was previously cooled to −20 ° C., to obtain 1,440 g of product. It consisted of 15 wt% (isopropanol): 83 wt% (para-dioxanone): 2.4 wt% (diethylene glycol). Transfer 1,440 g of the product obtained by the first recrystallization into an 8 L beaker, add 3 L of isopropanol to dissolve para-dioxanone, and lower the temperature of the resulting solution to 16 ° C. and stir the para-dioxanone crystals without a rod. After producing a certain amount of para-dioxanone crystals, the crystallization was further performed while gradually lowering the temperature, the formed crystals were filtered at room temperature, and then 100 ml of isopropanol, each of which was precooled to -20 ° C, as a solvent, was used. The product obtained by washing three times was 1,270g, was 17% by weight (isopropanol): 82.9% by weight (para-dioxanone): 0.08% by weight (diethylene glycol). 1,270 g of the second recrystallization was added to a 3 liter three-necked flask equipped with a Vigres column with boiling stone and distilled under reduced pressure. As a result, 980 g of para-dioxanone having a purity of 99.97% by weight (49% yield) Could get

Example 4 Use of Para-Dioxanone

10 g of para-dioxanone obtained in Examples 2 and 3 and 0.2 ml (0.029 mol, toluene solution) of catalyst tin octate were placed in each glass tube, and vacuum was maintained at 1 torr or less for 2 hours. The mixture was filled with nitrogen and polymerized at 80 ° C. for 3 days to obtain poly para-dioxanone having a viscosity of about 2.5. These polymers are suitable for preparing fibers. These polymers can be used in other medical polymers.

As described above, the present invention can purify para-dioxanone with a purity of 99.97% by weight or more through recrystallization using an aliphatic alcohol solvent and distillation under reduced pressure, and the present invention also provides a yield when using an existing aliphatic ester solvent. Para-dioxanone can be obtained with a yield of at least 35% by weight or more higher than 30% by weight of.

Claims (3)

(a) dissolving the para-dioxanone mixture in a solvent to prepare a mixed solution; (b) crystallizing para-dioxanone from the mixed solution; (c) filtering to obtain para-dioxanone crystals of higher purity than the mixture; (d) recrystallizing the para-dioxanone filtered in step (c) by repeating steps (a) to (c); And (e) A method for purifying para-dioxanone, comprising removing isopropanol under reduced pressure from the final product obtained in the above step and distilling high-purity para-dioxanone. A method for purifying para-dioxanone, characterized in that ethanol or isopropanol is used as a solvent for dissolving the para-dioxanone mixture. The method for purifying para-dioxanone according to claim 1, wherein the weight ratio of the para-dioxanone mixture and ethanol or isopropanol is 0.4: 1 to 2: 1. The method of claim 1, wherein the step of crystallizing and filtering the para-dioxanone mixture is carried out at a temperature of 18 ° C or less.