WO2009017261A1

WO2009017261A1 - Method for manufacturing ultrafine p dioxanone

Info

Publication number: WO2009017261A1
Application number: PCT/KR2007/003527
Authority: WO
Inventors: Hyun Mok Jeong
Original assignee: Medichem Co., Ltd
Priority date: 2007-08-02
Filing date: 2007-08-02
Publication date: 2009-02-05

Abstract

The present invention relates to a method for preparing ultrafine p-dioxanone. The method comprises the steps of performing dehydrogenation cyclization of diethylene glycol in the presence of a pure silica catalyst (SiO ) or a copper-chromium (Cu-Cr) supported silica catalyst to obtain a crude reaction product including p-dioxanone and impurities, recrystallizing the crude reaction product using a mixture solvent of isopropyl alcohol and C -C saturated hydrocarbon as recrystallization solvent and distilling the recrystallized p-dioxanone under reduced pressure in the presence of a hydroxyl blocking agent and a dehydrating agent to obtain the wanted p- dioxanone. The p-dioxanone exhibits low water content and ultrafine purity.

Description

METHOD FOR MANUFACTURING ULTRAFINE P-

DIOXANONE

Technical Field

[1] The present invention relates to a method for manufacturing ultrafine p-dioxanone.

The present invention also relates to a method for purifying the crude reaction product produced from catalytic dehydrogenation cyclization of diethylene glycol that comprises unreacted diethylene glycol, various alcohol compounds, organic acids and aldehydes as well as the targeted p-dioxanone. Background Art

[2] Poly -p-dioxanone is a useful biodegradable polymer material. Particularly, it is widely used for the source of absorbable monofilament sutures. For the poly- p-dioxanone based monofilament suture to have its characteristic superior flexibility, knotting stability, slipperiness, tensile strength, etc., the corresponding polymer has to have a large molecular weight. In this situation, ultrafine p-dioxanone monomer is essential required.

[3] In order to obtain ultrafine p-dioxanone effectively, it is important to prepare the crude p-dioxanone containing as little impurities as possible prior to the purification process.

[4] There are many available methods for the manufacturing of p-dioxanone. The most typical manufacturing process of p-dioxanone is a vapor-phase dehydrogenation cyclization of diethylene glycol in the presence of a catalyst. The most frequently used catalysts include a copper-chromium catalyst system (U.S. Patent Nos. 5,675,022, 5,391,768, 3,020,289 and 2,900,395) and a copper or copper-chromium supported catalyst system (U.S. Patent Nos. 5,310,845, 3,119,840 and 2,142,033; Japanese Patent Laid-Open Nos. 1998-120675 and 2000-351775). These catalysts have the problem that the catalytic lifecycle is short and the reaction selectivity is poor because of the catalytic inactivation caused by carbon coking or sintering. The addition of hydrogen gas during the catalytic reaction is employed in order to reduce carbon coking, but, the decrease of conversion ratio is reported after 140 hours (U.S. Patent No. 5,310,945) or after 100 hours (Japanese Patent Laid-Open No. 2000-351775).

[5] The reaction product of the dehydrogenation cyclization includes, in addition to the target compound p-dioxanone, various byproducts (impurities) such as unreacted diethylene glycol, ethylene glycol, ethanol, ethylene glycol acetate and diethylene glycol acetate, methoxyethanol, diethylene glycol ethyl ether, tetraethylene glycol and other alcohols, dioxane, dioxane and other ethers, acetic acid and aldehydes. In order to prepare ultrafine p-dioxanone, it is essential to perfectly remove those impurities. In general, the techniques of distillation and crystallization are employed to remove impurities. The common vacuum distillation technique cannot completely separate the impurities because the boiling points of the impurities are not quite distinct from that of p-dioxanone. As solution crystallization technique, U.S. Patent No. 5,391,768 discloses a method of recrystallizing p-dioxanone using an aliphatic ester (e.g., ethyl acetate) as recrystallization solvent. This method provides about 30 % of p-dioxanone yield. Korean Patent No. 301,218 employs an aliphatic alcohol (e.g., isopropyl alcohol, ethanol, etc.) as recrystallization solvent and provides p-dioxanone with better purity (99.97 %) and better yield (35 %). However, this method has the problem that the recrystallization has to be performed at a considerably low temperature (about -20 C) and the filtration also cannot be performed at room temperature. Further, the yield is still unsatisfactory. In addition, the process of recrystallization and washing has to be repeated several times to obtain the p-dioxanone suitable to be used for sutures (purity 99.99 wt% or better). As a solution to this problem, U.S. Patent No. 5,391,707 discloses a process of vacuum distillation by which benzyl bromide and pyridine are added in excess of the impurities to crude p-dioxanone to block the hydroxyl groups. But, the blocking agent is not only toxic and bad-smelling, but also produces large volume of distillation wastes. Similarly, Korean Patent No. 196,097 discloses a method of vacuum distillation employing methylene diphenyl diisocyanate (MDI) as blocking agent for the blocking hydroxyl groups in 2-3 equivalents of the impurities and employing dimorpholino diethyl ether (DMDEE) as catalyst, which provides p- dioxanone with 90 wt% of distillation yield and 99.99 wt% of purity. In U.S. Patent No. 5,675,022, crude p-dioxanone is purified through melt crystallization. According to this patent, the melt crystallization process is repeated at least 5 times to obtain p- dioxanone with 99.9 wt% of purity. But, the methods have the problem that the purity is relatively low and repeated purification and additional apparatuses are necessary. Disclosure of Invention Technical Problem

[6] An object of the present invention is to provide a method for stably preparing a crude reaction product including p-dioxanone and economically and effectively purifying the reaction product to obtain p-dioxanone with improved yield and purity compared with the conventional methods. Technical Solution

[7] The method for preparing ultrafine p-dioxanone in accordance with the present invention comprises the steps of performing dehydrogenation cyclization of diethylene glycol in a presence of pure silica catalyst (SiO ) or a copper-chromium (Cu-Cr) supported silica catalyst to obtain a crude reaction product including p-dioxanone and impurities, recrystallizing the crude reaction product using a mixture solvent of isopropyl alcohol and C -C saturated hydrocarbon as recrystallization solvent and distilling the recrystallized p-dioxanone under reduced pressure in a presence of a hydroxyl blocking agent and a dehydrating agent to obtain the targeted p-dioxanone.

Advantageous Effects

[8] Compared with conventional methods, the method in accordance with the present invention effectively provides p-dioxanone with higher yield (78-80 wt%), lower water content (less than 70 ppm) and better purity (99.99 wt% or better). Further, the p- dioxanone obtained by this method is stable for over 3 months at 15⁰C or lower temperature with no change in color or smell. Thus, it can prevent the coloration or bad smell of the products made from p-dioxanone, particularly the p-dioxanone polymers. Consequently, p-dioxanone polymers with superior quality can be attained. Mode for the Invention

[9] In the following, the present invention will be more fully illustrated.

[10] First, a crude reaction product including p-dioxanone is obtained by performing de- hydrogenation cyclization of diethylene glycol in a presence of pure silica catalyst (SiO ) or copper-chromium (Cu-Cr) supported silica catalyst. As described in the above, the reaction product includes various impurities as well as p-dioxanone. In an embodiment of the present invention, silica (SiO ) in which 16 wt% of copper- chromium (Cu-Cr) is supported is employed as catalyst. Copper is used in an amount of 90 wt% and chromium is of 10 wt%. Preferably, a fixed-bed reactor is used for the catalytic dehydrogenation cyclization of diethylene glycol. To the fixed-bed reactor containing diethylene glycol, a catalyst tower made of cylindrical stainless tube in which the catalyst is loaded is equipped prior to the reaction. The process of preparing the reaction product including p-dioxanone through the dehydrogenation cyclization of diethylene glycol is summarized in Scheme 1 below.

[H] Scheme 1

[12]

Catalyst _Cn ._ήp / rL°Jr° ^{+ DEG +} Side products

"^OH ^u 0 (2-8%) (1-2%)

Hydrogeπ(H₂) reaction product p-dioxanone

Diethylene glycol (DEG) (90-94%)

[13] Specific reaction conditions are as follows: supply rate of diethylene glycol =

300-600 mL per hour, preferably 380-470 mL per hour; reaction temperature at the catalyst tower = 240-280⁰C, preferably 240-260⁰C. Diethylene glycol is supplied to the catalyst tower along with hydrogen as vaporized by heating the reactor to 23O⁰C or above. Hydrogen is supplied at a rate of 500-800 mL per minute, preferably 600-700 rnL per minute. The resultant product mixture shows a 93-99 % of conversion ratio and 90-94 % of selectivity after 980-1040 hours of reaction.

[14] The crude reaction product is recrystallized using a mixture solvent of isopropyl alcohol and C -C saturated hydrocarbon. The recrystallization of the crude reaction product into which p-dioxanone is included is performed at a temperature of below 5⁰C. Preferably, the recrystallization is performed in the temperature range of -5⁰C to 5⁰C. The mixing proportion of the isopropyl alcohol and the C -C saturated hydrocarbon is from 2:8 to 7:3, preferably from 3:7 to 4:6, based on weight. The C -C saturated hydrocarbon may be selected from pentane, hexane, heptane and a combination thereof. Hexane is the most preferable. Based on 100 wt% of the mixture solvent, the reaction product including p-dioxanone is used in 65-85 wt%, preferably in 70-73 w%. Specifically, the reaction product including p-dioxanone is dissolved in the mixture solvent at an elevated temperature and the temperature is cooled to 5⁰C or lower. Heat is generated as p-dioxanone crystallizes. The supply rate of the crude reaction product is controlled so that the temperature is maintained 15⁰C or lower. After all the crude reaction product has been supplied, aging is performed at 5⁰C or below, preferably at -5⁰C to 5⁰C, most preferably at O⁰C to 5⁰C, for 1-2 hours. The p- dioxanone crystal is filtered at 15⁰C or lower and washed with the mixture solvent of 15⁰C or lower.

[15] The recrystallized p-dioxanone is distilled under reduced pressure in the presence of a blocking agent and a dehydrating agent to obtain ultrafine p-dioxanone. Preferably, the hydroxyl blocking agent is selected from LiH, BH , AlH and a combination

4 4 thereof. LiH is the most preferable. Preferably, the hydroxyl blocking agent is used in 50-80 wt% per 100 wt% of impurities. CaH is preferred for the dehydrating agent. Preferably, the dehydrating agent is used in 100-150 wt% based on 100 wt% of water contained in the recrystallized p-dioxanone. Specifically, the distillation under reduced pressure is performed as follows. The p-dioxanone obtained by the recrystallization is rendered at a low pressure at a temperature of 5O⁰C, at about 40-50⁰C, to remove the hexane and isopropyl alcohol remaining in the recrystallized p-dioxanone. Then, while purging with nitrogen, the hydroxyl blocking agent and the dehydrating agent are added and stirring is performed at 5O⁰C until the generation of hydrogen gas stops. Finally, distillation is performed under reduced pressure to obtain p-dioxanone.

[16] The resultant ultrafine p-dioxanone is obtained with a yield of 78-83 wt%, preferably 82-83 wt%, a water content of 70 ppm or less and a purity of 99.990 wt%, preferably 99.994 wt%, most preferably 99.999 %, or better.

[17] This is far better than the conventional methods, in which aliphatic alcohols are employed, in terms of both yield (48 wt%) and purity (99.97 wt%). Also, a much superior result is attained in terms of purity, cost, distillation waste generation, and so forth, when compared with the methods employing MDI and DMDEE or benzyl bromide and pyridine as hydroxyl group blocking agent.

[18] The following examples will further illustrate the present invention. However, it will be appreciated that the following examples are provided for the understanding of the present invention and they do not limit the scope of the present invention.

[19] Example 1

[20] Preparation of crude reaction product including p-dioxanone

[21] Example 1-1

[22] A catalyst tower made of a cylindrical stainless tube measuring 9 cm in internal diameter and 160 cm in height, in which 8 kg of a catalyst had been loaded, was equipped at a 2OL reactor. Then, 15 kg of diethylene glycol was supplied to the reactor. Hydrogen was supplied to the catalyst tower through the reactor at a rate of 600 mL per minute. The reactor and the catalyst tower were heated to a temperature of 230-235⁰C and 245-255⁰C, respectively.

[23] By controlling the heat source of the reactor, diethylene glycol was vaporized so that the diethylene glycol could be supplied at a rate of 450-470 mL per hour. After 30 hours of reaction, 1431 g of a crude p-dioxanone product was obtained from the catalyst tower. Conversion ratio was 96 % and selectivity was 94 %.

[24] Example 1-2

[25] After 980 hours of catalytic reaction in the same manner as in Example 1-1, 1416 g of a crude p-dioxanone product was obtained. Conversion ratio was 97 % and selectivity was 91 %.

[26] Example 2

[27] Recrystallization of crude reaction product including p-dioxanone

[28] Example 2-1

[29] 6.5 kg of hexane and 16 kg of isopropyl alcohol were added into a 50 L reactor. The mixture solvent was cooled to 4⁰C. Then, 17 kg of the crude p-dioxanone product with a purity of 92 wt% was added while maintaining the temperature of the reactor at 15⁰C or below. After 1.5 hours of aging at 5⁰C, the resultant p-dioxanone crystal was filtered at about 15⁰C. Then, 14.7 kg of recrystallized p-dioxanone was obtained by washing 3 times with 4 kg of the mixture solvent of 1O⁰C. Gas chromatography analysis showed that the purity of p-dioxanone excluding the solvent was 99.992 wt% (area ratio).

[30] Example 2-2

[31] 14.2 kg of recrystallized p-dioxanone was obtained in the same manner as in

Example 2-1, except for using crude p-dioxanone with a purity of 90 wt% instead of the crude p-dioxanone of 92 wt%. Gas chromatography analysis showed that the purity of p-dioxanone excluding the solvent was 99.993 wt% (area ratio). [32] Example 2-3

[33] 15.8 kg of recrystallized p-dioxanone was obtained in the same manner as in

Example 2-1, except for using a mixture solvent of 9.2 kg of hexane and 13.8 kg of isopropyl alcohol. Gas chromatography analysis showed that the purity of p-dioxanone excluding the solvent was 99.991 wt% (area ratio).

[34] Comparative Example

[35] 13.4 kg of recrystallized p-dioxanone was obtained in the same manner as in

Example 2-1, except for using 22 kg of isopropyl alcohol as solvent. Gas chromatography analysis showed that the purity of p-dioxanone excluding the solvent was 99.987 wt% (area ratio).

[36] Example 3

[37] Distillation of recrystallized p-dioxanone under reduced pressure

[38] Example 3-1

[39] 14.7 kg of recrystallized p-dioxanone was put in a 20 L reactor under nitrogen flow.

After dissolving at a temperature of 4O⁰C or below, distillation was performed under reduced pressure at 5O⁰C or below to obtain 840 g of a distillate. The distillate was a mixture solution of hexane and isopropyl alcohol including p-dioxanone. Gas chromatography analysis showed that the p-dioxanone content was 28 wt%. Water content measured under nitrogen flow was 230 ppm. Subsequently, 3.6 g of CaH was added under nitrogen flow and stirring was performed at 5O⁰C or below until the generation of hydrogen gas stopped. Then, 0.82 g of LiH was added and distillation was performed under reduced pressure of 1-2 mmHg to obtain 13.3 kg of p-dioxanone. Gas chromatography analysis showed that the purity of p-dioxanone was 99.999 wt% (area ratio) or better and the water content was 32 ppm. The distillation residual was a p- dioxanone polymer or oligomer containing p-dioxanone, with a melting point of 54-56⁰C. It weighed 420 g.

[40] Example 3-2

[41] 12.1 kg of p-dioxanone was obtained in the same manner as in Example 3-1, except for using 14 kg of recrystallized p-dioxanone with a purity of 99.984 wt% (area ratio) and adding 1.32 g of NaBH . Gas chromatography analysis showed that the purity of

4 p-dioxanone excluding the solvent was 99.990 wt% (area ratio).

[42] Example 3-3

[43] 12.8 kg of recrystallized p-dioxanone was obtained in the same manner as in

Example 3- 1 , except for using 14.4 kg of recrystallized p-dioxanone with a purity of 99.984 wt% (area ratio) and adding 0.98 g of AlH . Gas chromatography analysis showed that the purity of p-dioxanone excluding the solvent was 99.994 wt% (area ratio).

[44] As described, it should be evident that the present invention can be implemented through a variety of configurations in the aforementioned technical field without affecting, influencing or changing the spirit and scope of the present invention. Therefore, it is to be understood that the examples and applications illustrated herein are intended to be in the nature of description rather than of limitation. Furthermore, the meaning, scope and higher conceptual understandings of the present invention as well as modifications and variations that arise therefrom should be understood to be extensions of the present invention.

Claims

[1] A method for preparing ultrafine p-dioxanone which comprises the steps of: a) performing dehydrogenation cyclization of diethylene glycol in a presence of a pure silica catalyst (SiO ) or a copper-chromium (Cu-Cr) supported silica catalyst to obtain a crude reaction product including p-dioxanone and impurities; b) recrystallizing the crude reaction product using a mixture solvent of isopropyl alcohol and C -C saturated hydrocarbon as recrystallization solvent; and c) distilling the recrystallized p-dioxanone under reduced pressure in the presence of a hydroxyl blocking agent and a dehydrating agent to obtain the targeted p-dioxanone.

[2] The method as set forth in claim 1, wherein, in the step a), the catalyst is a copper-chromium (Cu-Cr) supported silica catalyst, the diethylene glycol is supplied at a rate of 300-600 mL per hour and the dehydrogenation cyclization is performed at a temperature of 240 to 28O⁰C.

[3] The method as set forth in claim 1, wherein, in the step b), the recrystallization is performed at a temperature of -5⁰C to 5⁰C.

[4] The method as set forth in claim 1, wherein the mixing proportion of the isopropyl alcohol and the C - C saturated hydrocarbon is in a range of 2:8 to 7:3 based on weight.

[5] The method as set forth in claim 1, wherein the hydroxyl blocking agent of the step c) is selected from the group consisting of LiH, BH , AlH and a combination thereof.

[6] The method as set forth in claim 1, wherein the dehydrating agent of the step c) is CaH 2.

[7] The method as set forth in claim 1, wherein the dehydrogenation cyclization of diethylene glycol of the step a) is performed under hydrogen atmosphere.

[8] The method as set forth in claim 1, wherein the resultant p-dioxanone has a water content of no more than 70 ppm and a purity of no less than 99.999 wt%.