JP3791752B2 - Enzymatic synthesis of lactic acid branched polymers - Google Patents
Enzymatic synthesis of lactic acid branched polymers Download PDFInfo
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- JP3791752B2 JP3791752B2 JP2000038341A JP2000038341A JP3791752B2 JP 3791752 B2 JP3791752 B2 JP 3791752B2 JP 2000038341 A JP2000038341 A JP 2000038341A JP 2000038341 A JP2000038341 A JP 2000038341A JP 3791752 B2 JP3791752 B2 JP 3791752B2
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- lactic acid
- general formula
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Description
【０００１】
【発明の属する技術】
本発明は、新規な乳酸分岐ポリマーおよびその製造方法に関するものである。
【０００２】
【従来の技術】
ポリ乳酸は汎用性のプラスチック、ドラッグデリバリー素材などの生体適合性の素材、農業、土木資材などの環境適合性の素材としての使用が期待されている。しかしながら、化学重合法から得られたポリ乳酸は有機金属触媒を含んでいるため、環境ホルモンなどの問題から化学重合法で得られたポリ乳酸を環境中に放出するのは非常に危険である。近年、その問題を解決するために、有機金属の代わりにリパーゼなどの酵素触媒を利用してポリ乳酸を合成する方法が報告されている。Macroml. Symp. 130, 285-304 (1998) しかし、この方法は原料となるラクタイドのコストが高いという問題がある。
【０００３】
【発明が解決しようとする課題】
本発明は、有機金属触媒の代わりに安全な酵素を利用し、また、原料として安価な、乳酸エステルを利用して乳酸分岐ポリマーを得ることをその課題とする。
【０００４】
【課題を解決するための手段】
本発明者らは、前記課題を解決すべく鋭意研究を重ねた結果、本発明を完成するに至った。
本発明によれば、下記一般式（１）で表される乳酸分岐ポリマーが提供される。
【化４】
さらに本発明によれば、前記乳酸分岐ポリマーを製造する方法において、下記一般式（２）で表される乳酸エステルと下記一般式（３）で表される脂肪族ジカルボン酸ジビニルエステルとを、Pseudomonascepacia 、 Pseudomonas fluorescence 及びCandida antarctica由来のリパーゼ並びにBacillussubtilis由来のプロテアーゼからなる群から選ばれ加水分解酵素の存在下で反応させることを特徴とする乳酸分岐ポリマーの製造方法が提供される。
【化５】
【化６】
【０００５】
【発明の実施の形態】
本発明の乳酸分岐ポリマーは、イソプロピルエーテル等の有機溶媒中で、加水分解酵素の存在下、前記一般式（２）の乳酸エステルと、前記一般式（３）の脂肪族ジカルボン酸ジビニルを反応させることによって合成することができる。
前記一般式（２）中、Ｒ2はアルキレン基を示し、その炭素数は１〜１２、好ましくは１〜６である。乳酸エステルとしては、乳酸メチルエステル、乳酸エチルエステル、乳酸プロピルエステル、乳酸ブチルエステル、乳酸イソアミルエステル、乳酸ヘキセン−１−イルエステルを挙げることができる。
前記一般式（３）中、Ｒ1はアルキレン基を示し、その炭素数は１〜１２、好ましくは２〜８である。脂肪族ジカルボン酸ジエステルとしては、マロン酸、こはく酸、グルタル酸、アジピン酸、ピメリン酸、スベリン酸、アゼライン酸、セバシン酸、ノナンジカルボン酸、ドデカンジカルボン酸等の脂肪族ジカルボン酸から誘導されるものを挙げることができる。
【０００６】
前記一般式（１）において、ｘは当該単量体成分のモル分率（％）を示し、０〜７０％、好ましくは０〜５０％であり、ｙは当該単量体成分のモル分率（％）を示し、１〜１００％、好ましくは３０〜１００％である。
前記一般式（１）で表される乳酸分岐ポリマーにおいて、その数平均分子量は、通常、１０００〜５０万、好ましくは２万〜５０万である。
【０００７】
前記乳酸分岐ポリマーを製造する場合の単量体である前記一般式（２）の乳酸エステル及び前記一般式（３）の脂肪族ジカルボン酸ジビニルの使用割合は、前記一般式（１）で表されるポリマーの組成に対応する割合であればよい。
【０００８】
本発明で用いる加水分解酵素としては従来公知のもの、例えば、Pseudomonas cepacia、 Pseudomonas fluorescence及びCandida antarctica由来のリパーゼの他、Bacillus subtilis由来のプロテアーゼを挙げることができる。本発明では特に、Pseudomonascepacia 及びPseudomonas fluorescence 由来のリパーゼを使用することが好ましい。
【０００９】
前記の加水分解酵素を用いて乳酸分岐ポリマーを製造する場合、反応温度は１０〜１００℃、好ましくは３０〜５０℃である。溶媒としてはイソプロピルエーテル、メチル−t−ブチルエーテル、ジメチルホルムアミド、ジメチルスルホキシド、ピリジンあるいはそれらの混合溶媒が挙げられる。反応溶媒中の乳酸エステルの濃度は１〜４０重量％、好ましくは１〜１０重量％である。脂肪族ジカルボン酸ジビニルエステルの濃度は１〜４０重量％、好ましくは１〜２０％、また、酵素の使用割合は、反応溶媒に対して、０.１〜２０重量％、好ましくは０.１〜２重量％である。乳酸エステルとしては乳酸メチルエステルが好ましい。
【００１０】
【実施例】
以下実施例を挙げて本説明をさらに詳細に説明するが、これらは単なる例示であって、本説明の範囲をなんら限定するものではない。
【００１１】
実施例１
乳酸メチル０.３６gおよびアジピン酸ジビニル１.３８gを含むイソプロピルエーテル８mlにPseudomonas cepacia由来のリパーゼ（天野社製）０.１gを加えて懸濁した。この酵素反応液を３０℃にて１３０rpmで７日間撹拌した。１週間後、ポリマーが析出してきたので反応溶媒を傾斜法によって取り除き、ポリマーを得た。このポリマーの分子量を測定したところ、数平均分子量で７,５００、重量平均分子量１１,５００であった。13C-NMRで構造解析を行った結果、下記式（４）に示したように乳酸メチルとジビニルアジピン酸が共重合したポリマーであることが確認された。
【００１２】
【化７】
【００１３】
【発明の効果】
本発明の乳酸分岐ポリマーは、酵素を触媒として使用しているため、有機金属触媒を含んでいない。そのため、これらのポリマーが環境中に放出したとしても安全性は非常に高い。また、一般的に乳酸、乳酸オリゴマーは生体内において高い機能性を示すことが報告されているため、乳酸分岐ポリマーはメディカル分野で用いられる機能性材料として有利に適用される。[0001]
[Technology to which the invention belongs]
The present invention relates to new lactic acid branched polymers and a method of manufacturing the same.
[0002]
[Prior art]
Polylactic acid is expected to be used as biocompatible materials such as general-purpose plastics and drug delivery materials, and environmentally compatible materials such as agriculture and civil engineering materials. However, since polylactic acid obtained from the chemical polymerization method contains an organometallic catalyst, it is very dangerous to release the polylactic acid obtained by the chemical polymerization method into the environment due to problems such as environmental hormones. In recent years, in order to solve the problem, a method of synthesizing polylactic acid using an enzyme catalyst such as lipase instead of an organic metal has been reported. Macroml. Symp. 130, 285-304 (1998) However, this method has a problem that the cost of lactide as a raw material is high.
[0003]
[Problems to be solved by the invention]
The present invention utilizes a secure enzyme in place of organic metal catalyst and inexpensive as a raw material, by using a milk ester as its object to obtain a lactic branched polymer.
[0004]
[Means for Solving the Problems]
As a result of intensive studies to solve the above problems, the present inventors have completed the present invention.
According to the present invention, a lactic acid branched polymer represented by the following general formula (1) is provided.
[Formula 4]
Furthermore, according to the present invention, in the method for producing the lactic acid branched polymer, a lactic acid ester represented by the following general formula (2) and an aliphatic dicarboxylic acid divinyl ester represented by the following general formula (3) are converted into Pseudomonascepacia: , method of producing lactic acid branched polymer characterized by being selected from the group consisting of Pseudomonas fluorescence and Candida antarctica lipase and Bacillussubtilis protease derived from the reaction in the presence of a hydrolase is provided.
[Chemical formula 5]
[Chemical 6]
[0005]
DETAILED DESCRIPTION OF THE INVENTION
The lactic acid branched polymer of the present invention reacts the lactic acid ester of the general formula (2) with the divinyl aliphatic dicarboxylate of the general formula (3) in the presence of a hydrolase in an organic solvent such as isopropyl ether. Can be synthesized.
In the general formula (2), R 2 represents an alkylene group, its carbon number is 1-12, preferably 1-6. Examples of the lactate ester include lactate methyl ester, lactate ethyl ester, lactate propyl ester, lactate butyl ester, lactate isoamyl ester, and lactate hexen-1-yl ester.
In the general formula (3), R 1 represents an alkylene group, its carbon number is 1-12, preferably 2-8. Aliphatic dicarboxylic acid diesters derived from aliphatic dicarboxylic acids such as malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, nonanedicarboxylic acid, dodecanedicarboxylic acid, etc. Can be mentioned.
[0006]
In the general formula (1), x represents a mole fraction (%) of the monomer component, 0 to 70%, preferably 0 to 50%, and y is a mole fraction of the monomer component. (%), 1 to 100%, preferably 30 to 100%.
In the lactic acid branched polymer represented by the general formula (1), the number average molecular weight is usually 1000 to 500,000, preferably 20,000 to 500,000.
[0007]
Lactic esters and the proportion of the aliphatic dicarboxylic acid divinyl of the general formula (3) of the monomer der Ru before following general formula in the case of producing the lactic acid branched polymer (2), the general formula (1) Any proportion corresponding to the composition of the polymer represented may be used.
[0008]
Examples of the hydrolase used in the present invention include those conventionally known, for example, lipases derived from Pseudomonas cepacia, Pseudomonas fluorescence and Candida antarctica, as well as Bacillus subtilis derived proteases. In the present invention, it is particularly preferable to use lipases derived from Pseudomonascepacia and Pseudomonas fluorescence.
[0009]
When producing a lactic acid branched polymer with hydrolytic enzymes prior to reporting, the reaction temperature is 10 to 100 ° C., preferably from 30 to 50 ° C.. Examples of the solvent include isopropyl ether, methyl t-butyl ether, dimethylformamide, dimethyl sulfoxide, pyridine, or a mixed solvent thereof. The concentration of the lactic acid ester in the reaction solvent is 1 to 40% by weight, preferably 1 to 10% by weight. The concentration of the aliphatic dicarboxylic acid divinyl ester is 1 to 40% by weight, preferably 1 to 20%, and the enzyme is used in an amount of 0.1 to 20% by weight, preferably 0.1 to 0.1% with respect to the reaction solvent. 2% by weight. Lactic acid methyl ester is preferred as the lactic acid ester.
[0010]
【Example】
Hereinafter, the present invention will be described in more detail with reference to examples. However, these are merely examples and do not limit the scope of the present description.
[0011]
Example 1
To 8 ml of isopropyl ether containing 0.36 g of methyl lactate and 1.38 g of divinyl adipate, 0.1 g of lipase derived from Pseudomonas cepacia (manufactured by Amano) was added and suspended. The enzyme reaction solution was stirred at 130 rpm at 30 ° C. for 7 days. One week later, since a polymer was precipitated, the reaction solvent was removed by a gradient method to obtain a polymer. When the molecular weight of this polymer was measured, it was 7,500 in number average molecular weight and 11,500 in weight average molecular weight. As a result of structural analysis by 13 C-NMR, it was confirmed that the polymer was a copolymer of methyl lactate and divinyl adipic acid as shown in the following formula (4).
[0012]
[Chemical 7]
[0013]
【The invention's effect】
Lactate branched polymers of the present invention, because it uses an enzyme as a catalyst, it does not contain an organometallic catalyst. Therefore, even if these polymers are released into the environment, the safety is very high. In addition, since lactic acid and lactic acid oligomers are generally reported to exhibit high functionality in vivo, lactic acid branched polymers are advantageously applied as functional materials used in the medical field.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000038341A JP3791752B2 (en) | 2000-02-16 | 2000-02-16 | Enzymatic synthesis of lactic acid branched polymers |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000038341A JP3791752B2 (en) | 2000-02-16 | 2000-02-16 | Enzymatic synthesis of lactic acid branched polymers |
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| Publication Number | Publication Date |
|---|---|
| JP2001224392A JP2001224392A (en) | 2001-08-21 |
| JP3791752B2 true JP3791752B2 (en) | 2006-06-28 |
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| Application Number | Title | Priority Date | Filing Date |
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| JP2000038341A Expired - Lifetime JP3791752B2 (en) | 2000-02-16 | 2000-02-16 | Enzymatic synthesis of lactic acid branched polymers |
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Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP4359718B2 (en) * | 2002-08-05 | 2009-11-04 | 学校法人慶應義塾 | Enzymatic depolymerization method of polylactic acid and method for producing polylactic acid using depolymerization product |
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