JP2665522B2 - New alpha-oxyacid polymer - Google Patents
New alpha-oxyacid polymerInfo
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- JP2665522B2 JP2665522B2 JP63146640A JP14664088A JP2665522B2 JP 2665522 B2 JP2665522 B2 JP 2665522B2 JP 63146640 A JP63146640 A JP 63146640A JP 14664088 A JP14664088 A JP 14664088A JP 2665522 B2 JP2665522 B2 JP 2665522B2
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Description
【発明の詳細な説明】 産業上の利用分野 本発明は生体吸収性ポリマーとして有用な新規α−オ
キシ酸ポリマーに関する。また、本発明は該α−オキシ
酸ポリマー製造に用いる新規モノマーにも関する。Description: TECHNICAL FIELD The present invention relates to a novel α-oxyacid polymer useful as a bioabsorbable polymer. The present invention also relates to a novel monomer used for producing the α-oxy acid polymer.
従来の技術および課題 近年、生体吸収性ポリマーの医療用材料への利用が進
んでおり、とりわけ、生体内における毒性や免疫原性が
低く、高い生体適合性を有するα−オキシ酸ポリマーが
広く利用されている。2. Description of the Related Art In recent years, bioabsorbable polymers have been increasingly used for medical materials, and in particular, α-oxyacid polymers having low toxicity and immunogenicity in vivo and high biocompatibility have been widely used. Have been.
一般に、α−オキシ酸ポリマーは、α−オキシ酸同志
が相互にエステル化して形成され、生体内で非酵素的加
水分解を受けてα−オキシ酸となり、代謝経路を通じて
体外へ排出される。従って、体内に蓄積される危険性が
ないので、生体の一時補修材や薬剤のキャリヤーとして
好適な素材であり、すでにポリグリコール酸(PGA)や
ポリ乳酸(PLA)およびその共重合体が繊維化され、吸
収性手術用縫合糸として市販され、臨床的に応用されて
いる。In general, an α-oxyacid polymer is formed by mutually esterifying α-oxyacids, undergoes non-enzymatic hydrolysis in a living body to become an α-oxyacid, and is excreted from the body through a metabolic pathway. Therefore, it has no danger of accumulating in the body, so it is a suitable material as a temporary repair material for living organisms and a carrier for drugs. Polyglycolic acid (PGA), polylactic acid (PLA) and its copolymers have already been converted into fibers. It has been marketed as an absorbable surgical suture and has been clinically applied.
しかしながら、PGAおよびPLAは結晶性が高く非水溶性
であるため、加水分解速度の制御および機能性の付与を
行うことが困難である。そのため、親水性と機能性の付
与をめざした素材の開発が要求され、特に、α−オキシ
酸の一種であるリンゴ酸のポリマーが注目されている。However, since PGA and PLA have high crystallinity and are water-insoluble, it is difficult to control the hydrolysis rate and impart functionality. Therefore, development of a material aiming at imparting hydrophilicity and functionality is required. In particular, a polymer of malic acid, which is a kind of α-hydroxy acid, is receiving attention.
リンゴ酸は、1分子内に二つのカルボキシル基をもつ
ため、エステル化による高分子形成の仕方によりリンゴ
酸のポリマーには、式: で示されるα−型結合の繰返し単位を有するα−ポリリ
ンゴ酸と、式: で示されるβ−型結合の繰返し単位を有するβ−ポリリ
ンゴ酸がある。α−ポリリンゴ酸の合成は式: で示されるマライドのジベンジルエステルの開環重合に
より[高分子学会予稿集35、2330(1985)]、また、β
−ポリリンゴ酸の合成は式: で示されるマロラクトンのベンジルエステルの開環重合
により[エー・シー・エス・ポリマー・プリプリンツ
(A.C.S.Polym.Prep.)20、608(1979);ポリマー・サ
イエンス・アンド・テクノロジー(Polym.Sci.Techno
l.)23、219(1983)]行なわれている。Since malic acid has two carboxyl groups in one molecule, the polymer of malic acid has the formula: And α-polymalic acid having an α-type repeating unit represented by the formula: There is a β-polymalic acid having a β-type repeating unit represented by The synthesis of α-polymalic acid has the formula: In the ring-opening polymerization of the dibenzyl ester of the maleide shown in [3], the proceedings of the Society of Polymer Science, 35, 2330 (1985)]
The synthesis of polymalic acid has the formula: (ACSPolym.Prep.) 20, 608 (1979); Polymer Science and Technology (Polym.Sci.Techno)
l.) 23, 219 (1983)].
しかしながら、これらのモノマーはいずれも合成が困
難であり、大量合成ができず、特に、α−ポリリンゴ酸
の収率は低く、その合成法は未だ確立されるに至ってい
ない。However, all of these monomers are difficult to synthesize and cannot be synthesized in large quantities. In particular, the yield of α-polymalic acid is low, and the synthesis method has not yet been established.
このように事情に鑑み、本発明者らは、リンゴ酸のα
−型結合単位を有するα−オキシ酸ポリマーの合成を効
率よく行うべく、鋭意研究を重ねた。その結果、リンゴ
酸とグリコール酸の混合単位を有する新規な六員環ジエ
ステルモノマーの合成に成功し、これから、新規なα−
オキシ酸ポリマーが効率よく得られることを見出だし、
本発明を完成するに至った。Thus, in view of the circumstances, the present inventors have found that malic acid α
In order to efficiently synthesize an α-oxyacid polymer having a -type binding unit, intensive studies have been made. As a result, we succeeded in synthesizing a new six-membered ring diester monomer having a mixed unit of malic acid and glycolic acid, and
They found that oxyacid polymers can be obtained efficiently,
The present invention has been completed.
課題を解決するための手段 本発明は、式(I): [式中、Rは水素またはカルボキシル保護基、nは、R
が水素の場合の分子量が約1,000〜300,000となるような
数を意味する] で示されるくり返し単位からなるα−オキシ酸ポリマー
を提供するものである。Means for Solving the Problems The present invention provides a compound of the formula (I): Wherein R is a hydrogen or carboxyl protecting group, n is R
Means a number such that the molecular weight is about 1,000 to 300,000 when is hydrogen.] The present invention provides an α-oxyacid polymer comprising repeating units represented by the following formula:
さらに、本発明は、式(I)のポリマーの合成に有用
なモノマーである式(II): [式中、Rは水素またはカルボキシル保護基を意味す
る] で示される新規化合物を提供するものである。Further, the present invention provides a compound of formula (II), which is a useful monomer for the synthesis of the polymer of formula (I): [Wherein, R represents hydrogen or a carboxyl protecting group].
式(I)および式(II)におけるRで示されるカルボ
キシル保護基としては、例えば、メチル、エチル、n−
プロピル、イソプロピル、t−ブチルなどの低級アルキ
ルおよびベンジルなどのアラルキルなどが挙げられ、好
ましくは、メチル、エチルあるいはベンジルである。Examples of the carboxyl protecting group represented by R in the formulas (I) and (II) include, for example, methyl, ethyl, n-
Lower alkyl such as propyl, isopropyl and t-butyl; and aralkyl such as benzyl. Preferred are methyl, ethyl and benzyl.
本発明の式(I)で示されるポリマーは、一般に、R
が水素の場合、約1,00〜300,000、好ましくは、10,000
〜100,000の分子量を有する。The polymer represented by the formula (I) of the present invention generally has R
When is hydrogen, about 1,00 to 300,000, preferably 10,000
It has a molecular weight of 100100,000.
なお、式(I)および(II)の化合物には、光学異性
体が存在するが、ラセミ体も含めてそれら全ての光学異
性体は本発明に包含される。The compounds of the formulas (I) and (II) have optical isomers, and all the optical isomers including the racemate are included in the present invention.
式(I)のポリマーは、式(II)のモノマーを、例え
ば、開始剤の存在下に溶液重合、または塊状重合させ、
所望により、存在する保護基を脱離させることによって
合成できる。また、式(II)のモノマーは、L−アスパ
ラギン酸を出発物質として自体公知の方法、例えば、次
の反応式Iに示す方法に従って製造できる。The polymer of formula (I) is obtained by subjecting the monomer of formula (II) to, for example, solution polymerization or bulk polymerization in the presence of an initiator,
If desired, the compound can be synthesized by removing an existing protecting group. The monomer of the formula (II) can be produced using L-aspartic acid as a starting material according to a method known per se, for example, the method shown in the following reaction formula I.
反応式Iには、本発明の式(II)の化合物である環状
六員環ジエステルモノマー、L−3−ベンジルオキシカ
ルボニルメチル−1,4−ジオキサン−2,5−ジオン(L−
BMD)および式(I)のグリコール酸−リンゴ酸共重合
体の合成方法を例示してある。すなわち、出発物質であ
るL−アスパラギン酸(a)のβ−位におけるカルボキ
シル基をエステル化し、例えば、ベンジルエステル化し
て保護誘導体(b)とした後、ジアゾ化加水分解を行
い、L−β−ベンジルマレート(c)を合成する。つい
で、溶媒、例えば、エーテル類、芳香族炭化水素または
ハロゲン化炭化水素、好ましくは、ジエチルエーテル
中、例えば、トリエチルアミンのような塩基の存在下、
該化合物を塩化ブロモアセチルとカップリングさせ、L
−ブロモアセチルベンジルマレート(d)を得る。さら
に、溶媒、例えば、ジメチルホルムアミド(DMF)、N
−メチルピロリドン(NMP)などの非プロトン性極性溶
媒、好ましくは、DMF中、例えば、炭酸水素ナトリウム
で分子内環化を行い、式(II)の化合物を得る。 In the reaction formula I, a cyclic six-membered ring diester monomer which is a compound of the formula (II) of the present invention, L-3-benzyloxycarbonylmethyl-1,4-dioxane-2,5-dione (L-
BMD) and a method for synthesizing the glycolic acid-malic acid copolymer of formula (I). That is, the carboxyl group at the β-position of L-aspartic acid (a) as a starting material is esterified, for example, benzyl-esterified to give a protected derivative (b), and then diazotized and hydrolyzed to give L-β- Synthesize benzylmalate (c). Then, in a solvent, for example, ethers, aromatic hydrocarbons or halogenated hydrocarbons, preferably in diethyl ether, for example, in the presence of a base such as triethylamine,
The compound is coupled with bromoacetyl chloride and L
-Bromoacetylbenzylmalate (d) is obtained. Further, a solvent such as dimethylformamide (DMF), N
Intramolecular cyclization with an aprotic polar solvent such as -methylpyrrolidone (NMP), preferably in DMF, for example with sodium bicarbonate, gives the compound of formula (II).
式(II)の化合物は、そのまま、あるいは、例えば、
再結晶等により精製した後、式(I)の化合物の合成に
用いる。The compound of formula (II) can be used as such or, for example,
After purification by recrystallization or the like, it is used for the synthesis of the compound of the formula (I).
式(II)の化合物を、窒素雰囲気下、溶媒、例えば、
トルエン中、開始剤、例えば、ジエチル亜鉛、オクチル
酸スズ、アルミニウムイソプロポキシドなどの存在下、
80〜120℃、好ましくは、100℃にて溶液重合を行い、グ
リコール酸とベンジルマレートとの共重合体(I−a)
を合成する。ついで、Rが水素であるポリマーを所望の
場合、式(I−a)のポリマーを、極性溶媒、例えば、
エタノールおよび酢酸エチルの混合溶媒中、触媒、例え
ば、二酸化白金触媒の存在下、水素化分解を行い、ベン
ジル基を脱離し、リンゴ酸−グリコール酸共重合体(I
−b)が得られる。In a nitrogen atmosphere, a compound of the formula (II) is dissolved in a solvent, for example,
In toluene, in the presence of an initiator such as diethyl zinc, tin octylate, aluminum isopropoxide, etc.
Solution polymerization is carried out at 80 to 120 ° C, preferably 100 ° C, and a copolymer of glycolic acid and benzylmalate (Ia)
Are synthesized. Then, if a polymer in which R is hydrogen is desired, the polymer of formula (Ia) is converted to a polar solvent, for example,
Hydrogenolysis is performed in a mixed solvent of ethanol and ethyl acetate in the presence of a catalyst, for example, a platinum dioxide catalyst, to remove the benzyl group, and to obtain a malic acid-glycolic acid copolymer (I
-B) is obtained.
別法として、窒素雰囲気下、式(II)の化合物を130
〜170℃にて融解し、開始剤の存在下に塊状重合させて
も式(I)の新規α−オキシ酸ポリマーが得られる。Alternatively, under nitrogen atmosphere, the compound of formula (II)
Melting at ~ 170 ° C and bulk polymerization in the presence of an initiator also yields novel α-oxyacid polymers of formula (I).
かくして、得られた本発明の式(I)の新規α−オキ
シ酸ポリマーは、ポリグリコール酸やポリ乳酸と同様
に、吸収性手術用縫合糸などの種々の医療用材料や薬剤
のキャリヤーとして使用できる。The thus obtained novel α-oxyacid polymer of the formula (I) of the present invention can be used as a carrier for various medical materials and drugs such as absorbable surgical sutures, like polyglycolic acid and polylactic acid. it can.
実施例 次に実施例を挙げて本発明をさらに詳しく説明する。
なお、α−オキシ酸ポリマー(I−a)および(I−
b)の分子量としては、ポリスチレンを基準とするGPC
による測定値を用いた。EXAMPLES Next, the present invention will be described in more detail with reference to examples.
The α-oxyacid polymers (Ia) and (I-
As the molecular weight of b), GPC based on polystyrene
Was used.
実施例1 L−3−ベンジルオキシカルボニルメチル−
1,4−ジオキサ−2,5−ジオン(L−BMD)の製造 L−アスパラギン酸20gを80%硫酸200mlに溶解し、70
℃に保ちながら、ベンジルアルコール500gを加えて反応
させ、β−位のカルボキシ基を保護したL−ベンジルア
スパルテートを得た。この生成物100gを1N硫酸1,400ml
に加え、0〜5℃にて撹拌しながら、亜硝酸ナトリウム
47gを含む水溶液100mlを約3時間にわたって滴下し、30
分間撹拌を続けた。さらに、亜硝酸ナトリウム10gを含
む水溶液30mlを約30分間にわたって滴下し、室温にて一
晩放置した。エーテルで抽出し、抽出液を硫酸ナトリウ
ムで乾燥し、濃縮し、残った粗結晶をベンゼンから再結
晶して、L−β−ベンジルマレートを得た。この化合物
20gおよびブロモアセチルクロリド18.4gをエーテル300m
lに溶かし、5℃以下に冷却し、1.1倍モル量のトリエチ
ルアミン9.9gを含むエーテル溶液50mlを30分間にわたっ
て滴下した。反応混合物をさらに室温にて6時間撹拌
し、濾過し、濾液に水50mlを加え、30分間撹拌した。数
回水を加えて分液を行い、エーテル層に硫酸ナトリウム
を加えて乾燥した後、濃縮し、L−ブロモアセチルベン
ジルマレート29.7gを得た。収率96%。1 H−NMR(アセトン−d6)δ(ppm):3.02(q,CH2CO,2
H)、4.02(s,OCH2CO,2H)、5.12(s,CH2Ph,2H)、5.50
(q,OCH,1H)、7.35(s,C6H5,5H) L−ブロモアセチルベンジルマレート10gのDMF50ml溶
液を、炭酸水素ナトリウム3.7gのDMF950ml溶液(不均一
溶液)に、室温にて約8時間かけて滴下した。さらに同
温度にて12時間反応させ、濾過し、DMFを濃縮し、残渣
をイソプロパノール50mlで洗浄した。濾過後、得られた
白金粉末をアセトン200mlに溶かし、不溶物を濾去し、
濾液を濃縮した。残渣を少量のイソプロパノールで洗浄
し、濾過して十分に乾燥した。この白色粉末を昇華し、
イソプロパノール400mlで再結晶して、針状結晶のL−
3ベンジルオキシカルボニルメチル−1,4−ジオキサン
−2,5−ジオン(L−BMD)2.3g(収率27%)を得た。融
点150℃。▲〔α〕D 25▼=−127゜。1 H−NMR(アセトン−d6)δ(ppm)3.18(q,CH2CO,2
H)、5.16(q,OCH2CO,2H)、5.20(s,CH2Ph,2H)、5.68
(t,OCH,1H)、7.38(s,C6H5,5H) 得られたL−ブロモアセチルベンジルマレートとその
環化生成物L−BMDのプロトンNMRスペクトルを第1図お
よび第2図に示す。グリコレート単位に基づくシグナル
が環化前では4.0ppmにシングレットに現れているのに対
して、環化後このシグナルは5.2ppmにABカルテットとし
て現れ、環化構造をとっていることを示す。また、IRに
はラクトンとベンジルエステルの吸収がそれぞれ1660cm
-1、1620cm-1に認められ、この構造と一致した。さら
に、元素分析の値も一致し、L−BMDの構造が確認され
た。Example 1 L-3-benzyloxycarbonylmethyl-
Production of 1,4-dioxa-2,5-dione (L-BMD) Dissolve 20 g of L-aspartic acid in 200 ml of 80% sulfuric acid,
While maintaining the temperature at 500 ° C., 500 g of benzyl alcohol was added and reacted to obtain L-benzyl aspartate in which the carboxy group at the β-position was protected. 100 g of this product in 1400 ml of 1N sulfuric acid
And sodium nitrite while stirring at 0-5 ° C.
100 ml of an aqueous solution containing 47 g was added dropwise over about 3 hours, and 30
Stirring was continued for minutes. Further, 30 ml of an aqueous solution containing 10 g of sodium nitrite was added dropwise over about 30 minutes, and the mixture was left overnight at room temperature. The mixture was extracted with ether, the extract was dried over sodium sulfate, concentrated, and the remaining crude crystals were recrystallized from benzene to obtain L-β-benzylmalate. This compound
20 g and 18.4 g of bromoacetyl chloride in 300 m of ether
After cooling to 5 ° C. or lower, 50 ml of an ether solution containing 9.9 g of a 1.1-fold molar amount of triethylamine was added dropwise over 30 minutes. The reaction mixture was further stirred at room temperature for 6 hours, filtered, 50 ml of water was added to the filtrate and stirred for 30 minutes. Water was added several times to carry out liquid separation, sodium sulfate was added to the ether layer, and the mixture was dried and then concentrated to obtain 29.7 g of L-bromoacetylbenzylmalate. 96% yield. 1 H-NMR (acetone-d 6 ) δ (ppm): 3.02 (q, CH 2 CO, 2
H), 4.02 (s, OCH 2 CO, 2H), 5.12 (s, CH 2 Ph, 2H), 5.50
(Q, OCH, 1H), 7.35 (s, C 6 H 5, 5H) an L- bromoacetyl benzyl maleate 10g of DMF50ml solution, the DMF950ml solution of sodium hydrogen carbonate 3.7 g (heterogeneous solution) at room temperature It was dropped over about 8 hours. The mixture was further reacted at the same temperature for 12 hours, filtered, DMF was concentrated, and the residue was washed with 50 ml of isopropanol. After filtration, the obtained platinum powder was dissolved in 200 ml of acetone, and insolubles were removed by filtration.
The filtrate was concentrated. The residue was washed with a small amount of isopropanol, filtered and dried thoroughly. Sublimate this white powder,
The crystals were recrystallized with 400 ml of isopropanol, and L-
2.3 g (yield 27%) of 3-benzyloxycarbonylmethyl-1,4-dioxane-2,5-dione (L-BMD) was obtained. Melting point 150 ° C. ▲ [α] D 25 ▼ = -127 ゜. 1 H-NMR (acetone-d 6 ) δ (ppm) 3.18 (q, CH 2 CO, 2
H), 5.16 (q, OCH 2 CO, 2H), 5.20 (s, CH 2 Ph, 2H), 5.68
(T, OCH, 1H), 7.38 (s, C 6 H 5 , 5H) Proton NMR spectra of the obtained L-bromoacetylbenzylmalate and its cyclized product L-BMD are shown in FIGS. 1 and 2. Shown in Before the cyclization, a signal based on the glycolate unit appeared in a singlet at 4.0 ppm, whereas after the cyclization, this signal appeared as an AB quartet at 5.2 ppm, indicating a cyclized structure. In addition, the absorption of lactone and benzyl ester was 1660 cm in IR, respectively.
-1 and 1620 cm -1 , which were consistent with this structure. Furthermore, the values of the elemental analysis were also consistent, and the structure of L-BMD was confirmed.
実施例2 α−オキシ酸ポリマー(I−a)の製造 窒素雰囲気下、実施例1で得られたBMD0.2gにトルエ
ン3mlを加え、100℃で溶解した。この溶液にジエチル亜
鉛のヘキサン中10wt%溶液26μを加え、100℃にて、
3時間重合させた。重合後、溶媒を濃縮除去し、得られ
たポリマーをアセトン3mlに溶かし、エーテル30ml中で
再沈澱させた。乾燥後、分子量2,300のポリL−BMD(I
−a)0.19gを得た。収率95%。1 H−NMR(アセトン−d6)δ(ppm)3.08(m,CH2CO,2
H)、4.80(s,OCH2CO,2H)、5.15(s,CH2Ph,2H)、5.66
(m,OCH,1H)、7.35(s,C6H5,5H) 実施例3 α−オキシ酸ポリマー(I−a)の製造 開始剤として、ジエチル亜鉛の代わりにオクチル酸ス
ズのトルエン溶液(0.1/ml)61μを用い、実施例2の
方法に従って分子量12,900の表記化合物0.185gを製造し
た。収率93%。Example 2 Production of α-oxyacid polymer (Ia) Under a nitrogen atmosphere, 3 ml of toluene was added to 0.2 g of the BMD obtained in Example 1 and dissolved at 100 ° C. 26 μl of a 10 wt% solution of diethyl zinc in hexane was added to this solution, and at 100 ° C.,
The polymerization was carried out for 3 hours. After the polymerization, the solvent was concentrated and removed, and the obtained polymer was dissolved in 3 ml of acetone and reprecipitated in 30 ml of ether. After drying, poly L-BMD (I
-A) 0.19 g was obtained. 95% yield. 1 H-NMR (acetone-d 6 ) δ (ppm) 3.08 (m, CH 2 CO, 2
H), 4.80 (s, OCH 2 CO, 2H), 5.15 (s, CH 2 Ph, 2H), 5.66
(M, OCH, 1H), 7.35 (s, C 6 H 5, 5H) Example 3 alpha-as producing initiator oxy acid polymer (I-a), tin octoate in toluene in place of diethyl zinc ( According to the method of Example 2, 0.185 g of the title compound having a molecular weight of 12,900 was prepared using 61 µm of 0.1 / ml). 93% yield.
実施例4 α−オキシ酸ポリマー(I−a)の製造 開始剤として、ジエチル亜鉛の代わりにアルミニウム
イソプロポキシドのトルエン溶液(0.1g/ml)31μを
用い、実施例2の方法に従って分子量2,900の表記化合
物1.96gを製造した。収率98%。Example 4 Production of α-oxyacid polymer (Ia) In place of diethylzinc, 31 μl of a toluene solution of aluminum isopropoxide (0.1 g / ml) was used as the initiator, and a molecular weight of 2,900 was obtained according to the method of Example 2. 1.96 g of the title compound were prepared. Yield 98%.
実施例5 α−オキシ酸ポリマー(I−a)の製造 窒素雰囲気下、実施例1にて製造したモノマー0.2g
(融点150℃)を160℃まで加熱し、完全に融解させた。
これにオクチル酸スズの10wt%トルエン溶液35μを加
えて脱気し、トルエンを除去した後、窒素中、160℃で3
0時間反応させた。反応混合物をアセトン3mlに溶かし、
エーテル30mlから再沈澱を行った。濾過し、乾燥して白
色粉末状の分子量23,000のポリL−BMD0.19gを得た。収
率95%。Example 5 Production of α-oxyacid polymer (Ia) 0.2 g of the monomer produced in Example 1 under a nitrogen atmosphere
(Melting point 150 ° C.) was heated to 160 ° C. and completely melted.
To this, 35 μl of a 10 wt% toluene solution of tin octylate was added to degas, and toluene was removed.
The reaction was performed for 0 hours. Dissolve the reaction mixture in 3 ml of acetone,
Reprecipitation was performed from 30 ml of ether. The mixture was filtered and dried to obtain 0.19 g of a white powdery poly L-BMD having a molecular weight of 23,000. 95% yield.
実施例6 α−オキシ酸ポリマー(I−b)の製造 実施例2で得られた該ポリマー0.09gを、メタノール
/酢酸エチル(1:3)溶媒20mlに溶かし、該溶液に二酸
化白金10mgを加えた。反応容器内を水素で満たし、温度
を30℃に維持しながら水素吸収がなくなるまで撹拌し
た。濾過して二酸化白金触媒を除去し、溶媒を濃縮し、
所望の分子量1,200のα−オキシ酸ポリマー(I−b)5
9mgを得た。収率96%。1 H−NMR(メタノール−d4)δ(ppm)3.18(d,CH2CO,2
H)、4.97(d,OCH2CO,2H)、5.82(m,OCH,1H) 水素化分解前後のα−オキシ酸ポリマー(実施例2で
得られた(I−a))および(実施例6で得られた(I
−b))のプロトンNMRスペクトルを第3図に示す。
(I−a)ではベンジル気に基づくシグナルが約7.4ppm
と5.2pmにそれぞれシングレットとなって現れている。
しかし、共重合体(I−b)にはこのシグナルは認めら
れず、ベンジル気がほぼ消失していることがわかる。Example 6 Production of α-oxyacid polymer (Ib) 0.09 g of the polymer obtained in Example 2 was dissolved in 20 ml of a methanol / ethyl acetate (1: 3) solvent, and 10 mg of platinum dioxide was added to the solution. Was. The reaction vessel was filled with hydrogen, and the mixture was stirred while maintaining the temperature at 30 ° C. until hydrogen absorption ceased. Filter to remove the platinum dioxide catalyst, concentrate the solvent,
Α-oxyacid polymer (Ib) 5 having a desired molecular weight of 1,200
9 mg were obtained. 96% yield. 1 H-NMR (methanol-d 4 ) δ (ppm) 3.18 (d, CH 2 CO, 2
H), 4.97 (d, OCH 2 CO, 2H), 5.82 (m, OCH, 1H) α-oxyacid polymer before and after hydrogenolysis ((Ia) obtained in Example 2) and (Example (I
FIG. 3 shows the proton NMR spectrum of -b)).
In (Ia), the signal based on benzyl gas was about 7.4 ppm.
And appear as singlets at 5.2pm respectively.
However, this signal was not observed in the copolymer (Ib), indicating that benzyl gas had almost disappeared.
また、集合条件を変えてもポリマーの比旋光度(アセ
トン中)が−30゜〜−32゜の範囲を示し変わらないこ
と、および13C−NMRにおいてカルボニルのシグナルが三
種類のシングレットとなっていることから、ポリマーは
グリコール酸とα−型リンゴ酸の交互重合体構造をとる
ことが判明した。In addition, the specific rotation of the polymer (in acetone) remains in the range of −30 ° to −32 ° even when the aggregation conditions are changed, and the carbonyl signal becomes three types of singlets in 13 C-NMR. Therefore, it was found that the polymer had an alternating polymer structure of glycolic acid and α-malic acid.
発明の効果 本発明によれば、グリコール酸とα−型リンゴ酸結合
単位を有する高い生体適合性の新規α−オキシ酸ポリマ
ーが収率よく得られる。Effects of the Invention According to the present invention, a high biocompatible novel α-oxyacid polymer having glycolic acid and α-malic acid binding unit can be obtained in good yield.
第1図および第2図は、各々、化合物(d)および式
(II)のモノマーのNMRスペクトルである。第3図は式
(I−a)および(I−b)のポリマーのNMRスペクト
ルである。1 and 2 are NMR spectra of the compound (d) and the monomer of the formula (II), respectively. FIG. 3 is the NMR spectra of the polymers of formulas (Ia) and (Ib).
───────────────────────────────────────────────────── フロントページの続き (56)参考文献 特開 昭63−92641(JP,A) 特開 昭60−101118(JP,A) Macromolecules,21 [11](1988)p.3338−3340 ────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-63-92641 (JP, A) JP-A-60-101118 (JP, A) Macromolecules, 21 [11] (1988) p. 3338-3340
Claims (2)
は、Rが水素の場合の分子量が約1,000〜300,000となる
ような数を意味する] で示されるくり返し単位からなるα−オキシ酸ポリマ
ー。1. The formula: Wherein R is hydrogen, lower alkyl or aralkyl, n
Means a number such that the molecular weight when R is hydrogen is about 1,000 to 300,000.] An α-oxyacid polymer comprising repeating units represented by the following formula:
味する] で示される化合物。2. The formula: [Wherein, R represents hydrogen, lower alkyl or aralkyl].
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JP63146640A JP2665522B2 (en) | 1988-06-14 | 1988-06-14 | New alpha-oxyacid polymer |
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JP2665522B2 true JP2665522B2 (en) | 1997-10-22 |
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EP0522422A3 (en) * | 1991-07-01 | 1993-03-17 | Mitsubishi Kasei Corporation | Process for producing a biodegradable polymer |
JP4741883B2 (en) | 2004-06-11 | 2011-08-10 | キヤノン株式会社 | Polyhydroxyalkanoate having ester group, carboxyl group and sulfonic acid group and method for producing the same |
WO2005121206A2 (en) | 2004-06-11 | 2005-12-22 | Canon Kabushiki Kaisha | Polyhydroxyalkanoate having vinyl group, ester group, carboxyl group and sulfonic acid group, and production method thereof |
US7557176B2 (en) | 2004-06-11 | 2009-07-07 | Canon Kabushiki Kaisha | Polyhydroxyalkanoic acid having vinyl, ester, carboxyl or sulfonic acid group and producing method therefor |
JP4455413B2 (en) | 2004-06-11 | 2010-04-21 | キヤノン株式会社 | Polyhydroxyalkanoic acid having vinyl group, ester group, carboxyl group and sulfonic acid group and method for producing the same |
WO2005121207A2 (en) | 2004-06-11 | 2005-12-22 | Canon Kabushiki Kaisha | Polyhydroxyalkanoate having vinyl group, ester group, carboxyl group, and sulfonic group, and method of producing the same |
US7510813B2 (en) | 2004-06-24 | 2009-03-31 | Canon Kabushiki Kaisha | Resin-coated carrier for electrophotographic developer |
WO2007133783A1 (en) * | 2006-05-15 | 2007-11-22 | Tyco Healthcare Group Lp | Halogenated cyclic lactones and polymers made therefrom |
FR2942800B1 (en) * | 2009-03-06 | 2012-04-20 | Minasolve | PROCESS FOR THE CATALYTIC POLYMERISATION OF 1,4-DIOXANES-2,5 DIONES AND THE CORRESPONDING POLYMERS |
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