JPH0813874B2 - New copolymer - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of use] The present invention relates to a novel copolymer which can be greatly expected to be used in the fields of medicine and medicine as a biodegradable and absorbable polymer and a method for producing the same.

[Background of the Invention]

In recent years, biodegradable and absorbable polymers have been spotlighted as polymer carriers for drag delivery systems.
Typical examples are polyglycolic acid, polylactic acid,
Poly-β-hydroxybutyrate and the like can be mentioned, but since none of these polyesters has a modifiable functional group, a new function cannot be imparted by a covalent bond and the range of use is limited. Has been.

On the other hand, poly-α-malic acid (molecular weight of about 5,000), which was discovered as a protease inhibitor in blue mold, is a polylactide having a carboxyl group in its side chain, and thus corresponds to a derivative of polyglycolic acid or polylactic acid. It can be seen as a chemically modifiable polylactide-type biodegradable and absorbable polyester, which can be expected to be widely used in the medical field. That is, it can be said that the malic acid polymer is a polymer material that should be noted as a bioabsorbable polymer that can impart a new function by chemically modifying a side chain carboxyl group.

Therefore, research on the synthesis method of this malic acid polymer was conducted by Lenz and Vert [ACS Polymer Preprints, 20 (1) ,
608 (1979); U.S. Pat. No. 4,265,247 (198
1)], Nakajima and the present inventors [Reports of The Faculty
Engineering Tottori University, 8 , 124 (1977)] and the present inventor [polymer processing, 34 , 382 (1985)], etc., but the malic acid polymers obtained so far have small molecular weights. 10 is a ^third order, not necessarily satisfactory results in terms of molecular weight is not obtained.

[Object of the Invention]

The present invention has been made in view of the above situation, and an object thereof is to provide a biodegradable and absorbable polymer having a high molecular weight and having a carboxyl group capable of being chemically modified in the molecule.

[Structure of Invention]

The present invention provides (1) general formula [I] (In the formula, m and n each independently represent an integer of 2 or more.) And a copolymer of α-malic acid and lactic acid having a molecular weight of 11,000 to 37,000, and (2) malide diester. Ring-opening copolymerization of benzyl ester and L-lactide, after which
A compound of the general formula [I], which is characterized by being prepared by debenzylation protection. (In the formula, m and n are the same as the above.), And the invention is a method for producing a copolymer of α-malic acid and lactic acid having a molecular weight of 11,000 to 37,000.

The copolymer of the present invention is, for example, malide dibenzyl ester which is a cyclic dimer of β-benzyl-L-malic acid. And L-lactide, which is a cyclic dimer of L-lactic acid Ring-opening copolymerization of and β-benzylmaleate
The lactic acid copolymer can be easily obtained by catalytic reduction and debenzylation protection.

Ring-opening copolymerization of malide dibenzyl ester and L-lactide is usually carried out in the presence of an organotin catalyst. Examples of the organotin catalyst include, but are not limited to, tin octylate, di-n-butyltin dilaurate, and tetraphenyltin. The polymerization temperature is not particularly limited, but is usually 150 to 300 ° C., and the polymerization time is appropriately determined in consideration of the polymerization temperature and other reaction conditions, the physical properties of the intended copolymer, and the like. The polymerization method itself may be carried out according to a known polymerization method. After the reaction, the reaction mixture is dissolved in a suitable solvent capable of dissolving it if necessary, and usually, after treating with acetic anhydride to protect the polymer end, this is subjected to a conventional method, for example, in a solvent which does not dissolve the target substance. It may be crystallized by injecting into
The mole fraction of β-benzylmalate in the obtained copolymer is different depending on the polymerization temperature, the polymerization time, the mole fraction of malide dibenzyl ester used as a raw material, etc., but the mole fraction of the malide dibenzyl ester used is When the polymerization temperature is about 0.3 to 0.5, the polymerization temperature is about 180 to 200 ° C., and the polymerization time is about 24 to 48 hours, the molar fraction of β-benzylmalate in the obtained copolymer is usually 5 to 25% (0.05 to 0.25).
When the proportion of malide dibenzyl ester used is increased, the molar fraction of β-benzylmalate in the resulting copolymer generally increases, but the molecular weight of the copolymer tends to decrease accordingly. The proportion of dodibenzyl ester used depends on the purpose and is not particularly limited.

Debenzylation protection of β-benzyl maleate / lactic acid copolymer is usually carried out by catalytic reduction using palladium / carbon, platinum black, Raney nickel or the like as a catalyst. The reaction temperature is usually room temperature, and ethyl acetate is usually used as the solvent, but the solvent is not particularly limited thereto. After the reaction, the catalyst is removed by a conventional method and the solvent is distilled off to obtain the desired α-malic acid / lactic acid copolymer. The molar fraction (n / m + n) of α-malic acid in the obtained copolymer is usually 5 to 25% of that of β-benzylmalate before debenzylation protection.
(0.05 to 0.25), so inevitably 5 to 25%
(0.05 to 0.25).

The malide dibenzyl ester used in the production method of the present invention is obtained by heating β-benzylmalate under reduced pressure (for example, 10 to 30) in the presence of a catalyst such as zinc oxide or antimony oxide.
mmHg, 100-200 ° C) and dehydration condensation is performed to easily obtain. The product may be isolated by sublimation by subjecting the reaction mixture to high temperature and high vacuum (for example, 180 to 220 ° C, 0.1 to 1 mmHg), or the catalyst may be removed by a conventional method. After that, the reaction solution may be separated by subjecting it to liquid chromatography.

β-Benzylmalate is usually synthesized from L-malic acid or L-aspartic acid as a starting material according to the following synthetic route or.

The malide dibenzyl ester used in the production method of the present invention is β-synthesized by any of the above synthetic routes.
It goes without saying that either a malide dibenzyl ester obtained from benzyl malate or a malide dibenzyl ester obtained from β-benzyl maleate synthesized by a method other than the above may be used.

According to the production method of the present invention, the copolymer of the present invention having a molecular weight of 10,000 or more is usually easily and effectively obtained.

Examples and Reference Examples are shown below, but the present invention is not limited to these Examples and Reference Examples.

〔Example〕

Reference Example 1. Synthesis of β-benzyl-L-malate (1) Synthesis of L-malic acid chloralide L-malic acid 13.4 g (0.1 mol) and chloral hydrate 16.5
g (0.1 mol) was mixed, and 25 ml of concentrated sulfuric acid was gradually added thereto with stirring. The mixed solution became a homogeneous solution and immediately solidified. After leaving it overnight, it was poured into ice water, separated, washed with water and dried to obtain a crude crystal. This is recrystallized twice from toluene and L
-Colorless needle crystals of maloyl chloride were obtained.

 Yield 61.5%. Melting point 139.1-140.0 ° C.

[Α] ▲ ²⁵ _D ▼ = + 85.6 ° (C = 2.50, benzene).

¹ H-NMR (CDCl ₃ ) δppm: 3.0 (d, 2H, CH ₂ ), 4.8 (t, 1H, C
H), 5.8 (s, 1H, CCl ₃ -CH), 8.8 (broad, 1H, COOH).

IR (KBr) ν cm ^-1 : 1680 (C = O), 1440, 1390 (CH ₂ ),
1300 (CCl _3), 1210 (ester).

(2) Synthesis of L-malic acid chloralide benzyl ester 10 g (38 mmol) of L-malic acid chloralide and 4.7 ml (45.6 mmol) of benzyl alcohol were dehydrated with acetone 200
It was dissolved in ml and ice-cooled with stirring. An acetone solution containing 9.4 g (45.6 mmol) of dicyclohexylcarbodiimide (DCC) was added dropwise to the solution. After stirring in an ice bath for 1 hour, the mixture was further stirred at room temperature for 3 days. After cooling the reaction mixture with ice, dicyclohexylurea (DCU) generated during the reaction was removed by passing, and the liquid was isolated by medium pressure liquid chromatography (developing solvent: n-hexane / ethyl acetate = 3/1). Volume ratio) and powdered L-
Obtained malic acid chloralidobenzyl ester.

 Yield 16.5%. Melting point 163.6-165.1 ° C.

 Rf: 0.35 (n-hexane / ethyl acetate = 3/1 volume ratio).

[Α] ▲ ²⁵ _D ▼ = + 25.7 ° (C = 1.0, chloroform).

¹ H-NMR (CDCl ₃ ) δppm: 3.0 (d, 2H, CH ₂ ), 4.8 (t, 1H, C
H), 5.1 (s, 2H, C ₆ H ₅ C H ₂ ), 5.7 (s, 1H, CCl ₃ -CH), 7.3 (b
road, 5H, C ₆ H ₅ ).

IR (KBr) ν cm ^-1 : 1720 (C = O), 1450, 1400 (CH ₂ ),
1300 (CCl _3), 1170 (ester), 740,700 (phenyl).

(3) Synthesis of β-benzyl-L-malate L-malic acid chloralide benzyl ester 0.45 g was added to 1N
-The mixture was placed in a mixed solution of hydrochloric acid (15 ml) and acetone (15 ml) and reacted with stirring at room temperature for 5 days. Acetone was distilled off from the reaction solution, and the mixture was extracted with n-hexane. This organic layer was separated by medium pressure liquid chromatography (developing solvent n-hexane / ethyl acetate = 3/1 volume ratio) to give a syrup β-
Benzyl-L-malate was obtained.

Yield 63.4%. [Α] ▲ ²⁵ _D ▼ = -8.6 ° (C = 1.0, methanol).

¹ H-NMR (CD ₃ COCD ₃ ) δppm: 2.9 (d, 2H, CH ₂ ), 4.7 (t, 1
H, CH), 5.1 (s, 2H, C ₆ H ₅ C H ₂ ), 6.7 (broad, 2H, OH, COO
H), 7.3 (broad, 5H , C 6 H 5).

IR (KBr) νcm ^-1 : 1720 (C = O), 1500 (phenyl),
1450,1380 (CH _2), 1240,1170 (ester), 740,700 (phenyl).

Reference Example 2. Synthesis of β-benzyl-L-malate (1) Synthesis of β-benzyl-L-aspartate To 10.1 g (75.1 mmol) of L-aspartic acid, 10.1 g (82.5 mmol) of 80% sulfuric acid and benzyl alcohol 23.9 ml
(231 mmol) was added, and the mixture was stirred at 70 ° C. After about 30 minutes, a homogeneous solution was obtained, but the solution was further stirred at the same temperature for 2 hours.
After the reaction, the mixture was concentrated under reduced pressure at the same temperature for 2 hours to remove water, and then the reaction mixture was poured into 50 ml of cold water containing 14 g of sodium hydrogencarbonate and sufficiently stirred. To this, 30 ml of ether was added, and the mixture was further stirred, crystals were taken, and the crude product was washed with cold water.
After drying, this was recrystallized with 15 times amount of water to obtain β-benzyl-
Acicular crystals of L-aspartate were obtained.

 Yield 43.4%. Melting point 216.3-217.2 ° C.

[Α] ▲ ²⁵ _D ▼ = + 28.4 ° (C = 0.50,1N-hydrochloric acid).

¹ H-NMR (D ₂ O) δppm: 3.1 (d, 2H, CH ₂ ), 4.1 (t, 1H, C
H), 5.2 (s, 2H , C 6 H 5 C H 2), 7.4 (broad, 5H, C 6 H 5).

IR (KBr) νcm ^-1 : 3400 (NH ₂ ), 1730 (C = O), 1500
(Phenyl), 1400 (CH ₂ ), 1220, 1160 (ester), 74
0,700 (phenyl).

(2) Synthesis of β-benzyl-L-malate 5 g (22.4 mmol) of β-benzyl-L-aspartate was dissolved in 67.5 ml (33.6 mmol) of 1N-sulfuric acid at 0 ° C. An aqueous solution of 2.4 g (33.6 mmol) of sodium nitrite was added dropwise thereto at the same temperature over 1 hour, and then stirred for 3 hours. 0.47 g (6.7 mmol) of sodium nitrite was further added to the reaction solution, and the mixture was allowed to stand at room temperature for one day and then extracted with ether to obtain a crude syrup. This was treated with activated carbon in methanol to obtain a colorless transparent syrup of β-benzyl-L-malate.

 Yield 94.7%.

¹ H-NMR and IR agreed with those obtained in Reference Example 1.

Reference Example 3. Synthesis of Malide Dibenzyl Ester In the presence of 0.12 g of zinc oxide, 5.9 g of β-benzyl-L-malate was dehydrated and condensed by heating under reduced pressure at 20 mmHg and 140 ° C. for 10 hours. After the reaction, zinc oxide was removed and the liquid was subjected to medium pressure liquid chromatography to separate the target product (developing solvent: n-hexane / ethyl acetate = 3/1 volume ratio). This was recrystallized three times with ethyl acetate to give colorless needle crystals of cyclic dimer malide dibenzyl ester.

 Yield 17%. Melting point 85.6-86.4 ° C.

 Rf: 0.59 (n-hexane / ethyl acetate = 3/1 volume ratio).

[Α] ▲ ²⁵ _D ▼: −0.80 ° (C = 2.00, methanol).

Elemental analysis: C ₂₂ H ₂₀ O ₈ Calculated (%) C: 64.07, H : 4.89 Found (%) C: 63.92, H : 4.92.

Mass spectrometry: m / e 412 (M ⁺ ).

¹ H-NMR (CD ₃ COCD ₃ ) δppm: 3.2 (d, 2H, CH ₂ ), 5.2 (s, 2
H, C ₆ H ₅ C H ₂ ), 6.8 (t, 1H, CH), 7.3 (broad, 5H, C ₆ H ₅ ).

IR (KBr) ν cm ^-1 : 1760 to 1740 (ester, C = O), 150
0 (phenyl), 1460, 1380 (CH ₂ ), 1290, 1260, 1230, 1150
(Ester), 750,700 (phenyl).

Reference Example 4 Synthesis of Malide Dibenzyl Ester 20. 11.9 g of β-benzyl-L-malate and 0.012 g of Sb ₂ O ₃ were added.
Dehydration condensation was performed by heating under reduced pressure at mmHg and 180 ° C. for 4 hours. After the reaction, the same treatment as in Reference Example 3 was carried out to prepare Reference Example 3.
The same quality of malide dibenzyl ester was obtained.

 Yield 6%.

Example 1. Synthesis of α-malic acid / lactic acid copolymer (1) Synthesis of β-benzylmalate / lactic acid copolymer Silanization of the inside of a polymerization tube using dichlorodimethylsilane,
After washing with dry toluene, it was thoroughly dried in a dryer at 120 ° C until just before use. 1.18 g (2.9 mmol) of malide dibenzyl ester and L-lactide were placed in this polymerization tube.
After adding 1.02 g (7.1 mmol) and 0.03 mol% of a tin octylate solution in toluene and performing sufficient nitrogen substitution, the toluene was completely removed under reduced pressure at room temperature to 50 ° C., and the tube was sealed. This was heated at 180 ° C. for 48 hours to perform ring-opening copolymerization. After the reaction, the reaction mixture was dissolved in 20 ml of dry acetone and treated with acetic anhydride to protect the polymer terminals,
While stirring, drop each drop into 600 ml of methanol,
A white precipitate of polymer was obtained.

Polymerization rate 29%. ¹ H-NMR or molar extinction coefficient of β-benzylmalate The molar fraction of β-benzyl maleate in the copolymer calculated from was 14%. _GPC 4.21 x 10 ⁴ .

¹ H-NMR (DMSO-d ₆ ) δppm: 1.3 (d, 3H, CH ₃ ), 3.1 (d, 2
H, CH ₂ ), 5.1 (s, 2H, C ₆ H ₅ C H ₂ ), 5.2 (t, 1H, C H -CH ₃ ), 6.7
~ 6.9 (t, 1H, C H CH ₂ CO), 7.3 (broad, 5H, C ₆ H ₅ ).

IR (KBr) ν cm ^-1 : 1740 (Ester, C = O), 1580, 1500
(Phenyl), 1450, 1380 (CH ₂ ), 1250, 1180 (ester), 750,700 (phenyl).

(2) Synthesis of α-malic acid / lactic acid copolymer β-benzylmalate / lactic acid copolymer obtained in (1)
62 g was dissolved in 5 ml of ethyl acetate, 0.18 g of palladium carbon (5%) was added thereto, and catalytic reduction was carried out at room temperature through hydrogen gas. After 12 hours, the debenzylation reaction was completed. After removing the palladium-carbon by passing the reaction solution, by concentrating the solution under reduced pressure,
A hygroscopic powdery target substance was quantitatively obtained.

The complete progress of the debenzylation reaction was confirmed by the disappearance of ¹ H-NMR absorption of 7.3 ppm (C ₆ H ₅ ) of the produced polymer.

¹ H-NMR (DMSO-d ₆ ) δppm: 1.3 (d, 3H, CH ₃ ), 3.0 (d, 2
H, CH ₂ ), 5.2 (t, 1H, C H -CH ₃ ), 5.5 (t, 1H, C H CH ₂ CO).

IR (KBr) ν cm ^-1 : 3400 (OH), 1750 to 1700 (ester, carboxylic acid, C = O), 1450, 1380 (CH ₂ ), 1250, 1150
(Ester), 1100 (OH).

Solubility: Soluble in dioxane, acetonitrile, chloroform, methylene chloride, toluene (high temperature), tetrahydrofuran (THF).

 GPC (THF; RI) molecular weight = 36300, dispersity = 2.2.

Example 2. Synthesis of α-malic acid / lactic acid copolymer (1) Synthesis of β-benzyl maleate / lactic acid copolymer In the presence of 0.12 mol% tin octylate, 1.18 g (2.9 mmol) of malide dibenzyl ester was prepared. ) And L-lactide 0.
42 g (2.9 mmol) of ring-opening copolymerization was carried out at 180 ° C. for 48 hours. After the reaction, the same treatment as in (1) of Example 1 was carried out to quantitatively obtain the desired product.

 Polymerization rate 18%.

21% molar fraction of β-benzyl maleate. _GPC 1.42 × 10 ⁴ .

(2) Synthesis of α-malic acid / lactic acid copolymer β-benzylmalate / lactic acid copolymer obtained in (1)
Using 62 g, the reaction and treatment were carried out in exactly the same manner as in (2) of Example 1 to quantitatively obtain a powder of α-malic acid / lactic acid copolymer.

 GPC (THF; RI) molecular weight = 11600, dispersity = 3.1.

Physical properties such as ¹ H-NMR, IR and solubility are the same as in Example 1.

Example 3. Synthesis of β-benzylmalate / lactic acid copolymer 1.18 g (2.9 mmol) of malide dibenzyl ester in the presence of 0.04 mol% di-n-butyltin dilauryl acid.
And L-lactide 1.02 g (7.1 mmol) were subjected to ring-opening copolymerization 20
It was carried out at 0 ° C for 48 hours. After the reaction, the same treatment as in (1) of Example 1 was carried out to obtain the desired product.

 Polymerization rate 23%.

 13% molar fraction of β-benzylmalate.

Example 4. Synthesis of β-benzylmalate / lactic acid copolymer Ring-opening of 1.18 g (2.9 mmol) of malide dibenzyl ester and 1.02 g (7.1 mmol) of L-lactide in the presence of 0.02 mol% of tetraphenyltin. The copolymerization was carried out at 180 ° C. for 24 hours. After the reaction, the same treatment as in (1) of Example 1 was carried out to obtain the desired product.

 Polymerization rate 9%.

 8% molar fraction of β-benzyl malate.

〔The invention's effect〕

As described above, the present invention provides a novel copolymer and a method for producing the same, and the copolymer of the present invention has a carboxyl group that can be chemically modified in the molecule and has a high molecular weight. In addition, it has a remarkable effect in that it can be expected to have a wide range of uses in the fields of medicine and medicine as a biodispersible polymer.

Claims (3)

[Claims] 1. A general formula [I] (In the formula, m and n each independently represent an integer of 2 or more.) A copolymer of α-malic acid and lactic acid having a molecular weight of 11,000 to 37,000. 2. The molar fraction (n / m + n) of α-malic acid is 0.0.
The copolymer according to claim 1, which is 5 to 0.25. 3. A compound represented by the general formula [I], which is produced by ring-opening copolymerization of malide dibenzyl ester and L-lactide, followed by debenzylation protection. (In the formula, m and n are the same as above.), And a method for producing a copolymer of α-malic acid and lactic acid having a molecular weight of 11,000 to 37,000.