JP3371592B2 - Method for producing lactic acid polymer - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a lactic acid polymer useful as a biodegradable polymer as a substitute for medical materials and general-purpose resins.

[0002]

2. Description of the Related Art Since lactic acid polymers have a biodegradable function, they have been attracting attention in recent years as a drug sustained release system material, a medical material or a general-purpose resin substitute. Lactic acid polymers with a low molecular weight of about 0.2 dl / g or less are produced by polycondensation of lactic acid, and because of their fast biodegradation rate, they are used as materials for sustained drug release systems. On the other hand, those with a relatively high molecular weight with an intrinsic viscosity of about 0.4 dl / g or more are usually produced by ring-opening polymerization of lactide, and their biodegradation rate is moderately slow and their strength is high. Development is progressing as medical materials such as materials. Examples of ring-opening polymerization catalysts for lactide include T. Tsuruta et al., Makr.
omol.Chem., 75,211 (1964) contains diethylzinc-water or diethylcadmium in HR Richeldorf et al. Macromole.
cules, 21, 286 (1988) contains aluminum triisopropoxide, titanium tetrabutoxide, zirconium tetrapropoxide or tributyltin methoxide, R.
K. Kulkarni et al. J. Biomed. Mater. Res., 5,169 (1971) contains tetraphenyltin, and HRKricheldorf et al. JMSPure.
Appl. Chem., A30, 441 (1993) shows that lead oxide, zinc stearate or bismuth 2-ethylhexanoate are
eldorf et al. Makromol.Chem., Macromol.Symp., 73,47 (1993)
Although potassium alcoholate and the like have been reported in the above, none of the above catalysts except tin compounds gives a low polymer having an intrinsic viscosity of 0.35 dl / g or less. For tin compound catalysts, see I. Horacek et al., J. Appl. Polym. Sci., 50, 1 (199).
It has been reported in 3) that the SnCl ₂ 2H ₂ O catalyst gives high polymers with an intrinsic viscosity of 3.43 to 6.20 dl / g. Also, K. Chujo et al Ma
kromol.Chem., 100, 262 (1967) carried out a glycolide-lactide copolymerization reaction with an antimony fluoride catalyst to give a lactide.
It was reported that a copolymer with a reduced specific viscosity of 1.52 dl / g was obtained with a 5 mol% copolymer, but it was also shown that when the lactide was increased to 10 mol%, the reduced specific viscosity was reduced to 0.94 dl / g. ing. It is said that stanas octanoate catalyst is industrially used to obtain a high polymer. According to this technical background, the catalysts that provide lactic acid polymers having an effective strength as a structural material and an appropriate biodegradation rate and an intrinsic viscosity of 0.4 dl / g or more are limited to tin-based catalysts. However, tin compounds are not always safe for the human body, and especially when used in large amounts, such as bone implants, which are currently being strongly developed, such as fracture-implant materials, in terms of safety against residual catalyst. Was required.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a high molecular weight lactic acid by a catalyst system including elements such as tin compounds, which do not contain harmful metals such as antimony, lead or bismuth, and which are expected to be safe. To obtain a polymer.

[0004]

[Means for Solving the Problems] As a result of intensive studies for solving the above problems, the present inventors succeeded in obtaining a lactic acid polymer having an intrinsic viscosity of 0.4 to 3 dl / g by using the following catalyst. The present invention was completed. That is, according to the present invention, when a ring-opening polymerization of lactide is carried out to produce a high molecular weight polymer, a catalyst obtained by reacting a mixture of three components of component A) aluminum alkoxide, silicon halide and phosphoric ester is used. Condensate and B component) A composition comprising an alkyl group having 1 to 4 carbon atoms of trialkylaluminum and / or dialkylaluminum chloride, wherein the weight ratio of aluminum in the B component to the weight of the A component is 0.02 to 0.35. A method for producing a lactic acid polymer, which is characterized in that it is used.

The A component of the catalyst in the present invention is known to the applicant.
Such Japanese Patent Publication No. 49-11639 or Japanese Patent Publication No. 52-
Based on the catalyst described in 21039.
It Aluminum in the A component of the catalyst of the present invention
Examples of alkoxides include Al (OCH₃)₃, Al (OC₂H_Five)₃,
Al (O-nC₃H₇)₃, Al (O-isoC₃H₇)₃, Al (O-nC_FourH₉)₃, Al (O-i
soC_FourH₉)₃, Al (O-tC_FourH₉)₃, Al (O-secC_FourH₉)₃, Al (O-nC_FiveH
₁₁)₃, Al (O-isoC_FiveH ₁₁)₃, Al (O-neoC_FiveH₁₁)₃, Al (O-tC
_FiveH₁₁)₃, Al (O-nC₆H₁₃)₃, Al (O-isoC₆H₁₃)₃Carbon number
 Aluminum alloy consisting of 1 to 6 alkyl alkoxide
Real alkoxide, Al (OCH₂C₆H_Five)₃7 carbon number represented by
Aluminum thoria consisting of ~ 8 aralkyl oxides
Ralkyl oxide, Al (OC₂H_Five)₂Cl, Al (O-nC₃H₇)₂Cl, Al
(O-isoC₃H₇)₂Cl, Al (O-nC_FourH₉)₂Cl, etc., with 1 to 4 carbon atoms
Aluminum dialkoxide chloride made of lucoxide
De, Al (O-C₂H_Five) Cl₂, Al (O-isoC₃H₇) Cl₂, Al (O-nC_FourH₉) C
l₂Aluminum consisting of alkoxides with 1 to 4 carbon atoms
Mualkoxide dichloride and the like. Al (O-isoC₃
H₇)₃, Al (O-nC_FourH₉)₃Etc. are preferred.

Examples of the silicon halide in the component A of the same polymerization catalyst include SiF ₄ , SiCl ₄ , SiBr ₄ and SiI ₄ , and SiCl ₄ is preferred.

Phosphorus ester in component A of the same polymerization catalyst
As for tell, (CH₃)₃PO_Four, (C₂H_Five) ₃PO_Four, (C₃H₇)₃PO_Four,
(C_FourH₉)₃PO_Four, (C_FiveH₁₁)₃PO_Four, (C₆H₁₃)₃PO_Four, (C₇H₁₅)₃P
O_Four, (C₈H₁₇)₃PO_FourSuch as an alkyl group having 1 to 8 carbon atoms
Phosphoric acid trialkyl ester, (CH₂= CHCH₂)₃PO_Four,
[CH₂= C (CH₃) CH₂]₃PO_FourPhosphoric acid consisting of alkenyl groups such as
Trialkenyl ester, (C₆H_FiveCH₂)₃PO_FourRepresented by
Trial phosphate consisting of aralkyl group having 7 to 8 carbon atoms
Killester, (C₆H_Five)₃PO_Four, (CH₃C₆H_Four)₃PO_FourCarbon number
 A group consisting of 6 to 7 aryl or alkylaryl groups.
Acid triaryl or trialkylaryl ester
Le, (Cl₂CH₂CH₂)₃PO_FourHalo having 2 to 3 carbon atoms, represented by
Phosphoric acid trihaloalkyl ester consisting of an alkyl group,
(CH₃)₂HPO_Four, (C₂H_Five)₂HPO_Four, (C₃H₇)₂HPO_Four, (C_FourH₉)₂HPO
_Four, (C_FiveH₁₁)₂HPO_Four, (C₆H₁₃)₂HPO_Four, (C ₇H₁₅)₂HPO_Four, (C₈H
₁₇)₂HPO_FourPhosphoric acid consisting of an alkyl group having 1 to 8 carbon atoms
Hydrogen dialkyl ester, (C₆H_FiveCH₂)₂HPO_FourRepresented by
Diara hydrogen phosphate consisting of an aralkyl group having 7 to 8 carbon atoms
Luquil ester, (C₆H_Five)₂HPO_Four, (CH₃C₆H_Four)₂HPO_FourCharcoal
Consist of an aryl or alkylaryl group with a prime number of 6 to 7
Hydrogen phosphate diaryl or dialkylaryl ether
Stell, (CH₂= CHCH₂)₂HPO_Four, [CH₂= C (CH₃) CH₂]₂HPO_FourEtc.
Dialkenyl hydrogen phosphate ester consisting of alkenyl groups
Le, (CH₃)₂(CH₃CO) PO_Four, (C₂H_Five)₂(CH₃CO) PO_Four, (C₃H₇)₂
(CH₃CO) PO_Four, (C_FourH₉)₂(CH₃CO) PO_Four, (C_FiveH₁₁) PO_Four, (C
₆H₁₃)₂(CH₃CO) PO_Four, (C₇H₁₅)₂(CH₃CO) PO_Four, (C₈H₁₇)₂(CH₃
CO) PO_FourDiphosphates consisting of alkyl groups having 1 to 8 carbon atoms
Alkyl ester acetate, (CH₃)_FourP₂O₇, (C₂H_Five)_FourP₂
O₇, (C₃H₇)_FourP₂O₇, (C_FourH₉)_FourP₂O₇, (C_FiveH₁₁)_FourP₂O₇, (C₆H
₁₃)_FourP₂O₇, (C₇H₁₅)_FourP₂O₇, (C₈H₁₇)_FourP₂O₇Carbon number of 1 ~
 Tetraalkyl pyrophosphate consisting of 8 alkyl groups
Tell etc. are mentioned.

To prepare the component A of the catalyst of the present invention, the molar ratio of aluminum alkoxide to silicon halide is usually in the range of 10: 1 to 1:10, preferably 3: 1.
A range of ~ 1: 3 is selected. The molar ratio of phosphoric acid ester to the total of aluminum alkoxide and silicon halide is 5: 1 to 1: 5, preferably 4: 1 to
A range of 1: 2 is selected. The temperature of the heat condensation of these three components is 80 to 300 ° C, usually 100 to 200 ° C, and more preferably
110-180 ℃. Although the carbon content of the condensate decreases as the heat condensation progresses, the component A of the catalyst that can be used in the present invention preferably has a carbon content of 15 to 35% by weight.

Examples of the trialkylaluminum or dialkylaluminum chloride in the component B of the catalyst of the present invention include Al (CH ₃ ) ₃ , Al (C ₂ H ₅ ) ₃ , Al (C ₃ H ₇ ) ₃ ,
_{Al (C 4 H 9) 3} , Al (CH 3) 2 Cl, Al (C 2 H 5) 2 Cl, Al (C 3 H 7) 2 C
l, Al (C ₄ H ₉ ) ₂ Cl and the like.

The weight ratio of aluminum in component B to the weight of component A ranges from 0.02 to 0.35. This ratio is 0.02
If it is less than 1, the polymer yield is low, and only those having an intrinsic viscosity of less than 0.4 dl / g can be obtained. If this ratio exceeds 0.35, the polymer yield tends to increase, but the intrinsic viscosity is 0.4 dl.
Only less than / g can be obtained. The order of charging the components A, B and the lactide monomer or the solution thereof is not particularly limited.

The lactide polymerization reaction can be carried out by using the catalyst composed of the above-mentioned components A and B. The polymerization reaction is usually carried out in the presence or absence of a solvent at 10
~ 300 ℃, preferably 30 ~ 250 ℃, more preferably 40 ~
It can be carried out by contacting the catalyst with lactide in the temperature range of 230 ° C. As the solvent, aromatic hydrocarbons such as benzene, toluene, xylene, chloroform, dichloromethane, 1,2-dichloroethane, 1,1-dichloroethane, 1,2-dichloropropane, 1,2,3-trichloropropane, 1, Examples thereof include halogenated hydrocarbons such as 3-dichloropropene, chlorobenzene, and dichlorobenzene, heteroatom-containing hydrocarbons such as dimethylformamide and dimethylsulfoxide, and mixed solvents of two or more selected from them.

In the present invention, lactide which can be used for polymerization includes DD-lactide, LL-lactide and mesoDL.
-Lactide, racemic DL-lactide and a mixture of two or more selected from these.

The amount of catalyst used is 0.01 per 100 g of lactide.
A range of up to 5.00 g, preferably 0.03 to 2.00 g is suitable. It is desirable that the water content in the polymerization reaction system be as low as possible. Further, the reaction is usually carried out under conditions such as standing, stirring or shaking.

[0014]

The present invention will be described in more detail with reference to the following examples. The intrinsic viscosity was determined by extrapolating the reduced viscosity measured at 25 ° C. with 0.1, 0.2 and 0.4 dl / g chloroform solutions to a concentration of 0. (Reference example) (Production of component A of catalyst) 210 g of aluminum isopropoxide, 171 g of silicon tetrachloride and 276 g of tributyl phosphate were placed in a flask equipped with a stirrer, a thermometer and a distillation column, and nitrogen gas was passed to prevent moisture absorption. While heating while stirring, the temperature was raised to 120 to 165 ° C in about 40 minutes. During this period, gaseous substances and about 240 g of liquid substances were distilled out. The residual material in the container was about 330 g. After the residue was cooled, hexane was added and washing with gradient was repeated twice, and then dried to avoid moisture absorption to obtain a condensation product (component A). According to elemental analysis, the carbon content of this product is 23
% By weight.

Example 1 38 mg of the condensation product (component A) obtained in Reference Example was charged in a glass ampoule having an internal volume of 50 ml, heated under reduced pressure at 100 ° C. for 1 hour and cooled, and the inside was kept under a nitrogen atmosphere. To do. Separately, molecular sieve 4A was added, and 15 g of a dry 30% by weight dichloromethane solution of L-lactide and 38 mg of triethylaluminum diluted to 3% by weight with hexane were put and sealed. After reacting at 60 ° C for 8 days with shaking, the mixture was opened, and the contents were diluted with chloroform to reduce the viscosity. This was added to methanol, and the precipitate was washed well with methanol and collected by filtration. After drying at ℃, 2.74g of lactic acid polymer was obtained (yield 60%). The obtained lactic acid polymer has an intrinsic viscosity of 0.42 dl
It was / g.

Examples 2 to 16 A lactic acid polymer was obtained in the same manner as in Example 1 except that the catalyst, its amount, solvent, reaction temperature and reaction time shown in Table 1 were used. The yield and intrinsic viscosity of the obtained polymer are shown in Table 1.

Comparative Examples 1 to 4 A lactic acid polymer was obtained in the same manner as in Example 1 except that the catalyst, its amount, solvent, reaction temperature and reaction time shown in Table 1 were used. . The yield and intrinsic viscosity of the obtained polymer are shown in Table 1.

[0018]

[Table 1]

In Table 1, the numerical values 1) and 2) are the weight% with respect to the solution (30% by weight of lactide), 2) the type of component B ... * Diethylaluminum chloride,
** Tributylaluminum, others triethylaluminum 3) Weight ratio of aluminum in B component to A component weight 4) DCM; dichloromethane, DCE; 1,2-dichloroethane, DCB; O-dichlorobenzene It can be seen that a high polymer of lactide can be obtained by using the components A and B as catalysts in a specific ratio.

[0020]

INDUSTRIAL APPLICABILITY According to the present invention, the use of a catalyst containing no tin-based compound, which has a safety problem, has an intrinsic viscosity of about 0.4 to 4 which is useful as a biodegradable polymer as a substitute for a medical material or a general-purpose resin. A high molecular weight lactic acid polymer of 3 dl / g can be produced.

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Claims (3)

(57) [Claims] 1. Heating obtained by reacting a mixture of three components of component A) aluminum alkoxide, silicon halide and phosphoric acid ester as a catalyst in the ring-opening polymerization of lactide to produce a high molecular weight polymer. Condensate and B component) A composition comprising a trialkylaluminum having 1 to 4 carbon atoms of an alkyl group and / or a dialkylaluminum chloride and having a weight ratio of aluminum in the B component to the weight of the A component of 0.02 to 0.35 is used. A method for producing a lactic acid polymer, which comprises: 2. The method for producing a lactic acid polymer according to claim 1, wherein the carbon content of the component A is 15 to 35% by weight. 3. The method for producing a lactic acid polymer according to claim 1, wherein a heat condensate obtained by reacting a mixture of three components of aluminum propoxide, silicon tetrachloride and tributyl phosphate is used as the component A.