JP3065384B2 - Method for producing lactide 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 lactide polymer with high catalytic efficiency.

[0002]

2. Description of the Related Art Polylactic acid, which is known as a biodegradable polymer which is easily degraded in the body of an organism, selectively transports the pharmaceutically active substance to an affected part in the living body, where the lactic acid is decomposed to thereby convert the pharmaceutically active substance. It is expected as a carrier for pharmaceuticals in a drug delivery system with sustained release.

[0003]

Such polylactic acid can be produced by ring-opening polymerization of lactide.
Copolymers obtained by copolymerizing lactide and lactone and introducing a molecular chain of a lactone-based polyester are also known [Journal of Polymer Science Polymer Letters
Edition 21 (1983) 593]. This lactide-lactone copolymer has the advantage that the rate of decomposition of the copolymer in vivo can be arbitrarily adjusted according to the ratio of lactone in the copolymer.

However, as a catalyst in the above polymerization process _{(n-C 4 H 9 O} ) uses a ₄ Al ₂ O ₂ Zn, fewer product molecules of the copolymer per catalyst molecule,
There was a problem that the catalyst efficiency was poor.

There is also a report that a lactone or an epoxide is polymerized in the presence of a porphyrin aluminum complex, and a lactide is polymerized with the obtained polymer to obtain a block copolymer (Japanese Patent Laid-Open No. 2-84431). However, even in this method, at present, there is a problem that the produced polyol is colored.

[0006]

The present inventors have conducted research on a method for obtaining a lactide-based polymer with high catalytic efficiency. As a result, the present inventors have achieved the above object by using a double metal cyanide complex catalyst as a catalyst. Moreover, it has been found that a polymer having a narrow molecular weight distribution (ie, a value of weight average molecular weight / number average molecular weight is small) can be obtained.

Accordingly, the present invention is the presence of a double metal cyanide complex catalyst, a hydroxy compound having at least one hydroxyl group, characterized in that the ring-opening polymerization of lactide de The method of lactide polymer It is.

The present invention is also the presence of a double metal cyanide complex catalyst, a hydroxy compound having at least one hydroxyl group, that the ring-opening polymerization of lactide de及 beauty other ring-opening polymerizable cyclic monomer A method for producing a lactide-based polymer, which is a feature.

The invention or selecting various hydroxy compounds is the initiator, further, the type and copolymerization ratio of the ring-opening polymerizable cyclic monomer or adjusted or the structure of such a block copolymer chain or a random copolymer chain By doing so, a lactide-based copolymer capable of arbitrarily controlling the decomposition rate in vivo can be produced with high catalytic efficiency.

[0010] as a lactide de in the present invention, D- lactide, it can be mentioned L- lactide, and DL- lactide like. In the present invention, lactide is 2,5-
Dioxo-3,6-dimethyl-1,4-dioxane
U.

[0011] monoepoxides of 2 or more carbon atoms as another ring-opening polymerization of cyclic monomers in the present invention, but also the (but excluding lactide) cyclic ester and the like, but not limited to.

As the monoepoxides having 2 or more carbon atoms used in the present invention, for example, ethylene oxide, propylene oxide, 1,2-butylene oxide, 2,3-butylene oxide, epichlorohydrin, epibromohydrin and the like are preferable. Most preferably, it is propylene oxide.

In the present invention, the cyclic esters (provided that
(Excluding citides) include β-propiolactone, β-
Butyrolactone, γ-butyrolactone, 2 -oxo-
1,4-dioxane, .gamma.-valerolactone, .epsilon.-caprolactone, pivalolactone, alpha, alpha-diethylpropiolactone, 2,5-dioxomorpholine, ethylene carbonate, ethylene oxalate.

Further, there may be mentioned intermolecular cyclic diesters of glycolic acid, α-hydroxybutyric acid, α-hydroxyvaleric acid, α-hydroxyisovaleric acid, hydroxycaproic acid and 2-hydroxyisocaproic acid. Preferred are lactones, and ε-caprolactone is most preferred.

Hereinafter, the present invention will be described in more detail. The double metal cyanide complex in the present invention is considered to have a structure represented by the following general formula (1) as shown in U.S. Pat. No. 3,278,457-9.

M ¹ _a [M ² _x (CN) _y ] _b (H ₂ O) _c R _d (1) where M ¹ is Zn (II), Fe (II), Fe (III), Co
(II), Ni (II), Al (III), Sr (II), Mn (II), Cr
(III), Cu (II), Sn (II), Pb (II), Mo (IV), M
o (VI), W (IV), W (VI), etc., where M ² is Fe (II),
Fe (III), Co (II), Co (III), Cr (II), Cr (I
II), Mn (II), Mn (III), Ni (II), V (IV), V
And the like (V), R is an organic ligand, a, b, x 及 <br/> beauty y is a positive integer that varies by coordination number and valence of the metal, c 及 beauty d is It is a positive number that depends on the coordination number to the metal.

In the general formula (1), M ¹ is preferably Zn (II), and M ² is Fe (II), Fe (III), Co (II) or Co (II).
(III) and the like are preferred. As the organic ligand, for example, ketone, ether, aldehyde, ester, alcohol,
Amides and the like. The composite metal cyanide complex represented by the general formula (1) includes a metal salt M ¹ _Xa (M ¹ and a are the same as described above, X is an anion forming a salt with M ¹ ) and polycyano metallate (salt) Z _e [M ² _x (CN) _y ] _f (M ² , x, and y are the same as above. Z is hydrogen, an alkali metal, an alkaline earth metal, or the like, and e and f are valences of Z and M ² . and each of an aqueous solution of a positive integer) determined by the coordination number or by mixing a solution of a mixed solvent of water and an organic solvent, after contacting the organic ligand R to the double metal cyanide obtained extra It is produced by removing the solvent and the organic ligand R.

Polycyanometallate (salt) _Ze [M ² _x (C
In N) _y ] _f , Z can use various metals including hydrogen and alkali metals, but lithium salts, sodium salts, potassium salts, magnesium salts, and calcium salts are preferred. Particularly preferred are ordinary alkali metal salts, ie, sodium and potassium salts.

[0019] Lactide system in the present invention polymers are prepared by reacting in the presence of a catalyst in a mixture of hydroxy compounds having at least one hydroxyl group and easy <br/> Ji de. It is also possible to carry out the gradual addition reaction lactide de the reaction system.

[0020] Lactide polymers can be prepared by reacting in the presence of a catalyst to a mixture of hydroxy compounds having a lactide de, other ring-opening polymerizable cyclic monomer and at least one hydroxyl group. Further, the reaction may be carried out by gradually adding a mixture of lactide de and other ring-opening polymerizable cyclic monomer to the reaction system. Furthermore, the reaction can also be carried out while adding in sequence the lactide de and other ring-opening polymerizable cyclic monomer.

The reaction takes place at room temperature, but if necessary,
The reaction heating or may be cooled. Reaction temperature is 0
The temperature is preferably in the range of 150C to 150C.

The amount of the catalyst used is not particularly limited, but is suitably about 1 to 5000 ppm, more preferably 100 to 1500 ppm, based on the initiator used.
The catalyst may be introduced into the reaction system in a lump at first, or may be divided and introduced sequentially.

The hydroxy compound having at least one hydroxyl group in the present invention is preferably, for example, a polyhydroxy compound having 2 to 8 hydroxyl groups. Examples of the polyhydroxy compound include dihydric alcohols such as ethylene glycol and propylene glycol, trihydric alcohols such as glycerin, trimethylolpropane, and hexanetriol; There are alcohols such as alcohol.

Also, polyesters and polyetheresters obtained by reacting a cyclic ester such as polyethers or lactone having a lower molecular weight than the target product obtained by reacting a monoepoxide such as an alkylene oxide with these alcohols. Can also be used. Further, polyetheresters obtained by reacting a monoepoxide with a polycarboxylic anhydride may be used.

Further, bisphenol A, resole, compounds having a phenolic hydroxyl group and methylol group such as a novolac, ethanolamine, compounds having a hydroxyl group and other active hydrogen such as diethanolamine, 及 Beauty reaction monoepoxide such as these alkylene oxides There are polyethers having a lower molecular weight than the target product obtained by the reaction.

Further, there are polyethers having a lower molecular weight than the target product obtained by reacting a monoamine or polyamine having at least two hydrogen atoms bonded to a nitrogen atom with a monoepoxide such as an alkylene oxide. In addition, polyester polyols, phosphoric acid and derivatives thereof, and other polyhydroxy compounds can also be used. These polyhydroxy compounds may be used in combination of two or more.

[0027] The present invention is also applicable to a method for producing a lactide-de and other ring-opening polymerizable cyclic monomer and by ring-opening reaction lactide polymer of that to a monovalent hydroxy compound.

[0028] The monovalent hydroxy compound, if example embodiment, methanol, ethanol, butanol, hexanol,
Other monools, phenols, phenol derivatives such as alkyl-substituted phenols, and the like. Furthermore, polyethers and polyesters having a lower molecular weight than the target product obtained by reacting these with a monoepoxide such as an alkylene oxide or a cyclic ester such as a lactone,
Polyetheresters obtained by reacting monoepoxides with polycarboxylic anhydrides can also be used.

Further, one hydrogen atom bonded to a nitrogen atom
There are polyethers having a lower molecular weight than a target product obtained by reacting a monoamine or polyamine having one with a monoepoxide such as an alkylene oxide.

In the production of hydroxy compounds such as the above polyethers, polyether esters and polyesters, double metal cyanide complex catalysts can be used. However, the use of this catalyst is not limited.

[0031] The amount of lactide de can be arbitrarily selected in consideration of degradation in vivo of the desired polymer. The proportion of repeating units based on lactide in the lactide-based polymer is based on the cyclic monomer (excluding lactide).
Preferably at least 5 wt% relative to the total of the repeating units based on Ku), more preferably 10 wt%, 30 wt%
Is particularly preferred.

[0032] When using only <br/> lactide de as monomers to be polymerized to the hydroxy compound having at least one hydroxyl group in the present invention, the main chain of the lactide ring-opening
It is the unit only Tona Ru polymer production, when using the lactide-de及 beauty other ring-opening polymerizable cyclic monomer is a copolymer main chain is a lactide copolymer chains are produced. Copolymer of the lactide, block copolymer, not good either, such as a random copolymer.

In the case of producing a block copolymer of lactide, by repeating the polymerization of lactide de or other ring-opening polymerizable cyclic monomer, A-B-A type, A-B-A-
B type, any binary or more block copolymers such as A-B-C type are obtained.

[0034] By the method of the present invention, if example embodiment, poly lacto <br/> emissions - polylactide, poly epoxide - polylactide, Po
Li epoxide - polylactide - poly epoxides, poly La <br/> lactone - polylactide - diblock copolymer polylactone such as poly epoxide - polylactone - poly lactide <br/> de, polylactone - polylactide - it can be obtained triblock copolymer of poly epoxides.

In the case of producing a lactide polymer, a monomer ratio of preferred cyclic monomers is lactide de 1 0～90Wt
%, Monoepoxides 0-90 wt%, cyclic esters
(Excluding lactide) and 0~50wt%, particularly <br/> lactide de 3 0~90wt%, monoepoxides 0-50
wt%, cyclic esters (excluding lactide) 0
A ratio of 50% by weight is preferred.

According to the method of the present invention, a lactide polymer having a small weight average molecular weight / number average molecular weight (M _w / M _n );
That is, a polymer having _Mw / _Mn of 1.50 or less can be obtained.

On the other hand, regarding the removal of the double metal cyanide complex catalyst after the completion of the polymerization reaction, an alkali such as ammonia is added to decompose (ionize) the double metal cyanide complex.
After that, a complex is formed by adding a chelating agent, and this is easily removed by an operation of removing the complex by filtration using an adsorbent (JP-A-2-289617, JP-A-2-2828).
9618). However, the method of removing the double metal cyanide complex is not limited to these.

[0038]

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

Example 1 Polyoxypropylene triol 20 having a molecular weight of 1,000
g, DL-lactide 15 g, propylene oxide 5 g
Then, 0.010 g of a double metal cyanide complex catalyst (500 ppm based on the initiator triol) was charged into the reactor, and reacted at 120 ° C. for 4 hours in a nitrogen atmosphere. The obtained polymer was transparent.

The number average molecular weight (M _n ) of the polymer was found to be 2,000 and M _w / M _n was found to be 1.02 by gel permeation chromatography (hereinafter referred to as GPC). . Further, no unreacted monomer was detected by GPC and infrared absorption spectrum measurement.

Comparative Example 1 Using the same reaction as in Example 1 as a catalyst, (nC ₄ H ₉ O )
_The test was performed using ₄ Al ₂ O ₂ Zn. The obtained reaction product was cloudy, and GPC, infrared absorption spectrum, and the like were measured. As a result, no monomer was added to the initiator polyoxypropylene triol, and the monomers were polymerized.
To become poly Ma has been generated has been confirmed. It was also found that about 20% of unreacted monomer was present.

Example 2 Polyoxypropylene triol 1.0 having a molecular weight of 300
g and DL-lactide 35 g, ε-caprolactone 2.0
g, propylene oxide 13 g and double metal cyanide complex catalyst 0.0010 g (100
0 ppm) was charged into a reactor under a nitrogen atmosphere.
The reaction was performed at 4 ° C. for 4 hours. GPC measurement of the obtained polymer showed that _Mn of the polymer was 15000 and _Mw / _Mn was 1.20.

Example 3 Polyoxypropylene triol 1.0 having a molecular weight of 300
g and 50 g of DL-lactide, and 0.0010 g of a double metal cyanide complex catalyst (1000 g for the initiator).
ppm) into a reactor at 125 ° C. in a nitrogen atmosphere.
For 4 hours. GPC measurement of the obtained polymer showed that _Mn of the polymer was 14000 and _Mw / _Mn was 1.18. This polymer was prepared in Example 2
Was higher in viscosity and hardness than the polymer obtained in 1.

Comparative Example 2 Using the same reaction as in Example 3 as a catalyst, (n-C ₄ H ₉ O )
_The test was performed using ₄ Al ₂ O ₂ Zn. G of the obtained polymer
According to the PC measurement, _Mn of the polymer was 7000, and 30%
Some unreacted monomer was detected.

Example 4 5.0 g of polyoxypropylene diol having a molecular weight of 700
And 10.5 g of D-lactide and ε-caprolactone
0 g and double metal cyanide complex catalyst 0.0025 g
(500 ppm with respect to the initiator) was charged into the reactor, and reacted at 120 ° C. for 4.5 hours in a nitrogen atmosphere. The obtained polymer was treated with an ammonia buffer (NH ₃ —CH ₃ COO) containing a chelating agent (ethylenediaminetetraacetic acid).
After mixing and stirring with NH ₄ ), the mixture was dehydrated, an adsorbent was added, and the mixture was filtered. When the Zn (II) content of the obtained purified product was examined, Zn (II) derived from the catalyst was not detected.

Comparative Example 3 The same reaction as in Example 4 was carried out using a porphyrin catalyst (tetraphenylporphyrin aluminum chloride). The resulting polymer was remarkably colored due to the porphyrin catalyst. It was difficult to quantitatively remove the porphyrin complex contained in the polymer, and large absorption in the visible light region could not be completely eliminated.

[0047]

According to the method of the present invention, a lactide polymer having a narrow molecular weight distribution can be obtained. In addition, lactide de,
Monoepoxides and cyclic esters (but lactide
(Excluding) can be freely changed, so that the balance between hydrophilicity and hydrophobicity required for the biodegradable polymer and the rate of degradation in the living body can be freely controlled. Moreover, it is possible to obtain a good efficiency of such polymers.

──────────────────────────────────────────────────の Continued on the front page (58) Field surveyed (Int.Cl. ⁷ , DB name) C08G 63/08 C08G 63/82-63/87

Claims (5)

(57) [Claims] 1. A presence of a double metal cyanide complex catalyst, a hydroxy compound having at least one hydroxyl group, characterized in that the ring-opening polymerization of La <br/> Chi de, production of lactide polymer Method. Wherein the presence of a double metal cyanide complex catalyst, a hydroxy compound having at least one hydroxyl group, thereby opening polymerization La <br/> Chi de及 beauty other ring-opening polymerizable cyclic monomer A method for producing a lactide polymer. 3. Other ring-opening polymerizable cyclic monomer is 2 or more carbon atoms of monoepoxides and cyclic esters (except Lac
3. The production method according to claim 2 , wherein the production method is at least one member selected from the group consisting of : 4. lactide de is D- lactide is at least one selected from L- lactide and DL- lactide,
The method according to claim 1 , 2, or 3 . 5. lactide de, monoepoxides, and cyclic esters (but excluding lactide) is monomer ratio,
Lactide de 1 0~90wt%, monoepoxides 0-90
wt% and cyclic esters (excluding lactide) 0
The method according to claim 3 or 4, wherein the method is used at a rate of ５０50 wt%.