JP2575199B2 - Method for producing carbonate copolymer - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for producing a carbonate copolymer in which repeating units based on alkylene oxide, epihalohydrin and carbon dioxide are randomly arranged.

(Problems to be Solved by the Prior Art and the Invention) Polypropylene carbonate obtained by polymerizing propylene oxide and carbon dioxide using an organic zinc-based catalyst has a carbonate bond in a molecular chain and is biodegradable. And has thermal decomposition properties. For this reason, the above-mentioned polypropylene carbonate is considered to be used as a binder for preparing a ceramic green sheet or as a carrier for a drug in a drug delivery system.

Pharmaceutical carriers in drug delivery systems are preferably capable of introducing pharmacologically active substances or disease-directing substances by chemical bonding and controlling the amount of introduction, and therefore, any chemically active functional group in the molecular chain may be added. It is desirable to contain them in proportions.

(Means for Solving the Problems) The present inventor has already succeeded in producing a polymer having a chloromethyl group based on epichlorohydrin in the molecular chain by copolymerizing epichlorohydrin and carbon dioxide (Japanese Patent Application No. Sho 63). No. 185394).

Therefore, for the purpose of introducing a repeating unit based on epihalohydrin into the molecular chain of the above-mentioned polypropylene carbonate and imparting a chemically active halomethyl group, it is intended to add epihalohydrin to alkylene oxide and carbon dioxide to copolymerize. Tried. As a result, a copolymer in which repeating units based on alkylene oxide, epihalohydrin and carbon dioxide are randomly arranged can be obtained, and the composition ratio of the repeating units based on the above three components can be easily changed. The present inventors have found that the molecular weight distribution of the copolymer is narrow, and that a copolymer suitable as a carrier for a drug or the like in the aforementioned drug delivery system can be obtained, thereby completing the present invention.

That is, the present invention is represented by the following formulas [A], [B] and [C], characterized in that alkylene oxide, epihalohydrin and carbon dioxide are polymerized in the presence of a porphyrin aluminum complex and an active hydrogen compound. The sum of mol% of repeating units is 100, and a) Formula [A] (Where R is a hydrogen atom or an alkyl group) 5 to 70 mol% of a repeating unit represented by the following formula: a) Formula [B] (Where X is a halogen atom) 5 to 70 mol% of a repeating unit represented by the following formula: and c) a formula [C] Are randomly arranged (however, two or more repeating units represented by the formula [C] are not consecutively arranged), and the number average molecular weight is 500 to 50,000. This is a method for producing a carbonate copolymer.

In the formula [A], the alkyl group represented by R is not particularly limited in the number of carbon atoms, but from the viewpoint of polymerizability, has 1 to 1 carbon atoms.
It is preferably 4. In the formula [B], the halogen atom represented by X is preferably chlorine, bromine or iodine.

The ratio of the repeating units represented by the formulas [A], [B] and [C] is such that the repeating units represented by the formulas [A] and [B] are 5 to 70 mol%, respectively, and the formula [C Is 25 to 50 mol%. The higher the proportion of the repeating unit represented by the formula [B], the greater the number of chemically active functional groups and the easier it is to chemically modify the functional groups. There may be problems. Therefore, the content of the repeating unit represented by the formula [B] is preferably 10 to 50 mol%, more preferably 15 to 40 mol%. The repeating unit represented by the formula [C] can be contained in the carbonate copolymer at a maximum of 50 mol%. When the proportion of the repeating unit represented by the formula [C] is increased, the biodegradability of the obtained carbonate copolymer is improved. Therefore, in the present invention, 30 to 50 mol%, and more preferably 40 to 50 mol%. It is preferably within the range.

In the carbonate copolymer obtained by the production method of the present invention, the repeating units represented by the above formulas [A], [B] and [C] are randomly arranged. However, since two or more repeating units represented by the formula [C] cannot be consecutively arranged due to chemical bonding, the repeating unit represented by the formula [C] must have the formula [A] or It is occupied by the repeating unit represented by [B]. Therefore, the repeating unit represented by the formula [C] is always d) the formula [D] (However, R is a hydrogen atom or an alkyl group.) E) Formula [E] (However, X is a halogen atom.) Each repeating unit represented by the following formula is contained in the molecular chain of the carbonate copolymer.

The carbonate copolymer obtained by the production method of the present invention usually has a number average molecular weight in the range of 500 to 50,000. When the carbonate copolymer obtained by the production method of the present invention is used as a carrier for a drug in the above-mentioned drug delivery system, the number average molecular weight is preferably in the range of 1,000 to 20,000 from the viewpoint of moldability.

Further, the carbonate copolymer obtained by the production method of the present invention has a small molecular weight distribution represented by the ratio of the weight average molecular weight (w) to the number average molecular weight (n), usually w / n ≦ 1.5, Furthermore, w / n ≦ 1.3 can be satisfied. As described above, the carbonate copolymer obtained by the production method of the present invention can reduce the molecular weight dependency in a living body due to a small molecular weight distribution,
It can be said that it is more suitable as a carrier for a drug in the drug delivery system described above.

One end of the terminal group of the carbonate copolymer obtained by the production method of the present invention is a residue obtained by removing a hydrogen atom from an active hydrogen compound, and the other end is a hydroxyl group.
Therefore, when a compound having a double bond in the molecule is selected as the active hydrogen compound, a carbonate copolymer having a double bond at the molecular terminal can be obtained.

Further, by reacting a carbonate copolymer obtained by copolymerization with a compound having a double bond and a halogen atom in the molecule, such as allyl bromide, acrylic acid chloride or methacrylic acid chloride, carbonate copolymerization is performed. A double bond can be introduced into the terminal on the hydroxyl side of the union. Such carbonate copolymers are used as synthetic materials for stimuli-responsive gel compounds by utilizing the reactivity of double bonds at the molecular ends, or as special grade synthetic resin materials by copolymerization with vinyl chloride or propylene. can do. Examples of the terminal group having a double bond include an allyloxy group, an acryloyloxy group, a methacryloyloxy group, and a styryloxy group.

The carbonate copolymer obtained by the production method of the present invention generally exists as a white powder in the case of a polymer, and as a colorless and transparent wax in the case of a low molecular weight, such as chloroform, methylene chloride, and acetone tetrahydrofuran. But it is insoluble in methanol, water and the like.

The structure of the carbonate copolymer obtained by the production method of the present invention has an infrared absorption spectrum (hereinafter simply referred to as IR), a ¹ H-nuclear magnetic resonance spectrum (hereinafter simply referred to as ¹ H-NMR).
Call. ) And elemental analysis.

Further, the number average molecular weight (n) and the weight average molecular weight (
w) can be determined by gel permeation chromatography (hereinafter simply referred to as GPC). or,
The glass transition point (hereinafter simply referred to as Tg) of the polymer can be known by differential scanning calorimetry (hereinafter simply referred to as DSC).

As the alkylene oxide used in the production method of the present invention, known compounds such as ethylene oxide, propylene oxide, butylene oxide and pentylene oxide can be employed. Further, as the epihalohydrin, known compounds such as epichlorohydrin, epibromohydrin, epiiodohydrin and the like can be employed.

The porphyrin aluminum complex used as a catalyst is not particularly limited, but a compound represented by the following formula (F) is preferably used in the present invention because good copolymerization of the above three components can be performed. .

The porphyrin aluminum complex represented by the above formula [F] can be obtained by reacting a porphyrin compound represented by the following formula [G] with an organoaluminum compound.

[However, R _{1 to} R ₂₀ are the same as those in the above formula [F]. Specific examples of the porphyrin compound represented by the above formula [G] include tetrabenzporphyrin, tetranaphthoporphyrin, tetraphenyltetrabenzporphyrin, tetraphenyltetranaphthoporphyrin and the like.

Examples of the organoaluminum compound as a raw material of the porphyrin aluminum complex represented by the above formula [F] include dialkylaluminum halides having an alkyl group having 4 or less carbon atoms, such as diethylaluminum chloride and diethylaluminum bromide; trimethylaluminum, triethylaluminum Aluminum having an alkyl group having 4 or less carbon atoms such as tripropylaluminum, triisobutylaluminum, etc .; alkyl having a hydrogen atom and an alkyl group having 4 or less carbon atoms such as diethylaluminum hydride and diisobutylaluminum hydride Aluminum hydrides are effectively used. Of these, dialkyl aluminum hydrides are preferred.

Since the reaction conditions for the porphyrin compound and the organoaluminum compound vary depending on the type of raw materials and solvents used, it is only necessary to select suitable conditions in advance. In general, the reaction is carried out by adding an approximately equimolar amount of an organoaluminum compound to a porphyrin compound in an atmosphere of an inert gas such as nitrogen or argon, in the presence of a solvent, at a temperature of 0 to 50 ° C. for several tens of minutes to 10 hours. .

In general, the reaction proceeds sufficiently at normal pressure, but the pressure may be increased or reduced as necessary.

As the reaction solvent, hydrocarbons such as benzene, toluene, xylene and the like, and halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane are used.

When X in the formula [F] of the aluminum porphyrin complex thus obtained is a hydrogen atom or an alkyl group, X is reacted with an organic compound containing a hydroxyl group or water to convert X to an alkoxy group or a phenoxy group. , A hydroxyl group, and such a complex compound can also be used as a catalyst in the present invention. Examples of the porphyrin aluminum complex that can be preferably used in the present invention include a tetrabenzporphyrin aluminum chloride complex, a tetranaphthoporphyrin aluminum chloride complex, a tetraphenyltetrabenzporphyrin aluminum chloride complex,
Examples include tetraphenyltetranaphthoporphyrin aluminum chloride complex, tetrabenzporphyrin aluminum methyl complex, tetranaphthoporphyrin aluminum methyl complex, tetraphenyltetrabenzporphyrin aluminum methyl complex, tetraphenyltetranaphthoporphyrin aluminum methyl complex, and tetrabenzporphyrin aluminum methyl complex. Can be

As the active hydrogen compound used in combination with the porphyrin aluminum complex of the present invention, for example, alcohols, phenols, and carboxylic acids containing one or more hydroxyl groups or carboxylic acid groups in one molecule are effectively used. As alcohols, methanol, ethanol,
Aliphatic alcohols such as propanol and butanol;
Unsaturated alcohols such as allyl alcohol and 2-hydroxyethyl methacrylate; and aliphatic polyhydric alcohols such as ethylene glycol, triethylene glycol, tripropylene glycol, glycerin and pentaerythritol. Examples of the phenols include phenols such as phenol, bisphenol, vinyl phenol, and allyl phenol; and polyhydric phenols such as resorcin, P-dihydroxybenzene, and 2,4-toluene diol. Examples of the carboxylic acids include carboxylic acids such as acetic acid, acrylic acid, and methacrylic acid, and polyvalent carboxylic acids such as adipic acid, sebacic acid, maleic acid, fumaric acid, and terephthalic acid.

The active hydrogen compound is not limited to those specifically shown above, and various alcohols, phenols, and carboxylic acids are effectively used.

The polymerization conditions in the present invention are such that the polymerization is carried out in a solvent under an atmosphere substantially free of an active gas other than the reactive monomer gas. The solvent is not particularly limited as long as it is a non-aqueous solvent that does not react with the monomer or the porphyrin aluminum complex. For example, methylene chloride, benzene and the like are used.

The amount of alkylene oxide and epihalohydrin is
What is necessary is just to determine according to the ratio of the repeating unit based on said each component in the objective carbonate copolymer.

The use amount of the porphyrin aluminum complex is preferably in the range of 0.001 to 1 mol, and particularly preferably in the range of 0.001 to 0.1 mol, per 1 mol of the total of the alkylene oxide and epihalohydrin. The amount of the active hydrogen compound used is in the range of 1 to 50 times, preferably 1 to 25 times the mole of the porphyrin aluminum complex.

The pressure of carbon dioxide affects the proportion of the repeating unit represented by the above formula [C] in the obtained carbonate copolymer. In order to obtain the carbonate copolymer of the present invention, it is sufficient to select the pressure of carbon dioxide from the range of 1 to 50 atm, preferably from the range of 25 to 50 atm.

The polymerization temperature is generally employed in the range of -20 to 100 ° C. If the polymerization temperature is increased, the cyclic carbonate is easily produced as a by-product, so that the polymerization is preferably performed at 50 ° C. or lower.

Thus, 5 to 70 mol% of the repeating unit represented by the formula [A], 5 to 70 mol% of the repeating unit represented by the formula [B]
70 mol%, and a repeating unit represented by the formula [C] 25 to
50 mol% is randomly arranged (however, two or more repeating units represented by the formula [C] are not continuously arranged) to obtain a carbonate copolymer having a number average molecular weight of 500 to 50,000. be able to.

Further, among the carbonate copolymers obtained by the production method of the present invention, those in which X in the above formula (B) is a bromine or iodine atom include carbonate copolymers in which X is chlorine, such as KBr and KI. It can also be produced by reacting an alkali metal bromide or an alkali metal iodide.

(Effect) Since the carbonate copolymer obtained by the production method of the present invention has a chemically active haloalkyl group in the molecular chain, the active site is chemically modified to exhibit a function not present in conventional polypropylene carbonate. be able to. In addition, the amount of the haloalkyl group in the carbonate copolymer can be arbitrarily controlled according to the amount of the repeating unit based on epihalohydrin, and thus can be set to an appropriate amount depending on the type of the chemically modified product. Further, the carbonate copolymer obtained by the production method of the present invention has a narrow molecular weight distribution, and is therefore optimally used for those having a molecular weight dependence in the manifestation of the effect, such as a pharmaceutical polymer.

Therefore, a carbonate copolymer having a structure as produced in the present invention is immobilized by reacting a pharmacologically active substance or an affected part directing substance with a haloalkyl group, and selectively transports these substances to an affected part in a living body. Then, it can be used as a drug carrier in a drug delivery system in which these substances are gradually released by being decomposed there.

(Examples) Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to these examples.

Example 1 A mixture of 21 g of potassium phthalimide, 14.7 g of malonic acid and 18.9 g of zinc acetate dihydrate was heated at 360 to 370 ° C.
The zinc complex of tetrabenzporphyrin obtained after the reaction was demetalated with sulfuric acid to obtain tetrabenzporphyrin.

0.05 mmol of this tetrabenzporphyrin and 0.10 mmol of diethylaluminum chloride in 1 ml of methylene chloride
After reacting under nitrogen for 5 hours, vacuum drying was performed at 50 ° C. for 3 hours to remove excess diethylaluminum chloride to obtain a blue-green powder.

In a recovery flask containing 0.05 mmol of this tetrabenzporphyrin aluminum chloride complex (hereinafter referred to as (TBP) AlCl), 5 times the amount of methanol was put under a nitrogen atmosphere, and then 0.9 ml of propylene oxide and 1.0 ml of epichlorohydrin were added to make the mixture uniform. The mixture was transferred under a nitrogen stream to a 50 cc internal volume SUS autoclave in which CO _{2 had been} replaced in advance, and CO ₂ was charged under pressure at 50 kg / cm ² and polymerized at room temperature for 101 hours. The obtained reaction product was dissolved in chloroform, precipitated with methanol, and purified by reprecipitation to remove unreacted monomers and the like, followed by vacuum drying.

The structure of this polymer was determined by the following analytical means.

(Molecular weight and molecular weight distribution)

Number average molecular weight (n), weight average molecular weight (w) and their ratio based on calibration curve with standard polystyrene by gel permeation chromatography (GPC)
w / n was determined. As a result, n = 3600, w / n = 1.
It was 30.

[Molecular Structure] The functional group present in the chain was identified by an infrared absorption spectrum (IR) (the chart is shown in FIG. 1).

1740 and peak 750～780Cm ^-1 derived from a carbonate bond to 1230 cm ^-1 from the chemical shift value by the peak ¹ H-NMR spectrum derived from an ether bond to the peak 1100 cm ^-1 derived from the chloromethyl group in the molecular structure: The assigned proton species was detected.

Also, based on the integral ratio, the above (I) to (I)
The molar ratio of the repeating unit represented by V) was determined. As a result, (I) :( II) :( III) :( IV) = 44: 36: 13: 7
(Mol%).

^The carbon species present in the polymer was detected by ¹³ C-NMR spectrum measurement. The measurement is performed by the proton complete decoupling method, and the solvent is heavy benzene and light benzene 1:
One mixture was used. FIG. 2 shows the chart. FIG. 3 (a) is an enlarged view of a region particularly based on carbonyl carbon. Among these peaks, there are peaks which are not present in the propylene oxide / carbon dioxide binary polymer (FIG. 3 (b)) and the epichlorohydrin / carbon dioxide binary copolymer (FIG. 3 (c)). was detected.

From this, it was confirmed that the obtained polymer was not a simple mixture or block copolymer of propylene oxide and carbon dioxide or epichlorohydrin and carbon dioxide copolymer but a random copolymer of the above three components.

The ratio of the elements constituting the polymer was determined by elemental analysis, and the following values were obtained.

Measured weight ratio C40.3%, H4.6%, O35.0%, Cl20.1% or ¹ H-N
The theoretical elemental analysis values obtained from the molar ratio of propylene oxide: epichlorohydrin: carbon dioxide (25:35:40) obtained from MR are as follows.

The theoretical weight ratios C40.9%, H5.0%, O34.7%, and Cl19.3% were in good agreement with each other, confirming that the composition ratio determined from ¹ H-NMR was correct.

(Thermal properties)

The differential scanning calorimetry (DSC) was measured to determine the glass transition point (Tg) of the polymer. One point at Tg = −16 ° C. was observed.

Examples 2 to 5 A terpolymerization reaction of propylene oxide, epichlorohydrin and carbon dioxide was carried out under the conditions shown in Table 1 using (TBP) AlCl complex prepared in the same manner as in Example 1 and methanol. The analysis results of the obtained polymer are also shown in Table 1.

Further, from the results of ¹³ C-NMR, it was confirmed that each polymer was a random copolymer.

Example 7 After reacting 0.05 mmol of tetrabenzporphyrin obtained in the same manner as in Example 1 and 0.1 mmol of triethylaluminum in 1 ml of methylene chloride under nitrogen for 5 hours, the mixture was emptied to remove excess triethylaluminum. Vacuum drying at room temperature for 3 hours gave a blue-green powder. This tetrabenzporphyrin aluminum ethyl complex (hereinafter referred to as (TBP) AlEt
Call. ) To an eggplant flask containing 0.05 mmol, add 0.06 mmol of allyl alcohol and 1 ml of methylene chloride, and add
After reacting for an hour, allyl alcohol remaining unreacted with the solvent was removed under reduced pressure. A 5-fold molar amount of allyl alcohol was placed in a recovery flask containing 0.05 mmol of this complex under a nitrogen atmosphere, and then 0.9 ml of propylene oxide and 1 ml of epichlorohydrin were added.
The mixture was transferred to a 50 cc SUS autoclave with an O ₂ displacement under a nitrogen stream, charged with CO ₂ at a pressure of 50 kg / cm ² , and polymerized at room temperature for 100 hours.

The obtained reaction product was divided into 2 minutes, and 0.5 mmol of allyl bromide was added to one of them, and the mixture was reacted at 50 ° C. for 5 hours. Both reaction solutions were purified by reprecipitation with chloroform-methanol, and dried under vacuum to obtain two types of carbonate copolymers.

The structures of the two carbonate copolymers were determined by the following analytical means.

(Molecular weight and molecular weight distribution)

Asked by GPC. As a result, the number average molecular weight (
In n), all the carbonate copolymers had n = 4000 and the molecular weight distribution was w / n = 1.25.

[Molecular structure] The following peak was detected in the IR spectrum.

1740,1230Cm ^-1 to carbonate linkage peak 750～780Cm ^-1 to the peak 1100 cm ^-1 of the chloromethyl group in Example 1 in peak ¹ H-NMR spectrum of an ether bond (I) repeating unit represented by the ~ (IV) And the peak attributed as in the following formula were detected.

Further, the molecular weight of the carbonate copolymer per one allyloxy group at the molecular end determined from the integral ratio was n = 4200 when the carbonate copolymer reacted with allyl bromide did not react n = 2700. . From the results of GPC, the molecular weight of the carbonate copolymer per terminal group, which was estimated that both terminals and one terminal were allyloxy groups, was n = 2000 and n = 4000, respectively.
Therefore, the introduction ratios of allyloxy groups into the above two types of carbonate copolymers were 75% and 50% at both ends, respectively.

The composition ratio determined from the integral ratio is the molar ratio of the repeating unit represented by (I) to (IV) in Example 1, and
(I): (II): (III): (IV) = 56: 36: 4: 4.

^{From the 13} C-NMR spectrum, it was confirmed that the obtained polymer was a random copolymer.

(Thermal properties)

According to the DSC spectrum, the Tg of the obtained polymer was −13.
° C.

Examples 8 to 14 By changing the allyl alcohol and allyl bromide of Example 7 in various ways, tertiary random copolymers having different terminal group structures were synthesized. The reaction conditions and analysis results are summarized in Table 2.

However, the catalyst, active hydrogen compound, propylene oxide, the amount of epichlorohydrin charged, each 0.05mm
ol, 0.25 mmol, 12.5 mmol and 12.8 mmol, and the pressure of carbon dioxide was 50 kg / cm ² .

Example 15 1 g of the carbonate copolymer obtained in Example 1 was used in an amount of 100 ml.
Was dissolved in acetone, and 5 g (30 mmol) of KI was added. The mixture was allowed to react for 100 hours under room temperature light shielding, and KCl as a reaction product and unreacted KI that did not dissolve in acetone were separated. After drying the organic phase and converting it to chloroform, the organic phase is sufficiently washed with water to remove the contaminating KI, and the organic phase is dried over magnesium sulfate. A coalescence was obtained.

The yield of the obtained carbonate copolymer is 1.4 g,
It was in good agreement with the theoretical yield determined assuming that all chloromethyl groups were converted to methyl iodide groups.

GPC analysis of the obtained carbonate copolymer showed that the ratio w / n of the number average molecular weight (n) to the weight average molecular weight (w) was 1.30, and there was no disturbance in the molecular weight distribution before and after the reaction. It can be seen that it has not occurred.

Further, peaks assigned as follows were detected by ¹ H-NMR of the obtained polymer.

Further, since the peaks at 3.7 ppm and 3.58 ppm derived from the chloromethyl group disappeared, it was confirmed that the reaction had progressed 100%. Further, the polymer obtained from the integral ratio is a molar ratio of the repeating unit represented by the above (I) to (IV),
(I): (II): (III): (IV) = 44: 36: 13: 7 It was concluded that the copolymer was a ternary random copolymer.

Example 16 A reaction for converting a chloromethyl group in the carbonate copolymer obtained in Example 1 to methyl bromide was performed in the same manner as in Example 15 except that KI was changed to KBr.

By ¹ H-NMR of the obtained polymer, peaks assigned as follows were detected.

The disappearance of the 3.70 ppm peak derived from the chloromethyl group indicated that the reaction had progressed 100%. In addition, the polymer obtained from no change in w / n determined by GPC analysis and no decrease in molecular weight was observed,
In the molar ratio of the repeating units represented by the above (I) to (IV),
(I): (II): (III): (IV) = 44: 36: 13: 7 It was concluded that the copolymer was a ternary random copolymer.

BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1 and 2 show a chart of an infrared absorption spectrum and a ¹³ C-nuclear magnetic resonance spectrum of the carbonate copolymer of the present invention obtained in Example 1, respectively. FIG. 3 shows the carbonyl carbon regions of the ¹³ C-nuclear magnetic resonance spectra of the carbonate copolymer, the copolymer of propylene oxide and carbon dioxide, and the copolymer of epichlorohydrin and carbon dioxide, which were also obtained in Example 1. Show.

Claims (1)

(57) [Claims] 1. A method of polymerizing an alkylene oxide, epihalohydrin and carbon dioxide in the presence of a porphyrin aluminum complex and an active hydrogen compound.
The sum of mol% of the repeating units represented by the following formulas [A], [B] and [C] is 100, and a) Formula [A] (Where R is a hydrogen atom or an alkyl group) 5 to 70 mol% of a repeating unit represented by the following formula: a) Formula [B] (Where X is a halogen atom) 5 to 70 mol% of a repeating unit represented by the following formula: and c) a formula [C] 25 to 50% by mole of the repeating unit represented by the formula (C) is not randomly arranged (however, two or more repeating units represented by the formula [C] are not continuously arranged), and the number average molecular weight is 500 to 50,000. A method for producing a carbonate copolymer.