JPH02132123A - Polyepichlorohydrin carbonate - Google Patents

Abstract

PURPOSE:To synthesize in high catalytic efficiency the title copolymer from epichlorohydrin and carbon dioxide with narrow molecular weight using as catalyst a specific porphyrin-aluminum complex. CONSTITUTION:The objective polyepichlorohydrin carbonate having recurring unit of the formula with number-average molecular weight Mn and weight- average molecular weight Mw satisfying simultaneously the relationships: 500<=Mn<=50000 and Mw/Mn<=1.5. According to the reaction ratio for the epichlorohydrin and carbon dioxide, copolymer with the proportion of the recurring unit varied can be obtained; the greater the proportion, the copolymer will become more liable to be decomposed, therefore, being suitable as a drug carrier for drug delivery system.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel polyepichlorohydrin carbonate having a narrow molecular weight distribution.

(Prior art and problems to be solved by the invention) As catalysts that can capture carbon dioxide and carry out a copolymerization reaction with epoxide, organic zinc monobasic catalysts such as ZnEtz-820 system are used. It is known that a catalyst or a tetraphenylborphyline aluminum complex quaternary salt mixed catalyst is effective. It has been found that both catalyst systems result in fully alternating copolymers of carbon dioxide and eboxide.

However, none of the above catalysts is effective in the copolymerization reaction of shrimp chlorohydrin, an industrially useful monomer, and carbon dioxide, and especially in the latter system, formation of cyclic carbon inerts is observed. You can't get a polymer just by getting a

Regarding the copolymerization of shrimp chlorhydrone and carbon dioxide,
Japanese Patent Publication No. 48-12077 C describes the use of a triisobutylaluminum-sulfur mixed catalyst. However, the polymer obtained by this catalyst has a wide molecular weight distribution and its catalytic efficiency is low.

(Another Means to Solve the Problem) The present inventors have already discovered that polymers with uniform molecular weight distribution can be synthesized with high catalytic efficiency by polymerizing epoxide in a mixed system of a specific porphyrin aluminum complex and an active hydrogen compound. (Patent Application No. 1987-87341). The present inventors have discovered that by using this specific volufiline aluminum complex as a catalyst, a copolymer of shrimp chlorohydrin and carbon dioxide can be synthesized with a uniform molecular weight distribution with high catalytic efficiency. I have finally completed the .

That is, the present invention has the following formula (1) Cl{, fl -{ CH 2-C I1 - 0-C - 0 }
- Contains the repeating unit shown in (1), and has a number average molecular weight (FJn) and a weight average molecule ffi CMW>
and satisfies the following formula: 500≦Mn≦50000 M w /FA n≦1.5.

Polyhydric hydrin carbonate of the present invention (hereinafter referred to as
It is simply called PEHC. ) is generally obtained by copolymerization of epichlorohydrin and carbon dioxide as described below. Depending on the reaction ratio of shrimp chlorohydrin and carbon dioxide, P E H C having various proportions of the repeating unit represented by the above formula (1) can be obtained. When the reaction ratio of shrimp chlorohydrin is large, a repeating unit formed by alternating copolymerization of epichlorohydrin and carbon dioxide shown in the above formula (1) and the following formula (2) CH2Cj2 -{ C H , -C I-0}-
(A copolymer consisting of a repeating unit based on homopolymerization of epichlorohydrin shown by 21 is obtained.

In this case, the repeating units represented by the above formula (1) and the repeating units represented by the above formula (2) are arranged randomly. This can be seen in the differential scanning calorimetry (hereinafter simply referred to as DSC) chart (FIG. 5) of the polyepoxyhydrin carbonate of the present invention obtained in Example 1, which will be described later.
This is understood from the fact that there is only one glass transition point in this case. Further, when the reaction ratio of epichlorohydrin and carbon dioxide is equal, a complete alternating copolymer of epichlorohydrin and carbon dioxide is obtained as shown in the above formula (1).

The P E H C of the present invention generally contains 50 mol% or more of the repeating unit represented by the above formula (1) and the above formula (2).
) contains 50 mol% or less of the repeating unit represented by. Further, the repeating flower position represented by the above formula (1) is set to 60 mol% or more, further 70 mol% or more, and the above formula (2)
40 mol% or less of the repeating unit shown by, and even 3
It can also be P E H C containing 0 mol % or less.

The higher the proportion of the repeating unit represented by the above formula (1), the easier it is to decompose, so it is suitable as a pharmaceutical carrier for the drug delivery system described below.

The P EHC of the present invention has a number average molecule 1 (Lln) and a weight average molecule ffi (Mw) that both satisfy the following formula: 500≦nn≦50,0000FZW/FJAn≦1.5 do. When using the P E H C of the present invention as a carrier for pharmaceuticals in the drug delivery system described below, the following formula It is preferable that both of 1000≦Mn≦20,000 M W /Mn≦1.35 are satisfied.

l) EHC of the present invention exists as a white powder in the case of high molecular weight, and as a colorless and transparent viscous fluid in the case of low molecular weight. It is soluble in organic solvents, but insoluble in methanol, water, etc.

The structure of P E H C of the present invention can be confirmed by infrared absorption spectrum (hereinafter simply referred to as IR), +3C-nuclear magnetic resonance spectrum (hereinafter simply referred to as I3C-NMR), and elemental analysis. can. Further, the number average molecular ffi (In) and the weight average molecular weight (17w) can be determined by gel vermiacetic chromatography (hereinafter simply referred to as GPC).

Although the PEHC of the present invention may be produced by any method, the following method is generally suitably employed.

It can be produced by polymerizing shrimp chlorohydrin and carbon dioxide in the presence of an active hydrogen compound using the volufiline aluminum complex shown in the following formula (3) as a catalyst.

The volufiline aluminum complex represented by the above formula (3) can be obtained by reacting the vorufiline compound represented by the following formula (4) with an organoaluminum compound.

Rl1 1ze, 2 κI3 1N+4 [However, R, ~R2. is the same as the above equation (3).

] Specific examples of the vorphyline compound represented by the above formula (4) include tetrabenzborphyrin, tetranaphthoporphyrin, tetraphenyltetrabenzporphyrin, and tetraphenyltetranaphthoporphyrin.

”: Organoaluminum compounds that are raw materials for the porphyrin aluminum complex represented by formula (3) include dialkylaluminum halides having an alkyl group having 4 or less carbon atoms, such as diethylaluminum chloride and diethylaluminium bromide; trimethylaluminum, 1-realkylaluminums having an alkyl group having 4 or less carbon atoms, such as triethylaluminum, tribubylaluminium, triisobutylaluminum, etc.; alkyl groups having 4 or less carbon atoms, such as diethylaluminum hydride, diisobutylaluminum hydride, etc. and alkyl aluminum hydrides having a hydrogen atom are effectively used. Among these, dialkyl aluminum hydride cheeks are preferred.

Since the conditions for the reaction between the voluphyline compound and the organoaluminum compound vary depending on the type of raw materials and solvent used, suitable conditions may be selected in advance and carried out. Generally, the reaction is carried out by adding approximately equimolar amounts of an organoaluminium compound to a volufiline compound at a temperature of 0 to 50°C for several tens of minutes to ten hours in the presence of a solvent in an inert gas atmosphere such as nitrogen or argon. .

Further, although the reaction generally proceeds sufficiently at normal pressure, the pressure may be increased or reduced as necessary.

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

When X in the formula (3) of the thus obtained volufiline aluminum complex is a hydrogen atom or an alkyl group, it is reacted with an organic compound containing a hydroxyl group or water to convert X into an alkoxide group or a phenoxy group. , compounds converted to hydroxyl groups can be collected, and such compounds can also be used as catalysts. Examples of the vorphyline aluminum 1 and nail 1 that can be suitably used in the present invention include tetrabenzvonolephyline aluminum chloride complex, tetranaphthovorphyline aluminum chloride complex, tetraphenylte 1-lachensvorphyline aluminum chloride complex, and tetraphenyltetranaphthalene aluminum chloride complex. Examples include porphyrin aluminum chloride complex.

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.

Alcohols include aliphatic alcohols such as methanol, ethanol, propanol, and butanol; unsaturated alcohols such as allyl alcohol and 2-hydroxyethyl methacrylate; aliphatic alcohols such as ethylene glycol, triethylene glycol, tripropylene glycol, and glycerin. Examples include polyhydric alcohols. Examples of phenols include phenols such as phenol, bisphenol, and allylphenol, and polyhydric phenols such as P-dihydroxybenzene and 2.4-toluenediol. Examples of carboxylic acids include carboxylic acids such as acetic acid, acrylic acid, and methacrylic acid, and polyvalent carboxylic acids such as adibic 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 acid groups can be effectively used.

The polymerization conditions in the present invention are to carry out the polymerization in a solvent in an atmosphere substantially free of active gases other than the reaction monomer gas. The solvent is not particularly limited as long as it is a non-aqueous solvent that does not react with the heptanomer or the vorufiline aluminum complex. For example, methylene chloride, benzene, etc. are used.

The amount of porphyrin aluminum complex used is in the range of 0.001 to 1 mol per 1 mol of shrimp chlorohydrin.
In particular, it is preferably used in a range of 0.001 to 0.1 mol. In addition, the amount of active hydrogen compound to be used is 1 to 50 times the mole of volufiline aluminum complex, preferably 1
It is in the range of ~25 times the mole.

The polymerization reaction temperature and pressure are -20 to 1 atm, with a carbon dioxide pressure of 1 to 50 atm, preferably 25 to 50 atm.
Polymerization is carried out at a temperature of 00°C.

If the polymerization temperature is increased, cyclic carbonate [.] tends to be produced as a by-product, so the temperature is preferably 50°C or lower.

(Effect) The P E H C of the present invention has a weight average molecule ffi (la
The ratio of w) to the number molecule 1 (Mn) is small, and the molecular weight distribution is narrow. Therefore, it can be used extremely effectively in applications such as pharmaceutical polymers whose effects are dependent on molecular weight.

Furthermore, since it has a reactive chloromethyl group in its molecule, it can exhibit functions not found in conventional polypropylene carbonate by chemically modifying this active site.

Therefore, the PEHC of the present invention is immobilized by reacting a drug-active substance or a substance directed to the affected area with the chloromethyl group, and selectively transports these substances to the affected area in the body, where it is released into the body. It can be used as a carrier for pharmaceuticals in drug delivery systems for sustained release of substances.

(Example) The present invention will be explained below with reference to Examples.
The invention is not limited to these examples.

Example 1 Potassium phthalimide 21g2 Maron lff14.7g
, zinc acetate dihydrate 1 8. A zinc complex of tetrabenzborphyline obtained by reacting 9 g of the mixture at 360 to 370'C for 2 hours under a nitrogen stream was demetalized with sulfuric acid to obtain tetrabenzborphyline.

This tetrabenzvorufiline 0. 0 5 mmol
and diethyl aluminum chloride 0. 10 mm
After reacting in methylene chloride for 5 hours under nitrogen, excess diethylaluminum chloride is distilled off? The powder was vacuum dried at 50° C. for 3 hours to obtain a blue-green powder. This tetrabenzborphyline aluminum chloride complex (hereinafter referred to as (TBP) MC7!) (0.
In a eggplant flask containing 0.05 mmol, add 9 times the molar amount of methanol and 0.05 mmol. 8 Add methylene chloride from 17 under nitrogen atmosphere, then add epichlorohydrin from 27. 7
The mixture was made homogeneous by adding 5n + mol, and was transferred under a nitrogen stream to a SUS autoclave with an internal volume of 120cc, which had been replaced with CO2 in advance, and the CO2 was replaced with 50kg/co.
! was charged under pressure and polymerized at room temperature for 1) 5.5 hours.

The IR spectrum of the obtained polymer was carbonate 1.
1 7 4 0 cm-' and 1 2 3 derived from the bond
Absorption at 0 cm-' is observed (Fig. 1). In addition, the number average molecular fl(yn) determined by gel permeation chromatography (GPC) is 5800, and the ratio W w / Fl n to the weight average molecular weight (!i7w) is 1.3 l.
(Figure 2).

According to DSC (Fig. 5) of the obtained polymer, one glass transition point was observed at -0.9°C.

In the C-NMR spectrum (proton complete decasopring mode) measurement (CCbDb7'8 medium), a peak assigned to the chloromethyl carbon of the homobolymer (35pp
m) was not observed, 1 5 4. A peak attributed to the carbonyl carbon of polycarbonate was observed at 5 ppm (Figure 3). In addition, in the 13c NMR spectrum (off-resonance proton decasopring mode), as shown in Figure 4, the peak b of the following formula (1) is split into two, and the peaks c and a are split into three. No splitting was observed in the peak of d. From this, each grade 3,
It was found that these were secondary and quaternary carbons. 13 at the same time
c 1, When quantitative measurement was performed by IMR, the integrated intensity ratio around b peak, c peak, and a peak was 1.
:1:1, and the other d peak is 0.
The intensity ratio was 77.

The above three kinds of "(,-NMR spectroscopy) revealed that the carbon dioxide-based repeating units of the obtained polymer were 4
It was 3 mol%. From this, the above polymer is
86 mol% of repeating units based on alternating copolymerization of epichlorohydrin and carbon dioxide shown in the following structure (1),
Based on the homopolymerization of epichlorohydrin shown in the following structure (2), it was confirmed that it was a polyepichlorohydrin carbonate in which 14 mol% of repeating units were randomly arranged.

CH, II (21 -{ CH Z - CH - 0 }
-The elemental analysis value of the polymer is C36. 2%
8 4. 2 %0 3 1. 6% C/! 2 B
．． 0%, and the C 3 5.
8% H4.0%0 3 2. 1% Cff 2
8. This is almost the same as 2%.

Further, the number of polymers produced per one volufiline aluminum complex was 9.5, and the total number of molecules of the produced polymer was approximately equal to the sum of the numbers of added methanol and vorufiline aluminum complex molecules. or,
Shrimp chlorohydrin? The yield was 79%.

Example 2 (TBP) MCI obtained in Example 1! ．． 0. 0
Into a round bottom flask containing 1 mmol of methanol, 15 times the molar amount of the complex was put in an N2 atmosphere, and then 21 mmol of shrimp chlorohydrin was added to make the mixture homogeneous. Transfer to a manufactured autoclave under a stream of nitrogen and CO
z 50 kg/ca was charged under pressure and polymerized at room temperature for 40 hours.

The IR spectrum of the obtained polymer shows 1740 cm-' and 1230 cm-' derived from force-bonate bonds.
Absorption for m days was observed.

In addition, the number average molecule ffi (Mn) determined by GPC is 10
30, the ratio Mw/M to the weight average molecule ffi (Mw)
n was 1.21.

As in Example 1, the glass transition point determined by DSC was only found at one location.

``The measurement of the C-NMR spectrum showed a spectrum similar to that observed in Example 1.

Furthermore, the repeating unit based on carbon dioxide determined from this measurement was 35 mol%, 70 mol% of the repeating unit shown by structure (1) in Example 1, and 30 mol% of the repeating unit shown by structure (2). It was confirmed that these were randomly arranged polymers. In addition, the elemental analysis value of the polymer is
C 3 6. 3%, H4.2%, 0 2 6. 8%
, cl. 3 2. 7%, ``C3 6.0% H 4.1% of the polymer with the composition estimated from C-NMR.
0 3 1. I% Cl 2 8. Almost coincides with 8%.

Furthermore, the number of polymers produced per volufiline aluminum complex was 16.9, and the total number of molecules of the produced polymers was approximately equal to the sum of the numbers of added methanol and vorufiline complexes.

Moreover, the yield in terms of shrimp chlorohydrin was 15%.

Examples 3 to 7 In addition to using (TBP)/'l(J. obtained in Example 1 as a catalyst and changing the type and amount of the active hydrogen compound to be added as shown in Table 1) was prepared with epichlorohydrin and CO in a manner similar to that described in Example 1.
The copolymerization reaction of No. 2 was carried out for a predetermined period of time.

The results are shown in Table 1.

In addition, as in Example 1, the glass transition point of each polymer was determined by DSC at only one location.

Comparative example l 50t/0. 4 mmol of sulfur and 10 d of dioxane were added, and the system was pressurized to about 20 atmospheres with argon and discharged several times to replace the air in the system with argon.

Next, 2 mmol of triisobutylaluminum was added under an argon stream and reacted for about 10 minutes.

Next, 40 mmol of shrimp chlorohydrin was added, the system was pressurized to 50 atm with carbon dioxide gas, and polymerization was carried out for 40 hours while stirring.

After the reaction is complete, add a small amount of methanol-hydrochloric acid to the reaction system,
The reaction was stopped.

What is the total yield of the polymer obtained? ．． At 3 g, the methanol-insoluble polymer is 43%, the repeating unit based on carbon dioxide is 20 mol%, and there is no molecular weight distribution and FA w/M
n was 2.5.

[Brief explanation of drawings]

Figures 1, 2, 3, 4, and 5 show the infrared absorption spectrum, molecular weight distribution, and I30 nuclear magnetic resonance spectrum of polyhydrin carb 2-1- obtained in Example 1. (proton complete decanting mode), +
'C-nuclear magnetic resonance spectra (off-resonance proton decoupling mode) and differential scanning calorimetry charts are shown, respectively.

Claims (1)

[Claims] (1) Contains repeating units represented by the following formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ and has a number average molecular weight (@M@
n) and the weight average molecular weight (@M@w) are expressed by the following formula 500≦@
A polyepichlorohydrin carbonate characterized by satisfying both of M@n≦50,000 @M@w/@M@n≦1.5.