JPH0739485B2 - New block copolyether glycol manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to 3-methyl oxetane (hereinafter abbreviated as MOX).
Α-tosyl-ω-tosyl oxypoly (2-methyl trimethylene glycol) ((methyl methyl glycol) (PMTG) obtained by the ring-opening polymerization of α-tosyl-ω-tosyl oxypoly (2-methyl trimethylene glycol) ( (DTs-PMTG) is synthesized and reacted with an alkali metal alcoholate of poly (ethylene glycol) (PEG) to form an ABA block of poly (ethylene glycol) and poly (2-methyl trimethylene glycol).・ A method to obtain copolyether glycol (PEMG).

ABA block copolyether consisting of poly (alkylene oxide) block chains such as hydrophobic poly (propylene oxide) block chains and hydrophilic poly (ethylene oxide) block chains is a soft segment It is known that the polyether / polyester and polyether / polyurethane block copolymers possessed by are excellent in physical properties as an elastomer and exhibit a function of suppressing the adhesion of platelets. It is useful. At the same time, as a factor that exerts a function of suppressing platelet adhesion, the chemical composition of the hard segment and the soft segment, as well as the hydrophilic and hydrophobic blocks of the ABA block copolyether that constitutes the soft segment The proportion, and also the length of the hydrophilic and hydrophobic blocks, are important factors. This is because these factors are factors that determine the so-called micro phase separation structure closely related to the above function. That is, it is well known that the morphology formed by the microphase separation mechanism and the relative hydrophilicity and hydrophobicity of the phase-separated microdomains are important factors for the expression of the function of suppressing platelet adhesion. .

The quantitative relationship between them is being clarified one after another academically, but in the present invention, the hydrophilic block part is a poly (ethylene oxide) block chain, and the hydrophobic block part is a poly (oxy-2-oxy) block chain. A method for producing an ABA type block copolyether glycol composed of (methyl trimethylene) block chains, which is a block copolyether having a new hydrophilic / hydrophobic balance.
The present invention relates to a method for providing glycol.

In particular, the present invention relates to a production method in which the ratio of the hydrophilic block and the hydrophobic block that determine the microphase-separated structure, which is an important factor for function expression, and the length thereof are regulated.

The microphase-separated structure is a structure exhibiting an excellent function also as a separation membrane, and the block, copolyether, glycol according to the present invention has a hard segment of polyester, polyurethane, polyurethaneurea, or the like that gives mechanical properties as a support. Was used as a segment. block·
Copolymers also provide excellent materials for this application.

(Prior art) Originally ABA type block copolyether glycol is B
A method of adding a monomer of the A block polyether component from both ends of the block polyether by cation or anion polymerization to extend the chain is used. As long as this method is used, the polyether chain length of the B block is Even if it can be controlled, it is difficult to control the polyether chain length of the A block portion added to it, and the chain length of the A block portion existing on both sides of the B block portion is controlled to a desired remarkable length. It is even more difficult to control. Furthermore, the presence of ABA-type block copolyether monoalcohol with a hydroxyl group on one end terminal, which is secondarily generated during polymerization, indicates that polyester, polyurethane, polyurethane, etc. using ABA type block copolyether glycol
It is particularly undesirable in the synthesis of block copolymers such as urea.

The present invention solves these problems, ABA type block copolyether glycol having a high chemical structure that can completely control the fine microphase separation structure necessary for the expression of functions such as blood compatibility. It is a manufacturing method.

(Structure) That is, the present invention relates to poly (2-methyl trimethylene.
(Glycol) with a tosyl group at both terminal hydroxyl groups, α-
Tosyl-ω-tosyl oxypoly (2-methyl trimethylene glycol) was synthesized and reacted with the alkali metal alcoholate of poly (ethylene glycol) to regulate the block structure of the poly (ethylene glycol) block (block A). ) And a poly (2-methyl trimethylene glycol) block (block B) with the following structure: ABA type block copolyether glycol The total number average molecular weight of the ABA type block copolyether glycol is in the range of 300 to 35,000, and the number average molecular weight of the B block portion is in the range of 300 to 5,000.

Tosylation of hydroxyl groups at both terminals of poly (2-methyl trimethylene glycol) is achieved by reacting poly (2-methyl trimethylene glycol) with butyl lithium to obtain poly (2-methyl trimethylene glycol) lithium alcoholate. It is characterized by reacting this with p-toluene sulfonyl chloride, and is characterized by using sodium alcoholate or potassium alcoholate as the metal alcoholate of poly (ethylene glycol).

If necessary, it is produced in combination with a purification method such as column chromatography.

Next, a concrete synthesizing method will be specifically shown by Examples.

An example of synthesizing poly (2-methyl trimethylene glycol) corresponding to the B-type block portion of the ABA type block copolyether glycol production of the present invention is shown. This synthesis is carried out by a known method as shown in JP-A-58-126828.

[Poly (2-methyl trimethylene glycol) (:
Synthesis example of PMTG hereinafter)] Metallic sodium was added to 3-methyl oxetane dehydrated by adding granular caustic potash, and distilled at atmospheric pressure at 67 to 68 ° C.
Put 25 ml in a flask with nitrogen replaced and dry ice-
Cool to −70 ° C. in a methanol bath. Acetic anhydride 0.33 ml (3.23 × 10 ^-3 mol), 1,4 butanediol 1 ml (1.
After adding 12 × 10 ^-2 mol), perchloric acid 0.30 ml (3.49 × 10
^-3 mol) was gradually added dropwise. It takes about 2 hours to reach room temperature (15
The temperature was raised to ~ 25 ° C), and the mixture was allowed to stand at that temperature for about 100 hours to allow the polymerization reaction to proceed. After completion of the reaction, about 3 times the amount of water was added, and the mixture was heated with stirring at a temperature of 80 to 90 ° C for 2 hours. Approximately 50m of 1 / 2N alcoholic KOH is added to the organic layer except the water layer.
Then, the mixture was refluxed under stirring for 2 hours to change both ends of the polymer to diol type. After adding a small amount of benzene, the solvent of the reaction system was distilled off. Ethyl ether was added to the residue to dissolve it, and then the mixture was filtered. The filtrate was treated with activated carbon to decolorize it and then filtered again. The ether was distilled off from the filtrate to obtain a product of the polymerization reaction. Vapor Pressure of the obtained product or PMTG
The number average molecular weight (using tetrahydrofuran as a solvent) by Osmometer (Knauer) was 800.

Example 1 α-tosyl-ω-tosyl oxypoly (2-methyl.
Synthesis of trimethylene glycol (abbreviated as DTs-PMTG hereinafter) 10 g (0.0125 mol) of PMTG (Mn = 800) was dissolved in benzene to make the total volume 50 ml. The reaction system maintained in an N ₂ atmosphere was cooled to about 4 ° C., 20 ml of a hexane solution of butyllithium (abbreviated as LiBu) (LiBu is 0.0375 mol) was rapidly added to the mixture under stirring, and then p-toluenesulfonyl chloride ( A solution obtained by dissolving 7.15 g (0.0375 mol) of TsCl in about 5 ml of benzene was added dropwise. The temperature was raised to room temperature, and the mixture was reacted under stirring for about 12 hours. After the reaction was completed, the reaction solution was filtered, and benzene was distilled off from the filtrate.

Since the product contained unreacted TsCl, unreacted PMTG, and low molecular weight tosyl compound, purification was performed by column chromatography.

A glass column having an inner diameter of 2.5 cm and a height of 80 cm was used, and silica gel No. II-A (250 g of Hanai Chemical Co., Ltd.) was used as a carrier. The composition of the eluent was 0-1.5 n-. Hexane, ethyl acetate, methylene chloride = 700/250/70 (vol), 1.
The range of 5 to 2.5 is n-hexane, ethyl acetate, methylene chloride, acetone = 700/250/70/50 (vol), and the range of 2.5 to 3.0 is n-hexane, ethyl acetate, acetone = 400/400 /
A mixed eluent of 200 (vol) was used. Flow rate is about 50 ml / hr
Adjusted to.

Separation of the target product DTs-PMTG was confirmed by thin layer chromatography of the outflow fraction.

Under this condition, DTs-P
MTG is separated.

Poly (ethylene glycol) ・ Poly (2-methyl ・
(Trimethylene glycol) ABA type block copolyether glycol synthesis (abbreviated as PEMG hereafter) A graduated cylinder with a cock in the center mouth, and a 500 ml three-necked flask equipped with reflux condensers on the left and right
5.09 g was finely crushed and put into the system, and the system was brought into a dry nitrogen atmosphere. (Polyethylene glycol PEG) (Mn = 400) 25.45g
Was dissolved in 250 ml of tetrahydrofuran THF and added to the flask, and the mixture was heated with stirring on a water bath and kept at the reflux temperature. 7.00 g of DTs-PMTG (Mn = 1,100) was dissolved in 70 ml of THF and added dropwise to the system. After reacting for 24 hours, the temperature was lowered to room temperature. The precipitate was removed by filtration, the filtrate was neutralized with 1 / 2N hydrochloric acid, the aqueous phase was removed using a separatory funnel, and a small amount of benzene (3
Add ~ 5 ml), stir and let stand, and the solution will separate into two layers (benzene + THF layer and water + THF layer). Benzene + TH
The F layer is taken out, the solvent is distilled off with an evaporator, the residue is dissolved in 100 ml of water, placed in a separating funnel, and 5 ml of benzene is added and stirred. Since the solution was separated into a benzene layer and a micelle layer, the micelle layer was taken out, and the solvent was distilled off with an evaporator to obtain PEMG.

Vapor Pressure Osmometer of the obtained PEMG (Knauer)
The number average molecular weight (using tetrahydrofuran as a solvent) was 1,615 and was measured using a pycnometer.
The specific gravity at 5 ° C was 1.053. The infrared absorption spectrum is shown in FIG. Absorption due to the terminal hydroxyl group is observed at 3,400 cm ^-1 , and absorption due to the ether bond is observed at 1,080 cm ^-1 .

Further, the glass transition temperature measured with a scanning differential calorimeter DSC-2 manufactured by Perkin Elmer at a heating rate of 10 ° C./min is shown in FIG.
It was -70.1 degreeC as shown in FIG.

Structure confirmation of PEMG Fig. 3 shows proton / NMR of PEMG obtained by the above-mentioned synthesis method from poly (2-methyltrimethylene glycol) PMTG having a number average molecular weight of 800 and poly (ethylene glycol) PEG having a number average molecular weight of 400 ( The spectrum is shown in FIG. The attribution of each peak in the spectrum corresponds to the number of each hydrogen in the structural formula in FIG. 3 and the number of the peak. In addition, in order to quantify the terminal hydroxyl groups of PEMG, PE
MG was reacted with trichloro-acetyl-isocyanate to urethane the terminal hydroxyl group, and a spectrum was obtained by proton NMR (400 MHz). The urethane-terminated PEMG is abbreviated as PEMG-TCAI, and the measurement results are shown in FIG. In FIG. 4, the number of each hydrogen in the structural formula is associated with the number of the spectrum, and the attribution of absorption by each proton is shown.

The composition ratio of the PEG block and the PMTG block in PEMG can be determined from the ratio of the integrated values of peak (1) and peak (2) in Fig. 4, and the peak (1 ') and peak corresponding to the end of the PEG block The molecular weight of the PEG block part can be determined from the ratio of the integrated values of (1).

From the above measurement results, PEMG having a number average molecular weight of 1,600 having PEG blocks having a number average molecular weight of 400 on both sides of a PMTG block having a number average molecular weight of 800, and having hydroxyl groups at both ends, namely poly (ethylene glycol) poly (2- It was confirmed that ABA type block copolyether glycol (methyl methyl trimethylene glycol) was used.

Example 2 10 g (9.62 × 10 ⁻³ mol) of poly (2-methyltrimethylene glycol) (PMTG) having a number average molecular weight of 1,040 was dissolved in benzene to make 100 ml, and the reaction system was placed in a nitrogen atmosphere. Hold at about 4 ° C. 20.0 ml of a hexane solution of butyl lithium (hereinafter abbreviated as LiBu) while stirring the reaction system
(LiBu is 28.85 × 10 ^-3 mol) was quickly added, and then 5.50 g (28.85 × 10 ^-3 mo) of p-toluenesulfonyl chloride was added.
A solution of l) in about 10 ml of benzene was added dropwise. After the dropping was completed, stirring was continued for 12 hours. The reaction solution was filtered, and benzene was distilled off from the filtrate. In this product, unreacted p-toluenesulfonyl chloride, unreacted
Since it contained PMTG and low molecular weight tosyl compounds, it was purified by column chromatography. Purification conditions are in Example 1
Is the same as.

Using this α-tosyl-ω-tosyl oxypoly (2-methyl trimethylene glycol) poly (ethylene glycol) poly (2-methyl trimethylene glycol) ABA type block copolyether glycol (PEMG) Was synthesized.

On the other hand, 4.15 g of caustic soda was finely crushed and placed in a 500 ml three-necked flask equipped with a graduated cylinder with a cock and a reflux condenser, and the reaction system was placed in a dry nitrogen atmosphere, and then 51.85 g of polyethylene glycol (number average molecular weight 1,000) was added. The solution dissolved in 500 ml of tetrahydrofuran was added to the flask and heated at a reflux temperature by heating while stirring on a water bath. Α-Tosyl-ω-tosyl oxypoly (2-methyl trimethylene glycol) purified on this
(Number average molecular weight 1,348) 7.00 g of tetrahydrofuran 70
The solution dissolved in ml was added dropwise. After reacting for 24 hours, the mixture was cooled to room temperature, filtered to remove the precipitate, and the filtrate was neutralized with 1 / 2N hydrochloric acid. The water tank was removed with a separatory funnel, 5 ml of benzene was added, and the mixture was allowed to stand with stirring, the separated benzene-tetrahydrofuran layer was taken out, and the solvent was distilled off with an evaporator. Dissolve the residue in 100 ml of water, put in a separatory funnel, add 5 ml of benzene and stir. Since the solution was separated into a benzene layer and a micelle layer, the micelle layer was taken out and the solvent was distilled off with an evaporator to obtain PEMG.

This product had a number average molecular weight of 3,050 as measured by a Vapor Pressure Osmometer, and a proton NMR (400 MHz) spectrum of the product in which the terminal hydroxyl group was urethanized with trichloroacetyl isocyanate was obtained as in Example 1. From this analysis result, it was confirmed that PEMG having hydroxyl groups at both ends, in which a polyethylene glycol block having a number average molecular weight of 1,000 was added to both sides of a poly (2-methyltrimethylene glycol) block having a number average molecular weight of 1,040, was obtained.

(Effects of the Invention) The method for producing a block copolyether glycol of the present invention is a method for obtaining an ABA type block copolyether glycol having an extremely high purity in terms of chemical structure capable of completely controlling a fine microphase-separated structure. Its specific application is useful in the field of blood-compatible medical materials and separation membranes utilizing mechanical properties.

[Brief description of drawings]

FIG. 1 shows an infrared absorption spectrum of poly (ethylene glycol) poly (2-methyl trimethylene glycol) of the present invention. FIG. 2 shows the measurement results of the scanning differential calorimeter of poly (ethylene glycol) poly (2-methyl trimethylene glycol) of the present invention. 3 and 4 show the poly (ethylene glycol) poly (2-methyl trimethylene glycol) of the present invention.
The nuclear magnetic resonance absorption spectrum of is shown.

Claims (3)

[Claims] 1. A tosyl group is introduced into hydroxyl groups at both terminals of poly (2-methyl trimethylene glycol) to synthesize γ-tosyl-ω-tosyl oxypoly (2-methyl trimethylene glycol). The following consisting of a poly (ethylene glycol) block (block A) and a poly (2-methyl trimethylene glycol) block (block B) (block structure is regulated) by reacting ethylene glycol) with an alkali metal alcoholate. Structure of ABA type block copolyether glycol Manufacturing method 2. The tosylation of hydroxyl groups at both terminals of poly (2-methyl trimethylene glycol) according to claim (1) is carried out by adding butyl lithium to poly (2-methyl trimethylene glycol). A method for producing a block copolyether glycol, which comprises reacting to form a lithium alcoholate of poly (2-methyl trimethylene glycol), and reacting it with p-toluene sulfonyl chloride. 3. A method for producing a block copolyether glycol, characterized in that, as the alkali metal alcoholate of poly (ethylene glycol), sodium alcoholate or potassium alcoholate is used in claim (1).