JPH06145341A - Glycerol ether ester - Google Patents

Abstract

PURPOSE:To provide a glycerol ether ester which can be used as a surfactant and improves the stability of a drug compd. in the blood when used as a component of liposome. CONSTITUTION:The title compd. is represented by the formula wherein R<1> is a 1-24C hydrocarbon group or a 2-22C aliph. acyl group; R<2> and R<3> are each H or a 2-22C aliph. acyl group, provided at least one of R<1>, R<2>, and R<3> is the aliph. acyl group; AO is 2-4C oxyalkylene; and n is 5-1,000.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel glycerin derivative, glycerin ether ester, and more particularly to glycerin α-monopolyalkylene glycol ether ester.

[0002]

BACKGROUND OF THE INVENTION As a derivative of glycerin in which polyalkylene glycol and a fatty acid are bound, fatty acid ester of glycerin polyalkylene glycol ether, polyalkylene glycol ether of glycerin monofatty acid ester, etc. are known and used as a surfactant. ing.

[0003]

Although these compounds are prone to an addition reaction between the α-hydroxyl group and the β-hydroxyl group of glycerin, when the number of addition moles of alkylene oxide is increased, oxyalkylene groups are present in all hydroxyl groups. Similarly, all hydroxyl groups are esterified in addition and when glycerin is reacted with a fatty acid, in any case, selectively introducing an oxyalkylene group or an aliphatic acyl group into a specific hydroxyl group of glycerin. Was difficult.

An object of the present invention is to provide a glycerin α-monopolyalkylene glycol ether ester in which an oxyalkylene group is bonded only to one α-position of glycerin.

[0005]

The present invention is a glycerin ether ester represented by the formula (1).

[0006]

[Chemical 2]

(Wherein R ¹ is a hydrocarbon group having 1 to 24 carbon atoms or an aliphatic acyl group having 2 to 22 carbon atoms, R ² and R ³ are hydrogen atoms or an aliphatic acyl group having 2 to 22 carbon atoms. Yes,
At least one of R ¹ , R ² , and R ³ is an aliphatic acyl group, AO is an oxyalkylene group having 2 to 4 carbon atoms, and n is 5 to 1000. ) As the hydrocarbon group having 1 to 24 carbon atoms represented by R ¹ , a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, a heptyl group. , 2-ethylhexyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, hexadecyl group, isocetyl group, octadecyl group, isostearyl group, oleyl group, octyldodecyl group, docosyl group, Decyltetradecyl group, benzyl group, cresyl group,
There are butylphenyl group, dibutylphenyl group, octylphenyl group, nonylphenyl group, dodecylphenyl group, dioctylphenyl group, dinonylphenyl group, styrenated phenyl group, etc., straight chain, branched chain, saturated or unsaturated fat There are group hydrocarbon groups and aromatic hydrocarbon groups.

Examples of the acyl group represented by R ¹ , R ² and R ³ include acetic acid, propionic acid, butyric acid, isobutyric acid, caproic acid, caprylic acid, 2-ethylhexanoic acid, pelargonic acid, capric acid, undecylenic acid, Acyl groups derived from fatty acids such as lauric acid, myristic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, erucic acid, isopalmitic acid, isostearic acid There is.

Examples of the oxyalkylene group having 2 to 4 carbon atoms represented by AO include oxyethylene group, oxypropylene group, oxybutylene group, oxytetramethylene group and the like, and two or more kinds thereof are added. Good 2
When more than one species are added, the state of addition may be random or block. Typical methods for producing the compound of the present invention include the following methods.

1,3-Dioxolane such as isopropylidene glycerol is added with an alkylene oxide having 2 to 4 carbon atoms and then hydrolyzed to synthesize glycerin α-monopolyalkylene glycol ether, which is then used as a fatty acid or a fatty acid anhydride. A method of esterification with a fatty acid chloride or the like and represented by the following reaction formula.

[0011]

[Chemical 3]

[0012] Alcohol or phenol is subjected to an addition reaction with an alkylene oxide having 2 to 4 carbon atoms, and the resulting polyoxyalkyl ether is reacted with epihalohydrin under an acidic catalyst to obtain an α-monohalohydrin derivative of glycerin. Next, an alkali is caused to act on this to give an epoxy compound by dehalogenation alkali, and the epoxy group is further opened with an acid catalyst to obtain glycerin α-monopolyalkylene glycol ether, then fatty acid,
It is a method of esterification with a fatty acid anhydride, a fatty acid chloride or the like and is represented by the following reaction formula.

[0013]

[Chemical 4]

[0014] Alcohol or phenol is subjected to an addition reaction with an alkylene oxide having 2 to 4 carbon atoms, and the end of the obtained polyoxyalkylene ether is halogenated with a halogenating agent such as thionyl bromide. , 3-dioxolane is reacted in the presence of an alkali and then hydrolyzed to obtain glycerin α-monopolyalkylene glycol ether, which is then esterified with a fatty acid, a fatty acid anhydride, a fatty acid chloride or the like. It is represented by.

[0015]

[Chemical 5]

After reacting a dihydroxy α-monohalohydrin such as glycerin with a carbonyl compound such as acetone to obtain a 1,3-dioxolane halide,
In the presence of an alkali or by reacting with the polyoxyalkylene ether obtained in or, glycerin 1,3-
After obtaining α-polyalkylene glycol ether of dioxolane, it is hydrolyzed to synthesize glycerin α-monopolyalkylene glycol ether, which is then esterified with fatty acid, fatty acid anhydride, fatty acid chloride, etc. It is represented by.

[0017]

[Chemical 6]

[0018]

The glycerin ether ester of the present invention is a fatty acid ester in which a polyoxyalkylene group is bonded only to one α-position of glycerin. The glycerin ether ester of the present invention can be used as a surfactant, and when it is used as a component of liposome, the stability of the compound having a medicinal effect in blood can be improved.

[0019]

The present invention will be described below with reference to examples. In addition,
The unit of pressure kg / cm ² is gauge pressure, and% is% by weight. Example 1 132 g (1 mol) of isopropylidene glycerol and 2.0 g of potassium hydroxide were placed in a 5 liter autoclave, the system was replaced with nitrogen gas, and the temperature was raised to 100 ° C. to 100 to 15
2300 g (5%) of ethylene oxide under conditions of 0 ° C and 10 kg / cm ² or less
(2.2 mol) was added over 3 hours, and the reaction was continued for another hour. Next, the reaction mixture was cooled to 50 ° C. while distilling off unreacted ethylene oxide through nitrogen gas, 62.5 g (1.56 mol) of sodium hydroxide was added thereto, the atmosphere was replaced with nitrogen, and the temperature was raised to 100 ° C. with stirring. Next, methyl chloride was blown from the bomb, and the temperature was kept at 100 ° C. for 3 hours while adjusting the blowing tube so that the pressure in the container was 1 atm. Then, while blowing nitrogen gas, the mixture was cooled to 60 ° C. and excess methyl chloride was distilled off. The pH of the reaction mixture was adjusted to 1.0 with a 10% aqueous hydrochloric acid solution, and the mixture was stirred at 60 ° C. for 1 hour. Then the pH of the reaction mixture is adjusted with 50% sodium hydroxide.
The temperature was adjusted to 6.5, and acetone generated by heating at 100 ° C. and 100 mmHg or less for 1 hour was distilled off together with water, and the precipitated salt was filtered off to obtain 2073 g of the compound A represented by the formula (A).

[0020]

[Chemical 7]

The hydroxyl value of the obtained compound A was 46.6 (calculated value was 45.9) and the freezing point was 51.1 ° C. Then, in a 500 ml eggplant-shaped flask, 241 g (0.1 mol) of Compound A, 60.0 g (0.2 mol) of methyl oleate and 0.
Take 2g, and while passing nitrogen, under reduced pressure of 20mmHg, at 80 ℃ 3
After carrying out the time transesterification reaction, 1 g of Kyoward 600 (trade name, manufactured by Kyowa Chemical Industry Co., Ltd.) was added as a silica-based adsorbent, and the mixture was mixed at 80 ° C. for 1 hour in a nitrogen atmosphere and then filtered to obtain the formula (1 ) The compound (1) of the present invention represented by
I got 1g.

[0022]

[Chemical 8]

The compound (1) thus obtained has a hydroxyl value of 0.3.
(Calculated value 0), ester value was 38.7 (calculated value 38.1), and freezing point was 43.1 ° C. Example 2 241 g (0.1%) of the compound (A) obtained in the same manner as in Example 1
Mol) and 26 g (0.1 mol) of methylmyristate to obtain 255 g of the compound (2) of the present invention represented by the formula (2).

[0024]

[Chemical 9]

The compound (2) thus obtained has a hydroxyl value of 21.0.
(Calculated value 21.4), ester value was 21.5 (calculated value 21.4), and freezing point was 48.2 ° C. Example 3 Hereinafter, a block adduct of ethylene oxide and propylene oxide was synthesized in the same manner as in Example 1, and methyl laurate was reacted in the same manner as in Example 1 to give a compound of the present invention represented by the formula (3). Compound (3) was obtained.

[0026]

[Chemical 10]

The hydroxyl value of the obtained compound (3) is 0.2.
(Calculated value 0), ester value was 102 (calculated value 101), and freezing point was 8.2 ° C. Example 4 30 g (0.23 mol) of isopropylidene glycerol and 6.3 g of potassium hydroxide were placed in a 5-liter autoclave, the system was replaced with nitrogen gas, and the temperature was raised to 100 ° C. 100
Premixed ethylene oxide (3500 g, 79.4 mol) and propylene oxide (13) under conditions of ~ 150 ° C and 10 kg / cm ² or less.
A mixture of 18 g (22.7 mol) was added over 5 hours, and the reaction was continued for another hour. Next, after cooling to 50 ° C while distilling off unreacted ethylene oxide through nitrogen gas,
Adjust the pH of the mixture to 1.0 with 10% aqueous hydrochloric acid and
The mixture was stirred at 60 ° C for 1 hour. Next, adjust the pH of the mixture to 6.5 with 50% sodium hydroxide and adjust to 100 ° C and 100 mmHg or less to 1
Acetone generated for a period of time was distilled off together with water, and the precipitated salt was filtered off to obtain 4790 g of the compound B represented by the formula (B).

The hydroxyl value of compound B was 8.1 (calculated value 8.0).

[0029]

[Chemical 11]

Next, 480 g (0.023 mol) of compound B was added to 9.4 g (0.047 mol) of lauric acid and 1.5 g of paratoluenesulfonic acid.
Then, the esterification reaction is carried out at 90 to 100 ° C under a nitrogen atmosphere under a reduced pressure of 30 mmHg or less for 5 hours. After the reaction, Kyoward 600 (Kyowa Chemical Industry Co., Ltd.) 1.5
g was added, and the mixture was treated at 80 ° C. for 1 hour in a nitrogen atmosphere and then filtered to obtain 479 g of the compound (4) of the present invention represented by the formula (4).

[0031]

[Chemical 12]

The hydroxyl value of compound (4) was 2.6 (calculated value 2.
7), and the ester value was 5.4 (calculated value 5.3). Example 5 491 g (1.5 mol) of docosyl alcohol and sodium hydroxide
6.2 g was put into a 5 liter autoclave, the system was replaced with nitrogen gas, and then the temperature was raised to 100 ° C, 100-150 ° C, 10 kg /
Under the condition of cm ² or less, 1450 g (32.9 mol) of ethylene oxide was added for 3 hours, and then 1188 g (16.5 mol) of 1,2-butylene oxide was added over 1 hour for reaction, and the reaction was continued for another 1 hour. Next, this reaction product was cooled to 80 ° C., neutralized with diluted hydrochloric acid, dehydrated under reduced pressure with an evaporator, and then the salt produced by filtration was removed to obtain an ethylene oxide-butylene oxide block of docosyl alcohol represented by the formula (C). 2850 g of polymer C was obtained. The hydroxyl value of the obtained compound (C) was 29.0 (calculated value 27.1).

CH ₃ (CH ₂ ) ₂₁ O (CH ₂ CH ₂ O) ₂₀ (C ₄ H ₈ O) ₁₀ H (C) Next, compound C 2500 g (1.3 mol) and tin tetrachloride 3.5 g are added to a 5 liter autoclave. After substituting the inside of the system with nitrogen gas, add 125 g (1.4 mol) of epichlorohydrin over 1 hour under the conditions of 50 to 70 ° C. and 3 kg / cm ² or less, and then further
The reaction was continued for 30 minutes. Thereafter, 390 g of a 20% aqueous sodium hydroxide solution was added, and the mixture was stirred at 70 to 80 ° C. for 2 hours and allowed to stand for 30 minutes, then the separated aqueous layer (lower layer) was removed, and washed with 1 liter of water twice. After washing with water, transfer to a four-neck flask and
% Aqueous sulfuric acid solution (2 liters), and the mixture is stirred at 80 to 90 ° C for 3 hours and allowed to stand for 30 minutes, and then the separated aqueous layer (lower layer) is removed.
After further washing twice with water of 1 liter each, dehydration under reduced pressure with an evaporator and filtration were carried out to obtain 2510 g of monoglyceryl ether D of the ethylene oxide-butylene oxide block polymer of docosyl alcohol represented by the formula (D). . The hydroxyl value of the obtained compound D is 56.0 (calculated value 56.1).
Met.

[0034]

[Chemical 13]

Next, compound D30 was added to a 500 ml four-necked flask.
0 g (0.15 mol) and 10 g of pyridine were taken, and 31.6 g (0.31 mol) of acetic anhydride was added dropwise at 90 to 100 ° C under a nitrogen atmosphere for esterification. After esterification reaction, under reduced pressure of 30 mmHg or less
Pyridine and acetic acid were distilled off at 80 ° C, 1.0 g of KYOWARD 300 (Kyowa Chemical Industry Co., Ltd.) was added as a silica-based adsorbent, and the mixture was treated at 80 ° C for 1 hour in a nitrogen atmosphere and then filtered to obtain the formula (5 290 g of the compound (5) of the present invention represented by

[0036]

[Chemical 14]

The hydroxyl value of the compound (5) was 0.1 (calculated value 0) and the ester value was 53.6 (calculated value 53.8).

[Brief description of drawings]

FIG. 1 is an infrared absorption spectrum diagram of the compound (2) of the present invention.

Claims (1)

[Claims] 1. A glycerin ether ester represented by the formula (1). [Chemical 1] (In the formula, R ¹ is a hydrocarbon group having 1 to 24 carbon atoms or 2 carbon atoms.
~ 22 aliphatic acyl groups, R ² and R ³ are hydrogen atoms or C 2-22 aliphatic acyl groups, R ¹ , R ² ,
At least one of R ³ is an aliphatic acyl group, AO is an oxyalkylene group having 2 to 4 carbon atoms, and n is 5 to 1000. )