JPH06157506A - Production of isopropylidenebenzylglycerol - Google Patents

Abstract

PURPOSE:To efficiently and safely produce 1,2-O-isopropylidene-3-O- benzylglycerol which is a starting raw material for lipid synthesis at ambient temperature in a short time and at a high yield by simple reactional process without producing any byproduct. CONSTITUTION:1,2-O-Isopropylidene glycerol is made to react with a benzyl halide in a nonpolar solvent in the presence of a phase-transfer catalyst consisting of a quaternary ammonium salt and an alkali metal hydroxide and water.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing 1,2-O-isopropylidene-3-O-benzylglycerol which is a starting material for synthesizing acylglycerol and phospholipid.

[0002]

2. Description of the Related Art Diacylglycerols and phospholipids having stereospecificity have been attracting attention from the fields of pharmaceuticals, cosmetics and foods as compounds showing physiological activity due to recent advances in biochemistry. In order to synthesize these lipids, methods using starting materials that can define the stereospecificity and regiospecificity of the glycerin skeleton of the target have been investigated.

Conventionally, isopropylidenebenzyl glycerol, epichlorohydrin, glycidol, benzyl glycidyl ether, benzyl glycidyl ditosylate, chlorohydroxybutyronitrile, chloropropanediol and the like are known as compounds conventionally used as these starting materials. Has been.

In particular, the following method is known as a method for synthesizing isopropylidenebenzyl glycerol. 1) A method in which isopropylidene glycerol and benzyl halide are made into a toluene solution and heated to reflux with sodium metal as a catalyst to react (J. Chem. Soc., 5
91 , 2663, 1951). 2) A method of reacting isopropylidene glycerol and benzyl halide in a dehydrated ethyl ether solution by heating under reflux with sodium metal as a catalyst (J. Am. Che.
m. Soc. , 63 , 3244, 1941).

However, in the above methods 1) and 2), heating of metal sodium, which has a high risk, as a catalyst for 12 hours or more,
There is a problem in that reflux is necessary, and in order to improve the yield, it is necessary to use more dangerous metal potassium or more expensive alkyl halide. Further, toluene and ethyl ether which are reaction solvents are industrially unsuitable solvents because they have a high boiling point or a high volatility and must be used as an anhydride. Furthermore, the yield of isopropylidenebenzyl glycerol by these synthetic methods is reported to be 66 to 71%, but in the follow-up experiment conducted by the present inventors, it was 45%.
There is also a problem that the yield is low because only a moderate yield is obtained.

There is known a method of synthesizing 1,3-diacylglycerol from benzyl glycidyl ether and a fatty acid by adding a quaternary ammonium salt as a phase transfer catalyst in the presence of an alkali metal hydroxide aqueous solution (J. Am. Oil
Chem. Soc. , 66 , 822, 1989). However, this method is a completely different reaction system in which the starting material and product are different from those of the present invention, the reaction scale is very small, and it is necessary to continue holding ethanol for 20 hours or more while heating under reflux. Furthermore, after completion of the reaction, the reaction solution requires a treatment step such as solvent washing, silica gel column separation, and centrifugal separation / liquid chromatography purification, which is not suitable for an industrial synthetic method.

A method for synthesizing an alkyl glycidyl ether as a starting material of 1-O-alkyl-glyceryl ether from epichlorohydrin and an aliphatic alcohol by adding a quaternary ammonium salt as a phase transfer catalyst in the presence of an aqueous alkali metal hydroxide solution. Is known (J. Am. Oi
Chem. Soc. , 65 , 1299, 198
8). However, this method also differs from the present invention in starting materials and products, is a completely different reaction system, and requires three-step reaction to synthesize 1-O-alkyl-glyceryl ether from epichlorohydrin, In addition, it is necessary to isolate each product and carry out an individual reaction in the middle of the reaction in which two kinds of products are formed, and the reaction process is complicated.

[0008]

SUMMARY OF THE INVENTION The object of the present invention is to carry out a simple reaction step without producing a by-product, a short reaction time, an efficient, safe and high yield of 1,2-
It is to propose a method for producing O-isopropylidene-3-O-benzylglycerol.

[0009]

The present invention is directed to 1,2-O-
In a method for producing 1,2-O-isopropylidene-3-O-benzylglycerol by reacting isopropylidene glycerol with benzyl halide, the presence of a quaternary ammonium salt, an alkali metal hydroxide and water in a non-polar solvent A method for producing 1,2-O-isopropylidene-3-O-benzylglycerol, which comprises reacting 1,2-O-isopropylideneglycerol and benzyl halide below.

In the production method of the present invention, 1,2-O-isopropylidene-glycerol, which is one of the starting materials, is 1,2-O-isopropylidene-rac-glycerol and (+)-1,2-O. -Any chirality such as isopropylidene-sn-glycerol can be used. In this case, the chirality of the reaction product can be specified by selecting the chirality of the starting material. For example, if (+)-1,2-O-isopropylidene-sn-glycerol is used as a starting material,
The reaction product is (+)-1,2-O-isopropylidene-3, which is a starting material for synthesizing a lipid having a natural three-dimensional structure.
-O-benzyl-sn-glycerol was obtained, 1,2
Starting from -O-isopropylidene-rac-glycerol, 1,2-O-isopropylidene-3-O-
Benzyl-rac-glycerol is obtained.

As the other starting material, benzyl halide, benzyl chloride, benzyl bromide or the like can be used. The starting material is used in a ratio of 1,2-O-isopropylideneglycerol and benzyl halide in an equimolar ratio, so that the molar ratio of 1,2-O-isopropylideneglycerol: benzyl halide is 1: 1 to 1: 1. 1.
It is desirable that the ratio is 4, preferably 1: 1 to 1: 1.2.

The non-polar solvent used in the present invention is n
Hydrocarbon type compounds represented by -hexane, n-heptane, petroleum ether and cyclohexane are preferable. The amount of the non-polar solvent used is 500 to 1000 ml, preferably 600 to 800 ml per 1 mol of 1,2-O-isopropylideneglycerol.

Examples of the quaternary ammonium salt used in the present invention include decyltrimethylammonium chloride, octadecyltrimethylammonium chloride, octadecyl-methyl-bis-polyoxyethylene (4) ammonium hydrogen chloride, and tetra-n-butylammonium bromide. , Tetra-n-butylammonium hydrogensulfate, dodecyl-dimethyl-carboxymethylammonium betaine, octadecyl-dimethyl-carboxymethylammonium betaine and the like.

The amount of the quaternary ammonium salt used is 1,2-
O-isopropylidene glycerol is 0.
It is preferably from 0.1 to 0.1 mol, and more preferably from 0.04 to 0.06 mol. By using such an amount, the target product can be obtained in a short time and in a high yield.

Examples of the alkali metal hydroxide used in the present invention include sodium hydroxide and potassium hydroxide. The amount of these used is 0.5 to 3 mol, preferably 1.5 to 2.5 mol per 1 mol of 1,2-O-isopropylideneglycerol. By using such an amount, the target product can be obtained in a short time and in a high yield.

In the production method of the present invention, the quaternary ammonium and the alkali metal hydroxide are used together with water and used as a phase transfer catalyst. The amount of water used is 1,2-O
50 to 50 mol / mol of isopropylidene glycerol
It is desirable that the amount is 400 ml, preferably 150 to 200 ml.

In the reaction, 1,2-O-isopropylidene glycerol and benzyl halide are dissolved in a non-polar solvent,
A method of adding an aqueous alkali metal hydroxide solution and a quaternary ammonium salt to this solution, a method of adding water, an alkali metal hydroxide and a quaternary ammonium salt to a solution in which both starting materials are dissolved, and both starting materials It is possible to employ a method of adding a quaternary ammonium salt aqueous solution and an alkali metal hydroxide to a solution in which is dissolved. In either case, the nonpolar solvent and water are separated into two layers, so it is preferable to carry out stirring.

The reaction conditions are preferably a temperature of 10 to 30 ° C., preferably 15 to 25 ° C., and may be room temperature.
The pressure may be normal pressure. The reaction time is 4 to 7 hours, preferably 5 to 6 hours.

After completion of the reaction, the aqueous layer is removed, the non-polar solvent layer is washed with water, the solvent is distilled off, and the residue is distilled under reduced pressure. 1,2-O-isopropylidene-3
-O-benzylglycerol can be separated.

The thus obtained 1,2-O-isopropylidene-3-O-benzylglycerol can be used as a starting material for synthesizing a lipid having a natural structure. For example, this compound is acylated at the sn-1 and -2 positions under acidic conditions to induce 1,2-diacylbenzylglycerol having an arbitrary acyl chain, and debenzylation of the diacyl compound is followed by phosphorylation. Further, addition of various bases can produce phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, etc. (for example, Chemistry).
and Physics of lipids, 2
6 , 405, 1980).

[0021]

As described above, according to the present invention, 1,2-O-isopropylidene glycerol and benzyl halide are added in the presence of a quaternary ammonium salt, an alkali metal hydroxide and water in a non-polar solvent. Since 1,2-O-isopropylidene-3-O-benzylglycerol was produced by the reaction, the following effects can be obtained. 1) The reaction process is simple. 2) No by-products are produced. 3) The reaction proceeds even at room temperature, and the reaction time is short. 4) Good reaction efficiency. 5) It is safe because it does not use dangerous substances such as metallic sodium and metallic potassium. 6) The target product can be obtained in high yield.

[0022]

The present invention will be described in more detail with reference to the following examples. In the text, percentages represent% by weight. Example 1 (Production Example 1 of 1,2-O-isopropylidene-3-O-benzylglycerol) In a 500 ml eggplant-shaped flask, 13.3-g (0.1 mol of 1,2-O-isopropylidene-rac-glycerol) ) And 13.0 g (0.1 mol) of benzyl chloride were weighed, and 70 ml of cyclohexane was further added to dissolve them. To this solution, 1.7 g (0.005 mol) of tetra-n-butylammonium hydrogensulfate and 20 ml of 50% potassium hydroxide aqueous solution were added, and the mixture was vigorously stirred at room temperature.

After 5 hours, thin layer chromatography (TL
C, mobile phase: n-hexane / ethyl ether / acetic acid, 7
A spot having an Rf value of 0.25 indicating the formation of the desired product was confirmed with 0/30/1, a coloring agent: 2 ', 7'-dichlorofluorescein reagent), and then the reaction solution was transferred to a separating funnel. The aqueous layer was removed, and the cyclohexane layer was washed well with water. After the cyclohexane layer was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain a yellow oily substance.

This oily substance was distilled under reduced pressure to give a boiling point of 114-1.
A colorless liquid substance (1,2-O-isopropylidene-3-O-benzyl-rac-glycerol) at 15 ° C / 3 mmHg was obtained. The yield was 19.5 g (yield 87.1%). The analytical values of this product are as follows.

1) TLC; Mobile phase: n-hexane / ethyl ether / acetic acid, 70 /
30/1 2 ', 7'-dichlorofluorescein reagent Color development: yellow Rf value: 0.25 (1 point) 2) Mass spectrum; m / z 222 [M] ⁺ 3) Specific gravity; d = 1.03 g / ml 4) ¹ H-NMR; δ (CDCl ₃ , ppm) 1.34 (C-CH ₃ , s, 3H), 1.40 (C-C).
_{H 3, s, 3H),} 3.49 (sn-3, -CH 2 -O,
m, 1H), 3.72 (sn -1, -CH 2 -O, t,
1H), 4.01 (sn-1 , -CH 2 -O, t, 2
H), 4.29 (sn-2, = CH-O, q, 1H),
_{4.54 (O-CH 2 -,} s, 2H), 7.30 (-C 6
H ₅ , s, 5H)

Example 2 (Production Example 2 of 1,2-O-isopropylidene-3-O-benzylglycerol) (+)-1,2-O-isopropylidene-sn-glycerol 13 was put in a 500 ml eggplant type flask. 0.3 g (0.
1 mol) and 17.1 g (0.1 mol) of benzyl bromide
Were weighed, and 70 ml of hexane was added to dissolve them. To this solution, 1.6 g (0.005 mol) of tetra-n-butylammonium bromide and 20 ml of 40% sodium hydroxide aqueous solution were added, and the mixture was vigorously stirred at room temperature.

After 5 hours, TLC (mobile phase: n-hexane / ethyl ether / acetic acid, 70/30/1, coloring agent:
2 ', 7'-dichlorofluorescein reagent) was used to confirm spots with an Rf value of 0.25 indicating the formation of the desired product, then the reaction solution was transferred to a separating funnel to remove the aqueous layer, and the cyclohexane layer was washed thoroughly with water. did. The hexane layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to give a yellow oil.

This oily substance was distilled under reduced pressure to give a boiling point of 114-1.
Colorless liquid at 15 ° C / 3mmHg ((+)-1,2-
O-isopropylidene-3-O-benzyl-sn-glycerol) was obtained. The yield was 17.9 g (yield 80.0
%)Met. The analytical values of this product are as follows.

1) TLC; the same conditions as in Example 1 Rf value: 0.25 (1 point) 2) Mass spectrum; m / z 222 [M] ⁺ 3) Specific gravity; d = 1.03 g / ml 4) ¹ _{H-NMR; δ (CDCl 3} , ppm) 1.34 (C-CH 3, s, 3H), 1.40 (C-C
_{H 3, s, 3H),} 3.49 (sn-3, -CH 2 -O,
m, 1H), 3.72 (sn -1, -CH 2 -O, t,
1H), 4.01 (sn-1 , -CH 2 -O, t, 2
H), 4.29 (sn-2, = CH-O, q, 1H),
_{4.54 (O-CH 2 -,} s, 2H), 7.30 (-C 6
H ₅ , s, 5H)

Comparative Example 1 1,3-O-isopropylidene-rac-glycerol (13.3 g, 0.1 mol), metallic sodium (2.3 g, 0.1 mol) and dehydrated toluene (50 ml) were placed in a 500 ml eggplant type flask. It was weighed out and heated under reflux for 20 hours under dehydration conditions. Furthermore, 39.0 g of benzyl chloride
(0.3 mol) was added and heating under reflux was continued for 70 hours.

Then, sodium chloride precipitated in the reaction vessel was filtered off, and the reaction solution was washed with dehydrated toluene. Toluene was removed from the reaction solution under reduced pressure, and further unreacted 1,2-O-isopropylidene-distilled by vacuum distillation at 110 ° C.
rac-Glycerol and benzyl chloride were removed to obtain a colorless liquid substance. Yield 10.1g (Yield 45.0
%)Met. The analytical values of this product are as follows.

1) TLC; the same conditions as in Example 1 Rf value: 0.25 (1 point) 2) Mass spectrum; m / z 222 [M] ⁺ 3) Specific gravity; d = 1.03 g / ml

Claims (1)

[Claims] 1. A method for producing 1,2-O-isopropylidene-3-O-benzylglycerol by reacting 1,2-O-isopropylideneglycerol with benzyl halide, which comprises: 1,2-O in the presence of ammonium salt, alkali metal hydroxide and water
-A method for producing 1,2-O-isopropylidene-3-O-benzylglycerol, which comprises reacting isopropylideneglycerol with benzyl halide.