JPH0219113B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing α-acetyllactones.

The α-acetyllactones in the present invention have the general formula (In the formula, n means an integer of 1 to 4.) It is a compound represented by:

Among these α-acetyllactones, for example α
-Acetyl-γ-butyrolactone is a vitamin
It is well known as a useful synthetic intermediate for _B1 .
Furthermore, cyclopropyl methyl ketone derived from α-acetyl-γ-butyrolactone is an important intermediate in the five-carbon carbonization process for forming isoprenoid skeletons that exist in large numbers in nature. on the other hand,
The present inventor has discovered that these α-acetyllactones are useful raw materials for synthesizing 1-[(ω-1)oxoalkyl]theobromine, which is used as an agent for improving sequelae caused by cerebral thrombosis. .

Conventionally, methods for producing these α-acetyllactones include a method of carrying out an ester condensation reaction between lactones and acetate or its derivatives in the presence of a basic substance (Japanese Patent Publication No. 31-5370, Japanese Patent Publication No. 31-1989).
8271), or a method in which acetoacetic ester and ethylene oxide are reacted in alcohol using sodium alcoholate or caustic soda (Japanese Patent Publication No. 12662-1982). However, the former method produces acetoacetate or a condensation reaction product of two molecules of lactone as a by-product, and is therefore not preferred when expensive lactones are used. In addition, the latter method uses α-acetyl-γ
-Applicable only to the synthesis of butyrolactone.

Therefore, an object of the present invention is to provide a method for producing α-acetyllactones that produces few by-products and has a wide range of applicability.

The method for producing α-acetyllactones according to the present invention has the general formula (In the formula, X means a halogen or RSO ₂ O group, R means an alkyl group or an aryl group, and n means an integer from 1 to 4.) By alkylation reaction, the general formula (In the formula, n means an integer of 1 to 4).

The compound represented by the general formula () (hereinafter,
After the reaction of diketene with ω-haloalcohols or the reaction of diketene with diols, the hydroxyl group is halogenated with a halogenating agent such as thionyl chloride or phosphorus tribromide, or with methanesulfone. It can be easily obtained in high yield by reacting acid chloride, p-toluenesulfonic acid chloride, etc. to sulfonylation.

The intramolecular alkylation reaction of the compound is carried out in the presence of a basic substance, thereby making it possible to obtain the compound. Basic substances used in the intramolecular alkylation reaction include alkali metals such as lithium and sodium; metal alcoholates such as sodium ethoxide and potassium t-butoxide; metal hydrides such as sodium hydride and lithium hydride; water Metal hydroxides such as sodium oxide and potassium hydroxide; bicarbonates such as sodium bicarbonate and potassium bicarbonate;
Hydrogen abstracting agents such as carbonates such as soda carbonate and potassium carbonate; amines such as triethylamine, pyridine, pyrrolidine, and diazabicycloundecene can be used.

The reaction takes place in a solvent. The solvent used in the reaction varies depending on the combination with the above-mentioned basic substance, but ordinary organic solvents can be used, such as hydrocarbon solvents such as benzene and toluene; ether, tetrahydrofuran, etc. Ether solvents; halogenated hydrocarbon solvents such as chloroform and methylene chloride; alcohols such as ethanol and t-butanol; dimethylformamide,
Amide solvents such as N-methylpyrrolidone; dimethylsulfoxide and the like can be mentioned. Also,
The amount of the basic substance used in the reaction is sufficient as long as it is equivalent to or more than the amount of the compound.
It is assumed to be 1.0 to 1.2 equivalents. The reaction starts from around 0℃ to 150℃
Although the reaction proceeds up to around 0.9°C at any temperature, the optimum temperature is determined by the basic substance or solvent used. Usually, it is preferable to carry out the reaction at a temperature between room temperature and around 100°C.

It is possible to obtain the target compound under the above conditions, but in order to increase the reaction rate, moderate the reaction conditions, or increase the reaction yield, metal iodides such as sodium iodide, potassium iodide, etc. Quaternary ammonium salts such as benzyltrimethylammonium chloride and tetraethylammonium chloride;
18-crown-6, dibenzo-18-crown-6
When used in combination with crown ethers such as, the compound can be obtained in high yield.

The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto.

Example 1 (Production of α-acetyl-γ-butyrolactone) 165 g of acetoacetic acid 2-chloroethyl ester
(1.0 mol) to 500 ml of t-butanol and 118 g (95%, 1.0 mol) of potassium t-butoxide are added. After stirring the reaction solution under heating and reflux for 10 hours,
Cool to room temperature. The reaction solution was neutralized by adding cold HCl water, and then extracted with benzene. After drying the organic layer over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The remaining oil was distilled under reduced pressure to obtain α
- Acetyl-γ-butyrolactone 102g (80%,
(boiling point 106-108°C/5mmHg) was obtained.

Example 2 (Production of α-acetyl-δ-valerolactone) 179 g of acetoacetic acid 3-chloropropyl ester
(1.0 mol) is slowly added to 500 ml of xylene and 23 g (1.0 mol) of finely granulated sodium at room temperature.
After the metal sodium has disappeared by heating slowly, the reaction is carried out under heating and reflux for 10 hours. After cooling the reaction solution, it is added to a cold 5% aqueous sulfuric acid solution to neutralize it. Extract with benzene and dry the organic layer over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the remaining oil was distilled to yield 99 g of α-acetyl-δ-valerolactone (70%, boiling point 134-140°C/4 mm
Hg) obtained.

Claims (1)

[Claims] 1. General formula (In the formula, X means a halogen or an RSO ₂ O group, R means an alkyl group or an aryl group, and n means an integer of 1 to 4.) General formula characterized by chemical reaction (In the formula, n means an integer of 1 to 4.) A method for producing α-acetyllactones represented by: 2. The production method according to claim 1, wherein the intramolecular alkylation reaction is carried out in the presence of a basic substance. 3 Basic substances include alkali metals such as lithium and sodium, sodium ethoxide, potassium t-
Metal alcoholates such as butoxide, metal hydrides such as sodium hydride and lithium hydride, metal hydroxides such as sodium hydroxide and potassium hydroxide,
The manufacturing method according to claim 2, which is bicarbonates such as sodium bicarbonate and potassium bicarbonate, carbonates such as sodium carbonate and potassium carbonate, and tertiary amines such as triethylamine, pyridine, and diazabicycloundecene.