BG61808B1 - Method for the preparation of menthylisovalerate - Google Patents

Abstract

The invention relates to a method for the preparation ofmenthylisovalerate (menthyl ester of the isovalerianic acid),which is one of the active components of the Validol medicamentouspreparation having the formulaThe menthylisvalerate is produced by reaction between L-(-), D-(+)or D, L-menthol and isovalerylchloride in the absence of a solventat continuous removal of the separating hydrogen chloride by inertgas or thermal desorption. A product of very high yield and purityis produced avoiding the use of toxic and cancerogenous reagents.It interacts chemically at ease and when conventional equipment isused it becomes easily applicable under industiral conditions.4 claims

Description

The invention relates to a process for the preparation of menthylisovalerate of formula

Mentilisovalerate (menthylisovalerate, isovaleric acid menthyl ester) is a major component of the drug substance Validol, which is used for the preparation of sedative drugs.

BACKGROUND OF THE INVENTION

A method for the preparation of menthylisovalerate [Liebigs Analen der Chimie 369, 339] has been described in the literature, wherein the ester is prepared by reacting menthol with isovaleryl chloride in benzene and pyridine media. The yield is about 60%.

The disadvantages of this method are the low yield of the ester and the use of toxic and environmentally hazardous organic solvents.

SUMMARY OF THE INVENTION

The process according to the invention consists in the reaction of menthol with isovaleryl chloride in the absence of solvent, the hydrogen chloride being continuously removed from the reaction mixture by inert gas or thermal desorption.

The menthol may be L - (-), D - (+) - or D.L-menthol.

The advantages of the process according to the invention are that menthylisovalerate is produced in very high yields, avoiding the use of toxic and carcinogenic reagents.

The following examples illustrate the invention without limitation.

Examples of carrying out the invention

Example 1.

398.0 g (393.6 ml, 3.30 mol) of isovaleryl chloride are charged into a one liter reactor equipped with a mechanical stirrer, thermometer, reflux condenser and a funnel to add solid.

To this, 523.5 g (3.35 mol) of solid crystalline L - (-) menthol were added portionwise through constant stirring and nitrogen purging. The temperature of the reaction system should not exceed 40 ° C when added. After all the menthol was added, the reaction mixture was allowed to cool to 20 ° C and then heated to 90 ° for 4 h.

After completion of the reaction, the reaction mixture was cooled to room temperature and washed with 200 ml of 4% aqueous sodium hydroxide solution, transferred to a separatory funnel, the aqueous alkali layer was separated, and the organic was washed with water to pH 5.5. 6.0.

The menthylisovalerate thus obtained was dried over Na ₂ SO ₄ for 6 h, filtered and 804 g of menthylisovalerate were obtained, [a] _D ²⁰ = -47.6 (99.8% of theoretical yield).

EXAMPLE 2 398.0 g (393.6 ml, 3.30 mol) of isovaleryl chloride were charged into a 1 liter reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a funnel to add a solid.

To the funnel, 523.5 g (3.35 mol) of solid crystalline D - (+) - menthol were added portionwise with constant stirring. The temperature of the reaction system should not exceed 40 ° C when added. After all the menthol was added, the reaction mixture was allowed to cool to 20 ° C, then heated to 90 ° C for 4 h. After completion of the reaction, the reaction mixture was cooled to room temperature and washed with 200 ml of 4% aqueous sodium hydroxide solution, transferred to a separatory funnel, the aqueous alkali layer was separated and the organic was washed with water to pH 5.56, 0. The menthylisovalerate thus obtained was dried over Na ₂ SO ₄ for 6 h, filtered and 803 g of menthylisovalerate were obtained, [a] _D ²⁰ = +47.6 (99.7% of theoretical yield).

Example 3.

398.0 g (393.6 ml, 3.30 mol) of isovaleryl chloride are charged into a one liter reactor equipped with a mechanical stirrer, thermometer, reflux condenser and a funnel to add solid.

To the funnel, 523.5 g (3.35 mol) of solid crystalline D, L-mchtwi were added in portions under constant stirring and purging with nitrogen. The temperature of the reaction system should not exceed 40 ° C when added. After all the menthol was added, the reaction mixture was allowed to cool to 20 ° C, then heated to 90 ° C for 4 hours, purging with nitrogen throughout. After completion of the reaction, the reaction mixture was cooled to room temperature and washed with 200 ml of 4% aqueous sodium hydroxide solution, transferred to a separatory funnel, the aqueous alkali layer was separated, and the organic was washed with water to pH 5.5. 6.0. The menthylisovalerate thus obtained was dried over Na ₂ SO ₄ for 6 h, filtered and 10 watt 802.7 g of menthylisovalerate were obtained (99% of theoretical yield).

Claims (4)

Claims What is claimed is: 1. A method for the preparation of menthylisovalerate in which menthol is reacted with isovaleryl chloride, characterized in that the interaction between them is carried out by continuous removal of the hydrogen chloride liberated in the reaction. A method according to claim 1, characterized in that L - (-), D (+) - or O, L-menthol are used. A method according to claim 1, characterized in that the removal of the hydrogen chloride is carried out using an inert gas. A method according to claim 1, characterized in that the removal of the separated hydrogen chloride is carried out by thermal desorption.