JPS6140214B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing phalnesylacetic acid.

Phalnesyl acetate is an important compound, for example, as a raw material for geranyl falnesyl acetate, which is widely used clinically as an anti-ulcer agent.

Conventionally, many methods for producing phalnesyl acetic acid or its ester have been reported, and these can be broadly classified into the following four methods.

Falnesyl acetate is obtained by reacting nerolidol with orthoacetate. (Japanese Patent Publication No. 50-29518).

Falnesyl acetate is obtained by reacting malonic acid ester with nerolidol (Tokukosho
53-24051).

Decarboxylating falnesyl malonic acid monoester to obtain falnesyl acetate (Tokukosho
39-28230).

Phalnesyl acetate is obtained by reacting geranylacetone with a triphenylphosphonium halide compound (Japanese Unexamined Patent Publication No. 29437/1983).

However, the yield of method (2) is low, and the method (2) uses nerolidol as a raw material, brominates it, reacts it with malonic acid ester, and then partially deesterifies it to produce falnesyl malonic acid monoester. This method is not suitable for mass production over a long period of time, and the method has drawbacks such as difficulty in obtaining the triphenylphosphonium halide compound, so the conventional method has naturally been the most preferred. However, this method also has the disadvantage that isomerization occurs depending on the strength of the acid, and this must be strictly regulated.

Therefore, the present inventor conducted various studies in order to develop an industrial method for producing phalnesyl acetic acid that eliminates such drawbacks, and as a result, completed the present invention.

The present invention is shown by the following reaction formula.

(In the formula, R represents a lower alkyl group) That is, the present invention reacts nerolyl acetate () with lithium dialkylamide to form a lithium derivative, and reacts this with an alkyl chlorocarbonate to form nerolyl alkyl malonate. (), heat-treated this with aluminum isopropoxide, and then hydrolyzed the resulting product to produce falnesyl malonic acid (),
In this method, this is further decarboxylated to produce phalnesyl acetic acid ().

The present invention is carried out as follows.

First, nerolyl acetate () and lithium dialkylamide are reacted in a suitable inert solvent. Although lithium dialkylamide may be prepared in a separate reaction system, for example, a butyllithium hexane solution is added to a solvent solution of dialkylamine to cause the reaction to produce lithium dialkylamide in the reaction solution, and nerolil is added to the reaction solution. Preferably, the reaction is carried out with the addition of acetate. As a solvent, tetrahydrofuran, dimethyl sulfoxide, dimethyl formamide, etc. are used, and the reaction is carried out at −50 to −
If carried out at 80°C, it will complete in a few minutes and give a lithium derivative. This lithium derivative was obtained by adding alkyl chlorocarbonate to this reaction solution without isolating it.
If the reaction is carried out at a low temperature around 50°C, nerolyl alkyl malonate () can be obtained.

Next, nerolyl alkyl malonate () and aluminum isopropoxide were mixed without solvent at 140 ~
When heated at a temperature of 150°C, a rearrangement reaction occurs to give alkyl phalnesylmalonate. If this is hydrolyzed in the presence of an alkali such as caustic soda or caustic potash, farnesylmalonic acid (2018) can be obtained.

Decarboxylation of falnesyl malonic acid () is carried out by a conventional method.
For example, it is carried out by heat treatment at a temperature of 150° C. for 3 to 5 hours under reduced pressure.

As mentioned above, according to the present invention, phalnesyl acetic acid () can be obtained from nerolyl acetate by a simple operation, and the overall yield is extremely high at 70% or more.

Next, an example will be given and explained.

Example: Dissolve 27.5 g of diisopropylamine in a mixed solvent of 270 ml of dry tetrahydrofuran and 90 ml of dry hexamethylphosphoramide, dropwise add 176 ml of butyl lithium hexane solution (14.5-17%) at below 0°C, and further stir at the same temperature for 10 minutes. put. This-
Cool to 78℃, add 18g of nerolyl acetate,
After 10 minutes, 29.5 g of ethyl chlorocarbonate was added, and after 2 to 3 minutes, the mixture was left at room temperature to return to room temperature. Tetrahydrofuran was distilled off under reduced pressure, acidified with 10% hydrochloric acid, extracted with ether, and dried over Glauber's salt. The ether is distilled off and the residue is aluminum isopropoxide.
Add 18g and heat in an external bath at 140-150℃ for 2 hours.
Then, the temperature is returned to room temperature, ether is added, and the mixture is acidified with 10% hydrochloric acid and extracted with ether. Ether was distilled off, 250 ml of 95% ethanol was added to the residue, 25 g of caustic potash was added, and the mixture was refluxed for 3 hours. Most of the ethanol is distilled off under reduced pressure, the residue is acidified with 10% hydrochloric acid, and extracted with ether. The ether layer was dried with Glauber's salt and the ether was distilled off. The residue is heated at 150-160° C. for 4 hours under reduced pressure (8 mmHg) to remove the urethane formed. Remove remaining liquid under high vacuum (2
×10 ^-3 mmHg) and collected the fractions between 160 and 165°C, yielding 12.96 g of phalnesyl acetic acid (yield 72%).
is obtained.

IR: Figure 1 NMR: 1.6-1.7ppm (CH ₃ × 4, 12H) Around 2.0ppm (CH ₂ × 4, 8H) 2.3-2.4ppm (CH ₂ × 2, 4H) 4.8-5.3ppm (=CH × 3,3H) 11.08ppm (COOH, 1H)

[Brief explanation of the drawing]

FIG. 1 shows an infrared absorption spectrum of phalnesyl acetic acid obtained according to the present invention.

Claims (1)

[Claims] 1. Heat treating nerolyl alkyl malonate with aluminum isopropoxide and hydrolyzing the resulting product to produce falnesyl malonic acid,
A method for producing phalnesyl acetic acid, which comprises then decarboxylating it. 2. Reacting nerolyl acetate with lithium dialkylamide to form a lithium derivative, reacting this with alkyl chlorocarbonate to form nerolyl alkyl malonate, heat treating this with aluminum isopropoxide, and then producing a resultant. 1. A method for producing phalnesyl acetic acid, which comprises hydrolyzing to produce phalnesyl malonic acid, and further decarboxylating the same.