JPS6069052A - Production of aliphatic (2e,4e)-dienoic acid and its ester - Google Patents

Abstract

PURPOSE:To produce the titled compound useful as a preparation raw material of polymeric liposome and a useful physiologically active compound, by adding and reacting an alkali metal alkoxide to a mixture of an aliphatic aldehyde and a phosphonocrotonic acid derivative. CONSTITUTION:The aliphatic (2E,4E)-dienoic acid and its ester of formula III is produced by reacting the aliphatic aldehyde of formula I (n is 6-16) with the phosphonocrotonic acid derivative of formula II (R<1> is H or lower alkyl; R<2> is lower alkyl). The above reaction is carried out by adding an alkali metal alkoxide (e.g. soduim ethoxide) to a mixture of the aldehyde of formula I such as enantoaldehyde, caprylaldehyde, etc, and the compound of formula II such as 4-diethylphosphonocrotonic acid methyl ester, to obtain the compound of formula III[e.g. ethyl (2E,4E)-octadecadienoate]. The amount of the alkali metal alkoxide is preferably about 1.05-1.25mol per 1mol of the compound of formula I . EFFECT:The product can be purified easily to obtain a high purity compound.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method for producing fatty bk(23,4E)-dienoic acids and esters thereof, and more specifically, the general formula % () [wherein 1 is a hydrogen atom or a lower alkyl group, n is 6-1
Ball the integer number 6. ] Aliphatic C2B, 4K)
- A method for producing dieno acids and esters thereof.

Aliphatic (23,4J〇-
Dienic acids and their esters are important compounds as raw materials for the production of cylinder molecules and compounds with useful physiological activity.

Conventionally, fat kc 2ff expressed by general formula (3),
As a method for producing 4E)-diene α and its ester, for example, the method described in Indian Journal Opchemistry, Vol. 13, p. 1358 (1975) is known. In this method, sodium hydride is added to a detrahydrofuran solution using the general formula % (2) [where R2 represents a lower alkyl group]. R1 is the same as above. A phosphonocrotonic acid conductor represented by the formula % (3) was added dropwise, and then n was an integer of 6 to 16. ) is gradually added dropwise to the target (21.4N
) is the way to get a body. However, in this method, (2
E, 4 top) In addition to the body, (2z.

4m) isomers such as (21,
41) High-performance column chromatography is required for purification of the (1E, 4E) body, and the purity of the (1E, 4E) body purified using sieve-performance column chromatography is 87.
%, and the yield is only about 60%, which is extremely disadvantageous from an industrial perspective.

In view of the current situation, the present inventors aimed to obtain an aliphatic compound (2E) represented by the above general formula L3J using simple operations.

4B)-Dienoic acids and their esters y! We have been conducting extensive research to develop a method that can produce it with a high purity of 1-97% or higher. In the research process, the desired (2E, 43) body was first obtained using the same procedure as the conventional method, except that an alkali metal alkoxide such as sodium ethoxide was used instead of the sodium hydride used in the conventional method. I was looking forward to getting it. However, even with this method,
(2E.

In addition to the 4N) form, isomers such as the (2Z, 4E) form frequently occur as by-products, and therefore, high-performance column chromatography is required to purify the (2B, 41) form. Purified using chromatography (zE
. In the course of time, a mixture of the phosphonocrotonic acid derivative of general formula (2) and the aliphatic aldehyde of general formula (3) is added with an alkali metal alkoxytone such as sodium ethoxide for the purpose (2E, 4B).
When adopting the method of obtaining the body, (2Z, lK
The formation of isomers such as ) isomers is suppressed, and the (2E, 4fl) isomer can be obtained in good yield. Therefore, local column chromatography is not required for purification of the (Ig, 41) isomer, and the purification procedure is simple. It has been found that the (2E, tl) form with a purity of 97% or more can be obtained in a yield of 60% or more. The present invention was completed based on the findings of W.

That is, the present invention uses the general formula ≦+v/≦U) −≦U^ [where n is an integer from 6 to 16]. An aliphatic aldehyde represented by the general formula % (2) [wherein l represents a hydrogen atom or a lower alkyl group, and R2 represents a lower alkyl group. ] is reacted with the phosphonocroton mvjs form represented by the general formula % formula % (3) [where l and n are the same as above. In producing the aliphatic C2B,4E)-dienoic acid represented by Fat & (Ig, 4ff)- characterized by adding an alkali metal alkoxide to a mixture with 4 crotonic acids vj
This invention relates to a method for producing dienic acid and its ester.

According to the method of the present invention, 4E)-diene and its ester can be produced with a high purity of 97% or more in the fat 'l1kC2 represented by the general formula (,1). Moreover, at that time 14
111, there is no need to use high-performance column chromatography; if the target product is in the form of a free acid, a simple recrystallization step is required, or if the target product is in the form of an ester, In some cases, the desired product can be obtained in high purity by simple operations such as distillation or purification by ordinary column chromatography. Therefore, the method of the present invention is industrially extremely advantageous.

The aliphatic aldehyde of general formula (1) used in the present invention has the following formula: 8-1'2! l, specifically enanthaldehyde, capryaldehyde, capricaldehyde,
Examples include lauric aldehyde, myristic aldehyde, and palmitaldehyde. Further, the phosphonocrotonic acid spindle of general formula (2) used in the present invention is also an avowed compound. Examples of lower alkyl groups represented by p-(kLl and kL2) in general formula (2) include methyl group, ethyl group, n-propyl group, inobutyl group, n-butyl group, inobutyl group, tert-butyl group, etc. carbon a1-4
Examples include alkyl groups. Specifically, the phosphonocrotonate fatty acids of general formula (2) include ethyl 4-diethylphosphonocrotonate, ethyl 4-diethylphosphonocrotonate, methyl 4-dimethylphosphonocrotonate, and 4-diethylphosphonocrotonate.
Examples include diethylphosphonocrot/V-improvir. Also, a wide range of alkali metal alkoxide compounds or those manufactured by Shubei Kogyo used in the present invention can be used, such as sodium ethoxide, sodium methoxide, sodium butoxide, potassium ethoxide, potassium butoxide, and the like.

In carrying out the first aspect of the present invention, first, the above ml of the compound of general formula (i) and the compound of general formula (2) are mixed in a suitable solvent. The mixing ratio of the compound of general formula C1) and the compound of general formula (phantom compound) is not particularly limited and can be selected from a wide range, but usually the latter is 0.8 to 1.5 of the former. + & mole, preferably temple mole ~1.
It is better to make it twice the molar amount. The solvent used is preferably an ether solvent, such as tetrahydrofuran, dioxane, dimethoxyethane, diisopropyl ether, dibutyl ether, and the like. Such a solvent is usually used in an amount of about 2 to 30 times, preferably about 5 to 15 times the weight of the total amount of the compound of general formula (1) and the compound of general formula (2).

In the present invention, an alkali metal alkoxide is then added to the mixture obtained above. The alkali metal alkoxide to be added is not particularly limited and is selected from a wide range of 17L, but it is usually equivalent to 1.5 times the mole of the compound of general formula (1), preferably 1.0
It is preferable to use 5 to 1.25 times the mole amount. The alkali metal alkoxide is usually added to the upper ml mixture in a state dissolved in an alcohol such as methanol, ethanol, impropanol or butanol. The method of addition is not particularly limited, but preferably the temperature of the mixture 'Ik: about -10
The alkali metal alkoxide is preferably gradually added dropwise over a period of 5 to 3 hours while maintaining the temperature at ~50°C (preferably 0 to 20°C) and stirring. Normally 1~ to the same temperature after finishing lower legs
When it lasts for about 5 hours, the desired fat of general formula (3) &
(2Fi,41)-dienoic acid and its ester are produced.

In the 4h tray in which the compound of the general formula t2J used as a starting material is in the form of an ester, the targeted ornament is produced in the form of an ester. By hydrolyzing this mV in accordance with a conventional method, it can be converted into the form of the chemical component qrt' acid of general formula (3).

If the compound of general formula (3) produced in the above procedure is in the acid form, the (2E, 4jC) form can be split into a pure form by recrystallizing the reaction product with hexane, etc. can. When the compound of the general formula (3) produced in 1 mL of the ester is in the form of an ester, it can be purified to a high purity by distillation or conventional column chromatography.

Examples 1u11 and comparative examples are given below to further clarify the present invention.

Example 1 21.2 g (0.1 mol) of myristylaldehyde and 25.0 g (0.1 mol) of ethyl 4-diethylphosphonocrotonate (
o, x mol) is dissolved in 200 ml of tetrahydrofuran, and a solution of 7.5 g (0.11 mol) of sodium ethoxy) is dissolved in 200 ml of tetrahydrofuran and added dropwise over 1 hour with stirring at 10-20°C. After completion of the dropwise addition, the mixture was stirred at 20°C for 2 hours. Add the reaction solution to a 50% aqueous solution of 300% water.
ml and extracted with hexane. This hexane bath liquid contained 32.8 g of solid matter (106% yield), and the solid content was analyzed by gas chromatography (filling agent PgG20).
M, 3 m glass column 200 °C), 87% of (I
B, 4E) Contained ethyl octadecadienoate. When a hexane solution of keratin was passed through a glass column with a diameter of 3 cm packed with 100 g of silica gel for column chromatography (60-200 mesh), it was concentrated (2
n, 4E)-ethyl octadecadienoate 18.6 g
(yield: 6%). Gas chromatography analysis (redundant PEG20Δ1.3m glass column, 200'C) of the product revealed a purity of 97%, and the award-winning L2Z,4E)-
Contains ethyl octadecadienoate.

Comparative Example 1 (Same usage as in Example 1, carried out according to conventional reaction procedure) 5.3 g (0.22 mol) of sodium hydride was mixed with 167 ml of tetrahydrofuran and stirred at 20"C, then 4-diethylphosphor Ethyl nocrotonate 25.0
g (0.1 mol) is added dropwise. l men bottom end shun 10°
Stir at C for 2 hours. 21.2 g (0.1 mol) of myristylaldehyde was added dropwise to the awns while stirring at 10°C, and after the dropwise addition was completed, the mixture was left at room temperature overnight.

Anti-2 liquid? ! - Pour into excess cold water and extract with ether. After drying with sodium sulfate, the ether is removed.

A solid content of 32.3 g was obtained. If we analyze the solid content with gas chromatography molecules (the analysis conditions are the same as in practical application 1), it is 64% (2E
, 4ffi) contained ethyl octadecadienoate.

This li! dIJ! Silica gel for high performance liquid chromatography (15-25mesh) dissolved in beggar hexane
@ Og Y Separation and purification using a high-performance preparative column with a diameter of 2 cm packed at a temperature and pressure of 300 kg/cm", and a hexane solution (2ff, 4 M)-ethyl octadecadienoate A/18.5 g (yield 60%).Product?
Gas chromatography analysis (analysis conditions are the same as in Example 1) shows 87
% NM, (22°4F,) body and (2[E,4Z
) was included in the isomer of the body.

Comparative Example 2 Sodium ethoxide 7.5 gc 0.11 mol) was dissolved in tetrahydrofuran 200 ml K ML, 10-2
While stirring at 0 DEG C., 25-() g (0.1 mol) of ethyl 4-diethylphosphonocrotonate are added dropwise. After the dropwise addition was completed, the mixture was stirred at 20°C for 1 hour. Further 10~20℃
While stirring at
, 1 mol) was added dropwise, and after the addition was completed, the mixture was stirred at 20°C for 4 hours.

The reaction solution was added to 300 ml of 50% saline solution and extracted with hexane. The solid content in this hexane solution was 32.4
When the solid content was analyzed by gas chromatography (the analysis conditions were the same as in Example 1), 31% (2E, 4 fl
) Contained ethyl octadecadienoate. This hexane solution was passed through the preparative silica gel column described in Comparative Example 1 and concentrated to obtain 8.6 g (yield: 28%) of ethyl (2F1.1 g)-octadecadienoate. When the product was subjected to gas chromatography with molecular T (light-suppressing agent PE020M, 3m glass column, 200°C), it was 86% #11 degree, with a large amount of (2E).

4Z)-ethyl octadecadienoate and (2Z, 4B)-
Contains ethyl octadecadienoate.

Example 2 18.6 g of ethyl (2E, 4B)-octadecadienoate obtained in Example 1 was hydrolyzed with a 15% alcoholic potassium solution, and after removing the alcohol, it was soaked in an aqueous hydrochloric acid solution. When the ether was extracted, the ether was removed, and the obtained solid was recrystallized with hexane, (2F, 4E)-
13.4 g (yield: 80%) of octadecadiene was obtained. The product was converted into methyl ester with diazomethane, and gas chromatography analysis (drafting as in Example 1) revealed a purity of 99.0%. Also, the melting point of this compound is 71°C,
Its NMR spectrum was as shown in FIG. 1, and its IR spectrum was as shown in FIG.

Example 3 Fatty iron aldehyde of general formula (2) listed in Table 1 below was reduced to 0.
．． The corresponding fat & (2B, 4E)-dienoic acid of general formula (3) was obtained in the same manner as in Examples 1 and 2, except that 1 mol was used. The results are shown in Part 1 below.

Table 1 *Yields indicate theoretical yields**H8t is a gas chromomolecule r (photonic agent PEG20M) after methyl esterification with diazomethane.

3m glass column, 200°C) L, from its integral value
I met.

[Brief explanation of the drawing]

Figures 1 to 5 show the normal spectra of the compounds obtained according to the present invention. It is a diagram. (that's all)

Claims (1)

[Claims] ■ General formula % formula % (1) [In the formula, n is a number from 6 to 16. An aliphatic aldehyde represented by the general formula % (2) [In the formula, 1 represents a hydrogen atom or a lower alkyl group, and R2 represents a lower alkyl group. [In the formula, kLl and n are the same as above. In producing the aliphatic (2fi,4B)-dienoic acid represented by A method for producing r''=fatty 1(2E,41)-dienoic acid and its ester, which comprises adding an alkali metal alkoxide to the mixture with the derivative.