JPH0369901B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing cis-1,3-dibenzyl-2-oxoimidazolidine-4-alkoxycarbonyl-5-carboxylic acid.

As a method for esterifying dicarboxylic acids, a method of reacting with alcohol in the presence of a catalyst such as sulfuric acid or hydrochloric acid is conventionally known, but when this method is used, mainly diesters are obtained,
Even if a monoester is obtained, the yield is low;
This is exactly the same in the esterification of cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid (hereinafter simply referred to as dicarboxylic acid), which is the raw material of the present application. cis-1,3-dibenzyl-2-oxoimidazolidine-4-alkoxycarbonyl-5-carboxylic acid (hereinafter simply referred to as half ester).
cannot be obtained in high yield, and in order to obtain the half ester, it is necessary to diesterify the dicarboxylic acid and then partially hydrolyze it, or to convert the dicarboxylic acid into an acid anhydride and then esterify it. However, there was no known method for obtaining a half ester, which is a partially esterified product, directly from a starting dicarboxylic acid in an industrially advantageous manner and in a high yield.

As a result of various studies on industrially advantageous production methods for half esters, the present inventors found that by simply heating dicarboxylic acid and alcohol without using a catalyst, half esters can be produced specifically. The present inventors have discovered a completely unexpected fact based on conventional knowledge that the compound can be obtained in high yield, leading to the present invention.

That is, the present invention provides a method for producing half esters directly from dicarboxylic acids in high yield and industrially advantageously by reacting dicarboxylic acids and alcohols at 50 to 200°C.

The dicarboxylic acid used as a raw material in the present invention can be easily produced using fumaric acid as a raw material, for example, as shown in the following formula.

(In the above formula, R represents a benzyl group) Examples of the alcohol which is the other raw material include methanol, ethanol, n-propanol, iso-propanol, n-butanol,
Common lower alcohols such as isobutanol, n-pentanol, n-hexanol, allyl alcohol, ω-butynyl alcohol, 2-pentenyl alcohol, 3-hexenyl alcohol, cyclopentanol, cyclohexanol, and cycloheptanol are exemplified. Ru. The amount of alcohol used is at least 1 equivalent or more, preferably 2 equivalents or more, based on the raw material dicarboxylic acid.

This reaction is carried out in the presence or absence of a solvent, but if a solvent is used, it can be used without particular limitation as long as it is inert to the reaction, such as toluene, benzene, chlorobenzene, etc. , tetrahydrofuran, methyl ethyl ketone and the like.

Alternatively, the alcohol described above can also be used as a solvent.

There is no particular restriction on the amount of such solvent used.

The reaction temperature ranges from 50 to 200°C, preferably from 70 to 180°C. When the reaction temperature is higher than the boiling point of the solvent, the reaction can be carried out using an autoclave.

The presence of a catalyst is not required to carry out this reaction, and only by heating the dicarboxylic acid and alcohol at 50 to 200°C as described above,
Although the desired half ester can be easily obtained in high yield, for the purpose of increasing the reaction rate and shortening the reaction time, for example, formic acid, acetic acid,
Organic carboxylic acids such as propionic acid and valeric acid, potassium, calcium, magnesium, zinc, iron,
Phosphates and sulfates of copper, manganese, cobalt, etc.
Sulfites, organic carboxylates and organic sulfonates, organic quaternary ammonium salts such as tetrabutylammonium bromide, benzyltrimethylammonium chloride, tricaprylmethylammonium chloride, dodecyltrimethylammonium chloride, caprylbenzyldimethylammonium chloride, higher fatty acids Surfactants such as salts, polyoxyethylene alkyl phenol ethers, higher aliphatic alcohols, etc. can also be used as accelerators.

Of course, as mentioned above, the use of such a promoter is not an essential reaction condition for the present invention, and its use is completely optional, and there is no restriction on the amount used. The amount used is usually in the range of 1/200 to the same weight as the dicarboxylic acid.

Such reactions provide half esters easily and in good yields, which can be easily isolated by conventional separation means such as concentration, crystallization, etc.

The following half esters are exemplified in this manner.

cis-1,3-dibenzyl-2-oxoimidazolidine-4-methoxycarbonyl-5-carboxylic acid, cis-1,3-dibenzyl-2-oxo-
imidazolidine-4-ethoxycarbonyl-5-
Carboxylic acid, cis-1,3-dibenzyl-2-oxo-imidazolidine-4-n-propoxycarbonyl-5-carboxylic acid, cis-1,3-dibenzyl-2-oxo-imidazolidine-4-iso-
Propoxycarbonyl-5-carboxylic acid, cis-
1,3-dibenzyl-2-oxo-imidazolidine-4-n-butoxycarbonyl-5-carboxylic acid, cis-1,3-dibenzyl-2-oxo-imidazolidine-4-iso-butoxycarbonyl-
5-carboxylic acid, cis-1,3-dibenzyl-2
-Oxo-imidazolidine-4-n-pentyloxycarbonyl-5-carboxylic acid, cis-1,3
-dibenzyl-2-oxo-imidazolidine-4
-n-hexyloxycarbonyl-5-carboxylic acid, cis-1,3-dibenzyl-2-oxo-imidazolidine-4-cyclohexyloxycarbonyl-5-carboxylic acid, cis-1,3-dibenzyl-2-oxo- Imidazolidine-4-cyclopentyloxycarbonyl-5-carboxylic acid, cis-1,3-dibenzyl-2-oxo-imidazolidine-4-cycloheptyloxycarbonyl-5
-carboxylic acid, cis-1,3-dibenzyl-2-
Oxo-imidazolidine-4-allyloxycarbonyl-5-carboxylic acid, cis-1,3-dibenzyl-2-oxoimidazolidine-4-ω-butenyloxycarbonyl-5-carboxylic acid, cis-
1,3-dibenzyl-2-oxo-imidazolidine-4-2-pentenyloxycarbonyl-5-
carboxylic acid, cis-1,3-dibenzyl-2-oxo-imidazolidine-4-3-hexenyloxycarbonyl-5-carboxylic acid, and thus, according to the invention, can be produced directly from dicarboxylic acids in good yields and industrially. Half esters can advantageously be obtained.

The present invention will be explained below with reference to Examples.

Example 1 17.7 g of cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid, 5 g of ethanol, and 150 ml of toluene were charged into a four-necked flask equipped with a stirrer and a thermometer, and the mixture was heated for 8 hours. Heat to reflux. After the reaction is completed, the reaction solution is concentrated under reduced pressure to a volume of about 80 ml. This and hexane
Add 30 ml to crystallize, filter this and cis-
18.5 g (yield: 96.8%) of crystals of 1,3-dibenzyl-2-oxoimidazolidine-4-ethoxycarbonyl-5-carboxylic acid were obtained.

Melting point: 94-95℃ In addition, in the above example, 0.2g of acetic acid was added to the reaction system.
was further added and the same procedure was carried out except that the heating reflux time was changed to 5 hours to obtain cis-1,3-dibenzyl-
18.3 g of crystals of 2-oxyimidazolidine-4-ethoxycarbonyl-5-carboxylic acid (yield: 95.8
%) was obtained.

Example 2 In a flask similar to that used in Example 1, cis-
1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid 17.7g, methanol 4g
Then, add 150 ml of toluene and heat under reflux for 4 hours. Then add 4g of methanol, and then add 4g of methanol.
Heat to reflux for an hour. After completion of the reaction, post-treatment was carried out in the same manner as in Example 1 to obtain cis-1,3-dibenzyl-2-oxoimidazolidine-4-methoxycarbonyl-
17.9 g (yield 9.5%) of 5-carboxylic acid crystals were obtained.

Melting point: 130-131°C In the above example, 0.3 g of tetrabutylammonium bromide was further added to the reaction system, heated under reflux for 4 hours, and then post-treated in the same manner as in Example 1 to obtain cis-1,3-dibenzyl-2. 17.8 g (yield: 96.7%) of crystals of -oxoimidazolidine-4-methoxycarbonyl-5-carboxylic acid were obtained.

Example 3 The reaction was carried out in the same manner as in Example 1 except that 5 g of isopropyl alcohol was used as the alcohol raw material and the heating reflux time was 7 hours, and post-treatment was performed to produce cis-1,3-dibenzyl-2-oxoimidazolidine. 19.2 g (yield 97.1%) of crystals of -4-isopropoxycarbonyl-5-carboxylic acid were obtained.

Melting point: 109-111°C In the above example, 7.5 g of isopropyl alcohol was used, 0.25 g of potassium bisulfite was added to the reaction system, and the heating reflux time was 4 hours. After the reaction was completed, insoluble materials were removed from the reaction solution. 19.3 g of crystals of cis-1,3-dibenzyl-2-oxoimidazolidine-4-isopropoxycarbonyl-5-carboxylic acid were obtained in exactly the same manner except that
(yield 97.5%).

Example 4 17.7 g of cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid, 6 g of methanol, and 150 ml of benzene were added to an autoclave equipped with a thermometer and a stirring device.
React at 120°C for 6 hours. After the reaction is completed, the reaction solution is concentrated by distilling off benzene and methanol under reduced pressure. To the residue, add 100ml of toluene and 20ml of hexane.
ml and filtered it to give cis-1,3
-dibenzyl-2-oxoimidazolidine-4-
Crystals of methoxycarbonyl-5-carboxylic acid 18.0
g (yield 98.2%) was obtained.

Melting point: 129-130°C In the above example, 0.5% of copper acetate was added to the reaction system.
The reaction was carried out in exactly the same manner except that g was further added and the reaction was carried out at 120°C for 3 hours. After the reaction was completed, the reaction solution was poured into water.
Perform the same procedure except washing with 50 ml to clean the system.
17.6 g (yield: 95.7%) of crystals of 1,3-dibenzyl-2-oxoimidazolidine-4-methoxycarbonyl-5-carboxylic acid were obtained.

Example 5 In a flask similar to that used in Example 1, cis-
17.7 g of 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid, 10 g of cyclopentanol and 150 ml of toluene are added, and the mixture is heated under reflux for 8 hours. After the reaction is complete, transfer the reaction solution to 80ml under reduced pressure.
Concentrate to. Add 40 ml of hexane to this to crystallize it, and filter it to crystallize cis-1,3-dibenzyl-2-oxoimidazolidine-4-cyclopentyloxycarbonyl-5-carboxylic acid.
20.2g (yield 95.8%) was obtained.

Melting point: 135-137°C In addition, in the above example, cis-1,3-dibenzyl- 20.5 g of crystals of 2-oxoimidazolidine-4-cyclopentyloxycarbonyl-5-carboxylic acid (yield 97.2%)
I got it.

Comparative Example 1 17.7 g of cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid, 5 g of ethanol, 0.2 g of sulfuric acid, and 150 ml of toluene were placed in a four-necked flask equipped with a stirrer and a thermometer. Charge and heat under reflux for 6 hours. After the reaction was completed, the reaction solution was washed twice with 30 ml of water, concentrated under reduced pressure, and solidified.
19.3g was obtained. Analysis of the reaction mixture by liquid chromatography revealed that 85% of cis-1,3-dibenzyl-2-oxoimidazolidine-4-ethoxycarbonyl-5-carboxylic acid, cis-1,
It contained 15% 3-dibenzyl-4,5-diethoxycarbonyl-2-oxoimidazolidine. (Total yield 95%) Comparative Example 2 Into a four-necked flask equipped with a stirrer and a thermometer, 17.7 g of cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid and sulfuric acid were added.
Charge 0.5 g and 150 ml of methanol, and heat under reflux for 4 hours. After the reaction was completed, methanol was distilled off from the reaction solution under reduced pressure, and then recrystallized from 80 ml of toluene and 20 ml of hexane.
18.6 g of crystals of 1,3-dibenzyl-4,5-dimethoxycarbonyl-2-oxoimidazolidine
(yield 97.4%).

Melting point 111-112℃

Claims (1)

[Claims] 1. Cis-1,3-dibenzyl-2-oxoimidazolysine-4,5-dicarboxylic acid and alcohol are reacted at 50 to 200°C. A method for producing 2-oxoimidazolidine-4-alkoxycarbonyl-5-carboxylic acid. 2. The method according to claim 1, wherein the reaction is carried out in the presence of a promoter. 3 The accelerator is an organic carboxylic acid or its metal salt,
The method according to claim 2, wherein the method is at least one selected from organic sulfonic acid metal salts, inorganic acid metal salts (phosphoric acid, sulfuric acid, or sulfite), organic quaternary ammonium salts, and surfactants. .