JPS6241664B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention has the structural formula () [1・1'-bicyclohexyl]-1 expressed as
Regarding the method for producing -carboxylic acid-2-(diethylamino)ethyl ester, the hydrochloride thereof is usually referred to as dicyclomine hydrochloride.

Dicyclomine hydrochloride can be used to treat gastrointestinal spasms,
It is a useful compound as a therapeutic agent for gastric/duodenal ulcers, spasmodic diseases of the bile duct or gallbladder, etc.

Conventionally, the method for producing dicyclomine hydrochloride is as follows: (1) Benzyl cyanide and 1,5-dibromopentane are reacted with a base such as sodium hydride in dimethylformamide to form 1-phenylcyclohexyl cyanide. , hydrolyzed with acid or alkali to give 1-phenylcyclohexanecarboxylic acid, (a) nuclear hydrogenated and then converted to carboxylic acid chloride with thionyl chloride, 2-
(diethylamino) React with ethanol to form an ester and use hydrochloric acid gas to obtain the hydrochloride, or (b) thionyl chloride to form a carboxylic acid chloride, react with 2-diethylamino)ethanol to form an ester, and then perform nuclear hydrogenation with hydrochloric acid gas. (2) Dicyclohexyl ketone is α-chlorinated with sulfuryl chloride, and then refluxed with potassium hydroxide in dioxane to obtain bicyclohexyl-1-carboxylic acid, followed by carboxylic acid chloride, 2-(diethylamino ) Method for obtaining ethyl ester, (3) Using 1-bromocyclohexanecarboxylic acid ester as a Grignard reagent, performing a condensation reaction with cyclohexanone, followed by hydrolysis, dehydration, and hydrogenation steps to obtain bicyclohexyl-1-carboxylic acid. After acidification, carboxylic acid chloride, 2-
(diethylamino)ethyl ester, (4) cyclohexyl cyanide and cyclohexyl bromide are condensed by the action of sodium amide, treated with sulfuric acid in ethanol to obtain bicyclohexyl-1-carboxylic acid ethyl ester, and 2-( (5) Bicyclohexyl-1-carboxylic acid obtained by the above method etc. is mixed with potassium carbonate in acetone,
A method of obtaining the compound by refluxing it with 2-(diethylamino)ethyl chloride hydrochloride is known.

However, these conventional methods require the use of expensive chemicals, chemicals that are not easily available industrially, and have limitations on production equipment due to the generation of acidic gas during the reaction. It has disadvantages from an industrial point of view, such as being susceptible to damage. Therefore, these conventional methods are not necessarily satisfactory as industrial methods for producing dicyclomine hydrochloride.

As a result of intensive research into the synthesis of dicyclomine hydrochloride, the present inventors discovered an easy and inexpensive manufacturing method and completed the present invention.

That is, the present invention is based on the structural formula () [1・1'-bicyclohexyl]-2 represented by
-all and structural formula () [1・1'-bicyclohexyl]-1 expressed as
- At least one type of ol and formic acid are reacted in the presence of concentrated sulfuric acid, and the structural formula () [1・1'-bicyclohexyl]-1 expressed as
-carboxylic acid, and this was made into an aqueous solution of an alkali metal salt, and then reacted with an aqueous solution of 2-(diethylamino)ethyl chloride hydrochloride, and the structural formula () [1・1'-bicyclohexyl]-1 expressed as
The present invention relates to a method for producing -carboxylic acid-2-(diethylamino)ethyl ester.

To illustrate one embodiment of the present invention, first, [1・1'-
Bicyclohexyl]-2-ol and [1.
A solution of at least one 1'-bicyclohexyl]-1-ol dissolved in formic acid is reacted while being dropped into concentrated sulfuric acid to form [1,1'-bicyclohexyl]-1-carboxylic acid. After the reaction is completed, the reaction solution is poured into crushed ice, and then extracted with an organic solvent such as diethyl ether to separate the organic layer. An aqueous alkali solution such as sodium hydroxide is added to the organic layer to extract the carboxylic acid as an alkali metal salt into the aqueous layer. This aqueous layer may be subjected to an esterification reaction without being purified as it is, or it may be acidified by adding hydrochloric acid to the aqueous layer to obtain carboxylic acid as crystals, and then subjected to an esterification reaction as an alkali metal salt. . An aqueous solution of 2-(diethylamino)ethyl chloride hydrochloride is added to the aqueous solution of the alkali metal salt of [1,1'-bicyclohexyl]-1-carboxylic acid to carry out an esterification reaction. After the reaction is complete, an organic solvent such as toluene is added to the reaction solution to extract the product, the organic layer is washed with water and dried, and the organic solvent is distilled off under reduced pressure to obtain liquid [1,1'-bicyclohexyl]-1- Carboxylic acid-2-(diethylamino)ethyl ester is obtained. If this ester is converted into a hydrochloride salt by a known method, dicyclomine hydrochloride will be obtained.

[1,1'-bicyclohexyl]-2-ol used in the present invention is obtained by azeotropically dehydrating cyclohexanone using benzene, toluene, xylene, etc. as a solvent in the presence of an acid catalyst such as p-toluenesulfonic acid. -(1-Cyclohexenyl)cyclohexanone is obtained, and then the unsaturated bond and the carbonyl group are simultaneously reduced in the presence of a Raney-nickel catalyst using methanol, isopropyl alcohol, etc. as a solvent, whereby it can be easily and inexpensively produced. [1,1'-bicyclohexyl]-1-ol can be obtained in good yield by the reaction of cyclohexanone with a Grignard reagent obtained from chlorocyclohexane or bromocyclohexane and magnesium.

Concentrated sulfuric acid and formic acid used in this method are each used in an amount of 5 to 1 mole of at least one of [1,1'-bicyclohexyl]-2-ol and [1,1'-bicyclohexyl]-1-ol. Not
30 moles and 1 to 10 moles may be used. Concentrated sulfuric acid and formic acid may be used in even larger excess;
It has no economic merit and is not desirable. In this reaction, the temperature of the reaction solution is -10 to 50°C, preferably 0 to 30°C, and the reaction is carried out for 1 to 6 hours.

Although the details of the mechanism of this chemical reaction are not clear, at least one of the alcohols represented by the structural formulas () and () is first dehydrated by the action of concentrated sulfuric acid, and the carbonium ion produced is rearranged to a more stable ion. At the same time, it is thought to react with carbon monoxide produced by the action of concentrated sulfuric acid and formic acid to produce a carboxylic acid represented by the above structural formula ().

The ester represented by the structural formula () can be obtained by reacting an aqueous solution of an alkali metal salt of a carboxylic acid represented by the structural formula () while dropping an aqueous solution of 2-(diethylamino)ethyl chloride hydrochloride. can. In this reaction, the temperature of the reaction solution is 20 to 100°C, preferably 30 to 80°C, for 1 to 6 hours. As the alkali metal salt of carboxylic acid, sodium salt and potassium salt are used. The reaction solvent may be only water, but in addition, ether compounds such as ether, tetrahydrofuran, isopropyl ether, aromatic hydrocarbons such as benzene, toluene, xylene, chlorinated carbons such as chloroform, dichloromethane, carbon tetrachloride, dichloroethane, etc. hydrogen,
The reaction may be carried out by adding an appropriate amount of acetone or methyl ethyl ketone. After the reaction is completed, the reaction solution is cooled to room temperature, and diethyl ether, hexane, benzene,
By extracting with an organic solvent such as toluene, washing the organic layer with an alkaline aqueous solution to recover unreacted carboxylic acid, washing with water, and further concentrating, [1.1'-
Bicyclohexyl]-1-carboxylic acid-2-(diethylamino)ethyl ester is obtained.

Dicyclomine hydrochloride can be obtained by dissolving the thus obtained ester represented by the structural formula () in a solvent, and then blowing hydrogen chloride gas into the solution or adding hydrochloric acid dropwise thereto. As the solvent, acetone, methyl ethyl ketone, acetonitrile, isopropyl alcohol, ethanol, benzene, toluene, etc. are used. The formed crystals are filtered and dried under reduced pressure to obtain dicyclomine hydrochloride.

[1,1′-bicyclohexyl]-1-carboxylic acid 2-(diethylamino) obtained by the method of the present invention
Since ethyl ester has unstable properties peculiar to amines, it is common to obtain it as a hydrochloride, but in addition to hydrochloride, mineral acids such as hydrobromic acid and sulfuric acid, and organic acids such as formic acid and acetic acid are used. , fumaric acid, maleic acid, etc., and can also be obtained by quaternizing with a lower alkyl halide.

Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 540 g of 97% sulfuric acid was placed in the reaction flask from 1.
Cooled to 10° C. with vigorous stirring. 3 to this
Subsequently, 50.0 g of [1,1'-bicyclohexyl]-2-ol was dissolved in 50.5 g of formic acid, and the solution was added dropwise over 3 hours while maintaining the reaction solution at 10-20°C. After stirring at 10-20° C. for 1 hour after the completion of the addition, the reaction mixture was poured into 1 kg of crushed water with stirring, producing a white solid. To this was added 200 ml of toluene and stirred, the toluene layer was separated, and the aqueous layer was re-extracted with 200 ml of toluene. The toluene layers were combined into one, and 200 ml of a 5% aqueous sodium hydroxide solution was added thereto for extraction. After separating the aqueous layer, the toluene layer was dissolved in a 5% aqueous sodium hydroxide solution.
After re-extracting with 200 ml, the alkaline layers were combined and washed with 200 ml of toluene. While cooling the alkaline layer,
While stirring, the mixture was made acidic by adding concentrated hydrochloric acid to obtain white crystals. The crystals were filtered by suction, washed twice with 100 ml of water, and then dried under reduced pressure to give 48.5 g of white crystals as [1.1'-bicyclohexyl]-1.
-Carboxylic acid was obtained (melting point: 120-121℃, yield:
84.1%). The IR and NMR spectra of this product matched those of the standard product.

This [1,1'-bicyclohexyl]-1-carboxylic acid was heated and dissolved in 370 g of a 5% aqueous sodium hydroxide solution and kept at 70°C. While stirring this aqueous solution, 70.9 g of a 50.4% aqueous solution of 2-(diethylamino)ethyl chloride hydrochloride was added dropwise over 2 hours. The reaction solution was further stirred at 70-80°C for 1 hour, and then cooled to room temperature. After adding 100 ml of toluene to this, the mixture was washed twice with 100 ml of a 5% aqueous sodium hydroxide solution, and the washing with water was repeated until the toluene layer no longer showed alkalinity.

After drying the toluene layer with sodium sulfate, toluene was removed under reduced pressure to obtain 45.4 g of a pale yellow liquid. This liquid was found to be [1,1'-bicyclohexyl]-1-carboxylic acid-2-(diethylamino)ethyl ester from IR and NMR spectra.

This ester was dissolved in 250 ml of diethyl ether, and when hydrogen chloride gas was blown into the solution while stirring while cooling, white crystals were produced. The crystals were filtered, dried, and recrystallized from 450 ml of methyl ethyl ketone to obtain 43.1 g of white crystals (melting point: 172.6-173.1°C). IR and NMR of this crystal
The spectra were consistent with those of the standard dicyclomine hydrochloride.

Example 2 540 g of 97% acid was placed in the reaction flask of 1, and the mixture was cooled to 10° C. while stirring vigorously. Add 3ml to this
of formic acid was added dropwise, and then 50.0 g of [1,1'-bicyclohexyl]-2-ol was dissolved in 50.5 g of formic acid, and the solution was added dropwise over 3 hours while the reaction solution was maintained at 10-20°C. After further stirring for 1 hour at 10-20°C, the reaction mixture was poured into 1 kg of crushed ice to produce white crystals. Add 200ml of toluene to this, separate the toluene layer, and then remove the water layer from the toluene layer.
Extracted with 200ml. Combine the toluene layers into one,
After repeated washing with water until the pH reached 5-6, 200 g of 5% aqueous sodium hydroxide solution was added. After separating the aqueous layer, the toluene layer was extracted with 200 g of a 5% aqueous sodium hydroxide solution, and the alkali layers were combined and washed with 200 ml of toluene.

This alkaline layer was heated to 70℃ and while stirring
70.9 g of a 50.4% aqueous solution of 2-(diethylamino)ethyl chloride hydrochloride was added dropwise over 2 hours. The reaction solution was further stirred at 70-80°C for 1 hour, and then cooled to room temperature. Add 100ml of toluene to this and
After washing twice with 100 ml of % sodium hydroxide aqueous solution, washing with water was repeated until the toluene layer no longer showed alkalinity. After drying the toluene layer with anhydrous sodium sulfate, the toluene was removed under reduced pressure, and the
g of pale yellow liquid was obtained. IR and
The NMR spectra matched those of the ester obtained in Example 1. Dissolve this liquid in 150ml of acetone, cool it, and add 35% hydrochloric acid.
When 13.8 g was added dropwise, white crystals were formed. After filtering out the crystals, they were recrystallized from 150 ml of acetonitrile to obtain 39.3 g of white dicyclomine hydrochloride crystals (melting point: 172.1-173.7). The IR and NMR spectra of this product matched those of the standard product.

Example 3 Put 810 g of 97% sulfuric acid into the reaction flask from 1.
Cooled to 15° C. with vigorous stirring. 3 to this
After dropping 75.0 g of [1,1'-bicyclohexyl]-1-ol into 76.0 g of formic acid, the solution was added dropwise over about 3 hours while maintaining the reaction solution at 15-25°C. Thereafter, the same treatment as in Example 1 was carried out, and 37.2
[1,1'-bicyclohexyl]-1-carboxylic acid was obtained as white crystals of g (melting point: 120.5~
121.3°C, yield: 42.8%). This was heated and dissolved in 285 g of a 5% aqueous sodium hydroxide solution and kept at 70-80°C. While stirring, a 50.4% aqueous solution of 2-(diethylamino)ethyl chloride hydrochloride 55.0%
g was added dropwise over 2 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain 38.3 g of [1,1'-bicyclohexyl].
-1-carboxylic acid-2-(diethylamino)ethyl ester was obtained. This was dissolved in 100 ml of isopropyl alcohol, and 12.9 g of 35% hydrochloric acid was added dropwise while cooling. The generated crystals were filtered and dried under reduced pressure to obtain 36.4 g of white crystals of dicyclomine hydrochloride (melting point: 172.6-173.6°C). This product's IR and
The NMR spectra matched those of the standard.

Claims (1)

[Claims] 1 Structural formula () [1・1'-bicyclohexyl]-1 expressed as
-When obtaining carboxylic acid-2-(diethylamino)ethyl ester, structural formula () [1・1'-bicyclohexyl]-2 represented by
-all and structural formula () [1・1'-bicyclohexyl]-1 expressed as
-By reacting at least one type of ol with formic acid in the presence of concentrated sulfuric acid, the structural formula () [1・1'-bicyclohexyl]-1 expressed as
-[1,1'-bicyclohexyl]-1-carboxylic acid-, which is characterized in that it is made into a carboxylic acid, then made into an aqueous solution of an alkali metal salt, and reacted with 2-(diethylamino)ethyl chloride hydrochloride.
A method for producing 2-(diethylamino)ethyl ester.