JPS644510B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for isolating aminocarboxylic acid derivatives. More specifically, in isolating an acid addition salt of an aminocarboxylic acid derivative produced by subjecting an acid addition salt of an aminocarboxylic acid halide having an amino group to an acylation reaction with phenylpropionate in the presence of a Lewis acid. , the Lewis acid complex generated during the acylation reaction and the remaining Lewis acid,
An industrially excellent aminocarboxylic acid whose desired aminocarboxylic acid derivative can be isolated very easily by adding a strong alkali aqueous solution, heating it, decomposing it, and later isolating it. This invention relates to a method for isolating derivatives.

The following formula [′] [In the formula, R ₁ is a 1,4-cyclohexylene group, 1,
Represents a 4-phenylene group or -( _CH2 ) _o- . Here, n represents an integer from 2 to 6. R ₂ ' represents a hydrogen atom or a lower alkyl group. ] The aminocarboxylic acid derivatives or acid addition salts represented by were previously proposed (Japanese Patent Application No. 55-98636, JP-A-57-24337; JP-A-55-113366, JP-A-57-53442). Publications; Japanese Patent Application No. 163231/1983; Japanese Patent Application No. 88155/1982; Japanese Patent Application No. 20820/1982;
57-136553), this is a novel compound synthesized for the first time by the present inventors, and it is a compound that has excellent peptic ulcer action.

The aminocarboxylic acid derivative has the following formula [] H ₂ N-CH ₂ -R ₁ -COX ... [] [where R ₁ is a 1,4-cyclohexylene group, 1,
Represents a 4-phenylene group or -( _CH2 ) _o- . Here, n represents an integer from 2 to 6. X represents a halogen atom. ] Aminocarboxylic acid halide hydrochloride represented by and the following formula [] [In the formula, R ₂ represents a lower alkyl group. ] It is produced by carrying out an acylation reaction called a Friedel-Crafts reaction with a phenylpropionate ester represented by the following in the presence of a Lewis acid.

As mentioned above, in the Friedel-Crafts acylation reaction performed using a Lewis acid, a Lewis acid complex is produced and an excess of Lewis acid remains, so when isolating the acylated product, Usually, the Lewis acid complex and the remaining Lewis acid are decomposed by adding a large amount of water, and then the formed acylated product is extracted under acidic conditions with the same solvent used for the acylation reaction or another organic solvent. The method is adopted.

However, when an acid addition salt of an aminocarboxylic acid halide having an amino group not protected by a protecting group such as an acetyl group is used as a raw material for the acylation reaction as in the present invention, as shown in the above formula [], Since acylated products are produced in the form of corresponding acid addition salts, the general method of extraction with organic solvents under acidic conditions as described above does not require extraction with highly polar solvents such as ethyl acetate or chloroform. Even when used, extraction of the acylated product is difficult. Furthermore, when extraction is performed under neutral conditions, a gel of hydroxylated compounds derived from Lewis acids precipitates, making extraction and separation using organic solvents extremely difficult.

Therefore, the present inventors conducted an acylation reaction in the presence of a Lewis acid using an acid addition salt of an aminocarboxylic acid halide having an amino group as shown in the above formula [], and isolated the resulting acylated product. As a result of intensive research with the aim of finding an efficient method, we discovered that when isolating the resulting acylated product, we added a strong alkaline aqueous solution to the Lewis acid complex produced in the acylation reaction and the remaining Lewis acid. The present invention was achieved based on the discovery that the acylated product can be isolated very efficiently by decomposition by heating, followed by decantation or extraction with an organic solvent.

That is, the present invention provides the following formula [] H ₂ N-CH ₂ -R ₁ -COX ... [] [In the formula, R ₁ is a 1,4-cyclohexylene group, 1,
Represents a 4-phenylene group. X represents a halogen atom. ] Acid addition salt of aminocarboxylic acid halide represented by and the following formula [] [In the formula, R ₂ represents a lower alkyl group. ] The following formula produced by acylation reaction with phenylpropionate represented by [] in the presence of a Lewis acid. [In the formula, R ₁ and R ₂ are the same as defined above. ] When isolating the acid addition salt of the aminocarboxylic acid derivative represented by the formula, the Lewis acid complex produced in the acylation reaction and the remaining Lewis acid are removed by adding a strong alkaline aqueous solution of sodium hydroxide or potassium hydroxide. A method for isolating an aminocarboxylic acid derivative represented by the above formula [], which comprises decomposing it by heating and then isolating it.

The raw material compound used in the production of the aminocarboxylic acid derivative of the present invention is an acid addition salt of an aminocarboxylic acid halide represented by the above formula []. In the above formula [], R ₁ represents a 1,4-cyclohexylene group or a 1,4-phenylene group. X is chlorine,
Represents a halogen atom such as bromine. As the acid addition salt, hydrochloride is particularly preferred. Examples of such acid addition salts of aminocarboxylic acid halides include trans-4-aminomethylcyclohexanecarboxylic acid chloride hydrochloride, 4-aminomethylbenzoic acid chloride hydrochloride, and ε-aminocaproic acid chloride hydrochloride.

The other raw material compound is a phenylpropionic acid ester represented by the above formula [], where R ₂ represents a lower alkyl group, and such lower alkyl groups include, for example, a methyl group, an ethyl group,
Examples include propyl group and butyl group. Examples of such phenylpropionate esters include phenylpropionate methyl ester, phenylpropionate ethyl ester, and phenylpropionate propyl ester.

Examples of Lewis acids include aluminum chloride,
Examples include aluminum compounds such as aluminum bromide, iron compounds such as ferric chloride, zinc compounds such as zinc chloride, tin compounds such as stannic chloride, and titanium compounds such as titanium chloride. Among these, aluminum compounds such as aluminum chloride and aluminum bromide are preferred.

To carry out the acylation reaction using these compounds, a method similar to that employed in the usual Friedel-Frafts reaction is employed. That is,
The acid addition salt of the aminocarboxylic acid halide of the above formula [] is used in moles of 0.9 to 1.1 times the phenylpropionate ester of the above formula [], and the Lewis acid is equimolar to the acid addition salt of the aminocarboxylic acid halide. ~10 times the mole, preferably 2 to 3 times the mole. In addition, as a reaction solvent, halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, dichloroethane, and tetrachloroethane, inert solvents such as nitrobenzene, and carbon disulfide are used, and the acylation reaction is carried out by a conventional method. will be carried out.

Thus, by acylation reaction, the following formula [] [In the formula, R ₁ and R ₂ are the same as defined above. ] An acid addition salt of an aminocarboxylic acid derivative represented by the following is produced.

In the present invention, the acid addition salt of the aminocarboxylic acid derivative is isolated as follows.

That is, first, the Lewis acid complex generated during the above acylation reaction and the remaining Lewis acid are decomposed by adding a strong alkaline aqueous solution of sodium hydroxide or potassium hydroxide and heated, and then isolated. It is done by

And such a strong alkaline aqueous solution is 8 normal or more,
Preferably a concentration of 10 to 16 normal is preferred. The amount of the strong alkaline aqueous solution used is 2 mol or more, preferably 3 to 7 mol, per 1 mol of the Lewis acid used in the acylation reaction.

By heating using such a strong alkaline aqueous solution,
The Lewis acid complex produced in the above acylation reaction and the remaining Lewis acid are decomposed as follows.

That is, after the above acylation reaction, the reaction mixture is cooled, and then a relatively small amount of a strong alkali aqueous solution is gradually added at first. This causes the Lewis acid complex and the remaining Lewis acid to gel, and by subsequently adding a strong alkaline aqueous solution, the gel gradually dissolves to give a cloudy reaction mixture, which is then preferably 30℃~80
By heating at a temperature of 40° C. to 60° C., more preferably 40° C. to 60° C., fine white cloudy particles are aggregated and gradually become a viscous slurry solution.

If necessary, an appropriate amount of the same solvent as used in the above acylation reaction is added to the slurry solution thus obtained, stirred thoroughly, and then the organic layer and the slurry solution are separated by decantation or the like. The acylated product can be easily collected by obtaining the organic layer. Furthermore, after separation by decantation or the like, the slurry solution is further extracted using the same solvent used in the acylation reaction to almost completely separate the desired acylated product. can. The acylated product can be isolated by conventional means of washing the resulting organic layer with saturated brine or the like, drying with sodium sulfate or the like, separating, and concentrating.

By doing this, the following formula [] [In the formula, R ₁ is the same as defined above, and R ₂ represents a lower alkyl group. ] An aminocarboxylic acid derivative represented by is isolated.

That is, here, since the acid addition salt of the aminocarboxylic acid derivative produced in the above acylation reaction is isolated using a strong alkaline aqueous solution as described above, its amino group is not in the form of an acid addition salt but in the form of a free amino group. isolated.

In addition, after such isolation operation, if necessary, a hydrolysis reaction which is known per se with an acid such as hydrochloric acid, hydrobromic acid, or sulfuric acid is carried out to obtain the ester of the aminocarboxylic acid derivative obtained by the above isolation operation. The group can be hydrolyzed. In this case, the aminocarboxylic acid derivative is obtained as an acid addition salt of the acid used for hydrolysis.

The aminocarboxylic acid derivative represented by the above formula ['] or its acid addition salt thus isolated is a compound having excellent peptic ulcer action and is extremely useful as a pharmaceutical. Therefore, the isolation method of the present invention can be said to be an efficient and industrially excellent isolation method for extremely useful compounds, and the significance of the present invention is extremely large.

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

Example 1 (i) Add 230 g of thionyl chloride to a solution of 100 g of tranexamic acid suspended in 500 ml of benzene,
After reacting at 45-48℃ for 3 hours, concentrate to 135
g Tranexamic acid chloride hydrochloride was obtained. Next, this was suspended in 1,400 ml of 1,2-dichloroethane, and then 255 g of thoroughly pulverized anhydrous aluminum chloride was added while maintaining the temperature at 10°C. after that
A solution of 99 g of phenylpropionic acid methyl ester, equivalent to 0.95 equivalent, in 150 ml of 1,2-dichloroethane was added dropwise over 20 minutes, followed by immediate heating and reaction in the range of 55° to 60° C. for 2 hours.

After the Friedel-Crafts reaction was completed, 740 ml of a 16N aqueous sodium hydroxide solution was added dropwise over 2 hours while cooling with ice. The reaction solution becomes a white suspension 50
When heated to ℃, it becomes a slurry and the supernatant liquid separates, so this is decanted and removed, and 1,2-dichloroethane is added to the slurry solution.
After adding 2000 ml and stirring for 20 minutes, the supernatant liquid was similarly decanted.

The decanted solution was washed with 600 ml of saturated brine, dried over sodium sulfate, separated, and concentrated to obtain 176 g of crystals. The crude yield was 96%. (Contains some phenylpropionate methyl ester) (ii) Furthermore, 1200 ml of 3N hydrochloric acid was added to this and hydrolyzed at 60°C for 5 hours. The crystals precipitated after concentration
By washing with 1000 ml of acetone to remove by-produced phenylpropionic acid, 181 g of p-(trans-4-aminomethylcyclohexylcarbonyl)-phenylpropionic acid hydrochloride was obtained.
The total yield was 92%. Recrystallization from water-acetone gave a purified product with a melting point of 240-243°C. The elemental analysis value, NMR spectrum, and IR spectrum were consistent with those of the specimen, of which the NMR values were as follows.

NMR (CD ₃ OD) δ (ppm): 7.8 (2H, d, J = 8.5Hz), 7.3 (2H, d, J
= 8.5Hz) 2.5-3.0 (6H, m), 1.0-2.1 (10H, m) Example 2 (i) 68g of tranexamic acid chloride hydrochloride in 800ml
After suspending in 1,2-dichloroethane, 10
130 g of anhydrous aluminum chloride was added while maintaining the temperature at °C, and then a solution of 50 g of phenylpropionic acid methyl ester dissolved in 80 ml of 1,2-dichloroethane was added dropwise. Heat immediately;
After reacting for 2 hours at 55-60℃, add 292ml of 12N sodium hydroxide aqueous solution while cooling with ice.
was added dropwise for 1 hour. The reaction solution was heated to 45°C and stirred for 20 minutes, then allowed to stand, the resulting supernatant was decanted, and 1000 ml of the slurry residue was added.
1,2-dichloroethane was added and decanted in the same manner. Wash the decant with saturated saline,
Upon concentration, 90.5 g of crystals were obtained. The crude yield was 98%.

(ii) The crystals were then suspended in 600 ml of 3N hydrochloric acid and
Hydrolyzed at ℃ for 5 hours. After concentration, the precipitated crystals were washed with 400 ml of acetone to obtain 92.3 g of p-
(trans-4-aminomethylcyclohexylcarbonyl)-phenylpropionic acid was obtained.
The yield was 93%. The NMR of this product almost matches that of Example 1, supporting its structure.

Example 3 (i) 4-Aminomethylbenzoic acid chloride hydrochloride 65
g was suspended in 800 ml of 1,2-dichloroethane,
A solution of 125 g of anhydrous aluminum chloride and 49 g of phenylpropionic acid methyl ester dissolved in 75 ml of 1,2-dichloroethane was added while maintaining the temperature at 10°C. After reacting at 55° to 60°C for 2 hours, 370 ml of 16N potassium hydroxide aqueous solution was added dropwise over 1 hour while cooling with ice. After stirring at 60℃ for 20 minutes, the resulting supernatant liquid was decanted and collected, and the residue was again diluted with 1,2-dichloroethane.
1000 ml was added and decanted in the same manner. After washing the decant with saturated brine and distilling off the solvent,
83.4 g of crystals were obtained. The crude yield was 94%.

(ii) 600 ml of 3N hydrochloric acid was added to the crystals, and the mixture was heated at 60°C for 5 hours to perform hydrolysis. The crystals obtained after concentration were washed with 500 ml of acetone to obtain p-(4-
84.9 g of aminomethylbenzoyl)-phenylpropionic hydrochloride was obtained. The yield was 89%. This product was recrystallized from water-acetone to obtain a purified product with a melting point of 186-192°C. Its elemental analysis values, NMR spectrum, and IR spectrum were consistent with those of the standard sample, of which the NMR values were as follows.

NMR ( _CDCl3 ) δ (ppm): 7.3-8.0 (8H, m), 4.2 (2H, S) 2.5-3.2 (4H, m)

Claims (1)

[Claims] 1 The following formula [] H ₂ N-CH ₂ -R ₁ -COX ... [] [In the formula, R ₁ represents a 1,4-cyclohexylene group or a 1,4-phenylene group. X represents a halogen atom. ] Acid addition salt of aminocarboxylic acid halide represented by and the following formula [] [In the formula, R ₂ represents a lower alkyl group. ] The following formula produced by acylation reaction with phenylpropionate represented by [] in the presence of a Lewis acid. [In the formula, R ₁ and R ₂ are the same as defined above. ] When isolating the acid addition salt of the aminocarboxylic acid derivative represented by the formula, the Lewis acid complex produced in the acylation reaction and the remaining Lewis acid are removed by adding a strong alkaline aqueous solution of sodium hydroxide or potassium hydroxide. A method for isolating an aminocarboxylic acid derivative represented by the above formula [], which comprises decomposing it by heating and then isolating it. 2. A method for isolating an aminocarboxylic acid derivative according to claim 1, which comprises heating to 30°C to 80°C. 3. The method for isolating an aminocarboxylic acid derivative according to claim 1 or 2, wherein the acid addition salt of the aminocarboxylic acid derivative represented by the above formula [] is a hydrochloride. 4. The method for isolating an aminocarboxylic acid derivative according to any one of claims 1 to 3, wherein the Lewis acid is an aluminum compound.