JPH0563473B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for purifying imidazole derivatives.

More specifically, Cimetidine, or N
-cyano-N'-methyl-N''-[2-{(5-methyl-1H-imidazol-4-yl)methylthio}
The present invention relates to a method for purifying [ethyl]guanidine or its related compounds.

[Prior art] Japanese Patent Application Laid-open No. 59-7172 describes the following formula: Here, R ¹ , R ² and R ³ are lower alkyl groups,
Represents a lower alkenyl group or aralkyl group,
Alternatively, R ¹ and R ² may form a heterocyclic ring together with adjacent nitrogen atoms, Q represents an acid residue, and N-cyano-N'-methyl-N''- A method for producing N-cyano-N′-methyl-N″-[2-{(5-methylimidazol-4-yl)methylthio}ethyl]guanidine by reacting (2-mercaptoethyl)guanidine is disclosed. There is. And, Example 1~
3 contains N-cyano-N'- produced from the corresponding quaternary ammonium salt and the corresponding guanidine.
Methyl-N″-[2-{(5-methylimidazole-
A method for obtaining a purified product from a crude product containing 4-yl)methylthio}ethyl]guanidine by recrystallization using acetonitrile as a solvent is described.

In Japanese Patent Application Laid-open No. 54-59275, the following formula is Here, A is an imidazole base formed by combining the carbon atoms in the formula, X ₁ is a hydrogen atom,
is a lower alkyl group or a halogen, and m is 2 or 3. A compound represented by the following formula Here, R ₁ is a hydrogen atom or a lower alkyl group, and R ₂ is a hydrogen atom, a nitro group, or a cyano group. Here, a method for producing a heterocyclic compound represented by the following is disclosed, in which the definitions of A, X ₁ , R ₁ , R ₂ and m are the same as above. In Example 1, dilute sulfuric acid was added to a crude product containing 2-[(4-imidazolyl)methylthio]ethylguanidine produced from the corresponding raw material compound according to the above method, and then ethanol was added. A method for recrystallizing the resulting product from aqueous ethanol is described. Example 2 also includes N-[2-{(4-methyl-5
-imidazolyl)methylthio}ethyl]-N-nitroguanidine from methanol, Example 3 includes N-cyano-N'-methyl-
A method for recrystallizing N″-[2-{(4-methyl-5-imidazolyl)methylthio}ethyl]guanidine from acetonitrile-ether, Example 4 includes N
A method for recrystallizing -cyano-N'-methyl-N''-[2-{(4-methyl-5-imidazolyl)methylthio}ethyl]guanidine from isopropyl alcohol-ether; −
A method for recrystallizing N'-[2-{(4-methyl-5-imidazolyl)methylthio}ethyl]guanidine from acetonitrile, Example 6 includes N-cyano-
Recrystallizing N′-[2-{(4-bromo-5-imidazolyl)methylthio}ethyl]N″-methylguanidine from nitromethane, Example 7
-Cyano-N'-methyl-N''-[3-{(4-methyl-5-imidazolyl)methylthio}propyl]guanidine from isopropyl alcohol-ether; Recrystallization of N'-methyl-N''-[2-(4-imidazolylmethylthio)ethyl]guanidine from acetonitrile is described in each case.

JP-A-54-100372 discloses that 4-methylimidazole is reacted with formaldehyde or an oligomer of formaldehyde in an aqueous solution at a temperature of 25 to 160°C in the presence of an excess amount of hydrogen chloride.
A method for making methyl-5-chloromethyl-imidazole-hydrochloride is disclosed. In Examples 1 and 2, 4-methyl-5-chloromethyl-imidazole hydrochloride prepared from the raw material compound according to the above method was filtered as a precipitate from the reaction mixture, and the precipitate was filtered with HCl-containing ether. Washing (in Example 2, further washing with ether),
A method of drying in vacuum is described.

JP-A-50-105664 is the aforementioned JP-A-54-59272.
This is a parent application whose number is a divisional application, and the same embodiments as those disclosed in the parent application are described.

As mentioned above, all of the purification methods described in the above-mentioned publications disclose methods for purifying the imidazole derivative produced by the reaction as a free form or as a mineral acid salt (sulfate or hydrochloride).

Furthermore, in Japanese Patent Publication No. 53-24422, the following formula Here, X ₁ ″ and X ₂ ″ are H, lower alkyl,
OH, benzyl, halogen, amino or (CH ₂ ) _l
Y(CH ₂ )mNH ₂ or X ₁ ″ and X ₂ ″ may be combined with at least two atoms constituting the A ring to form a ring.

A is an unsaturated heterocyclic group formed by combining with the carbon atoms shown in the formula, contains at least one nitrogen atom, and may further include other heteroatoms, l and m is an integer from 0 to 4, the sum of l and m is 3, and Y is oxygen, _sulfur or NH. , R ₁ is lower alkyl, acyl or dialkylaminoalkyl, and E is oxygen or sulfur. Here, X ₁ and X ₂ are H, lower alkyl,
OH, benzyl, halogen, amino or or X ₁ and X ₂ may be combined with at least two atoms constituting the A ring to form a ring, and the definitions of A, Y, l, m, E and R ₁ are as above. Disclosed is a method for producing a compound represented by:

As mentioned above, the method disclosed in JP-A-53-24422 is a method for producing urea or thiourea derivatives, as is clear from the definition of E in the above formula. In (C) of Example 1 of the same publication, 4(5)-((2-aminoethyl)thiomethyl)imidazole corresponding to the above raw material amine compound (compound represented by a formula containing X ₁ ″, X ₂ ″) is prepared by reacting cysteamine hydrochloride with 4(5)-chloromethylimidazole hydrochloride in the presence of sodium ethoxide, and then reacting with picric acid to obtain dipicrate. ing.

In addition, in Japanese Patent Application Laid-Open No. 129550/1989, the following formula Here, R ₁ is Het-CH ₂ -S(-CH ₂ ) _o -- Here, Het is a 5- or 6-membered nitrogen-containing hetero compound such as imidazole, pyridine, thiazole, isothiazole, thiadiazole, isoxazole or triazole. a ring optionally substituted with lower alkyl, hydroxyl, halogen or amino, n means 2 or 3, R ₂ is substituted with lower alkyl, phenyl, hydroxyl or mercapto or SR ₄ or NHR ₅ when R ₃ is other than hydrogen, R ₆ is hydrogen, lower alkyl or R ₁ , R ₄ and R ₅ each mean lower alkyl, and R ₆ may be combined with R ₄ or R ₅ to further form a 5-membered ring such as thiazoline or imidazoline, and a method for producing the same is disclosed.

In Example 6, N,N'-bis-
A method for producing [2-{(5-methyl-4-imidazolyl)methylthio}ethyl]acetamidine trihydrochloride via tripicrate of acetamidine, Example 7 includes 2-[2-{(5 -Methyl-
4-Imidazolyl)methylthio}ethyl]amino-2-imidazoline dihydrochloride via picrate of the same imidazoline, Example 10 describes N,N'-bis-[2-{(5-methyl A process for preparing -4-imidazolyl)methylthio}ethyl]-N'-methylguanidine via its tripicrate salt is described.

Japanese Patent Publication No. 53-24422 and Japanese Patent Publication No. 1983-24422
In any of the methods disclosed in Publication No. 129550, the picrate described is a compound different from the compound targeted by the present invention.

[Problems to be Solved by the Invention] An object of the present invention is to provide a method for purifying an imidazole derivative having an N-cyano-N′-lower alkyl-N″-guanidinyl-ethylthiomethyl group as a substituent. It is in.

Another object of the present invention is to provide an industrially advantageous purification method for the imidazole derivative, which allows the imidazole derivative to be obtained in high purity.

Further objects and advantages of the present invention will become apparent from the description below.

According to the invention, such objects and advantages of the invention include the following formula () Here, R is a lower alkyl group, and R ¹ is a hydrogen atom or a lower alkyl group.
The following formula () By reacting with picric acid represented by the following formula () Here, the definitions of R and R ¹ are the same as above. A picrate represented by is produced, the picrate is separated from the resulting reaction mixture, and the separated picrylate is decomposed to form the above formula (). This is achieved by a method for purifying imidazole derivatives, which is characterized by liberating the represented imidazole derivatives.

The imidazole derivative targeted by the present invention is a compound represented by the above formula ().

In the above formula (), R is a lower alkyl group,
R ¹ is a hydrogen atom or a lower alkyl group.

The lower alkyl group represented by R and R ¹ is,
For example, a lower alkyl group having 1 to 4 carbon atoms is preferred. Such lower alkyl groups may be linear or branched; examples include methyl,
Mention may be made of ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or t-butyl.

Examples of the imidazole derivative represented by the above formula () include N-cyano-N′-methyl-N″-[2-{(5-methyl-1H-imidazol-4-yl)methylthio}ethyl]guanidine, N -cyano-N'-methyl-N''-[2-{(2,5
-dimethyl-1H-imidazol-4-yl)methylthio}ethyl]guanidine, N-cyano-N'-methyl-N''-[2-{(2-ethyl-5-methyl-1H-imidazol-4-yl) Methylthio}ethyl]guanidine, N-cyano-N'-methyl-N''-[2-{(5-methyl-2-n-propyl-1H-imidazole-
4-yl)methylthio}ethyl]guanidine, N-cyano-N′-methyl-N″-[2-{(2-n
-butyl-5-methyl-1H-imidazole-4
-yl)methylthio}ethyl]guanidine, N-cyano-N'-ethyl-N''-[2-{(5-methyl-1H-imidazol-4-yl)methylthio}ethyl]guanidine, N-cyano-N'-Methyl-N''-[2-{(2-methyl-5-methyl-1H-imidazol-4-yl)methylthio}ethyl]guanidine,N-cyano-N'-methyl-N''-[2-{( 5-Methyl-2-n-propyl-1H-imidazole-
4-yl)methylthio}ethyl]guanidine, N-cyano-N'-ethyl-N''-[2-{(2-n
-butyl-5-methyl-1H-imidazole-4
-yl)methylthio}ethyl]guanidine, N-cyano-N′-methyl-N″-[2-{(2-n
-butyl-5-methyl-1H-imidazole-4
-yl)methylthio}ethyl]guanidine, N-cyano-N'-n-propyl-N''-[2-
{(5-methyl-1H-imidazol-4-yl)
Methylthio}ethyl]guanidine, N-cyano-N′-n-butyl-N″-[2-{(5
-Methyl-1H-imidazol-4-yl)methylthio}ethyl]guanidine.

The crude imidazole derivative of the above formula () can be produced by various methods. For example, N-cyano-N'-methyl-N''-[2-
The method for producing cimetidine via (butane-2,3-dionyl)thioethyl]guanidine is described in British Patent No. 2025969 and Spanish Patent No.
It is disclosed in specification No. 455991 and Japanese Patent Application Laid-Open No. 60-92257. These methods are adapted for the production of crude imidazole derivatives of the above formula () according to the invention.

In addition, the N-cyano-
A method for producing cimetidine by reacting N'-methyl-N''-[2-(butane-2,3-dionyl)thioethyl]guanidine with an ammonium salt of a carboxylic acid and formaldehyde, and a method for producing cimetidine using the above formula ( ) can also be used to produce other imidazole derivatives.

That is, N-cyano-N'-lower alkyl-
N″-[2-(butane-2,3-dionyl)thioethyl]guanidine is reacted with an ammonium salt of a carboxylic acid and a lower aliphatic aldehyde such as formaldehyde or acetaldehyde to produce an imidazole derivative of the above formula (). I can do it.

Examples of ammonium salts of carboxylic acids used in the above method include ammonium formate, ammonium acetate, ammonium monochloroacetate, ammonium dichloroacetate, ammonium trichloroate, ammonium methoxyacetate, ammonium propionate, ammonium butyrate, ammonium isobutyrate, and ammonium benzoate. Ammonium salts of monocarboxylic acids having 1 to 8 carbon atoms are preferred.

Examples of the reaction solvent used in the above method include alcohols such as methanol, ethanol, propanol, isopropanol, and butanol;
Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; esters such as methyl acetate and ethyl acetate;
Preferred are nitriles such as acetonitrile and propionitrile, and amides such as formamide and N,N-dimethylformamide.

The molar ratio of the ammonium salt of carboxylic acid to the guanidine is 2 to 20, preferably 3 to 15, the molar ratio of aldehyde is 1 to 10,
Preferably it is 1.2 to 5.

The ratio of the solvent to the guanidine used is usually 1 to 80 times by weight, preferably 5 to 70 times by weight.

The reaction temperature is usually -10 to 150°C, preferably
The temperature ranges from 15 to 120°C. The time required for the reaction varies depending on the reaction temperature and other conditions, but is usually 0.2 to 50 hours, preferably 0.3 to 50 hours.
The range is 40 hours.

In the method of the present invention, regardless of the method for producing the imidazole derivative of the above formula (), the produced crude product is first The imidazole derivative () in the crude product and picric acid are reacted with picric acid to form the following formula (). Here, the definitions of R ¹ and R are the same as above, causing the generation of a picrate expressed as .

Picric acid can be used in a ratio of 0.5 to 10 mol, preferably 1 to 3 mol, per 1 mol of the imidazole derivative ().

Preferably, the reaction producing picrate is carried out in the presence of a solvent. Preferred solvents include lower aliphatic alcohols such as methanol, ethanol, n-propanol and iso-propanol; ethers such as diethyl ether, dioxane and tetrahydrofuran; halogenated hydrocarbons such as methylene chloride and chloroform; methyl acetate and acetic acid. Examples include aliphatic esters such as ethyl; aromatic hydrocarbons such as benzene and toluene. Among these, ethanol and ethyl acetate are used as particularly suitable solvents. The solvents can be used alone or in combination of two or more.

Picric acid is preferably added as a solution dissolved in a solvent to the crude product or reaction mixture of the imidazole derivative, or to a solution thereof dissolved in a solvent.

The reaction temperature is usually 0 to 50°C, more preferably 10 to 30°C. The reaction time varies depending on the reaction temperature, but is usually 0.5 to 50 hours, more preferably 3 to 20 hours.

Picrate is produced as a solid that is insoluble or sparingly soluble in the reaction solvent.

The produced picrate is then subjected to e.g. filtration,
It is separated from the reaction mother liquor in the resulting reaction mixture by a separation operation such as centrifugation.

The separated picrate is then decomposed to liberate the imidazole derivative of formula () above.
The decomposition of picrate can be carried out, for example, by bringing an inorganic acid such as hydrochloric acid or sulfuric acid into contact with picrate.

The decomposition operation of picrate can be advantageously carried out by mixing the picrate with an aqueous solution of an inorganic acid and a water-immiscible organic solvent, for example. By such an operation, the decomposed imidazole derivative (2) can be distributed mainly to the aqueous layer, and the picric acid can be mainly distributed to the organic layer.

Preferred organic solvents that are immiscible with water include ethers such as diethyl ether and dipropyl ether; aliphatic esters such as methyl acetate and ethyl acetate; and aromatic hydrocarbons such as benzene and toluene. can.
Among these, ethyl acetate and toluene are preferably used.

The aqueous layer is then separated from the organic layer and neutralized with excess inorganic base such as sodium carbonate, sodium bicarbonate. After neutralization, the imidazole derivative () is extracted from the aqueous layer with an organic solvent that is immiscible with water. Such organic solvents include:
For example, ethers such as diethyl ether and dipropyl ether; aliphatic esters such as methyl acetate and ethyl acetate; and aromatic hydrocarbons such as benzene and toluene are preferably used. Among these, ethyl acetate and toluene are particularly advantageously used.

To isolate the purified imidazole derivative, for example, the organic layer is separated from the aqueous layer, the organic layer is dried with a desiccant, concentrated, the resulting residue is dissolved in an organic solvent, and activated carbon is added and stirred. do.

Examples of organic solvents for dissolving the residue include ethers such as diethyl ether, dioxane, and tetrahydrofuran; methanol, ethanol, n
Examples include lower aliphatic alcohols such as propanol and iso-propanol; halogenated hydrocarbons such as methylene chloride and chloroform; aliphatic esters such as methyl acetate and ethyl acetate; aromatic hydrocarbons such as benzene and toluene. .
Among these, isopropanol and dioxane are particularly preferred.

The above treatment with activated carbon is carried out in an amount of 0.01 to 100 parts by weight per 1 part by weight of the imidazole derivative () obtained;
More preferably, it is 0.1 to 10 parts by weight. The treatment temperature is 0 to 150°C, more preferably 10 to 80°C.
Stirring time is 0.5 to 50 hours, more preferably 3 to 20 hours.
It's time. After the activated carbon treatment, the activated carbon is removed, for example by filtration. The purified imidazole is obtained by maintaining the obtained organic solvent solution at a temperature of, for example, -20°C to 100°C, more preferably 0 to 30°C, for 1 to 50 hours, more preferably 3 to 20 hours. Crystallize the derivative. Crystals of the imidazole derivative are separated and obtained, for example, by filtration, centrifugation, or the like.

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

Example 1 (1) In a 100ml flask equipped with a condenser and a thermometer,
N-cyano-N′-methyl-N″-[2-(butane-2,3-dionyl)thioethyl]guanidine
4.83g (20mmol), paraformaldehyde
1.57g (50mmol), ammonium acetate 6.17
g (80 mmol) and isopropanol 50 ml
I prepared it. The reaction temperature was raised from room temperature to 50°C over 4 hours, and stirred at 50°C for 1 hour.
A reaction mixture containing cimetidine was thus obtained. High performance liquid chromatography analysis revealed that the reaction mixture contained cimetidine in an amount corresponding to a 65% reaction yield.

(2) Add 20ml of water to this reaction mixture and then
A solution of 2.34 g (8.7 mmol) of 85% picric acid in 30 ml of ethanol was added dropwise over a period of 5 minutes. Thereafter, the mixture was stirred at room temperature for 10 hours, and yellow crystals were precipitated. The results were filtered and dried. It showed the following physical properties.

Melting point: 187.4°C (decomposed) ¹ H-NMR spectrum (DMSO-d ₆ , ppm);
2.28 (3H, s), 2.56 (2H, t, J=7Hz),
2.66 (3H, s), 2.70 (3H, s), 3.30 (2H,
t, J=7Hz), 3.82 (2H, s), 8.62 (2H,
s), 8.82 (1H, s).

Mass spectrometry (FD) 253 (molecular ion peak of cimetidine).

Elemental analysis (excluding sulfur element) Calculated value C: 39.9% H: 4.0% N: 26.2% Measured value C: 40.3% H: 4.1% N: 26.1% Based on the above physical properties, the yellow crystals were determined to be picrate of cimetidine. .

(3) Add 1N− to 7.35 g of cimetidine picrate.
100 ml of HCl and 1 portion of ethyl acetate were added to decompose the picrate and liberate cimetidine. The ethyl acetate layer was separated and removed from the aqueous layer, the aqueous layer was made alkaline with excess sodium bicarbonate, and then extracted with 200 ml of ethyl acetate. After separating the ethyl acetate layer, add 200% ethyl acetate to the aqueous layer again.
ml was added to extract and the ethyl acetate layer was separated. The separated ethyl acetate layers were combined and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered off and concentrated under reduced pressure to obtain a white solid.

This white solid was dissolved in 43 ml of isopropanol, 0.57 g of activated carbon (White Sagi C) was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, activated carbon was removed using a Millipore filter, and the filtrate was stirred at 5°C for 12 hours to precipitate white crystals. Filter the white crystals, wash with 4 ml of isopropyl alcohol, and dry under reduced pressure to obtain 1.98 g of purified cimetidine.
(Cimetidine recovery rate 45%) was obtained. That is,
This product had a melting point of 142°C, and its infrared absorption spectrum and ¹ H-NMR spectrum matched those of the cimetidine sample.

Example 2 The pH of Example 1 (2) was 5.9 when 20 ml of water was added to the reaction mixture, and the pH of Example 1 was adjusted to 6.8 with 5N sodium hydroxide. Exactly the same operation as in 3) was performed. The recovery rate of cimetidine was 45%.

Claims (1)

[Claims] 1. The following formula () Here, R is a lower alkyl group, and R ¹ is a hydrogen atom or a lower alkyl group.
The following formula () By reacting with picric acid represented by the following formula () Here, the definitions of R and R ¹ are the same as above, to produce a picrate represented by, to separate the picrate from the resulting reaction mixture, and to decompose the separated picrate to be represented by the above formula (). A method for purifying an imidazole derivative, characterized by liberating an imidazole derivative.