JPS58201768A - Preparation of imidazole derivative - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as an intermediate of histamine H2-receptor antagonist, economically, in an industrial scale, by the Curtius reaction using a novel 3-[(5-methylimidazol-4-yl)methylthio]-propionic acid as a starting material. CONSTITUTION:The objective 4-(2-aminoethyl)thiomethyl-5-methylimidazole of formula III is prepared by (1) reacting the novel 3-[(5-methylimidazol-4-yl)methylthio]propionic acid of formula I or its reactive derivative at the carboxyl group with hydrazine and nitrous acid or with an alkali metal azide, and (2) subjecting the resultant carboxylic acid azide of formula II to Curtius reaction. The novel compound of formula I used as a starting material can be prepared easily by reacting 4-hydroxymethyl-5-methylimidazole with 3-mercaptopropionic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 4-(2-aminoethyl)thiomethyl-5
−゛Regarding a new manufacturing method for methylimidazole□
be.

This compound of formula ('I) is useful as an intermediate in the production of pharmaceuticals known as histamine H2-receptor antagonists.9 Usually, industrially, 4'-hydroxymethyl-5-dimethylimidazole is reacted with cysteamine. (Japanese Unexamined Patent Publication No. 47-23471).
However, screwsteamine used in this reaction is a 41 compound that is expensive and unstable to air oxidation, and is not necessarily suitable as a raw material for industrial production.

This time, the present inventors □ et al. investigated a separate synthesis method for the compound of formula ('I), and found that 3-((5-methylimidazol-4-yl)
The starting material is methyl□ruthio]propionic acid. We have developed a new manufacturing method using the Curtius reaction. The present invention relates to this production method, which is advantageous compared to conventional methods in that it avoids the use of cysteamine.

According to the invention, the compound of formula (I) is prepared by reacting a carboxylic acid of formula 9 or its activated derivative at the carboxyl group with hydrazine and nitrous acid or with an alkali azide. It is obtained by converting the carboxylic acid azide into the corresponding amine by Curtius reaction.

The carboxylic acid of formula (II), which is a raw material for the production method of the present invention, is a new compound that has not been described in any literature. We have developed a simple method for reacting 3-mercaptopropionic acid with 4-hydroxymethyl-5-methylimidazole.
The 3-mercaptopropionic acid used in this production method is a cheap and easily available raw material, and therefore this carboxylic acid (1) is also an extremely suitable compound as a raw material for industrial production. .

Examples of activated derivatives of the carboxyl group of carboxylic acid (II) include esters, acid halides, and acid anhydrides.

In particular, lower alkyl esters or acid chlorides are practically advantageous. These activated derivatives are of formula 9 (It
) can be easily obtained by esterification using a conventional method as a raw material or by acid halogenation (see reference side below).

To carry out the process of the invention, for example, a carboxylic acid of formula (If) or an activated derivative thereof is reacted with hydrazine, usually in a solvent, optionally with heating. To give a very general example used in this reaction, a lower alkyl ester of a carboxylic acid of the formula (I It is a time reaction. When the acid hydrazide thus obtained is subsequently treated with nitrous acid, acid azide (1) is produced. This reaction typically involves water and acetic acid.

In the presence of a mineral acid such as hydrochloric acid or an organic acid such as acetic acid, using a lower alcohol, tetrahydrofuran, ethyl ether, benzene, dichloromethane, etc. or a mixture thereof as a solvent.

This is done by adding sodium nitrite solution.

Alternatively, the carboxylic acid azide of formula (1).

Activated derivatives of carboxylic acids of the formula (Ill), preferably acid chlorides, can also be obtained by the action of an alkali azide, such as endothorium azide.
This reaction is usually carried out at low temperature in a mixed solvent of water and an organic solvent that does not participate in the reaction, such as ethyl ether, tetrahydrofuran, dioxane, benzene, ethyl acetate, dichloromethane, etc.

Since the carboxylic acid azide of formula (1) thus obtained is very easily decomposed, 9 it is usually used immediately in the Curtius reaction without being isolated.

The reaction can be carried out under commonly known conditions, and hydrolysis in the presence of an acid after the rearrangement yields the desired amine, a compound of formula (Il). To explain, 1 This transition usually occurs with acid azide (
It is usually carried out by heating under neutral or acidic conditions in the same reaction solution in which 1) was produced, and in cases where the solvent is water or acetic acid, hydrolysis after the transfer may also occur. At the same time, the desired amine (I) is produced. In addition, when the reaction solvent is a lower alcohol, the product obtained after the transfer is the corresponding urethane, and in that case, if it is hydrolyzed after or without isolation, the desired amine (
I) is obtained.

Isolation and purification of product (I) is carried out by a conventional method, and the operation is extremely simple since the nine reactions proceed almost quantitatively. Furthermore, when the present invention is utilized for the production of a histamine H2-receptor antagonist, it is also possible to incorporate the reaction solution as it is into the subsequent production process without isolating the product.

As described above, the present invention makes it possible to easily and inexpensively produce 4-(2-aminoethyl)thiomethyl-5-methylimidazole (1), which is a useful intermediate for pharmaceutical production, using the Crudeus reaction. It's a method. The yield of the product obtained by this production method is extremely high for this type of reaction, and considering that the entire reaction can be carried out in one step, the present invention is particularly suitable for industrial scale production. It is very useful as a manufacturing method.

EXAMPLES The present invention will be specifically explained below with reference to Examples and Reference Examples.

Reference example (a) 4-hydroxymethyl-5-methylimidazole hydrochloride 10. Of and 3-mercaptopropionic acid 7
．． 11 was added to 35% hydrochloric acid (100%) and heated under reflux for 3 hours. After concentrating the reaction solution under reduced pressure, the residue was recrystallized from methanol-ethyl ether to yield 3-((5-methylimidazol-4-yl)methylthio]propionic hydrochloride 1.
5.39' (yield 96%) is obtained.

Melting point 106-108 C0 Engineering R spectrum ν am 3150, 2650.1'100.1635.1!45
．． 1425° 1255° NMR spectrum (DM80-de) δ: 2.
30 (2H, 8), 2.60 (4H, 8).

3.85 (2H,B), 8.95 (LH,S
).

12.10 (3H, br, s).

(b) The above 3-[(5-methylimidazole-4
Thioyl chloride 11
Add L and 3f and heat under reflux for 2 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in a mixture of water and chloroform, and then neutralized with sodium hydrogen carbonate. The chloroform layer is separated, dried and the solvent is distilled off to obtain 3-[(5-methylimidazol-4-yl)methylthio]propionic acid methyl ester 13.0r (96%).

Engineering R spectrum ν am 1'72514301241511951165NMR
Spectrum (DM80-eL6) δ: 2.25
(3H,8), 2.60 (2H,t).

2.65 (2H, t), 3.65 (3H,
s).

3.70 (2H, s), '7.515 (IH,
s).

12.00 (LH!l).

Example 1 3-[(5-methylimidazol-4-yl)methylthio]propionic acid methyl ester 8.5f and 100
% hydrazine hydrate, 9 f., is added to 30 methanol and heated under reflux for 4 hours.

9- After concentrating the reaction solution under reduced pressure, the residue was recrystallized from methanol to give 1.1 t of 3-[(5-methylimidazol-4-yl)methylthio]propionic acid hydrazide (yield 91%).
) is obtained.

Melting point 144-145 [1'0 R spectrum C axCm 3300.2800,1660,15)5,1455.
14015°040 O NMR spectrum (DM80- +16) δ: 2
．． 10 (3H,s), 2.40 (2H,t).

2.55 (2H,t), 3.60 (2H,s
).

6.25 (3H,'br,s), 7.40 (x5
s).

9.00 (LH, br, s).

3'-((5-methylimidazole-4) obtained above
-yl)methylthio]propionic acid hydrazide 1.01
was dissolved in a mixture of 2N hydrochloric acid (10-) and acetic acid (10-), 0.36 f of sodium nitrite was added to the mixture under water-cooling and stirring, and the mixture was heated at room temperature for 30 minutes9, then 60~
Stir for 30 minutes while heating at 70°C. After concentrating the reaction solution under reduced pressure, the residue was dissolved in water and neutralized with potassium carbonate. After removing water under reduced pressure again.

Dissolve the residue in isopropyl alcohol and remove the insoluble inorganic salts. After drying the filtrate under reduced pressure.

Recrystallization from methanol-ethyl ether containing hydrogen chloride gives 4-(2-aminoethyl)thiomethyl-5-methylimidazole dihydrochloride 1.11 (yield 96%).

Melting point: 185-18'/r0 This product mixes with the standard product and shows no melting point depression, and the infrared absorption spectrum and thin layer chromatography completely match the standard product.

Example 2 3-((5-methylimidazol-4-yl)methyl,
Thio]propionic acid hydrazide 1. Using Of as raw material,
The inorganic salt was separated from the isopropyl alcohol solution of 4-(2-aminoethyl)thiomethyl-5-methylimidazole produced in the same manner as in Example 1, and the P solution was dissolved in an isopropyl alcohol solution of 0.68 f of cyanamide dithiocarbonate dimethyl ester. Add. After stirring for 4 hours at room temperature.

Evaporate the solvent and wash the residue with water. The precipitate was separated and recrystallized from ethanol-ethyl ether to give N-cyano-N'-(2-(15-methylimidazole-4-
yl)methylthioethyl)-s-methylisothiourea 1
．． 121F (yield 89%) is obtained. Melting point 14
'/-149c0 This product mixes with the standard product and shows no drop in melting point, and its infrared absorption spectrum and thin layer chromatography completely match the standard product.

Example 3 3-[(5-methylimidazol-4-yl)methylthio]propionic acid 1. Of and thionyl chloride 1. Of
The mixture is heated and stirred for 1 hour at 60-70 U in 20-20% of benzene. After concentrating the reaction solution under reduced pressure.

The obtained acid chloride is added to a solution prepared by dissolving 0.542 of sodium azide in a mixed solution of 4 d of water and 12 d of dioxane while cooling with water and stirring. After adding 2N hydrochloric acid l- to the reaction solution, the mixture was stirred for 30 minutes while heating at 6O-70C, and then the reaction solution was concentrated under reduced pressure.

The residue is dissolved in water and subjected to the same post-treatment as in Example 2 to obtain 4-(2-aminoethyl)thiomethyl-5-methylimidazole dihydrochloride 0.64F (yield 62%).

Example 4 3-((5-Methylimidazol-4-yl)methylthio]propionic acid hydrazide 0.5F was dissolved in 2.2% hydrogen chloride-ethanol solution 10-10%, and nitric acid was added to the plate under stirring at room temperature). After adding .18f in three portions, the reaction mixture was heated under reflux for 3 hours. After distilling off the solvent under reduced pressure, dissolve the residue in a mixture of water and chloroform and add hydrogen carbonate)
Neutralize with IJum. The chloroform layer was separated, dried, the solvent was distilled off, and the residue was recrystallized from benzene-hexane to yield 0.47 t of ethyl N-[2-(5-methyl 13-imidazol-4-yl)methylthioethyl]carbamate. (Yield 83%) is obtained.

Melting point 62-64r0 Engineering R spectrum νKBrcm-1 3300-2600 1'715 1370 1260
1250190 O NMR spectrum (0DOI3) δ: 1,20 (3H,t), 2.20 (3H
,a).

2.60 (2H, t), 2.65 (2H, t).

3,'70 (2H,e), 4.10 (2H,q
).

750 (IH, s), 11.70 (IH, θ)
.

If the urethane obtained above is hydrolyzed with hydrochloric acid, 4-(
2-Aminoethyl)thiomethyl-6-methylimidazole dihydrochloride is obtained.

Patent applicant: Banyu Pharmaceutical Co., Ltd.

Claims (1)

[Claims] The acid azide produced by reacting 3-((5-methylimidazol-4-yl)methylthio]propionic acid or its activated derivative at the carboxyl group with hydrazine and nitrous acid or with an alkali azide is purified by Curtius reaction. A method for producing 4-(2-aminoethyl)thiomethyl-5-methylimidazole, which is characterized by converting it into an amine.