JPS597172A - Preparation of guanidine derivative - Google Patents

Abstract

PURPOSE:To prepare N-cyano-N'-methyl-N''-{ 2-[ ( 5-methylimidazol-4-yl )-methylthio]ethyl}guanidine by reacting quaternary ammonium salt of 4-methylimidazole with corresponding mercaptan. CONSTITUTION:The compound of formula I can be prepared by (1) reacting the compound of formula VI with the compound of formula III (R<1> and R<2> are lower alkyl, lower alkenyl, aralkyl or together with N form a heterocyclic group) and HCHO at 50-100 deg.C to obtain the tertiary amine of formula IV, (2) reacting the amine with the alkylation agent of formula V (R<3> is lower alkyl, lower alkenyl or aralkyl; Q is acid residue), and (3) reacting the resultant quaternary ammonium salt of formula II with a mercaptan of formula VII in a lower alcohol solvent such as methanol. EFFECT:The compound can be obtained by one-pot reaction under mild condition, and accordingly, the yield is high. USE:Remedy for ulcer.

Description

[Detailed description of the invention] The present invention is based on the formula This invention relates to a new method for producing a guanidine derivative represented by:

More specifically, formula 9 [wherein R", R" and R3 are the same or different and represent a lower alkyl group, a lower alkenyl group or an aralkyl group, and R1 and R3 together with the adjacent nitrogen atom form a heterocyclic ring] Good too.

Q represents an acid residue] is reacted with N-cyano-N'-methyl-N'-(2-mercaptoethyl)guanidine to form N-cyano-N'-methyl-N'. -(2-((5-methylimidazole-4-
yl)methylthio]ethyl)guanidine, and 4-methylimidazole with the general formula % (1) [wherein R1 and R11 have the abovementioned meanings] An amine represented by the formula % and formaldehyde are reacted to obtain a tertiary amine represented by the general formula [wherein R1 and R2 have the above-mentioned meanings], and a tertiary amine represented by the general formula % formula % ( ) [wherein R3 and Q has the above-mentioned meaning] to react with an alkylating agent represented by the general formula [wherein R', R
” , R3 and Q have the above-mentioned meanings].

This was then added with N-cyano-N'-methyl-N'-(2-
Formula (1) characterized in that N-cyano-N'-methyl-N'-(2-((5-methyl, imidazol-4-yl)methylthio]ethyl)guanidine is obtained by reacting mercaptoethyl)guanidine. ) relates to a method for producing the compound.

The guanidine derivative represented by formula (1) is histamine ■
, - It is a compound that has receptor antagonistic action and is useful as a drug for treating ulcers.

Conventionally, there are several methods (4) for producing the compound of formula (I).
! 1977-'75114, 51-545451
and No. 51-125014, etc.) have been proposed.

All of these use 4-hydroxymethyl-5-methylimidazole or a compound derived therefrom as a raw material compound.

However, this 4-hydroxymethyl-5-methylimidazole is a compound that is difficult to obtain because there is no easy manufacturing method. In addition, known production methods for cimetidine have other problems such as complicated operations requiring multiple reaction vessels, difficulty in purification due to low yields, and increased production costs due to the use of a large excess of methylamine. Many problems remain.

The present inventors have conducted various studies on separate methods for synthesizing the compound of formula (1), and as a result, have developed a new synthetic route as shown below.

[In the formula, R1, R11l, R3 and Q have the above-mentioned meanings] The present invention provides the above steps (C) and (A)→
Regarding (B)→(0), it is advantageous compared to conventional production methods in that the use of 4-hydroxymethyl-5-methylimidazole can be avoided.

According to the present invention, the target compound (1) has the general formula (I[
) to the quaternary ammonium salt represented by N-cyano N'
-Methyl-N'-(2-mercaptoethyl)guanidine (■). Furthermore, the quaternary salt of general formula (It) is.

By reacting 4-methylimidazole (VI) with amines represented by general formula (1) and formaldehyde, 9
, is obtained by obtaining a tertiary amine represented by general formula (IV) and allowing an alkylating agent represented by general formula (V) to act thereon.

To explain the compounds of each general formula in the present invention, the substituents represented by R1, R'' and R3 in formula 2 are the same or different and represent a lower alkyl group, a lower alkenyl group, or an aralkyl group, and specifically, methyl group, ethyl group,
Propyl group, isopropyl group, allyl group, crotyl group,
It means a group such as a benzyl group. Of these, R
1 and t may be linked to each other to form a heterocyclic ring with the adjacent nitrogen atom, specific examples of which include rings such as pyrrolidine, piperidine and morpholine. Furthermore, Q represents an acid residue.

Specifically, it refers to acid residues such as chlorine, bromine, iodine, sulfate, alkylsulfonic acid, and the like.

When implementing step (C) of the present invention.

Quaternary ammonium salt represented by general formula (n) and formula (■
) are reacted in a solvent that does not participate in the reaction, preferably in the presence of a base.

The solvent used in this reaction is preferably a polar organic solvent9, such as methanol or ethanol.

Lower alcohols such as Impropatool are suitable.
The reaction is usually carried out in the presence of a base in an amount equivalent to or more than the equivalent mole of the quaternary salt (II), and suitable bases include sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, etc. .

Although the reaction temperature and reaction time are not particularly limited.

It is usually convenient to react at a temperature around room temperature for several hours.

Next, as another feature of the present invention, the quaternary ammonium salt (II) can be prepared by the Mannich reaction in step (A) and the alkylation reaction in step (B) using 4-methylimidazole (Vl) as a starting material. Profit.

Subsequently, in step (0), this is reacted with a mercaptan of formula (■) to obtain the target compound (1).

When carrying out this reaction, first, 4-methylimidazole (Vl) is mixed with reaction-corresponding amounts of amines (1) and formaldehyde in a solvent that does not participate in the reaction, preferably 5
The reaction is carried out under heating at 0 to 100C. As the solvent used in this reaction, polar solvents such as water, lower alcohols or acetic acid are suitable. The amine (1) used is its free base or its hydrochloride, and the formaldehyde used is its aqueous solution or paraformaldehyde.

Next, the tertiary amine of formula (IV) obtained by the above reaction and the alkylating agent (V) in an amount corresponding to the reaction.

The reaction is carried out under cooling or heating in a solvent that does not participate in the reaction. Examples of solvents used include lower alcohols, acetone, and chloroform.

Dioxane or dimethylformamide are suitable.

Subsequently, the quaternary ammonium salt of formula (II) obtained by the above reaction is reacted with the mercaptan of formula (■), and this reaction can be carried out under the same conditions as described above.

These reactions described above are usually carried out in a solvent.

The solvent used in both cases is methanol.

Lower alcohols such as ethanol are suitable.
For this reason, if a base or the like for neutralization is added as necessary, it is also possible to carry out all of the above continuous steps in the same solvent.

The compound of formula (1) obtained by the production method of the present invention is isolated and purified by conventional methods. The yield of the target product in this production method is generally as high as '70-95.

Furthermore, considering that all the reaction steps can be carried out under mild conditions and in one pot, the present invention is a very advantageous industrial production method.

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

Example 1 Metallic sodium 0.5Of and anhydrous methanol 50rnt
Sodium methoxide methanol solution prepared from
N-cyano N'-methyl-N'-(2-
Add 3.2 f of (mercaptoethyl) guanidine and stir at room temperature for 5 minutes. Add 6.04f of N-(5-methylimidazol-4-yl)methyl-N,N,N-)limethylammonium iodide to this solution in several portions.
Added in 0 minutes.

Stir for an additional hour at room temperature. After neutralizing excess sodium methoxide by adding 35% hydrochloric acid.

The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform:methanol;
Purify by silica gel column chromatography using 10:1 as an elution solvent. After evaporation of the eluate, the residue is recrystallized from IJ. (yield 89.7%).Melting point 141-142
C0 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 2 4-methylimidazole 2.005', piperidine hydrochloride 6.0OS' and 317% formalin 2.16
F was added to 20% of ethanol and heated under reflux for 3 hours.

After evaporating the solvent under reduced pressure, the residue is dissolved in water, neutralized with potassium carbonate, and extracted with chloroform. After evaporating the extract, the residue is recrystallized from benzene-hexane to obtain 4-
Piperidinomethyl-5-methylimidazole 4.0C1
(Yield 91.6 cm) is obtained. Melting point 162-
164 C0 4.0 Or of the above product in methanol 40
-, add 4.8C1 of methyl iodide and bring to room temperature for 2 hours.
Leave it for 0 hours. Methanol and excess methyl iodide were distilled off, and the residue was recrystallized from isopropyl alcohol-hexane to yield N-(5-methylimidazol-4-yl)methyl-N-methylpiperidium iodide 6.
80 r (yield 94.8%) is obtained. melting point
13'7-139 t:' 0 Above quaternary salt 3.40S
', methanol 3o- to sodium hydroxide 0.55
f and N-cyano-'-methyl-N'-(2-mercaptoethyl)guanidine 1.50F dissolved in the solution and stirred at room temperature for 2 hours. After neutralizing excess alkali by adding 35% hydrochloric acid. , the solvent is dried under reduced pressure and the residue is dissolved in hot isopropyl alcohol. After removing the insoluble inorganic salts, the P solution is dried under reduced pressure and the residue is dissolved in hot acetonitrile. The acetonitrile solution is treated with charcoal powder. After that, if you leave it in an ice room overnight, N-cyano~N'-methyl-N'-
(2-1:(5-methylimidazol-4-yl)methylthio]ethyl)guanidine 2.16 t (yield 85
．． 1%) is obtained. Melting point 139-14100 Example 3 4-methylimidazole 2.05f, diethylamine hydrochloride 2.471 and paraformaldehyde 0,'
Add i'6t to ethanol 2o- and heat under reflux for 4 hours.

After the reaction solution was cooled with water, 1.25% of a 2N sodium ethoxide ethanol solution was added thereto, the precipitated inorganic salt was separated, 3.55f' of methyl iodide was added, and the mixture was left at room temperature overnight.

Ethanol 50- to 0.659-metal sodium and N
-Cyano-N'-methyl-N'-(2-mercaptoethyl)guanidine3. '? '3F was dissolved, and the above reaction solution was added dropwise to this solution over a period of 30 minutes while stirring at room temperature.
After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using chloroform:methanol-40:1 as an eluent.
After evaporating the eluate, the residue is recrystallized from acetonitrile to give N-cyano-N'-methyl-N'~(2-1m(5-
methylimidazol-4-yl)methylthio]ethyl)
Guanidine 4.6+71F (yield: 4.1%) is obtained. Melting point: Yu40-1!2C0 Patent applicant: Banyu Pharmaceutical Co., Ltd. 633-

Claims (2)

[Claims] (1) Formula [In the formula, R1, R2 and R3 are the same or different and represent a lower alkyl group, a lower alkenyl group or an aralkyl group, and R1 and R2 may form a heterocyclic ring together with the adjacent nitrogen atom. Q represents an acid residue] is reacted with N-cyano-N'-methyl-N-(2-mercaptoethyl)guanidine to form N-cyano-N'-methyl-N"- (2-((5-
A method for producing a guanidine derivative, characterized in that methylimidazol-4-yl)mercaptoethyl)guanidine is obtained. (2) 4-methylimidazole with the formula [wherein R1 and R2 are the same or different and represent a lower alkyl group, a lower alkenyl group, or an aralkyl group,
Both may form a heterocyclic ring together with adjacent nitrogen atoms] and formaldehyde are reacted to form a tertiary amine represented by the formula [wherein R1 and R2 have the above-mentioned meanings]. This was obtained by formula [wherein R3 represents a lower alkyl group, a lower alknyl group, or an aralkyl group, and Q
represents an acid residue] to obtain a quaternary ammonium salt represented by the formula [where H1, R11, R3 and Q have the above-mentioned meanings]. Cyano-N'-methyl-N'-(2-mercaptoethyl)guanidine was reacted to form N-cyano-N'-methyl-N'-(2-((5-methylimidazole-4-
A method for producing a guanidine derivative, characterized in that guanidine is obtained.