JPH0586949B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention provides cimetidine (N-cyano-N'-methyl-N''-
[2-{(5-Methyl-1H-imidazol-4-yl)methylthio}ethyl]guanidine) and its similar compounds. [Prior Art] Several methods have been proposed for synthesizing cimetidine or its analogous compounds (for example, Japanese Patent Application Laid-open No. 75574/1983,
No. 125074, etc.), but these methods use expensive imidazole derivatives as starting materials and are production methods that involve multi-step reactions, so they have the drawback of high costs. [Problems to be Solved by the Invention and Methods for Solving the Problems] The present inventors have solved the problem using the general formula [] (wherein, X is a chlorine atom or a bromine atom, and R is a lower alkyl group. The same applies hereinafter). A new method for producing cimetidine and its analogous compounds using the cyanoguanidine derivative represented by the following as a starting material has already been proposed [Japanese Patent Application No. 61-203642 (Japanese Unexamined Patent Publication No. 63-60970), etc.].

[Chemical formula] The cyanoguanidine derivative represented by the general formula []

[In the formula, X is a chlorine atom or a bromine atom. ]

Methyl vinyl ketone derivatives represented by general formula

[In the formula, R is a lower alkyl group. ]

The mercaptoguanidine derivative represented by
It is synthesized by reacting with The method for producing this cyanoguanidine derivative is disclosed in the patent application entitled "Cyanoguanidine Derivative and Method for Producing the Same"
No.)]. In addition, a new production method using a specific α-acyloxyketone derivative ['] (R' is an aliphatic lower acyl group) derived from the cyanoguanidine derivative [] has already been proposed [Patent Application No. 1983- 278718
No. (Japanese Patent Publication No. 63-132877)].

[C] The present inventors further investigated a new method for producing cimetidine, etc., and found that the patent application filed by the applicant on the same date as the present application entitled "Formate of Formamidine" [Patent Application No. 62-24480 (Patent Application No. The conventional problems can also be solved by using the formate salt of formamidine disclosed in Japanese Patent Publication No. 1987-192747), and furthermore, the yield of cimetidine etc. can be further improved or the process can be simplified. I understood. That is, by using formamidine formate [] which can be obtained at low cost and in high yield, cimetidine etc. can be obtained in a higher yield than in the case of the above-mentioned Japanese Patent Application No. 61-203642, or cyanoguanidine derivative [] ] to α-acyloxyketone derivative [″] (in formula [′]

[Summary of the invention]

As mentioned above, the present invention relates to formamidine formate disclosed in an application filed by the applicant on the same date as the present application.

[ka] and general formula []

General formula [] characterized by reacting with a cyanoguanidine derivative represented by [Chemical formula]

This invention relates to a method for producing an imidazole derivative represented by: Formamidine formate, which is one of the raw materials of the present invention, can be produced by the method disclosed in the patent application filed by the applicant on the same date as the present application. The compound may be produced by reacting a formic acid derivative such as methyl orthoformate or ethyl orthoformate with ammonium formate, or by reacting ammonia with the above orthoformate using formic acid as a solvent, and then isolated and used. or they may be used without isolation from the reaction mixture. Moreover, as the other raw material, the cyanoguanidine derivative [], one produced by the method described above can be used. Although this reaction is possible without a solvent, it is preferably carried out in an organic solvent. Examples of organic solvents include aliphatic alcohols such as methanol, ethanol, propanol, isopropanol, and methyl cellosolve, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, and dioxane, and acetonitrile. Nitriles such as propionitrile, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, aliphatic carboxylic acids such as formic acid and acetic acid, heterocyclic aromatic compounds such as pyridine and picoline, formamide, dimethylformamide, Amides such as N-methylpyrrolidone can be exemplified. Preferably formamide,
These are dimethylformamide, isopropanol, and methyl cellosolve. The amount of solvent for compound [] is usually 2 to 50
twice by weight, preferably 5 to 30 times by weight, and the amount of compound [] charged is 1 to 50 times by mole,
Preferably, the amount is 2 to 20 times the mole, and the reaction temperature is 0 to 70°C, preferably 5 to 30°C, for 10 minutes to 5 hours, preferably 30 minutes to 3 hours. This operation produces an α-acyloxyketone derivative [′], but without isolation, the temperature is continued at 20 to 200°C, preferably 60 to 60°C.
Raise to 150°C for 10 minutes to 5 hours, preferably
Let react for 30 minutes to 3 hours. Although a catalyst is not particularly required in this latter stage, it is preferable to coexist with an inorganic phosphate. Examples of inorganic phosphates include hypophosphites such as sodium hypophosphite and potassium hypophosphite, phosphites such as sodium monohydrogen phosphite and potassium monohydrogen phosphite,
Hypophosphates such as sodium monohydrogen hypophosphate and sodium dihydrogen hypophosphate, metaphosphates such as sodium metaphosphate and potassium metaphosphate, polyphosphates such as sodium pyrophosphate and sodium tripolyphosphate, and ammonium hydrogen phosphate. Examples include anhydrous or hydrated orthophosphates such as sodium, diammonium sodium phosphate, etc., and preferred are sodium ammonium hydrogen phosphate, lithium ammonium hydrogen phosphate, potassium diammonium hydrogen phosphate, and diammonium phosphate.
Examples include anhydrous or hydrated orthophosphates such as sodium hydrogen. Moreover, these salts may be used in combination. The amount of inorganic phosphate charged for compound [] is
The amount is 0.1 to 10 times the amount, preferably 1 to 5 times the amount. In addition, without dividing this reaction into two stages as described above, the reaction temperature was set at 20
to 200°C, preferably 60 to 150°C, reaction time 10 minutes to 5 hours, preferably 30 minutes to 3 hours.
You can still get cimetidine by the hour.
At this time, similarly to the above, a catalyst is not particularly required, but it is preferable to coexist with an inorganic phosphate. After the reaction, commonly used separation and purification means such as column chromatography or recrystallization can be used to obtain the final target product, cimetidine represented by the formula [] or a similar compound thereof. Example 1 Formamide was added to 0.32 g (5 mmol) of ammonium formate and 0.53 g (5 mmol) of methyl orthoformate.
2.5 ml was added and stirred at 100°C for 2 hours. The formation of formamidine formate in this reaction was confirmed by NMR analysis after the formamide was distilled off under reduced pressure.
This was confirmed by analysis and the spectrum matching that of formamidine formate disclosed in the same-dated application filed by the present applicant. The temperature of this reaction solution was lowered to room temperature, and N-cyano-N'-methyl-
N″-[2-(2-chloro-3-oxobutylthio)
After adding 0.13 g (0.5 mmol) of ethyl guanidine and stirring at room temperature for 1 hour, 0.21 g (1 mmol) of sodium ammonium hydrogen phosphate tetrahydrate was added and reacted at 100°C for 2 hours. 1/5 of this reaction solution
was separated and analyzed by high performance liquid chromatography (column: ZORBAX-ODS (Dupont), solvent:
Water/MeOH/AcoH/ _Et3N =700/300/0.6/
0.6). As a result, it was found that cimetidine was produced at 61%. The remaining reaction solution was separated and purified by silica gel chromatography ((developing solvent:
MeOH/CHCl ₃ = 1/20 → MeOH/CHCl ₃ =
1/10), and the obtained oil was extracted with saturated sodium hydrogen chloride water and ethyl acetate. The ethyl acetate layer was dried with sulfur salt and concentrated to obtain white crystals of cimetidine. When this result was recrystallized from isopropanol, the melting point was 140-142°C. Furthermore, this crystal matched the ¹ H-NMR and mass spectrum (molecular ion peak 253) of the cimetidine standard product. Example 2 Formamide was added to 0.32 g (5 mmol) of ammonium formate and 0.53 g (5 mmol) of methyl orthoformate.
2.5 ml was added and stirred at 100°C for 2 hours. Example 1
After confirming the formation of formamidine formate in the same manner as above, N-cyano-N'-methyl-N''-[2-
(2-chloro-3-oxobutylthio)ethyl]
0.13 g (0.5 mmol) of guanidine and 0.21 g (1 mmol) of sodium ammonium hydrogen phosphate tetrahydrate were added and reacted at 100° C. for 2 hours. Cimetidine yield (HPLC): 53% Example 3 Formamidine formate 0.23 g (2.5 mmol),
N-cyano-N'-methyl-N''-[2-(2-chloro-3-oxobutylthio)ethyl]guanidine
Add 2.5 ml of formamide to 0.13 g (0.5 mmol),
The mixture was stirred at 20°C for 1 hour. At this point, 0.21 g (1 mmol) of sodium ammonium hydrogen phosphate tetrahydrate was added, and the mixture was stirred at 100° C. for an additional 2 hours. Cimetidine yield (HPLC): 51% Example 4 The reaction was carried out under the same conditions as Example 3 except that isopropanol was used instead of formamide. Cimetidine yield (HPLC): 39% Example 5 Formamidine formate 0.23 g (2.5 mmol),
N-cyano-N'-methyl-N''-[2-(2-chloro-3-oxobutylthio)ethyl]guanidine
Add 2.5 ml of formamide to 0.13 g (0.5 mmol),
After stirring at 20°C for 1 hour, the mixture was further stirred at 100°C for 2 hours. Cimetidine yield (HPLC): 29%

Claims (1)

[Claims] 1 Formamidine formate represented by the formula [] [Formula] and the general formula [] [Chemical formula] [In the formula, X is a chlorine atom or a bromine atom, and R is a lower alkyl group. [In the formula, R is the same as above. ] A method for producing an imidazole derivative represented by