JPH0586947B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application _Field ] The present invention relates to cimetidine (N-cyano-N'-methyl-N''-[2-
(5-Methyl-4-imidazolylmethylthio)ethyl]guanidine) and its similar compounds. [Prior art] Conventional methods for producing cimetidine include (i)
Route using 4-methylimidazole as a starting material (JP-A No. 49-75574, No. 51-54561, No. 51-125074)
etc.) or (ii) a route using diacetyl as a starting material (Spanish Patent 455991, Chemical Abstract 89146904), but for (i), using expensive 4-methylimidazole as a starting material,
Regarding (ii), each had its own problems, such as the raw material diacetyl having a foul odor and being difficult to handle, and the reaction yield being low. [Problems to be solved by the invention] In order to solve the above-mentioned problems, the applicant has already proposed a new route using the cyanoguanidine derivative shown in [ ] as a starting material (Patent Application No. 61 −203642) (Unexamined Japanese Patent Publication No. 63-60970)

[Summary of the invention]

In the present invention, in the presence of an inorganic phosphate, a compound of the general formula [] [wherein, X is a chlorine atom or a bromine atom, and R is a lower alkyl group]. A general formula characterized by reacting a cyanoguanidine derivative represented by ], ammonium carboxylate, and a formic acid derivative []

[Cyanoguanidine derivative]

The cyanoguanidine derivative [] used as a reaction raw material of the present invention has the general formula

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

The methyl vinyl ketone derivative 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.)]. [Ammonium carboxylate, formic acid derivative] Ammonium carboxylate used in the present invention is generally represented by R ⁰ COONH ₄ (or R ⁰ COOH·NH ₃ ). Here, R ⁰ represents an aromatic, aliphatic, or alicyclic residue, and may further have -COONH ₄ in the residue. As such ammonium carboxylate,
For example, ammonium formate, ammonium acetate,
Ammonium salts of aliphatic carboxylic acids such as ammonium propionate or ammonium salts of aromatic carboxylic acids such as ammonium benzoate, ammonium p-toluate, and ammonium naphthoate can be mentioned, and ammonium salts of aliphatic carboxylic acids, especially formic acid, can be mentioned. Ammonium is preferred. Furthermore, the formic acid derivatives used in the present invention are those excluding ammonium formic acid,
Formic acid esters such as methyl formate, ethyl formate, propyl formate, and phenyl formate; formamidine salts such as formamidine acetate and formamidine hydrochloride; and further orthoformate esters such as methyl orthoformate and ethyl orthoformate. Methyl orthoformate and formamidine acetate are preferred. [Inorganic phosphate] Inorganic phosphates used in the present invention include hypophosphites such as sodium hypophosphite and potassium hypophosphite, sodium monohydrogen phosphite, and monohydrogen phosphite. Phosphites such as potassium, hypophosphates such as sodium monohydrogen phosphate and sodium dihydrogen phosphate, metaphosphates such as sodium metaphosphate and caum metaphosphate, sodium pyrophosphate, sodium tripolyphosphate, etc. Anhydrous or hydrated orthophosphates such as polyphosphate, sodium ammonium hydrogen phosphate, and sodium diammonium phosphate can be mentioned, and preferred are sodium ammonium hydrogen phosphate, ammonium urium hydrogen phosphate, and lithium hydrogen phosphate. Examples include anhydrous or hydrated orthophosphates such as ammonium potassium and sodium dihydrogen phosphate. Moreover, these salts may be used in combination. [Reaction conditions, etc.] The reaction conditions may be conducted without a solvent or in an organic solvent, and the solvent may be methanol, ethanol,
Aliphatic alcohols such as propal, isopropanol, and methyl cellosolve; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, and dioxane; nitrites such as acetonitrile and propionitrile; dichloromethane and chloroform; Halogenated hydrocarbons such as carbon tetrachloride and cycloethane, aliphatic carboxylic acids such as formic acid and acetic acid, heterocyclic aromatic compounds such as pyridine and picoline, formamide, dimethylformamide, N-
Amides such as methylpyrrolidone can be exemplified.
Preferred are formamide, dimethylformamide, isopropanol, and methyl cellosolve. The amount of ammonium carboxylate to be charged to the compound [] is 1 to 50 times the mole, preferably 2 to 10 times the mole, and the amount of the formic acid derivative is 1 to 50 times the mole.
The amount of the inorganic phosphate is 0.1 to 10 times the mole, preferably 1 to 5 times the mole, and the solvent is 2 to 50 times the amount by weight, preferably 5 to 30 times the amount by weight. . Reaction temperature is 20 to 200℃, preferably 60 to 150℃
10 minutes to 5 hours, preferably 30 minutes to 3 hours.
Allow time to react. After the reaction is completed, the cimetidine derivative [] can be obtained by separating and purifying it according to a conventional method. Example 1 N-cyano-N'-methyl-N''-[2-(2-chloro-3-oxobutylthio)ethyl]guanidine 0.13 g (0.5 merimole), ammonium formate 0.32 g
(5 mmol), 0.53 g (5 mmol) of methyl orthoformate, and 0.21 g (1 mmol) of sodium ammonium hydrogen phosphate tetrahydrate were added with 2.5 ml of formamide, and the mixture was stirred at 100°C for 2 hours. 1/ of this reaction solution
5 was separated and analyzed by high performance liquid chromatography (column: ZORBAX-ODS (Dupont), solvent: water/MeOH/AcOH/Et ₃ N=700/300/
0.6/0.6). As a result, it was found that cimetidine was produced at a yield of 48%. The remaining reaction solution was separated and purified using silica gel column 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 tyl acetate. The ethyl acetate layer was dried with salt water and concentrated to give white crystals of cimetidine.
44 mg (yield 35%) was obtained. When this crystal was recrystallized from isopropanol, the melting point was 139-141℃.
It was hot. In addition, this crystal is a standard product of cimetidine.
It matched with the ^1HNMR spectrum and mass spectrum (molecular ion peak 253). Example 2 A reaction was carried out under the same conditions as in Example 1 except that 121 mg of lithium ammonium hydrogen phosphate was used instead of sodium ammonium hydrogen phosphate tetrahydrate. Cimetidine yield: 40% (HPLC). Example 3 A reaction was carried out under the same conditions as in Example 1 except that 153 mg of potassium ammonium hydrogen phosphate was used instead of sodium ammonium hydrogen phosphate tetrahydrate. Cimetidine yield: 39% (HPLC). Example 4 A reaction was carried out under the same conditions as in Example 1 except that 154 mg of sodium diammonium phosphate was used instead of sodium ammonium hydrogen phosphate tetrahydrate. Cimetidine yield: 40% (HPLC). Example 5 A reaction was carried out under the same conditions as in Example 1 except that 170 mg of diammonium potassium phosphate was used instead of sodium ammonium hydrogen phosphate tetrahydrate. Cimetidine yield: 35% (HPLC). Example 6 A reaction was carried out under the same conditions as in Example 1 except that 115 mg of ammonium dihydrogen phosphate was used instead of sodium ammonium hydrogen phosphate tetrahydrate. Cimetidine yield: 40% (HPLC). Example 7 A reaction was carried out under the same conditions as in Example 1 except that 132 mg of diammonium hydrogen phosphate was used instead of sodium ammonium hydrogen phosphate tetrahydrate. Cimetidine yield: 38% (HPLC). Example 8 A reaction was carried out under the same conditions as in Example 1 except that 156 mg of sodium dihydrogen phosphate dihydrate was used instead of sodium ammonium hydrogen phosphate tetrahydrate. Cimetidine yield: 35% (HPLC). Example 9 A reaction was carried out under the same conditions as in Example 1, except that 138 mg of disodium hydrogen phosphate was used instead of sodium ammonium hydrogen phosphate tetrahydrate. Cimetidine yield: 34% (HPLC). Example 10 A reaction was carried out under the same conditions as in Example 1, except that 136 mg of potassium dihydrogen phosphate was used instead of sodium ammonium hydrogen phosphate tetrahydrate. Cimetidine yield: 36% (HPLC). Example 11 105 mg of sodium ammonium hydrogen phosphate instead of sodium ammonium hydrogen phosphate tetrahydrate
The reaction was carried out under the same conditions as in Example 1 except that a mixture of 66 mg of diammonium hydrogen phosphate and 66 mg of diammonium hydrogen phosphate was used. Cimetidine yield: 44% (HPLC). Example 12 105 mg of sodium ammonium hydrogen phosphate instead of sodium ammonium hydrogen phosphate tetrahydrate
The reaction was carried out under the same conditions as in Example 1, except that a mixture of 71 mg of disodium phosphate and 71 mg of disodium phosphate was used. Cimetidine yield: 43% (HPLC). Example 13 A reaction was carried out under the same conditions as in Example 1, except that a mixture of 15.6 mg of sodium dihydrogen phosphate and 128 mg of disodium phosphate was used instead of sodium ammonium hydrogen phosphate tetrahydrate. Cimetidine yield: 39% (HPLC). Example 14 105 mg of sodium ammonium hydrogen phosphate instead of sodium ammonium hydrogen phosphate tetrahydrate
The reaction was carried out under the same conditions as in Example 1 except that a mixture of 78 mg of sodium dihydrogen phosphate and 78 mg of sodium dihydrogen phosphate was used. Cimetidine yield: 35% (HPLC). Example 15 163 mg of sodium ammonium hydrogen phosphate instead of sodium ammonium hydrogen phosphate tetrahydrate
The reaction was carried out under the same conditions as in Example 1 except that a mixture of 89 mg of diammonium hydrogen phosphate and 89 mg of diammonium hydrogen phosphate was used. Cimetidine yield: 36% (HPLC). Example 16 A reaction was carried out under the same conditions as in Example 1 except that 368 mg of trisodium tripolyphosphate was used instead of sodium ammonium hydrogen phosphate tetrahydrate. Cimetidine yield: 40% (HPLC). Example 17 A reaction was carried out under the same conditions as in Example 1 except that methyl cellosolve was used instead of formamide. Cimetidine yield: 30% (HPLC). Example 18 N-cyano-N′-methyl-N″-[2-(2-chloro-3-oxobutylthio)ethyl]guanidine 0.13 g (0.5 mmol), ammonium formate 0.32 g
(5 mmol), formamidine acetate 0.52 g (5 mmol), sodium ammonium hydrogen phosphate 4
2.5 ml of formamide to 0.21 g (1 mmol) of hydrate
was added and stirred at 100°C for 2 hours. Cimetidine yield: 42% (HPLC). Comparative Example 3.15 g of ammonium formate ( 50 mmol) and 5.30 g (50 mmol) of methyl orthoformate, and heated at 80℃ for 2 hours.
Stir for hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and a portion of the residue was analyzed by high performance liquid chromatography. (Column: ZORBAX-ODS
(Dupont), solvent: water/MeOH/AcOH/Et ₃ N=
700/300/0.6/0.6) Yield 27%.

Claims (1)

[Claims] 1. In the presence of an inorganic phosphate, the general formula [1] [Chemical formula] [In the formula, X is a chlorine atom or a bromine atom, and R is a lower alkyl group]. ] A general formula characterized by reacting a cyanoguanidine derivative represented by the following, ammonium carboxylate, and a formic acid derivative [Chemical formula] [In the formula, R is the same as above. ) A method for producing an imidazole derivative represented by