JPH0684340B2 - Formamidine formate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to cimetidine (N-cyano-N′-methyl-N ″-[2-{(5
-Methyl-1H-imidazol-4-yl) methylthio}
[Ethyl] guanidine) and its analogues, which is useful as a raw material for the production of formamidine formate.

[Prior art, problems to be solved by the invention, effects of the invention] Conventionally, some methods have been provided for producing cimetidine or a compound related to cimetidine (for example, JP-A-49-75574, (Kaisho 51-125074, etc.)
However, these methods have a drawback that the cost is high because they are production methods using expensive imidazole derivatives as starting materials and undergoing multi-step reactions.

The applicant of the present invention has prepared a cimetidine derivative obtained by using a cyanoguanidine derivative represented by the general formula [II] (wherein, X is a chlorine atom or a bromine atom, and R is a lower alkyl group; the same applies hereinafter) and a starting material thereof. A new method for producing similar compounds has already been proposed (Japanese Patent Application No. 61-203642).

In addition, a new production method has already been proposed via a specific α-acyloxyketone derivative [II ′] (R ′ is an aliphatic lower acyl group) derived from the cyanoguanidine derivative [II] (Japanese Patent Application No. Sho-200-200). 61-278718).

The inventors of the present invention further investigated a novel production method of cimetidine and the like, and found that the conventional formate salt of formamidine was used as disclosed in the patent application of the present applicant on the same date as the present application. It has been found that the problems can be solved, the yield of cimetidine and the like can be further improved, or the process can be simplified. That is, by using the formate salt [I] of formamidine provided in the present invention, which is inexpensive and can be obtained in high yield, cimetidine and the like can be obtained in higher yield than in the case of the above-mentioned Japanese Patent Application No. 61-203642. , Or Japanese Patent Application No. 61-278
Compared with the case of No. 718, a cyanoguanidine derivative [I
I] to α-acyloxyketone derivative [II ″] The formylation to form proceeds in good yield and can subsequently form an imidazole ring, and in that case, the formate salt of formamidine is also considered to act as a dehydrating agent. It has been found that cimetidine or a compound related to cimetidine can be obtained economically. Thus, the compound of the present invention is useful in a new production method of cimetidine and the like.

As for the formamidine salt, several salts such as hydrochloride and acetate are known (GAUTIER, J.-A., MIOCQ.
UE, M. & FARNOUX, CC (1975) .The Chemistry of Amid
ines and Imidates, edited by S.PATAI, P283.New York:
John Wiley) was unknown about formate. Even if an acetate salt is applied to the reaction instead of the formate salt, the desired product can hardly be obtained. Recently, a report on formamidine-tris (formato) -zinc (II) which is a zinc complex of formamidine (Richard E. Marsh (1
986) .Acta Cryst.C 42 , 1327 to 1328) was carried out, and this compound was treated with the compound of the present invention as shown by [HC (NH ₂ ) ₂ ] ⁺ • [Zn (HCO ₂ ) ₃ ] ^-. Not only is it different, but also the production method does not go through the compound of the present invention.

[Outline of Invention]

The present invention has the formula [I] And a formate salt of formamidine represented by

[Production Method of Substance of the Present Invention]

The formate salt of formamidine represented by the formula [I] is obtained by reacting ammonium formate with an orthoformate ester such as methyl orthoformate, ethyl orthoformate or using formic acid as a solvent to react ammonia with the above orthoformate ester. Can be manufactured by In the former case, the reaction may be carried out without solvent or in an organic solvent, and in the latter case, other organic solvent may be used together. Examples of such a solvent include lower alcohols such as methanol and ethanol, amides such as formamide and N, N-dimethylformamide, and acidic solvents such as formic acid. The amount of solvent with respect to ammonium formate or ammonia is 2 to 50 times by weight, preferably 5 to 30 times by weight, and the amount of orthoformate ester with respect to ammonium formate is 0.1 to 5 times by mole, preferably 0.3 to 3 times by mole. 20 to 200 ° C, preferably 50 to 150 ° C
The reaction is carried out for 10 minutes to 8 hours, preferably 30 minutes to 4 hours. After completion of the reaction, the desired product can be obtained by recrystallization.

[Usefulness of the Compound of the Present Invention]

As described above, the compound of the present invention is useful as a raw material in a new production method of cimetidine and the like, as shown in the production method of the imidazole derivative disclosed in the patent application filed by the present applicant on the same date as the present application. That is, the compound [I] of the present invention And cyanoguanidine derivatives [II] [Wherein X is a chlorine atom or a bromine atom, and R is a lower alkyl group] to [alpha] -acyloxyketone derivative [I
I ′] In comparison with the case of Japanese Patent Application No. 61-278718, it is possible to obtain a good yield, and subsequently, when forming an imidazole ring, continuously in the same reactor, that is, economically cimetidine or a cimetidine-related compound. [III] [Wherein R is a lower alkyl group] can be produced.

Example Preparation of formamidine formate 6.3 g ammonium formate (0.1 mol) and methyl orthoformate 2
3.5 g (0.2 mol) was added to a 100 ml reactor and heated at 100 ° C. When the reaction started, methanol and methyl formate were formed, so these were removed using the Dean Stark apparatus. The reaction took 3 hours. After the reaction, the reaction solution was depressurized with a vacuum pump for 30 minutes, and then 50 ml of dioxane was added and stirred to precipitate a solid. This solid was filtered and washed with 10 ml of cold ethanol to obtain 4.05 g of a white target product (yield). Rate 90
%).

Melting point: 102-103 ° C ¹ H-NMR spectrum (d ₆ -DMSO, ppm) 7.84 (1H, s) 8.40 (1H, s) Mass spectrometry (FD) 45 Elemental analysis Calculated value Measured value C (%) 26.66 26.67 H (%) 6.72 6.57 N (%) 31.10 30.92 The structure of this formamidine formate could also be determined by inducing it into the known formamidine picrate. In other words, 225 mg (2.5 mmol) of the formate salt of formamidine produced by the above method was added to ethanol.
Dissolve in 4 ml and add 572 mg (2.5 mmol) picric acid to this.
30 ml of the ethanol solution of was added dropwise. A yellow solid was precipitated upon stirring at room temperature. This solid is filtered and ethanol 5m
After washing with l, 562 mg of the target product, formamidine picrate, was obtained (yield 83%).

Melting point: 244 to 247 ° C. (literature value 246 to 247 ° C.) ¹ H-NMR (d ₆ -DMSO, ppm) 7.88 (2H, s) 8.64 (1H, s) Reference Example 1 Ammonium formate 0.32 g (5 mmol), 2.5 ml of formamide was added to 0.53 g (5 mmol) of methyl orthoformate,
The mixture was stirred at 100 ° C for 2 hours. The formation of formamidine formate in this reaction was confirmed by confirming that the spectrum was identical with that of formamidine formate after distilling off formamide under reduced pressure in vacuum. The temperature of this reaction solution was lowered to room temperature, and N-cyano-N'-methyl-N "-[2- (2-chloro-3-oxobutylthio)
Ethyl] guanidine (0.13 g, 0.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour, 0.21 g (1 mmol) of sodium ammonium hydrogenphosphate tetrahydrate was added, and the mixture was reacted at 100 ° C. for 2 hours. 1/5 of this reaction solution was divided and analyzed by high performance liquid chromatography (column: ZORBAX-ODS (Dupont),
Solvent: water / MeOH / AcOH / Et ₃ N = 700/300 / 0.8 / 0.8). As a result, it was found that 61% of cimetidine was produced. The remaining reaction solution was separated and purified by silica gel chromatography (developing solvent: MeOH / CHCl ₃ = 1/20 → MeOH / CHCl ₃ = 1/1
0), the obtained oil was extracted with saturated sodium bicarbonate water and ethyl acetate. The ethyl acetate layer was dried over Glauber's salt and concentrated to give white crystals of cimetidine. When this crystal was recrystallized from isopropanol, the melting point was 140 to 142 ° C. In addition, this crystal was in agreement with ¹ H-NMR and mass spectrum (molecular ion peak 253) of cimetidine standard product.

Reference Example 2 Formamidine formate 0.23 g (2.5 mmol), N-cyano-N'-methyl-N "-[2- (2-chloro-3-
2.5 ml of formamide was added to 0.13 g (0.5 mmol) of oxobutylthio) ethyl] guanidine, and the mixture was stirred at 20 ° C. for 1 hour. At this point, sodium ammonium hydrogen phosphate 4
0.21 g (1 mmol) of the hydrate was added, and the mixture was stirred at 100 ° C. for 2 hours.

Cimetidine yield (HPLC): 51% Comparative Reference Example An experiment was conducted in the same manner as in Reference Example 2 except that an equimolar amount of formamidine acetate was used instead of formamidine formate, and the desired cimetidine was found to be It was not obtained at all (yield 0%).

Claims (1)

[Claims] 1. A formula [I] Formamidine formate represented by