JP4461468B2 - Process for producing N- (2-amino-1,2-dicyanovinyl) formic acid derivative - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to alkyl N- (2-amino-1,2-dicyanovinyl) formimidate (hereinafter referred to as RMD) and N- (2-amino-1,2-dicyanovinyl) form useful as pharmaceutical intermediates. The present invention relates to a simple and efficient method for producing N- (2-amino-1,2-dicyanovinyl) formic acid derivatives such as amidine (hereinafter referred to as AMD).
[0002]
[Prior art]
N- (2-amino-1,2-dicyanovinyl) formamidine is a useful pharmaceutical intermediate, for example, the precursors of the anticancer drugs dacarbazine and temozolomide, the hepatoprotectant urazamide. There is a need for an efficient synthesis method that is an intermediate raw material of 1H-4 (5) -aminoimidazole-5 (4) -carboxamide (hereinafter abbreviated as AICA in the text).
[0003]
As methods for synthesizing AMD and RMD, the following methods have been known so far.
For AMD, see, for example, R.A. F. Shuman et al. (J. Org. Chem., 1979, 44, 4532) synthesize AMD by heating diaminomaleonitrile (hereinafter abbreviated as DAMN) and formamidine acetate in ethanol at reflux temperature. . However, the yield is only 2%, which is not practical for the industrial production of AMD.
[0004]
Regarding RMD, B.I. L. Booth et al. (J. Chem. Soc. Perkin Trans. I, 1990, 1705) are prepared from diaminomaleonitrile (hereinafter referred to as DAMN) to ethyl N- (2-amino-1,2-dicyanovinyl) formimidate (in the text). (Hereinafter abbreviated as EMD), and then a two-step method for synthesizing AMD from EMD. That is, in the first step, DAMN and triethylorthoformate were reacted in dioxane to synthesize EMD in a yield of 84%. In the second step, the reaction of EMD and ammonia was used, and aniline hydrochloride was used as a catalyst in chloroform. Thus, AMD is synthesized at a yield of 95% by performing at a low temperature of -20 ° C or lower.
[0005]
[Problems to be solved by the invention]
However, this method also has many problems such as complicated reaction operation, low temperature reaction, a large number of solvent types to be used, and possibility of environmental pollution by halogenated solvents, and is insufficient as an industrial production method.
As described above, RMD and AMD manufacturing methods known in the prior art are not satisfactory methods assuming industrial production.
An object of this invention is to provide the novel manufacturing method which manufactures RMD and AMD efficiently cheaply.
[0006]
[Means for Solving the Problems]
As a result of diligent investigations to solve the above problems, the present inventors have made alcohol elimination in the reaction of two steps of producing RMD from DAMN and trialkylorthoformate and then producing AMD from RMD and ammonia. Despite the necessity of removing alcohol from the reaction system in the reaction system, a method for solving many of the above-mentioned problems of the prior art by employing an alcohol-based solvent has been found, and further production of RMD and AMD By adopting the same kind of solvent in the process, an inexpensive method suitable for industrial production was found and the present invention was completed.
[0007]
The present invention relates to AMD {(N- (2-amino-1,2-amino-1,2-dicyanovinyl) formimidate)] which reacts with ammonia in C1-C5 alcohol. -Dicyanovinyl) formamidine}, wherein RMN is produced by reacting DAMN [diaminomaleonitrile] with trialkylorthoformate in C1-C5 alcohol, and further, the obtained RMD is C1-C5 alcohol. It is the manufacturing method of AMD made to react with ammonia in it, Furthermore, it is the manufacturing method of RMD which makes DAMN react with a trialkyl orthoformate in C1-C5 alcohol, and C1-C5 alcohol used at each process is methyl. The production method is alcohol or ethyl alcohol.
[0008]
The reaction formula of the present invention is shown for reference as follows.
In the formula, R represents a lower alkyl group.
[Chemical 1]
[0009]
DETAILED DESCRIPTION OF THE INVENTION
DAMN used in the present invention is an industrially available starting material that can be easily synthesized from a tetramerization reaction of hydrocyanic acid. Another starting material, a trialkylorthoformate, is also an industrially available starting material.
The reaction for synthesizing RMD from DAMN and tolylalkyl orthoformate can be carried out in an alcohol solvent at room temperature to heating. Examples of the alcohol solvent include methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, t-butanol, etc., but solubility of raw materials and products, easy recovery distillation In view of price, methanol and ethanol are particularly preferable.
[0010]
The alkyl group in the trialkyl orthoformate or RMD is preferably a C1-5 lower alkyl group, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, pentyl, Most preferred is methyl or ethyl.
Furthermore, as shown in the above reaction formula, a lower alkyl alcohol derived from the used raw material is by-produced during the reaction. Therefore, it is convenient for separation and recovery to use the same alcohol solvent as the by-product lower alkyl alcohol.
The reaction temperature depends on the reaction time employed, but at low temperatures, the reaction is slow and requires a long time. At high temperatures, the raw material disappears in a short time, but due to an increase in by-products (mainly cyclized product 4,5-dicyanoimidazole). It is necessary to pay attention to the decrease in purity. The reaction temperature is preferably from room temperature to the solvent reflux temperature, and the reaction time is preferably from 30 minutes to 10 hours.
[0011]
After completion of the reaction, RMD is isolated by filtration, but it is preferable to sufficiently precipitate RMD by cooling from 0 ° C. to room temperature in order to reduce RMD dissolved in the solvent and improve the yield.
High purity RMD can be obtained by such a method, but if it is necessary to further increase the purity, it can be purified by recrystallization.
Examples of alcohol solvents for the reaction of synthesizing AMD from RMD and ammonia include methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, t-butanol and the like. Methanol and ethanol are particularly preferable from the standpoints of solubility of the product, ease of recovery distillation, price, and the like.
[0012]
Although the reaction proceeds under cooling and at the solvent reflux temperature, it is preferable to start the reaction under cooling in consideration of the solubility of ammonia and the exotherm during dissolution. The reaction time is preferably 30 minutes to 10 hours.
After the reaction, AMD is isolated by filtration. In order to reduce the amount of AMD dissolved in the solvent and improve the yield, it is preferable that the AMD is sufficiently precipitated by cooling.
High-purity AMD can be obtained by such a method, but if a higher-purity product is required, it can be purified by recrystallization.
[0013]
EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, the scope of the present invention is not limited to an Example.
[0014]
【Example】
Example 1
Synthesis of methyl N- (2-amino-1,2-dicyanovinyl) formimidate wherein RMD of RMD is a methyl group 30.0 g of DAMN and 32.4 g of trimethylorthoformate were added to 60 ml of methanol at 65 ° C. under nitrogen atmosphere. The mixture was heated and stirred for 2 hours. The reaction solution was cooled to 5 ° C., and the precipitated crystals were separated by filtration and washed with 20 ml of methanol. The crystal was dried under vacuum to obtain 33.6 g of methyl N- (2-amino-1,2-dicyanovinyl) formimidate (yield 80.6%, purity 95.1%). The filtrate and washing solution were combined and the solvent was distilled off to obtain 2.4 g of methyl N- (2-amino-1,2-dicyanovinyl) formimidate secondary crystals (purity 26.5%).
[0015]
Example 2
Synthesis of ethyl N- (2-amino-1,2-dicyanovinyl) formimidate in which R of RMD is an ethyl group To 410 ml of ethanol, 200.0 g of DAMN and 301.6 g of triethyl orthoformate were added, and 65 ° C. in a nitrogen atmosphere. And stirred for 2 hours. The reaction solution was cooled to 3 ° C., and the precipitated crystals were separated by filtration. After washing with 60 ml of ethanol, the crystals were vacuum-dried to obtain 269.1 g of ethyl N- (2-amino-1,2-dicyanovinyl) formimidate (yield 88.6%, purity 98.0). %).
The filtrate and washing solution were combined and the solvent was distilled off to obtain 28.5 g of secondary crystals of ethyl N- (2-amino-1,2-dicyanovinyl) formimidate (purity 44.6%).
[0016]
Example 3
Ethyl N- (2-amino-1,2-dicyanovinyl) formimidate (40.0 g) was added to 245 ml of ethanol and the mixture was stirred and cooled to 5 ° C., and 23 g of ammonia was blown in over 2 hours and stirred for 7 hours. Excess ammonia was degassed at room temperature and reduced pressure and cooled to 5 ° C. The precipitated crystals were separated by filtration, washed with 20 ml of ethanol, and the crystals were vacuum-dried to obtain 28.1 g of AMD {N- (2-amino-1,2-dicyanovinyl) formamidine} (yield 85. 4%, purity 96.9%). The filtrate and washing solution were combined and the solvent was distilled off to obtain 4.4 g of AMD secondary crystals (purity 72.3%).
[0017]
【The invention's effect】
Without using a halogen-based solvent, the target N- (2-amino-1,2-) can be obtained in a high yield with a simple reaction operation and post-treatment operation with an alcohol solvent species or a single inexpensive alcohol solvent. Dicyanovinyl) formic acid derivatives can be synthesized with sufficient purity.

Claims (5)

Formula (I)
(In the formula, R represents a C1-5 alkyl group.) An alkyl N- (2-amino-1,2- dicyanovinyl ) formimidate represented by the following formula is reacted with ammonia in a C1-C5 alcohol. Formula (II) characterized by
A method for producing N- (2-amino-1,2-dicyanovinyl) formamidine represented by the formula: Diaminomaleonitrile is reacted with a trialkylorthoformate in a C1-C5 alcohol to obtain a compound of formula (I)
(In the formula, R represents a C1-5 alkyl group.) An alkyl N- (2-amino-1,2- dicyanovinyl ) formimidate represented by the formula: (2-Amino-1,2-dicyanovinyl) Formula (II) characterized by reacting formimidate with ammonia in C1-C5 alcohol
A method for producing N- (2-amino-1,2-dicyanovinyl) formamidine represented by the formula:  The method according to claim 1 or 2, wherein the C1-C5 alcohol is methyl alcohol or ethyl alcohol. Formula (I) characterized by reacting diaminomaleonitrile with a trialkylorthoformate in a C1-C5 alcohol
(In the formula, R represents a C1-5 alkyl group.) A method for producing an alkyl N- (2-amino-1,2- dicyanovinyl ) formimidate represented by :  The method for producing alkyl N- (2-amino-1,2-dicyanovinyl) formimidate according to claim 4, wherein the C1-C5 alcohol is methyl alcohol or ethyl alcohol.