JPS6011034B2 - Production method of cyanoquinoxaline 1,4-dioxides - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of certain novel compounds that have useful antibacterial properties and are valuable for their growth-promoting effects in animals.

More specifically, these novel compounds have a cyano substituent on the fused penzo ring, a methyl group at the C-3 position, and optionally a substituent on the carboxamide nitrogen. It is a derivative of carboxamide 1,4-dioxide. Quinoxaline 1,4-dioxides are a well-known group of compounds, some of which have been reported to be resistant to bacteria and/or useful as growth promoters in animals.

US Patent No. 3,660,398 and British Patent No. 13083
No. 7 both contain quinoxaline-2-ruboxamide 1 and 4.
Dioxides are disclosed, particularly 5, 6, 7 or 8
Various compounds have been described with substitution groups in the positions. However, all of these patents disclose quinoxaline-2-carboxamide 1 having a cyano substituent on the fused penzo ring.
・Disclosed 4-dioxides and became 1. The method for preparing 6-cyano-2,3-dimethyl-quinoxaline 1,4-dioxide is described in "The Journal of the Chemical Society" by Lundquist and Stacy.
of eChemical Society (London), 28 Shigeru (1953).

The object of the present invention is to develop a novel quinoxaline 1 having the formula:
- To provide 4-dioxides and acid addition salts thereof. [wherein the sia/substituent is in the 6 or 7 position, and RI is hydrogen or methyl, and R2 is hydrogen, alkyl having 1 to 3 carbon atoms, or 2-(N.N-dimethylamino)ethyl.

] The above-mentioned quinoxaline 1,4-dioxides are valuable as antibacterial agents and as growth promoters in animals.

A preferred group of quinoxaline 1,4-dioxides of the present invention is a group of compounds in the above formula (1) in which RI is methyl and R2 is alkyl having 1 to 3 carbon atoms.

A more preferable group of quinoxaline 1,4-dioxides of the present invention is a group of compounds in which RI is hydrogen in the above formula (1).

Among the compounds of the present invention, the following groups are important in terms of bacterial resistance and growth promoting properties.

6(7)-cyano N.N-3-trimethylquinoxaline-2-carboxamide 1,4-dioxide, 6(7)
-cyano-3-methylquinoxaline-2-carboxamide 1,4-dioxide, 6(7)-cyano-N-3-dimethylquinoxaline-2-carboxamide 1,4-dioxide, 6(7)-cyano-N-ethyl-3-methyl Quinoxaline-2-carboxamide 1,4-dioxide,
and 6(7)-cyano-N-(2-[N·N-dimethylamino]ethyl)-13-methylquinoxaline-2-carboxamide 1,4-dioxide.

In general, one aspect of the present invention is the formula [wherein the cyano substituent is in the 6 or 7 position, and RI is hydrogen or methyl, and R2 is hydrogen, alkyl of 1 to 3 carbon atoms, or N.N--dimethylamino)ethyl.

A process for producing a compound represented by the formula and an acid addition salt thereof, wherein the compound represented by the formula is combined with diketene and the formula (where RI and R2 have the same meanings as above).

) to produce pharmaceutically suitable salts of these compounds, if desired.
As mentioned above, an object of the present invention is to provide novel and useful quinoxaline 1,4-dioxides represented by formula (1), and the amount of quinoxaline 1,4-dioxide can be easily obtained by the method detailed below. can be easily synthesized.

The method for producing the compound represented by formula (1) involves the use of the following two-step process. That is, '1} React the diketene and a suitable amine in a solvent selected from the solvents listed above, and '2} Directly add the solution of the acetoacetamide derivative (m) thus obtained to 5-cyanobenzofuran. Treat with Zan 1-oxide.

(In the formula, RI and R2 have the same meanings as above.

) The reaction is usually carried out by contacting the reagents in a suitable solvent system at a temperature ranging from about 0 to 100°C, preferably from about 20 to 60°C. A suitable solvent is one that dissolves at least one of the reagents and does not adversely affect the starting reagents and the product. Examples of such solvents include:
Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane and dialkyl ethers of ethylene glycol, propylene glycol and diethylene glycol; lower alkanols such as methanol, ethanol and isopropanol; chloroform, methylene chloride and halogenated hydrocarbons such as 1,2-dichloroethane; quaternary amides such as N·N-dimethylformamide, N·N-dimethylacetamide and N-methylpyrrolidone, acetonitrile; and mixtures of these solvents. . Reaction times vary depending on many factors such as reactivity and concentration of reagents and reaction temperature.

As will be understood by those skilled in the art, the reaction proceeds faster at higher temperatures, so relatively short times are used to obtain the product in good yield, whereas at lower temperatures,
The reaction progresses slowly and therefore longer reaction times are used. Considering all the above factors, when the reaction is carried out at about 25 qo, the reaction time is several hours, e.g. about 2 to 24 qo.
Time is typically used. A variety of basic catalysts can be used in this process; typical examples of bases that can be used include ammonia; primary amines such as methylamine, ethylamine, butylamiso, cyclohexylamine, aniline and pendylamine; diethylamine, dimethyl Secondary amines such as amines, morpholine, piverdine, N-methylaniline and pyrrole; Tertiary amines such as triethylamine, N-methylmorpholine, N·N-dimethylaniline, pyridine and quinoline; sodium methoxide, sodium ethoxide and alkoxides such as potassium ethoxide; hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide; and hydrides such as sodium hydride and potassium hydride.

The amount of basic catalyst used is not critical and can range from as little as about 0.01 molar equivalent to several molar excesses relative to benzofurazan 1-oxide. A preferred amount is about 0.1 to 1.0 molar equivalents. If the basic catalyst is liquid at the reaction temperature, it can be used in sufficient quantities to add more solvent if desired. Although the compounds represented by formulas (0) and (m) can be used in excess to produce the compound represented by formula (1), they are usually brought into contact in approximately equimolar ratios.

If desired, the compound of formula (m) can serve as the reaction solvent if it is liquid at the reaction temperature. The products of the process of the invention can be isolated from the reaction medium by standard methods.

For example, if a product precipitates during the reaction, it can be recovered simply by filtration. On the other hand, if the product does not precipitate by itself, it can also be precipitated by diluting the reaction medium with a non-solvent such as hexane or water at the end of the reaction. Other methods of product recovery include, after removal of the solvent by evaporation, partitioning the resulting crude product between water and a water-immiscible organic solvent. After separating the two phases, the phase containing the product is evaporated to obtain the product. The basic catalyst can be added separately before the third stage, but instead only in the first stage the formula NHR
It is convenient to use the amine represented by IR2 in excess of the amount of diketene to be added.

In this way, there is unreacted amine that acts as a catalyst in the second stage. Another variant now used in the process used for the preparation of compounds of formula (1) is to react acetoacetamide with a primary or preferably secondary amine and to react equimolar amounts of enamine obtained with acetoacetamide. Including use in place of ingredients.

This enamine can be obtained by well-known methods [e.g., Szmuszkonicz, “Advances
In Organic Chemistry, Methods & Results (Advances in○r Bait nlcCh
emiskey, Methods and Res)'
', Interscience/Priceyers, Inc.
heRInc. ), New York, 1963, vol. W, p.
p. Typical examples of amines used are morpholine, pyrrolidone, piveridine, N-methylcyclohexylamine and dialkylamines such as dimethylamine, diethylamine, dibutylamine. When using the latter variant, there is no need to add a basic catalyst in addition to the amines involved in enamine formation. Yet another variant now being used in the process used for the production of compounds of formula (1) is
) in place of the acetoacetamide compound of formula C
Acetoacetate represented by H3COCQCOOR5 (where R5 is lower alkyl, phenyl, substituted phenyl, benzyl or substituted penzyl, and the substituted phenyl and substituted penzyl groups are lower alkyl, lower alkoxy, hydroxy, nitro, chloro, bromo and fluoro). It is possible to have up to three selected from the following.

). When using this particular variant, the ester and amine are usually used in approximately equimolar ratios, although an excess of either component is acceptable. Formula H
When using an excess of the amine represented by NNRIR2, it is usually not necessary to add additional basic catalyst.
5-cyanobenzofurazane 1-oxide can be produced from 4-chloro-3-nitrobenzonitrile by treating it with an azidoion source and then thermally decomposing the produced 4-azido-3-nitrobenzonitrile.

The formation of 4-azido-3-nitrobenzonitrile can be carried out using polar organic solvents such as acetonitrile, N·N-dimethylformamide, N·N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, or lower compounds such as methanol, ethanol or isopropanol. This is accomplished by reacting a substantially equimolar amount of 4-chloro-3-nitrobenzonitrile with the azidoion source in an alkanol at a temperature in the range of about 0 to 30°C for several hours, e.g., about 4 to 2 hours. .

Typically used azide ion sources include metal salts of triazo acids such as sodium azide and potassium azide; ammonium azide; ethylammonium azide, dibutylammonium azide, morpholinium azide, triethylammonium azide, pyridinium azide and N. N
amine salts of triazo acids such as -dimethylanilinium azide; tri(lower-alkyl)silyl azides such as trimethylsilylamide and triethylsilylamide. Conversion to benzofurazan 1-oxide can then be achieved by simply heating the solution of 4-azido-3-nitrobenzonitrile thus obtained. Usually 40~
A temperature in the range of 160oO, preferably about 60-100Qo is used for this second stage. And the temperature is about 6
In the range of 0 to 10 p0, several hours, for example about 2 to 1 addition time, are usually required. The 5-cyanobenzofurazane 1-oxide can be isolated by evaporating off the solvent.

Another variant of this process can be used when the formation of 4-azido-3-nitrobenzonitrile is carried out in a water-immiscible organic solvent.

For example, when the conversion to 4-azido-3-nitrobenzonitrile is complete, the reaction medium is diluted with excess water and the product is then extracted into a water-immiscible organic solvent.
The solution of 4-azido-3-nitrobenzonitrile thus obtained is then thermally decomposed by heating in the same manner as described above, and then the solvent is removed by evaporation to obtain shea/penzofurazan 1-oxide. Suitable water-immiscible solvents useful in this variant include esters such as ethyl acetate and butyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; and chlorinated hydrocarbons such as chloroform and methylene chloride. Although cyanobenzofurazane 1-oxide is shown here as a 5-monoisomer, it actually exists as a dynamic tautomeric compound containing both 5- and 6-isomers.

Moreover, due to the existence of this compatibility equilibrium in the starting materials, the above method for producing compounds of formula (1)
-Produces a mixture of cyanoquinoxaline 1,4-dioxide.

The ratio of isomers obtained will vary depending on many factors, such as the structure of the reactants, the reaction temperature, the reaction solvent and the method chosen for product isolation. In some cases both isomers are obtained in significant amounts, while in other cases one or the other isomer can be very predominant. If desired, the mixture of the two isomers can be separated into its components by conventional means, such as fractional crystallization or chromatography. In many cases, the isomer identification was not complete;
The nomenclature used herein for antimicrobial quinoxaline 1,4-dioxide is intended to refer to either the 6- or 7-monoisomer, as well as mixtures thereof. The in vitro antibacterial activity of the quinoxaline 1,4-dioxide of the present invention can be demonstrated by the conventional two-fold dilution method in Djfco.

Add bacteria to this solution, then test quinoxaline 1.
It was seeded with 4-dioxide and grown overnight under anaerobic conditions. The next day, a visual assessment of the test was performed. The minimum inhibitory concentration of a compound is the lowest concentration that prevents turbidity, ie, microbial growth. The in vitro effects of several compounds of the invention are shown in Table 1. Quinoxaline 1 and 4 of the present invention
-dioxide also exhibits in vivo antibacterial activity.

To measure this effect, the test compound was administered to mice infected by intraperitoneal inoculation with the pathogen. The subject compounds were administered using a multiple dose regimen and using the oral (PO) or subcutaneous (SC) route. Bacterial inoculum is varied from the amount needed to kill 100% of mice under the test conditions to about 1 tone below. At the end of the study, the effect of the compound was evaluated by counting the number of survivors in the treated mice. The results are also shown in Table 1, and mice were infected with Streptococcus pyogenes.
es) or Escherichia coli
) presented a compound effect that protects against lethal doses of .

Table 1 *Strep. The dose of the test compound in the protection test with Esch. 25 when using coli
He weighed a mere K9.

Compounds of formula (1) in which R2 is 2-(N·N-dimethylamino)ethyl form acid addition salts, and all such acid addition salts are intended to fall within the spirit and scope of the present invention. .

These salts can be prepared in a well known manner, for example by adding a solution of basic quinoxaline 1,4-dioxide in a suitable solvent (e.g. water, acetone, methanol, ethanol or butanol) to a solution of 1 molar equivalent of the appropriate acid. manufactured by mixing. If salt precipitates, collect it by filtration. Alternatively, it can be recovered by evaporation of the solvent or, in the case of aqueous solutions, by lyophilization. When the compound of the present invention is intended for therapeutic use, it is preferable to use a pharmaceutically suitable salt, but other salts can also be used for various other purposes. Such purposes include isolating and purifying a particular compound and interconverting it into a pharmaceutically suitable salt and its corresponding non-salt form. Of particular value are sulfates, hydrochlorides, hydrobromides, nitrates, phosphates, citrates, tartrates, pamates, perchlorates, sulfosalicylates and p-toluenesulfonic acids. It's salt. 'The quinoxaline 1,4-dioxide of the present invention is valuable not only for topical application as a disinfectant due to its in vitro antibacterial action, but also as an industrial fungicide, for example in water treatment, silt control, pigment preservation and wood preservation. For topical application of these compounds, it is currently convenient to mix the active ingredient with an agitated carrier such as a vegetable oil, if mineral oil, or a softening emulsion. Similarly, it can be dissolved or dispersed in liquid diluents or solvents such as water, alkanols, glycols or mixtures thereof. In many cases, it will be appropriate to use an active ingredient concentration of about 0.01 to 1% by weight of the total composition. The quinoxaline 1,4-dioxide of the present invention is useful for treating fungal infections in animals due to its in vivo antibacterial activity, and is particularly valuable as an animal growth promoter in pigs, livestock, and poultry.

When used in animals for this purpose, these compounds can be administered orally or parenterally, i.e. intramuscularly, subcutaneously or intraperitoneally, the dosage being approximately 1 to 1 kg/kg of body weight.
It is 100 c. However, a dosage in the range of about 5 to 50 9/kg body weight is usually sufficient. These compounds can be administered alone or mixed with various diluents and carriers in accordance with standard veterinary practice. When the compounds of this invention are intended for parenteral use, excipients such as water, isotonic saline, isotonic dextrose, Ringle's solution,
It can be mixed with non-aqueous diluents such as vegetable oils (cottonseed oil, sesame oil, corn oil) or dimethyl sulfoxide, etc.

Buffers, local anesthetics and/or inorganic acid salts are commonly added to impart desired pharmaceutical properties. For oral use, the quinoxaline 1'4-dioxide of the present invention can be mixed with various diluents, including aqueous diluents, non-aqueous diluents, and solid diluents, to form capsules, tablets, confectionery tablets, lozenges, and dried They can be in the form of mixtures, emulsions, solutions and dispersions.

A particularly valuable use of the compounds of the invention is as an animal growth promoter.

Low levels of one or more of the quinoxaline 1,4-dioxides described herein can be added to the diet of any healthy animal, including animals with an average concentration of about 1 to 10 and usually about 5 to 5 ■ Making quinoxaline 1,4-dioxide available in feed for extended periods of time, especially during most of its active growth period, when formulated with feed at wind levels, promotes growth rate and improves feed efficiency (per pound of body weight). increase the number of pounds of feed required. Examples of animals that can be processed by this method include poultry (chickens, ducks, turkeys), cows, sheep, dogs, cats, pigs, rats, mice, horses, goats, mules,
Examples include rabbits and mink. The beneficial effects on growth rate and feed efficiency exceed those normally obtained with a complete diet containing all the nutrients, vitamins, minerals, and other elements known to be necessary for minimally healthy growth of the animals mentioned above. It is. Thus, animals reach marketable size further and with less feed. Quinoxaline 1,4-dioxide can be formulated with animal feed or administered in equal amounts through the animal's water supply. EXAMPLES Hereinafter, the present invention will be illustrated by examples, but the present invention is not limited to these examples.

Example 1 6(7)-cyano 3-methylquinoxaline-2-carboxamide 1,4-dioxide 5oo c(0.003
1 mol) of 5-cyanobenzofurazane 1-oxide and 310 of 2 (0.0031 mol) acetoacetamide [Chickand Wils
more), J. Chem. Soc London, 19
78 (1910)] in 10' of tetrahydrofuran was cooled to 5°C under the ocean, and then 40°C.
% aqueous methylamine and 1 drop of catalyst were added every hour for the first 4 hours.

The reaction mixture was then allowed to stand overnight at ambient temperature, whereupon a crystalline precipitate appeared. The precipitate was collected in an oven and washed with tetrahydrofuran to reduce the melting point to 232-23.
410 females of 6(7)-cyano-3-methylquinoxaline-2-ruboxamide 1,4-dioxide having 0 (decomposition) (yield 54%) were obtained. Analysis C. Calculated value (%) for day 8N403: C, 54.1; day, 3.3; N, 22.
9 Experimental value (%) C, 53.8; Sun, 3.4: N, 22
．． 4 Example 26(7) - Cyano N-N-3-trimethylquinoxaline-2-carboxamide 1,4-dioxide 1.61 units (0.01 mol) of 5-cyanobenzofurazane 1-oxide according to the method of Example 1 1.2
When reacted with N.N. dimethylacetoacetamide (0.01 mole), 6(7)-cyano N.N.3-trimethylquinoxaline 2-carboxamide 1,4-dioxide 1 with a melting point of 186-190 qo was obtained. .07 evening (
A yield of 40% was obtained.

Analysis C, 3 days, calculated value (%) as 2N403: C, 57.4: days, 4.5; N, 20.
6 Experimental value (%) C, 56.8; day, 4.5; N, 20
．． 5 Example 3 Instead of acetoacetamide, equimolar amounts of N-methylacetoacetamide, N-ethylacetoacetamide, N-(n-butyl)acetoacetamide, N
・N-jethylacetoacetamide and N-methyl-N
The following compounds were prepared by repeating the method of Example 1, except that -(n-propyl)acetoacetamide was used in each case.

6(7)-Sia/1N-3-dimethylquinoxaline-2
-carpoxamide 1,4-dioxide, 6(7)-cyano N-ethyl-3-methylquinoxaline-2-carboxamide 1,4-dioxide, 6(7)-cyano N-(n-butyl)-3-methylquinoxaline-2-carboxamide 1・4-dioxide, 6(7)-cyano N・
N-diethyl-3-methylquinoxaline-2-carboxamide 1,4-dioxide, and 6(7)-cyano N
o3-Dimethyl-N-(n-propyl)quinoxaline-2-carboxamide 1,4-dioxide.

Example 4 6(7)-cyano N.3-dimethylquinoxaline-2
-Carboxamide 1,4-dioxide 0.84 mol (0.
A solution of 0.01 mol) of diketene dissolved in 50 mol of acetonitrile was cooled to 5°C under a rope bath, and then a solution of 4.7 mol of methylamine in 2.3 mol of diketene in 50 ml of acetonitrile was dissolved in 2.3 mol of diketene.
mol) was added dropwise.

The temperature was kept below 10° C. during the addition. After the addition was complete, the temperature of the solution was adjusted again to 5°C and then heated to 1.61 min (0.0
1 mole) of 5-cyanobenzofurazane 1-oxide to 2
A solution dissolved in neutral acetonitrile was added dropwise while cooling sufficiently so that the reaction temperature could be maintained at 10° C. or lower. Once the subsequent additions were complete, the reaction was warmed to ambient temperature and allowed to stand overnight. The precipitated solid was collected in a furnace and had a melting point of 203-2.
1.3 ml of crude product of 0.04 qo (decomposition) was obtained. By recrystallizing this crude product from methanol, the melting point was 218.
~22p○6(7)-cyano N.3-dimethylquinoxaline-2-carboxamide 1.4-dioxide 0.
I got 65 evenings. Analysis C, 2nd, Calculated value (%) as state 403: C, 55.8; Day, 3.9; N, 21.
7 Experimental value (%) C, 55.2; day, 4.1; N, 21
．． 2 Example 5 The following group of compounds were obtained by repeating the method of Example 4, except that in place of methylamine, an equimolar amount of the appropriate amine was used.

In a similar manner, the method of Example 4 was repeated, substituting equimolar amounts of the appropriate amine for the methylamine component, and the following homologues were obtained.

6(7)-cyano-N-isopropyl-3-methylquinoxaline-2-carboxamide 1,4-dioxide, 6
(7) -Cyano N-sec-butyl-3-methylquinoxaline-2-ruboxamide 1,4-dioxide, 6
(7)-Cyano-N.N.3-trimethylquinoxaline-2-carboxamide 1.4-dioxide, 6(7)-
Cyano N.N-di-n-butyl-3-methylquinoxaline-2-ruboxamide 1.4-dioxide, 6(7
)-cyano-N-(3-hydroxypropyl)-3-methylquinoxaline-2-carboxamide 1,4-dioxide, 6(7)-cyano-N-(2-[N·N-diethylamino]ethyl)-3-methylquinoxaline- 2-carboxamide 1, 4-dioxide, 6(7)-cyano N-(2-[N.N-di-n-propylamino]ethyl)-3-methylquinoxaline-2-carboxamide 1.
4-dioxide, 6(7)-cyano N-(3-[N・
N-dimethylamino]propyl)-13-methylquinoxaline-2-carboxamide 1,4-dioxide, 6(7
)-Cyano N-(3-hydroxypropyl)-N.3
-dimethylquinoxaline-2-ruboxamide 1,4-dioxide, 6(7)-cyano-N-(2-hydroxyethyl)-N-butyl-3-methylquinoxaline-
2-carboxamide 1,4-dioxide, 6(7)-cyano N-N-di(2-hydroxyethyl)-13-methylquinoxaline-2-carboxamide 1,4-dioxide, 6(7)-cyano N-(2-[ N,N-dimethylamino]ethyl)-N,3-dimethylquinoxaline-2
-Carboxamide 1,4-dioxide, 6(7)-cyanoN-N-di(2-[N-N-dimethylamino]ethyl)-3-methylquinoxaline-2-carboxamide 1
- 4-dioxide, and 6(7)-cyano N-(3-[N.N-di-n-propylamino]propyl)-13-methylquinoxaline-2-carboxamide 1,4-dioxide.

Example 6 6(7)-Cyano N-(2-[N·N-dimethylamino]ethyl)-3-methylquinoxaline-carboxamide 1,4-dioxide hydrochloride 100% of 0. was pulverized in hydrochloric acid with 3.15 mol (0.01 mol) of 6(7)-
Cyano N-(2-[N・N-dimethylamino]ethyl)-3-methylquinoxaline-2-carpoxamide 1.
4-dioxide was added to the sea bream azusa at ambient temperature.

After an additional 5 minutes, the mixture was lyophilized to give 6(7)-cyano-N-(2-[N.N-dimethylamino]ethyl)-3-methylquinoxaline-2-carpoxamide 1,4-dioxide as a solid. The hydrochloride was obtained. Example 7 6(7)-Cyano N-(3-[N·N-dimethylamino/]propyl)-3-methylquinoxaline-2-rupoxamide 1,4-dioxide p-toluenesulfonate 329-2 6(7)-cyano-N-(3-[N・N
-dimethylamino/]butyr)-3-methylquinoxaline-2-hydroxylupoxamide 1,4-dioxide dissolved in 30 parts of ethanol was added to a solution of 100 mg of ethanol at ambient temperature.
A solution of 72% p-toluenesulfonic acid dissolved in 10% ether/ethanol was added dropwise.

The mixed solution was then evaporated to dryness under vacuum.
6(7)-cyano N-(3-[N·N-dimethylamino]propyl)-3-methylquinoxaline-2-carboxamide 1,4-dioxide p-toluenesulfonate remained. Incidentally, 5-cyanobenzofurazane 1-oxide used in the above examples was produced as follows.

48.0 mol (0.263 mol) of 4-chloro-3-nitrobenzonitrile
vreandTurner), J. Chem. Soc London 1113 (1927)] in dimethyl sulfoxide was treated with 17.0 m (0.263 mol) of sodium azide in small portions at ambient temperature.

The resulting solution was incubated overnight at ambient temperature and then heated to 2400
poured into the water. ．． The aqueous solution thus obtained is
The organic extract was then washed with water and dried using anhydrous sodium sulfate. The dried solution was concentrated under vacuum to about half the volume and then
The mixture was heated to reflux for an hour. At this point, the ethyl acetate solution was cooled to ambient temperature and the remaining solvent was removed by vacuum evaporation, yielding 41.2 g of 5-thia/penzofurazan 1-oxide (97% yield) with a melting point of 73-70%. Ta. Analysis as C74N302

Claims (1)

[Claims] 1 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, the cyano substituent is at the 6th or 7th position, and R^1
is hydrogen or methyl, R^2 is hydrogen, carbon number 1-
3 alkyl or 2-(N·N-dimethylamino)ethyl. ] A method for producing the compound represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and diketene and the compound represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Formula where R^1 and R^2 have the same meanings as above.) Cyanoquinoxalines 1 and 4 are characterized in that they can be reacted with a compound represented by () to produce, if desired, a pharmaceutically suitable salt. -Production method of dioxides.