DE1804328A1 - 3-substituted quinoxalinones and process for their - Google Patents

Abstract

A) 3-Substd. 1,2,3,4-tetrahydro- quinoxaline-2-ones of general formula I where x = 0, 1 or 2 R,R',R" = the same or different H, MeO, EtO or Hal; R' may also be NO2 R3 = H or NAlk2 Specifically, x = 2, R' = 4-OMe. R,R" and R3 = H B) Process for the prepn. of 1,2-dihydro-quinoxaline-2-ones of formula (II) Spasmolytics raising the convulsive threshold. The salts with acids are water-sol. whereas those of known antieleptics are insol. and require solubilising agents for use. By reaction of o-phenylenediamines (III) with mixed aromatic-aliphatic esters of alpha-halogenated acids with or without a solvent to give I and treatment of I with dehydrogenating agents to give II. It can be shown that the NH2 of III and not the NHR3 first reacts with the hal. of IV and this is followed by ring closure. Treatment of I with KMnO4, K3Fe(CN)6 or H2SeO3 (selenious acid) converts it to II. Preferred III. N-C2H4NEt2-o-phenylenediamine. Preferred IV. alpha-halogenated phenylacetic, -propionic or -butyric acids with 3- or 4-OMe, OEt, Cl or NO2 in the Ph group.

Description

3-substituted quinoxalinones and process for the preparation of 3-substituted quinoxalin-2-ones The present invention relates to the creation of new 3-substituted tetrahydroquinoxalin-2-ones, which in the 3-position an optionally substituted phenyl radical or an aliphatic- aromatic radical in which the chain length of the aliphatic wedge of this radical is at most 2 -Ato-e, trn.Tcn and which are unsubstituted in the 1- position or can be substituted by a dialkylaminoalkyl radical; in particular, the invention relates to the creation of such compounds of general formula ern x = 0, 1 or 2, R, R 'and R ", which can be the same or different, symbolize hydrogen, methoxy, ethoxy or halogen and in which R' can also mean a nitro group; R" stands for a hydrogen atom or a dialkylaminoalkyl radical.

It has been found that 3-substituted tetrahydroquinoxalin-2-ones of the type specified above are antispasmodics with an anti-seizure effect, in which the seizure threshold is increased, although the salts of these compounds are water soluble.

With the new compounds it is thus possible to form antieleptics Providing real solutions while the well-known antieleptics, too far from their salts, are completely insoluble in water and therefore only in combination with Solubilizers can be administered.

It has been found that it is possible to add o-diamines of the o-phenylenediamine type with mixed aromatic-aliphatic acid esters halogenated in the α-position, with or without a solvent, to 1,2,3 correspondingly substituted in the 3-position: , 4-Tetrahydroquinoxalin-2-ones (which are tautomeric to the 2-hydroxy-3,4-dihydroquinoxalines substituted in the 3-position).

When using o-phenylenediamines that are substituted on a nitrogen, such as NH-diethylaminoethyl-c-phenylenediamine, and reacting in the same way with α-halogenated aromatic-aliphatic acid esters, the formation of two different quino-saline derivatives would be expected: R "" = dialkylaminoalkyl.

It could be shown, however, that the free primary amine was the first can react with the halogen of the acid ester, and that only the ring closure to secondary amine occurs. This course of the reaction can be achieved in particular by that the reactants act on each other at a low temperature and only then closes the amino acid formed as an intermediate to form a ring.

The inventive method for producing the above 3-substituted 1,2,3,4-tetrahydroquinoxalyn-2-one thus exists in its essence in that, by reaction, an aromatic-aliphatic halogenated in the α-position Acid ester with a maximum of 4 aliphatic carbon atoms with an optionally substituted o-phenylenediamine implements. According to a preferred embodiment of the invention, a is in a-position halogenated phenylacetic acid, phenylpropionic acid or phenylbutyric acid ester, in which the phenyl radical in the 3 or 4 position is replaced by methoxy groups, ethoxy groups, Halogen or nitro groups can be substituted with an N-dialkylaminoalkyl-o-phenylenediamine brought to reaction. It is expedient to work first at one temperature of not more than 400C and heated after reaction of the primary amino group with the halogen the reaction mixture to boiling. In the process according to the invention, preference is given to used as substituted o-phenylenediamine N-diethylaminoethyl-o-phenylenediamine and esters / as halogenated acid / 2-chloro-3- (p-methoxyphenyl) -propionic acid ethyl ester used.

The present invention also relates to an improved method for the preparation of 1,2-dihydro-quinoxalin-2-ones, which are optionally in the 3-position substituted phenyl radical or an aliphatic aromatic radical in which the chain length of the aliphatic part of this radical is at most 2 carbon atoms, carry and the are unsubstituted in the 1-position or substituted by a dialkylaminoalkyl radical could be.

This process envisions the production of these 1,2-thihydro compounds in a way before that via the above-mentioned new 3-substituted 1,2, 3,4-tetrahydroquinoxalin-2-ones In this improved process, the aforementioned are carried out in a first stage 1,2,3,4-Tetrahydroquinoxalin - 2-ones prepared in the manner indicated above and takes place in a second stage known dehydration Methods with oxidizing agents, such as potassium permanganate or potassium ferricyanide, or with dehydrating agents such as selenious acid to form 1,2-dihydroquinoxalin-2-one.

According to a special embodiment of this two-stage.

Process close the reaction to tetrahydro-quinoxalin-2-one and the dehydrogenation directly to one another without isolation of an intermediate product is made.

This improved process for making those substituted in the 3-position 1,2-Dihydroquinoxalin-2-one enables these compounds to be obtained starting from of cheap and commercially available substituted phenylacetic acids, where 3-phenyl-1,2-dihydroquinoxalin-2-ones can be obtained. But also the 3-aralkyl-substituted 1,2-Dihydroquinoxalin-2-ones are conveniently available using this new 2-step process, because the corresponding homologues of the phenylacetic acids according to the Perkin's method Cinnamic acid synthesis are readily available.

For example 1 1: 3-phenyl-1,2,3,4-tetrahydroquinoxalin-2-one.

54 g of o-phenylenediamine, 99 g of a-chlorophenylacetic acid ethyl ester, 51 g of triethylamine and 500 ml of alcohol are mixed and refluxed for 4 hours cooked. The crystals of triethylamine hydrochloride deposited after cooling are sucked off. The alcoholic mother liquor is concentrated, deposited Crystals collected. These are made with a small amount of the quinoxalinone that with the triethylamine hydrochloride had precipitated and from this by washing with Separated water was, combined, and recrystallized several times from alcohol.

White needles with a temperature of -203-204 ° C are obtained; Yield: 83 g (= 74% of theory).

Example 1 2; 3-phenyl-1,2-dihydroquinoxalin-2-one.

22.4 g of 3-phenyl-1,2,3,4-tetrahydroquinoxalin-2-one are in 300 ml of glacial acetic acid heated to boiling. Finely powdered potassium permanganate is made into small Portions added until the brown color persists (approximately 5.3 g in total).

The mixture is diluted in 600 ml of water. The deposited crystals are recrystallized three times from alcohol.

Somewhat yellowish needles with a temperature of 249 - 249 ° C are obtained.

Yield: 20.5 g (= 92% of theory).

Example 1 3: 3- (p-Methoxybenzyl) -1,2-dihydro-quinoxalin-2-one cloudy 3- (p-methoxybenzyl) -tetrahydro-quinoxalin-2-one] 13.8 g of o-phenylenediamine are mixed with 31 g of ethyl α-chloro-p-methoxyphenylpropionate and slowly heated to an internal temperature of 21,000. After the vigorous reaction has subsided, the melt is brought to 2500C for a short time and then cooled. The melt of the tetrahydroquinoxalinone solidifies to a crystal-clear greenish mass.

The reaction mixture is dissolved in 300 ml of glacial acetic acid by heating on a water bath solved. Add a few drops of 8.5 g of selenous acid to the warm glacial acetic acid solution Washed in water. The mixture is warmed until a vigorous reaction begins and heated in a water bath for 1 hour after they have subsided. The separated selenium is filtered off, the solution is concentrated to about half and then by addition diluted by 500 ml of water. The separated crude 3-p-methoxybenzyl-1,2-dihydro-quinoxalin-2-one is recrystallized twice from water and once from dilute acetic acid. Man receives white crystals with the B. = 19800. Yield: 19.1 g (= 56 ° / 0 of theory).

Example 4: 1-Diethylaminoethyl-3- (p-methoxybenzyl) -1,2-dihydro-quinoxalin-2-one.

121.5 g of ethyl 2-chloro-3- (p-methoxyphenyl) propionate, 105 g of N-diethylaminoethyl-o-phenylenediamine, 51 g of triethylamine and 800 ml of abs. alcohol are mixed and held at a temperature of 20-2500 for 72 hours. Afterward the mixture is refluxed for 12 hours. After cooling down will separated triethylammonium chloride sucked off. After distilling off the alcohol the viscous residue is dissolved in 500 ml of glacial acetic acid without further purification and 65 g of selenous acid are added with stirring. The solution is again 14 Heated for hours on a water bath. After filtering off the deposited selenium, the The solution is concentrated in vacuo, the residue is taken up in aqueous hydrochloric acid and the hydrochloric acid solution filtered. The base is made from the filtrate by making it alkaline deposited with sodium hydroxide solution and taken up in benzene.

Drying the benzene solution with sodium sulfate becomes the solvent removed and the residue twice at a bath temperature of 2000C and 0.01 Torr. distilled. The forerunners are separated from each other.

The viscous, light yellow oil solidifies with a few drops when driven Isopropanol crystalline.

After recrystallizing twice from isopropanol and then Recrystallize from a lot of petroleum ether with 95 g of yellowish-white leaves the F. = 690C obtained.

(Yield: 52% of theory.)

Claims (7)

P a t e n t a n s p r ü c h e: 1. Process for the preparation of 3-substituted Quinoxaline-2-orene, characterized in that one is halogenated in position aromatic-aliphatic acid ester, which has 2 to 4 aliphatic carbon atoms, with an, optionally substituted, o-phenylenediamine to form new 3-substituted ones 1,2,3,4-etriLydroquinoxalinone (2), which in the 3-position an, optionally substituted, Phenyl radical or an aliphatic-aromatic radical in which the chain length of the aliphatic part of this radical is at most 2 carbon atoms, and the in 1-position are unsubstituted or substituted by a dialkylaminoalkyl radical can be, and, if desired, the 1,2,3,4-tetrahydroquinoxalinones thus obtained (2) by methods known per se with oxidizing agents such as potassium permanganate or potassium ferricyanide, or with dehydrating agents such as selenous acid to the analogous 1,2-dihydroquinoxalin-2-ones are dehydrated. 2. The method according to claim 1, characterized in that one o-phenylenediamine with ethyl α-chlorophenylacetate to 3-phenyl-1,2,3,4-tetrahydroquinoxalin-2-one converts and, if desired, the compound obtained to 3-phenyl-1,2-dihydro-quinoxalin-2-one dehydrated. 3. The method according to claim 1, characterized in that one o-phenylenediamine with ethyl α-chloro-p-methoxyphenylpropionate to give 3- (p-methoxybenzyl) tetrahydroquinoxalin-2-one converts and, if desired, the compound obtained to 3- (p-methoxybenzyl) -1,2-dihydro-quinoxalin-2-one dehydrated. 4. The method according to claim 1, characterized in that N-diethylaminoethyl-o-phenylenediamine with ethyl 2-chloro-3- (p-methoxyphenyl) propionate and if desired the compound obtained to 1-diethylaminoethyl-3- (p-methoxybenzyl) -1,2-dihydro-quinoxalin-2-one dehydrated. 5. 3-substituted tetrahydroquinoxalin-2-ones of the general formula where x = 0, 1 or 2, R, R 'and R ", which can be the same or different, symbolize hydrogen, methoxy, ethoxy or halogen and where R' can also mean a nitro group, R"'stands for a hydrogen atom or a dialkylaminoalkyl radical. 6. 3-phenyl-1,2,3,4-tetrahydroquinoxalin-2-one. 7. 3- (p-methoxybenzyl) tetrahydro-quinoxalin-2-one.