DE1695064A1 - Substituted 1,2,8,9-tetraazaphenalenes and methods of preparation - Google Patents

Description

SUBSTITUTED 1,2,8,9-TETRAAZAPHENALENS AND METHOD OF MANUFACTURING

This invention relates to new nitrogen-containing compounds, in particular substituted 1,2,8,9-tetraazaphenalenes, their acid addition salts and their addition compounds with reactive esters of lower alkanols, or. · their quaternary ammonium salts _r and processes for producing these materials.

Compounds of the general formula I

NR ₁

(D

in which

R. hydrogen or a lower alkyl group with at most

6 carbon atoms and
R ^ is hydrogen, a halogenator, the hydroxyl group, a lower alkoxy group with a maximum of 6 carbon atoms or the carboxyl group,

and their addition salts with inorganic and organic acids, as well as their addition compounds with reactive esters of at most ό Alkanols containing carbon atoms have not yet been kanni:; ', ewoirdcn. As has now been found, these connections have / and their physiologically acceptable acid addition salts and the qudternary ammonium salts thereof valuable pharmacological,

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especially hypotensive and sedative properties, etc. therefore 41 * cardiovascular, especially as antihypertensive Jlittel can be used.

The new in the present description and in the claims Ring system known as 1,2,8,9-tetraazaphenals can also be called pyridazino [3,4,5-de) phthalazine according to Chemical Abstracts are designated

or

or 1H-pyridazino (S, 4 _t 5-delphthalazine.

In the following examples and in the claims however, using the designation "1,2,8,9-Tetraazaphenalen" the following nunsneration is used:

(9H -) "1,2,8,9-tetraazaphenals,

"Lower" alkyl and alkoxy groups contain a maximum of 6 carbon atoms in a straight or branched chain. Examples Here are the methyl, ethyl, propyl, isopropyl, autyl-, sec. Butyl, tert-butyl, pentyl, isopentyl and Hydroxyl groups, as well as those corresponding to these alkyl groups Alkoxy groups.

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BAD OHIGINAU

f f ί * »»

cliu compounds of the general formula I by a phthalazinone of the general formula III

(IH)

in which A ¹ denotes the formyl group or a functional derivative thereof, or the group -CH-NNH * and R, and R «have the meaning given under formula I.

iüi l; the at least equiraolar amount of hydrazine hydrate is heated, or that, if A ' _{denotes the group -CH = NNH 2} , such a hy.h-aaon is cycled by heating, if desired (a) a product of the formula I in which R denotes hydrogen , by treatment with a reactive ester of an alkanol containing at most 6 carbon atoms, converted into a salt of a compound of the formula I in which R 1 is a lower alkyl group, or (b ^v i a product of the formula I in which R _{2 is} a lower alkoxyj ^ group means, converted by hydrolysis into the corresponding Hydroxyderivju and (c) a product of the formula I converted into an addition salt with an inorganic or organic acid or it is converted to the corresponding addition compound by means of a reactive ester of an alkanol containing at most 6 carbon atoms :.

The compounds of the general formula III are her- -osteilen by adding a 2,6- (α, a-dibromomethyl) -benzoic acid of general formula IV or a ß-hydroxy-T-aldehydophthalide of the general formula V with an essentially squimolecular one Amount of hydrazine hydrate at either higher concentrations and / or shorter reaction times or by reacting in one Manufactures alcohol such as methanol, ethanol or methyl cellosolve.

If you have too large an excess of hydrazine hydrate related or when using * excess hydrazine hydrate

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the reaction does not: stops on the right side, one obtains an Ö-Aldeh} Jo-1 (211) phthalassinone hydrazone or directly a 1,2,8,9-Te.traü ζ α phe na 1 en.

Compounds of the formula I in which R 1 is hydrogen can be prepared in one operation by adding a compound of the general formula II

COOH

(ID

in which

A each denotes a formyl group or a functional derivative thereof, where a group A can be present together with the adjacent carboxyl group as a hydroxylactone or a functional derivative thereof, R _{2 has} the meaning given under formula I with

at least twice the molar amount of hydrazine hydrate is heated, the product is isolated and, if desired, converted into an addition salt Converted with an organic or inorganic acid or it by means of a reactive ester of at most 6 carbon atoms onLhaitendon Alkanols to the corresponding addition compound implements. .

Suitable starting materials of the general formula II are fol-sending compounds. Selenium first mentioned the 2 _t 6- (a, a-Dibroa "nethyl) -benzoee8uren of the general formula IV,

CHBr ₂

(IV)

in which R _{2 has} the meaning given above »You can

By chromating known 2,6-dimethylbenzoic acids in

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BATH ORIGINAL

5 r C i »C <'■

Carbon tetrachloride boi is reflux temperature with light, producing influential.

B "ei the hydrolysis of 2,6- (a, oc-dibromomethyl) benzoic \\\ lc weak bases such as sodium bicarbonate or sodium carbonate. ' otier with a strong base, such as sodium hydroxide, receives .Λίί.ι after ^ ns / Zuren with a mineral acid, such as. B. hydrochloric acid oücr sulfuric acid, in good yield compounds which are to be formulated as 3-hydroxy-7-aldehydophthalides or as their tautomers, ie as 2,0-dialdehydobenzoic acids ^ according to the general formula V

CHO

COOH

or _ I I (V)

° ^l ~ ^l CHO

in which R ^ has the meaning given above.

The exact structure of these hydration products could be Time cannot yet be clarified exactly. It appears to be either 3-hydroxy-7-aldehyde phthalides or a mixture of the two tautomeric forms to act. The pure 3-hydroxy-7-aldehyde phthalide can be isolated from this mixture. Both pure 3-hydroxy-7-aldehydophthalides and the mixtures give 1,2,8,9-tetraazaphenals in good yield by reaction with at least twice the molecular amount of hydrazine hydrate.

The reaction of a compound of the general formula II rille hydrazine hydrate is best carried out in aqueous solutions at ün .. Cd : kf: Lu:;:; L; e.aperatui: of the reaction mixture. .n: ■ .;. ti'.t.Lt>a; cl, 'iinir li.i'}; t swi-schua LO - 3 (50 Sl'.uadcn, ν.τ, ν.ιι ^ ϋ-

α α aa ι / ί η ae bad

Compounds of the formula I in which R _{2 is} a lower alkoxy

can be converted into the corresponding hydroxydurivat by acid hydrolysis be convicted.

By treating compounds of the formula I with reactive cats of alkanols which contain a maximum of 6 carbon atoms, addition compounds arise which, depending on the meaning of the symbol R-, are to be understood as true quaternary ammonium salts, or but by their behavior towards weak bases such as silver hydroxide or sodium bicarbonate, as addition salts of an N-alkylated one Tetraazaphenalens must be understood. The latter applies when a tetraazaphenal is unsubstituted on the nitrogen atom of the formula I, in which R 1 is hydrogen, with an aforementioned reactive ester which is a lower alkylating agent, is implemented. Will be more than one equivalent of the alkylating agent used, a real quaternary ammonium salt is formed.

The reaction of the compounds of general formula I with a lower alkylating agent is advantageous in a lower one Alkanol made at elevated temperature.

Lower alkylating agents are alkyl halides and alkyl sulfates and dialkyl sulfates, the alkyl radicals of which have not more than 6 carbon atoms have in question.

With regard to the pharmacological properties of the compounds of the general formula I, among the acid addition salts of these compounds, those of particular interest are those which do not show any physiological intrinsic effects in the dosages in question. Suitable salts are e.g. B. the salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, ¹ -, Rcifu.-iLt i.iu; uire, malic acid., maleic acid, a ^ onir.-

Λ: .1 : WÜ! ■ .'--, 'WciU.lii.iurC.

Ü 0 3 8 ^; 0 / ^; υ i -ι BAD ORIGINAL

IUo ii .-. Chi'olcendon Bobeispiele explain the implementation of ".ιοί * eri'inCunjsßoaiässen processes , but are not intended to restrict the scope of the invention in any way. The temperatures are given in degrees Celsius.

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example 1

1,2,8,9-tetraα2aphenalen

A suspension of 11.7 g of 3-hydroxy-7-aldehydophthalide (melting point 127-133 °) in 390 ml of water is slowly mixed with 47 ml of hydrazine hydrate while stirring. First a yellow precipitate is formed but dissolves when the mixture is refluxed with stirring. After 66 hours of refluxing, the slightly cloudy, yellow solution is treated with animal charcoal and filtered while hot; then the clear yellow filtrate is allowed to cool in the refrigerator. The substance precipitates in hair-thin yellow needles that melt at 287-293 °. Yield 55 %. By recrystallization in water, absolute ethanol and again in water, analytically pure 1,2,8,9-tetraazaphenal is obtained, which sublimes at about 190-240 ° and decomposes at 294-298 °.

The starting material, 3-hydroxy-7-aldehydo-phthalide, was made

manufactured as follows:

bis-2.6- / ga-dibromomethyl) benzoic acid

a) A solution of "36 g of 2,6-diraethy! benzoic acid (prepared according to Berger and Olivier, Rec. Trav. Chim. 46, (1927) 600)," in 120 ml of carbon tetrachloride is poured into a 3-liter 3-liter Neck flask equipped with a magnetic stirrer, a reflux condenser, a dropping funnel and an empty wash bottle, which is followed by a wash bottle filled with water. The solution is to close to the boiling temperature and then it hitzt from a short distance with a 250 Watt ^tungsten: lamp illuminated. A solution of 75 g of bromine in 350 ml of _t - carbon tetrachloride is then added dropwise so that the reaction comes to a vigorous boil. During the 30 minutes it takes to add, sicftfßfgqpftSjßssflJfcff develops and imagines

BAD OR [GINAL

vöisser precipitation. After the addition has ended, you drive continue heating and stirring until development of Hydrogen bromide gas stops. The reaction mixture is then cooled, filtered and the precipitate washed several times

bis with carbon tetrachloride. Colorless 2,6- / Γα, α-dibromomethyl) benzoic acid with a melting point of 203-206 ° is obtained in 90 % yield.

S-hydroxy ^ aldehyde phthalide

b) To 600 ml of a stirred 5 # aqueous sodium

37.2 g of 2,6- / £ <x, α-dibromomethyl) benzoic acid are slowly added to biscarbonate solution. This mixture is heated on a steam bath until a clear solution is obtained. It is then cooled and acidified with concentrated hydrochloric acid. A white precipitate forms, the IR spectrum of which shows that it is not entirely * pure 3-hydroxy-7-aldehydo-phthalide. The aqueous mother liquors are continuously extracted with chloroform for 24 "hours. After the solvent has evaporated, another 2.57 g of the same semisolid material remain. The total yield is 82 % of theory. Recrystallization from benzene / hexane gives pure 3-hydroxy -i-aldehydo-phthalide as colorless crystals with a melting point of 127-133 °.

Ό. Example 2

To a stirred solution of 20 ml of hydrazine hydrate in

^b * S-

JJJ ISO ml of water are added and then 9.3 g of 2,6-Ao ^; , a-dibromiiethyl)

o *

«S ^ benzoic acid. The mixture is refluxed for 95 hours

is »; '

© 'heated, then treated with animal charcoal and filtered hot. At the m

· * Cooling down, yellow needles crystallize from the piltrate. These are filtered washed with water and over phosphorus pentoxide

BATH ORIGINAL

getrobl | net. This gives 2.17 g!, ^ Bj ^ -Tetraazaphenalen vom Melting point 294-298 ° (decomp.) Its IR spectrum with the corresponds to an authentic comparison sample.

Ila game 3

1,2,8,9-tetraazaphenals

150 mg of 8-aldehydeo-l (2H) -phthalazinone-hydraaone are dissolved in 130 ml of dimethylformamide and refluxed with exclusion of moisture for a long time. From the reaction solution samples were taken after 15, 45 minutes, 22 and 45 hours, the 1,2,8,9-tetra content by thin-layer chromatography azaphenals were examined. The longer the reaction time, the more 1,2,8,9-tetraazaphenal was present. This material can can be easily recognized in UV light thanks to its intense blue fluorescence. Its Rf value on Eastman Type K silica gel paper 301 R is 0.5 with dimethylformamide-benzene 5: 1 as solvent and 0.8 with methanol as the solvent.

The reaction described above works even if you use it in Dimethylacetamide executes.

The 8-aldehydo-l (2H) * | ihtbÄlazinon-hydrazone is as follows manufactured; '

a) W ■ -

Give V6 g. ^ Hy ^ pjqE-T ^ ii ^ eiiydophthalid (see Example Ib) to a solution before the XOQ otX lÖQ & igeft hydraainhydrate and 65 ml of water and the whole 3Q Hinutee boils at reflux. The hot solution is filtered off and left to stand in the refrigerator overnight. It caused {altarK? _Istallt} which is filtered off washed with water ^ ^ 4 mi wäh7ej J (Jr Stiaiden iei 40 ° dried in a vacuum. This gives 3.25 g Sutjetanj »chromatographically uniform

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BATH ORIGINAL

JiI I ·· · · »

• t rttf I ··

it I lilt 'I

... »: ·. lysonrules i:; L. A sample was gubied at 120 ° / 0.05 torr. The melting point of both sub], imi er tem and unsublimateda Material is 235 - 237 °. * * ·

Example 4

1,2,8,9-TetranzaPhenalen

The mixture is refluxed with stirring for 24 hours a solution consisting of 0.94 g of 8-aldehyde-l (2H) -phthalazinone in 10 ml of hydrazine hydrate and 100 ml of water. The hot, yellow solution is then filtered and allowed to cool, whereupon yellow crises

away

stalls fail. This is filtered, washed with water, dried and recrystallized from ethanol. You get so 0.70 g of golden yellow 1,2,8,9-tetraazaphenal, its IR spectrum with corresponds to that of comparison samples.

At spj el ft I «2« 8 »9-Tetraazaphenalen-hydrochlorld

170 mg of 1,2,8,9-tetraazaphenal are dissolved in 20 ml of warm 6N hydrochloric acid, and the yellow solution is evaporated off in vacuo. The residue is dissolved in methanol, treated with chloroform and again concentrated in vacuo. The solid residue is then rubbed in ether to which a little methanol has been added, and the crystals thus obtained are filtered off. This gives 0.3 g of hydrochloride which is recrystallized from methanol-acetone. The light yellow crystals melt in the range of 254-257 ° to solidify again and finally decompose at 293-297 °.

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Example 6

1.2 '.B ₁ 9-Tetraazaphenalen- methanesulfonic onate

5 ml of methanesulfone are added dropwise with stirring. acid to a suspension of 5.1 g of 1,2,8,9-tetraazaphenals in 125 ml of absolute methanol. The whole thing is then 20 minutes with one Stirred at a temperature of about 60 °, then cooled and filtered. If you add ether to the mother liquor, even more yellowish falls Material from. 6.7 g of crude material are obtained, which is recrystallized twice from dimethylformamide. The melting point of the pure 1,2,8,9-tetraazaphenalen-netha.nsulfonates is at 288-293 ° (decomposition).

Example 7

• l ^ .e ^ Tetraazaphenalen- malelnat

To a solution of 170 mg 1,2,8,9-tetraazaphenal in 10 ml of ethanol are added to a warm solution of 117 mg of maleic acid. in 10 ml of ethanol. The solution is left to react for a few minutes and then left in the refrigerator overnight. The raw one Product precipitates out as blackish yellow needles (189 mg). One crystallizes from ethanol and receives the 1,2,8,9-tetraazaphenalene maleate as yellow needles with a melting point of 150-151 °.

Bf-i game 8

1.2.8.9-Tetraazaphenal6n-metho.1odide. or 9-Methvl-9H.1.2.8.9- tetraazaphenalene hydroiodide

A mixture of 266 mg of 1,2,8,9-tetraazaphenals, 5 ml of ethyl iodide and 24 :: _ absciu-Lora methanol is heated to reflux with the exclusion of moisture, 21 lur.clen. The yellow one

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BATH ORIGINAL

Solution is then evaporated to dryness under vacuum - and it remains 47 5 mg solid residue which crystallizes from methanol will. 1,2,8,9-Tetraazaphenalen-raethojodid are obtained. than yellow Needles, melting point after 2 further recrystallizations from methanol 279-281 ·.

3example 9

1,2,8,9-tetraazaphenalenedesthoiodide. or 9-ethyl-9H-.1.2 _P 8.9- tetraazaphenalene hydroiodide

A mixture of 3.4 g 1,2,8,9-tetraazaphenals, 100 ml absolute ethanol and 10 ml of ethyl iodide are refluxed for 20 hours while stirring and excluding moisture. The yellow solution is evaporated to dryness in vacuo and the residue is crystallized from ethanol. 3.95 g of raw material are obtained in this way 1,2,8,9-Tetraazaphenalen-äthoj odid, which, after twice Recrystallize as analytically pure yellow naldes from the melting point 260-262 ° is obtained.

Example 10

1,2,8,9-tetraazaphenalen-isopropyl iodide salt. _t 9H- * 1,2,8,9 »· tetraazaphenalen-hydroiodide

A solution of 10 ml of 2-propyl iodide, 150 ml of isopropanol and 3.4 g of 1,2,8,9-tetraazaphenalen are heated to reflux for 48 hours with exclusion of moisture and stirring. Man then cools, filtered and the filtrate evaporated to dryness. .. The dark colored residue becomes crystal from methanol-ether! s ^ ert. The crystals obtained are dissolved in water,

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BATH ORIGINAL

filter j and the filtrate is evaporated to dryness. The residue is recrystallized again from methanol-ether and light yellow crystals with a melting point of 256-257 ° are obtained.

Example 11 9-MethYl-1.2.8 _T 9-tetraazaPhenalen

34 mg of silver nitrate are dissolved in a few drops of water and 10 ml of methanol are added. Then only 2 ml of 0.1-n Sodium hydroxide solution and then a solution of 62.4 mg of quaternary 1,2,8,9-tetraazaphenalene methqiodide added * A yellow precipitate forms quickly. The mixture is stirred for 20 minutes at 50 ° and filtered then several times to remove as much of the fine precipitate as possible. The filtrate is then evaporated to dryness and the residue is taken up in hot chloroform. The solvent is evaporated and the residue is rubbed with ether at. This gives 29 mg of 9-methyl-1,2,8,9-tetraazaphenalene as a red-orange substance which melts at 190-200 ° with decomposition.

Example 12

.2 ₁ 8 ₁ 9-

A solution of 1.7 g of tetraaaphenalene and 1.2 si of dimethyl sulfate in 50 ml is heated with the exclusion of moisture Methanol for 24 hours. The solvent is then evaporated off and the remaining oil is allowed to stand in the cold overnight. The crystals which have formed are filtered off and, after recrystallization twice from methanol-ethar, melts 1,2,8,9-Tetraazaphenalenium-niethosulfat at 202-204 °, The purity of the product was determined by thin film chromatography

0091597 203S BAD ORIGINAL

proven. ·

_β Κ. '' · ■ ι im

Example 13

1 _T 2> 8.9- Tetraagaphenalen-.hrdrochlorld

1, 2,8,9-1fetraazaphenalenium ethersulphate is suspended in an excess of 5% strength aqueous sodium bicarbonate solution and this suspension is extracted several times with chloroform. The chloroform extracts are combined and then extracted with 3N hydrochloric acid. The acidic solution is evaporated to dryness and the residue crystallizes from ethanol ether. Light yellow 9-methyl-1,2,8,9-tetraataphenalene hydrochloride which is obtained Melting 276-278 °. The structure was confirmed by an NMR spectrum.

The same product is obtained by treating 9-methyl-1,2,8,9-tetraazaphenalen with 6-n hydrochloric acid.

example 14th 1.1- or L.

A solution of 1.7 g of 1,2,8,9-tetraazaphenalene, 5 ml of dimethyl sulfate in 30 ml of methanol is refluxed for 16 hours. On cooling, a pale yellow solution is obtained, which is concentrated to a syrup. This is taken up in water and this aqueous solution is brought to dryness at 70 °. The residue is rubbed in methanol and gives yellow needle-shaped crystals which, after recrystallizing twice from methanol-water, melt at 337-340 °. In the NMR spectrum, 2 equivalent ¹ methyl groups can be read according to who-i ^ r, ν is ae; · structure.

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Example 15 ■ * '

g-methyl-l ^ .e ^ g-t.etraazaphenalen-metho.iodid

A solution of 460 mg of 9th-methyl-1,2,8,9-tetraazaphenalene ' in 35 ml of methanol and 2 ml of methyl iodide is excluded refluxed from moisture for 32 hours. It is then cooled and filtered. 151 mg of yellow crystals are obtained, which recrystallized in dimethylformamide. They melt under Decomposes at 313-314 °.

Example 16 5-methoxy-l _? 2 _t 8,9-tetraazaphenalene

10.4 g of 3-hydroxy-5-methoxy-7-aldehydophthalide (melting point 174 °) are suspended in 1200 ml of water and 120 ml of 100% hydrazine hydrate are added. The resulting yellow solution is refluxed for 16 hours. The still hot solution is filtered and 5.4 g of yellow precipitate precipitates from the filtrate on cooling and is triturated twice in hot ethyl acetate. What remains is then recrystallized from a solvent mixture consisting of 800 ml of ethanol and 50 ml of ethyl acetate. Finally, 1.55 g of 5-methoxy-1,2,8,9-tetraazaphenalen are obtained as pale yellow crystals with a melting point of 291-294 °, decomposition j yield 15.5 % of theory.

The 3-hydroxy-5-methoxy-7-aldehydophthalide used as starting material is prepared as follows: a) 4-methoxy-2,6-dibromomethy-benzoic acid &> 6.3 g of 4-methoxy-2,6- dimethylbenzoe $ & ure (m.p.,

σ Λ 6-148, prepared according to Fuson, Corse and Wölldon, J. Am »Chem ..

^ J-:, e.g. 61, (1941) 2645-8) in 450 ml of carbon tetrachloride and gives a solution in a three-necked flask equipped with a stirrer, condenser and a dropping funnel. The solution will be

BATH ORIGINAL

Heated with stirring to almost the boiling point, illuminated with a 250 watt tungsten lamp and finally a solution of 22.4 g (7.5 ml) of bromine; 100 toi carbon tetrachloride is added dropwise. After the addition, the mixture is left to cook for a further 2 1/2 hours. During this time a white precipitate forms. It is filtered and 15.68 g of 4-methoxy ^ 2,6- (dibromomethyl) benzoic acid are obtained as a pure white material with a melting point of 196 * 197 °. This yield is 90 % of theory. The melting point can be increased ^{to 201-202 p by further recrystallization in benzene.}

b) 3-Hydroxy-5-methoxy-7-aldehyde-phthalide

- bis-Man gives 99.2 g of 4-methoxy-2,6- ^ dibromomethyl) benzoic acid

to 1500 ml of 5 # sodium carbonate solution and heat the solution while stirring on a steam bath. The resulting yellow solution is filtered hot, cooled and acidified with 6N hydrochloric acid. Man thus receives 12.56 g of white precipitate, which melts at 164-166 °. By continuous chloroform extraction can from the mother liquor 2.5 g of material can still be obtained. Recrystallization from benzene gives a melting point of 174-175 °. Yield 36 ^ of theory.

Example 17

_r j fc methoxy-1,2,8,9 * t; e craazaphenalen- nfithanesulfonat ^ »· '2.7 g of 5-methoxy-1,2,8,9-tetraazaphenalen are suspended

φ! in 150 ml of absolute methanol and 5 ml of methanesulfonic acid are added.

ύ% The mixture is heated on a steam bath for 15 minutes, using ο

"A waxy yellow solution is obtained. On cooling, methanesulfo- '

of 5-methoxy-1,2,8,9-tutraazaphenalene as a pale yellow lower-i alag. Recrystallization from methanol gives colored needles which melt at 255-257 °. Yield 86 / yr.

BATH ORIGINAL

Example 18 S-Hvdrojicy-i ^^ e ^ -tetraazaDhenalen-hvdrobroinid

2, Og 5-methoxy-1,2,8,9-tetraazaphenalen are during 5 1/2 hours in 30 ml of 48 # hydrobromic acid at reflux touched. A clear solution was obtained after 4 hours and during a yellow precipitate formed over the next 11/2 hours. It is allowed to cool and then the hydrobromide des is filtered ö-Hydroxy-l ^ je ^ -tetraazaphenalens. Wash with acetone, dries over phosphorus pentoxide and receives 1.1 g of substance, which does not melt below 340 ° ι.

Example 19

5-Brpm-l ₁ 2 _T 8 _T 9 - tetraazaphen ^ len

To a solution of 150 ml of 100% hydrazine; hydrate in 1500 ml of water are added to 8 g of S-hydroxy-ö-bromo-T-aldehydophthalene. This reaction mixture is refluxed for 144 hours and stirred, then cooled and filtered. 4.8 g of a yellow precipitate are obtained, which one as well as possible in Dissolve about 250 al of hot glacial acetic acid and filter. The filtrate is then treated with 5% aqueous sodium carbonate solution until it's neutral. A precipitate separates out, which is filtered and then dissolved as well as possible in 600 ml of 6N hydrochloric acid will. After this solution has been filtered through a glass frit most of the impurities are eliminated. The filtrate is evaporated to dryness and the residue is evaporated with acetone

rubbed. This gives 2.3 g of substance, which in 400 ml of warm water be suspended and neutralized with SjCiger sodium carbonate solution will. It is filtered and the bottle is washed with water and acetone, dries and so holds 1.85 g of S-

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t · t ι »■■ ·

; -: · ..r.alen. This is after repeated cleaning in hydrochloric acid and Original recrystallize from a mixture of 500 ml Dime thy If ormamiö. and 1 l of ethanol were obtained as analytically pure, golden yellow "platelets" (1.03 g), which have a melting point of over 350 °.

The starting material, S-hydroxy-ö-bromo-T-aldehydophthalide is made as follows:

a) 2.29 g of 4-bromo-2,6-dimethylbenzoic acid (prepared according to Fuson, Scott and Lindsey J. Am. Chem. Soc. 63, (1941), 1679) are suspended in 120 ml of carbon tetrachloride and this reaction mixture is boiled under Stir at reflux while lighting with a 250 watt tungsten larape. A solution of 6.4 g of bromine in 30 ml of carbon tetrachloride is then added dropwise over the course of 20 minutes. After a further 15 minutes, a white precipitate begins to separate out. The reaction is allowed to run for a further 3 hours, then cooled and nitrated. The precipitate is washed with a little carbon tetrachloride and air dried. 4.8 g of white 4-bromo-2,6-dibromomethylbenzoic acid are obtained in this way, which after recrystallization from benzene emits noise at 219-221 °. Yield: 88 % of theory.

b) Ka :. add 10.9 g of 4-bromo-2,6-dibromomethylbenzoic acid ΙόΟ ml of 5j6 aqueous sodium carbonate solution and heat one half Hour on a water bath. A little white precipitate forms during heating, but it disappears again. the The solution is filtered hot, then cooled and treated with 6N hydrochloric acid j

acidified. The precipitate is filtered, washed with water \

i and dried under vacuum. 1.66 g of white 3-hydroxy-5-brora-7-aldehydophthalide are obtained with a melting point of 187-189 °, which is used further without further purification. By continuous chloroform extraction the mother liquors can still gain 0.54 g of substance will.

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- • 20 -

Example 20 S-bromo-l ^ .S ^ -tetraazaphenalen-hydrochloride

250 mg of crude 5-bromo-1,2,8,9-tetraazaphenalen are in Bring 6-N hydrochloric acid to the boil and filter to rid it of impurities. The filtrate is cooled and again filtered, then evaporated to dryness in vacuo. The residue is rubbed in acetone and crystallized. One filtered and washes the crystals with acetone and ether. This gives pale yellow S-bromine-1 ^ jS ^ -tetraazaphenalene hydrochloride, which is not melts below 340 °.

Example 21 5-Bromo-1 _T 2 _T 8 «9-tetraazaphenalenemethanesulfonate

125 mg of 5-bromo-1,2,8,9-tetraazaphenalene are suspended in 10 ml of absolute methanol and 0.2 ml of methanesulphonic acid are added. The reaction mixture is then refluxed for 5 minutes, filtered and allowed to cool slowly. It slowly crystallize small yellow crystals from solution. It is filtered and washed with cold methanol and these crystals are dried. The 5-bromo-1,2,8,9-tetraazaphenalen-methanesulphonate sdimilzt at 264-268 ° with decomposition.

Example 22 5> -n-butoxy-l, 2,8,9-teträazaphenal _r s

It is refluxed with stirring for 22 hours

until-

Mixture is obtained from 27.8 g of 4-n-butoxy-2,6- <pibromomethy: i) -foenzoe-7 acidic 130 ml hydrazine hydrate and 1300 ml v / water. The solution will be then filtered unity and the filtrate cooled. It occurs

009850/2096 ORIGINAL BATHROOM '

light yellow precipitate, which is filtered off, washed with water and is dried in vacuo. This crude product is chromatographed on an aluminum oxide (Woelm) degree of activity ΙΓ cleaned according to Brockmann. The solvent is chloroform. The fractions are analyzed for their Checked purity. The fractions which only contain pure 5-n-butoxy-1,2,8,9-tetraazaphenalene are combined, the chloroform is filtered off in vacuo, and the residue is triturated with ethyl acetate. The pale yellow substance melts at 229-237 °. The IR spectrum confirms the expected structure.

The 4-n-butoxy-2,6-dibromomethyl-benzoic acid is as follows

manufactured :

hisa) 4-n-butoxy-2 _< 6Hdibromomethyl! 0-benzoic acid

47.2 g of 4-n-butoxy-2,6-dimethylbenzoic acid (prepared according to Honkanen, Chem. Abstr. £ 5 (1961) 15400) are dissolved in 2b Carbon tetrachloride, refluxed with stirring and illuminated with a 250 watt tungsten lamp. To this solution is added dropwise a solution of 45 ml of bromine in 300 ml of carbon tetrachloride is added. After the addition is complete, the mixture is refluxed for a further 4 hours stirred further. It is then cooled, part of the solvent is distilled off under reduced pressure and finally left in Stand refrigerated overnight. A white precipitate forms, which is filtered, washed with carbon tetrachloride and poured over

; Phorphorpentoxyd is dried. This gives 24.4 g of crude

until-

4-n-Butoxy-2,6- (dibromomethy ^ -benzoic acid, which after two

Recrystallize from benzene as shiny white needles from the enamel * point 187-188 ° is obtained.

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Example, 23 ■

5-carboxy -1.2 «8.9-tatraazaphenalen

10.48 g of 4-carboxy-2,6- <dibromomethyD-benzoic acid methyl ester are suspended in 50 ml of 5% aqueous sodium bicarbonate solution and heated on the steam bath for 60 minutes. The solution is then filtered hot, the filtrate is cooled and acidified with hydrochloric acid. The acidic solution is then concentrated to half its original volume under reduced pressure and finally extracted continuously with chloroform for 24 hours. Concentrating the chloroform extract gives a solid white intermediate product that was used immediately.

1.3 g of this product are dissolved in 15 ml of 100% hydrazine hydrate and 150 ml of water and refluxed for 173 hours. The yellow solution is then filtered hot and cooled -and acidified with glacial acetic acid. 1.16 g of substance precipitate, which is filtered, dried and then dissolved in 100 ml of 5% sodium bicarbonate solution be solved. It is filtered through a. Glass frit and acidify the piltrate with glacial acetic acid. The precipitate is filtered, washed thoroughly with water and air dried. Man thus receives white 5-carboxy -1,2,8,9-tetraazaphenalen, which is over 340 ° melts. The NMR spectrum corresponds to the expected configuration.

The starting material can be made as follows:

Ms-

a) 4-Carboxy -2 _f 6-Λä ₁ α-dlbromomethyl) -benzoic acid methyl ester

10.4 g of methyl 4-carboxy-2,6-dimethylbenzoate (obtained according to Cachia and Wahl Bull. Soc. Chim. France 1958 _T 313) are dissolved in 700 ml of hot carbon tetrachloride, the solution is stirred and illuminated with a 250 watt tungsten lamp. A solution of 11 ml of bromine in 75 ml of carbon tetrachloride is then added dropwise

009850/2096 BAD ORlGJNAU

• ι ι - ie «

C * «ι - tr

. After the addition is complete, the mixture is stirred for a further 4 hours and on Boiled under reflux. Then it is allowed to cool and filtered. The precipitate is recrystallized twice from benzene-hexane and the Ester is made from srap in shiny white needles. 2115-213 °.

OQ985Q / 2t ^f 6

Claims (1)

Claims 1. Substituted 1,2,8,9-tetraazaphenalenes of the general formula I. (D in which R, hydrogen or a lower alkyl group with at most 6 carbon atoms and
R ₂ denotes hydrogen, a halogen atom, a hydroxy or lower alkoxy group with a maximum of 6 carbon atoms, or the carboxyl group, and their addition salts with inorganic or organic acids, and their addition compounds with reactive esters of alkanols containing not more than 6 carbon atoms. 2. 1,2,8,9-tetraazaphenals. 3. 1,2,8,9-Tetraazaphenalen-ethyodide or 9-ethyl-9H-1,2,8,9-tetraazaphenalen-hydroj odid. 4. 1,2,8,9-Tetraazaphenalen-isopropyl iodide or 9-isopropyl-9H-1,2,8,9-tetraazaphenalen-hydroj odid. 5. 9-methyl-9H-tetraazaphenalene. 6. 9-methyl-9H-tetraazaphenalene methoiodide. 7. 5-alkoxy-1,2,8,9-tetraazaphenals with a maximum of 4 carbon atoms in the alkoxy group. 8. 5-Hydroxy-1,2,8,9-tetraazaphenalene. 009850/2096 nw »uiiK * u * _. ν / j .. —_ BAD ORIGINAL 9. Process for the preparation of substituted 1,2,8,9-tetraazaphenalenes of the general formula I as defined in claim 1, their acid addition salts and their addition compounds with reactive esters of alkanols containing not more than 6 carbon atoms. characterized in that one (1) a connection of formula III (III) in which A ^{1 is} the formyl group or a functional derivative thereof, or the group -CH = NNH ₂ and R. and R _{2 have} the meaning given under formula I, heated with the at least equimolar amount of hydrazine hydrate, or that (2) if A ^{1 is} the group -CH = NNH ₂ , a sdbhes hydrazone is cyclized by heating, or that (i) for the preparation of a product of the formula I in which R, Hydrogen means a compound of the formula II 0OH (II) in which · A each denotes a formyl group or a functional derivative thereof, one group A together with the neighboring group Carboxyl group can be present as a hydroxylactone or a functional derivative thereof, and R _{2 has} the meaning given under formula I, heated with at least twice the amount of hydrazine hydrate, if desired (a) a product of the formula I in which R * is hydrogen, converted into a by treatment with a reactive ester of an alkanol containing at most 5 carbon atoms Salt of the formula I, in which R, a lower AikyL-1.-U ₁ .j.ο biHleutet, (1>) a product of the formula I, generally which R ^ a .ii, .- . · .Ν. Λϊ'χϋ. / Group means by hydrolysis id «i3 juCbprot i ~ 009850/2096 wο hydroxydorivat and (c) a product of formula 1 in an addition salt with an inorganic or organic acid or it is converted to the corresponding addition compound by means of a reactive ester of an alkanol containing not more than 6 carbon atoms implements. 14.170 / DAP / ms BATH ORIGINAL 001350/2098