DE1670160A1 - Process for the preparation of triazolo-tetrazolo-pyridazine derivatives - Google Patents

Description

C. P. Boehringer & Soehne

GmbH Mannhe im

1468

, Process for the preparation of triazolo-tetrazolo-pyridazine derivatives

The present invention relates to a process for the preparation of triazolo-tetrazolo-pyridazine derivatives Formula I.

(D,

in which X is a valence stroke or a vinyl group, Y is an oxygen or sulfur atom and

R is a hydrogen or halogen atom, a lower alkyl, alkoxy, alkyl mercapto or amino group, which optionally is substituted by lower alkyl or acyl radicals, mean.

It has been found that the substances I have a high germistatic effect. Because the substances are sometimes surprising have good antibacterial properties in the urine

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they are suitable for the treatment of urinary tract infections.

The process according to the invention for the preparation of the triazolotetrazolo-pyridazine derivatives I is characterized in that either in a known manner

a) Hydrazones of the general formula II

χ—

in which R, X and Y have the meaning given have and Z is hydrogen or a nitro group,

treated with oxidizing agents or b) Carboxylic acid hydrazides of the general formula III

(III),

in which R, X, Y and Z have the meaning given,

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optionally heated with the addition of a dehydrating agent, or

c) Amidrazones of the general formula IV

(IV),

in which R, X, Y and Z have the meaning given
to have,

optionally heated with the addition of an ammonia-binding agent, and in the event that Z is hydrogen, the substances obtained are subsequently nitrated in a manner known per se, the substances in which R represents an amino group optionally substituted by lower alkyl or acyl radicals, also subsequently converted into one another
will.

To carry out the process according to the invention, substances II are used with conventional oxidizing agents such as bromine,
Iron (III) chloride, etc. _t preferably with lead tetra-aeetat, in a suitable inert solvent, such as ethanol or glacial acetic acid, wherein the reaction is significantly accelerated by heating to about 100 °.

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The hydrazones II used as starting products are manufactured in the usual manner by condensation of aldehydes of the general formula V. '"

with hydrazines of the general formula VI

H ₂ N-HN- u

(VI)

manufactured.

The hydrazines VI are obtained by reacting 4- or 5-R-substituted ones J-chloro-o-hydrazino-pyridazines with aqueous nitrous Acid to the corresponding 6-chloro-tetrazolo- [l, 5-b] -pyridazines, which are converted into u-hydrazino-tetrazolo- [l, 5-b] -pyridazines by heating with hydrazine hydrate.

The inventive dehydrating cyclization of the substances III takes place in the simplest case by heating, in which case inert solvents are also used and the water formed can be trapped by a dehydrating agent, e.g. phosphorus oxychloride.

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The substances used as starting materials III are in the usual way by heating the hydrazines VI with acids of the general formula VII

- COOH (VII)

manufactured. Instead of the free acids VII, their reactive derivatives, for example the halides, esters, etc., can also be used. can be used. A particularly advantageous variant of the process according to the invention is that one on the isolation of the compounds III dispensed with and (optionally in the presence of a dehydrating agent) in a high-boiling inert Solvent heated until immediately the ring-closed Triazolo-tetrazolo-pyridazine derivatives are formed.

The inventive cyclization of the amidrazones IV can by simple heating, optionally in an inert solvent. By adding an ammonia-binding agent (especially a dilute acid) the reaction is significantly accelerated and can even be carried out at room temperature.

The amidrazones IV used as starting materials are obtained by reacting hydrazines VI with imido ethers of the general Formula VIII

(VIII)

manufactured. The reaction is preferably carried out in an inert solution

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solvents, such as aqueous alcohol, at room temperature or carried out at slightly increased temperatures.

Pur in the event that Z in substances II, III or IV is hydrogen means, the triazolotetrazolopyridazines formed are subsequently nitrated and thus converted into substances I. convicted. The nitration is preferably carried out in a solvent like acetic anhydride. In the event that R represents a free amino group, this is under the conditions mentioned acetylated, but at the same time protected from attack by the nitrating acid. The acetyl group leaves then, if desired, split off by saponification. Conversely, of course, in the case of substances I in which R is a means free amino group, R subsequently with a customary N-alkylating agent or N-acylating agent in an alkylamino- or acylamino group.

The process of the invention is shown in the examples below explained in more detail.

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example 1

3- (5-Nitro-2-furyl) -s-triazolo-C4, 3-b 1 -tetrazole) - [1 ', 5'-f k> yridazine

1 * 37 g of l- (5-nitro-2-furfurylidene) -2- (6-tetrazolo- [l, 5-b] -pyridazinyl) hydrazine are added in portions to a stirred solution of 3 * 34 g of lead tetra-acetate in 50% ml of glacial acetic acid at 80 ° C entered so that one always waits for the previous portion to dissolve until the next portion is added. The mixture is then stirred for a further 15 minutes at 80 ° C., the precipitated crystals are filtered off with suction from the cooled solution, washed with glacial acetic acid and dried. Yield: "0.9 [beta]> mp 185-188 ⁰ (dec.).

The 1- (5-nitro-2-furfurylidene) ~ 2- (6-tetrazolo- [l, 5-b] pyridazinyl) hydrazine used as the starting product is produced in the following way:

4 g of 3-chloro-6-hydrazino-pyridazine is suspended iiger in 32 ml 12> aqueous acetic acid, carrying with performing at 0 ⁰ C a solution of 1.84 g of sodium nitrite in 13 ml water was added dropwise a, stirred for about 15 minutes after, filtered off, washed with water, dried, and thus 3.5 e 6-chloro-tetrazolo [l, 5-b] pyridazine (mp. 107-109 ⁰ C).

1 * 55 G of this crude product are suspended in 3 ml of ethanol, are to 1.8 ml of 80 / Ages aqueous hydrazine hydrate and cook according to the violent reaction subsided, a further 1 hour under reflux. It is then evaporated to dryness in vacuo, the residue is rubbed with 3 ml of ice water, filtered off with suction and, after drying, 1.4 g of crude u-hydrazino-tetrazolo- [1,5-b] -pyridazine are obtained.

1 * 3 C 5-nitro-2-furfural are in 18 ml of 80 # aqueous ethanol dissolved, treated with 1.4 g of crude 6-hydrazino-tetrazolo- [l, 5-b] -pyridazine and refluxed for 1 hour. After cooling down

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167Ü160

-O-

the crystals obtained are filtered off with suction (2.3 g) by recrystallization from 9 ml of dimethylformamide, 1.8 g of 1- (5-nitro-2-furylidene) -2- (6-tetrazolo- [1,5-b] pyridazinyl) hydrazine are obtained (Foaming at 266-270 °). However, recrystallization is not suitable for further reaction with an oxidizing agent necessary; rather, the crude product can be used.

Example 2

3- [2- (5-Nitro-2-furyl) vinyl 1-s-triazolo- (4,3-b) -tetrazolo- P [l ', 5'-f3-pyridazine

1.2 g of 5-nitrofuryl-acrolein- (6-tetrazolo- [1,5-b] pyridazinyl) hydrazone one carries in portions with stirring in an 80 ° C solution of 3 * 6 g of lead tetra-acetate in 56 ml of glacial acetic acid so that the next portion is only added when the previous one has dissolved (entry time about 1 to 2 hours). As soon as the last portion is no longer clear, add another 0.6 g of lead tetra-acetate. After cooling down, this will be precipitated yellow crystals are suctioned off and 0.57 g of 3- [2- (5-nitro-2-furyl) vinyl] -s-triazolo- (4,3-b) -tetrazolo are obtained [1,5'-fJ-pyridazine, mp 210-212 ° C (foaming).

ψ The 5-nitrofuryl-acrolein- (6-tetrazolo- [l, 5-b] -pyridazinyl) hydrazone used as the starting product is produced in the following way:

2,26 o-Hydrazino-tetrazolo- [l, 5-b] -pyridazine is added to a hot solution of 2.5 g of β- (5-nitro-2-furyl) -acrolein in 28 ml of 80 t aqueous ethanol , then reflux for 2 hours. After cooling, the precipitated crystals are filtered off with suction, washed with ethanol and 3.9 g of 5-nitrofuryl-acrolein- (6-tetrazolo- [l, 5-b] -pyridazinyl) -hydrazori ^ after recrystallization from 20 ml of dimethylformamide are obtained foams at 26O ⁰ C.

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Claims (1)

Claim Process for the preparation of triazole-tetrazolopyridazine derivatives of formula I. (D, in which X is a valence stroke or a vinyl group, Y is an oxygen or sulfur atom and R is a hydrogen or halogen atom, a lower alkyl, alkoxy, alkyl mercapto or. Amino group, which optionally is substituted by lower alkyl or acyl radicals, mean characterized in that either a) hydrazones of the general formula II (II), in which R, X and Y have the meaning given and Z is hydrogen or a nitro group, 009845/1888 . treated with oxidizing agents or b) Carboxylic acid hydrazides of the general formula III (III), in which R, X, Y and Z have the meaning given to have, optionally heated with the addition of a dehydrating agent, or q) Amidrazones of the general formula IV in which R, X, Y and Z have the meaning given, 009845/1858 optionally heated with the addition of an ammonia-binding agent, and in the event that Z is hydrogen, the obtained substances subsequently nitrated in a manner known per se, the substances in which R is optionally is amino group substituted by lower alkyl or acyl radicals, also subsequently converted into one another will. C., 3 C.: -. "'58