DE2311510A1 - PROCESS FOR THE PREPARATION OF 1-HYDRAZINO-PHTHALAZINE.HYDROCHLORIDE - Google Patents

Description

Process for the production of 1- Hydrazino-phthalazin.Hydroch l orid

(Priority: July 20, 1972 - Yugoslavia - P 1833/72)

The present invention relates to the production of 1-hydrazinophthalazine hydrochloride the formula

H ₂ -HCl

This compound has a sympatholytic effect and will used in the treatment of various types of hypertension.

For the production of 1-hydrazino-phthalazin.Hydrochlorid were previously developed several methods, which, however, have a number of shortcomings.

The production is based on costly raw materials that are difficult to access or relies on expensive and specific equipment. The procedures described are mainly related on the reactions of the hydrazine with the substituted phthalazine or 1,2-disubstituted benzene.

The first group represents the methods which are used by 1-halogen, 1-mercapto- or 1-aminophthalazines or their common starting compound Running out of phthalazone (Helvetica Chimica Acta 34 (1959), 204j British Patent 629 177; U.S. Patent 2,484,029; Med.Prom. SSSR, 14 (1960) 2, 13-17? Acta Polon, Pharm. 11: 27 (1955); 3ap. Patent 5526 (154) etc. The phthalazone is produced by the reaction of phthalaldehyde acid, 3-broin-phthalide, 3-amino-phthalide or diphthalidyl ester with hydrazine hydrate (Beilstein's Handbook of Org.Chemie 24 12 and E II 24 70). An analog

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Production method based on phthalaldehyde acid derivatives, is in French patent 1,335,759 and still-at some References described. The common shortcoming of all of these methods is the extremely costly production of Phthalaldehyde acid or its derivatives.

There is a technically feasible way of producing this acid in the oxidation of ITaphthalene by means of potassium permanganate, whereby one has to use a six-fold excess by weight of the expensive potassium permanganate.

The other technically feasible syntheses of the starting materials such as phthalide or phthalimidine require complicated and expensive ones Apparatus, since the reactions are carried out by catalytic hydrogenation of the corresponding dioxo compounds in pressure vessels (Liebigs Annalen der Chemie, 574, 64 (151)

The second group of methods is the ^2-u-yano benzaldehyddiacetat (Brit. Patent 719,183), or α, α, α, α ', α'-pentachloropropane-xylene (double. "Patent 1,438,827), whose preparation is not easy is, · off.

It has now been found that the i-hydrazino-phthalazin.Hydrochlorid easily and in practically quantitative yield from the easily accessible i-hydrazino-4-chlorophthalazine by the Hydrogenolysis of the halogen is obtained when the !! ^ halogenation by means of molecular hydrogen in the presence of palladium as a catalyst according to the following reaction scheme

.HOl

is performed·

The process is carried out in such a way that the 1-hydrasino-4-halogenophthalazine dissolved or dispersed in water, lower alcohols or another advantageous solvent

3 0 S 8 8 5/1 3 9 1

and palladium on colloidal or inert support in the presence or absence of hydrohalic acid binders or, most advantageously, is hydrogenated with the addition of hydrochloric acid.

The hydrogenation is carried out at room temperature and normal pressure, to accelerate the hydrogenation also at elevated temperature and Pressure done. It is surprising that at a temperature of 80 ° 0 and a hydrogen pressure of 15 atm no side reactions take place because it is known that under similar conditions there is hydrogenolysis of the N-N bonds in such Compounds comes (Zymalkovski "Catalytic Hydrogenations im Organic-chemical laboratory ", Ferdinand Enke Verlag Stuttgart, 1965 pp. 304-313).

The starting material i-hydrazino-4-chlorophthalazine is according to following reaction scheme

obtained, i.e. through the reaction of the phthalic anhydride with ■ kydrazine hydrate is converted into a? 84% yield of 1,4-dihydroxyphthalazine obtained, which after chlorination gives the 1,4-dichlorophthalazine in a 90% yield. From the so 1,4-dichlorophthalazine produced is modified according to the Procedure described in Ηϊΐν. Chimica Acta, 34 (1959), 204, which synthesizes i-hydrazino-4-chlorophthalazine. To In this process the reaction is carried out with an eight-fold molar excess of hydrazine hydrate. The modified Process, i.e. by-the replacement of 5 & 0I ^ ydrazine hydrate by 1 mol of ammonia is the i-hydrazino-4-chlorophthalazine in 90% yield obtained.

Derageifiäss put the inventive method so? / Ie the Manufacture of the raw materials a technical progress ciar,

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because the above reactions proceed in simple apparatus of inexpensive raw materials, which the chemical industry produces in large quantities, can be carried out.

The method according to the invention is illustrated by the following examples explained:

, Example 1 *. . ·.-.-.

To a mixture of 8.3 g (41.5. M mol) of 1,4-dichlorophthalazine, 85 ml 96% ethanol and 3.5 ml of 25% aqueous ammonia are m at 60 ⁰ C 7 ml (about 140 mole ) Hydrazine hydrate was added dropwise. The mixture is then heated to boiling for 5 minutes and the i-hydrazino-4-chlorophthalazine is filtered off with suction.

The yield is 7.5 g (94 %) .

The resulting product is charcoal catalyst in 120 ml of methanol and 45 ml 0.5% i-ge hydrochloric acid in the presence of 1.0 g of 10? 6igen Pd / 4 hours at 5O ⁰ C and atmospheric pressure. The still warm mixture is filtered, the catalyst is washed with hot water, the combined filtrates are evaporated to a third of the original volume in vacuo and cooled, and the 1-hydrazinophthalazine hydrochloride which has crystallized out is filtered off with suction and dried at ^{105 ° C.} The yield is 6.9 g (91 ⁰ A), melting point 272-275 ° C (decomp.) «

Example 2

5.9 g (20 m mol) of i-hydrazino-4-chlorophthalazine are dissolved in 65 ml of methanol and 20 ml of 0.5 % strength hydrochloric acid in the presence of 0.5 g of 10 ^ strength palladium / carbon catalyst at 20 ^° C and 1 atm hydrogenated for 7 hours. After working up as in Example 1, 3 »3 g. 1-hydrazino-phthalazin.Hydrochlorid, mp. 271-274 ⁰ C is obtained.

Example 3

The 1-hydrazino-A- chloro-phthalazine as in Example 2 atm at a temperature of 80 ⁰ C and a hydrogen pressure of 15 half an hour hydrogenated. The yield of 1-hydrazinophthala.zin. Hydrochloric! is 3.5 g (90% of theory). 272-275 ⁰ C. m.p.

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Example 4

5i9 Si-hydrazino-4-chlorophthalazine are as in Example 3 in 85 ml of 70% methanol in the presence of 0.5 6 5% Pd / BaSO ^ catalyst hydrogenated for 2 hours.

The yield is 5.3 g (85 % of theory), Schiap. ⁰

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Claims (5)

"- ■ DA-9213 PATENT CLAIMS ' 1. Process for the preparation of 1-Hydrezino-phthalazin.Hydrochlorid, characterized in that the i-hydrazino-4-halogenophthalazine by hydrogenation on palladium catalysts in suitable solvents in the presence of binders for the resulting hydrohalic acid, or, most advantageous ^ with the addition of hydrochloric acid at a temperature of up to 80 ⁰ C and a hydrogen pressure of 15 atm is dehalogenated. 2. The method according to claim 1, characterized in that the catalysts used are colloidal or customary Palladium applied to the carrier can be used » 3. Process according to Claims 1 and 2, characterized in that the solvents used are water, methanol and other suitable solvents or their mixtures used v / ground, - 4. Process according to Claims 1 to 3, characterized in that the i-hydrazino-4-chlorophthalazine at room temperature and under normal pressure in methanolic hydrochloric acid in the presence of a 2-10? OIgen palladium / carbon catalyst hydrogenated vnlrd. 5. Process according to Claims 1 to 3, characterized in that the i-hydrazino-4-chloro-phthalazine in dilute methanolic hydrochloric acid on palladium catalyst? tor en is hydrogenated at a temperature of 80 ⁰ C. and under a hydrogen pressure of up to 15 atm. i 309885 / 13Ö1