DE2224382A1 - Allopurinol prodn - by hydrolysis of 4-chloro-pyrazolo (3,4-d)-pyrimidine - Google Patents

Abstract

Prepn. of 4-hydroxy-pyrazolo 3,4-d pyrimidine (allopurinol) (I) by subjecting 4-chloro-pyrazolo 3,4-d -pyrimidine (II) to alkaline hydrolysis in the presence of hydrogen peroxide. (I) is a known xanthine oxidase inhibitor useful in the treatment of gout. The hydrolysis proceeds almost quantitatively and yields a partic. pure product. The starting material (II) need not be isolated before hydrolysis to (I); in fact, the (II)-contg. reaction mixt. obtd. by the procedure of DT.1950076 can be used directly as the starting material.

Description

"Process for the preparation of 4-hydroxy-pyrazolo [3,4-d] pyrimidine" The invention relates to a process for the preparation of 4-hydroxy-pyrazolo / 3,4-d7pyrimidine, of the formula which is an important pharmacological agent as it inhibits the enzyme xanthine oxidase. This compound can thus be used as a remedy for gout.

There are already various processes for the preparation of 4-hydroxy-pyrazolo [3,4-d] pyrimidine became known. The oldest method is in the German patent specification 1 118 211. This process is carried out by 4-hydroxy-6-mercapto-pyrazolo / 3 , 4-d7pyrimidine reduced with Raney nickel. The exit prevention for this proceeding must be made by a rather complicated process so that this Procedure has not found its way into technology.

Another method for the preparation of 4-hydroxy-pyrazolo- / 3,4-d7pyrimidine is described in DT-AS 1 950 076. The procedure described there is thereby carried out that one 4,6-Diqhlor-5-formyl-pyrimidine in an inert solvent at Temperatures between -30 and + 10 ° C in the presence of a tertiary amine with hydrazine and the 4-chloro-pyraolo [3,4-d] pyrimidine obtained is heated with an alkali. The hydrolysis of that present in the 4-position of the pyrazolo [3,4-d] pyrimidine Chloratcms proceeds relatively slowly, since it is well known that the chlorine atoms, which are attached to aromatic Carbon atoms are bound only difficultly by means of hydrolysis by an OH group can be replaced. DT-AS 1 950 076 also states that this hydrolysis is carried out can be facilitated by the presence of mercaptoethanol. Dealing with Mercaptoethanol is, however, very undesirable, since this compound has an extraordinary effect Has an unpleasant odor.

The present invention was now based on the object of a method for the preparation of 4-hydroxy-pyrazolo [3,4-d] -pyrimidine from 4-chloro-pyrozole [3,4-d] pyrimidine that can be done quickly and easily. It was surprisingly found that the replacement of one of the 4-position of a pyrazolo [3,4-d] pyrimidine nucleus is easily replaced by alkaline Hydrolysis can be converted into a hydroxyl group if the hydrolysis is converted into The presence of hydrogen peroxide.

Thus, according to the invention, a method for producing 4-hydroxy-pyrazolo [3,4-d] pyrimidine by alkaline hydrolysis of 4-chloro-pyrazolo / 3,4-d7-pyrimidine proposed, which is characterized by being in the presence of hydrogen peroxide is working.

The reaction is almost quantitative and provides a special one pure product.

The method according to the invention can be used in a wide variety of media are listed. Aqueous alcoholic solutions have proven particularly valuable. Particularly a mixture of water and methyl alcohol is preferred as the reaction medium.

The hydrogen peroxide is preferably used in an amount that there are about 25-60 g / l H202 in the reaction mixture. When the invention The process is carried out in an alkaline medium. A wide variety of alkalis can be used be used. NaOH concentrations of 9 - 40 g / l have proven effective.

In the process according to the invention, it is advantageous to proceed in such a way that one the 4-chloro-pyrazolo / 3,4-d7pyrimidine dissolves in a mixture of methanol and water, whereupon an aqueous solution of hydrogen peroxide and sodium hydroxide solution is added.

The reaction temperature rises. External cooling prevents that the temperature of the reaction mixture is too high. Preferably she shouldn't rise above 500C. You can then stay at the same temperature for a while heat. By adding acid, especially hydrochloric acid, the product can be made from the Reaction solution to be filled out.

The process according to the invention for the preparation of 4-hydroxypyrazolo / 3,4-d / pyrimidine has another decisive advantage. That as the starting material too The 4-chloro-pyrazolo / 3,4-d7pyrimidine used does not need to be isolated Connection can be used, but it can be done directly after the first stage of the Process of the DT-AS 1 950 076 obtained reaction mixture, which 4-chloro-pyrazolo- / 3,4-d / pyrimidine contains, can be used as the starting material.

All that is needed is that obtained in accordance with the reaction stage mentioned Reaction mixture with. an aqueous solution of hydrogen peroxide and sodium hydroxide solution realize.

The mechanism of the reaction is likely to be similar to that of the so-called

RADZISZEWSKI reaction proceed (J. Org. Chem. 26, 659 (1961)).

Here nitriles react with alkaline hydrogen peroxide to form acid amides, oxygen and water: So it would have to be formulated: The invention will now be explained in more detail by the following examples.

Example 1 4-chloropyrazolo / 3,4-d7pyrimidine (1.54 g) prepared from 4,6-dichloro-5-formylpyrimidine and hydrazine according to DAS 1 950 075, is in 50 ml Suspended methanol, and while stirring, a mixture of 7 ml of 2N NaOH is slowly and 6.1 ml of 30% hydrogen peroxide were added, a clear solution being formed.

The mixture heats up to about 500 and is still about 1 hour at kept this temperature. A quantitative analysis of the solution using paper chromatography and UV measurement gives an allopurinol content of 1.32 g, corresponding to a yield of 96.5% of theory. After cooling, the mixture is carefully treated with 5N hydrochloric acid brought to pH 5, the product crystallizing out (1.1 g). Another 0.2 g will be obtained from the mother liquor.

Melting point? 3200; UV spectrum Amax 250 nm (0.1 N HC1) (£ = 7750); paper chromatography ' homogeneous.

Example 2 94 g of 4,6-dichloro-5-formylpyrimidine, prepared according to "Monatshefte für Chemie "96, 1507 (1965), are partially dissolved in 660 ml of methanol, partially suspended and the mixture brought to a temperature of 150 by means of a cooling brine.

34 pil hydrin hydrate (80%) are dissolved in 206 ml with stirring Methanol, and then 72 ml of diethylamine slowly added, the temperature of the reaction mixture is kept at 150. The 4,6-dichloro-5-formylpyrimidine goes into solution during the reaction and a crystalline product is obtained the end. The reaction mixture is now slowly heated to about 30 °, the formed precipitate dissolves. By measuring the UV spectrum (imax 262 nm) and Test by means of a thin-layer chromogram (silicate gel, chloroform / methanol = 95: 5, Rf 0.63) can easily be detected, since in the reaction mixture the quantitative The resulting compound 4-Cholorpyrazolo [3,4-d] pyrimidine is now present Reaction solution slowly with thorough mixing with a solution containing 370 ml of 30% hydrogen peroxide, 104 ml of 50% sodium hydroxide solution and 350 ml of water, added, with an increase in the temperature of the reaction mixture by external cooling prevented to over 500. Now it is slowly heated to approx. 600 and then still Boiled under reflux for 15 minutes. A sample analyzed after cooling results a content of 71.8 g of allopurinol in the total solution, corresponding to a yield of 98% of theory. 125 ml of 5N hydrochloric acid are now slowly added; where 62 Crystallize the product in pure form from the solution. The work-up the mother liquor he gives a further 19.1 g of allopurinol.

Claims (4)

P A T E N T A N S P R Ü C H Process for the preparation of 4-hydroxy-pyrazolo [3,4-d] -pyrimidine by alkaline hydrolysis of 4-chloro-pyrazolo- [3,4-d] pyrimidine, d a d u r c h it is not noted that one works in the presence of hydrogen neroxide. 2. The method according to claim 1, characterized in that it is in aqueous alcoholic solution, especially in aqueous methanolic solution, extracted will. 3. Verification according to claim 1 or 2, characterized in that a solution or dispersion of 4-chloro-nyrazolo- [3,4-d] pyrimidine is presented, and that an aqueous alkaline hydrogen peroxide solution at such a rate it is added that the reaction temperature does not rise above 50.degree. 4. The method according to claim 3, characterized in that the reaction mixture about 1 hour after the addition of the aqueous alkaline hydrogen peroxide solution is kept at a temperature of 500C.