DE1950076C2 - Process for the production of 4-hydroxy-pyrazolo- square bracket to 3,4-square bracket to pyrimidine - Google Patents

Description

30th

The invention relates to a process for the preparation of 4-hydroxy-pyrazo! O [3,4-d] pyrimidine of the formula

OH

NN
H

35

40

Which is an important pharmacological agent, because it inhibits the enzyme xanthine oxidase. This compound can thus be used as a remedy for gout will.

According to German patent specification 11 18 211, mon can produce 4-hydroxypyrazolo [3,4-d] pyrimidine by reducing 4-hydroxy-6-mercapto-pyra7olo [3,4-d] pyrimidine with Raney nickel. The starting compound for this process has to be prepared by a rather complicated procedure. The process for the preparation of this starting compound is given in German patent 10 67 030. According to this patent specification, pyrazole-3,4-dicarboxylic acid is first converted into the corresponding diacid chloride with thionyl chloride, whereupon the diacid chloride is reacted with ammonia to form pyrazole-3,4-dicarboxamide. The latter is oxidized with alkaline sodium hypochlorite to give 4,6-dihydroxypyrazolo [3,4-d] pyrimidine. Selective conversion of the hydroxyl group in the 6-position by means of phosphorus pentasullide leads to J ₁ IMn to the starting material for the process mentioned in the introduction, namely 4-hydroxy-6-mcrcaptopyrazolo [3,4-d] pyrimidine. The last-mentioned stage in particular creates difficulties, since the 4-position hydroxyl group can also be converted into a mercapto group on treatment with phosphorus pentasulfide.

According to one in Journ. At the. Chem. Soc, 78 (1956); P. 784 ff., The method described can be 4-hydroxy-pyrazolo [3,4-d] pyrimidine produce by using ethoxymethylene malbendinitrile with hydrazine reacted, initially 3-amino-4-cyanpyrazoI receives. Treatment of this product with sulfuric acid results in hydrolysis of the cyano group to the carboxamide group, so that 5-Am] no-4-carboxamidopyrazole is formed. The reaction of this product with Formamide gives 4-hydroxy-pyrazoio [3,4-d] pyrimidine. The compound produced by this process is heavily contaminated by by-products and can only very cumbersome and with loss to be cleaned. Especially during the implementation of ethoxymethylene malononitrile with hydrazine, heavily contaminating by-products are produced Cause skin inflammation. Because of the therapeutic use of this compound for long-term therapy in gout, however, the highest purity of the substance must be required.

In French patent specification 12 34 107 a process for the preparation of 4-hydroxy-pvra'olo- [3,4-d] pyrimidine is disclosed described, in which ethoxymethylene cyanoacetic ester is reacted with hydrazine and that 3-Amino-4-carbethoxy-pyrazole obtained cyclized with formamide at 190 to 200.degree. These process steps must produce the ethoxymethylene cyanetate from cyanoacetate and ethyl orthoformate go ahead, so that the method is a three-step process, which also does not involve simple starting substances work.

The French patent specification 15 59 613 describes a process for the preparation of 4-hydroxy-pyrazolo [3,4-d] pyrimidine via the method already mentioned in the above-mentioned publication in Journ. At the. Chem. Soc, loc. Cit., Mentioned intermediate 3-amino-4-carboxamidopyrazole. Starting from formamidine and cyanoacetamide, 3-amino-2-cyanoacrylamide and its reaction with hydrazine in two stages to S-amino ^ -carboxamido-pyrazole, so that the process is a three-stage synthesis with a total yield of 51.5 ° _o represents. However, this process can hardly work economically, since the starting substances formamidine and cyansicetamide are by no means easily accessible. In particular, the production of formamidine is very difficult and expensive

The aim now is the present invention underlies a process for the preparation of ^ -hydroxypyrazolo [3,4-d] pyrimidine to create which is more economical and easier to carry out.

It was found that the desired 4-hydroxy-pyrazolo [3,4-d] pyrimidine is much easier to obtain, if one assumes a connection with a finished pyrimidine structure and the pyrazole core on it condensed.

The invention thus relates to a process for the preparation of 4-hydroxy-pyrazolo [3,4-djpyrimidine, which is characterized in that 4,6-dichloro-5-formyl-pyrimidine is rlnPi in an inert solvent at temperatures between -30 and | 10 ¹ C, preferably between -20 and OC, in particular between -15 and -10 ⁰ C, in the presence of a generic amine is reacted with hydrazine and the 4-chloro-pyrazolo [3,4-d] pyrimide obtained is heated with an alkali.

The starting material for the invention Process, namely 4,6-dichloro-5-formyl-pyrimidine,

can be obtained by a simple process. The reaction is preferably carried out under an inert

carried out in the monthly magazine for chemistry, 96 (1965), p. 1567, atmosphere.

is described. According to this process, 4,6-di- It would theoretically also be possible to manufacture

hydroxypyrimidine at the same time as phosphorus oxychloride of 4-hydroxy-pyrazoIo [3,4-djpyrimidins von 4-Hy-

Ride and dimethylformamide reacted, starting with the 5-droxy-S-formyl-o-chloro-pyrimidine and the-

4,6-DichIor-5-formyi-pyrimidine in high yield ses to implement with hydrazine. Try in this

(about 80%). However, the starting point for this direction proved to be a failure.

Stage, namely 4,6-dihydroxypyrimidine, can easily be obtained if one tries 4,6-dichloro-5-formyl-pyrimidine

from malonamide and formamide in a yield of hydrazine under the usual reaction conditions

96 "·" are produced. Io to implement, one gets a complicated reaction

As a solvent for the first stage, the mixture of components can be used inert solvents are used, in which cyclization and substitution between the, such. B. methanol or other primary, secondary the hydrazine and the 4- and 6-Steüungen of the Pyri- or tertiary alcohols, acetone or other low-midins have taken place.

molecular ketones, as well as other common 15 under the conditions of the claimed solvent, like methylene chloride or Tetiahydro- driving, namely Lei lower temperatures and in furan. Presence of a tertiary amine, reacts against it

The hydrazine is preferably used as, surprisingly, only one chlorine atom of the 4,6-di-

Hydrazine hydrate, which in one of the above chloro-5-formyl-pyrimidines with the hydrazine, and the

specified solvent is dissolved. ao ring closure between the 4- or 6-position of the pyrimic

Examples of tertiary amines, the dins for the first stage and the formyl group present in the 5-position

can be used are: trimethylamine, occurs. The reaction proceeds with high yields.

Triethylamine, dimethylaniline and pyridine. The invention is illustrated by the following examples

The 4,6-dichloro-5-formyl-pyri- is preferably explained in more detail,

midin at the 1st stage drop by drop with a hydrazine 25

solution added to a local hydrazine over- Example 1
avoid shot. A local excess of hydrazine

could result in the formation of products. To 7.04 g (0.040 mol) 4,6-dichloro-5-formyI-pyrimi-

in which both chlorine atoms of 4,6-dichloro-5-formyldin are in 150 ml of methanol under nitrogen

pyrimidine reacted. 30-15 ° C for 15 minutes 2.56 ml 80% hy-

The tertiary amine can mi; the 4,6-dichlorodrazine hydrate (0.040 mol), dissolved in 22.5 ml of methanol,

5-formyl-pyrimidine are presented. But it has also been added dropwise. Then 5.6 ml of triethylamine (0.040

possible, the tertiary amine added slowly at the same time with the mole) in 10 ml of methanol, whereupon the

Add hydrazine or later. The reaction mixture is kept at -15 ° C for 15 minutes. The

If the mixture is at a temperature of -15 ° C, it is about 15 to 35 ° C and allowed to warm to + 20 ° C in 60 minutes.

60 minutes to complete. After the reaction, the methanol is then evaporated off in vacuo,

the mixture slowly, e.g. B. for one hour, 50 ml of 2N sodium hydroxide solution are added to the residue

warm to room temperature. (0.100 moles) are added and the mixture is allowed to cook for 1 hour

The solvent can be kept ^{at 100 ° C. for the second stage.} The mixture is neutralized beforehand by evaporation, if necessary under concentrated hydrochloric acid and evaporated under reduced pressure. It is not necessary to dry it out. The residue is washed well with water 4-chloro-pyrazo! O [3,4-d] pyrimidine from the reaction and recrystallized from hot water, the mixture is separated off before the reaction with the resulting 4.0 g (0.030 mol) of 4- Hydroxy-pyrazolo liquor to 4-hydroxy-pyrazolo [3,4-d] pyrimidine before [3,4-d] pyrimidine. The yield is 74% of that taken. Implementation of the 4-chloro-pyrazolo- 45 theory. λ _ηιαχ 250 nm (n / 10-HCl); F.> 360 ° C.
[3,4-d] pyrimidine to the corresponding 4-hydroxy compound proceeds particularly smoothly when working in the presence of mercaptoethanol. Especially with example 2
the latter operation is a prior separation
of the solvent unnecessary. 50 Example 1 is repeated, but after the

For the second stage, 2 N sodium hydroxide solution can be added to the reaction mixture with 120 ml Excess are added, whereupon the mixture 2 η sodium hydroxide solution and 2.8 ml of mercaptoethanol are added

^{is held at 100 °} C. for about 1 hour. On acidification and the mixture falls for 2 hours while being turned off, the desired 4-hydroxy-pyrazolo [3,4-d] flow is heated. After cooling it is acidified, pyrimidine out. The product can also be passed through. 4.5 g (0.033 mol) of 4-hydroxy-pyrazolo absorption on activated charcoal and subsequent elution with [3,4-d] pyrimidine are obtained. The yield is 82 " _o

Isolate aqueous ammoniacal methanol. Theory. X _ma z 250 nm (n / 10-HCl); F.> 360 C.

Claims (5)

Patent claims: 1. A process for the preparation of 4-hydroxypyrazolo [3,4-d] pyrimidine, dadurchgekenn-ζ eich η et that 4,6-dichloro-5-formyl-pyrimidine in an inert solvent at temperatures between -30 and +10 ⁰ C is reacted with hydrazine in the presence of a tertiary amine and the 4-chloro-pyrazolol3.4-d] pyrimidine obtained is heated with an alkali. 2. The method according to claim 1, characterized in that the hydrazine is used in the first stage in dissolved form the ^ o-dichloro-S-formyl-pyrimidine adding dropwise, then adding the tertiary amine and then slowly bringing the mixture to room temperature warmed up. 3. The method according to claim 1 or 2, characterized in that the second stage is carried out in the presence of mercaptoethanol. * ° 4. The method according to claim 1 to 3, characterized in that the first stage at a Temperature between -20 and 0 "C performs. 5. The method according to claim 1 to 4, characterized in that the first stage at a * 5 Temperature between -15 and -10 C carries out.