DD276688A1 - PROCESS FOR PREPARING NEW 1,3,5-SUBSTITUTED 6-HYDROXYPYRAZOLO [3,4-B] PYRAZINE - Google Patents

Abstract

The process for the preparation of 1,3,5-substituted 6-hydroxypyrazolo & 3,4-b! Pyrazines (formula I) has the task of providing a technically uncomplicated and economically advantageous synthesis route, according to which these compounds which have fluorescence properties can be prepared , The object is achieved in a one-pot reaction by 1,3-substituted 4,5-diaminopyrazoles formed from 1,3-substituted 5-amino-4-nitrosopyrazoles by reduction in the form of a catalytic hydrogenation without isolation directly in the hydrogenation solution with a-Oxocarbonsaeurederivaten be condensed. The novel heterocycles are obtained after uncomplicated workup by crystallization in high yield and purity. Formula I

Description

wherein R ¹ and R ^{2 have} the above meaning, by catalytic hydrogenation in a polar protic solvent in 1,3-substituted 4,5-diaminopyrazoles of the general formula!

V \

in which R ¹ and R ^{2 have} the abovementioned meaning, which are reacted with α-oxocarboxylic acid derivatives of the general formula IV

R ³ -CO-COOR ⁴ IV

wherein R ^{3 has} the above meaning and R ^{4 is} an alkyl, cycloalkyl or aryl group, are reacted to the target compounds of formula I.

2. The method according to claim 1, characterized in that the Diaminopyrazolderiv / Ue of the general formula III required for the reaction are preferably used in the form of the hydrogenation solution of the compounds II filtered off from the catalyst.

3. The method according to claim 1 and 2, characterized in that the reaction of the Diaminopyrazolderivate of the general formula IH with the α-Oxocarbonsäurederivaten of the general formula IV takes place at room temperature.

4. The method according to claim 1,2 and 3, characterized in that platinum dioxide is used as the hydrogenation catalyst.

5. The method according to claim 1,2, 3 and 4, characterized in that as polar protisohes

¹ solvent for the catalytic hydrogenation and the subsequent reaction of the reactants a lower, water-miscible alcohol, such as. As methanol or ethanol is used.

Field of application of the invention

Dio invention has not yet produced an ancestor for the production of the so-called 1,3,5-substitiortor 6-hydroxypyrazolo | 3,4-blpyrozino. From the Litoretur it is notorious that pyrazolo | 3,4 | -condonsiorte hotorocyclone are by oino hoho fluoroszonzintonsity boi angewgung with ultraviolottor radiation gokonnzoichnot (II Gi indborg, SV Tabak, AN Kost, Zh. Obshch. Khim. 11963 |, 33, 525 ). Dio according to the invention Vorbondon bositzon Anwondungsoigonschafton as potontiollo Fluoroszonzfarbstoffo. .

Characteristic of the known technical solutions

From the literature compounds of the structure according to the invention (formula I) are not known. Structurally similar compounds of the pyrazolo [3,4-b] pyrazine type are described in two publications. First, these are 5,6-substituted derivatives having the same substituents in the 5,6-position as hydrogen, methyl and phenyl groups, or backbone of the 5,6-position via a carbocyclic (eg phenanthrene-) or heterocyclic (eg, tetrahydrofurane) -) system (i.I. Grandberg, GW Kluchko, Zh. Obshch. Khim. (1962), 32, 1898), whereby the pyrazolo [3,4-b | pyrazine system is prepared by condensation of The 4,5-diamino-3-methyl-1-phenyl-pyrazole is obtained by the classical reduction of 5-amino-4-nitroso 3-methyl-1-phenyl-pyrazole with zinc / hydrochloric acid according to Mohr (E. v. Mohr, J. Prakt., Former [19091, 79.1]). Isolate diamino compound in pure, solid form, are associated by their high susceptibility to oxidation and instability with considerable yield losses.In addition to the above reduction with zinc, this also applies to the described Re production methods of the nitroso compound with Ammoniumsulf'd (E.v.Mohr, ibid) and tin-Il-chloride / hydrochloric acid (A.Michaelis, H.Kiopstock, Liobigs Ann. Chem. [1907], 354, 103).

The decomposition phenomena of 4,5-aminopyrazoles also observed in our own work are typical of 1,2-diaminoazoles. Thus it is known that e.g. Also, 3,4-diamino-pyrazolin-5-ones are susceptible to oxidation (G.Weber, Diss. A, Karl Marx University Leipzig 1980). Synthesis attempts to obtain 1,3-substituted 4,5-diaminopyrazoles by reductive cleavage of the corresponding 5-amino-4-phenylazo precursors with stannous chloride / hydrochloric acid (A.Michaelis, et al., Ibid.) And with Raney nickel / hydrogen under overpressure (G.Rackner, J. Hoffmann, [Hoechst AG! DDR patent 152936 [1b811) are disadvantageous in that the cleavage aniline as an oily, difficult to separate and hinders the purification of the diamine byproduct is obtained , so that can not be dispensed with a costly, yield-reducing workup. In a second publication 1,5,6-substituted 3-methyl-pyrazolo [3,4-b] pyrazines are described (P.Giori, ACVeronese, T. Poli, CB Vincentini, M. Manfrini, M. Guarneti, J. Med Heterocyclic Chem. [1986], 23, 585). They are prepared either by reaction of 1-substituted 5-amino-4-nitrosopyrazoles with β-dicarbonyl or heterodicarbonyl compounds in anhydrous tetrahydrofuran with addition of sodium hydride or by reacting these carbonyl compounds with 1-substituted 3-methylpyrazolo [3,4-cl , 2,5] -oxadiazin-3 (5H) -one, which can be prepared from the above nitroso compounds with the extremely toxic diphosgene (Chlorameisensä'etretromlormethylester) synthesized.

Object of the invention

The object of the invention is to provide a process by which 1,3,5-substituted 6-hydroxypyrazolo [3,4-b] pyrazines can be prepared in a technically uncomplicated and economically advantageous manner.

Explanation of the essence of the invention

The invention has for its object to provide a synthetic route for 1,3,5-substituted 6Hydroxypyrazolo [3,4-b] pyrazines, according to which these heterocycles are industrially simple and economically advantageous to produce. The object is achieved according erfindungsgernäß in that a by catalytic hydrogenation of 1,3-substituted 5-amino-4-nitrosopyrazolnn of the general formula II,

where R ¹ and R ^? either an alkyl or an aryl radical, optionally substituted, means a solution of 1,3-substituted 4,5-diaminopyrazolone of the general formula I ¹ obtained in a polar protic solvent.

wherein R 'and R' are the same as BodouHing habon, with a-oxocurbone deodorant activation of the allgomoinone formula IV,

R ¹ CO-COOR ⁴ IV

wherein R ³ is oxyalkoxycarbonylmothylonyl, cycloalkoxycarbonylmothylonyl or aryloxycarbonylmothylonyl group or an alkylrost and R ⁴ oinoalkylcycloalkyldorarylgruppo bodouton, which is grafted to give 1,3,5-substituted 6-hydroxypyrraolo [3,4b] pyrene / ino the illgomoinon Formol I orhalton wordon,

in the R ¹ , R ^? and R ^{3 have} the above meaning.

It is surprising that it is the catalytic process! Hydrogenation makes it possible to produce virtually quantitatively the diamino compound of the formula III required for the reaction in a very short reaction time and high purity.

As a result, a variety of disadvantages of previously known synthesis methods are avoided.

There are no inorganic or organic by-products which would have to be separated off. The reaction proceeds very rapidly in polar protic solvents, but is not bound to absolute solvents. When using noble metal hydrogenation catalysts such as platinum dioxide, the reduction is gentle at room temperature and atmospheric pressure. The diamine is obtained directly in neutral to weakly acidic solution (methanol, ethanol, optionally mixed with acetic acid), without the need for elaborate extraction and IsolationsschriUe must be applied with pH change.

It is also surprising that the diamine-containing, filtered hydrogenation at room temperature with the a-Oxocarbonsäurederivaten according to formula IV quickly and in good yields to the target compounds (formula I). The inherent susceptibility to oxidation of the substance class can be excluded by the fact that the hydrogenation solution containing the diamine is filtered under vacuum into the solution of the second reactant and reacted immediately.

The 1,3,5-substituted-6-hydroxypyrazolo [3,4-b] pyrazines according to the invention are obtained in high purity after only one recrystallization, so that unambiguous analytical characterization and further use become possible.

The invention will be explained using exemplary embodiments.

embodiment

0.01 mol of the respective 1,3-substituted-5-amino-4-nitrosopyrazole be placed in 50 ml of ethanol and treated with 2 ml of acetic acid. The catalyst used is a spatula tip of platinum dioxide. After an average of 20 minutes, about 0.51 of hydrogen is absorbed. The finely divided platinum is filtered off under reduced pressure and the filtrate is added directly to the ethanolic solution of the second reactant (0.01 mol of the corresponding a-oxocarboxylic acid derivative). The reaction solution is stirred for 2 hours and the precipitated product is filtered off with suction. Concentration of the mother liquor provides further product. The entire residues are recrystallized from ethanol.

(e-hydroxy-S-methyl-i-phenyl-pyrazolol S-b-pyrazine-o-ylacetic acid methyl ester (R '= C ₆ H ₆ , R ^; = CH ₃ , R ³ = CH ₂ COOCH ₃ in formula!) Yield: 2 , 5g (84% of theory) mp 144-145 ° C

pale yellow crystals

(6-Hydroxy-3-methyl-1-phenyl-pyfazolo-3,4-blpyrazine-5-yl) -acetic acid ethyl ester (R '= C ₆ H ₆ .R ^? = CH ₃ , R ³ = CHjCOOCjH ₅ in formula I) Yield: 2.6 g (83% of th.) M.p. 145-146 ° C

yellow crystals

Claims (1)

1. A process for the preparation of novel 1,3,5-substituted-6-hydroxy-pyrazolo [3,4-b] pyrazines of general formula I, in which R ¹ and R ^{2 are} either an alkyl radical or an aryl radical, optionally substituted, and R ^{3 is} an alkoxycarbonylmethylene, cycloalkoxycarbonylmethylene or aryloxycarbonylmethylene group or an alkyl radical, characterized in that 1,3-substituted 5-amino-4-nitrosopyrazoles of the general formula II 2