DE3036390A1 - Antiinflammatory intermediate 7H-pyrrolo-(2,3-D)-pyrimidine derivs. - prepd. by dealkylation of 7-phenyl:ethyl derivs. by reaction with hydrochloric, phosphoric or poly:phosphoric acid - Google Patents

Abstract

derivs. (I) are new, (where R is H, amino, OH, halogen, SH, alkylmercapto, alkoxy, alkylamino, aralkylamino, arylamino, or furfurylamino, the alkyl residues, opt. being substd. by halogen and the aryl residues opt. being substd. by halogen, alkyl, CF3 or alkoxy; and R1 and R2 are alkyl, phenyl, or phenyl substd. by halogen, CF3, alkyl or alkoxy, or R1 and R2 together represent a 2-5C alkylene chain opt. substd. by alkyl). The new cpds. are useful as intermediates for biologically active substances, esp. anti-inflammatory agents.

Description

New pyrrolo-pyrimidines,. Process for their manufacture

and their use in the manufacture of biological agents The present invention relates to a new chemically unique process for Production of new pyrrolo-pyrimidines which are used as intermediates for the synthesis can be used by biological agents, in particular by anti-inflammatory drugs can.

It has already become known to use secondary or tertiary amines debenzylate or dealkylate. These reactions are usually based on the Hydrogenolysis with palladium catalysts or on the reduction with sodium in liquid Ammonia (F.W. Korte, Methodicum Chimicum, 6, p. 598 (1974)). When the amine component of a heterocyclic system, these usual processes lead to those previously known Cases not successful (T. Denzel, Arch. Pharm. (Weinheim) 307, 177 (1974) and J. Chem. Soc. Perkin 1, 1979, 938-942).

It is also known compounds with a heterocyclic amine moiety defurfurylate with selenium dioxide or with polyphosphoric acid (T. Denzel ot al, Arch. Pharm. (Weinheim) 309, 486 (1976)), Pyrrolo- * Pyrimidines, in position 7 are benzylated or furfurylated, however, can be according to these known processes do not dealkylate in useful yields.

Other pyrrolo-pyrimidines are already available as natural products and as synthetic compounds prepared become known (E.C. Taylor et al, J. Am. Chem. Soc. 86, 951 (1964)).

The present invention relates to new pyrrolo-pyrimidines of the general formula I. in which R stands for hydrogen, amino, hydroxy, halogen, mercapto, alkylmercapto, alkoxy, alkylamino, aralkylamino, arylamino or furfurylamino, the alkyl radicals mentioned being optionally substituted by halogen, and the aryl radicals mentioned being optionally substituted by halogen, alkyl, Trifluoromethyl or alkoxy, and R1 and R2 are identical or different and each represent alkyl or phenyl, which is optionally substituted by halogen, trifluoromethyl, alkyl or alkoxy, or together represent an alkylene chain having 2 to 5 carbon atoms, which is optionally substituted by alkyl is.

Compounds of the general formula are of particular interest I in which R stands for hydrogen, amino, hydroxy, chlorine, bromine, mercapto, alkoxy with 1 to 4 carbon atoms, alkylamino or alkyl mercapto each with 1 to 4 carbon atoms in the alkyl groups or for a furfurylamino, benzylamino or phenylamino radical stands, which is optionally replaced by halogen, trifluoromethyl, alkyl or alkoxy with each 1 to 4 carbon atoms is substituted and R1 and R2 are identical or different are and each represent alkyl having 1 to 4 carbon atoms or phenyl or together represent an alkylene chain with 3 to 4 carbon atoms.

The invention also relates to a process for the preparation of pyrrolo-pyrimidines of the general formula 1, in which pyrrole derivatives of the general formula II in which R1 and R2 have the meaning given above, with formic acid derivatives of the general formula III in which R 'stands for an amino group or a hydroxyl group, are reacted in the presence of formic acid and optionally in the presence of inert organic solvents at elevated temperature to give substituted pyrrolo-pyrimidine derivatives of the general formula IV in which R ', R1 and R2 have the meaning given above, characterized in that the compound of the general formula In with an excess of acids from the group of concentrated hydrochloric acid, phosphoric acids or polyphosphoric acid at temperatures between 200C and 1500C, optionally in the presence of Water dealkylates, and optionally the compounds obtained, in which R 'is a hydroxyl group, reacts with phosphorus oxychloride, and the resulting chloride is converted by known methods with amine compounds or thiocarboxyl compounds to give the corresponding amino and mercapto derivatives of the substituent R of general formula I.

The last step is only required if the substituent R in the general formula I has a meaning other than hydroxyl or amino. The implementation takes place analogously to that of J. F. Gerster et al. J. Med.

Chem. 10, 326 (t967).

A particularly advantageous method consists in the use of Polyphosphoric acid in the dealkylation step.

The reaction temperature can be varied within a range of 100%. In general, between 20 and 100.degree. C., preferably between 50 and 100.degree. C., are used.

When carrying out the dealkylation, the one in question is used Acid in large excess. Preferably, 1 part by weight of the pyrrolo-pyrimlt is used compound of the general formula IV the acid in question in an excess from 2 to 25 cow tons, in particular from 5 to 10 parts by weight, are used. The reaction can, depending on the type of acid used, either in suspension or in solution be performed.

Working up is carried out in the customary manner by diluting the reaction mixture with water and subsequent neutralization with a base, preferably with alkali hydroxides or with concentrated ammonia solution. Then the deposited precipitate from suitable inert organic solvents, which optionally with water are mixed, crystallized. Suitable inert solvents are, for example called, hydrocarbons such as toluene, benzene, petroleum ether, alcohols such as methanol, Ethanol or butanol.

The present invention also relates to the new substituted pyrrolo-pyrimidine derivatives of the general formula IV in which R ', R1 and R2 have the meaning given above.

These compounds of the formula IV have not yet become known, can, however, be prepared in a simple manner by the above-mentioned process will.

With knowledge of the state of the art, it could not be expected that the phenylethyl group changes from the 7-position when exposed to acids of the pyrrolo-pyrimidine ring in yields of more than 80% of theory let. With regard to the experiences of F.-W Korte, (Methodicum Chimicum 6, p 598, (1974)) debenzylation with polyphosphoric acid is not easily possible. Such debenzylations can be carried out hydrogenolytically in some cases perform relatively low yields. A hydrogenolytic dealkylation of the However, general formula IV could not be carried out. The state of the art thus gave no indication of the method according to the invention. One would rather have have to expect that with the sometimes quite high reaction temperatures by the The presence of strong acids opens or at least opens the heterocyclic ring system changed. It is to be described as extremely surprising that one goes through the dealkylation according to the invention the new compounds of the general formula I in very high Purity and in a yield that is clearly above 80 * based on theory.

In the preparation of compounds of the general formula IV in which R 'hydroxyl is useful as a reactant of the general Formula III to use formic acid in a 10 to 30 molar excess. In the preparation of of compounds of the general formula IV in which R 'denotes an amine group, formamide (III) is preferably used in an appropriate excess.

The pyrrole derivatives of the formula used as starting compounds II can be prepared by known methods by condensation of hydroxy ketones such as benzoin, acetoin or adipoin with the amine of phenylethyl in the presence of catalytic amounts of a strong acid such as hydrochloric acid or p-toluenesulfonic acid, at elevated temperature to oC -aminoketones. These cr -amino ketones are subsequently condensed with malononitrile to give the compounds of general formula II. It has been found that the use of D- or L-phenylethylamine without Influence on the condensation reaction. Appropriately, therefore, the racemate can be used.

The pyrrole derivatives of the general formula II are worked up according to known methods by evaporation of the solvent and recrystallization the residue from suitable solvents.

The Pyrrolo-Pyrimidlnderivate of the general formula IV are so far not yet known. However, they can be according to the reaction scheme given above by reacting the pyrrole compounds of the formula II with formic acid derivatives of Formula III in the presence of inert organic solvents, in particular of Dimethylformamide, obtained at temperatures between 80 and 1300C. The isolation The compound of the formula IV is worked up by customary methods Precipitation in the cold, filtration and recrystallization from suitable solvents.

The invention. Compounds of general formula I represent valuable starting products for the synthesis of biologically active ingredients, in particular anti-inflammatory drugs and substances that have an effect on the central nervous system from them can be in a simple manner by substitution of nitrogen in the 7-position different pyrrolo-pyrimidine derivatives with valuable properties (see DT-OS 28 18 676).

In addition to their properties as starting materials for chemical syntheses The compounds of general formula I themselves have valuable pharmacological properties Properties. You have e.g.

anti-inflammatory effect and are therefore suitable for manufacture of pharmaceutical preparations.

The following examples are intended to explain the invention without illustrating it restrict.

Examples of the preparation of compounds of the general formula I 1) 4-Amino-5,6-dimethyl-7H-pyrrolo [2,3-d] -pyrimidine 5.32 g (0.02 mole) 4-amino-5,6 dimethyl-7H-7-phenylethylpyrrolo [2,3-d] pyrimidine are dissolved in 80 g of polyphosphoric acid stirred at 600C for three hours. After hydrolysis with water, it is concentrated with Ammonia solution -neutralized. The. precipitated crystals are washed with water and recrystallized from ethanol.

Melting point 2810C, yield 4.55 g (93.6% of theory) analogous to that above Example described was prepared: 2) 4-Amino-5,6-diphenyl-7H-pyrroloL2,3-41pyrimidine M.p. 3260C, yield 4.6 g (81.3% of theory) 3) 4-hydroxy-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine Mp. 362 "C, yield 3.10 g (95.1% of theory) 4) 4-Hydroxy -., 6-tetramethylene-7H-pyrroloE, 3-d7pyrimidine M.p. 2970C, yield 1.45 g (76.7 * of theory) 5) 4-hydroxy-5,6-diphenyl-7H-pyrrolo [2,3-d] pyrimidine Melting point 3650C, yield 1.95 g (67.9 of theory). Example 6 4-Chloro-5,6-dimethyl-7H-pyrrolo [2,3-d] -dpyrimidine 1.83 g (0.01 mol) of 4-hydroxy-5, 6-dimethyl-7H-pyrrolo 2,3-d, 7-pyrimidine are refluxed for four hours in 30 ml of phosphorus oxychloride. After cooling down the excess solvent is drawn off in vacuo and the residue is hydrolyzed and recrystallized from ethanol.

Melting point 2480C, yield 1.4 g (77.3% of theory). Example 7 4-Benzylamino-5,6-dimethyl-7H-pyrrolo [2,3] pyrimidine 1. 81 g (0.01 mol) of 4-chloro-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine will. refluxed in an excess of benzylamine for five hours Crystals which precipitate on cooling are recrystallized from ethanol.

M.p. 2120C Yield 1.7 g (67.9% of theory) Example 8 4-Mercapto-5,6-dimethyl-7B-pyrrolof2,3-dg-pyrimidine 1.81 g (0.01 mol) of 4-chloro-5,6-dimethyl-7H-pyrrolo [7,3-d] pyrimidine are treated with a Excess thiourea in ethanol refluxed for four hours. The at Crystals which precipitate when cooling down are recrystallized from ethanol.

Mp. 3150C Yield 1.30 g (66.4% of theory) Example 9 4-Furfurylamino-5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine 1.81 g (0.01 mol) of 4-chloro-5,6-dimethyl-7H-pyrrolo), 3-dZpyrimidine are mixed with a Excess furfurylamine in ethanol refluxed for five hours. The at Crystals which precipitate when cooling down are recrystallized from ethanol.

Mp. 199 ° C, yield 1.4 g (57.9% of theory) Analogue of the compound described above was prepared: Example 10 4- (p-bromoanilino) 5,6-dimethyl-7H-pyrrolo [2,3-d] pyrimidine Mp. 3080C, yield 1.9 g (60.9% of theory)

Claims (8)

Claims 1. Pyrrolo-pyrimidines of the general formula I in which R stands for hydrogen, amino, hydroxy, halogen, mercapto, alkylmercapto, alkoxy, alkylamino, aralkylamino, arylamino or furfurylamino, the alkyl radicals mentioned being optionally substituted by halogen, and the aryl radicals mentioned being optionally substituted by halogen, alkyl, Trifluoromethyl or alkoxy, and R1 and R2 are identical or different and each represent alkyl or phenyl, which is optionally substituted by halogen, trifluoromethyl, alkyl or alkoxy, or together represent an alkylene chain having 2 to 5 carbon atoms, which is optionally substituted by alkyl is. 2. Compounds of general formula I according to claim 1 in which R for hydrogen, amino, hydroxy, chlorine, bromine, mercapto, alkoxy with 1 to 4 carbon atoms, Alkytamino or alkyl mercapto each with 1 to 4 carbon atoms in the alkyl groups or represents a furfurylamino, benzylamino or phenylamino radical1 if necessary by halogen trifluoromethyl, alkyl or alkoxy with je.tbi 4 Carbon atoms is substituted and v R1 and R2 are the same or different and each represent alkyl having 1 to 4 carbon atoms or phenyl or together represents an alkylene chain with 3 to 4 carbon atoms. 3. Compounds of the general formula IV in which R1 and R2 have the meaning given in claim 1 and represent hydroxyl or amino. 4. A process for the preparation of compounds dt general formula I according to claim 1, in which pyrrole derivatives of the general formula II in which R1 and R2 have the meaning given above, with formic acid derivatives of the general formula III in which R stands for an amino group or a hydroxyl group, converted in the presence of formic acid and optionally in the presence of inert organic solvents at elevated temperature to give substituted pyrrolo-pyrimidine derivatives of the general formula IV in which R ', R1 and R2 have the meaning given above, characterized in that the compound of the general formula IV with an excess of acids from the group of concentrated hydrochloric acid, phosphoric acids and polyphosphoric acid at temperatures between 200C and 150 ° C, optionally in Dealkylated in the presence of water, and optionally the compounds obtained, in which R 'is a hydroxyl group, reacts with phosphorus oxychloride, and the chloride formed is converted by known methods with amine compounds or thiocarboxyl compounds to give the corresponding amine and mercapto derivatives of the substituent R of the general formula I. 5. The method according to claim 4, characterized in that for the dealkylation uses polyphosphoric acid and the reaction b between 50 and 1000C performs. 6. The method according to claim 4, characterized in that the Acid in the dealkyiation step in an excess of 2 to 25 parts by weight on the. Compound IV begins. 7. Use of. Compounds of general formula I according to claim 1 for the preparation of pyrrolo-pyrimidine derivatives which are substituted in the 7-position are. 8. Use of. Compounds of general formula I according to claim 1, in the manufacture of active pharmaceutical ingredients.