DE1135914B - Process for the preparation of ketosidopurines - Google Patents

Description

Process for Making Ketosidopurines The invention relates to a process for the production of ketosidopurines.

Process for the preparation of nucleosides, such as. B. adenosine, inosine, Guanosine and the like, in which the sugar residue is that of an aldose, are known. Such nucleosides are intermediates in the production of the corresponding ones Nucleotides, e.g. B. acenic acid (adenosine monophosphate), adenosine triphosphate and the like, which are essential cell metabolites. The corresponding nucleosides and nucleotides in which the sugar residue is a ketosis are not yet has been described, and it has not yet been recognized that such compounds have valuable properties.

The invention relates to a process for the preparation of such nucleosides of the general formula: wherein R1, R2 and R3 are a hydrogen or halogen atom, a mercapto or hydroxy group, a low molecular weight alkyl, aralkyl, aryl, alkylmercapto, aralkylmercapto, aryncapto, alkoxy, aralkoxy or aryloxy radical or a radical of the general formula -N (R4) R5 and R4 and RS denote a hydrogen atom or a low molecular weight alkyl, aralkyl or aryl group and X denotes the remainder of a ketose sugar having 5 to 7 carbon atoms.

The term "low molecular weight alkyl group" is intended to mean an alkyl radical With 1 to 8 carbon atoms, such as the methyl, ethyl, propyl, butyl, amyl, Hexyl, heptyl, octyl groups and their isomers are understood. A low molecular weight Aralkyl group is an aralkyl radical with 7 to 13 carbon atoms, such as the benzyl, Phenylethyl, a-naphthylmethyl, benzhydryl group. As a low molecular weight aryl group should be an aryl radical with 6 to 12 carbon atoms, such as the phenyl, tolyl, xylyl, Naphthyl, biphenyl group apply. The same applies to the low molecular weight Alkyhnercapto-, Aralkyl mercapto, aryl mercapto, alkoxy, aralkoxy and aryloxy groups. Under the The term »ketose sugar« should mean ketopentoses, such as D- and L-xylulose, D- and L-ribulose, Ketohexoses, such as D- and L-psicose, D- and L-fructose, D- and L-sorbose, D- and L-tagatose and ketoheptoses, such as D-alloheptulose, D-sedoheptulose, D- and L-glucoheptulose, D-mannoheptulose and L-galactoheptulose are understood. The ketohexoses and ketoheptoses can both in the furanose and in the pyranose form, but the ketopentoses only exist in the furanose form.

The compounds of the general formula (I) are prepared by adding a halogen mercury derivative of a purine of the general formula: wherein R1, R2 and R3 have the meaning given above or one or more of the three substituents are an acylamino group, with a polyacyl ester of a 2-haloketopentose, -hexose or -heptose of an inert solvent at a temperature between 50 and 150 ° C and that Polyacyl-ketosidopurine obtained is hydrolyzed in a manner known per se, the compound of the general formula (I) being obtained.

The acyl groups with which, for example, on the purine structure of the starting compound existing amino groups should be appropriately protected, derive from carboxylic acids with 1 to 12 carbon atoms. These carboxylic acids can optionally with Halogen atoms or nitro, cyano, thiocyan or low molecular weight alkoxy radicals be substituted.

The reaction between a halogen mercuride derivative of a purine general formula (II) and the polyacyl-2-haloketose is according to the invention in carried out the manner that the reactants to a temperature of about 50 to about 150 ° C, preferably from 120 to 150 ° C, in the presence of an inert Solvent heated. The reaction time depends on the reaction temperature and is generally about 1 to 3 hours. As an inert solvent, for. B. Benzene, toluene, xylene, decalin, carbon tetrachloride are used.

The polyacylketosidopurine formed as an intermediate can be used from the reaction mixture using conventional methods, for example by Evaporation of the applied solvent, isolate and deacylate without purification. But you can also use the resulting polyacyl-ketosidopurine before the deacylation purify, for example by recrystallization or by a countercurrent distribution process using a suitable solvent system. The deacylation is in carried out in a known manner. A particularly suitable method is to that the polyacyl derivative with a saturated solution of ammonia in methanol treated at a temperature below 30 ° C and preferably close to 0 ° C, analogously that of D a v o 11 and Lo wy in "Journal of the American Chemical Society", vol. 73 (1951), p.1650, described method. The desired compound of the general Formula (I) is isolated from the reaction mixture and, if necessary, in the usual way Way, e.g. B. by means of the countercurrent distribution method using an appropriate one Solvent system, cleaned.

Many of the purines of general formula (II), according to the process Can be used as starting material are known compounds that either - occur in nature or the production of which is described in the literature. Adenine, guanine, xynthin, hypoxanthine, and uric acid are widespread in nature. The production of 2-methoxy-, 2-mercapto-, 2-Methyhnercapto-, 2,6-Diamino-, 2-Amino-8-phenyl-, 6-Methylamino-, 6-Dimethylamino-, 8-phenyl-, 8-methyl-, 8-oxy-, 2,8-dioxy-, 6,8-dioxy-, 8-mercapto-, 8-amino-, 8-methylamino- and 8-dimethylaminopurine. U.S. Patent 2,705,715 is Condensation of 2-substituted-mercapto-4,5-diamino-6-disubstituted-aminopyrimidines described with carbon disulfide in the presence of pyridine, using 2-methylmercapto-6-dimethylamino-8-mercaptopurine, 2-methylmercapto-6-diethylamino-8-mercaptopurine, 2-methylmercapto-6-methylanihno-8-mercaptopurine and 2-methylmercapto-6-butylbenzylamino-8-mercaptopurine. Robins and Christenson have in "Journal of the American Chemical Society", Vol. 74 (1952), p. 3624, the reaction of uric acid, xanthine and hypoxanthine with phosphorus oxychloride in the presence of a tertiary aliphatic amine described, one being the corresponding dialkylaminopurine and bis-dialkylaminopurine. This reaction can lead to the production of Dialkylaminopurines of the formula (II) are used. The latter connections and the corresponding alkylaralkylamino, diaralkylamino, diarylamino and alkylarylaminopurines of the formula (II) can also be achieved by reacting the corresponding mercaptopurines (das 6-mercaptopurine has been described in US Pat. No. 2,724,711) with the appropriate amine in the manner described by Albert and Brown (supra) will.

The purines of the general formula (II), in which one or more of the groups R1, R2 and R3 represent a halogen atom, can by reacting the corresponding oxy compounds with a phosphorus oxyhalide in the presence of a tertiary amine according to that of Bendich et al in Journal of the American Chemical Society "76: 6073-6077 (1954) for the conversion of 6-oxypurine processes described in 6-chloropurine. Many of the halopurines of the general formula (II) have been described (see »Reports of the Germans Chemischen Gesellschaft ", Vol. 30 (1897), p.220, and Vol. 31 (1898), p. 2551," Journal of the Chemical Society ", 1947, pp. 943-948, U.S. Patent 2,628,235).

The following indicated procedures for which protection is not sought can also be used to prepare the purines of the general formula (II) will.

a) The compounds of the general formula (II) in which R1 and R2 have the meaning given above and R3 represents an oxy group, can by Acylation and cyclization of the corresponding substituted 4,5-diaminopyrimidine according to the von Traube in "Reports of the German Chemical Society", Vol. 33 (1900), p. 3035, given method. When the acylating agent is an aryl carboxylic acid halide, the corresponding 8-aryl derivatives are obtained, as described by Albert and Brown (supra).

b) The compounds of the formula (II) in which R1 and R2 are the above have given meaning and R3 is a mercapto group, can by thioformylation and subsequent cyclization of the corresponding substituted 4,5-diaminopyrimidines according to Todd et al. in Journal of the Chemical Society, 1936, p. 1557, can be obtained. The 8-mercaptopurines produced in this way can then convert to the corresponding 8-amino-, 8-monosubstituted amino- and 8-disubstituted ones Aminopurine by reaction with ammonia or the corresponding amine according to the Albert and Brown (supra). One can but also the 8-mercaptopurines by treatment with an alkyl or aralkyl halide etherify. The thioethers obtained can be subjected to hydrogenolysis, whereby form the corresponding purines which do not contain any substituents in the 8-position.

The halogen mercuride derivatives of the purines of the general formula (II), according to the procedure as an ex. material can be used by implementation of a mercury halide, preferably mercury chloride, with a purine of the general type Formula (II) based on that of Davoll and Lowy (op. Cit.) For the production of chloromercuride derivatives of the 6-Acetamidopurine and 6-Benzamidopurine specified processes.

The polyacyl-2-halogen-ketoses used as starting material can from the corresponding ketoses according to that of Fischer in »Reports of the German Chemicals Gesellschaft ", Vol. 44 (1911), p. 1899, for the preparation of tetraacetylglucosyl bromide described method are produced.

The compounds of general formula (I) have therapeutic Activity on. For example, 6-amino-9-D-psicofuranosylpurine is an effective one Antibiotic and an effective anticancer agent. 6-Mercapto-9-D-psicofuranosylpurine has been shown to be effective against Sarcoma 180 and S. hemolyticus in vivo. 6-Oxy-9-D-psicofuranosylpurine shows marked activity against in vivo S. hemolyticus.

When used in human therapy, the process products can be used with solid or liquid pharmaceutical carrier materials combined and put into the form tablets, powder packs or capsules or for oral use or parenteral administration dissolved or suspended in suitable solvents will.

The method of the invention is to - the following examples are explained on hand. (Protection is not claimed for the process for the preparation of the polyacyl esters of 2-haloketones used as starting compounds.

Example 1 6-Amino-9-D-psicofuranosylpurine A solution of 3 g (0.0166M01) D-psicose in 15 cc (0.161 mol) acetic anhydride and 15 cc of dry pyridine was added at 2 ° C for 2 hours and then at Let stand room temperature. The resulting solution was poured into ice water and, after separation, the oil was extracted with chloroform. The chloroform solution was washed successively three times with 150 cc of n-hydrochloric acid each time, once with saturated sodium bicarbonate solution and finally with water. The chloroform solution was then dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated to dryness in vacuo at 40 ° C. 5.8 g of pentaacetyl-D-psicose were obtained in this way in the form of a yellow oil; [a] ö` = 7.5- (c = 2.2 in ethanol). The solution of 3.0 g of the pentaacetyl compound thus obtained in 115 cc of absolute ether was saturated at 0 ° C. with dry hydrogen chloride. The solution was then left to stand for 42 hours at 2 ° C., after which the ether and the hydrogen chloride were distilled off under reduced pressure at 20 ° C., the last traces of hydrogen chloride were removed from the residue by treating it with a few small portions of carbon tetrachloride and benzene and removing each portion by distillation under reduced pressure. Tetraacetyl-D-psicofuranosyl chloride was thus obtained in the form of a yellow oil. This compound was dissolved in a small amount of anhydrous xylene and the solution was added to an anhydrous suspension of 4 g of chloromercuriacetyladenine in 100 cc of xylene. The mixture was heated under reflux with stirring for 3 hours, the heated suspension was filtered while hot and the filtrate was evaporated to dryness under reduced pressure. The 6 - acetylamino - 9 - D - tetraacetylpsicofuranosylpurine thus obtained was treated with 100 cc of a methanolic ammonia solution saturated at 0 ° C. The mixture obtained was left to stand at 0 ° C. for 18 hours, the solid precipitate which had separated out was filtered off and the filtrate was evaporated to dryness at 30 ° C. under reduced pressure. The resulting brown solid residue was subjected to 985 passes in a Craig countercurrent sparger in a butanol to water solvent system. The contents of the tubes with the tip at K = 0.3 were combined and evaporated to dryness in vacuo. The residue was dissolved in 50% aqueous acetone, treated with decolorizing animal charcoal, evaporated to almost dryness and left to stand overnight. The crystalline product was separated from the supernatant liquid on a porous clay plate and recrystallized from 50% aqueous acetone. This gave 6-amino-9-D-psicofuranosylpurine in crystalline form with a melting point of 190 to 195 ° C., the mixed melting point of which showed no decrease with an authentic sample; [a] δ = -55 ° (c = 0.5 in dimethyl sulfoxide).

Example 2 6-Amino-9-D-fructofuranosylpurine A solution of 11.92 g (0.02 mol) of tetrabenzoyl-D-fructofuranose (prepared by the method of P. Brigl and R. Schinle, "Reports of the German Chemical Society", Vol. 67 [1934], P. 127) in 50 cc of acetyl chloride was mixed with gaseous hydrogen chloride at room temperature treated. The gas was bubbled slowly through the solution for 3 hours, which was then followed let stand overnight. Obtained after removal of the acetyl chloride in vacuo a viscous syrup is used as a residue, which can be obtained by adding carbon tetrachloride, which was then removed in vacuo, freed from the remaining hydrogen chloride. The syrup obtained was placed under high vacuum for a few hours to remove the rest remove volatile impurities. This amorphous residue was direct used for condensation with chlormercuric purine.

A solution of 14.4 g (0.023 mol) of the tetrabenzoyl-D-fructofuranosyl chloride thus obtained in 40 cc of carbon tetrachloride was added to a well-dried suspension of 10 g (0.025 mol) of chloromercuric acetyladenine in 200 cc of xylene. The mixture obtained was heated to 105 to 110 ° C. for 2 hours, then the insoluble material was filtered off from the hot solution and the filtrate was poured into 1.5 liters of a mixture of hexanes. The precipitate thus formed was filtered off, washed with the same solvent and dried to obtain 7 g of impure 6-acetylamino-9-D-tetrabenzoyl-fructofuranosylpurine. A solution of 5 g of this compound in 200 cc of methanol was saturated with ammonia at 20 ° C., the mixture was left to stand at this temperature overnight, filtered and the filtrate was evaporated to dryness. The residue was taken up in a mixture of 150 cc of water and 150 cc of ether, the aqueous phase was separated off and extracted again with ether. After nitrogen had been passed through the aqueous solution in order to remove the remaining ether, the solution was treated with 12 g of animal charcoal and the mixture was stirred for 30 minutes. The animal charcoal was filtered off, washed with cold water, dried and extracted with hot 90% acetone. The acetone extract was evaporated in vacuo and the aqueous residue was subjected to freeze-drying. The amorphous residue was then dissolved in a small amount of ethanol. On standing, crystalline material separated from the solution, which was filtered off and recrystallized from methanol. This gave 6-amino-9-D-fructofuranosylpurine in the form of colorless crystals with a melting point of 219.5 to 220.5 ° C .; [a] δ = -I-92 ° (c = 1 in dimethylformamide).

Analysis for Cl1H15N505 Calculated ... C, 44.44; H 5.09; N 23.560%; found ... C, 44.55; H 5.53; N 23.310 / 0.

Claims (2)

PATENT CLAIMS: 1. Process for the preparation of ketosidopurines of the general formula: wherein R1, R2 and R3 are a hydrogen or halogen atom, a mercapto or hydroxy group, a low molecular weight alkyl, aralkyl, aryl, alkylmercapto, aralkylmercapto, arylmercapto, alkoxy, aralkoxy or aryloxy radical or a radical of the general formula - N (R4) R5 and R4 and RS denote a hydrogen atom or a low molecular weight alkyl, aralkyl or aryl group and X denote the remainder of a ketose sugar with 5 to 7 carbon atoms, characterized in that a halogen mercuride derivative of a purine of the general formula: wherein R1, R2 and R3 have the meaning given above or one or more of the three substituents are an acylamino group, with a polyacyl ester of a 2-haloketopentose, -hexose or -heptose in the presence of an inert solvent at a temperature between about 50 and 150 ° C implemented and the polyacylketosidopurine obtained is hydrolyzed in a manner known per se to give the corresponding ketosidopurine. 2. The method according to claim 1, characterized in that the polyacylketosidopurine by treatment with ammonia in methanol solution at a temperature between about 0 and about 30 ° C is deacylated. Publications considered: »Journal of the American Chemical Society ", 73: 1650 to 1655 (1951); Vol. 77 (1955), p. 5900 to 5905; Vol. 80 (1958), pp. 3738 to 3742, 3962, 4896 to 4899. At the time of publication A priority document and a declaration of transfer are laid out for the registration been.