Patent GB-782440-A (GB)
Title: Improvements relating to the production of aminoglycosidopurines
IPC: C07H19/16
Filed: 1955-01-18
Abstract: The invention comprises compounds of the general formula <FORM:0782440/IV (a)/1> (wherein R1 represents a hydrogen or halogen atom or an amino, dialkylamino or alkylmercapto group, R2 represents a hydrogen or halogen atom or an alkylmercapto group, and X represents an aminoglycosido radical, an acylaminoglycosido radical or a fully acylated aminoglycosido radical, or an aminoglycosido radical having substituents subsequently introduced into the amino group, the amino or substituted amino group replacing a free hydroxy group in the glycosido radical, which is attached at its 1-position), but excluding puromycin and its mono- and tri-acyl derivatives except when prepared as below, and a process for preparing the above compounds by condensing a heavy metal salt of a purine with an acylated 1-halo-aminoglycoside or a titanium tetrachloride complex thereof, and then if desired, subjecting the product to selective O-deacylation (with simultaneous deacylation of any acylamino group in the purine moiety) or to complete deacylation and/or to any of the following transformations: (a) introducing substituents into the free amino group if present in X; (b) replacing any methymercapto group in the purine moiety by hydrogen by refluxing with Raney nickel; (c) epimerizing the aminoglycosido moiety.  The initial condensation is advantageously effected in an inert non-hydroxylated organic solvent at 60-140 DEG  C. for a period not exceeding 70 hours, selective O-deacylation under mild alkaline conditions (e.g. with methanolic sodium methoxide) and complete deacylation under strong alkaline conditions (e.g. with caustic soda).  The products are useful as pharmaceuticals (e.g. trypanocides) or as intermediates therefore, e.g. 6 - dimethylamino - 9 - (31 - amino - 31-deoxy - b  - D - ribofuranosyl) - purine on treatment with carbobenzoxyglycyl chloride in dimethylformamide, followed by hydrogenolysis yields the trypanocidal compound 6-dimethylamino - 9 - (31 - glycylamino - 31 - deoxy - b  - D-ribofuranosyl)-purine. In examples: (1) the titanium tetrachloride complex of 1-chloro-2:5 - dibenzoyl - 3 - acetylamino - 3 - deoxy-D-ribofuranoside (a ,b -mixture) is refluxed with the chloromercury salt of 2-methylmercapto-6-dimethylaminopurine and diatomaceous earth in ethylene dichloride and the product (b -isomer isolated) is warmed with desulphurizing Raney nickel in b -methoxyethanol to replace the methylmercapto group by hydrogen and then refluxed with methanolic sodium methoxide to remove the benzoyl groups; (2) the same product is obtained by starting with the chloromercury salt of 6-dimethylaminopurine and omitting the desulphurization step; (3) the product of (1) or (2) is warmed with barium hydroxide solution to hydrolyse the acetylamino group; (4) a -1-chloro-2-acetylamino-2-deoxy-D-glycopyranoside triacetate is refluxed with the chloromercury salt of 2-methylmercapto - 6 - dimethylaminopurine and diatomaceous earth in toluene, and the product is O-deacetylated by refluxing with methanolic sodium methoxide; (5) the initial product of (4) is desulphurized as in (1) before deacetylation; (6) the TiC4- complex of 1-chloro-2:5-dibenzoyl - 3 - acetylamino - 3 - deoxy - a  - D-arabinofuranoside is treated as in (1); (7) the product of (6) is esterified with methanesulphonyl chloride and the product refluxed with sodium acetate in b -methoxyethanol to produce 6-dimethylamino-9-(21:51-diacetyl-31-acetylamino - 31 - deoxy - a  - D - ribofuranosyl)-purine, which is O-deacylated with methanolic sodium methoxide; (8) the acetylamino group in the product of (7) is hydrolysed as in (3); (9) the initial product of (1) is debenzoylated without previous desulphurization; (10) the TiCl4 complex of 1-chloro-2:5-dibenzoyl-3-acetylamino - 3 - deoxy - D - ribofuranoside (a ,b -mixture prepared in situ) is refluxed with the chloromercury salt of 6-benzamidopurine and diatomaceous earth in ethylene dichloride and the product is O- and N-debenzoylated (but not deacetylated) by means of methanolic sodium methoxide, from which the isomers are fractionally crystallized; (11) the product of (10) is deacetylated as in (3); (12) the TiCl4 complex of 1-chloro-5-acetylamino-5-deoxy-b -D-ribofuranose diacetate (prepared in situ) is refluxed with the chloromercury salt of 2-methylmercapto - 6 - dimethylaminopurine in ethylene dichloride and the product is desulphurized and O-deacetylated as in (1); (13) 1 - chloro - 2:3:N - triacetyl - 5 - carbomethoxyamino - 5 - deoxy - b  - D - ribofuranoside is treated as in (1); (14) the product of (13) is hydrolysed as in (3); (15) 2:5-di-O-benzoyl-3-phthalimido - 3 - deoxy - b  - D - ribofuranosyl chloride is refluxed in xylene with a mixture of bis - (6 - chloropurinyl) - mercury and 6-chloro-chloromercuripurine to produce 6-chloro-9 - (21:51 - di - O - benzoyl - 31 - phthalimido 31 - deoxy - b  - D - ribofuranosyl) - purine; (16) the mixture of 6-chloropurine derivatives in (15) is replaced by bis-(2:6-dichloropurinyl)-mercury; and (17) by 6-methylmercaptochloromercuripurine; (18) the product of (17) is desulphurized as in (1).  In examples of the introduction of substituents into the amino group, 6-dimethylamino-9-(31-amino-31-deoxy-b -D -ribofuranosyl)-purine is reacted with: (a) benzyl chlorocarbonate in dimethylformamide in the presence of triethylamine; (b) phthalic anhydride in dimethylformamide (heated under reflux); (c) ethyl chlorocarbonate, as in (a); (d) p-toluenesulphonyl chloride, as in (a); (e) 10-undecenoyl chloride, as in (a); (f) benzaldehyde in aqueous alcohol with subsequent hydrogenation in ethyl acetate in the presence of a palladium-charcoal catalyst; (g) formaldehyde and hydrogen in aqueous solution in the presence of a palladium-charcoal catalyst.  Starting materials.  1-Haloacylaminosugars are prepared by (a) reacting hydrogen chloride in an inert solvent (e.g. acetic acid or ether) with an acylated aminosugar (preferably having a phthaloyl group on the amino nitrogen), or (b) treating an acylated aminosugar (obtainable from an alkyl glycoside) with TiCl4 in ethylene dichloride to form the TiCl4-chlorosugar complex which (if it is not to be used as such) is decomposed by washing with water.  Examples (1) and (6) describe the preparation of the starting materials thereof from compounds prepared as follows: 1-acetyl-2:5-dibenzoyl-3-acetylamino - 3 - deoxy - D - ribofuranoside (a ,b -mixture) by O-deacetylating b -methyl 3-acetylamino - 3 - deoxy - D - ribofuranoside diacetate, dibenzoylating the product, warming the dibenzoyl compound with acetic and hydrochloric acids, and heating the resulting 2:5-dibenzoyl - 3 - acetylamino - 3 - deoxy - D-ribose with acetic anhydride and pyridine; 1 - Acetyl - 2:5 - dibenzoyl - 3 - acetylamino - 3-deoxy - D - arabinofuranoside (a ,b -mixture) similarly (omitting the initial O-deacetylation step) from a -methyl 3-acetylamino-3-deoxy-D - arabinofuranoside. Purine-mercury compounds.-The starting material of Example (15) is prepared by adding a hot solution of HgCl2 in ethanol to a hot solution of 6-chloropurine in dilute caustic soda solution, that of (16) similarly from 2:6-dichloropurine, and that of (17) similarly from 6-methylmercaptopurine.