SU439981A1 - The method of obtaining derivatives of 8-azapurinone-6 - Google Patents

Description

modemism sogokhnometrichsky kolichssi; Compound I and the corresponding base and the iirimer of the indicated base, with an increased temperature in irisuttvii or without a solvent, with the following crystallization from an appropriate solvent, for example a hydroxyl solvent, for example water. The method of obtaining 8-azapurI1H-6-o; derivatives for the proposed method, as well as the method of obtaining the initial 2,5-diamPN pyrimndon-6, are given below. Example 1. A solution of 50 ml of concentrated hydrochloric acid in 50 ml of water is stirred at 0 ° C and treated with 1.5 g of sodium nitrite. The resulting solution was stirred at 0 ° C and treated with 2.54 g of 4,5-diamino-2- (2-methoxy-feil) -pyrimidoia-6 for 30 minutes; then another 1.5 g of sodium nitrite is added; after a certain holding time, the stirred mixture is heated to room temperature; The precipitate is filtered off, washed with water and dissolved in a dilute aqueous solution. This solution is filtered to pH 6 with glacial acetic acid. The precipitate is filtered off, washed well with water, sucked dry and recrystallized from meth "ol. 1.9 g of 8-aza-2- (2-methoxyphenyl) -purin-6-one are obtained with t. Il. 239 ° C (decomposition). Further purification is carried out by recrystallization from pyridine, washing with dilute hydrochloric acid and water; PLANT 8-aza-2- (2-methokophenyl) -purin-6-cn with so pl. 254-255 ° C (decomposition). Similarly, using 4,5-diamin-2-phenylpyrimid-6-one as the starting material; crude 4,5-diamine-2- (2-ethoxyphenyl) -hyrimid-6-oi; crude 4,5-diamin-2- (2-aropo "syphenyl), -pyrimid-6-one; crude 4,5-diamin-2- (2-isopropoxyphenyl) pyrimpd-6-one; crude 4,5-d. diamni-2- (2-butoxyphenyl) -pyrim "db-ot1; 4,5-diamvn-2- (2-isobuto "syphenyl) pyrim, id-6-one; crude 4,5-diam1H-2- (2-8GO / .butoxyphenyl) pyrimid-6-one; 4,5-diamin-2- (2-pento-xyphenyl) pyrimide-6-o; 4,5-dia.min-2- (2-isopentoxyphenyl) -pyrimid-6-one; crude 4,5-diami1N-2- (2-methylmer1Ptophenyl) -pnrnmid-6-oi; 4,5-days "-2- (2-phenoxyphenyl) -pervmide-6-o"; 4,5-diamsh -2- (2-benzylokeifeiyl) -pyrimid-6-one, 4,5-diamin-2- (2,4-dimethoxyphenyl) -n, irimid-6-oi; 4,5-diami n-2 (2,5-d1I1methoxyf: enyl) -pyrimid-6-one, crude 4,5-diam1H1H-2- (4-benzyloxy-2-methoxyphenyl) -pyrimid-6-oi, 4 , 5-diamium-2 (5-beys Iloxy-2-methoxyphenyl) -pyrimid-6-OH and 4,5-diami.n-2- (2,5-dibenzenexyphenyl) -phermid-6-o; and get, respectively 8-aza-2-phenylpuria-6-o 1, so pl. 280 ° C (with decomposed, it); 8-aza-2- (2-etkoife1Nil) -lurii-6-one, so pl. 216-218 ° C (at once); 8-aza-2- ((2-propoxyphenyl) -pripe-6-op, mp 238-240 ° C; 8-aza-2- (2-isopropoxyphenyl) -iuri "-6-one, t. PL.218-219 ° С (with | decomposition); 8-aza-2- (2-butoxy: fe1Nil) -purine-6-0 N, t, Pl. 188-190 ° С; 8-aza-2- (2-isobutoxyphenyl) -iurn-6-oii, t. Ill. 226-227 ° C (with decomposition); 8-aza-2- (2-v7o /;. Butoxyphenyl) -1purine-6-0 N, t 205-208 ° С (with decomposition); 8-aza-2- (2-11ento "syphenyl) -turii-6-oi, so on. il. 175-176 ° С; 8-aza-2- ( 2-isoieitoxyphenyl) iurin-6-OI, mp 186-188 ° C, (with decomposition); 8-aza-2- (2-hekeilo1 Xyphenyl) -purin-6-one; mp. 130- 132 ° C; 8-aza-2- (2-methylmercapto-phenyl) -purin-b-one man-hydrate, mp 224-227 ° C; 8-aza-2- (2-b "3, ilocoiphenyl) -purine -6-one, mp 240-242 ° С (with decomposition); 8-aza-2- (2,4-dimethoxyphenyl) -puri "-6-oi, mp 257-258 ° С ( with decomposition); 8-aza-2- (2,5-dimeto "siphenyl) -purin-b-one, mp 252-255 ° C (with decomposition), 8-aza-2- (4-benzyloxy- 2-1Mark €,) - purI H-6-0 1, mp 242-244 ° C, 8-aza-2- (5-benzyloxy-2-methoxy-fibnyl) -purin-6-one, mp 258-260 ° C, and 8-aza-2- (2,5-dibenzyloxyfe-1Nl) -purn-6-o ", t. Il. 212-214 ° C. Example 2. 200 mg of the obtained 8-aza-2- (2-methoxy-feiyl) -purin-6-she, in Example 1, are dissolved in 4 ml of 2N. an aqueous solution of caustic soda; the stirred solution is treated dropwise with glacial acetic acid. When the pH is above 11, a creamy precipitate falls out, it is filtered off, recrystallized from a mixture of ethanol and diethyl ether and dried in air for about 25 minutes. 100mg of sodium soda or 8-aza-2- (2-meth o KSifepil) -purii-6-oa are obtained in the form of a crystalline hydrate; each mole of salt is associated with 2.4 moles of water; melts with decomposition at 50-250 ° C. Example 3. 0.33 g of an 85% aqueous solution of potassium hydroxide in 13 ml of dry methanol is added to a hot solution of 0.7 g of choline chloride in 36 ml of isoprapanol. The mixture is cooled to 0 ° C, potassium chloride is filtered off and washed with isopropanol (2X3 ml). To the combined filters and npoiMbiBKa-M was added 1.13 g of 8-aza-2- (2-meT0-hydroxyphenyl) -puri.i-6-one obtained in Example 1 and the mixture was heated for 4 minutes on a steam bath. The warm mixture is filtered and diluted with 100 ml of dry diethyl ether. The resin that separated out crystallized on standing at 0 ° C 3 overnight, the crystals were filtered off, washed with dry diethyl ether, recrystallized from a mixture of dry ethanol and diethyl ether, and dried to give 1.2 g of the choline salt of 8-aza-2- (2- methoxyphenyl) -purin-6-it throughout its hemihydrate, so pl. 158-160 ° C. Example 4. 2.4 g of 8-aza-2- (2-methokeipheyl) -purin-6-O: Boil with a reflux chiller for 5 minutes with a solution of 0.23 g of metallic sodium in 25 ml of anhydrous tanol and cool. 75 ml of anhydrous diethyl ether are added, the precipitate is filtered off and recrystallized from a mixture of anhydrous ethanol and anhydrous diethyl ether. Obtain 0.75 g of sodium salt-Aza-2- (2-; methoxyphenyl) -purin-6-it, hemihydrate, so pl. 310 ° C (decomposition). Example 5. 237 g of a mixture of 8-aza-2- (2-methoxy-ae. Iyl) -11urin-6-o; 1a, 400 ml of triethanolamine and 3 l of Bose D1 of the 1st ethyol; - agglomerate with a freezing refrigerator for 1 hour Rahtvor filtered and left at 2 hours. The precipitated precipitate is filtered off and recrystallized from anhydrous ethanol to give 216 g of the tri-thiolamine 8-aza-2- (2-methokeiphenyl) -purin-6-On salt, mp. 130-139 ° C.

In a similar way, but replacing trizthanolamine with derylamine and triethylamine, diethylamine eol 8-aza-2- (2-methoxyphenyl) -pufin-6-palma (containing 0.4 mol of water of crystallization) is obtained, so pl. 138-142 ° C and triethylamine eol 8-aza-2- (2-methoxyfelyl) -purI | N-6-one, so pl. 184-197 ° C.

Example 6. A solution of 4 g of 8-aza-2- (2-methoxyfe1nyl) -purine-6-oia, 4 ml of diethanolamine, and 40 ml of anhydrous ethanol are boiled with a 5 ml condenser. Then, it is half-saturated to half a volume: em and diluted with 60 ml of anhydrous diethyl ether. The pellets were recrystallized from 55 ml of anhydrous ethanol and 3.4 g of diethanolamic ester 8-aza-2- (2-methoxyephenyl (-puria-b-opa) was obtained, mp 142-114 ° C.

In a similar way, but replacing the initial diethagylamine with ethylenediamine and octadecylamine, ethylene diamine is obtained 8-aza-2- (2-; metho Xefeil) -purin-6-one (containing 0.25 mole of creeplating water), so pl. 208-209 ° С (dilution), and octadecyl. 8-aza-2- (2-methokeiphenyl) -puri-p-6-oia amino salt, t. Pl. 97-98 ° C, respectively.

Example 7. 1.15 g of 1- (3,4-dioxyfbnyl) -2-isonropylaminoethanol sulfate are refluxed for 5 minutes with a solution of 0.1 g of caustic patra in 10 ml of anhydrous ethanol. The sodium sulfate is filtered off and 1.0 g of 8-aza-2- (2-methoxyfeiyl) -purine-6-oia is added to the filtrate; the mixture is refluxed for 5 minutes, then it is filtered, the filtrate is diluted with anhydrous diethyl ether, the precipitated precipitate is filtered and recrystallized from propapol, and after curing at 105 ° C, 0.35 g of 1- {3,4-dio .Xyphenyl) -2-isopropylaminoethanol salt of 8-aza-2- (2-.methoxyphenyl) -iuRIN-6-0ia, content of 0.33 mol of water of crystallization, t. nl. 155 ° C (decomposition).

Example 8. 3 g of sodium nitrite are slowly added with stirring to a solution of 100 ml of tertiary hydrochloric acid in 100 ml of water at a temperature from 0 to -5 ° C in a bath with a mixture of ice and saline. Then, 5.1 g of 2- (2-allyloxyphenyl) -4,5-diami.pyrimid-6-one is added in portions over 30 minutes with stirring at a temperature of from -5 to 0 ° C; the cooling bath is removed and the mixture is stirred overnight at compat temperature. The precipitate formed is filtered off and dissolved in a solution of 10 ml of ammonium ammonium hydroxide monohydrate in 100 ml of water. The solution is heated with

activated carbon, fn.p truot n filtrate 1 od: sour ice under 1 1 y; eyc; ioii acid. The precipitated precipitate is filtered, recrystallized I13 Mstaiola and get 1.7 g of 2- (2-allyloxyphenyl) -8-azapypy: p-6-ona, so pl. 173-175 ° C. Similarly, but using raw 4,5-diamio-2- (2-methoxy-5-methylfefenyl) iirIMID-6-one and raw 4,5-diamio-2- (5-t / (city

butyl-2-methoxyphenyl) -pyrimide-6-oi, respectively, are prepared with 8-aza-2- (2-methoxy-5-methylpheyl) -puriium-6-op, so pl. 230-232 ° C (with decomposition), and 8-aza-2- (5-treg. Butyl-2-methoxyphenyl) -pripe-6-one, so pl. 260-262С (with decomposition).

Example 9. 2 g of the crude sodium salt of 4-amino-2- (2-decyloceriphenyl) -5-nitrosopyrimide-6-one suspend in 100 ml of water and add so much caustic acid to 65 ° C

a clear solution was obtained; at 65 ° C, 1.8 g of sodium dithionate are added in portions and the mixture is cooled to 10 ° C. With vigorous stirring, 25 ml of concentrated hydrochloric acid is added. Dare to cool to

OS and add 2 g of nitrite) atri. The mixture is triturated and after 4 hours the upper liquid layer is decanted. The gummy residue is redissolved in 2N. aqueous ammonia solution, treated with charcoal and filtered. Filtrate

acidified with 2 n. hydrochloric acid and a waxy precipitate are extracted with ethyl acetate. The extract is dried over magnesium sulfate and evaporated to dryness; the residue is triturated with petroleum ether (mp. c. 40-60 ° C). The resulting residue is extracted with 40 ml of anhydrous diethyl ether and the extract is filtered into a solution of 1 ml of ethylenediamine in 10 ml of anhydrous diethyl ether. The precipitated precipitate is filtered off, washed thoroughly with anhydrous ethyl ether, recrystallized from a mixture of anhydrous ethanol and anhydrous ethyl ether and obtain 0.15 g of ethylene diamine salt of 8-aza-2 - (2-decyloxyphenyl) -purine-6-one with mp.

115-118 ° C. This salt is triturated with 2 n. acetic acid, the precipitate is filtered off, washed with water and dried at 56 ° C and 0.3 mm RT. Art. over phosphorus thioxide over 5.5 teas. 0.11 g of 8-aza-2- (2-decyloxyphenyl) iirip-6-one is obtained with m. Il. FROM - 115 ° C.

Example 10. 1.2 g of 8-aza-2- (2-methoxyphenyl) -lurine-6-o. Prepared for Example 1 were added to a hot solution of 0.7 g of 2-amino-2-oxymethylpropan-1. , 3-diol in 20 ml of anhydrous ethanol and the solution is boiled with a refluxer of 5 minutes. After cooling, 60 ml of anhydrous diethyl ether are added, the resulting precipitate is filtered off, washed with a mixture of acetone and dipethyl ether, recrystallized from a mixture of methanol and diethyl ether to obtain 1.1 g of 2-amino-2- (oxpmethyl) -propan-1,3- in Poland

salts of 8-aza-2- (2-methoxyphenyl) -purin-6-one monohydrate with m.p. 148-152 ° C (decomposition). Example I. 1.1 g sodium nitrite is added to the stirred mixture 15 ml of concentrated hydrochloric acid and 15 ml of water 5 at 0 ° C. Within 10 minutes, 2.1 g of 4.5-diam is added at the intermixture of vanyi and 0 ° C. And | H-2- (5-methyl-2-propoxyphenyl) pyrimide-6-ana and mixed at 0 ° C, another 30 ppm. Another 1.1 g of itritic sodium is added, cooling the bath is well removed and ne: displacement continues for another 4 hours. The precipitate was filtered off, washed with water and dissolved in 2: n. ammonia water solution. The solution is filtered and acidified with glacial acetic acid 15. The precipitate is filtered off, washed with water and recrystallized from aqueous ethanol; 0.95 g of 8-aza-2- (5-methyl-2-propoxyphenyl) -puri "-5-ana with m.p. 235-236 ° C (decomp.). 20 Example 12. The treatment is carried out a, in accordance with Examples 1, 8, 9 and II, and 8-aza-2- (2-hydroxy-benyl) -purin-6-one is obtained. m.p. 283-284 ° C (with decomposition), 8-aza-2- (5-o-xi-2-methoxyphenyl) -puriium-b-oi, so pl. 288-290 ° C 25 (with decomposition), 8-aza-2- (2,5-dioxyphenyl) -purine-b-o ", which slowly decomposes at 300-310 ° C. The subject of the invention is a process for the preparation of 8-azapurinan-6 derivatives of the formula I, where R is a hydrogen atom, hydroxy group, straight or branched alkoxy group with 1-10 carbon atoms, straight or branched alRI III B CHAKenyloxy group with 2-10 carbon atoms , a fanoxy group, a phenylalkoxy group with a straight or branched alkoxy chain with 1-6 atoms of 1M " carbon or " straight or branched almylthio group, with 1-6 carbon atoms; R2 and Kz are the same or different, a hydrogen atom, a hydroxy group, a straight or branched alkyl or alkoxy group with 1-6 carbon atoms or a phenylalkoxy group with a straight or branched alkoxy chain with 1-6 carbon atoms; or salts thereof, wherein. that the production of os 4,5-diaMI1Nopyrimido1-6 of the formula I NH2 (P), where RI, Hz and Kz have the indicated meanings, is reacted with nitrite, for example with an alkali metal nitrite, in the presence of an aqueous acid, for example hydrochloric, at O- 30 ° C and isolate the target product or convert it to salt in the usual manner.