SU1181546A3 - Method of producing condensed pyrimidine derivatives as racemates or optical isomers - Google Patents

Abstract

Nitrogen bridgehead compounds of the general formula (I> <IMAGE> [wherein R is H, alkyl or alkoxycarbonyl R<1> is H or alkyl; or R and R<1> together form -(CH=CH)2- R<2> is H, halogen, alkyl, phenyl or a 5- or 6-membered heterocyclic saturated ring, R<3> is H, optionally substituted phenyl, acyl, carboxy, alkoxycarbonyl -CN, carbamoyl, alkylcarbamoyl, alkyl, alkanoylcarbamoyl, acid- hydrazido, or -CO-NH-N=C (R<12> R<13>) (wherein R<12> and R<13>) are alkyl, carboxyalkyl, alkoxycarbonyl-alkyl or phenyl) or R<2> and R<3> form -(CH2)t (t is 3 or 4> Z is oxygen and n is 0, 1 or 2 and a) if R<11> is H and R<9>-R<10> and R<7>-R<8> form chemical bonds then R<4> is H or phenyl, YR<5>R<6> represents oxygen or Y represents nitrogen and R<5> is alkyl optionally substituted by hydroxy, carboxy or alkoxycarbonyl or phenyl optionally substituted by nitro, alkyl, alkoxycarbonyl and/or halogen; mono- or bi-cyclic nitrogen-containing heteroaryl, hydroxy aminothiocarbonyl, aminothiocarbonylamino or phenylamino, R<6> represents an unshared electron- pair, or H or alkyl, and in these two cases a salt is formed or R<5> and R<6> form -(CH2)p- (p is 4 or 5) and a salt is formed with N+ or b) if R<9> is H and R<10>-R<11> and R<8>-R<7> form chemical bonds, then R<4>, R<5>, R<6> and Y are as given under item (a); or c) if R<8>-R<9> and R<10>-R<11> form chemical bonds, then R<4> is H or phenyl, YR<5>R<6>R<7> represents halogen, or YR<6>R<7> represents oxygen and R<5> is H or alkyl; or YR<6>R<7> represents sulfur and R<5> is cyano; or Y represents nitrogen and R<5> is alkyl optionally substituted by hydroxy, carboxy, or alkoxycarbonyl; phenyl optionally substituted by nitro, C1-4alkyl, alkoxycarbonyl and/or halogen; or mono- or bicyclic nitrogen containing heteroaryl, R<6> is H or alkyl, or R<4> and R<6> form -(CH2)m- (m is 3 or 4) or R<5> and R<6> form -(CH2)p- (p is 4 or 5) and R<7> represents an unshared pair of electrons] and the tautomers and salts thereof. The novel compounds possess physiological activity.

Description

where R is R, n and X have the indicated

meanings

treated with alkaline carbonate

metal at room temperature

1181546

followed by isolation of the whole product in the form of a racemate or optical isomer.

The invention relates to novel derivatives of condensed pyrimidines or optical isomers which possess pharmacological activity and are used in the thesis of biologically active compounds. . The known reaction of aminomethylenation of the activated methylene group of azoles under the action of imini salts at 0-150 ° C, followed by treatment with alkali metal carbonate at room temperature. 1. The purpose of the invention is to obtain new pyrimidine derivatives, KOTojMie, which can be used in the synthesis of biologically active substances. The goal is achieved according to the method of obtaining condensed pyrimidine derivatives of the general formula (Sn, where R is hydrogen or alkyl with 1-4 carbon atoms; R is alkyl with 1-4 carbon atoms; R is halogen, hydrogen or phenyl R. - alkoxycarbonyl with 2-5 carbon atoms, carboxy-, cyano-, carbohydrazidogroup, phenyl, alkylaminocarbonyl with 1-4 carbon atoms frrmyl or alkyl with 1-4 carbon atomsj R-alkyl with 1-4 carbon atoms ipi phenyl; R is alkyl with 1-4 carbon atoms, or R and Ry together with the common nitrogen atom form piperidine "0 or 1, or 2, in racemic or their optical isomers, which is that the general formulas (.gr. 1.TUC, 1 5, R - RJ, and n have the indicated meaning, their optical isomers are fed to the interaction with the imimenal formula HlTP where R and R5 have the values -, X - halogen, at O - and the resulting compound of the general formula M v I (cn, 1 where R is Ry, p and X have the indicated values, are treated with an alkali metal carbynate at room temperature followed by isolation of the target product as racemate or optical isomer. Example 1. 3.7 g of dimethylformamide is added dropwise at 5-10 ° C to a solution containing 5.6 g of phosgene in 50 ml of dichloromethane. To the suspension obtained, a solution of 3-ethoxycarbonyl-1-6-methyl-4-ca-6,7,8,9-tetrahydro-4H-pyrido (1,2-a pyrimidine (g ) in 20 m of dichloromethane and stirring; the solvent is distilled off for 2 h. The solid residue is suspended in ether, the insoluble crystals are filtered out and dried and 15.2 g (93%) of 3-ethoxycarbonyl-6-methyl-9- ( dimethyliminomethyl) -4-OXO-6,7,8,9-tetrahydro-AN-pyridor, 2-a pyrimidine with mp (decomposed). Found: C 55.08, H 6.81, N 12.78j Cr 10.90. C yHjiOlNjOj Calculated,%: C.54.94; H 6.77; 12.86; C1 10.82. Example 2. 15.2 g of chloride 3 is The xycarbonyl-6-methyl-9- (dimethyliminomethyl) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido 1,2-a pyrimidine is suspended in 40 ml (20% by weight) aqueous sodium carbonate solution. The precipitated crystals are filtered and dried. 11.5 g (85%) of 3-ethoxycarbonyl-6-methyl-9- (dimethylaminomethylene) -4-oxo-4H-pyri, co l, 2-pyrimidine are obtained, which melts after recrystallization from ethanol at 135-137 ° C. Found: C 61.52-, H 7.33 $ N 14.29. Ci4H2iNj03 Calculated,%: C, 61.84; H 7.27 N 14.42. Examples 3-10. 10.0 mmol of the starting material (Table 1) was diluted with 7.3 g of dimethylfoamide and 3.1 g of phosphorus trichloride was added to the reaction mixture at 15-20 ° C. The reaction mixture is stirred at room temperature for 2 hours and then drunk on 30 ice. A 20% w / v% aqueous solution of sodium carbonate sets the pH of the solution to 6-6.5. The precipitated crystals are filtered off, washed with water, dried and recrystallized. The compounds obtained and their physical characteristics are listed in Table. 1. 464 Examples 11-13. 10.0 mmol of the starting material (Table 2) is dissolved in 15 ml of dichloroethane. 1.5 g of dimethylformamide and 3.1 g of phosphorus trichloride are added to the solution at 15-20 ° C. The reaction mixture was stirred for half an hour at room temperature and then stirred for 2 hours and poured onto 20 g of ice. The pH of the reaction mixture was adjusted to 6.5-7 with an aqueous solution of sodium carbonate. The phases are separated and the aqueous phase is extracted with 2-15 ml of dichloroethane. The combined organic phases are dried with anhydrous sodium sulfate. The dichloroethane is distilled off and ether is added to the residue. The precipitated crystals are filtered, washed with water, dried and then boiled with ether. The compounds obtained and their physical characteristics are listed in Table. 2. Examples 14-17. 10.0 mmol of the starting material (Table 3) was dissolved in 7.3 g of dimethylformamide. 4.3 g of phosphorus oxochloride are added to the reaction mixture at 15-20 °. The reaction mixture was stirred for half an hour at room temperature and 1 hour in a boiling water bath, then the cooled reaction mixture was poured onto 30 g of ice. 20 w / v% aqueous solution of sodium carbonate. establish the pH of the resulting solution of 6.5-7.0. The precipitated crystals are filtered, washed with water and then crystallized. The compounds obtained and their physical characteristics are listed in Table. 3. Examples 18-21. 5.0 mmol of the starting material (Table 4) is dissolved in 7 ml of dichloroethane. 1.3 N-methylformanilide and 1.5 g of phosphorus oxochloride are successively added to the solution. The reaction mixture was stirred at room temperature for 30 minutes and then boiled for 2 hours. After cooling, the reaction mixture is poured onto 10 g of ice and the pH of 7 is adjusted to 20% by weight with a solution of sodium carbodate. The organic and aqueous phases are separated and the aqueous layer is shaken with ml of diethor ethane. The combined organic solutions were dried with anhydrous sodium sulfate and then the dichloroethane was distilled off. The residue from the distillation is treated with alcohol, and then 10 ml of ether. The crystals which precipitate upon cooling are filtered, dried with ether and dried.

The compounds obtained and their physical characteristics are listed in Table. four.

PRI meri s 22-29. 10.0 mmol of starting material (Table 5) was dissolved in 7.3 g of dimethylformamide. 3.1 g of phosphorus oxochloride are added to the reaction mixture at 15-20 ° C. The reaction mixture is stirred for 1 hour at room temperature. TeMnepaTyiie, for 1 hour at 55-60 ° C and then for 30 minutes at. The resulting salt of 9- (dimethyliminomethyl) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido 1, 2-a pyrimidine is hydrolyzed without isolation with the following method to 9-formyl-4-oxo-1, 6, 7,8-tetrahydro-4H-pyrido 1,2-a pyrimidine: cooled to room temperature, the reaction mixture is dried on ice and the pH of the solution is adjusted to 6-6.5 with 20% w / v solution of sodium carbonate. The precipitated crystals are filtered, washed with water, dried and crystallized from the table. 5 solvent.

The compounds obtained and their physical characteristics are listed in Table. five.

Example 30. 10.0 mmol of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido 1, 2-a2 pyrimidine was dissolved in 7.3 g of dimethylformamide. 1.55 g of phosphorus oxochloride is added dropwise to the solution at 15-20 ° C. The reaction mixture is then allowed to stand at room temperature for 24 hours. The resulting salt of 9- (dimethyliminomethyl) -6-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido 1, 2-a3 pyrimidine without the extracts are hydrolyzed by the following method to 9-formyl-6-methyl-4-oxo-1, 6,7,8-tetrahydro-4H-pyrido 1,2-a pyrimidine: the mixture is poured onto 30 g of ice and 20 w / v% The solution of sodium carbonate is adjusted to a pH of 6-6.5. 0.96 g of product is obtained. The mother liquor is shaken with 2-10 ml of benzene. Combined benzene extracts su: an with anhydrous sodium sulfate.

the solvent is distilled off and the residue is treated with ethanol.

Obtain 0.44 g of product, total 73%.

Found%:

C, 62.74; H 6.41;

N 14.51.

C in pg GoA calculated

%: C, 62.49; H, 6.30; N 14.57.

Examples 31-33. 10.0 mmol of the starting material (Table 6) was dissolved in 7.3 g of dimethylformamide. 3.1 g of phosphorus oxochloride are added to the reaction mixture at 15-20 ° C. The reaction mixture is stirred for 1 hour at room temperature, 1 hour at 55-60 ° C and 30 minutes at 90 ° C. The resulting salt of 9- (dimethyliminomethyl) -: 4-oxo-6,7,8,9-tetrahydro-4HpirioC1 2-aJ pyrimidine, without isolation, is transferred in the following way to 9-ethoxymethylene-4-oxo-6,7,8,9- tetrahydro-4H-pyrido 1,2-aJnHpHMHdin: the reaction mixture is treated with 20 ml of ethanol, absoluted with magnesium ethoxide, then stirred for 1 h at, poured into 100 ml of water and 20% w / v sodium carbonate solution set at pH 7 the crystals are filtered, washed with water, dried and recrystallized from the solvent shown in the table.

The compounds obtained and their physical characteristics are listed in Table. 6

Example 34. To a mixture containing 5.0 mmol of 3-phenyl-6-met. Ш1-4-ОКСО-6, 7,8,9-tetrahydro-4H-pyrido 1, 2-a pyrimidine and 1.77 g N , N-diethylbenzamide, 1.5 g of oxochloride-phosphorus is added at 15-20 ° C. The reaction mixture is stirred for half an hour at and then for 1 hour at 90 ° C. The resulting salt of 9- (diethyliminophenylmethyl) -3-phenyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido 1,2-a pyrimidine without isolating It is hydrolyzed as follows: after cooling, 15 g of ice-cold water is added to the reaction mixture and then stirred for half an hour. The precipitated crystals are filtered, washed with water and dried.

0.6 g (34.8%) of 9-b nzoyl-3-phenyl-6.-Methyl-4-oxo-1, 6,7,8-tetrahydro-4H-pyrido 1-, 2-a pyrimidine is obtained. After recrystallization: from ethanol, the compound melts: at. . Found,%: C, 76.41; H, 5.83; N, 8.25. Cj2H2oNiOi. Calculated,%: C 76.72 $ H 5.85 / N 8.13. . , Example 35. To a mixture containing 10.0 mmol of 3-ethoxycarbonyl-6-methyl-4-oxo-6., 7,8,9-tetrahydp-4H-pyridot1,2-a pyrimidine and 3.54 g K , N-diethylbenzamide, at 15-20 ° C, 3.1 g of oxo-chloro phosphorus are added. The reaction mixture is stirred for half an hour at and then for 1 hour at 90 ° C. The resulting salt is 9- (di ethyliminophenylmethyl) -3-ethoxycarb NIL-4-PXO-6,7,8,9-tetrag-rchro-4H-pyridor, 2- a) pyrimidine without being isolated in 9- (diethylaminophenylmethyl) -3-ztoxycarbonyl-4-ca-6,7,8,9-tetrahydro-4H-pyrido fl, 2-aj pyrimidine in the following way. The cooled reaction mixture is poured onto 30 g of ice. The acidified reaction mixture is extracted with 315 ml of ether. The aqueous solution is neutralized with 20 w / v% sodium carbonate solution and then extracted with 3-.30 ml of benzene. The combined benzene fractions are dried with anhydrous sodium sulfate and then benzene is distilled off. The oily residue is stirred with 10 ml of a 0.5 N hydrochloric acid solution for 1 hour at room temperature and 1 hour at. The crystals which precipitate after cooling are filtered off, washed with water and dried. Get it. 1.25 g (36.8%) of 9-benzoyl-3-ethoxycarbonyl-6-methyl-4-oxo-1., 6,7,8-tetrahydro-4H-pyrido. 1, 2-aZpyrimtsdina. After recrystallization from ethanol, the compounds are combined. Melting is melting at 166-167 0. Found:%: C 67.24; H 5.92: i N 8.18. C jHjgN O ,. . Calculated,%: C 67, H 5.92; N 8.23. Example 36 2.18 g of 6-methyl -2,3- (1-methyltrimethylene) -4-oxo-6,7,8,9-tetrahydro-4H-pyrido Cl, 2-a pyrimidine are dissolved in 7.3 g dimethylformamide. 3.1 g of 5468 phosphorus oxochloride is added dropwise to the reaction mixture at 15–20 ° C and peregreded. The reaction mixture is stirred for 90 minutes. The resulting chloride is 6-methyl-79- (dimethyliminomethyl) -2,3- (1-methyltrimethylene) -4-OXO-6,7,8,9-tetrahydro-4H-pIrido 1,2 -aj pyrimidine is processed without isolation in the following way: the reaction mixture is poured onto 50 g of ice and stirred for 15 minutes, and hydrolyzed to 6-methyl-9- (dimethylaminomethylene) -2.3- (1-methyl-trimethylene) -4-OXO-6, 7,8,9-tetrahydro-4H-pyrido 1, 2-a pyrimidine 20% w / v% sodium carbonate solution (adjust the pH of the reaction mixture to 7). The precipitated crystals are filtered off, washed with water and dried. 1.18 t (46%) of 6-methyl-9-formyl-2 .3- (1-methyltrimethylene) -4-oxo-1, 6,7,8-tetrahydro-H-pyrido 1, 2-a pyrimtstsina are obtained. After recrystallization from ethanol, the compound melts at. Found,%: C 68.45; H 7.32; N 11.38. C H jNjOj. C, 68.27; H 7.37, N 11.37. Example 37. To a mixture containing 0.95 g of Z-cyano-6-methyl-4-OXO-6, 7,8,9-tetrahydro-4H-pyrido 1,2-a pyrimidine and 1, 5 N-methylpyrrolidone, 2.3 g of phosphorus oxochloride are added. The reaction mixture is stirred for half an hour at room temperature, for 1 hour at and 1 hour in a boiling water bath. The cooled reaction mixture is poured onto 15 g of ice and then extracted with 210 ml of chloroform. A 20% w / v% solution of sodium carbonate is used to adjust the pH of the aqueous phase to 6.5-7.0. The precipitating product is filtered off, washed with water and dried. This gives 0.6 g (44%) of 3-cyano-6-metsh-4-oxo-9- (K-methyl-2-pyrrolidinyl) -6,7,8, 9-tetrahydro-4H-pyrido 1,2-aJ pyri-. midina. After recrystallization from ethyl acetate, the compound melts at 151-152s. Found, I: C, 66.20; H 6.76; 20.79. C. ..... Calculated%: C 66.65j H 6.70; N20.77. 9, Example 38. 3.28 g of (i -) - 6-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido 1,2-a} pyrimidine (+ 133 °, / s 2ft , methanol) is dissolved in 14.6 F dimethylformamide. To the reaction mixture at 15-20 ° C was added 3.06 g of phosphorus oxochloride. The reaction mixture is left to stand for 24 hours at room temperature and then it is drunk on 60 g of finely divided ice. The pH of the solution is adjusted to 6.5-7.0 with a 20% w / v solution of sodium carbonate. The reaction mixture is extracted with 3-30 ml of benzene. The combined benzene fractions are dried with anhydrous sodium sulfate, then the benzene is distilled off. 15 ml of diethyl ether was added to the residue. The precipitated crystals are filtered off, washed with distil ether and dried. 1.5 g (40%) of (+) - 9-formyl-6-methyl-4-oxo-1, 6,7,8-tetrahydro-4H-pyrido 1 are obtained, 2-a pyrimidine, which melts at 102-104C. (oLl ° n-25% / s 2 /, methanol). Example 39. 11.8 g of (+) - 3-ethoxycarbonyl-6-methyl-4-oxo-6, 7,8,9-tet rahydro-4H-pyrido 1, 2-a pyrimidine (O. p +122, 5, 2, ethanol) is dissolved in 70 ml of dichloroethane. At 15-20 ° C, 7.3 g of dimethylformamide and 15.3 g of phosphorus oxochloride are added. The reaction mixture is stirred for half an hour at room temperature and 2 hours at 60 C. The reaction mixture is cooled and poured onto 1 50 g of ice. A 20% w / v% sodium carbonate solution was adjusted to a pH of 6.5-7. The O.Vv phase was separated and the aqueous phase was extracted with a ml of dichloroethane. The combined dichloroethane fractions were dried with anhydrous sodium sulfate. The solvent is distilled off and 50 ml of diethyl ether is added to the residue. The precipitated crystals are filtered off, washed with diethyl ether and dried. 11.4 g (78Z) (-) - 3-ethoxycarbonyl-9- (dimethylaminomethylene) -6-metsh-1-4-oxo-6,7,8,9-tetrahydro-4H-pyrido 1, 2-a-pyrimidine are obtained After recrystallization from ethyl acetate, the compound melts at 115-116 ° C. (), with 2, methanol). Example. 40. 23.6 g of (+) - 3-goxycarbonyl-6-methyl-4-oxo4610 -6,7,8,9-tetrag1Zdro-4H-pyrido 1,2-a pyrimidine (+112.5, s 2, ethanol) dissolved in 73 g of dimethylformamide. 30.6 g of phosphorus oxochloride are added to the solution at 15-20 ° C. The reaction mixture is stirred at room temperature for 2 hours. Then the reaction mixture was poured onto 300 g of finely co-ice and a pH of 7 was adjusted to 20 w / v% with sodium carbonate solution. The solution was extracted with 4100 ml of benzene. The combined benzene fractions are dried with anhydrous sodium sulfate, and then benzene is distilled off. The residual oil is dissolved in 130 ml of a 0.5 N hydrochloric acid solution and stirred for 1 hour at room temperature and 1 hour at. A 20 wt / vol. Solution of sodium carbonate is adjusted to a pH of the two-phase reaction mixture of 5. Then the reaction mixture is shaken with 1-100 and 2-50 ml of benzene. The combined benzene fractions are dried with anhydrous sodium sulfate. The benzene is distilled off and 40 ml of diethyl ether and 10 ml of petroleum ether are added to the residue. The precipitated crystals are filtered, washed with ether and dried. 17.2 g (65%) of (+) - 3-ethoxycarbonyl-6-methyl-9-formyl-4-oxo-1, 6,7,8-tetrahydro-4H-pyrido 1, 2-a3 pyrimidine are obtained. The compound is purified by chromatography on a column (silica gel), after which it melts at 93-94 ° C. (+39, 2, methanol). Example 41 5.0 mM 9- (L-phenyl-L-methylaminomethylene) -6-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido 1,2-a pyrimidine is dissolved in 3 , 6 g of dimethylformamide. 1.55 g of phosphorus oxocioride is added dropwise to the solution at 15-20 C. The reaction mixture was stirred for half an hour at room temperature and 1 hour in a boiling water bath. The cooled reaction mixture is poured onto 15 g of finely divided ice and the pH of the solution is 6.5-7.0 using a 20% w / v solution of sodium carbonate. The precipitated crystals are filtered and washed with water. 0.9 g (58%) of 9- (N-phenyl-N-methyl-aminomethyl) -3-formyl-6-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido-1,2-a-pyrimidine is obtained. . After pe11. Recrystallization from ethanol compound melts at 260-261 ° C. Example 42. 5.0 mmol 3-eth with jarbonyl-A-oxo b, 7,8,9-tetrahydropyrrole-1 (2-a7-pyrimidine is dissolved in 7, Q-dichloroethane, and 0.73-dimethylformamide and 1 55 g of phosphorus oxohpornor. The reaction mixture is stirred for half an hour at room temperature, 1 hour with and half an hour in a boiling water bath. The cooled reaction mixture is poured onto 15 g of finely divided ice and 20% w / v of sodium carbonate is set at pH 6.5-7.0. The phases are separated. The aqueous layer is extracted with 2-10 m of dichloroethane. The combined organic layers are dried with anhydrous sodium sulfate. and the solvent was distilled off. 10 m diethyl ether was added to the oily residue and the crystals were filtered to give 0.75 g (58%) of 8- (dimethyl aminomethylene) -3-ethoxycarbonyl-4-cc-4,6,7 , 8-tetrahydropyrrolo 1,2-aJ pyrimidine, mp, Found:%: C 59.30 j H 6.50; N 15.96. 13 n eO Calc, T .: C 59.18; H 6.37; N 15.78 cl Example 43. 5.0 mmol of 3-cyano-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido 1,2-a pyrimidine is dissolved in 7, 0 ml of dichloroethane. 1.2 formanilide and 1.55 g of phosphorus oxochloride are added to the mixture. The reaction mixture was allowed to stand at room temperature, poured onto 15 g of finely divided ice and a pH of 6.5-7.0 was adjusted to 20% w / v% sodium carbonate. The phases were separated and the aqueous layer was extracted with 2-10 ml of dichloroethane. The combined organic layers are dried with anhydrous sodium sulfate and then the solvent is distilled off. The oily residue is treated with ethanol, then it is crystallized from ethanol-diethyl ether. 0.85 g (58%) 3-cyano-9- (phenylaminomethylene) -6-methyl-4-oxo-6, 7,8,9-tetrahydro-3H-pyrido 1, 2-a pyrimidine is obtained. After recrystallization from ethanol, it melts at 207 ° C. 46 Found,%: C 69.86; H 5.74, N 19.02. . Calculated,%: C 69.85; H 5.50} N 19.17. Example 44. O, 95 g of 3-cyano-6-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido 1, 2-a2 pyrimidine is dissolved in 3,1 dimethylformamide. To the reaction mixture, 1.55 g of phosphorus oxochloride is added at 15–20 ° C, then stirred at room temperature for 2 hours. Thereafter, the mixture is decomposed with 10 ml of absolute ethylene magnesium ethanol and boiled for half an hour. The separated reaction mixture was poured into 50 ml of ice water, and the pH of the mixture was constantly maintained at 7 with 20% w / v - sodium hydroxide solution. The precipitated crystals are filtered and washed with water. 0.9 g (74%) of 3-cyano-9-ethoxymethylene-6-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido f 1,2-aZ pyrimidine is obtained. After recrystallization from ethanol, the compound does not depress the melting point of the mixed sample with the product obtained earlier. Example 45. Analogously to Example 44, a starting point is obtained, starting from 3-ztoxycarbonyl-6-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido 1,2-a pyrimidine, 3H-ethoxycarbonyl-9-ethoxymethylene -6-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido 1, 2-a pyrimidine. The compound does not depress the melting point with the product of the previously mixed sample. Example 46 5.0 mmol of 3-cyano-6-methyl-4-oxr-6, 7,8,9-tetrahydro-4H-pyrido 1, 2-aJ pypyrimidine is dissolved in 10 ml of diethylether. 1.3 g of N-methylformanilide and 1.5 g of phosphorus oxochloride are added to the solution. The cooled reaction mixture is poured onto 10 g of ice. The pH of solution 7 is adjusted to pH 20 with a solution of 7% w / v% sodium carbonate. The organic and aqueous phases are separated and the aqueous layer is extracted with 2-10 ml of dichloroethane. The combined dichloroethane fractions are dried with anhydrous sodium sulfate. After filtration, the dichloroethane is distilled off. The residue is treated with ethanol. The residue is crystallized from a mixture of 5 ml of tillacetate and 15 ml of diethyl ether. The precipitating crystals are cooled, filtered and rinsed with ethyl acetate. 1.25 g (82%) of 3-cyano-methyl-9- (N-methylanilinomethylene) -4-OXO-6, B, 9-tetrahydro-4H-pyrido 1, 2-aj pyrimidine are obtained, which is recrystallized from ethyl alcohol melts at 161-163 ° C. Found: C, 70.53; H 6.03; N 18.03. . Calculated,%: C, 70.57; H 5.92; N 18.29. Example 47. 50 mmol of 3-methoxycarbon-6-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido tl, 2-a pyrimvdin is stirred for 30 minutes at room temperature and 60 minutes with reflux in a mixture, containing 70 ml of dichloroethane, 7.3 g of N, N-dimethylformamide and 15.3 g of phosphorus oxochloride. The cooled reaction mixture is dried onto 150 g of ice and a 20% w / v% solution of sodium carbonate is brought to neutrality. The two phases are separated and the aqueous layer is extracted with 275 ml of dichloroethane. The combined organic phases are dried with anhydrous sodium sulfate and then concentrated. The residue is treated with ethyl acetate, then it is crystallized from ethanol (30 ml). 7.8 g (70%) of 3-methoxycarbonyl-6-methyl-9-dimethylaminomethylene-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido 1,2-a pyrimidine are obtained, which after recrystallization from ethanol melts at 180 ° C. Found,%: C 60.30; H 7.10; N 14.96. C .-, | Hi9NjOj. Calculated,%: C 60.03; H 6.91; N 15.17. Example 48 5.0 mmol of 6,8-dimethyl-4-bxo-6,7,8,9-tetrahydro-4H-pyrido 1,2-a pyrimidine-3-carboxamide is dissolved in 3.15 g of dimethylformamide. To the reaction mixture, 1.5 g of phosphorus oxochloride are added dropwise at 20 g. Then the reaction mixture is stirred for 2 hours at room temperature. After that, the reaction mixture, whose pH is adjusted to neutral with 20% w / v% sodium carbonate solution, is poured onto 15 g of ice. The precipitated crystals after cooling are filtered and washed with water. . 1 g (78%) of 3-cyano-6,8-dimethyl-9-dimethylaminomethylene-4-oxo-b, 7,8,9-tetrahydro-4H-pyrido tl, 2-a-pyrimidine is obtained, which after recrystallization from ethanol melts at 133-135 0. Found,%: C 65.28; H 7.13 N 21.56. . Calculated,%: C 65.095 H 7.02 N 21.69. Example 49 5.0 mmol of 3-ethyl-2, 6-dimethyl-4-oxo-6,7,8,9-tetragyro-4H-pyrido tl 2 and pyrimvdine is dissolved in 3.65 g of dimethylformamide. At 15-20 0, 1.5 g of phosphorus oxochloride are added to the reaction mixture. The mixture is stirred for 1 hour at room temperature, 1 hour at D 55-60 s and half an hour at 90 ° C. The resulting salt of 3-ethyl-9-dimethylimino. methyl 2,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido l, 2-a pyrimidine, without isolation, is hydrolyzed by the following method in 3-ethyl-9-formyl-2, 6-dimesh1 -4-oxo-1,6,7,8-tetrahydro-4H-pyrido 1, 2-a pyrimidine: the cooled reaction mixture is poured onto 15 g of ice and 20% w / v% sodium carbonate solution is adjusted to pH 6.0 -6,5. The precipitating crystals are filtered and flushed with water. This gives 0.85 g (72.5%) of a crystalline substance which, after recrystallization from ethyl acetate, melts at. Found,%: C 66.64; H 7.74; N 11.96. C h gaOz. Calculated%: C 66.60-, H N 11.86, Example 50. 3.8 mmol of 2-phenst-6-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido Cl, 2 α-pyrimidine is suspended in 3 g of dimethylformamide. 1.5 g of phosphorus oxochloride is added dropwise to the reaction mixture at 15–20 ° C. Then the mixture is stirred for 30 minutes at room temperature and 2 hours at 55-60 ° C. The cooled reaction mixture is vented to 15 g of ice and 20 w / v%. solution

15

the pH of the solution is adjusted to sodium carbonate. The precipitating crystalline substance is filtered and washed with water.

1.1 g (89.4) of 2-phenyl-3-formyl-6-methyl-9-dimethylaminomethylene-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido 1,2-aj pyrimidine are obtained. After recrystallization from ethanol, the compound melts at 205 C.

Found,%: C 69.85; H 6.67; N 13.08.

.

Calculated,%: C, 70.34; H 6.52; N 12.95.

Example 51. 1.5 mmol of 7-ethoxycarbonyl-3-phenyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido l, pyrimidine are boiled for 1 h in a mixture of 5 ml of dichloroethane, 0.22 g dimethylformamide and 0, L6 g of phosphorus oxochloride. The cooled reaction mixture is poured onto 5 g of ice and a pH of 7 is adjusted to 20% by weight with a solution of sodium carbonate. The phases are separated and the aqueous layer is extracted with a ml of dichloroethane. The combined organic phases are dried with anhydrous sodium sulfate and the solvent is distilled off. The remaining 9-dimethylaminomethylene-7-ethoxy Arbenyl-3-phenyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido .1,2-a3-pyrimidine is hydrolyzed in the following way: stir for 3 hours at room temperature in 3 ml of 0.5N hydrochloric acid solution. The precipitated crystal is filtered off and flushed with water. Obtain 0.3 g (61%) of 7-ethoxycarbyl-3-phenyl-9-formyl-4-oxo-1, 6,7,8-tetrahydro-4H-pyrido l, 2-a pyrimidine, which, after recrystallization from ethanol melts at.

Found, Z: C, 66.80; H 5.63, N 8.48.

Ci8Hi {i.N204Calculated,%: C, 66.25; H 5.56; N 8.58.

Example 52.5, O mmol 6-methyl-4-oxo-2-piperidyl-6,7,8,9-tetrahydro-4H-pyrido 1,2-a pyrimidine was dissolved in 3.65 g of dimethylformamide. 1.5 g of phosphorus oxochloride is added to the reaction mixture at 15-20 ° C. The mixture is stirred for 6 hours at room temperature.

54616

then drink 20 g of ice. A 20% w / v% solution of sodium carbonate is adjusted to pH 6.0-6.5. The neutral solution is extracted with ml of benzene. The combined benzene fractions were dried with anhydrous sodium sulfate, the solvent was distilled off. The residue is treated with ethyl acetate. Oily

the substance is triturated with petroleum ether.

0.6 g (43%) of 9-formyl-6-methyl-4-oxo-2-piperidyl-1, 6,7,8-tetrahydro-4H-pyrido are obtained.

1,2-a} pyrimidine, which, after recrystallization from ethanol, melts at 20b-207 ° C.

Found,%: C 64.84; H 7.74; N 15.40.

.NjOj. .

Calculated,%: C 65.43; H 7.69; N 15.26.

Example53. 10.0 mmoles of 3-ethoxycarbonylethyl-6-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido 1,2-a2 pyrimidipa is dissolved in 7.3 g of dimethylformamide. 3.1 g of phosphorus oxochloride are added dropwise to the reaction mixture at 20 ° C.

The mixture is then stirred for 1 hour at room temperature and 2 hours at 60 ° C. The reaction mixture is cooled and poured onto 30 g of ice. 20 w / v% carbonate solution

sodium is adjusted to pH 7. The precipitated crystalline substance is filtered off after cooling and washed with water.

2.2 g (79%) of 3-ethoxy are obtained.

bonylethyl-9-formsh-6-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido 1,2g pyrimidine, which after recrystallization from ethanol melts at 112 ° C.

Found,%: C 61.62, H 7.02, N 9.51.

 .

Calculated,%: C 61.63-, H6.90; N 9.58.

Example 54. Analogously to Example 50, a preparation is obtained, starting from 10 mM of (+) - 3-carboxy-6-metsht-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido 1,2-a pyrimidine (+116 ,

C 2, methanol), 1.2 g (38%)

(-) - 3-carboxy-9-dimethylaminomethylene-6-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido 1 52-aZpyrimidine. After 17 recrystallisations from ethanol, the compound at (aiij -497 ° + 5, c 1, methanol), Example 55. Similarly to Example 46, starting from 10.0 m 3-ethoxycarbonyl-6-methyl-4-oxo-6, 7 , 8,9-tetragon-1CHro-4H-pyrido P, 2-aj pyrimidine, 2.3 g of N-formylpiperidine and 3.1 g of phosphorus oxo-chloride 3-, 25 g (98%) 3-ethoxycarbon-9-piperidinadinemethyl-6- methyl 4-oxo-6, 7,8,9-tetrahydro-4H-pyrido 1,2-aZpyrimidine. After recrystallization from ethanol, the compound does not depress the melting point of the mixed sample with the compound obtained earlier. Example 56. 10.0 mmol of 3,6-dimethyl-4-oxo-6,7,8,9-tetrahyd oo-4H-pyrido 1,2-aJ pyrimidine is dissolved in 20 ml of dichloroethane. The reaction mixture is stirred with 2.3 g of N-formylpiperidine and 3.1 g of phosphorus oxochloride for 30 minutes at room temperature and 1 hour at reflux. The cooled reaction mixture was poured onto 20 g of ice, 20 weight / vol. The pH of the solution of sodium carbonate is adjusted to pH 7. The phases are separated and the aqueous layer is extracted with ml of dichloroethane. The combined dichloroethane fractions are dried with sodium sulphate, then the solvent is distilled off. The resulting 3,6-dimethyl-9-piperidinomeptiene-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido 1,2-a pyrimidine is stirred in 15 ml of hydrochloric acid 1 at room temperature. The precipitated crystalline product is filtered off and washed with water. 1.1 g (53%) of 9-formyl-3, 6-dimethyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido Cl, 2-a are obtained. pyrimvdina. After recrystallization from ethanol, the compound does not depress the melting point with the product obtained according to example 26. Example 57. Similarly, in Examples 11-13, using 3-ethoxycarboNYL-4-Oxo-4, 6,7,8,9, as the starting material, 10-hexahydroazepino 1,2-aj-pyrimidine to obtain 3-ethoxycarbonyl-9- (dimethylaminomethylene) -4-OXO-4,6,7,8,9,10-hexahydroazepino 1,2-pyrimidine with a yield of 52% t. pl. 138 ° C. 46 18 Found: C 61.93-, H 7.38, N 14.51. is ziNjOj. Calculated,%: C, 61.84; H, 7.2; N 14.42. Example 58. Analogously to Examples 11-13, using 3-ethoxycarbonyl-6-methyl-4-oxo-4, 6,7,8-tetrahydropyrrolo Cl, 2-α-pyrimidine-adine as the starting material, 3-ethoxycarbonyl-9- ( dimethylaminomethylene) -6-methyl-4-oxo-4, 6,7,8-tetrahydropyrrolo 1, 2-aJ pyrimidine in 60% yield, which after crystallization from ethyl acetate melts at. Found,%: C 60.90 j H 7.06 v N 15.04. . Calculated,%: C 60.64j H 6.91; N 15.15. Example 59. Analogously to Examples 3-10, using Z-carboxy-4-oxo-4-6, 7,8-tetrahydropyrrolo 1,2-a as a pyrimidine as the starting material, 9-dimethylaminomethylene} -3-carboxy-4- is obtained. oxo-4, 6,7,8-tetrahydropyrrolo 1,2-aZ pyrimidine with a yield of 81%, which after crystallization from dimethylformamide melts at 292295 ° C. Found,%: C 56.25; H 5.66, N 17.76. C HijNjOj. Calculated,%: C 56.16; H 5.57; N 17.86. Example 60. Analogously to Examples 22-29, using 2,3-trimethylene-7-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido C1,2-aZ pyrimidine as the starting material, 2 are obtained , 3-trimethylene-7-methyl-9-formyl-4-OXO-1, 6,7,8-tetrahydro-4H-pyrido 1, 2-aJepip J idin in 25% yield, which after separation on an chromatographic column with an oxide aluminum (eluent - benole) melts at 137c. Found,%: C, 66.95; H 6.85; N 12.20. . Calculated,%: C 67.22 j-H 6.94 N12.06. Example 61 .10.0 mopy of 2,3-tetramethylene-4-oxo-6,7,8,919 -tetrahydro-4H-pyrido (1,2-aJ pyrimidine is dissolved in 7.3 g of dimethylformamide and added at 15–20 ° C 3, 1 phosphorus oxychloride.The reaction mixture is stirred for 2 hours with and for 1 hour in a boiling water bath, then cooled and poured onto 30 g of ice, the pH of the resulting solution is adjusted by means of a 20% sodium carbonate solution. to 7.0. The isolated crystals are separated by filtration, washed with water, and then 2,3-tetramethylene-9-formyl-4-oxo-1,6,7,8-tetrahydro-4H-pyridoran, 2-a pyrimidine are obtainedwith a yield of 67%, which, after being separated on a silica gel chromatographic column on 60 (Merck, 0.2-0.5 mm) (benzene zluent), melts at 160-161 ° C. Found: C 67.14; H 6; 87; N 11.94. C jHigNjOs. Calculated,%: C 67.22; H 6.94 N 12.06. Example 62. Similarly, for example 61, using 2,3-tetramethylene-6-methyl as the starting material -4-oxo-6, 7,8,9-tetrahydro-4H-pyrido p, 2-a pyrimidine, get 2,3-tetramethylene-6-methyl-96-formyl-4-oxo-1,6,7, 8-tetrahydro-4H-pyrr, o 1,2-a pyrimidine with a yield of 58%, which melts at 128 s. Found,%: C 67.95; H 7.23i N 11.55. Ci H-ijNzOi. Calculated,%: C 68.27; H, 7.36; N 11.38. Pharmacological data. The allergic reactions that occur due to the interaction between antigens and antibodies occur in different organs and tissues in different ways. Asthma is one of the most common forms of allergy. Disodium chromoglucate (cromoline sodium) (1,3-CI (2-carboxychromon-5-yloxy) -2-hydroxypropane, intal) is widely used for treatment. The action of compounds of the general formula t is superior to 1yg of the action of disodium chromium glucate. In tab. 7 summarizes the results of experiments on passive cutaneous anaphylaxis. These experiments were performed on rats. 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371181546

Test compounds

Disodium Chromoglucate

8-C (fvinylamino) methylene 3-3-carboxy-4-oxo-4,6,7,8-tetrahydropyrrolo f1,2-ha | pyrimidine acetate

8- (phenylamino) meth- jle-3-carboxy-6-methyl-4-oco-4, 6,7,8-tetrahydropyrrolo O, 2-a} pyrimidine

9- (Hydroxyfennpamine) methylene 3-carboxy-6-methyl-4-OXO-6, 7,8,9-tetrahydro-4H-pyrido Ql, 2-aJ pyrimidine.

9- (3-Methylphenylamino) metelen} -3-carboxy-6-methyl-4-OXO-6

9- (2-Carboxyphenylamino) methylene-3-carboxy-6-methyl-4-CGCCO-6, 7,8,9-tetrahydro-4H-pyrido 1, 2-a2 pyrimidine

9- (4-Carboxyme, 1-phenylamino) methylene-3-carboxy-6-methyl-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido 1,2-a pyrimidine

9- (3-Pyridylamino) methylene-3-carboxy-6-metsh1-4-oxo-6, 7,8,9-tetrahydro-4H-pyrido 1,2-a j pyrimodine

38 Table 7

 / i M / kg, in the PGA test

1.0 15.4 20.2

4.1 0.8.

t, 1

5.8

2.4

Claims (1)

The method of obtaining condensed pyrimidine derivatives of the general formula / B 4 HC (CH ₂ ) iAy ^N Ri O, where R is hydrogen or alkyl with 1-4 carbon atoms; R., - alkyl with 1-4 carbon atoms i - halogen, hydrogen or phenyl; Rj is alkoxycarbonyl with 2-5 carbon atoms., Carboxy- '' cyano, carbohydrazido group, phenyl, alkylaminocarbonyl with 1-4 carbon atoms, formyl or alkyl with · 1-4 carbon atoms; R ₄ is alkyl with 1-4 carbon atoms or phenyl; Ry is alkyl with 1-4 carbon atoms, or P> ₄ and Ry together with a common nitrogen atom form a piperidine ring, L = 0 or 1, or 2, in the form of racemates or optical isomers, characterized in that the compounds of the general formula where R-Rj and η have the indicated meanings, or their optical isomers are reacted with an iminium salt of the general formula where R ₄ and Ry have the indicated meanings; X is halogen at 0-150 ° C and the resulting compound of the general formula SU W, 1181546 where R - R _tf , n and X have the indicated meanings, are treated with alkali metal carbonate at room temperature, followed by