SU665805A3 - Method of producing derivatives of pyrido (1,2a) pyrimidine or their optically active isomers or their salts - Google Patents

Description

(54) METHOD FOR PRODUCING PYRIDO DERIVATIVES, 2-a

PYRIMIDINE OR THEIR OPTICALLY ACTIVE

ISOMERS, OR THEIR SALTS

one

The invention relates to a process for the preparation of novel condensed pyrimidine derivatives, or their optically active isomers, or their salts, which can be used in medicine.

Methods for reducing a double bond by catalytic hydrogenation in the presence of catalysts or complex metal hydrides are well known in the literature.

The aim of the invention is the synthesis of novel biologically active pyrido 1,2-a pyrimidine derivatives.

The goal is achieved by the described method of producing pyrido {1,2-a-lirimidine derivatives of the general formula

N

J

with OPEC,

R and R are alkyl groups,

hydrogen atom or alkyl group C

1-6,

2

or their optically active isomers, or their salts.

The method consists in the fact that condensed pyrimidine derivatives of the general formula II being in the racemate form or in the optically active form

ten

in which R, iR and R2 are as defined above,

or their salts are reduced by catalytic hydrogenation or complex metal hydride.

In the case of catalytic hydrogenation, the process is preferably carried out at atmospheric pressure or under pressure, preferably athe, in the presence of a palladium catalyst on activated carbon or skeletal catalyst at a temperature from 0 to 150 ° C,

As complex metal hydrides, sodium borohydride, sodium bis (2-methoxyethoxy) aluminum hydride, potassium borohydride, lithium aluminum and borohydride are preferably used. When recovering with complex metalpidridam, the choice of solvent depends on the reduction1, its means. Suitable reduction media are alcohols, preferably methanol and ethanol, aromatic hydrocarbons, for example benzene, toluene, or ethers, preferably dithyl, tetrahydrofuran or diokean.

In catalytic hydrogenation, the reaction mixture is tripled after catalyst separation. If the reduction is carried out with metal hydrides, the processing depends on the solvent. After decomposition of the excess reducing agent, in the case of the addition of organic solvents, the solvent is evaporated. When working in an aqueous medium, the reaction mixture is preferably extracted with chloroform or benzene and the compound of general formula I is obtained by evaporation of the organic phase. Condensed pyrimidine derivatives of general formula II or their salts, more preferably chlorides, bromides, methyl sulfonates, etc., are used as the starting material.

To obtain condensed pyrimidine derivatives of the general form I, one can also proceed from optically active condensed pyrimidine derivatives of the general formula II.

The condensed pyrimidine derivatives of general formula II used as starting materials are known and, accordingly, can be obtained by known methods.

Example 1. 1,6-Dimethyl-3 - (N-methylcarbamo "l) -4 - oxo - 1,6,7,8,9,9 aah - hexahydro-4H-pyrido | 1, 2-a Pyrimidine.

23.5 g of 1,6-dimethyl-3- (M-methylcarbamoyl) 4-oxo - 1,6,7,8 - tetrahydro - 4H - nirido 1,2-a pyrimidine with 300 ml of ethanol in the presence of 15 g of 10% Palladium on active carbon is hydrogenated at atmospheric pressure and at room temperature. After uptake of 1 mol of hydrogen, the catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue is recrystallized twice from ethanol. 1,6-Dimethyl-3- (S - methylcarbamoyl) -4 - oxo - 1,6,7,8,9,9 aa - hexahydro4H-pyrido 1, 2-a pyrimidine is melted at 203-204 ° C.

Calculated,%: C 60.74; H 8.07; N 17.71.

Found,%: C 60.95; H 8.03; N 17.83.

Example 2. 1,6-Dimethyl-4-oxo - 1,6,8,9, 9aazh-hexahydro-4H - pyrido 1,2-a pyrimidine-3-carboxam D.

6.6, g 1,6ah-Dimethyl-4-oxo - 1,6,7,8-tetrag. Hydro-4H-pyrido 1,2-a pyrimidine - 3-carboxamide in 300 ml of methanol in the presence of:

4.5 g of 10% palladium on active carbon is hydrogenated at atmospheric pressure and at room temperature. After a bang, yen

1 mol of hydrogen, the catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue is recrystallized three times from ethanol. 2.6 g of 1,6-dnmethyl-4-0Xo - 1.6,7,8,9,9aa.,; Hexahydro-4H-pyrido 1,2-a pyrimidip-3-carboximide are obtained; m.p. 205-206 ° C.

Calculated,%; C, 59.18; P 7.67; N 18.82. Paydepo,%: C 59.07; P 7.68, N 18.85. Example 3. It is operated as described in Example 2, but (-) - 1.6a.l: -dimethyl-4 - oxo1, 6,7,8 - tetrahydro-4H-pyrido 1,2- and nirimidine-3-carboxamide; a -70 ° C (c2, in methanol).

Prepared in 40% yield with (-) - l, 6D-dimethyl - 4 - oxo-1,6,7,8,9,9 aax hexahydro - 4P - pyrido 1,2-a pyrimidine carboxam. 227 ° (c 1, in ethanol); m.p. 221222 ° C.

Calculated,%: C59,18; P 7.67; N 18.82. Found,%: C 59.31; H 7.71; N 18.80. Example 4. It was operated as described in Example 2, but (+) -1,6-dimethyl-4-oxo1, 6,7,8, tetrahydro-4H-pyrido | 1,2-a pyrimidine-3-amide of carboxylic acid; a ° - + 70 ° С (с 2, in methanol).

Receive with a yield of 41% (+) -1,6ed-dimethyl-4 - oxo-1,6,7,8,8,9-hexahydro - 4Npyrido 1,2-a pyrimidine - 3-carboxamide; a + 228 ° (c 1, in ethanol);

m.p. 220-222 ° C.

Calculated,%: 59.18; H 7.67; N 18.82. Found,%: C 59.19; H, 7.80; N, 18.75.

Example 5. 14.5 g of the salt of sulfuric acid monomethyl ester of (H -) - 1,6a-Dimethyl4-oxo - 1,6,7,8 - tetrahydro - 4H-pyrido 1,2-a pyridip-3-carboxamide; but

this salt + 37.5 ° (2, in methanol) is dissolved in 150 ml of water and the solution is cooled below 20 ° C. Then, 1.82 g of sodium borohydride in 13 ml of water H is added dropwise to the solution. The reaction mixture is transferred

2h at room temperature. After that, the pH of the solution is adjusted to neutrality.

and the solution is extracted twice with chloroform but 50 ml. The organic phases are combined and evaporated under reduced pressure. The residue is recrystallized from ethanol. 7.8 g of (+) -1,6-dimethyl-4-oxo-1, 6, 7, 8, 9aah-hexahydro4H-pyrido 1, 2 -a and nirimidine-3-carboxamide are obtained; -f268 ° (c 1, in ethanol); m.p.

209-210 ° C.

Calculated,%: C 59.18; H 7.67; N 18.82.

Found,%; C, 59.02; H 7.65; N 18.84.

Example 6. Work, -as described in

Example 5, but the monomethyl sulfuric acid salt is used as the starting material; (-) -1,6 -x-dimethyl-4-oxo-1,6,7,8 tetrahydro-4H-pyrido 1,2-a pyrimidine-3- . carboxyamide; o.1f -37,5 ° (c 1, in methanol.) .. ....

Loluchay with. yield 79% {.-) -1,6ah-dimeti. l-4 - oxe - 1,6,7,8,9,9 aah - hexahydro4H - item IridO 1,2 - and pyrimidinecarbo "emid; m.p. 209-210 ° C; -26G (with 1, in ethanol).

Calculated,%: C 59.18; H 7.67; N 18.82.

Found,%: C 59.15; H 7.71; N 18.78.

Example 7. 9.0 g of a salt of 1,6-dimethyl-4-ox-3- (N - methylcarbamoyl) - 1,6,7,8-tetrahydro-4H-pyrido 1, 2-a pyrimidine with mopomethyl sulfuric acid dissolved in 100 ml of water. The solution is cooled below 10 ° C and 1.8 g of sodium borohydride are added normally over 15 minutes. The reaction mixture is stirred for 2 hours and then the pH of the solution is adjusted with hydrochloric acid to 3-4. The solution is extracted with chloroform. The organic phase is dried over sodium sulfate, filtered and extracted by reduced pressure. 5.5 g of 1,6-dimethyl - OKCO-3- (N - austilcarbamoyl1, 6,7,8,9a-hexahydro - 4P - pyrido 1,2-a pyridine are obtained. After recrystallization from ethanol, the product melts at 177-179 ° s

Calculated,%; C, 60.74; H 8.07; N 17.71.

Paideno,%: C, 60.53; H 8.11; N 17.72.

Example 8. South 1.7-dimethyl-4-oxo-1, 6,7,8-tetrahydro-4H-2-nirimidine 3-carboxamide is dissolved in 120 ml of water and the solution is cooled below 20 ° C. Then, 2.5 g of sodium borohydride in 20 ml of water is added dropwise to the solution, and the reaction mixture is stirred for 2 hours at room temperature. The RP solution of the solution is then brought to neutrality and the solution is extracted three times with 50 ml of chloroform. The organic phases are combined and evaporated at a reduced pressure. The residue is crystallized from ethanol. 6 g (89%) of 1,7-dimethyl-4-oxo-1,6,7,8, 9a-hexahydro-4H pyrid 1,2-a pyrimidine 3-carboxamide are obtained; m.p. 242-244 ° C.

Calculated,%: C 59.18; H 7.67; N 18.82.

Paydeno,%: C 59.95; P 7.60; N 18.63.

Example 9. 20 g of 1,8-dimethyl-4-oxo1, 6,7,8-tetrahydro-4H-pyrndo 1,2-a pyrimidine-3-carboxamide are dissolved in 240 ml of water and the solution is cooled below 20 ° C. Then, 5 g of sodium borohydride in 40 ml of water is added to the solution through the channels and the reaction mixture is stirred at room temperature for 2 hours. Then the RP solution is brought to neutrality and the solution is extracted three times with chloroform but 75 ml. Or-ganic phases. Obedin and evaporated under reduced pressure. The residue is recrystallized from methanol. 12 g (89%) of 1,8-dimethyl-4-oxo1, 6,7,8,9a-hexahydro-4P-pyrido 1,2-a are obtained

m.p. 215-

nirimidin-3 carboxamide;

217 ° C. . ...

Calculated,%: C 59.18; H 7.67; N 18.82.

Paydeno,%: C 59.25; H 7.76; N 19.03. Example 10. 5 g of 1,8-dimethyl-4-oxo1, 6,7,8-tetrahydro-4H-1,2-a pyridide nirimidine-3-carboxamide. dissolved in 300 ml of ethanol. in the absence of 4.5 g of palladium on activated carbon and hydrogenated at atmospheric pressure and room temperature. After termination, the hydrogen catalyst is filtered off and the filtrate is evaporated under reduced pressure. 3.1 g (90%) of 1,8-dimethyl - 4 - oxo-1,6,7,8,9a-4H-pyrido G1,2-a Nirimidine-3-carboxamide are obtained. The product, after recrystallization from methanol, melts at 215-216 ° C.

5.94 g of phenyl-1,6-dimethyl-4-oxo-1,6,7,80 tetrahydro-4P-pyrido-1,2-a pyrimidine 3-carboxamide is dissolved in 300 ml of ethanol in the presence of 1 g of 10% palladium on activated carbon and hydrogenated at atmospheric pressure and room temperature. After termination of the hydrogen scale, the catalyst is filtered off, the filtrate is evaporated under reduced pressure. 5.9 g (98%) of a slowly crystallizing residue are obtained in the form of an oil, which is recrystallized from ethyl acetate.

1,6-Dimethyl-4-oxo-1,6,7,8,9 hexahydro-4H-pyrido1 1,2-a pyrimidine 3-carboxamide is obtained; so nl 122-125 ° C.

Calculated,%; C 68.20; P 7.07; N 14.04.

Found,%: C 68.49; H 7.03; N 13.84.

Claims (1)

1. A method of producing pyrimidine nirido 1,2-a derivatives of the general formula Ri IT LI N made where R and R - alkali groups Ci.-6; R2 is a hydrogen atom or an alkyl group. na, or their optically active isomers, or their salts, are distinguished by the fact that condensed pyrimidine derivatives of the general formula which are in the form of racel ata or in optically active form V N R xN CONHR . where R, R and R2 have the above values, or theirSOLES are reduced by catalytic hydrogenation or by complex metal hydride, 7 §. A method according to claim 1, characterized in that the catalytic hydrogenation is carried out in the presence of a catalyst from lalladi on activated carbon or skeletal catalyst. 5 3. The method of pl. 1 and 2, characterized in that the catalytic hydrogenation is carried out at atmospheric pressure or at overpressure. 4. Method according to paragraphs. 1-3, characterized by the fact that the process is carried out at a pressure of from 1 to 15 MPa. 5. Method according to paragraphs. 1-3, characterized in that it recovers what is provided at a temperature of 150 ° C. 6. A method according to claim 1, characterized in that sodium borohydride, sodium bis (2-methoxyethoxy) aluminum hydride, potassium borohydride or lithium aluminum hydride are used as the complex metal hydride. Sources of information taken into account in the examination 1. Weigand-Hilgetas. Experimental methods in organic chemistry. M., “Himi, 1968, p. 28 ff.