NO152607B - OUTPUT MATERIALS FOR USE IN THE PREPARATION OF THERAPEUTIC ACTIVE PYRIDINE DERIVATIVES. - Google Patents

Description

The present invention relates to starting materials for use in the production of therapeutically active pyrimidine derivatives.

The starting materials are characterized by their general formula:

where R denotes hydrogen or C 1 -C 4 -alkyl, R"*" denotes C 1 -C 4 -alkyl, carboxy, C 1 -C 4 -Alkoxycarbonyl, carboxamide or cyano, and optically active antipodes and salts thereof. Compounds of general formula I containing carboxy groups form salts with pharmaceutically acceptable bases such as alkali metal salts, e.g. sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, ammonium salts, and with organic amines such as triethylamine salts, ethanolamine salts, etc. Optical isomers of the compounds of general formula I are also within the scope of the invention. The starting materials of general formula I, salts and optically active isomers thereof, can e.g. is prepared by the following methods (a) or (b): a) a racemic or optically active monohalogen compound of general formula ;or ;b) a racemic or optical compound of the general formula: ;in which R and R"'" are as indicated above, is reacted with a brominating agent, and if desired, that an R^ group in a compound of general formula I is converted into another R 1 group and, if desired, that a racemate of general formula I is separated into the optically active antipodes. According to method variant (a), a compound of general formula (II) in which R and R are as defined above is reacted with at least one equivalent amount of a brominating agent. Preferably, the brominating agent is used in an amount of 1 - 1.5 molar equivalents. According to method variant (b), a compound of general formula (III) in which R and R are as defined above is reacted with at least two molar equivalents of a brominating agent. The preferred amount of brominating agent is 2 - 2.5 molar equivalents, calculated for the compounds of formula (III), Conventional halogenating agents known in the art can be used as brominating agent. Elemental bromine, bromine compounds such as 1,3-dibromo-5,5-dimethylhydantoin, N-bromo-caprolactam, tribromo-acetofenone, copper (II) bromide and complexes such as pyridinium bromide-perbromide, phenyltrimethylammonium nium perbromide, tetramethylammonium tribromide, . dioxane dibromide, pyrrolydone-2-hydro-tribromide can be used, optionally in the presence of a catalyst, e.g. a Lewis acid such as aluminum bromide and chloride, phosphorus trichloride, sulphur, calcium oxide, UV irradiation, dibenzoyl peroxide, etc. The bromination is carried out in a known manner. Compounds of general formula (II) and (III) are reacted respectively with the suitable brominating agent in an inert solvent, e.g. alkanecarboxylic acid, halogenated hydrocarbon etc, preferably in acetic acid or chloroform. Optionally, acid-binding agents such as triethylamine, acetamide, sodium acetate etc. can also be used. The reactions are carried out at a temperature between 0 and 160° C, preferably at 20 - 60° C. Compounds of general formula (I) or their salts either precipitate from the reaction mixture and can be removed, e.g. by filtration, or separated from the reaction mixture by evaporation of the solvent. Compounds of general formula (I) can be purified by known techniques, such as recrystallization, chromatography, etc. A compound of general formula (I) can be converted, if desired, into another compound of general formula (I) by standard methods. ;The new starting materials of formula I are used in the new and inventive methods described in Norwegian patent applications no. 801379 and 801380 for the production of therapeutically active pyrimidine compounds which are known from Norwegian patent applications no. 784392 and 784393. ;The invention is further illustrated in the following - following examples. ;Example 1 ;1.4 g (0.005 mol) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid dissolved in 15 ml of chloroform, dried over sodium sulphate. A solution of 0.3 ml (0.005 mol) bromine in 5 ml chloroform was added dropwise to the solution under vigorous stirring and at room temperature. The reaction mixture was then stirred at room temperature for 1/2 hour, and allowed to stand overnight. The precipitated crystals were filtered off and washed with a small amount of chloroform. 10 ml of water and 10 ml of chloroform were added to the precipitate, and the pH of the aqueous phase was adjusted to 2 with a 5% by weight sodium bicarbonate solution while stirring. The organic phase was separated, the aqueous phase was shaken with two 10 ml portions of chloroform. The combined organic phases were dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from methanol. 0.3 g (16.4%) of 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid was obtained, with sm.p. 165 - 166° C. ;Analysis for C^gH^Qt^O-jBr: ;Calculated: C 32.81% H 2.75% N 7.65% Br 43.65 ;Found : C 33.22% H 2.78% N 7.65% Br 43.58% ; Example 2 ; 1.4 g (0.005 mol) 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H- pyrido[1,2-a]pyrimidine-3-carboxylic acid was dissolved in 30 ml of glacial acetic acid. A solution of 0.3 ml (0.05 mol) bromine in 2 ml glacial acetic acid was added dropwise to the solution with stirring and at room temperature. The reaction mixture was then stirred at 40 - 60° C. for 1/2 hour, after which the acetic acid was distilled off under reduced pressure. 10 ml of water and 10 ml of chloroform were added to the residue, and the pH of the aqueous phase was adjusted to 2 with a 10% by weight solution of sodium bicarbonate while stirring. The organic phase was separated, the aqueous phase was shaken with two 10 ml<1>s portions of chloroform. The combined organic phases were dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from methanol. ;0.8 (53.8%) 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid was obtained with sm.p. 164 - 166° C. The product gave no melting point depression when mixed with the product according to example 1. ;Example 3 ;14 g of crystalline sodium acetate and 10.4 g (0.05 mol) of 6-methyl-4-ox6-6,7 ,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid was dissolved in 100 ml of glacial acetic acid. 5.4 ml (0.1 mol) bromine was added dropwise to the solution very slowly and at room temperature and with stirring. The reaction mixture was then stirred at room temperature for 2 hours, after which the solvent was distilled off under reduced pressure. 50 ml of water and 50 ml of chloroform were added to the residue, and the pH of the aqueous phase was adjusted to 2 with a 5% by weight solution of sodium carbonate while stirring. The organic phase was separated, the aqueous phase was shaken with two 50 ml<1>s portions of chloroform. The combined organic phases were dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from methanol. ;9.4 g (51.3%) 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid was obtained with a melting point of 165 - 166° C. The product gave no melting point depression when mixed with the product according to example 1 example 2. ;Example 4 ;By following the procedure described in example 2, but substituting racemic ( +)-9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid with optically active (+)-9-bromo -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid, (+)-9,9-dibromo- 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid with m.p. 157 - 159° C. Yield: 49.0 ;[a]<20> = +47.5° (c = 1, methanol). ;D ;Analysis: for C^gN^g^O-jBr: ;Calculated: C 32.81% H 2.75% N 7.65% Br 43.66% ;Found : C 33.11% H 2, 60% N 7.56% Br 43.44% ;Example 5 ;By following the procedure described in Example 3, but substituting racemic (+)-6-methyl-4-oxo-6,7,8, 9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid with optically active (-)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l, 2-a]pyrimidine-3-carboxylic acid, (+)-9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a ]-pyrimidine-3-carboxylic acid with m.p. 157 - 158° C. The product gave no melting point depression when mixed with the product according to example 4. Yield: 51.2%, ;[a]^°= +47.5° (c = 1, methanol). ;Example 6 ;By following the procedure described in Example 2j but substituting racemic (+)-9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1 ,2-a]pyrimidine-3-carboxylic acid with optically active ]-)-9-bromo-6-methyl-4-oxo-6,7,8,9-tetra-hydro-4H-pyrido[l,2-a ]pyrimidine-3-carboxylic acid, (-)-9,9-di nrom-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine was obtained -3-carboxylic acid with m.p. 157 - 159° C. Yield: 49.5%, [ a]* 0 = -47.5° (c = 1, methanol).

Analysis for C-^H^Q^O^Br:

Calculated: C 32.81% H 2.75% N 7.65% Br 43.65%

Found : C 33.21% H 2.72% N 7.60% Br 43.62%

Example 7

By following the procedure described in Example 3, but substituting racemic (+)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H—-.pyrido [1,2-a] pyrimidine-3-carboxylic acid with optically active (+)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidine-3-carboxylic acid, it was obtained (-)-9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]-pyrimidine-3-carboxylic acid with m.p. 157 - 159° C. Yield: 51.5%, [α]<20> = -47.5° (c = 1, methanol). The product gave no melting point depression when mixed with the product of Example 6.

Example 8-11

1.4 g of crystalline sodium acetate and 0.005 mol of a starting compound shown in Table I were dissolved in 10 ml of glacial acetic acid. 0.54 ml (0.01 mol) bromine was added dropwise to the solution

at very low speed, with stirring and at room temperature. The reaction mixture was then stirred for 2 hours at room temperature, after which the acetic acid was distilled off under reduced pressure. To the residue was added 10 ml of chloroform, and the suspension was stirred for 15 minutes at room temperature. The crystals were filtered off and washed with chloroform. The filtrate was evaporated. The residue was recrystallized from the solvent indicated in Table I.

Example 12 - 17

1.4 g of crystalline sodium acetate and 0.005 mol of a starting compound shown in Table II were dissolved in 10 ml of glacial acetic acid. 3.2 g (0.01 mol) of pyridinium bromide-perbromide was added in portions to the suspension while stirring and at room temperature. The reaction mixture was then stirred at room temperature for 2 hours, and acetic acid was distilled off under reduced pressure. 10 ml of water was added to the residue and it was shaken with three 10 ml portions of chloroform. The combined organic phases were dried over anhydrous sodium sulfate and the solvent was distilled off in vacuo. The residue was recrystallized from methanol.

Example 18

By following the procedure described in;-; -Example 8, but starting from 3,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, 9,9-dibromo-3 ,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one with m.p. 114 - 115° C. Yield: 3 0.0%.

Analysis for <C>10H12<N>2<O>Br2:

Calculated: C 35.74% H 3.59% N 8.34% Br 47.56%

Found : C 35.74% H 3.72% N 8.22% Br 47.85%

Example 19

To a solution of 2.1 g (0.01 mol) 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid in 20 ml of chloroform, 3.6 g (0.02 mol) of N-bromosuccinimide was added portionwise while stirring. The reaction mixture was refluxed for 5 hours and the chloroform was distilled off under reduced pressure. To the residue was added 20

ml of water and the suspension was stirred at room temperature for 15 minutes. The insoluble crystals were filtered off, dried and crystallized from methanol. 1.5 g (41.0%) of 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid was obtained with m.p., 163 - 164° C.

Example 20

By following the procedure described in Example 8, but replacing 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid with 3 -ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one and recrystallizing the crude product from a 50% aqueous ethanol solution, it was obtained 9,9-dibromo-3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one with m.p. 90 - 92°C. Yield: 57.2%.

Analysis for C^2H^gN2<-)Br2 :

Calculated: C 39.59% H 4.43% N 7.69% Br 43.9%

Found : C 39.21% H 4.25% N 7.59% Br 43.76%

Claims (1)

Starting materials for use in the production of therapeutically active pyrimidine derivatives, characterized in that they have the general formula: where R denotes hydrogen or C^-C^-alkyl, R 1 denotes C1-C4- alkyl, carboxy, C^-C^-alkoxycarbonyl, carboxamide or cyano, and optically active antipodes and salts thereof.