CS241025B2 - Method of fussed pyrimidine-4-ons' dihalogenated derivatives production - Google Patents

Abstract

Geminal dihalogen derivatives of condensed pyrimidine-4-one compounds of the general formula <IMAGE> [wherein R represents hydrogen, lower alkyl, or lower alkoxycarbonyl; R<1> represents hydrogen, lower alkyl, ester group, carboxy or a derivative thereof, cyano, phenyl or halogen; R<2> represents hydrogen, lower alkyl or phenyl; X represents halogen; n is the integer 0, 1 or 2] and the salts and optically active antipodes thereof are of interest as chemical intermediates; some also exhibit a variety of physiological activities and may be formulated into pharmaceutical compositions in conventional manner. The novel compounds can be made by halogenating a corresponding starting material wherein one or both X-substituents are hydrogen.

Description

Process for the preparation of dihalogenated derivatives of fused pyrimidin-4-ones of general formula (I)

(I) wherein the substituents are as defined in the definition, as well as the optically active antipodes of the racemates and salts thereof, characterized in that a racemic or optically active derivative of the general formula JI is reacted

wherein the substituents are as defined above, with a halogenating agent in an amount of up to 2.5 molar equivalents in the presence of an inert organic solvent.

The invention relates to a process for the preparation of dihalogenated derivatives of fused pyrimidin-4-ones. These compounds have therapeutic effects and can be incorporated into pharmaceutical preparations. In addition, they are valuable intermediates for the synthesis of other compounds with antiallergic and / or anti-asthma properties, some of the compounds thus obtained have an analgesic, anti-inflammatory, anti-platelet aggregation, anti-sclerotic, anti-asthmatic and / or antiallergic activity.

It is well known that some condensed pyrimidine compounds have analgesic and other central nervous system effects as described in British Patent Specification No. 1,209,946. A typical compound of this type is 3- (ethoxycarbonyl) -1,6-dimethyl-4. -oxo-6,7,8,9-tetrahydro-4Hpyridof 1,2-apyrimidinium methosulfate (Probon ^R , Rimazolium), which has excellent analgesic properties and is widely used in medicine [Arzneimittelforschung 22 (1972) 815].

The compounds of formula I can be obtained by the process of the invention

where

R is hydrogen or alkyl of 1 to 4 carbon atoms,

R @ ¹ represents a hydrogen atom, a C1 -C4 alkyl group, a carboxyl group, a C2 -C5 alkoxycarbonyl group, a carbamoyl group, a cyano group, a phenyl group or a bromine atom,

R ² is hydrogen, alkyl of 1 to 4 carbon atoms or phenyl,

X represents a chlorine or bromine atom, n represents an integer of 0, 1 or 2 as well as optically active antipodes, racemates and salts of these compounds.

Alkyl groups or alkyl moieties of other groups, for example C 1 -C 4 alkoxy groups in a straight or branched aliphatic saturated hydrocarbon chain, i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl .

The term "halogen atom" includes chlorine or bromine atoms.

Preferred compounds of the invention are those compounds of formula I wherein the substituents have the following meanings:

R is hydrogen, alkyl of 1 to 4 carbon atoms, preferably methyl,

R @ ^{1 is} carboxy, C2 -C5 alkoxycarbonyl, preferably methoxycarbonyl or ethoxycarbonyl, cyano, carbamoyl; alkyl of 1 to 4 carbon atoms, preferably methyl or phenyl,

R ² is hydrogen or alkyl of 1 to 4 carbon atoms, preferably methyl,

X is chlorine or bromine, n is an integer of 0, 1 or 2.

The compounds of formula I which contain a carboxyl group may form salts with non-toxic bases, for example alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, ammonium salts and salts with organic amines, for example with triethylamine, ethanolamine and the like. The optical isomers of the compounds of formula I are also within the scope of the invention:

The novel compounds of formula I, their pharmaceutically acceptable salts and their optically active isomers can be obtained, for example, by reacting a compound of formula II

where

Y represents a hydrogen, chlorine or bromine atom;

R, R ¹ , R ² and ⁿ are as defined above, with a halogenating agent in an amount of 1 to 2.5 molar equivalents in the presence of an inert organic solvent and, if necessary, converting the carboxyl group R ¹ in the compound of formula I R, R ^2, X and n are as defined above, into another radical R ¹ and decarboxylation bromination or brominated compound of formula I wherein R ¹ is hydrogen and R, R ^2, X and n are as hereinbefore defined.

The halogenating agents may be any of the known halogenating agents known in the art. These may be elemental halogens such as bromine or chlorine, halogenated compounds such as bromine and chlorine compounds and other halogenated derivatives such as sulfuryl chloride, phosphorus pentachloride, N-chlorosuccinimide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, N - bromoprolactam, tribromoacetophenone, trichloromethane, sulfuryl bromide and sulfuryl chloride, tert-butyl hypochlorite, hypobromite, 1,2,4,6-tetrachloroacetamilide, 1,2-dibromotetrachloroethane, copper (I) bromide and copper (I) chloride, and tetrachloride bromide; Dioxandibromide /

pyrrolidone-2-hydrobromide and the like, optionally in the presence of a catalyst such as a Lewis acid such as aluminum bromide, aluminum chloride, phosphorus trichloride, sulfur, calcium oxide, dibenzoyl peroxide, optionally ultraviolet radiation and the like.

The halogenation is carried out in a conventional manner. The compounds of formula (II) are usually reacted with an appropriate halogenating agent in an inert solvent such as an alkanecarboxylic acid, a halogenated hydrocarbon, and the like, preferably acetic acid or chloroform. Optionally, acid binding agents such as triethylamine, acetamide, sodium acetate and the like can also be used.

The reaction can be carried out at a temperature of 0 to 160 ° C, preferably 20 to 60 ^° C. The compounds of the formula I or their salts precipitate out of the reaction mixture and can be separated by filtration or separated from the reaction mixture by evaporation of the solvent. The compounds of formula (I) may be purified by conventional means, for example, recrystallization, chromatography and the like.

The compounds of formula I obtained as described above can optionally be converted to another compound of formula I by known methods. In particular, the conversion relates to the substituent R1. Compound··. of formula (I) in which R @ 1 is a carboxyl group may be decarboxylated to an organic, for example lower alkanecarboxylic acid, lower alkanol, or inorganic solvent such as water at 0 to 200 ^DEG C., optionally in the presence of an inorganic acid , such as hydrogen halide, sulfur and the like. The obtained compound of formula I in which R ¹ represents hydrogen and R, R2, X and n have the above ·. as used herein, may be isolated or reacted with a molar equivalent of a halogenating agent. Compounds of formula (I) wherein R 1 is halogen are obtained.

The above reactions are also part of the process according to the invention.

Compounds of formula I in which R has a different meaning from hydrogen have a center of asymmetry. The optically active antipodes of the compounds of formula I can be obtained starting from optically active compounds of formula II. It is also possible. Compounds having a carboxyl group as substituent R 1 can be resolved by reacting the racenphate with a suitable optically active base, for example an optically active threo-1- (pn.itrof). enyl) -2-aminopropane-1,3-diol and the diastereoisomers obtained are separated by virtue of their different physical properties, for example by crystallization to liberate the optically active antipode from the obtained salt, for example by reaction with a strong base. .

The starting materials of the formula II are known [ArzneirnitteliOrschung (1972), 22, 815J or can be obtained in a known manner.

Some of the compounds of formula (I) have analgesic and anti-inflammatory effects, have platelet aggregation inhibitory activity, anti-sclerotic activity, anti-asthma and / or antiallergic activity, others of which are valuable intermediates for the production of other antiallergic and / or anti-asthmatic compounds.

The compounds of formula (I) may be formulated as pharmaceuticals. compositions by admixing with an inert solid or liquid carrier. Preparations. can be obtained in a known manner.

The preparations may be intended for oral or parenteral administration or for inhalation, in particular tablets, dragees, capsules, powders. forged mixtures, aerosols,. aqueous suspensions or solutions, injectable solutions or syrups.

The pharmaceutical preparations may contain solid diluents or carriers, sterile aqueous solvents or non-toxic organic solvents. Oral formulations generally contain sweetening or flavoring agents.

The invention will be illustrated by the following. examples. '

He translated

9-Bromo-6-methyl-4-oxo-6,7,3,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid (1.4 g, 0.005 mol) was dissolved in 15 g. ml of chloroform, dried over sodium sulfate. A solution of 0.3 ml (0.005 mol) of bromine in 5 ml of chloroform was added. dropwise with stirring at room temperature. The reaction mixture was then stirred at room temperature for 1/2 hour and then allowed to stand overnight. The precipitated crystals are filtered off and washed with a small amount of chloroform. . '

10 ml of water and 10 ml of chloroform are added to the precipitate, and the pH of the aqueous phase is adjusted to 2 by adding 5% by weight of sodium bicarbonate while stirring. The organic phase is separated, the aqueous phase is shaken twice with 10 ml of chloroform each. The organic phases are combined, dried over anhydrous sodium sulphate and the solvent is evaporated off under reduced pressure. 0.3 g of the residue thus obtained was recrystallized from methanol. 9,9-Dibromo-6-methyl-4-oxo-6,7,8,9-6,6-biphenyl-1 H -pyrido [1,2- a] was obtained in a yield of 16.4%. 165 DEG -166 DEG C. pyrimidine-3-carboxylic acid.

Analysis for C 10 H 10 N 2 O 3 Br 2: · calculated:

C, 32.81; H, 2.75; N, 7.65.

% C, 33.22;% H, 2.78;% N, 7.65;

Example 1 a d 2

Dissolve 1,4 g of [0,055 mol] of 9-methyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2a] pyrimidine-3-carboxylic acid ml of glacial acetic acid. A solution of 0.3 ml (0.005 mol) of bromine in 2 ml of glacial acetic acid was added dropwise to the resulting solution. stirring at room temperature. The reaction mixture was then stirred at 40-60 ° C for 1/2 hour and then 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 by addition of 10% by weight sodium bicarbonate solution with stirring. The organic phase is separated, the aqueous phase is shaken twice with 10 ml of chloroform each. The organic phases are combined, dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue obtained is recrystallized from methanol.

0.8 g (53.8%) of 9,9-dirrom-6-methyl-4-oxo-6,7,8,8-tetrahydro-4H-pyrido [1,2-a] pyrrolidin-3- The carboxylic acid having a melting point of 164 to 166 DEG C. shows no depression of the melting point when mixed with the resulting compound obtained by the method of Example 1.

Example 3 g of crystalline sodium acetate and 10.4 g (0.05 mol) of 6-methyl-4-oxo-6,7,8,8-tetrahydro-4H-pyrido [1,2- a] pyrimidine-3-carboxylic acid is dissolved in 100 ml of glacial acetic acid. To the solution was added

5.4 to 5 (0.1 tonne of bromine) dropwise at room temperature with stirring. The reaction mixture was stirred at room temperature for 2 hours, then the solvent was removed under reduced pressure. 50 ml of water and 60 ml of chloroform, and the pH of the aqueous phase is adjusted to 2 by adding 5% by weight sodium carbonate with stirring, the organic phase is separated, the aqueous phase is shaken twice with 50 ml of chloroform. The solvent was distilled off under reduced pressure and the residue was recrystallized from methanol.

9.4 g of 9.9-douromo-O-methyl-4-oxo-6,7,8,8-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3 are obtained in a yield of 51.3%. 165 DEG-166 DEG. There is no reduction in melting point when mixed with the product obtained in Example 1 nero · 2. :

He attaches

The procedure of Example 2 was followed, but the racemic (±) -9-γ-η 6 -mero-4-oxo-6,7,8,9-etrahydro-4 H -pyrido-4 H -pyrido-4 H -pyrrolidine-4 H- Replace with (+) -9-bromo-6-10-ethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-d] pyrido [1,2-c] oxalic acid; [alpha] -pyrrolidine-3-carboxylic acid to give (+) -9,9-dibromo-6-methyl-4-oxo-6,7,8,8-tetrahydro-4H-pyrido [1,2- and pyrimidine-O-carboxylic acid, m.p. 157-159 ° C, yield 49.0%.

[ _.alpha. ] _D @ ²⁰ = + 47.5 DEG (c = 1, methanol-ol.

Analysis for C 10 H 10 NaO 6 Br calculated:

% H,% N, 7.65;% Br, found:

% C, 33.11;% H, 2.60;% N, 7.56.

Example 1 a d 5 ·

The procedure of Example 3 is followed, but the racemic (±) -6-methyl-4-oxo-6,7,8,8-tetrahydro-4H-pyrido [1,2- b] pyrimidine-3-carboxylic acid is racemic. replaced with optically active (-) -6-methyl-4-oxo-6,7,8, e-tetrahydr o-4-H-pyrido [1,2-a] pyrimidine-3-carboxylic acid to give (+ ) -9, Э-Dirromo-6-methyl-4-oxo-6,7,8, et -etrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid, m.p. 157-158 ° C . This product, when mixed with the product of Example 4, does not cause any lowering of the melting point. Yield 51.2%.

[a) ₂₀ D = + 47.5 ° (c = 1, methanolj.

Example 1 a d 6

The procedure of Example 2 is followed, but racemic (±) -9-bromo-6-methyl-4-oxo-6,7,8,9-etrahydro-4H-pyrido [1,2-a] pyrimidin-3 -carroxylic acid is replaced by optically active (-) -9-bromo-6-methyl-4-oxo-6,7,8,9-etrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid, to give (-) - 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-etrahydro-4H-pyrido [1,2- a] pyrimidine-3-carboxylic acid of · 157 DEG-159 DEG C. Yield: 49.5%.

[.Alpha.] _D @ 20 = -47.5 DEG. (C = 1, methane).

Analysis for C 17 H 17 N 2 O 5 Br.

calculated:

H, 2.75% H, 7.65 ° / o N, 43.65% / o Br, found:

% C, 33.21;% H, 2.72;% N, 7.60%; Br.

Example 7

The procedure is analogous to Example 3 except that racemic (±) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid with (+) -6-methyl-4-oxo-6,7,8,9-etrahydro-4H-pyrido [1,2- a] pyrimidine-3-carboxylic acid to give (-) - 9,9-dibromo-5-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid, m.p. 157-159 ° C. 51.5 ° / o.

[.Alpha.] D @ ²⁰ = -447.5 DEG (c = 1, methanol).

When mixed with the resulting product of Example 6, there was no reduction in the resulting melting point.

Examples 8 to 11

1.4 g of crystalline sodium acetate and 0.005 mol of the starting compound listed in Table I are dissolved in 10 ml of glacial acetic acid. 0.54 ml (0.01 mol) of bromine is slowly added dropwise to the obtained solution under stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then the acetic acid was distilled off under reduced pressure. To the obtained residue was added 10 ml of chloroform and the resulting suspension was stirred at room temperature for 15 minutes. The separated crystals were collected by filtration and washed with chloroform. The filtrate was evaporated and the residue was recrystallized from the solvent in Table I.

Examples 12-17

1.4 g of crystalline sodium acetate and 0.005 mol of the starting compound listed in Table II are dissolved in 10 ml of glacial acetic acid. A solution of 3.2 g (9.01 mol) of pyridinium bromideuperbromide was added portionwise to the obtained solution with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then the acetic acid was distilled off under reduced pressure. To the resulting residue was added 10 mL of water and the solution was shaken. three times with 10 ml of chloroform each. The organic phases are combined, dried over anhydrous sodium sulphate and the solvent is evaporated off under vacuum. The residue thus obtained is recrystallized from methanol.

Examples 18 to 20

0.05 mol of the starting compound,. listed in Table III are dissolved or suspended in 80 ml of dichloromethane and a solution of 13.5 g (0.1 mol) of sulfuryl chloride in 20 ml of dichloromethane is added at room temperature to the solution or suspension obtained. The reaction mixture is vortexed until gas evolution ceases, typically 3 to 4 hours. Then the solvent was removed by distillation and the residue was crystallized from ethanol. In this way the compounds listed in Table III are obtained in a yield of 70 to 80%.

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Example 21

Example 24

Dissolve 2.2 g of crystalline sodium acetate and 0.8 g (0.005 mol) of 6-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one in 10 ml. glacial acetic acid. To the resulting solution was added dropwise 1.0 mL (0.018 mol) of bromine with stirring at room temperature. The reaction mixture was then stirred at 50-60 ^° C for 1/2 hour, then the acetic acid was distilled off under reduced pressure. Chloroform (10 ml) was added to the residue and the suspension was stirred at room temperature for 15 minutes. The crystals formed are filtered off and washed with chloroform, and the filtrate is evaporated in vacuo. After recrystallization of the residue from the solvent, 1.5 g of 3,9,9-tribromo-6-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine- was obtained in 74.8% yield. Mp 157-159 ° C.

Analysis calculated for:

% C, 26.96;% H, 2.26;% N, 6.98;% Br, 59.79.

% C, 26.80;% H, 2.06;% N, 7.00.

Example 1 a d 22

The procedure of Example 8 was followed, but starting from 3,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one to give 9,9- dibromo-3,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one, m.p. 114-115 ° C.

Yield 30.0%.

.Analysis for C 10 H 12 N 4 O 5 calculated:

H, 3.59; N, 8.34; 47.56. % C, 74% C, 3.72% H, 3.72% N, 47.85% Br.

P. ř íк 1 and d 23

To a solution of 2.1 g. (0.01 mol) of 6-methyl-4-o: O-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid in 20 N-bromosuccinimide (3.6 g, 0.02 mol) was added portionwise with stirring while stirring in chloroform. The reaction mixture was heated under reflux for 5 hours, after which time the chloroform was distilled off under reduced pressure. 20 ml of water were added to the residue and the resulting suspension was stirred at room temperature for 15 minutes. The insoluble crystals were collected by filtration, dried and recrystallized from methanol. In this manner . 1.5 g of acid are obtained in a yield of 41.0%

9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid, m.p. 163-164 ° C.

This product, when mixed with the product of Example 1, does not cause the melting point to decrease.

To a solution of 1.04 g (0.005 mol) of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid in 10 ml of chloroform, 1.33 g (0.01 mole) of N-chlorosuccinimide are added with stirring, and the reaction mixture is refluxed for 5 hours, then the chloroform is distilled off under reduced pressure. After stirring at room temperature for 15 minutes, the crystals are filtered off, dried and recrystallized from methanol to give 0.7 g of 9,9-dichloro-6-methyl-4-oxo-6 acid (50.5%). 7,8,9-tetrahydro-4H-pyrido [1,2-a ipyrimldin 3-karbO'Xylové mp 190-191 ^{г С.} This product, when mixed with the product of Example 18 does not cause any melting point depression. _

Example 1 a d 25 _____

The procedure is as in Example 8. However, instead of 6-methyl-4-oso-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidine-3-carboxylic acid, 3 is used. ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-ene and the crude product is recrystallized from 50% aqueous ethanol. There was thus obtained 9.9 dibromo-3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4H-pyridol-1,2-a] pyrimidin-4-one, m.p. C.

Yield 57.2%.

Analysis for C18H18NiOBr2 requires:

39.59% N ,. 4.43% H, 7.69% found:

% C, 39.21;% H, 4.25;

N, 43.90% Br,

N, 43.76% Br.

At 1 and d 26

The procedure was as described in Example 8, but substituting 3-phenyl-6-methyl-4o: 6,7,8,9-tetrahydro-4H-pyrido; 1,2-a] pyrimidine-3-carboxylic acid. methyl 6 _: 7,8,9-tetrahydro-4H-pyrido (1,2-apyridin-4-one and the crude product was recrystallized from ethanol to give 9,9-dibromo-3-phenyl-6-methyl -6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-4-one, m.p. 154-156 ^° C.

Yield 70.4%.

Analysis for Culí:: №ОВгг calculated:

H, 3.54; N, 7.04; Br, 40.14.

N, 7.21; Br, 40.25.

241023

Example 27

2.08 g (0.1 M of ethyl 4-o-o-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrimidine-3-carboxylate) are dissolved in 10 ml of an aqueous acetic acid solution. 75% w / v and 2.72 g (0.02 mole) of sodium acetate are added followed by a solution of 3.2 g (0.02 mole) of bromine in 10 ml of 75% v / v acetic acid The mixture is stirred at 60 DEG C. for a further 1/2 hour and then diluted with 150 ml of water and shaken three times with 4 ml of chloroform each time. It was recrystallized from ethanol to give 2.2 g of ethyl 8,8-dibromo-4-oxo-6,7,8,9-tetrahydropyrrolo [1,2- a] pyrimidine-3-carboxylate in 60% yield. mp 97-100 ° C.

Analysis for СгоНюЫгОзВг calculated:

% H, 2.75;% N, 7.65; Br: 43.66.

% C, 33.28;% 2.62;% N, 7.52;% Br, 43.27.

Example 1 a d 28

The procedure described in Example 27 was followed but substituting ethyl 4-oxo-5,6 for ethyl 4-oxo-4,6,7,8-tetrahydropyrrolo [1,2-a] pyrimidine-3-carboxylate; 7,9,10-hexahydro-4H-pyrimido-1,2-a] azepine-3-carboxylate and the reaction is carried out at 90 ^° C for 1 hour, yielding 53% yield.

2.1 g of ethyl 10,10-dibromo-5,6,7,8,9,10-hexahydro-4H-pyrido [1,2-a] azepine-3 carboxylate.

_Rf = 0.8 using a mixture of benzene and methanol, 4: 1, Kieselgel 60 Fvj :).

Analysis calculated for C ^ HHiiNNiClBBrj:

C 36.57, H 3.58, N 7.10, Br 40.55, found *

% C, 36.32;% H, 3.49;% N, 7.02;

Example 29

The procedure described in Example 21 was followed except that 6-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one was replaced by 2-phenyl-6- methyl 6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-4-one. 3,9,9-Tribromo-2-phenyl-6-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine is thus obtained in a yield of 54.5%. -4-on. Melting point: 164-166 ° C.

Elemental analysis for: C 18 H 18 N 2OBrs calculated:

% C, 37.77;% H, 2.75;% N, 5.87;

% C, 38.04;% H, 2.58;% N, 5.95.

Example 1 a d 30

1.0 g (0.005 mol) of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxylic acid, 0.3 g (0.005 mol) potassium hydroxide and 2.7 g (0.02 mol) of sodium acetate are suspended in 10 ml of anhydrous ethanol, and the suspension is stirred at room temperature and 1.0 ml (0.02 mol) of bromine is added dropwise. The resulting mixture was stirred for an additional hour and then evaporated in vacuo to the residue. The residue is recrystallized from methanol to give 0.4 g of 3,9,9-tribromo-6-methyl-6,7,8,9-tetrahydro-4H-pyrido [1, 20.0% yield]. 156 DEG -157 DEG C. When this title compound is mixed with the compound of Example 21, no reduction occurs. melting points.

Example 31

1.6 g (0.01 mol) of 6-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] pyrimidin-4-one and 2.8 g (0.02 mol) of acetate Sodium hydroxide solution is dissolved in 20 ml of glacial acetic acid and added while stirring at room temperature

6.4 g (0.02 mol) of pyridinium bromide-bromine complex each. The resulting mixture was stirred at room temperature for a further 30 minutes and then the solvent was removed by distillation under reduced pressure. Water (10 ml) was added to the residue and the suspension was stirred at room temperature for 30 minutes. The crystals were collected by suction filtration and washed with a small amount of water to give 0.5 g of 9.9 dlbromo-6-methyl-6,7,8,9-tetrahydro-4H- in the yield of 15.6%. (1,2-a) pyrimidin-4-one, m.p. 130-132 ° C.

Elemental analysis: calculated for СэНюМгОВгг:

Found: C, 33.57; H, 3.13; N, 8.70; Br, 49.63.

C, 33.76; H, 3.09; N, 8.67; Br, 49.49.

Example 32

3,2 g · (0,01 mol) 9,9-dibromo-6-methyl-5,7

Dissolve 8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one and 1.4 g (0.01 mol) of sodium acetate in 20 ml of glacial acetic acid. While stirring at room temperature, 0.54 g (0.01 mol) of bromine is added dropwise. The mixture was stirred at room temperature for a further 30 minutes and then the solvent was distilled off under reduced pressure. To the residue was added 1 ml of water and the mixture was shaken three times with 5 ml of chloroform each. The organic phases are combined, dried over sodium sulphate and evaporated in vacuo. The residue is recrystallized from methanol. In this way, 22 g of 3,9,9-tribromo-6-methyl-6,7 are obtained in a yield of 55 why.

8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one at 156-159 [deg.] C. There is no lowering of the melting point in the mixture with the compound of Example 21.

Claims (11)

Subject A process for the preparation of dihalogenated derivatives of fused pyrimidin-4-ones of general formula I XX i. where R represents a hydrogen atom or an alkyl of 1 to 5 carbon atoms 4 carbon atoms, R @ 1 represents a hydrogen atom, a C1 -C4 alkyl group, a carboxyl group, a C2 -C5 alkoxycarbonyl group, a carbamoyl group, a cyano group, a phenyl group or a bromine atom, R 2 is hydrogen, C 1 -C 4 alkyl or phenyl; X represents a chlorine or bromine atom, n represents an integer of 0, 1 or 2, as well as optically active antipodes, racemates, and salts of these compounds, characterized in that a racemic or optically active derivative of the formula II is reacted Y represents a hydrogen, chlorine or bromine atom, R, R ¹ , R 2 and n are as defined above, with a halogenating agent in an amount of 1 to 2.5 molar equivalents in the presence of an inert organic solvent and, if necessary, converting the carboxyl group R 1 in the compound of formula I R 2, X and n are as defined above, to another R ¹ group by decarboxylation or bromination, or subjected to bromination with a compound of formula I in the invention wherein R 1 is hydrogen and R, R ² , X and n are as defined above. 2. The process of claim 1, wherein at least one molar equivalent of the halogenating agent is used. 3. The process according to claim 1, wherein the halogenating agent is elemental halogen, halogenated acid imide or inorganic acid halide. 4. A process according to claim 3 wherein the halogenating agent is bromine, N-bromosuccinimide or sulfuryl chloride. 5. The process of claim 1 wherein the reaction is carried out in an alkanecarboxylic acid or a halogenated hydrocarbon. 6. The process of claim 1, wherein the acid binding agent is used, preferably in the presence of an alkali metal acetate. 7. A process according to any one of claims 1 to 6, wherein the compound of formula I wherein R1 is a carboxyl group and R, R2, X and ⁿ are as defined in item 1 to form a compound of formula I is decarboxylated. wherein R 1 is hydrogen. 8. The method of claims 1 to 6, wherein:. A compound of formula (I) wherein R 1 is carboxyl and R 1, R ² , X and ⁿ is reacted. are as defined in item 1, with a brominating agent to form a compound of formula I wherein R ¹ is bromine. 9. The process of claim 8, wherein the brominating agent is elemental bromine. 10. A process according to any one of claims 1 to 6, wherein a compound of formula I is reacted wherein R1 is hydrogen and R1, R2, X and n are as defined in item 1 with a brominating agent to form a compound. of formula (I) wherein R ¹ is bromo. 11. The process according to claim 1, wherein the starting materials are compounds of the formula II in which:. R 1 is carboxyl, R, R ² , X and ⁿ are as defined in item 1 to form compounds of formula I wherein R 1 is carboxyl.