DD150605A5 - PROCESS FOR PREPARING DIHALOGEN-SUBSTITUTED CONDENSED PYRIMIDIN-4-ON DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of novel dihalo-substituted fused pyrimidin-4-one derivatives, e.g. of 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) -pyrimidine-3-carboxylic acid or 9,9-dichloro-6- Methyl 4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid and its optically active antipode. The compounds thus prepared are primarily intermediates for d. Production of remedies for allergies and asthma. For the preparation of 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) -pyrimidine-3-carboxylic acid, a solution of 9-bromo -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) -pyrimidinecarboxylic acid in chloroform with a solution of bromine in chloroform.

Description

The invention relates to novel dihalo-substituted, fused pyrimidin-4-one derivatives of the general formula The novel compounds are primarily intermediates for the preparation of agents for allergy and asthma.

Characteristic of the known technical solutions:

It is known that the pyrido (1,2-a) -pyrimidine derivatives have analgesic and other central nervous system effects (British Patent No. 1,209,946).

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One of the "preferred of these compounds is the 1,6-dimethyl-3-ethoxycarbonyl-6-methyl-4-oxo-4H-pyrido / 1,2-a) -pyridinium methosulfate (PROBOH ¹¹ , Rimazolium) (Arzneimittelforschung 22, 815, 1972).

Aim of the invention;

The invention relates to a process for the preparation of the compounds of the formula I in which

R is hydrogen, a lower alkyl or lower one. alkoxycarbonyl,

R is hydrogen, a lower alkyl group, a carboxyl group or a carboxyl derivative or a cyanogroup, a phenyl group or a halo

gentaom,

R is hydrogen, a lower alkyl or phenyl group,

X is halogen and η is O, 1 or 2, may be provided.

By the term "lower alkyl group" as used in the description are meant per se as well as in compositions, for example "lower alkoxy group" straight or branched, aliphatic.saturated hydrocarbon groups having 1 to 6, preferably 1 to 4 carbon atoms, so for For example, methyl, ethyl, n-propyl, isopropyl, η-butyl, secs-butyl, tert-butyl, n-pentyl, neo-pentyl, n-hexyl, etc.

By the term "carboxyl derivative" as used in the description is meant the customary carboxylic acid derivatives, for example lower alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl or other ester groups,

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optionally mono- or di-substituted by lower alkyl, aryl or aralkyl carbamoyl groups, cyano, Carbonsäurehydrazinogruppen or hydroxamic acid (-CO-MHOH).

The term "aryl group" denotes, both per se and in compositions, for example: aryloxy group, optionally substituted aromatic groups having 6 to 10 carbon atoms (for example a phenyl or naphthyl group or their substituted derivatives).

The term "aralkyl group" denotes, both per se and in compositions, for example: aralkyloxy group, phenyl or faphthyl-substituted alkyl groups having 1 to 3 carbon atoms, for example a benzyl, b-phenylethyl, 1,2-diphenylethyl, 2,2-diphenylethyl group, etc.

The term "halogen atom" refers to a chlorine, bromine or iodine atom.

Of the compounds according to the invention, preference is given to those in which the substituents have the following meanings:

R _{1 is} hydrogen or lower alkyl, in particular methyl; R is carboxyl, lower alkoxycarbonyl, in particular. Methoxycarbonyl or ethoxycarbonyl, cyano, carbamoyl, lower alkyl, especially methyl, or phenyl;

R is hydrogen or lower alkyl, in particular methyl;

X chlorine or bromine atom; η 0, 1 or 2.

From the carboxyl group containing compounds of

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general formula I can be formed with physiologically acceptable bases salts, for example alkali metal salts, such as sodium and potassium salts, Erdkalimetallsalze, such as calcium and magnesium salts, ammonium salts, furthermore, the salts formed with organic amines such as triethylamine salts, ethanolamine salts, etc.

The invention also extends to the optical isomers and to the process for their preparation.

Explanation of the essence of the invention:

The inventive method for the preparation of the compounds of general formula I and the optically active isomers is carried out by

a) compounds of general formula II,

Wherein the meaning of R, R, R, X and the same as above, is reacted with a halogenating agent, or

b) compounds of general formula III,

In which the meaning of R, R, R, X and η is the same as above, is reacted with a halogenating agent and, if desired, the resulting compound of the general formula I is subjected to the following reactions: the substituent R is converted into another substituent R ¹ ; decomposes a racemic compound of general formula I into its optical antipodes.

According to variant a) of the process according to the invention, the compound of the general formula II is reacted with at least the molar equivalent amount, preferably with a 1 to 1.5 molar equivalent amount of the halogenating agent.

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2 2 10 5 3

According to variant b) of the process according to the invention, the compound of the general formula III is reacted with at least one two molar equivalent amount, preferably with a 2 to 2.5 molar equivalent amount of the halogenating agent.

As halogenating agent, the usual halogenating agents can be used. There are, for example, elemental halogen (for example, chlorine, bromine, iodine) other halogen compounds (bromine-chlorine, iodine-chlorine) and other halogen derivatives (sulfuryl chloride, phosphorus pentachloride, N-chloro-succinimide, U-bromine -succinimide, N-iodo-succinimide, 1,3-dibromo-5,5-dimethyl-hydantoin, IT-bromo-caprolactam, tribromo-acetophenone, trichloro-methanesulphonyl-bromide and -chloride tert-butyl hypochlorite, bromide and iodide, 1,2,3,4-tetrachloroacetanilide, 1,2-dibromo-tetrachloroethyne, copper (II) bromide, and chloride) and halogen complexes (pyrium bromide perbromide, Phenyl-ammonium-tribromide, dioxendibromide, pyrfolidone-2-hydrotibribride, etc.). If desired, the reaction may be carried out in the presence of a catalyst, for example, Lewis acid (aluminum chloride, aluminum bromide, phosphorus trichloride), sulfur, calcium oxide, UV- Light, dibenzoyl peroxide uaw. be performed.

The halogenation reactions can be carried out in the usual way. The starting materials of the general formula II and III are generally reacted in the presence of an inert solvent with the halogenating agent used. As the solvent, alkanecarboxylic acid, chlorinated hydrocarbons, etc., preferably acetic acid and chloroform may be used. Triethylamine, acetamide, sodium acetate are used ·

The reaction is carried out at temperature ranges from 0 to 16O ° C, preferably at 20 to 60 ⁰ C.

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The compound of the general formula I, which forms during the reaction or the acid addition salt thereof, precipitates from the reaction mixture and can be isolated by filtration or by distilling off the solvent. The compounds of the general formula I obtained can be purified by customary processes (recrystallization, chromatography).

If desired, the compound of general formula I obtained can be converted into another compound of general formula I. The reaction is carried out on group R. These subsequent reactions are carried out in a manner known per se under the reaction conditions customary for reactions of this type.

A carboxyl group present as substituent R may be decarboxylated by heating in the presence of an acid (eg, hydrogen halide, sulfuric acid, etc.) in an organic solvent (eg, lower alkane carboxylic acid, lower alcohols) or in an inorganic solvent (eg, Vaser), with the corresponding , at the place of the carboxyl group hydrogen-containing derivative is formed. This compound can be reacted after isolation or without isolation with halogenating agents in molar amount. Thus, compounds of general formula I are obtained in which R represents a halogen atom.

These subsequent reactions are also part of the invention.

Those compounds of the general formula I which have, as R, substituents other than hydrogen,

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contain an asymmetric center and can exist as optically active compounds or as a racemate. The optically active compounds of the general formula I can be obtained, for example, by using optically active starting materials of the general formulas II or III in process variants a) or b), or by adding a racemic compound of the general formula I into their optically active antipodes disassembled «This. can be done in a conventional manner. Carboxyl-containing compounds of the general formula I can for example be separated into the optical isomers by reacting the racemate with an optically active base. (For example, with threo-l- / p-nitrophenyl / 2-aminopropane ~ 1,3-diol), the members of the forming diastereomeric salt pair due to their different physical properties - for example by crystallization - separated from each other and the separated optical antipodes of the general formula I by treatment with a strong base releases from the salt.

The compounds of the general formula III used as starting materials are known substances (HU-PS 156 119, 158 085, 162 384 and 162 373, Nl-PA 7 212 286) or can be prepared by analogous methods.

The compounds of general formula II used as starting materials are partially known substances (Drug Research: 22, 815, 1972) or can be prepared analogous methods.

Some compounds of the general formula I have analgesic, anti-inflammatory, antiplatelet, antiasthmatic-antiallergic effects, others are important intermediates in the preparation

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of anti-asthmatic anti-allergic compounds.

The compounds of the general formula I can be used in pharmacy in the form of the active ingredient as well as preparations containing inert solid or liquid, inorganic or organic carriers. The preparations are made in the usual way ...

The preparations may be formulated in oral, parenteral or inhalable form, for example as a tablet, dragee, capsule, candy, powder mix, aerosol spray, aqueous suspension or solution, solution for injection or syrup. The preparations may contain suitable solid extenders and carriers, sterile aqueous solvents or non-toxic organic solvents. The oral sweeteners and flavorings may be added to the preparations for oral administration.

Exemplary embodiments:

The invention will be explained in more detail with reference to the following examples, but is not limited to these examples.

example 1

1.4 g (0.005 mol) of 9-bromo-6-methyl-4-0X0-6,7,8,9-tetrahydro-4H-pyrido) 1,2-a) pyrimidine-carboxylic acid are dissolved in 15 ml of sodium sulfate dissolved dried chloroform. To the solution is slowly added dropwise with stirring at room temperature a solution of 0.3 ml (0.005 mol) of bromine in 5 ml of chloroform dropwise. The reaction mixture is stirred for half an hour at room temperature and then allowed to stand overnight. The precipitated crystals are filtered and washed with a little chloroform.

29 1 ft e & f ο ο

10 ml of water and 10 ml of chloroform are added to the filtered product, whereupon the pH of the aqueous phase is adjusted to 2 by addition of 5% strength by weight sodium bicarbonate solution while stirring. The organic phase is separated, the aqueous Extracted twice with 10 ml of chloroform each time · The combined organic phases are dried over acidified sodium sulfate and evaporated under reduced pressure. The residue is 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-i -3-carboxylic acid are obtained. M .: 165 to 166 ° C

Analysis for CJ ₀ H ₁₀ N ₂ OoBr ₂

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) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid are dissolved in 30 ml of acetic acid solved. To the solution is slowly added dropwise with stirring at room temperature a solution of 0.3 ml (0.005 mol) of bromine in 2 ml of acetic acid. The reaction mixture is stirred for half an hour at 40 to 60 ⁰ C, after which the acetic acid is distilled off under reduced pressure. To the residue are added 10 ml of water and 10 ml of chloroform, and the pH of the aqueous solution is adjusted to 2 with 10% by weight sodium carbonate solution. The organic phase is separated and the aqueous phase extracted twice with 10 ml of chloroform. The combined organic phases are dried over annealed sodium sulfate and the solvent is distilled off under reduced pressure. The residue is recrystallized from methanol.

- 10 -

2 2 10 5 3 _ ₁₀ _

0.8 g (53.8%) of 9,9-dibromo-6-methyl-4-oxo-6 _s 7,8,9-tetrahydro-4H-pyrido (l, 2-a) pyrimidine-3-carboxylic acid obtained with the product of Example 1 no melting point depression.

* Example 3

14 g of crystalline sodium acetate and 10.4 g (0.05 mol) of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid are dissolved in Dissolved 100 ml of acetic acid. The solution is slowly added dropwise with stirring, at room temperature, 5 »4 ml (0.1 mol) of bromine. The reaction mixture is stirred for two hours at room temperature, after which the solvent is distilled off under reduced pressure. 50 ml of water and 50 ml of chloroform are added to the residue, whereupon the pH of the aqueous phase is adjusted to 2 with 5% strength by weight sodium carbonate solution. The organic phase is separated, and the aqueous phase extracted twice with 50 ml of chloroform. The combined organic phases are dried over acidified sodium sulfate and the Lösungsmitzel distilled off under reduced pressure. The residue is recrystallized from methanol.

9 »4 g (51.3 %) of 9,9-dibromo-6-methyl-4-OX0-6,7,8,9-tetrahydro-4H-pyrido) 1,2-a) pyrimidine-3-carboxylic acid receive. The product does not give melting point depression with the products of Examples 1 and 2. M.p .: 165 to 166 ⁰ C.

Example 4

The procedure is as described in Example 2 with the difference that instead of racemic (*) - 9-bromo-6-methyl-4-OX0-6,7,8,9-tetrahydro-4H-pyrido (l, 2-a) -pyri-

- 11 -

2 10 5 3

mid-3-carboxylic acid optically active (+) - 9-bromo-6-methyl-4-O-O-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid optically active (+) - 9-bromo-6-methyl-4-oxo-6m7m8m9-tetrahydro-4H-pyrido (1,2-a) pyriraidine-3-carboxylic acid is used

(+) - 9,9-Dibromo-6-methyl-4-oxo-6,7 »8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3" -carboxylic acid. :

157 to 159 ⁰ C, (ώ) ² $ =, + 47.5 ° (c = 1, methanol).

Yield σ 49.0 %

Analysis for ⁰ Xo ¹¹ IO ^ ° 3 ^Br

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

It is carried out according to the method described in Example 3 with the difference that instead of racemic (+) - 6-methyl-4-oxo ~ 6,7,8,9-tetrahydro-4H-pyrido (1,2-a ) pyrimidine-3-carboxylic acid optically active (+) - 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (l, 2-a) pyrimidine-3-carboxylic acid is used. ~ "

-Man obtained (+) - 9,9-dibromo-6 _{T-methyl-4-oxo-6,} .7 _f 8,9-tetrahydro-4H-pyrido (l, 2-a) pyrimidine-3-carboxylic acid, with gives no melting point depressions to the product of Example 4.

Yield; 51 %. mp .; 157-158 ⁰ C. (^) = ²⁰ + 47.5 ° (c = 1, methanol).

BejSpJeI ₁ 6

It is according to the manner described in Example 3 ge works with the difference that instead of racemer (-) -. 9

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Broin-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrodido (1,2-a) pyrimidine-3-carboxylic acid optically active (-) -9-bromo-6-met-Jay1 -4-0X0-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid is used.

This gives (-) - 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid. Yield: 49.5 %. M.p .: 157 ⁰ C. bis'159 (ρν) ^2%. = -47.5 ° (c β 1, methanol)

Analysis for C ₁ Q ¹¹ IO ^ ° 3 ^Br 2

Calculated: C 32.81 % \ H 2.75 % \ N 7.65 % \ Br 43.65%; Found: C 33.21 % \ H 2.72 % \ H 7.60 %, Br 43.62%.

Example 7

The procedure is as described in Example 3 with the difference that instead of racemic (^) - 6-methyl -4-0X0-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid optically active (+) - 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid is used.

Are obtained (-) - 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (l, 2-a) pyrimidine-3-carboxylic acid with the product Example 6 gives no melting point depression. ._. __.

Yield: _51.5%% m.p .: 157-159 ° C, (^>) p ⁰ = -47.5 ° (c = 1, methanol).

Examples 8 to 11

1.4 g of crystalline sodium acetate and 0.005 mol of the starting material indicated in Table 1 are dissolved in 10 ml of acetic acid. The solution is added with stirring at room temperature.

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slowly added dropwise 0.54 ml (0.01 mol) of bromine. The reaction mixture is stirred for two hours at room temperature and the acetic acid is distilled off under reduced pressure. To the residue is added 10 ml of chloroform, and the resulting suspension is stirred for 15 minutes at room temperature. The crystals are filtered off and washed with chloroform. The Piltrat is evaporated. The residue is recrystallized from the solvent indicated in Table 1,

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Example starting material

Final product Yield mp (%) ()

Recirculation · Solvent

formula

Analysis (%) calculated found

CHIT Br

6-methyl-4-oxo-9,9-dibromo-6,7,8,9-tetra-6-methyl

hydro-4H-pyrido 4-oxo-6,7-38,8 I65-6

~ (1,2-a) pyrimi- 8,9-tetradine-3-carbon-hydro-4H-p-acid rido (1,2-a) -

pyrimidine-3-carboxylic acid

methanol

32.81 2.75 7.65 43.65 33.12 2.60 7.59 43.62

6-Methy1-4-oxo-

6,7,8,9-tetra

hydro-4H ~ pyridine

do (l, 2-a) pyridine

midin-3-carboxylic

acid ethyl

-eater

9,9-Dibroin-6-methyl-4-oxo-6,7,8,8-tet- 90.0 rahydro-4H-pyrido (1,2-a) -j-pyrimidine-3 - carboxylic acid, ethyl ester I

oil

36.57 3.58 7.10 40.55 36.84 3.54 7.06 40.38

6-methyl-4-oxo-9,9-dibromo-6-6,7,8,9-tetra-methy-1, 4-oxohydro-4H-pyrido-6,7,8,9-tetra- - (l, 2-a) pyrimi- hydro-4H-pyrido-din-3-carbox- (l, 2-a) -pyriamide din-3-caroxamide

Metha- C _n JL. _Ol nol ^{λ J} " ^L

32.90 3.03 11.51 43.78 33.03 3.21 21.40 43.88

6-methyl-4-oxo-9,9-dibromo-6-6,7,8,9-tetra-methyl-4-oxohydro-4H-pyrido-6,7,8,9-tetra- ( l ₉ 2-a) pyrimi- hydro-4H-pyridine-3-carbonitrile do (l, 2-a) pyridine

midin-3-carbonitrile

Methacol

10 * 9 * 3

43.61 2.61 12.11 46.05 34.77 2.86 12.09 46.26

22 1 05 3

Example 12 to 17

1.4 g of crystalline sodium acetate and 0.005 mol of Auagangsstoffes given in Table 2 are dissolved in 10 ml of acetic acid. To the solution, while stirring, at room temperature, added portionwise 3.2 g (0.01 mol) of pyridinium bromide perbromide. The reaction mixture is stirred for two hours at room temperature, after which the acetic acid is distilled off under reduced pressure. 10 ml of water are added to the residue and the solution is extracted three times with 10 ml of chloroform each time. The combined organic phases are dried over acidified sodium sulphate and evaporated in vacuo. The residue is recrystallized from methanol.

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table

Example starting material Bndprodukt Yield mp. No. {%) (O _n )

formula

analysis

calculated found. CHIi Br

(+) - 6-methyl-4- (+) - 9.9

-oxo-6,7,8,9-tetbromo-6-methyl-hydro-4H-pyri-4-oxo-6,7,8- 50,7 I65-6CdO (1,2-a) pyrimi - 9-tetrahydrodine-3-carboxylic acid -4H-pyrido-

- (l, 2-a) pyridine

midin-3-carboxylic

acid

10 ^H 10 ^H 2 ° 3 ^Br 2

32.81 2.75 7.65 43.66 32.71 2.60 7.78 43.72

(-) - 6-Methyl-4- (+) - 9,9-dibromo-oxo-6,7,8,9-tet- 6-methyl-4-oxo-hydro-4H-pyri- -6,7 , 8,9-tetra-50.0 157-8 do (1,2-a) pyrimi- nylhydro-4H-pyridodine-3-carboxylic acid - (1,2-a) pyrimidine-f

-3-§3, rbonsäure () g ⁰ = ₊₄₇ , 5 ^Ö , 32.81 2.75 7.65 43.66 32.99 2.80 7.72 43.79

(G = I, methanol)

(+) - 6-methyl-4- (-) - 9,9-dibromo-o-o-β, γ, δ, -ββΐ, -6-methyl, 1-4-oxo-hydro 4H-pyrido-6, 7,8,9-tetra- (1,2-a) pyrimidine-hydro-4H-pyrido-3-carboxylic acid - (1,2-a) pyrimidine

din-3-carboxylic acid

U) f = -47.5 ° (c = 1 methanol)

3 ^Br 2

3.2.81 2.75 7.65 43.66 32.60 2.67 7.42 43.45

Table 2 (continued)

Starting material Final product Yield Schmep * Formula

(%) _β Xo ₀ )

Analysis (%)

calculated found

CH Έ Br

4-0x0-6, 7, 8, 9-te, 9,9-dibromo

Rahydro-4H-pyrido 4-oxo-6,7- 45, 5 136-8 C _Q HoN _o 0JBr _P

- (l, 2-a) pyridinium 8,9-tetra- * ° " * ^c

3-carboxylic acid hydro-4H-py-

rido (l, 2 ~ a) ~

-pyrimidin

-3-carboxylic acid 30.71 2.29 7.96 45.40

30.59 2.46 8.06 45.60

7-methyl-4-oxo-9,9-dibromo-7

-6,7,8,9-tetra-methy1-4-oxo-65,5 264-5 hydro [4H-pyrido-6,7,8,9-tetra (1,2-a) -pyrimidine hydro- 4H-pyrido-3-carboxylic acid - (1,2-a) pyrimidine

din-3-carboxylic acid 32.81 2.75 7.65 43.66 32.73 2.80 7.77 43.49

8-methyl-4-oxo-9,9-dibromo-8-

-6,7,8,9-tetrahydro-methy1-4-oxo. 4H-pyrido (1,2-a) - 6,7,8,9-tetra-pyrimidine-3-car-hydro-4H-pyridoboic acid - (1,2-a) -pyrimi-

din-3-carboxylic acid

32.81 2.75 7.65 43.66 32.72 2.81 7.72 43.55

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Examples 18 to 20

To a solution or suspension of 0.05 mol of the compound indicated in Table in 80 ml of dichloromethane 13.5 g (0.1 mol) of sulfuryl chloride in 20 ml of dichloromethane are added dropwise at room temperature, whereupon the reaction mixture until the evolution of gas (3 to 4 Hours) is cooked. The solvent is distilled off, and the Rücketand recrystallized from ethanol.

Yield: 70 to 80 % _m

table

Example starting material

End product Schmp, <o ")"

formula

Analysis (%)

calculated found C H IT Br

6-Methyl-4-oxo-9,9-dichloro-6,7,8,9-tetra-6,6-methyl-4-hydro-4H-pyrido-oxo-6,7,8,9- (l, 2-a) pyrimidine-tetrahydro-3-carboxylic acid 4-H-pyrido-

- (l, 2-a) pyrimidine-3-carboxylic acid

194

^C 10 ^H 10 ^IT 2 ⁰ 3 ^C1 2

43,34 3,60 10,11 25,58 43,20 3,65 10,05 25,63

6-Methyl-4-O-Ox-6-9,9-dichloro-6-7,8,9-tetrahydro-methyl-4-oxo-4H-pyrido (1,2-a) -6,7 , 8,9-tetra- -pyriraidin-3-carboxylic-hydro-4H-pysäure ethyl ester rido (l, 2-a - ^ä

pyrimidin ~ 3-

I ι carboxylic acid j

ethyl ester

47,23 4,62 9,18 23,23 47,02 4,65 9,08 23, l6

6-methyl-4-oxo-6,7,9,9-dichloro-6-8,9-tetrahydro-methyl-4-oxo-4H-pyrido (1,2-a) -6,7, 8,9-tetra-pyrimidine-3-carboxy-hydro-4H-pyridoamide - (1,2-a) -pyrimidine

din-3-carboxamide

^C 10 ^H LA ° 2 ^C1 2

43.48 4.01 15.21 25.67 43.27 4.02 15.31 25.78

22 1OS 3 _ ₂₀ _

Example 21

2.2 g of crystalline sodium acetate and 0 ₉ 8 g (0, p05 mol) of 6-methyl-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidin-4-one are dissolved in 10 The solution is added dropwise with stirring at room temperature, 1.0 ml (0.018 mol) of bromine dropwise. The reaction mixture is stirred for half an hour at 50 to 60 ⁰ C, then the acetic acid is distilled off under reduced pressure. To the residue is added 10 ml of chloroform, and the suspension is stirred at room temperature for 15 minutes. The crystals are filtered off and washed with chloroform. The filtrate is evaporated in vacuo. The residue is recrystallized from methanol. 1.5 g (74.8 %) of 4,9,9-tribromo-6-methyl-6,7; 8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidin-4-one are obtained

M .: 157 to 159 ⁰ C

Analysis for C ₉ HnN ₂ OBr ₃

calculated: 0.26.96 % \ H 2.26 % \ Ή 6.98 %; Br 59.79 %, found: C 26.80 % \ H 2.06 %; N 7.00 % \ Br 59.00%.

Example 22

The procedure is as described in Example 8, with the difference that as a starting material 3,6- dimethy1-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-4- on is used.

This gives 9,9-dibromo-3,6-dimethyl-6,7,8,9-tetrahydro-4H-

-pyrido (1,2-a) pyrimidin-4-one.

Yield: 30.0%>, mp .: 114-115 ⁰ C.

Analysis for ^c io ^H 12 ^N 2 ^OBr 2

Calculated: C 35.74 % \ H 3.59 % \ > 8.34 % \ Br 47.56 %; found: C 35.74%; H 3.72 % \ N 8.22 %; Br 47.85 %.

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2 0 1 ft ζ ^ <c IUO «3 - 21 -

Example 23

To a solution of 2.1 g (0.01 mol) of 6-methyl-4-O-Ox-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid in 20 ml Chloroform are added with stirring, in portions, 3 »6 g (0.02 mol) of N-bromo-succinimide. The reaction mixture is refluxed for 5 hours and then the chloroform is distilled off. To the residue, 20 ml of v / ater and given the Suspesnion ^x utes stirred for 15 Mi at room temperature. The insoluble crystals are filtered off, dried and recrystallized from methanol. 1.5 g (41.0 %) of 9,9-dibromo-6-methyl-4-OEO-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid will get.

fichmp .: 163 to 164 ⁰ C The product gives no melting point depression with the product of Example 1

Example 24

To a solution of 1.04 g (0.005 mol) of 6-methyl-4-o-β, 7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidine-3-carboxylic acid in 10 ml of chloroform are added in portions with stirring 1 » 33 g (0.01 mol) of M-chloro-succinimide. The reaction mixture is refluxed for 5 hours, after which the chloroform is distilled off under reduced pressure. 10 ml of water are added to the residue, and the resulting suspension is stirred at room temperature for 15 minutes. The crystals are filtered off, dried and recrystallized from methanol.

0.7 g (50.5 %) of 9,9-dichloro-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (Ij2-a) pyrimidine-3-carboxylic acid are obtained, which gives no melting point depression with the product of Example 18. Mp .: I90 to 191 ⁰ C.

- 22 -

2 2 1 OS 3 _ ₂₂ _

Example 25

The procedure is as described in Example 8 with the difference that instead of 6-methyl-4-oxo-6,7,8,9-tetrah7dro-4H-pyrido (l, 2-a) pyrimidine-3-carbonic acid 3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) -pyrimidin-4-one. The crude product is recrystallized from 50% by volume aqueous ethanol.

This gives 9,9-Mbrom ~ 3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido (l, 2-a) pyrimidin-4-one. M.p .: 90 to 92 ⁰ C. Yield: 57.2.

Calculated: C 39.59 % i H 4.43 % \ M "7.69 % \ Br 43.9 % \ Found: C 39.21 %; H 4.25 % \ N 7.59 % ', Br 43 , 76%.

Example 26

The procedure is as described in Example 8 mm, with the difference that instead of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (l, 2-a) pyrimidine-3 carboxylic acid 3-phenyl-6-methyl-6,7,8,9-tetrahydro-4H-pyrido (1,2-a) pyrimidin-4-one is used. The crude product is recrystallized from ethanol.

One receives g ^

4H-pyrido (l, 2-a) pyrimidin-4-one. Mp .: 154 to 156 ° C.

Yield: 70.4 %.

Analysis for C ₁

Calculated: C 45.26 %; H 3.54 % \ H 7.04 % \ Br 40.14 % \ Found: C 45.26 % \ H 3.54 % \ N 7.21 %; Br 40.25 %.

Ex iel 2 ¹ J

2.08 g (0.01 mol) of ethyl 4-oxo-4,6,7,8-tetrahydropyrido (1,2-a) pyrimidine-3-carboxylate are dissolved in 10 ml of 75% strength by weight

- 23 -

Acetic acid, after which 2.72 g (0.02 mol) of sodium acetate are added. Thereafter, a solution of 3.2 g (0.02 mol) of bromine in 10 ml of 75% by weight acetic acid is added dropwise with stirring. The reaction mixture is stirred for half an hour at 6O ⁰ C, then diluted with 150 ml of water and extracted by shaking three times with 4 ml of chloroform. The combined chloroform phases are dried over sodium sulfate and then evaporated. The oily residue crystallizes while standing. The crude product is recrystallized from ethanol.

2.2 g (60 %) of ethenyl-8,8-dibromo-4-oxo-4,6,7,8-tetrahydro-pyrido (1,2-a) pyrimidine-3-carboxylate are obtained.

Mp .: 97 to 100 ⁰ C.

Analysis for C ₁₀ H ₁₀ N ₂ O ₃ Br

Calculated: C 32.81 % \ H 2.75 % \ N 7.65 % \ Br 43.66 % \ Found: C 33.28 % - _% H 2.62 % \ H 7.52 % \ Br 43.27 % ,

Example 28

The procedure is as described in Example 27, except that instead of ethyl 4-oxo-4,6,7,8-tetrahydropyrido (1,2-a) pyrimidine-3-carboxylate ethyl 4-oxo-5,6,7j8,9,10-hexahydro-4H-pyrimido (1,2-a) azepine-3-carboxylate is used. The reaction is carried out at 90 ^° C. for one hour.

Athyl-10,10-dibromo-5,6,7,8,9,10-hexahydro-4H- is obtained.

-pyrido (1,2-a) azepine.3.carboxylate.

Yield: 2.1 g (53 %) R _f = 0.8 (benzene-methanol = 4 Tl, silica gel 60) Analysis: C ₁₂ H .IJ ₂ O 3 Br ₂

Calculated: _{c 36y57%} . H 3,58 ^; Έ 7.10%; Br 40.55%; Found: C 36.32 % \ H 3; "49 % \ N 7.02 %; Br 41.02 %.

- 24 -

- 27

Ci)

(Π)

af

(Π)

Claims (2)

Invention claim le process for the preparation of optically active and racemic compounds of the general formula I, wherein R is hydrogen, a lower alkyl or lower alkoxycarbonyl, R is hydrogen, a lower alkyl group, a carboxyl group or a carboxyl derivative or a cyano group, a phenyl group or a halogen atom, R is hydrogen, a lower alkyl or phenyl group, X is halogen and η is 0, 1 or 2, characterized in that a) compounds of general formula II, wherein R, R, 2 R, X and η are as defined above, with. reacting a halogenating agent, or b) compounds of general formula III, 1 2
wherein the meaning of R, R, R, X and η is the same as above, with a halogenating agent and, if desired, replaced in the resulting compound of general formula I, the substituent R in another substituent R or a racemic compound of the general formula I. decomposed into their optical antipodes · 2, Process according to item 1, variant a, characterized in that the halogenating agent is used in at least molar equivalent amount. 3. Method according to item 1, variant b, characterized in that the halocarbonating agent is at least two molar 22 1 05 3 - 25 - valent amount is used 4. 'Method according to item 1, characterized in that as Halogenating agent elemental halogen, halogenated acid imide or acid halide is used. 5. The method according to item 4, characterized in that is used as the halogenating agent is bromine, N-bromo-succinimide or sulfuryl chloride. 6. The method according to item 1, characterized in that the reaction is carried out in the presence of an inert organic solvent, preferably in alkanecarboxylic acid or in chlorinated hydrocarbon. Method according to item 1, characterized in that the reaction is carried out in the presence of an acid binder, preferably alkali metal acetate. '-' δ ", process according to item 1 to 7, characterized in that 'for the preparation of compounds of general formula I, wherein R is hydrogen and the meaning of R, R, X and η is the same as in point 1-, compounds of general formula I, wherein R is a Carboxyl group and the meaning of R, R, X and η is the same as in point 1, decarboxylated. 9. The method according to item 1 to 8, characterized in that for the preparation of compounds of general formula I, wherein R is halogen and the meaning of R, R, X and η is the same as in item 1, compounds of general formula I wherein R is a carboxyl group and the meaning of R, R, X and η is the same as in item 1, with a halogenating agent implements «· '- · - 26 - 2 2 10 5 3. _ ₂₆ _ LO, process according to item 9, characterized in that elemental halogen is used as halogenating agent, Process according to items 1 to 7, characterized in that, for the preparation of compounds of the general formula I in which R is halogen and the meaning of R, R, X and η are the same as in point 1, compounds of the general formula I in which R is hydrogen. 2
tet and the meaning of R, R, X and η is the same as in item 1, with a halogenating agent. 12c Process according to item 1, characterized in that the preparation of compounds of general formula I, wherein R is a carboxyl group, and the meaning 2
of Rj R, X and η is the same as in point 1, as Starting materials Compounds of the general formula II or III, wherein R is carboxyl group 2
and the meaning of R, R, X and η are the same as in Point 1 is. Hierlil pages Formulas