DE2856382A1 - HALOGENIC CONDENSED PYRIMIDINE COMPOUNDS AND METHOD FOR PREPARING THE COMPOUNDS - Google Patents

Description

Halogen-containing condensed pyrimidine compounds and processes for making the compounds

abstract

The invention relates to new compounds of the general formula

where O

R for hydrogen or alkyl with 1-4 carbon atoms

stands,
R denotes hydrogen or alkyl with 1-4 carbon atoms or alkoxycarbonyl in the alkyl part with 1-4 carbon atoms,

R stands for carboxyl or nitrile, HIg stands for halogen and
η means 0, 1, 2.

The new compounds are valuable intermediates of pharmacologically active compounds.

The invention also relates to processes for preparing the new compounds.

S09B28 / 0782

■ λ; -.j>>

HALOGENIC CONDENSED PYRIMIÜIN COMPOUNDS AND METHOD OF MAKING THE CONNECTIONS

The present invention relates to new halogen-containing compounds of the general formula HIg

R ^x O

and method of making the same »

A1505-77

; ■ c / η 7 P 2

28S6382 -6

The new compounds are generally characterized by the formula I - wherein R for hydrogen or alkyl with 1-4 carbon atoms, R is hydrogen or alkyl with 1-4 carbon atoms

or alkoxycarbonyl in the alkyl part with 1-4 carbon atoms,
2
R is carboxyl or nitrile, HIg is halogen and
η stands for 0, 1 or 2.

The compounds of the general formula I are prepared by using compounds of the general formula

II

1 2
- in which R, R, R and η are as indicated above - treated with such a halogenating agent which is suitable for halogenating the active methylene group.

The invention also relates to stereoisomers of the compounds of the formula I and their optically active To shape.

The usual halogenating agents known from the literature can be used as halogenating agents. There are, for example, elemental halogen (eg, bromine, chlorine, dodine), halogen compounds (bromine-chlorine, Ood-chlorine) and other halogen compounds (sulfuryl chloride, phosphorus pentachloride, N-chloro-succinimide, 1,3-bromine -5,5 ~ dimethyl-hydantoin ₃ N-bromo-succinimide, N-iodo-succinimide, N-bromo-caprolactam, tü-tribromo-acetophenone, trichloro-methane-sulfonyl-bromide and -chloride,

909828/0782

tert, butyl hypochlorite, bromide and iodide, 1,2,4,6-tetrachloroacetanilide, 1,2-dibromo-tetrachloroethane, copper / II / bromide and chloride and halogen complexes (pyridinium brom -perbromide, phenyl-trimethyl-ammonium perbromide, tetramethyl-ammonium-tribromide, dioxane -dibromide, pyrrolidone-2-hydrotribromide etc.) in question · The reaction can, if desired, in the presence of a catalyst ₉ e.g. Lewis acid (aluminum chloride, aluminum bromide, phosphorus trichloride), sulfur, calcium oxide, UV light, dibenzoyl peroxide, etc.) and / or acid binders (triethylamine, acetamide, calcium chlorate, sodium acetate etc.) _} .

The halogenation reactions can be carried out by customary methods. The starting materials of the general formula II are generally in the presence of an inert solvent with the halogenating agent used implemented. The compound of general formula I, which is during the Reaction forms or the acid addition salt thereof separates out of the reaction mixture and can removed by filtration and isolated by distilling off the solvent. The received Compounds of the general formula I can with the usual methods (recrystallization, chromatography) getting cleaned.

Those compounds are particularly preferred

1 2

of the general formula I, where R is hydrogen, R is carboxyl or nitrile, R is hydrogen or methyl, η = 1 _a HIg is bromine or chlorine.

The compound of the general formula I which ^{contains a nitrile group as R 2} can optionally be converted into the corresponding by hydrolysis with alkali or acid

8 ^ 9828/0782

Carboxylic acid are transferred.

The compounds of general formula I are important intermediates in the preparation of analgesic, anti-inflammatory, antiplatelet agents, antipyretic, tranquillizer, antibacterial, fungistatic, antiasthmatic, antiallergic or compounds that have a beneficial effect on the heart and circulation.

The compounds can, for example, with amines or hydrazine. _w en are reacted and one thus obtains in the 9-position optionally substituted amino or hydrazino-containing pyrido / l _a 2-a7pyrimidine derivatives which have valuable anti-asthmatic action.

The compounds of general formula II used as starting materials are known substances that by analogous methods can be prepared (Britiahe patent specification No. 1 209 946j Dutch patent application No. 72.12286).

Further details of the invention can be taken from the following examples without the scope of protection of the invention.

example 1

120 g (0.58 mol) of 6-methyl-4-oxo-6 _e 7,8,9-tetrahydro-4H-pyrido / 1,2-a / pyrimidine-3-carboxylic acid are added to 400 ml of acetic acid. To the suspension a solution of 31.4 ml (0.58 mol) of bromine is added dropwise in 100 ml of acetic acid slowly with stirring at 20-30 ⁰ C. The reaction mixture is stirred for half an hour at room temperature, heated at 40-50 ⁰ C, whereupon a solution is obtained. 250 ml of water are added to the solution, whereupon the pH is adjusted to 2 by adding 10% sodium carbonate. The precipitated crystals

8/07

are filtered and dried. 130 g (78.1%) of 9-bromo-6-methy1-4-0X0-6,7,8,9-tetrahydro-4H-pyrido / 1,2-a_ / pyrimidine-3rcarboxylic acid are obtained, the product melts 3 ^Br calculated after recrystallisation from methanol at 154-155 ⁰ C. analysis for the formula ^C io ^H ll ^N ° 2: C 41.83%, H 3.86%, N 9.76%, Br 27.83% " found: C 41.67%, H 3.75%, N 9.62%, Br 28.06%.

Example 2

10.5 g (0.05 mol) 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido / 1,2-a_ / pyrimidine-3-carboxylic acid and 16 g (0.05 Mol) pyridinium brömid-perbromid are dissolved in 75 ml of acetic acid. The solution is stirred at 60 ° C. for 2 hours. 25 ml of water are then added to the reaction mixture and the pH is adjusted to 2 by adding 10% sodium carbonate. The product is extracted three times with 100 ml of chloroform. The combined organic phases are dried over calcined sodium sulfate and evaporated under reduced pressure. The residue is recrystallized from methanol and is obtained 9 _Λ 3 g (64.8%) of 9-bromo-6-methyl-4-oxo-6,7,8 _e 9-tetrahydro-4H-pyrido / l, 2-a / pyrimidine-3-carboxylic acid, melting point: 154-155 ⁰ C, the product gives with the product of Example 1 no melting point depression.

Example 3 ι

3.78 g (0.02 mol) 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido / 1,2 ~ a_ / pyrimidine ~ 3-carbonitrile are dissolved in 10 ml acetic acid * to the solution a solution of 1.1 ml (0.02 mol) of bromine is slowly added dropwise in 5 ml of acetic acid with stirring at 20-30 ⁰ C. The reaction mixture is stirred for half an hour at room temperature, the acetic acid is distilled off under reduced pressure. The residue is recrystallized from methanol and

one receives 3.05 g (56.9%) θ-

tetrahydro ~ 4H-pyrido / l, 2-a7pyrimidin-3-carbonitrile, mp 157-158 ⁰ C.

Analysis for the formula: ^c ₁₀ ^H 10 ^N 3 ^OBr calculated: C 44.79%, H 3.75%, N 15.67%, Br 29.80%, found: C 44.67%, H 3.61 %, N 15.57%, Br 30.46%.

Example 4

20.8 g (+) - 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido / 1,2-aypyrimidine-3-carboxylic acid (/ ~ «7n ° = + 106 °, c = 2, methanol) are dissolved in 80 ml of acetic acid and a solution of 15.9 g is added to the reaction mixture Bromine in 20 ml acetic acid within 15 minutes · The reaction mixture is stirred for one hour and meanwhile gradually heated to 40 C * The reaction mixture is with

50 ml of water are diluted and the pH is adjusted to 2-3 by adding 20% sodium hydroxide and the mixture is extracted by shaking with 3x50 ml of chloroform. The combined chloroform solutions are dried over sodium sulphate and evaporated after filtration. The residue is crystallized from methanol. 24.8 g of (-) - 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido / 1,2-a / pyrimidine are obtained -3-carboxylic acid, melting point: 153-155 ⁰ C. Z ~ "* _ 7q ° = -45 °, c = l, methanol.

Analysis for the formula: ^c io ^H ll ^N 2 ° 3 ^Br bere.ch.net: C 41.83%, H 3.86%, N 9.76%, Br 27.83%, found: C 41.75 %, H 3.81%, N 9.79%, Br 27.91%.

Example 5

The procedure is as in Example 2, but (-) - 6-methyl-oxo-6,7,8,9-tetrahydro-4H-pyrido / 1,2-a / pyrimidine-3-carboxylic acid (/ "" J ^ ₀ = -115, c = 2, methanol). (+) - 9-Bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido / 1,2-a / pyrimidine-3-carbon-

-152 ° C • Γ .76%, +45 0 c = l, C ₁₀ H ₁₁ N 2 ° 3 ^ΒΓ , 67%, 3.86%, N 9 Br 27 83%, 3.79%, N 9 Br 27 90%.

acid, melting point: 151-152
Methanol
Yield: 35%
Analysis for the formula
calculated: C 41.83%, H.
found: C 41.70%,

Example 6

0.52 g of 7-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido / 1,2-a / pyrimidine-3-carboxylic acid is dissolved in 4 ml of acetic acid and 0.8 g is added Pyridinium hydrobromide perbromide to the solution. The reaction mixture is ^{stirred at 60 °} C. for 22 hours. The reaction mixture is
cooled and crystallized. The eliminated
Crystals are filtered and washed with methanol. 0.6 g (65%) of 9 ~ bromo-7 ~ methyl-4 ~ oxo-6,7,8,9-tetrahydro-4H-pyrido / 1 _a 2-a7pyrimidine- hydrobromide _e
Melting point: 244 ⁰ C, from which the free base is released and recrystallized from methanol and 9-bromo-7-methyl-4-oxo-6,7 _e 8,9-tetrahydro-4H-pyrido / l _a 2- a / pyrimidine, melting point: 138-140 ⁰ C.

Analysis for the formula: ^c irj ^H ii ^N 2 ° 3 ^Br

Calculated: C 41.83%, H 3.86% ^ Ή 9.76%, Br 27.83%, found: C 41.97%, H 3.90%, N 9.56%, Br 27.74 % ·

Example 7

4-Oxo-4,6,7,8-th trahydro-pyrrololo / 1,2-a-7pyimidine-3-carbonitrile (0.52 g) is dissolved in 5 ml of dichloromethane. A solution of 1.06 g of pyridinium hydrobromide perbromide in 5 ml of dichloromethane is added to the solution obtained. The reaction mixture is stirred for 24 hours
Dichloromethane is decanted from the yellowish-brown oil which has separated out and in a mixture of 5 ml
Ethanol and 40 ml. Water dissolved. The solution is with

88-88 28/07

Shaken out chloroform. The chloroform solution is dried over sodium sulphate, filtered and evaporated. The residue is recrystallized from methanol. 0.2 g (25%) of 8-0111-4-0x0-4,6,7,8-tetrahydropyrrolo / 1 _e 2-a7pyrimidine-3-carbonitrile analysis for the formula: C ₃ HgN _{3 are obtained} OBr calculated: C 40.03%, H 2.52%, N 17.50%, Br 33.29%, found: C 40.18%, H 2.48%, N 17.62%, Br 33, 11%.

983828/0782

The compounds of the general formula I obtained according to the invention can be converted into the compounds of general formula Ia

Yes,

wherein

R stands for hydrogen or AlXyl group _with 1-4 carbon atoms and

R for hydrogen, alkyl group with 1-4 carbon atoms, Styryl group, carboxyl group or carboxyl derivative or but

R and R together form a - (CH = CH) ,, - group, the broken line denoting a further CC bond, while in every other Palle there is a single bond in the 6,7-position,

R stands for hydrogen, hydroxyl group or alkyl group with 1-4 Carbon atoms,

R ^J hydrogen, alkyl or alkanoyl group with 1-4 carbon atoms, aryl group, carboxyl group or carboxyl derivative or a group with the formula - (CH ,,) -COOH (where m is

d m

a number between 1 and 3) or their reaction the carboxyl group tfeblldetna derivative means

R for hydrogen, optionally duroh hydroxyl or carboxyl substituted alkyl group with 1-4 carbon atoms, for trifluorine thy l group, optionally substituted aryl groups with 6-10 carbon atoms, for phenylalkyl

903828/0782

28S6382

group with 1-3 carbon atoms in the alkyl part or for an optionallya substituted heterooyolus,

·

R for hydrogen, alkanoyl group with 1-4 carbon atoms, optionally substituted benzoyl or heteroaroyl group but stands odor

5

R and R together with the adjacent nitrogen atom form a piperidino,! Pyrrolidino or morpholino ring, or else

5

R and R together with ·; .- · - ■ -. adjacent nitrogen atom

6 7 form a group of the general formula -N-CR R, in which R stands for hydrogen and R for optionally substituted phenyl group,

be converted by reaction with an amine of the general formula

vmr in

h and H '! Le to formula ta; in. < ^r P />; fibene H ^ rleutung connection of allρ; βίψ-> in <:> n formula

SGi £ 28/0782

2Sbt> 382

1 2 "3 Ά p
R, R, R, R, R, R and the broken line those given for formula Ia

Has meaning

which then - if necessary without insulation - is oxidized with atmospheric oxygen.

The reaction is preferably never carried out in the presence of an acid binder · The preferred acid binders are alkali metal carbonates (sodium or potassium carbonate) and alkali metal hydrogen carbonates (e.g. sodium or Ka?,:. umhydrogenoarbonat), the. Alkali salts of eohwacher orjr: bischer starlings (e.g. sodium acetate) or the excess of the amine. used. the

The reaction can be carried out in an inert solvent. Particularly aromatic hydrocarbons, for example benzene, toluene, xylene, or esters, are used as the reaction medium

Example ethyl acetate, alcohols, for example methanol or

Ethanol, or dimethylformamide use. The reaction can in a temperature range of 0-200 C, preferably at room temperature, however, they can also be carried out with warming or at the boiling point of the reaction mixture.

The compounds of general formula Ia have several pharmacological

Effects on: they are anti-inflammatory, analgesic, anti-aterogenic, inhibit the thrombus aggregate lon, regulate the circulation and the heart function, act on the central nervous system, have a tronquillant « Effect, furthermore PG-antap; onistisohe, antibacterial and antifungal effect as well as an anti-ulcer effect. The compounds of the general formula I a are therefore in the Human and veterinary medicine can be used. Particularly stand out is the effect against allergies and against asthma.

909P? Fi / 0782

Of the compounds Ta, those in where R is hydrogen and

R ^{1 represents} hydrogen or lower alkyl group, preferably methyl group,

R stands for carboxyl group,

R for optionally one to three times identical or different Substituted hydroxyl, alkoxy, alkyl group with 1-4 carbon atoms, nitro, carboxyl, trifluoromethyl, methylenedioxy, amino and / or halogen Phenyl or naphthy! Group or pyridyl group and / or

R 'denotes hydrogen, formyl, acetyl, bonzoyl or nicotinoyl group.

Compounds of the formula Ia in which R is hydrogen,
R for methyl in 6-position,
R ^ for hydrogen,

R for carboxyl group,

H
R stands for optionally substituted phenyl group and R 'for water.

Some examples of this are

9- (Phenyl-hydrazono) -6-methyl-4-oxo-6, 7,8, Q-tetra ^ Jiydro-'fH-pyrido 1,2 -a.

pyrimidine-3-carboxylic acid and

C +) - 9- (Phenyl-hydrazono) -6-methyl- ⁱ l-oxo-6, 7,8, g-tetrahydro- ^ H-pyrido Jj , 2-a, pyrimidine-3-carboxylic acid.

The compounds of the formula Ia are the subject of the patent application UE-? 28 54 1T5.

9 0 9 fi 7.% / 0 7 8 2

BATH ORIGINAL

The compounds of the general formula I obtained according to the invention

can also be used in the compounds of the general formula Tb

, 5

1 b

O
wherein

the upper broken line is also present in the 8,9 position, if applicable. κ- means another CC bond, R stands for hydrogen or an alkyl group with 1-4 carbon atoms and

R represents hydrogen, an alkyl group with 1-4 carbon atoms, a styryl group, a Cax'boxyl group or a derivative thereof, or else

R and R together form a group of Joruel - (CH-CH) ₂ - and in this part the broken line in the 6,7-3 position means another CC bond, while in every other case in the 6,7 position one There is a non-compliance obligation,

2
R stands for hydrogen, an alkyl group with 1-4 carbon atoms or a hydroxyl group,

R stands for hydrogen, alkyl or alkanoyl groups with 1-4 carbon atoms each, for aryl group, carboxyl group or its derivative or for a group of the general formula - (CH ₂ ) -COOH (in which m is 1, 2 or 3) or the one on the A derivative of this group formed by a carboxyl group,

R is hydrogen, optionally duroh hydroxyl or carboxyl

eubatitulated alkyl group has 1-4 carbon atoms, Trlfluoromethyl group, optionally aubatitulated aryl group with 6-10 carbon atoms, rienylalkyl group with 1-3 carbon atoms in the alkyl part or optionally substituted heterooyollahe group means

Ir for hydrogen, alkyl or alkanol groups with 1-4 each Carbon atoms, for aryl group with 6-10 carbon

atoms, phenylalkyl group with 1-3 carbon atoms im

Alkyl part, for optionally substituted benzoyl or

Heteroaryl group or R and R ⁵ together mi '; the adjacent nitrogen atom

Piperidino, pyrrolidino or morpholino ring or R and R combine with the adjacent nitrogen atom for a group of the general formula

- N

R ⁷

6 7

are, in which R is hydrogen and R is optionally substituted phenyl group,

be converted by reaction with an amine of the general formula

² Y 5
R and R have the meaning given for formula Ib, to form a compound of the general formula

9Θ982Β / 0782

1 2 1 k p

where R, R, R, R, R, R and the dashed line has the meaning given to formula Ib,
which - if necessary without isolation - is then oxidized with atmospheric oxygen.

The reaction ^is preferably carried out in the presence of an acid binder. Al3 sulfur binders are preferably alkali carbonates (for example sodium or potassium carbonate), alkali hydrogen carbonates (for example sodium or potassium hydrogen carbonate), the alkali salts of weak organic acids (for example sodium acetate) or an excess of amine

in Ersge. The reaction can be in the presence of a inert solvent can be made «als Reektionsciedium aromatic hydrocarbons (for example benzene, toluene, xylene), esters (for example

Il .M-

Ethyl acetate), alcohols (e.g. methanol, ethanol) or dimethylformamide are used. The reaction may proceed at temperatures zwlsohen ο and 200 C, at room temperature or action mixture at boiling point of R _e to be made.

The compounds of general formula Ib have anti-inflammatory, analgesic, the aggregation of platelets inhibiting, anti-aterogenic, tranquillante, PG-antagonistic, anti-bacterial, influencing the central nervous system and antifungal effects and are also effective against ulcer and regulate the function of the heart and circulation.

9Θ9828 / 0 78 2

Particularly noteworthy is its effect against allergies and asthma. For this Basically, the compounds of the general formula Ib can be used in human and veterinary medicine.

Of the compounds Ib, those in where R is hydrogen and

R represents hydrogen or an alkyl group with 1-4 carbon atoms, preferably Methyl group,

R stands for carboxyl group,

HR stands for phenyl, naphthyl or pyridyl group, which is optionally one to three times identical or different by hydroxyl group, alkyl or alkoxy group each with 1-4 carbon atoms, nitro, carboxyl, trifluoromethyl, methylenedioxy and / or amino group and / or halogen can be substituted, and / or

R for hydrogen, methyl group, lower alkanoyl group, acetyl, benzoyl or nicotinoyl group.

Particularly effective are compounds of the formulas Ib in which R is hydrogen, R for methyl group in 6-position,

ρ R "for hydrogen,

3 R for carboxyl group,

ij R for optionally substituted phenyl group and

ς R stands for hydrogen.

An example of this is 9-phenylamino-6-methyl-4-oxo-6,7-dihydro-4H-pyrido-Π, 2-ä] pyrimidine-3-carbon-

acid »their salts and their optically active antipodes. j

The compounds of the formula Ib are the subject of the patent application DE-P 28 54 112.

ΘΘ9828 / 0782

Claims (12)

Claims (^
Iy Optically active and racetne compounds of the general formula R represents hydrogen or alkyl with 1-4 carbon atoms, _Ί represents for hydrogen atom or alkyl with 1-4 carbon atoms, or alkoxycarbonyl with 1-4 carbon atoms in the alkyl part, R ^{2 represents} carboxyl or nitrile, HIg represents halogen and η means 0, 1, 2. 2. Compounds according to claim 1, characterized in that in the general formula I R is hydrogen or methyl, R is hydrogen, R ^{2 is} carboxyl or nitrile, η = 1 and halogen is bromine or chlorine. 3. g pyrido / l, 2-a _- 7-pyrimidine-3-carboxylic acid and its optically active antipodes. 4 _# 9-bromo-7-methyl-4-oxo-6.7 _J 8,9-tetrahydro-4H- pyrido / l, 2-a / pyrimidine-3-carboxylic acid and its optical active antipodes. 5. g pyrido / l "2-a / pyrimidine ~ 3-carbonitrile and its optical active antipodes, 9Θ-982 8/0 782 6. Process for the preparation of optionally optically active halogen-containing compounds of the general formula R for hydrogen or alkyl with 1-4 carbon atoms stands,
R ^{1 represents} hydrogen atom or alkyl with 1-4 carbon atoms or alkoxycarbonyl with 1-4 carbon atoms in the alkyl, part, R ^{2 represents} carboxyl or nitrile, HIg represents halogen and
η Ο, 1/2 means characterized in that one raceme or optically active compound of the general formula II 1 2
- in which R, R, R and η are indicated as above - with a halogenating agent suitable for halogenating an active methylene group, optionally in the presence of a catalyst or an acid binder, and, if desired, a compound obtained in general 909928/07 ^ 2 Formula I into another compound of the general Formula I converted by methods known per se and / or, if desired, a racemic compound obtained from general formula I resolved. 7. The method according to claim 6 "characterized in that" as the starting material ■ an optionally optically active compound of the general formula II, wherein R is hydrogen or Is methyl, R is hydrogen or methyl and 2
R and η are as indicated above - used. 8. The method according to claim 6, characterized in that there is used as the starting material an optionally optically active compound, wherein 1 2 η means 0 or 1, R, R and R as in claim 1 are used. 9. Process according to Claims 4-6, characterized in that one is used as the halogenating agent elemental halogen or its compounds are used. 10. The method according to claims 6-8 “characterized in that one is used as the halogenating agent Halogen complexes used 11. The method according to claims 6-8, characterized in that one is used as the halogenating agent those halogen compounds are used which can give off halogen. 12. The method according to claim 6, characterized in that there is a compound of general formula I - in which R is nitrile - in a compound of the general formula I - in which R stands for carboxyl - hydrolyzed.