GB2086903A

GB2086903A - Novel Quinazolinones and Their Use in the Preparation of Triazoloquinazolinone Derivatives

Info

Publication number: GB2086903A
Application number: GB8133732A
Authority: GB
Original assignee: Roussel Laboratories Ltd
Current assignee: Roussel Laboratories Ltd
Priority date: 1980-11-10
Filing date: 1981-11-09
Publication date: 1982-05-19
Also published as: GB2086903B

Abstract

Novel quinazolinone derivatives of general formula II, <IMAGE> (wherein X represents a hydrogen or halogen atom or a nitro, trifluoromethyl, methyl or methoxy radical; n is 2, 3, 4 or 5; and R1 and R2, which may be the same or different, each represents a hydrogen atom or a C1-5 alkyl or C1-5 hydroxyalkyl radical or, together with the nitrogen atom to which they are attached, they represent a saturated heterocyclic ring optionally containing a further heteroatom and/or optionally being substituted by one or more substituents selected from hydroxy, C1-5 alkyl, C1-5 hydroxyalkyl, C3-6 cycloalkyl, formyl, C1-5 acyl, C2-6 alkoxycarbonyl and aryl radicals (said aryl radicals themselves being optionally substituted by a halogen atom or a trifluoromethyl radical), with the proviso that any -NH- groups in -NR1R2 are in protected form, are useful in a process for the preparation of compounds of formula I, <IMAGE> by reacting the compound of formula II with a formylating agent followed, if required by removal of any protecting groups and/or reaction with an acid to form a salt.

Description

SPECIFICATION Process for the Preparation of Triazoloquinazolinone Derivatives This invention relates to a new process for the preparation of certain triazoloquinazolinone derivatives as well as to new quinazolinones of use in this process.

In British Patent Specification No. 2069495 there are described certain antihistaminic and bronchospasmolytic 1aminoalkyl[1 ,2,4]triazolo[5,1 b]quinazolin-5(1 H)one derivatives wherein the amino group may be substituted or form part of a saturated heterocyclic ring, as well as a process for their preparation. We have now found a novel process for preparing these previously described compounds, especially those wherein the amino group forms part of a piperazine ring.

Thus according to the present invention we provide a process for the preparation of compounds of general formula I,

wherein X represents a hydrogen or a halogen, e.g.

fluorine, chlorine or bromine atom or a nitro, trifluoromethyl, methyl or methoxy radical; n is 2, 3, 4 or 5; and R1 and R2, which may be the same or different, each represent a hydrogen atom or a C15 alkyl or C15 hydroxyalkyl radical or, together with the nitrogen atom to which they are attached, they represent a saturated heterocyclic ring optionally containing a further heteroatom and/or optionally being substituted by one or more substituents selected from hydroxy, C15 alkyl, C15 hydroxyalkyl, C36 cycloalkyl. formyl, C1 acyl, C26 alkoxycarbonyl and aryl radicals (said aryl radicals themselves being optionally substituted by a halogen atom or a trifluoromethyl radical) and acid addition salts thereof, which comprises reacting a compound of formula II,

(wherein X, n R, and R2 are as hereinbefore defined with the proviso that anyNH-groups inNR,R2 are in protected form) with a formylating agent followed, if required, by removal of any protecting groups and/or reaction with an acid to form a salt whereby the desired compound is obtained.

When R1 and/or R2 represents a C,, alkyl radical, this may, for example, be a methyl, ethyl, propyl, iospropyl, butyl, tert.-butyl or pentyl radical. When R and/or R2 represents a C,, hydroxyalkyl radical this may, for example, be a hydroxypropyl, hydroxybutyl, hydroxypentyl or preferably a hydroxyethyl radical.

When R, and R2, together with the nitrogen atom to which they are attached, represent a saturated heterocyclic ring, this may, for example, be a pyrrolidino, piperidino, morpholino or piperazino ring. Substituents which may optionally be present on the heterocyclic ring include, for example, hydroxy, methyl, ethyl and hydroxyethyl radicals; C34 cycloalkyl radicals such as e.g. cyclopropyl and cyclohexyl; formyl, acetyl, carbamoyl, thiocarbamoyl, Cr-5 mono- or dialkylcarbamoyl or -thiocarbamoyl and C, alkylsulphonyl radicals; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and isobutoxycarbonyl radicals; and aryl radicals such as e.g. phenyl radicals.

The process of the invention is of particular use in the preparation of compounds of general formula I wherein the radicalNR,R2 represents a piperazine or N-substituted piperazine ring.

Preferred formylating agents are trialkyl orthoformates, such as e.g. trimethyl and triethyl orthoformate, conveniently in dimethylformamide. Other formylating agents which can be used include, for example, formic acid as well as dimethylformamide dimethyl acetal and diethyl acetal or dimethylformamide in conjunction with a suitable acid halide, e.g. a halide of a carboxylic acid having a pK8 greater than or equal to 4, such as benzoyl chloride. The reaction is preferably effected in the presence of an acid agent such as, for example, ptoluenesulphonic acid and preferably under reflux in an inert solvent such as e.g. toluene.

Where the radical --NR,R, includes a -NHgroup this group should be protected during reaction with the formylating agent. Suitable protecting groups include, for example, formyl, acyl and alkoxycarbonyl groups. Such protecting groups may subsequently be removed according to methods known per se. Compounds of general formula I wherein the radicalNR,R2 represents a heterocyclic group such as piperazinyl group may, after the deprotection step, if desired be converted into substituted derivatives by replacement of a hydrogen atom according to methods known per se with, for example, a carbamoyl, alkylsulphonyl or thiocarbamoyl group.

The compounds of general formula II are novel compounds forming a further feature of this invention. They may, for example, be obtained by reaction of a compound of formula Ill,

(wherein X is as hereinbefore defined) with a compound of formula IV,

(wherein n R, and R2 are as hereinbefore defined with the proviso that anyNH-groups in -NR1R2 are in protected form). The reaction of the compound of formula Ill with the compound of formula IV is preferably effected at elevated temperatures e.g. about 1 800C when reaction is generally complete in about 6 hours.

The compounds of general formula Ill, when they are not known, may be prepared, if desired, by reaction of a compound of formula V,

(wherein X is as hereinbefore defined) with hydrazine hydrate at temperatures greater than 1 00 C. The compounds of general formula V may in turn be prepared, for example, by reaction of a compound of formula VI,

(wherein X is as hereinbefore defined) with ammonium thiocyanate, preferably in the presence of an inert solvent such as digol.

The compounds of general formula IV, when they are not known, may be prepared for example, by reduction of a compound of formula VII,

(wherein n, R, and R2 are as hereinbefore defined with the proviso that anyNH-groups in -NR1R2 are in protected form) by means of sodium borohydride in the presence of cobaltous chloride and of an alcohol such as e.g. methanol or by means of catalytically activated hydrogen.

Reduction may be effected in one or more stages. Thus, for example, it may be advantageous to carry out the reduction in the presence of an acylating agent such as e.g. acetic anhydride, the corresponding acylated derivative thus obtained then being hydrolysed to give the desired compound of formula IV.

The compounds of general formula VII may in turn be prepared, if desired, by reaction of a compound of formula VIII, Cl(CH2)n~1CaN (Vill) (wherein n is as hereinbefore defined) with a compound of formula IX,

(wherein R, and R2 are as hereinbefore defined with the proviso that anyNH-groups in -NR1R2 are in protected form) in the presence of triethylamine and of toluene.

The following non-limiting Example serves to illustrate the present invention: Example Ethyl 4-[4-(1 ,5-dihydro-7-methyl-5- oxo[1 ,2,4]triazolo[5,1 -b]quinazolin-1- yl)butyl]piperazine-1 -carboxylate a) Ethyl 4-(3-cyanopropyl)piperazine-1 - carboxylate 4-Chlorobutyronitrile (124 g, 1.2 M) was dissolved in toluene (600 ml) and the mixture obtained was heated to reflux under a Dean Stark separator for 1 hour. The resultant solution was cooled then ethyl piperazine-1-carboxylate (158 g, 1 M) and triethylamine (170 ml, 1.2 M) were added and the mixture was heated to reflux for 24 hours. The resulting suspension was cooled to 200 then ether (1 litre) was added and the precipitate of triethylamine hydrochloride was filtered off. The filtrate was decolourised with charcoal and evaporated to leave a brown oil which was distilled under reduced pressure b.p 0.05 mm 140--500 Yield 200 g.

b) ethyl 4(4aminobutyl)piperazine-1 - carbocylate b,) by reduction with cobaltous chloride A solution of ethyl 4-(3-cyanopropyl)piperazine-1-carboxylate (200 g) and cobaltous chloride hexahydrate (20 g) in methanol (2 litres) was cooled in ice and sodium borohydride (125 g) was added in portions with stirring at a temperature of less than 100. When the addition was complete the mixture was stirred at 200 for 1 6 hours then concentrated HCI (~300 ml) was added until the black suspension turned blue. The solvent was removed under vacuum then the residue was dissolved in water (2 litres) and filtered. The solution was adjusted to pH 8 with potassium carbonate then washed with carbon tetrachloride (200 ml) to remove nonpolar impurities.The pH of the solution was increased to 9-1 0 by the addition of more potassium carbonate then saturated with sodium chloride and extracted with chloroform (6x250 ml). The combined extracts were dried (MgS04) and evaporated to leave a light brown oil which was distilled under reduced pressure to give a pure fraction b.p.03 mm 135--400. Yield 30 g.

b2) by catalytic reduction --1 stage Ethyl 4-(3-cyanopropyl)piperazine-1 - carboxylate (60 g) was dissolved in a 10% w/w solution of ammonia in ethanol. 5% rhodium on alumina (6 g) was added thereto and the mixture obtained was hydrogenated at 400C and 4 atmospheres pressure until uptake of hydrogen ceased. The mixture was cooled to room temperature, the catalyst was filtered off and the solvent removed under vacuum. The residual oil was distilled under reduced pressure b.p.o 15-02 mm 12630 . Yield 20 g.

b3) by catalytic reduction -2 stage i) ethyl 4-(4-acetamidobutyl)piperazine-1 - carboxylate Raney nickel T-1 (20 g - wet weight) was washed twice with acetic anhydride then added to a solution of ethyl 4-(3 cyanopropyl)piperazine-1 -carboxylate (100 g) in acetic anhydride (300 ml). Sodium acetate (30 g) was added and the resultant mixture was hydrogenated at 4 atmospheres pressure and 500C until uptake of hydrogen ceased (approx, 2 hours). The mixture obtained was cooled to room temperature and poured into water (600 ml).

When the reaction has subsided (temperature rose to 600) the catalyst was filtered off and washed with water. The filtrate was basified to pH 8-9 with sodium hydroxide solution (N250 g in 250 ml water) then filtered through 'celite' to remove nickel salts. The filter pad was washed thoroughly with water and chloroform then the filtrate was extracted with chloroform (2 x 500 ml).

The organic solution was dried (MgS04) and evaporated then crystallised by addition of ether.

(2 crops) Yield 105 g (88%).

ii) ethyl 4-(4-aminobutyl)piperazine 1-carboxylate Ethyl 4-(4-acetamidobutyl)piperazine-1- carboxylate (6 g) was dissolved in a mixture of conc. hydrochloric acid (12 ml) and water (24 ml) and the resultant solution was heated to reflux for 5 hours. The solution was then cooled to room temperature, basified with potassium carbonate and extracted with chloroform (3x 100 ml). The combined extracts were dried (MgS04) and evaporated to leave a pale yellow oil which slowly solidified. Yield 4 g (79%).

c) Ethyl 4-[4-(3-amino-6-methylquinazolin-2ylamino)-butyl]-piperazine-1 -carboxylate A mixture of ethyl 4-(4-aminobutyl)piperazine1-carboxylate (10 g), 3-amino-2-hydrazino-6methylquinazolin-4(3H)one (5 g) and ptoluenesulphonic acid (0.5 g) was heated to 1800 (bath temperature - reaction mixture 1 600) for 4 hours. After cooling to 1000 the reaction mixture was dissolved in toluene (250 ml) then washed with water (2x 100 ml) and filtered through 'celite'. The product was retained in toluene solution for use in the next stage.

d) Ethyl 4[4-( I ,5-dihydro-7-methyl-5- oxo[1 .2,41-triazolo[5.1 -bjquinazolin-1 - yl)butyl]piperazine-1 -carboxylate p-Toluenesulphonic acid (0.25 g) was added to the solution from the previous stage (c) then the mixture was heated to reflux under a Dean-Stark separator for 30 minutes. The solution was cooled slightly then triethyl orthoformate (7.5 ml) was added and the mixture heated to reflux for 20 hours. The solution was cooled then reduced in volume (to 25 ml) under vacuum. The residue was triturated with ether (200 ml) to give a buff crystalline solid, which was filtered off, washed with ether and dried under vacuum. Yield 6.3 g.

Claims

1. A process for the preparation of compounds of general formula, I

(wherein X represents a hydrogen or halogen atom or a nitro, trifluoromethyl, methyl or methoxy radical; n is2,3,40r5;and R1 and R2, which may be the same or different, each represents a hydrogen atom or a C15 alkyl or C15 hydroxyalkyl radical or, together with the nitrogen atom to which they are attached, they represent a saturated heterocyclic ring optionally containing a further heteroatom and/or optionally being substituted by one or more substituents selected from hydroxy, C15 alkyl, C15 hydroxyalkyl, C3 cycloalkyl, formyl, C,, acyl, C26 alkoxycarbonyl and aryl radicals (said aryl radicals themselves being optionally substituted by a halogen atom or a trifluoromethyl radical) and acid addition salts thereof, which comprises reacting a compound of formula II,

(wherein X, n, R, and R2 are as defined above with the proviso that anyNH-groups in -NR1R2 are in protected form) with a formylating agent followed, if required by removal of any protecting groups and/or reaction with an acid to form a salt whereby the desired compound is obtained.

2. A process as claimed in claim 1 wherein the formylating agent is a trialkyl orthoformate.

3. A process as claimed in claim 1 or claim 2 wherein the reaction is effected in the presence of an acid agent.

4. A process as claimed in any preceding claim wherein the reaction is effected under reflux in an inert solvent.

5. A process as claimed in any preceding claim wherein a compound of formula I is formed in which R1 and R2, together with the nitrogen atom to which they are attached, represent a saturated heterocyclic ring optionally containing a further heteroatom, which compound of formula I is then converted into a corresponding compound of formula I wherein the said heterocyclic ring is substituted by one or more substituents as defined in claim 1.

6. A process as claimed in claim 5 for the preparation of compounds of general formula I wherein the heterocyclic ring represented by R, and R2, together with the nitrogen atom to which they are attached, is substituted by a carbamoyl, alkylsulphonyl or thiocarbamoyl group.

7. A process as claimed in any preceding claim for the preparation of compounds of general formula I wherein R and R2, together with the nitrogen atom to which they are attached, represent a piperazine or N-substituted piperazine ring.

8. A process for the preparation of compounds of general formula I as claimed in claim 1 substantially as herein described.

9. A process for the preparation of compounds of general formula I as defined in claim 1 substantially as herein described in the Example.

10. Compounds of general formula I as defined in claim 1 whenever prepared by a process as claimed in any one of claims 1 to 9.

11. Compounds of general formuta II,

(wherein X, n, R, and R2 are as defined in claim 1 with the proviso that anyNH-groups in -NR1R2 are in protected form).

12. Ethyl 4-[4-(3 )am ino-6-methylquinazolin-2- ylamino)-buwljpipernzine1 -carboxylate.

1 3. A process for the preparation of compounds of general formula II as claimed in claim 11 which comprises reacting a compound of formula Ill,

(wherein X is as defined in claim 1) with a compound of formula IV,

(wherein n, R1 and R2 are as defined in claim 1 with the proviso that any -N H-groups in -NR1R2 are in protected form).

14. A process as claimed in claim 13 wherein the reaction is effected at temperatures of about 1800C.

15. A process as claimed in claim 13 or claim 14 wherein the compound of formula Ill is obtained by reaction of a compound of formula V,

(wherein X is as defined in claim 1) with hydrazine hydrate at temperatures greater than 1 000C.

1 6. A process as claimed in claim 1 5 wherein the compound of formula V is obtained by reaction of a compound of formula VI,

(wherein X is as defined in claim 1) with ammonium thiocyanate.

1 7. A process as claimed in any one of claims 13 to 16 wherein the compound of formula IV is obtained by reduction, in one or more stages, of a compound of formula VII,

(wherein n, R, and R2 are as defined in claim 1 with the proviso that anyNH-groups in -NR1R2 are in protected form), by means of sodium borohydride in the presence of cobaltous chloride and of an alcohol or by means of catalytically activated hydrogen.

18. A process as claimed in claim 17 wherein the reduction of the compound of formula VII is carried out in the presence of an acylating agent and the corresponding acylated derivative thus obtained is hydrolysed.

19. A process as claimed in claim 17 or claim 1 8 wherein the compound of formula VII is obtained by reaction of a compound of formula VIII, Cl-(CH2)n-1-C#N (VIII) (wherein n is as defined in claim 1) with a compound of formula IX,

(wherein R1 and R2 are as defined in claim 1 with the proviso that anyNH-groups inNR,R2 are in protected form).

20. A process for the preparation of compounds of general formula II as claimed in claim II substantially as herein described.

21. A process for the preparation of compounds of general formula II as claimed in claim 11 substantially as herein described in the Example.

22. Compounds of general formula II as defined in claim 11 whenever prepared by a process as claimed in any one of claims 13 to 21.

23. Each and every novel method, process, compound and compositions herein disclosed.