CS202070B2 - Method of preparing 2-/4-substituted piperazin-1-yl/-4-amino-6,7-dimethoxy-quinazolines - Google Patents

Description

The present invention relates to a novel process for the preparation of 2- (4-substituted piperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline. The end products prepared by the process of the present invention are known compounds, valuable in their ability to lower blood pressure in hypertensive mammals. More specifically, these hypotensive compounds are certain 2- (4-substituted piperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline and 2- (4-substituted piperazin-1-yl) -4-amino-6,7 8-trimethoxyquinazoline as claimed in U.S. Pat.

511 836 and 3 669 968.

U.S. Patent No. 3,551,836 claims certain procedures for the preparation of 2- (4-substituted piperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline, for example by reaction of 2-chloro-4-amino-6,7 -dimethoxyquinazoline with the appropriate 1-substituted piperazine by reacting 2- (4-substituted piperazin-1-yl) -4-chloro-6,7-dimethoxyquinazoline with ammonia or alkylation by alkanoylation, aroylation or alkoxylation of 2- (1-piperazinyl) -4- amino-6,7- (3-methoxyquinazoline). U.S. Patent No. 3,669,968 discloses the preparation of 2- (4-substituted piperazin-1-yl) -4-amino-6,7,8-trimethoxyquinazoline by reaction of 2-chloro-4-amino-6,7,8-trimethoxyquinazoline with with the corresponding 1-substituted piperazine.

U.S. Patent No. 3,935,213 claims the preparation of 2- (4-substituted piperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline and the corresponding 6,718-trimethoxyquinazoline by a process comprising either 1) reaction of the appropriate 4,5 -dimethoxysubstituted or 3,4,5-trimethoxy-substituted 2-amino-benzonitrile with certain 1,4-disubstituted piperazines, or 2) reaction of the corresponding 4,5-dimethoxy- or 3,4,5-trimethoxy substituted 2-aminobenzamidine with the same 1,4-disubstituted piperazines.

Compounds of formulas:

Wherein Y is hydrogen, alkyl of 1 to 5 carbon atoms, hydroxyalkyl of 2 to 5 carbon atoms, alkanoyl of 2 to 7 carbon atoms, allyl, propargyl, 2-methallyl, phenyl, benzyl, benzoyl, chlorobenzoyl, bromobenzoyl , trifluoromethyl, methoxyphenyl, methylphenyl, methylbenzoyl, trifluoromethylbenzoyl, furoyl, benzofuroyl, thenoyl, pyridinecarbonyl, 3,4,5, -trimethoxybenzoyl, alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy and alkenyloxycarbonyl having 4 to 6 carbon atoms in the alkenyloxy group having 4 to 6 carbon atoms; US Patent δ. However, the other intermediates used in the process of the present invention are novel.

The present invention provides a process for the preparation of 2- (4-substituted piperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline of formula I

wherein R ₁ is hydrogen or methoxy

R ₂ is alkenyl of 3-5 carbon atoms, benzoyl, furoyl, thienylcarbonyl, alkoxycarbonyl having 2 to 5 carbon atoms, alkenyloxycarbonyl having 4-5 carbon atoms or (2-hydroxyalkoxy) carbonyl having 4-5 carbon atoms, characterized by The composition of claim 1, wherein one mole of the compound of the general formula ΙΪ

wherein X is a chlorine or bromine atom R 1 is a hydrogen atom R 1 is a group -CHgCgH 1 R 8 and wherein

R1 is hydrogen, chlorine, bromine, methyl, methoxy or nitro, and R1 is as defined above, reacted with one mole of a compound of formula III

H1Q <-R _a (III), wherein Rg is as defined above, in an inert organic solvent at a temperature of from 50 to 200 ° C, to form an intermediate compound of formula IV

wherein R _1, R _2, R and R are as defined above, and this intermediate is further subjected to catalytic hydrogenolysis to give the final product of formula X.

A particularly preferred temperature range for carrying out the process of the present invention by the reaction between the compound of Formula II and Formula III is 80 to 130 ° C.

A particularly preferred hydrogenolysis catalyst is palladium.

While the process of the present invention is useful for the preparation of the known hypotensive agents of formula I, it is particularly useful for the preparation of two particularly valuable compounds of formula I, namely 2- [4- (2-furoyl) piperazin-1-yl] -4-amino- 6,7-dimethoxyquinazoline and 2- [4- (2-hydroxy-2-methylpropyl-1-yloxycarbonyl) -piperazin-1-yl] -4-amino-6,7,8-trimethoxyquinazoline, known as prazosin and trimazosin. 2- [4- (2-methylprop-2-enyloxycarbonyl) piperazin-1-yl) -4-amino-6,7,8-trimethoxyquinazoline is a valuable starting material for the preparation of trimazosin (US Pat. No. 3,669,968). Prazosin and trimazosin have recently been reported to have a therapeutic effect in humans (Cohen, Journal of Clinical) Pharmacology, 10, 408 (1970), De Guia, et al., Current Therapeutio Research, 1559 (1973).

The present invention relates to a process for the preparation of a compound of formula I or a hydrochloride or hydrobromide, by reacting a compound of formula II with a compound of formula III, which first yields an intermediate, a compound of formula IV or a salt thereof with an acid. The reaction of the compounds of formulas II and III is carried out in the presence of a suitable inert, organic solvent.

A suitable solvent is one which sufficiently dissolves the reaction components and does not adversely affect the reactants or reaction products. Examples of such solvents are alkanols such as isopropanol, butanol, isobutanol, isoamyl alcohol, 2-methyl-2-pentanol and 3,3-dimethyl-1-butanol, glycols such as ethylene glycol and diethylene glycol, glycol ethers such as ethylene glycol monomethyl ester, diethylene glycol monoethylether,

1,2-dimethoxyethane and diethylene glycol dimethyl ether, tertiary amides such as N, N-dimethylformamide, Ν, Ν-diethylacetamide and N-methylpyrrolidone, dimethylsulfoxide and pyridine.

While the reaction can be carried out over a wide range of temperatures, a temperature of 50 to 200 ° C is preferred. A particularly preferred temperature range is from 80 to 130 ° C. The time required to complete the reaction depends on several factors, such as the reaction temperature, the reactivity of the respective starting materials, and the concentration of the reactants. At lower temperatures, a longer reaction time of ¹ is required, while at higher temperatures the reaction is completed in a shorter time. In general, a period of from 15 minutes to 50 hours is sufficient.

The reaction of a compound of formula II with a compound of formula III forms an intermediate of formula IV, which is then further reacted to give the desired compound of formula I. Thus, the process of the present invention can be carried out according to the following reaction scheme:

NHj (I)

Compounds of formulas IX and III used as reaction components in the process of the present invention are those wherein X is a chlorine or bromine atom, and particularly preferred are compounds wherein X is a chlorine atom and R 1, R 6, R 6 and R 6 are as defined above. .

In carrying out the process of the present invention, as depicted in the above scheme, compounds of formula II are preferred, wherein X is chlorine or bromine,

R 1 is hydrogen or methoxy and R 1 is hydrogen and R 1 is -CH 2 C 9 H 2 R 2, wherein R 2 is as defined above. These compounds of formula II are reacted with the compound of formula III described above to give intermediates of formula IV in the form of hydrochloride or hydrobromide. If these compounds of formula IV are desired, it is preferred that the reaction be carried out using approximately equimolar amounts of the reaction components for reasons of economy and efficiency. However, this is not essential for a successful reaction, and an excess of any of the reactants may also be used. Preferably, the intermediate compound of formula IV can be isolated in the form of hydrochloride or hydrobromide, each of which is substantially insoluble in the reaction solvent, and thus can be obtained by simple filtration and washing. Alternatively, the above salt can be reacted during workup with an alkaline ^one reagent such as sodium hydroxide, potassium hydroxide, potassium carbonate or sodium methoxide and then the free base is extracted into a water immiscible solvent, such as chlorinated roform, dichloromethane or benzene and isolated by evaporation to dryness. If desired, either the compound of formula IV or a salt thereof can be further purified by standard methods such as crystallization or column chromatography. However, they are often obtained in sufficient purity so that they can be used to further react to the compounds of formula I without further purification.

As noted above, the compounds of formula (IV) or their hydrohalides can be further reacted by removing the 4-amino substituents, R 1 and R 2 to give the desired compound of formula I. Preferred meaning of R 8 is benzoyl, furoyl, thienylcarbonyl, alkoxycarbonyl. two to five carbon atoms; and (2-hydroxyalkoxy) carbonyl having four or five carbon atoms. It is preferred that the benzyl group R1 be removed by catalytic hydrogenolysis. The term catalytic hydrogenolysis as used herein is well known to those skilled in the art of hydrogenation and is illustrated in the following examples.

Catalytic hydrogenolysis can be performed by various well known methods, such as those discussed by Augustin in Catalytic Hydrogenation, Marcel Dekker, Inc.,

New York, 1965, pp. 39-42. A particularly preferred process is to contact a compound of formula IV ', wherein R ₃ is hydrogen and R ₄ is -CH ₂ C ₈ H ₄ R ₅ with hydrogen in an inert solvent in the presence of a suitable catalyst at an appropriate temperature and pressure, and for a sufficiently long time for complete hydrogenolysis. Then, the desired product of formula (I) may be isolated by conventional methods, including removal of the catalyst and isolation of the product from the solvent.

As used herein, the term inert solvent means any medium that is a solvent or a suitable suspending agent for reaction components that is stable under hydrogenolysis conditions and that does not impair the activity of the catalyst or does not react with the reaction component or reaction product. Polar organic solvents are generally suitable and include lower alkanols such as methanol, ethanol and butanol, water-soluble cyclic and non-cyclic ethers such as dioxane, tetrahydrofuran, diethylene glycol monoethyl ether, 2-ethoxyethanol, lower alkanoic acids such as acetic acid or acid propionic, aqueous media containing the foregoing solvents and dilute aqueous hydrochloric acid. These solvents and others are commonly known in hydrogenation and are therefore not critical.

The temperature is also not critical, as in other hydrogenolytic reactions. Thus, from 0 to 100 ° C can be used with good results. A preferred temperature range is from 10 to 60 ° C, and a particularly preferred temperature is room temperature, especially in terms of comfort. At temperatures below 0 ° C, the reaction proceeds too slowly, while at temperatures above 100 ° C the decomposition of the starting material can take place. The higher the temperature, the greater the reaction rate. However, the reaction is normally complete within 1 to 24 hours.

Suitable catalysts for preparing the desired products of formula I by hydrogenolysis are platinum, palladium, rhenium, rhodium and ruthenium either supported or unsupported as well as the corresponding catalyst compounds of these metals, such as oxides or chlorides. Examples of suitable catalyst supports are coal, silica and barium sulfate. A particularly preferred catalyst is palladium in terms of economy and performance.

The catalyst is normally used in an amount of from 10 to 100% by weight, based on the starting compounds of the formula IV used.

The pressure used during hydrogenolysis is not critical, for example, sufficient results can be obtained at pressures ranging from atmospheric pressure to 10 MPa.

Intermediates of formula II wherein R 1 is hydrogen, R 1 is hydrogen and R ₄ is benzyl are disclosed in U.S. Patent No. 3,511,836 and the same patent discloses intermediates of formula IV with the same meanings for R 1, R 1, R 2. ^ and R ₂ as mentioned above.

Intermediates of formula II are prepared from the corresponding 2,4 dihalogen-6,7-dimethoxyquinazoline or 2,4-dihalogen-6,7,8-trimethoxyquinazoline wherein the halogen atom is a chlorine or bromine atom. The preparation of these dihalogen compounds has already been described in U.S. Patent Nos. 3,511,836 and 3,669,968 and in Curd et al., J. Chem. Soc. (Londond) 777 (1947) and J. Chem. Soc. 1759 (1948).

The present invention is described in more detail in the following examples.

He did

4-Benzylamino-2-chloro-6,7-dimethoxyquinazoline

6.48 g (0.025 mmol) of 2,4-dichloro-6,7-dimethoxyquinazoline and 104 ml of tetrahydrofuran are placed in a 200 ml three-necked round-bottomed flask. Heat the flask in an oil bath maintained at 70 ° C. To the flask was then added 2.68 g (0.025 mol) of benzylamine and the resulting mixture was heated with stirring for one hour. An additional portion of 2.68 g of benzylamine was added and heating was continued for one hour, after which an additional 2.68 g of benzylamine was added. The mixture was then heated for an additional two hours, then hot filtered to remove the precipitated benzylamine hydrochloride. The filtrate is concentrated to half the volume, two volumes of hexane are added and the resulting mixture is stirred for 30 minutes for granulation. Filtration and drying afforded 6.0 g (73%) of the title compound, mp 190-195 ° C. The structure was verified by NMR spectroscopy and mass spectrum.

Example. 2

2- [4- (2-Puroyl) piperazin-1-yl] -4-benzylamino-6,7-dimethoxyquinazoline

In a 200 ml three-necked round flask equipped with a thermometer, a condenser and a drying tube was placed 66 ml of isoamyl alcohol and 6.0 g (0.18 mol) of 4-benzylamino-2-chloro-6,7-dimethoxyquinazoline. To this mixture was added a solution of 3.6 g (0.020 mol) of 1- (2-furoyl) piperazine in 50 mL of isoamyl alcohol. The resulting mixture was heated to boiling (130 ° C) for 4 hours, cooled to 20 ° C, filtered, washed with ethyl ether and air dried. This gives the hydrochloride of the title compound. This compound is converted to the free base by dissolving in 150 ml of hot methanol, adding 1.3 g of sodium methoxide, stirring for 10 minutes at 50 ° C, cooling the hay at 20 ° C, adding 100 ml of water, followed by extraction with two 100 ml portions. ml portions of chloroform.

Concentration of the extracts to dryness yielded 6.0 g (70%) of the title compound, m.p.

Mp 220-225 ° C.

If the above procedure was carried out at 80 ° C for 24 hours, the results obtained are substantially unchanged.

If the reaction is repeated using carbitol (diethylene glycol monoethyl ether) as solvent and heating is carried out either at 200 ° C for 20 minutes or at 50 ° C for 48 hours, the title compound is similarly obtained.

Proton NMR Spectrum (perdeuterated dimethylsulfoxide) showed ppp (delta): 3.9 (s, 8H, _CH2), 4.0 (s, 6H, CH? O), 4.9 (d, 2H, benzyl CH) 6.6 - 8.1 (multiplet, 10H, aromatic protons).

Example 3

2- [4- (2-Puroyl) piperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline (Prazosln)

To a Paar flask was charged 1.0 g (2.1 mmol) of 2- [4- (2-furoyl) piperazin-1-yl-4-benzylamino-6,7-dimethoxyquinazoline and 15 ml of ethanol, water (ca. 5 ml) until turbidity and then 400 mg of palladium on carbon catalyst (50% wet). The resulting mixture was shaken in a Paar hydrogenation apparatus for 18 hours at 50 psi, filtered, and the filtrate was suspended in 50 mL of chloroform and filtered again. The filtrate was concentrated in vacuo to 10 ml, granulated for 15 minutes and filtered to give 450 mg (56%) of the title compound, mp 263-265 ° C, identified by thin layer chromatography on silica gel plates (ethyl acetate / diethylamine 95: 5). ) and comparing the infrared spectrum with that of an authentic prazosin sample.

Claims (6)

OBJECTS OF THE INVENTION 1. A process for the preparation of 2- (4-substituted piperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline (I). CH3O. CH ₃ O 1 NH _and (I), 202Q70 wherein R 1 is hydrogen or methoxy and R 8 is C 3 -C 5 alkenyl, benzoyl, furoyl, thienylcarbonyl, C 2 -C 5 alkoxycarbonyl, C 4 -C 5 alkenyloxycarbonyl or C 4 -C 5 (2-hydroxyalkoxy) carbones or their hydrochlorides, or hydrobromides, characterized in that one mole of the first reactant of the formula II (II) wherein X is a chlorine or bromine atom, R 8 is hydrogen and R 6 is -CH 8 C 8 H 8 R 8, wherein R 8 is hydrogen, chlorine, bromine, methyl, methoxy or nitro, and R1 is as defined above, reacted with an equimolar amount of the second reactant of formula III HNN-R 6 (III), wherein R 8 is as defined above, in an inert organic solvent at a temperature of from 50 to 200 ° C to give an intermediate of formula IV (IV) wherein R ₁ , R 8, R 8 and R 8 are as defined above and this intermediate is further catalytically hydrolyzed. 2. A process according to claim 1, wherein the reaction between the compounds of formula IIa and the compound of formula III is carried out at a temperature of from 80 to 130 ° C. 3. Method according to claim 1 or 2, characterized in that the starting materials used are compounds of the above formulas IX and III where R ₁ is hydrogen and R g is 2-furoyl and R 8, and X are as defined above. 4. A process according to claim 1 or 2, wherein R @ ₁ is methoxy and R @ 8 is 2-methyl-2-hydroxy-1-propyloxycarbonyl and R @ 8 is a starting compound. and X are as defined above. 5. A method according to claim 1 or 2, characterized in that vinyl acetate copolymers with the compounds used as compounds of formulas II and III wherein R ₁ is methoxy and R ₂ is 2-methyl-2-propenyloxycarbonyl and R, R₁ and X are as defined above. 6. Process according to claims 1-5, characterized in that as starting compound a compound of formula II wherein X is Cl and R ₁ and R are as defined above.