CS202071B2 - Method of preparing 2-/4-substituted piperazin-1-yl/-4-amino-6,7-dimethoxyquinazolines - Google Patents

Description

(54) A process for preparing 2- (4-substituted piperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline

The present invention relates to a novel process for preparing 2- (4-substituted piperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline derivatives. The products prepared according to the present invention are known compounds, valuable for 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, The present invention also relates to certain 2-halo-6,7-dimethoxy-4- (substituted amino) quinazolines and 2-halo-6, 8-trimethoxyquinazoline as claimed in U.S. Patent Nos. 3,511,836 and 3,669,968. 7,8-trimethoxy-4- (substituted amino) quinazolines and corresponding compounds wherein the 2-halo substituent is replaced by certain 4-substituted piperazinyl groups which are novel intermediates.

U.S. Patent No. 3,511,836 claims certain processes for the preparation of 2- (4-substituted piperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline, for example by reacting 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, alkanoylation, aroylation or alkoxylation of 2- (1-piperazinyl) -4-amino- 6,7-dimethoxyquinazoline.

US Pat. 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 the appropriate 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 6,7,8-trimethoxyquinazoline by a process comprising either: 5-dimethoxy-substituted or 3,4,5-trimethoxy-substituted 2-aminobenzonitrile with certain 1,4-disubstituted piperazines, or 2) reaction of the appropriate 4,5-dimethoxy or 3'4 _; 5-trimethoxy substituted 2-aminobenzamide with the same 1,4-disubstituted piperazines.

Compounds of formulas:

ch ₃ o ^ Y

NHCH2C6H5

nhch ₂ c ₆ h ₅ 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, theooyl, pyridinecarbonyl, 3,4,5-trimethoxybenzoyl, alkoxycarbonyl of 1 to 6 carbon atoms in the alkoxy and alkenyloxycarbonyl and 3 to 6 alkenyloxycarbonyl groups; are disclosed in U.S. Patent No. 3,511,836. However, the other intermediates used in the process of the present invention are novel.

The present invention provides a process for the preparation of a compound of formula I (I) wherein R ₁ is hydrogen or methoxy and

R ₂ is alkenyl of 3-5 carbon atoms, benzoyl, furoyl, thienylcarbonyl, · alkqxykarbonyl having 2-5 carbon atoms, alkenyloxycarbonyl having 4-5 carbon atoms or (2-hydroxyalkoxy) carbonyl having 4-5 carbon atoms or their hydrochlorides or hydrobromides, characterized in that one mole of the compound of formula (II) is used

wherein R ₁ is as defined above, X is chlorine or bromine, and R 1 and R 2 together with the nitrogen atom to which they are attached form a cyclic imido group, preferably a phthalimido group, a maleimido group or a succinimido group, react with a compound of formula III

And (III), wherein R 8 is as defined above, in an inert organic solvent at a temperature of from 50 to 200 ° C, to form an intermediate of formula IV

where R., R _? R, and R are as defined above, and this intermediate is further reacted at a temperature of 0 to 100 ° C to give the final product of formula I either by hydrolysis or reduction with an equimolar amount of hydrazine in the presence of an organic solvent inert to the reaction.

A particularly preferred temperature range for the reaction between compounds II and III is from 80 to 130 ° C.

A particularly preferred temperature for further reaction of the intermediate of formula IV by hydrolysis or using hydrazine is from 20 to 50 ° C.

If hydrolysis is used, it is preferably carried out in the presence of hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.

While the process of the present invention is useful for preparing the known hypotensive agents of formula X, 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-methylprop-1-yloxycarbonyl) -piperazin-1-yl-4-amino-6,7,8-trimethoxyquinazoline known as prazosine and trimazosine. 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. 3,660,968). Prazosin and trimazosin have recently been reported to have a therapeutic effect in humans (Cohen, Journal of Clinical Pharmacology 10, 408 (197Q), De Guia, et al., Current Therapeutic Research, 15, 339 (1973)).

The present invention also relates to novel and useful intermediates of formula II aj-uu.cttiij.xi uuttuiittiiu

where X, Rp 3 have

The present invention of formula IV as defined above, and their acid salts.

it also relates to novel and useful intermediates, compounds of general interest

(IV), wherein R ₁ , R p, R j and R 6 are as defined above and their acid salts.

In the above formulas (II) and (IV), said cyclic imido group is made up of substituents and an 8 and a nitrogen atom, to which are preferably attached a phthalimidose of 202071, a maleimide or a succinimido group. The present invention relates to a process for the preparation of a compound of formula (I) above, or a hydrochloride or hydrobromide thereof by reacting a compound of formula (II) with a compound of formula (III). and III is carried out in the presence of an appropriate inert organic solvent. A suitable solvent is one which sufficiently dissolves the reactants 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 ether, 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 is required, while at higher temperatures the reaction is completed in a shorter time. Generally, _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. The preparation of compounds of the present invention can be illustrated by the following reaction scheme:

Compounds of formulas II and III used as reactants in the process of the present invention are those wherein X is chlorine or bromine, and particularly preferred are those wherein X is chlorine and R8 and R8 are as defined above and are taken together with the atom nitrogen to which they are attached by a cyclic imido group. Examples of these cyclic imido groups are phthalimido, succinimido, maleimido, glutarimido and imido groups derived from other cyclic dicarboxylic anhydrides such as diglycolic anhydride, thioglycolic acid, cyclohexane-1,2-dicarboxylic acid, 4-bromophthalic acid and 3-bromophthalic acid acid. Preferred cyclic imido groups are phthalimido, succinimido and maleimido.

In the process according to the invention as shown in výěe said reaction progresses preferred to use compounds of formula II wherein X is chlorine or bromine, is hydrogen or methoxy and R ₂ is a hydrogen atom and and, together with the nitrogen atom to which they are attached, they are phthalimido, maleimido or succinimido. These compounds of formula (II) are reacted with those described above. compounds of formula III to give intermediates of formula IV in the form of hydrochlorides or hydrobromides.

If these compounds of formula IV are desired, it is preferred to carry out the reaction using approximately equimolar amounts of reactants in terms of economy and efficiency.

However, this is not essential to the course of the reaction and an excess of any reactant may be present. The intermediate of formula IV can advantageously be isolated in the form of the hydrochloride or hydrobromide, which are substantially insoluble in the reaction solvent and can be isolated by filtration and washing. Alternatively, the above salts may be reacted with an alkaline agent such as sodium hydroxide, potassium hydroxide, potassium carbonate or sodium methoxide during treatment of the reaction mixture and the free base isolated by extraction into a water-insoluble solvent such as chloroform, dichloromethane or benzene. and evaporation to dryness. If desired, either the compound of formula IV or a salt thereof can be further purified by conventional methods such as crystallization or column chromatography. However, often these compounds are sufficiently pure to further react to the compounds of Formula I without the need for such further purification.

As mentioned above, the compounds of formula IV or their hydrohalides can be further reacted by removing the 4-amino substituents R1 and R1 by hydrolysis or hydrazinolysis to give a compound of formula I.

The hydrolysis is carried out under alkaline conditions in the presence of, for example, sodium hydroxide or potassium hydroxide or under acidic conditions using a suitable acid. Examples of suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, hydroiodic acid, dichloroacetic acid or trifluoroacetic acid. It has been found that the use of hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid is particularly suitable and effective for the hydrolysis of the preferred cyclic imido compounds of the formula IV. It is preferred to carry out the hydrolysis using one of these acids at a temperature in the range from 0 to 100 ° C, especially a preferred temperature range for such hydrolysis from 20 to 50 ° C. At temperatures below 0 ° C, the rate of hydrolysis is slow. Far more decomposition products are produced at temperatures above 100 ° C.

The molar ratio of the above acids to the compounds of formula IV can be varied within a wide range, so that a molar ratio of from 1: 1 to 200: 1 can be used to achieve satisfactory results. The time required to achieve complete hydrolysis is dependent on the reaction temperature, and if the reaction is carried out at 100 ° C, it is sufficiently long for only a few minutes, if the reaction is carried out at 0 ° C, a time of up to 24 hours. The hydrolysis can be carried out in an aqueous medium or in an aqueous-organic medium containing a water-immiscible organic solvent, such as chloroform, methylene chloride, benzene or toluene.

Upon completion of the hydrolysis, which can be determined by thin layer chromatography on silica gel in a 95: 5 ethyl acetate: diethylamine solvent mixture, the desired product of formula I can be isolated in the form of a salt with the acid used for hydrolysis, using conventional methods. However, it is far more convenient to adjust the reaction mixture to an alkaline pH by the addition of sodium hydroxide, potassium hydroxide or sodium carbonate, and the compound of formula I is then extracted as the free base, for example using the above organic solvents optionally used in the hydrolysis. The ISP product is then easily isolated by evaporation.

Alternatively, as mentioned above, the intermediate of formula IV can be further reacted with hydrazine to give the final product of formula I. The use of hydrazine to remove phthaloyl from phthalimido acids or the corresponding lower alkyl esters is known in the literature, see for example Boissannas, Advances in Org. Chem., 2> 179-183 (1963) and Sheehan et al., Jour. Amer. Chem. Soc. 76, 6329 (1954). It has now been found that the above intermediates of formula IV contain the above cyclic imido groups and in particular those containing phthalimido, maleimido or succinimido groups also react to give the desired products of formula I. The reaction is carried out in the presence of an inert organic solvent. Examples of organic solvents that can be used for this reaction are lower alkanols such as ethanol, propanol, isopropanol, butanol and isoamyl alcohol, N, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, dimethylsulfoxide, diethylene glycol dimethyl ether and diethylene glycol monoethyl ether.

The hydrazine used for the reaction may be substantially pure or a derivative such as hydrazine hydrate, hydrazine hydrochloride or hydrazine sulfate may be used. When an acid salt is used, hydrazine is released in situ by addition of a suitable acid neutralizing base. Examples of such suitable bases are sodium methoxide, potassium carbonate, triethylamine, triethanolamine and sodium hydroxide. While a molar excess of hydrazine of up to five moles per mole of the intermediate of formula IV can be successfully used in this reaction, it is preferable to use an equimolar amount of hydrazine for reasons of closest possible side reactions and, moreover, for economics. The reaction with hydrazine is preferably carried out at a temperature of from 0 to 100 ° C. A particularly preferred range is from 20 to 50 ° C. At temperatures above 100 C ^N undesirable side reactions take place, while at temperatures below 0 ° C, the reaction rychlor: slow.

Of course, the time required to complete the reaction depends on the temperature and the type of reaction components and solvent used. Typically, however, the reaction with hydrazine is complete within 1 to 4 hours. The reaction of hydrazine with the above cyclic imido compounds also forms a cyclic hydrazine by-product such as phthaloyl hydrazide in the case of phthalimide intermediates. The reaction mixture may be freed from cyclic hydrazide by-products and the desired product of formula I may be isolated by known methods such as evaporation in vacuo to dryness, trituration of the residue with a dilute strong mineral acid such as hydrochloric acid or sulfuric acid in which the cyclic hydrazide is present. only sparingly soluble, then by filtration and adjusting the filtrate to alkaline pH, the desired product is isolated by extraction or filtration.

The novel intermediates of formulas II and IV are different from compounds of similar structure in terms of differences in methods by which groups R 1 and R 2 can be removed to give the desired compounds of formula I. This means that compounds of the prior art are analogous to the compounds of formula II, but where R 6 is hydrogen and R 6 is benzyl, react with compounds of formula III to form the corresponding known compounds similar to compounds IV, but wherein R 6 is hydrogen and is benzyl. To remove the benzyl group, the compound of formula IV is subjected to hydrogenolysis. In contrast, the novel compounds of formula II of the present invention react with compounds of formula III to form new intermediates of formula IV, which then provide the desired compounds of formula I by hydrolysis or by reaction with hydrazine, as described previously.

The above-described intermediates of formula II can be prepared from the appropriate 2,4-dihalo-6,7-dimethoxyquinazoline or 2,4-dihalo-6,7,8-trimethoxyquinazoline wherein halogen is a chlorine or bromine atom. The preparation of these dihalogen compounds is described in U.S. Patent Nos. 3,511 1,836 and 3,669,968 and in Curd et al., J. Chem. Soc. (London) 777 (1947 and ibid. 1759 (1948)).

In the preparation of the novel intermediates of formula (II), one of the 2,4-dihalogenchinazolines described above is reacted with the corresponding cyclic imide in an organic solvent inert to the reaction and in the presence of a strong base such as sodium hydride, potassium hydride, calcium hydride, sodium methoxide, potassium ethoxide, lithium butoxide or butyllithium, under anhydrous conditions. After completion of the reaction, the compound of formula II is isolated by conventional methods, for example by quenching the reaction mixture in excess of water or dilute acid and filtering, washing and drying to give the desired product. If said amide or urethane is used, dilution in dilute acid is preferred.

Examples of the respective cyclic imides are any of the above, preferred cyclic imides are phthalimide, maleimide and succinimide.

Examples of useful organic solvents inert to the reaction are Ν, Ν-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, ethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dimethylsulfoxide, toluene and benzene. Preferred inert organic solvents are Ν, Ν-dimethylformamide and tetrahydrofuran.

In carrying out the reaction for the preparation of the novel intermediates of formula (II), sodium hydride is an advantageous strong base in terms of economy and efficiency. The molar ratio of said strong base to said 2,4-dihalogen quinazoline is at least 1: 1 and a molar ratio of from 1: 1 to 2: 1 is commonly used.

While the above reaction is carried out over a wide temperature range, a temperature range of 0 to 150 ° C is preferred, and a range of 65 to 100 ° C is particularly preferred. At temperatures below 0 ° C the reaction is too slow and at a temperature of 150 ° C a considerable amount of undesirable by-products is obtained. The reaction rate is higher at higher temperatures and the time required to complete the reaction depends on the temperature _? as well as the type of reactants and solvents. However, the reaction is usually complete within 2 to 24 hours.

The present invention is illustrated by the following examples.

Example 1

2-Chloro-4-phthalimido-6,7-dimethoxyquinazoline

50 ml of N, N-dimethylformamide, 14.7 g (0.010 mol) of phthalimide and 0.48 g (0.010 mol) of 50% w / w sodium hydride are placed in a 100 ml three-necked flask equipped with a thermometer, stirrer and drying tube. After stirring at room temperature for 30 minutes, a clear solution was obtained.

To this was added 2.59 g (0.010 mol) of 2,4-dichloro-6,7-dimethoxyquinazoline and the resulting mixture was heated at 100 ° C for 5 hours. The reaction mixture was cooled to room temperature, 150 mL of water was added and the precipitated product was filtered off, dried in vacuo to give 3.1 g of the title compound, m.p. 255 ° C. The structure was shown by NMR and mass spectrum. Yield 84%.

Example 2

2- [4- (2-Furoyl) piperazin-1-yl] -4-phthalimido-6,7-dimethoxyquinazoline

In a 35 ml single-necked round-bottomed flask equipped with a condenser and a drying tube was placed 1.0 g (0.0027 mol) of 2-chloro-4-phthalimido-6,7-dimethoxyquinazoline, 10 ml of isoamyl alcohol and a solution of 0.550 g (0.003). mol) of 1- (2-furoyl) piperazine. The resulting mixture was heated at 130 ° C for 4 hours and then cooled to room temperature. Hexane (35 ml) was added to the reaction mixture, and the precipitated product was filtered off, dried, yielding 0.70 g (47%) of the hydrochloride of the title compound. The purified free base was obtained from the salt by silica gel column chromatography (5.1 cm x 30.5 cm), eluting with a mixture of ethyl acetate and diethylamine (90:10). The purified product had mp 305 ° C.

If the above procedure was repeated using the solvent in place of isoamyl alcohol and the reaction was carried out at the indicated temperature and reaction time, the title compound was obtained analogously.

Solvent Reaction temperature Reaction time

C clock

200 isobutanol

1,2-dimethoxyethane diethylene glycol monoethyl ether

Example 3 A solution of 2- (4- (2-furoyl) piperazin-1-yl) -4-phthalimido-6,7-dimethoxyquinazoline (95 mg, 0.185 mmol) in concentrated hydrochloric acid (2.0 mL) was stirred at RT for 2 h. room temperature. Chloroform (4.0 ml) was added and the pH adjusted to 10 by addition of sodium carbonate solution. The chloroform phase was separated, evaporated to dryness to give 55 mg (77.6%).

2- [4- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline m.p. 270 ° C. The structure was confirmed by comparing the infrared spectrum with that of an authentic sample and by thin layer chromatography on silica gel using a 95: 5 mixture of ethyl acetate and diethylamine solvents.

Example 4

A suspension of 5.14 g (0.01 mol) of 2- [4- (2-furoyl) piperazin-1-yl] -4-phthalimido-6,7-dimethoxyquinazoline in 200 ml of isoamyl alcohol was heated until dissolved and added. 0.55 g (0.011 mol) of hydrazine hydrate. The resulting solution was stored at 20 ° C for 18 hours and then evaporated to dryness under reduced pressure. The residue is triturated with 30 ml of 0.5 N hydrochloric acid and stored at 4 ° C for two hours. The precipitated phthalhydrazide was filtered off, the filtrate was basified with sodium hydroxide solution (pH 10) and extracted with chloroform. Concentration of the extracts to dryness gives 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline.

Claims (8)

SUBJECT OF THE INVENTION A process for the preparation of 2- (4-substituted-piperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline of formula I (X) wherein R ₁ is hydrogen or methoxy and 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 or hydroohloridů or hydrobromides, characterized in that one mole of the compound of formula (II) xde R ₁ is as defined above, X is chlorine or bromine; and R 3 and R 4 together with the nitrogen atom to which they are attached form phthalimido, maleimido or succinimido, react with one mole of a compound of formula III (III), wherein R 8 is as defined above, in an organic solvent inert to the reaction, at from 50 to 200 ° C to give an intermediate of formula IV wherein R 1, R 6, R 6 and R 6 are as defined above, then reacting the intermediate at 0 to 100 ° C by hydrolysis or reaction with an equimolar amount of hydrazine in the presence of an inert organic solvent to give the final product of formula I. 2. The process according to claim 1, wherein the reaction between the compounds of formulas II and III is carried out at a temperature of from 80 to 130 [deg.] C. 3. The process according to claim 1, wherein the hydrolysis is carried out in the presence of hydrochloric, hydrobromic, sulfuric or phosphoric acid. and. A process according to any one of claims 1 to 3, wherein the further reaction of the intermediate of formula IV is carried out at a temperature of from 20 to 50 ° C. 5. Process according to claims 1-4, characterized in that as the starting compounds of formulas II and III where R ₁ is hydrogen and R g is 2-furoyl and R, R₁ and X are as defined above. 6. A process according to any one of claims 1 to 4, wherein the starting materials are compounds of formulas II and III. wherein R 1 is methoxy and R 8 is 2-methyl-2-hydroxy-prop-1-yloxycarbonyl and R 1, R 2 and X are as defined above. 7. A process according to any one of claims 1 to 4, wherein the compounds of formulas II and III are used as starting materials, wherein R1 is methoxy and R8 is 2-methyl-2-hydroxyprop-1-yloxycarbonyl and R1 and X have: the above meaning. 8. Process according to claims 1-7, characterized in that as starting material a compound of formula II wherein X is Cl and R _1, R and R are as defined above.