PL111221B1 - Preparation of 2-/4-substituted piperazinyl-1/-4-aminoguinazolines - Google Patents

Description

This invention relates to a novel process for the preparation of certain 2-(4-substituted piperazinyl-1)-aminoquinazolines which lower blood pressure in hypertensive mammals. More specifically, these antihypertensive agents are certain 2-(4-substituted piperazinyl-1)-amino-6,7-dimethoxyquinazolines, the use of which is disclosed in U.S. Patent No. 3,511,836. The novel intermediates are 2-halo-6,7-dimethoxy-4-substituted aminoquinazolines. U.S. Patent No. No. 3,511,836 teaches several methods for preparing 2-(4-substituted-piperazinyl-1-)-4-amino-6,7-dimethoxyquinazolines. For example, by reacting 2-chloro-4-amino-6,7-dimethoxyquinazolines with the corresponding 1-substituted piperazine, by reacting 2-(4-substituted-piperazinyl-1-)-4-chloro-6,7-dimethoxyquinazolines with ammonia, or by alkylating, alkanoylating, aroylating, or alkoxylating 2-(1-piperazinyl)-4-amino-6,7-dimethoxyquinazolines. In contrast to the new method of preparing the compounds in question, the known method is low in yield, since, as can be seen from examples I and LX of the specification No. 3,511,836, the first reaction stage is 60-70% efficient, i.e. the remaining steps, for which no data are given, would have to have a yield higher than 90% for the total yield of the known process to be comparable to the yield obtained in examples I-III illustrating the method according to the invention, which is 31%. Moreover, the known method requires a multi-stage reaction, while the new method proceeds in two stages. Compounds of formula 1 and formula 2, wherein Y denotes a hydrogen atom, an alkyl group with 1-5 carbon atoms, a hydroxyalkyl group with 2-5 carbon atoms, an alkanecarbonyl group with 2-7 carbon atoms, a benzoyl group, a furoyl group, a benzofuroyl group, a theoyl group, a benzoyl group, a chlorobenzoyl group, a bromobenzoyl group, a trifluoromethyl group, a methoxyphenyl group, a methylphenyl group, a methylbenzoyl group, a trifluoromethylbenzoyl group, a furoyl group, a benzofuroyl group, a theoyl group, a pyridinecarboxylic acid alkyl ester group, in which the alkyl group is contains 1-6 carbon atoms and the alkanyl carboxylic acid ester group in which the alkenyl group contains 3-6 carbon atoms are known from U.S. Patent No. 3,511,836. However, other intermediate compounds useful in the process according to the invention are new compounds. The process according to the invention for the preparation of the compound of formula 3 consists in reacting equimolar amounts of the compound of formula 4 and the compound of formula 5 in an organic solvent inert towards the reagents at a temperature of 50-200°C, whereby an intermediate product is obtained. In formulae 3, 4 and 5, X represents a chlorine or bromine atom, R1 represents a hydrogen atom, R2 represents a furoyl group, and R3 and R4 together with the nitrogen atom to which they are attached form a phthalimide, maleimide or succinimide ring group. The reaction gives a compound of formula G, in which R1, R2, R3 and R4 have the meanings given above. The compound of formula 6 is hydrolyzed or reacted with an equimolar amount of hydrazine at a temperature of 0-100°C in the presence of an organic solvent inert towards the reagents. A particularly preferred temperature range for the reaction of the compound of formula 4 with the compound of formula 5 is 80-130°C. A particularly preferred temperature for the hydrolysis of the intermediate compounds of formula 6 or their reaction with hydrazine is 20-50°C. If hydrolysis is carried out, it is preferably carried out in the presence of an acid such as hydrochloric, hydrobromic, sulfuric or phosphoric acid. The process of the invention is useful in the preparation of the known antihypertensive agents of formula III and is particularly useful in the preparation of a particularly valuable compound of this group, namely 2-[4-(2-furayl)piperazin-1]-4-amino-6,7-dimethoxyquinazoline, known as prazosin. Prazosin has recently been described as a therapeutic agent for humans [Cohen, Journal of Chemical Pharmacology, 10, 408 (1970); De Cuia et al., Current Therapeutic Research, 15, 339 (1973)]. New intermediate compounds useful in the process according to the invention are compounds of formula 4, wherein X, R1, R3 and R4 have the meanings given above, and acid addition salts thereof. Also useful as intermediates in the process according to the invention are compounds of formula 6, wherein R1, R1, R3 and R4 have the meanings given above, and acid addition salts thereof. The process for preparing compounds of formula 3 and their salts with hydrogen chloride or hydrogen bromide, as mentioned, consists in reacting a compound of formula 4 with a compound of formula 5, initially obtaining an intermediate of formula 6 or a salt thereof, which product is further reacted to obtain compounds of formula 3. The reactions of compounds of formulae 4 and 5 are carried out in the presence of an organic solvent suitable for the reactants. A suitable solvent is one that will dissolve the reactants and will not adversely affect the reactants or reaction products. Examples of such solvents are alcohols such as isopropanol, butanol, isobutanol, isoamyl alcohol, 2-methylpentanol-2, 3,5-dimethylbutanol-1, glycols, glycol ethers such as ethylene glycol monomethyl ether, 1,2-dimethoxyethane and diethylene glycol dimethyl ether, tertiary amides such as N,N-dimethylformamide, N,N-diethylacetamide and N-methylpyrrolidone, dimethyl sulfoxide and pyridine. Although the reactions can be carried out over a wide temperature range, the preferred temperatures are between 50°C and 200°C, with temperatures between 80°C and 130°C being particularly preferred. The time required to carry out the process and achieve practically complete conversion depends on several parameters, such as, for example, the reaction temperature, the reactivity of the individual starting compounds in the process and the concentration of the reactants. It will be obvious to those familiar with the subject that at lower temperatures a longer reaction time is required, while at higher temperatures the reaction takes place in a shorter time. However, a reaction time of 15 minutes to 50 hours is usually sufficient. The reaction of compounds of formula 4 with compounds of formula 5 leads to an intermediate of formula 6, which is further reacted to obtain compounds of formula 3. The process according to the invention is illustrated in the diagram in the drawing. As mentioned, the compounds of formulae 4 and 5 used as reagents in the process according to the invention are compounds in which X is a chlorine or bromine atom, with Y being particularly preferred as a chlorine atom, R1 and R2 have the above-mentioned meanings, and R3 and R4 represent phthalimide, succinimide or and in the first stage of the reaction, intermediates of formula 6, their hydrochlorides or hydrobromides, are obtained. If such compounds of formula 6 are required, it is advantageous to carry out the reaction using approximately equimolar amounts of the reagents for reasons of economy and yield. However, this does not have a fundamental influence on the success of the reaction, since an excess of one of the reagents can be used. The intermediate compounds of formula (VI) may conveniently be separated in the form of the hydrochloride or hydrobromide salts, which are usually insoluble in the solvent used and can therefore be simply obtained by filtration and washing. Alternatively, said salts may be treated during the work-up of the reaction mixture with an alkaline reagent, such as, for example, sodium hydroxide, potassium hydroxide, potassium carbonate or sodium alkoxide, followed by extraction of the free base with a water-immiscible solvent, such as, for example, chloroform, dichloromethane or benzene, and evaporation to dryness. If desired, either the compound of formula (VI) or the salts thereof may be further purified by conventional methods, such as crystallization or column chromatography. However, these compounds are often sufficiently pure for subsequent reaction to form compounds of formula III without such further purification. As previously mentioned, compounds of formula VI or the hydrogen halide salts are hydrolyzed or reacted with hydrazine to remove the 4-amino substituents R3 and R4 to provide compounds of formula III. Hydrolysis of compounds of formula VI can be carried out under alkaline conditions in the presence of, for example, sodium hydroxide or potassium hydroxide, or under acidic conditions using an appropriate acid. Examples of such suitable acids include hydrochloric, bromochloroacetic, sulfuric, phosphoric, hydriodic, dichloroacetic and trifluoroacetic acids. It has been found that for the hydrolysis of the preferred ring imide compounds of formula VI it is particularly convenient and efficient to use an appropriate acid selected from hydrochloric, hydrobromic, sulfuric, and phosphoric acids. It is advantageous to carry out the hydrolysis with one of these acids at a temperature in the range of 0-100°C, and a particularly preferred temperature range for the hydrolysis is 20-50°C. At temperatures below 0°C the rate of hydrolysis is very slow. At temperatures higher than 100°C, excessive amounts of decomposition products are formed. The molar ratio of acids to the compound of formula 6 can vary within a very wide range, so molar ratios from 1:1 to 200:1 can be used with satisfactory results. The time required to achieve practical completion of the hydrolysis varies with the reaction temperature, but typically a few minutes are sufficient when the hydrolysis is carried out at 100°C, while up to 24 hours may be required when the hydrolysis is carried out at 0°C. The hydrolysis may be carried out in an aqueous or aqueous-organic medium using an organic solvent immiscible with water, such as, for example, chloroform, methylene dichloride, benzene or toluene. After hydrolysis is complete, which can be readily determined by thin-layer chromatography on silica gel, for example using a 95:5 ethyl acetate-diethylamine solvent system, the resulting product of formula III can be isolated as a salt of the acid used in the hydrolysis using well-known methods. However, it is usually more convenient to adjust the reaction mixture to an alkaline pH by adding, for example, sodium hydroxide, potassium hydroxide or sodium carbonate, and then extract the compound of formula III as the free base, for example using one of the solvents optionally used in the hydrolysis mentioned above. The product is then readily obtained by evaporation of the solvent. Alternatively, the intermediates of formula (VI) may be reacted with hydrazine to obtain the final product of formula (III). The use of hydrazine to remove the phthaloyl group from phthalimidic acids or their corresponding lower alkyl esters is known, for example, from Boissanuas, Advances in Org. Chem. 3, 179-183 (1963) and Sheehan et al., Journal of Amer. Chem. Soc. 76, 6329 (1954). It has been found that compounds of formula (VI) containing one of the previously mentioned ring imide groups, and in particular those containing a phthalimide, maleimide or succinimide group, also react to give the desired compound of formula (III). The reactions are carried out in the presence of an organic solvent which is inert towards the reagents. Examples of organic solvents that can be used for this reaction are lower alcohols such as ethanol, propanol, isopropanol, butanol, and isoamyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, diethylene glycol dimethyl ether, and diethylene glycol monoethyl ether. The hydrazine used in the reaction is used in practically pure form or as a derivative such as hydrazine hydrate, hydrazine hydrochloride, or hydrazine sulfate. If addition salts are used, the hydrazine is generated in situ by adding a suitable base to neutralize the acid. Examples of suitable bases for this purpose are sodium methoxide, potassium carbonate, triethylamine, triethanolamine, or sodium hydroxide. Although hydrazine can be successfully used in the process in excess amounts of up to five moles per mole of compound of formula (VI), it is preferred to use an equimolar amount of hydrazine to minimize the possibility of side reactions and for economic reasons. Preferably, the reaction with hydrazine is carried out at a temperature of 0°C to 100°C. A temperature range of 20°C to 50°C is particularly preferred. At temperatures above 100°C, undesirable side reactions occur, while at temperatures below 0°C, the reaction rate is very slow. The time required to practically complete the reaction will, of course, vary with the temperature and the precise nature of the reactants and solvent. However, in general, the reaction with hydrazine to give the final product of formula 3 will be practically complete in 1-48 hours. The reaction of hydrazine with cyclic imide compounds also gives a cyclic hydrazide byproduct, such as, for example, phthalylhydrazide when a phthalimido intermediate is used. The reaction mixture can be freed from the hydrazide ring compounds and the product of formula III isolated by known methods, for example by evaporating under reduced pressure to dryness, triturating the residue with a dilute strong mineral acid, such as hydrochloric acid or sulfuric acid, in which the hydrazine rings are usually only sparingly soluble, then filtering and adjusting the pH of the filtrate to alkaline, and then isolating the product by extraction or filtration. The new intermediates of formulae 4 and 6 differ from known compounds of similar structure in that the R 3 and R 4 groups are removed to obtain the compound of formula 3 by other means. This means that the known compounds of formula 4, where Rg is a hydrogen atom and R4 is a benzyl group, react with the compounds of formula 5 to give the corresponding known compounds of formula 6, where R3 is a hydrogen atom and R4 is a benzyl group. In order to remove the benzyl group, the compound of formula 6 is subjected to hydrogenolysis. In contrast, the new compounds of formula IV give compounds of formula VI, which in turn give compounds of formula III by hydrolysis or by reaction with hydrazine. The intermediates of formula IV described above are prepared from the corresponding 2,4-dihalo-6,7-dimethoxyquinazolines or 2,4-dihalo-6,7,8-trimethoxyquinazolines, in which the halogen is chlorine or bromine. The preparation of the said compounds is described in U.S. Patent Nos. 3,511,836 and 3,669,968 and by Curda et al., Jour. Chem. Soc. (London), 777 (1947); ibid., 1759 (1948). In the preparation of the new intermediates of formula IV, one of the above 2,4-dihaloquinazolines is reacted with the appropriate cyclic imide in an organic solvent inert to the reagents in the presence of a strong base such as, for example, sodium hydride, potassium hydride, calcium hydride, sodium methoxide, sodium ethoxide, lithium butoxide, and butyllithium, under anhydrous conditions. After the reaction has practically ended, the product of formula IV is separated by conventional methods known in the art, for example by cooling the reaction mixture in an excess of water or dilute acid and filtering, washing, and drying the resulting product. Quenching in dilute acid is preferred when an amide or urethane, rather than an imide, is used in the reaction. Examples of reagent-inert solvents which may be used are N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dimethylsulfoxide, toluene and benzene. Preferred inert organic solvents are N,N-dimethylformamide and tetrahydrofuran. In the reaction to obtain the new intermediates of formula IV, the preferred base from the standpoint of economy and yield is hydride. sodium, the molar ratio of strong base to 2,4-dihaloquinazoline generally used is at least 1:1, and preferably 1:1 to 2:1. Although the above reactions can be carried out over a wide temperature range, temperatures in the range 0°C to 150°C, especially 65°C to 100°C, are preferred. Below 0°C the reaction is extremely slow, while at temperatures above 150°C excessive amounts of undesirable by-products are obtained. Of course, the rate of reaction is faster at higher temperatures, and the time required for completion varies with temperature as well as with the nature of the reagents and solvent. However, the reaction is usually complete within 2-24 hours. The following examples illustrate the process of the invention. Example 1 2-Chloro-4-phthalimide Q-6J7-d'Umethoxyquinazoline To a 100 ml three-necked round-bottomed flask fitted with a thermometer, a stirrer and a drying tube are added 50 ml of N,N-dimethylformamide, 1.47 g (0.010 mole) of phthalimide and 0.48 g (0.010 mole) of 50% w/w sodium hydride. After stirring at room temperature for 30 minutes, a clear solution was obtained, to which was then added 2.59 g (0.010 mole) of 2,4-dichloro-6,7-dimethO-oxyquinazoline and the resulting mixture was heated at 100°C for 5 hours. The reaction mixture was cooled to room temperature, 150 ml of water were added and the precipitated product was isolated by filtration and dried under reduced pressure to give 3.1 g (84% yield) of the title compound, melting at 255°C. The structure was confirmed by HMR and mass spectrometry data. Example II 2-[4-(2-Furoyl)piperazin-1]-4-phthalimido-6,7-dimethoxyquinazoline. To a 35 ml round-bottomed one-necked flask fitted with a condenser and drying tube were placed 1.0 g (0.0027 mole) of 2-chloro-4-thalimido-6,7-dimethoxyquinazoline, 10 ml of isoamyl alcohol, and a solution of 0.550 g (0.003 mole) of 1-(2-furoyl)piperazine. The resulting mixture was heated at 150°C for 4 hours and then cooled to room temperature. To the reaction mixture was added 35 ml of hexane, and the precipitated product was filtered and dried to give 0.70 g (47%) of the hydrochloride salt of the title compound. The purified free base was obtained from this salt by chromatography on silica gel in a 5.08 cm x 30.48 cm column, eluting with ethyl acetate-diethylamine (90:10). The purified product melted at 305°C. If the above procedure is repeated, but using the indicated solvents in place of isoamyl alcohol, and the indicated temperatures and reaction times, the title compound is obtained in a similar manner. 45 50 35 Solvent Isobutanol 1,2-dimethoxyethane diethylene glycol monoethyl ether Reaction temperature °C 50° 80° * 200° Reaction time hours 48 30 1 65 Example 3 A solution of 95 milligrams (0.185 millimoles) of 2-[4-(2-furoyl)piperazin-1]-4-phthalimido-6,7-dimethoxyquinazoline in 2.0 ml of concentrated hydrochloric acid was stirred at room temperature for 2 hours. 4.0 ml of chloroform was then added and the mixture was adjusted to pH 10 by adding potassium carbonate solution. The chloroform layer was separated and evaporated to dryness to give 55 mg (77.6%) of 2-[4-(2-furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline, m.p. 270°C. The structure was confirmed by comparison of the infra-red spectrum with that obtained from an authentic sample and by thin-layer chromatography on silica gel using a 95:5 ethyl acetate-dimethylamine solvent system. Example 4 A suspension of 5.14 g (0.01 mole) of 2-[4-(2-furoyl)piperazin-1-yl]-4-p,thalimido-6,7-dimethoxyquinazoline in 200 ml of isoamyl alcohol was heated. until a solution was obtained and 0.55 g (0.01 mole) of hydrazine hydrate was added. The resulting solution was stored at 20°C for 18 hours and then evaporated to dryness under reduced pressure. The residue was triturated with 30 ml of 0.5 N hydrochloric acid solution and stored at 4°C for 2 hours. The solution was filtered to remove the precipitated phthalyl hydrazide. The filtrate was made alkaline (pH 1.0) with sodium hydroxide, the solution was extracted with chloroform and the extracts were evaporated to dryness to give 2-(4-(2-furoyl)piperazin-1-yl)-4-amino-6,7-dimetho- oxyquinazoline. Patent claims are 1. A method for preparing a compound of formula 3, wherein R 1 is a hydrogen atom and R 2 is a furoyl group or an acid addition salt of this compound with hydrochloric or hydrobromic acid, characterized in that equimolar amounts of a compound of formula 4, wherein R 1 has the above-mentioned meaning, X is a chlorine or bromine atom and R 3 and R 4 together with the nitrogen atom to which they are attached form a phthalimide, maleimide or succinimide ring group, and a compound of formula 5, wherein R 2 has the above-mentioned meaning, are reacted in a solvent inert towards the reagents at a temperature of 50-200°C to obtain a compound of formula 6, wherein R1, R2, R3 and R4 have the above-mentioned meanings, are subjected to hydrolysis or reaction with an equimolar amount of hydrazine at a temperature of 0-100°C in the presence of an organic solvent inert towards the reagents. 2. A process according to claim 1, characterized in that the reactions of the compound of formula 4 with the compound of formula 5 are carried out at a temperature of 80-130°C. 3. A process according to claim 1 or 2, characterized in that the hydrolysis is carried out in the presence of hydrochloric, hydrobromic, sulfuric or phosphoric acid. 4. A process according to claim 1 or 3, characterized in that the reactions of the intermediate compound of formula 6 are carried out at a temperature of 20-50°C. formula r 1 R, /^\ h/zor 3 HlflHRt formula a ^ n WTcr + HN N-R,—- kJLri CH*° n t ch3o A R3 Ha R3 R4 formulaW / formula,6 r{ji-R* Schemal formula 3 DN-3, 2.147/81 Price 45 zl PL PL PL PL PL PL PL

Claims (1)

1.