DE2725019A1 - PROCESS FOR THE PREPARATION OF SUBSTITUTED AMINOCHINAZOLINE DERIVATIVES AND INTERMEDIATE PRODUCTS THEREFORE - Google Patents

Description

Process for the preparation of substituted amino quinazoline derivatives and intermediates therefor.

The invention relates to a new process for the preparation of substituted amino quinazoline derivatives and to intermediates therefor. According to the procedure of

The end products obtained in accordance with the invention are known chemical compounds which are valuable because of their suitability for lowering blood pressure in hypertensive patients. More specifically, these antihypertensive compounds are certain 2- (4-substituted piperazin-1-yl) -4-amino-6,7-dimethoxyquinazolines and 2- (4-substituted piperazin-1-yl -) - 4-amino-6, 7,8-trimethoxyquinazolines described in U.S. Patents 3,511,836 and 3,669,968. The invention also relates to certain 2-halo-6,7-dimethoxy-4- (substituted-amino) -quinazolines, 2-halo-6,7,8-trimethoxy-4- (substituted-amino) -quinazolines and the corresponding compounds in which the 2-halogen substituent has been replaced by certain 4-substituted piperazinyl groups, which are new intermediates.

U.S. Patent 3,511,836 describes various processes for the preparation of 2- (4-substituted piperazin-1-yl) -4-amino-6,7-dimethoxyquinazolines; for example by reacting 2-chloro-4-amino-6,7-dimethoxyquinazoline with the appropriate 1-substituted piperazine, by reacting a 2- (4-substituted piperazin-1-yl) -4-chloro-6,7-dimethoxyquinazoline with ammonia or by alkylation, alkanoylation, aroylation or alkoxylation of 2- (1-piperazinyl) -4-amino-6,7-dimethoxyquinazoline. US Pat. No. 3,669,968 describes the preparation of 2- (4-substituted piperazin-1-yl) -4-amino-6,7,8-trimethoxyquinazolines by reacting 2-chloro-4-amino-6,7, 8-trimethoxyquinazoline with the appropriate 1-substituted ated piperazine.

U.S. Patent 3,935,213 describes the preparation of 2- (4-substituted-piperazin-1-yl) -4-amino-6,7-dimethoxy-quinazolines and the corresponding 6,7,8-trimethoxyquinazolines by processes which contain either (1) the reaction of the appropriate 4,5-dimethoxy-substituted or 3,4,5-trimethoxy-substituted 2-aminobenzonitrile with certain 1,4-substituted piperazines, or (2) the reaction of the appropriate 4,5-dimethoxy- or 3 , 4,5-trimethoxy-substituted 2-aminobenzamidines with the same compounds of the formulas wherein Y is hydrogen, alkyl with 1 to 5 carbon atoms, hydroxyalkyl with 2 to 5 carbon atoms, alkanoyl with 2 to 7 carbon atoms, alkyl, propargyl, 2-methallyl, phenyl, benzyl, benzoyl, chlorobenzoyl, bromobenzoyl, trifluoromethyl, methoxyphenyl, methylphenyl, methylbenzoyl , Trifluoromethylbenzoyl, furoyl, benzofuroyl, thenoyl, piridine carbonyl, 3,4,5-trimethoxybenzoyl, carboxylic acid alkyl ester in which the alkyl group has 1 to 6 carbon atoms, and carboxylic acid alkenyl ester in which the alkenyl group has 3 to 6 carbon atoms, are in the US patent 3,511,836. However, other intermediates which are suitable for the process of the invention are new compounds.

According to the invention there is a process for the preparation of a compound of the formula proposed, which is characterized in that one mole of a first reactant of the formula with one to two moles of a second reactant of the formula in an inert organic solvent at a temperature of 50 ° to 200 ° C, in which R [deep] 1 is hydrogen or methoxy, R [deep] 2 is alkenyl with 3 to 5 carbon atoms, benzoyl, furoyl, thienylcarbonyl,

Is alkoxycarbonyl of 2 to 5 carbon atoms or (2-hydroxyalkoxy) carbonyl of 4 or 5 carbon atoms, X is chlorine or bromine, R [deep] 3 is hydrogen and R [deep] 4 is -CH [deep] 2C [deep] 6H [deep] 4R [deep] 5, -COOCH [deep] 2C [deep] 6H [deep] 4R [deep] 5, -COR [deep] 6, -COCF [deep] 3, -CHO or COOR [deep] 6 or R [deep] 3 and R [deep] 4 together with the nitrogen atom to which they are bonded form a cyclic imido group, preferably a phthalimido, maleimido or succinimido group, R [deep] 5 hydrogen, chlorine, Is bromine, methyl, methoxy or nitro and R [deep] 6 is alkyl of 1 to 4 carbon atoms or -C [deep] 6H [deep] 4R [deep] 5.

A particularly preferred temperature range corresponds to 80 ° to 130 ° C.

When the above procedure is carried out with reactants (II) and (III) wherein R [deep] 2 is benzoyl, furoyl, thienylcarbonyl, alkoxycarbonyl of 2 to 5 carbon atoms, or (2-hydroxyalkoxy) carbonyl of 4 or 5 carbon atoms, R [deep] 3 is hydrogen and R [deep] 4 -CH [deep] 2C [deep] 6H [deep] 4R [deep] 5, it is advantageous to convert equimolar amounts of said reactants. An intermediate compound of the formula wherein R [deep] 1, R [deep] 2, R [deep] 3 and R [deep] 4 are as defined above, is obtained, and this intermediate compound is then further converted to the end product of the formula (I) by catalytic hydrogenolysis implemented. A particularly preferred catalyst for hydrogenolysis is palladium.

When the process of the invention is carried out with a first reactant of formula (II) wherein R [deep] 3 and R [deep] 4 together with the nitrogen atom to which they are attached form a phthalimido, maleimido or succinimido group, it is also advantageous to use an equimolar amount of each reactant to form an intermediate of formula (IV). In any case, said intermediate product is further reacted at a temperature of 0 ° to 100 ° C. to give the end product of the formula (I), namely (a) by hydrolysis or (b) by reaction with an equimolar amount of hydrazine in the presence of an inert organic solvent.

A particularly preferred temperature for the further reaction of the intermediate of the formula (IV) by hydrolysis or with hydrazine corresponds to 20.degree. To 50.degree.

If hydrolysis is used, it is advantageous to carry it out in the presence of hydrogen chloride, hydrogen bromide, sulfuric acid or phosphoric acid.

When the process of the invention is carried out on a compound of formula (II) wherein R [deep] 3 is hydrogen and R [deep] 4 COOCH [deep] 2C [deep] 6H [deep] 4R [deep] 5, -COR [deep] 6, -COCF [deep] 3, -CHO or COOR [deep] 6, wherein R [deep] 5 and R [deep] 6 have the meaning given above, the desired compound of the formula (i) or the hydrochloride or hydrobromide addition salt thereof is formed directly. In the latter case it is advantageous to react one mole of the first reactant of the formula (II) with two moles of the second reactant of the formula (III).

Although the process of the invention is suitable for the preparation of said known antihypertensive agents of formula (I), it is particularly useful for the preparation of two particularly valuable compounds of formula (I), namely 2- [4- (2-furoyl) piperazine -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, which are known in the art 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 (U.S. Patent 3,669,968). Prazosin and trimazosin have recently been reported to be therapeutically useful in humans (Cohen, Journal of Clinical Pharmacology, 10, 408 [1970], Current Therapeutic Research, 15, 339 [1937].

The invention also proposes new and useful intermediate compounds of formula (V)

before, wherein X and R [deep] 1 have the meaning given above, R [deep] 30 is hydrogen and R [deep] 40 -COOCH [deep] 2C [deep] 6H [deep] 4R [deep] 5, -COCF [deep] 3, -CHO or -COOR [deep] 6 or R [deep] 30 and R [deep] 40 together with the nitrogen atom to which they are bonded are a cyclic imido group, preferably a phthalimido, maleimido or Succinimido group, and R [deep] 5 and R [deep] 6 have the meaning given above.

The invention also proposes useful intermediate compounds of the formula (VI) before, in which R [deep] 1 and R [deep] 2 have the meaning given above and R [deep] 31 and R [deep] 41 together with the nitrogen atom to which they are attached, a cyclic imido group, preferably a phthalimido , Maleimido or succinimido group.

The invention proposes a method for producing a

Compound of the above formula (I) or a hydrochloride or hydrobromide addition salt thereof by reacting a compound of the formula (II) with a compound of the formula (III).

In certain cases, as will be described in more detail below, an intermediate compound of the formula (IV) or an acid addition salt thereof is first obtained, which is then further converted to a compound of the formula (I). The reaction of compounds of the formulas (II) and (III) is carried out in the presence of a suitable reaction-inert organic solvent. A suitable solvent is one that substantially dissolves the reactants but does not adversely react with the reactant or the reaction product. 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 monoethylene and diethylene glycol dimethyl ether, tertiary amides such as N, N-dimethylformamide, N, N-diethylacetamide and N-methylpyrrolidone, dimethyl sulfoxide and pyridine. Although the reaction can be carried out over a wide range of temperatures, a temperature in the range of 50 to 200 ° C is preferred. A particularly preferred temperature range corresponds to 80 ° to 130 ° C. The duration required for the procedure to achieve a virtually complete conversion will vary with various factors such as reaction temperature, reactivity, the particular starting materials used, and the concentration of the reactants. At low temperatures, a longer reaction time is required, while at higher temperatures the reaction is completed in a shorter time. A reaction time of 15 minutes up to 50 hours is generally sufficient.

In certain cases, when a compound of the formula (II) is reacted with a compound of the formula (III), an intermediate compound of the formula (IV) is formed which is then further converted to the desired compound of the formula (I). Accordingly, the process of the invention can be carried out by one of two methods, referred to as Method A and Method B, as shown in the following reaction scheme.

The compounds of formulas (II) and (III) used in the process of the invention are those in which X is chlorine or bromine and, in particularly preferred compounds, X is chlorine, R [deep] 1 is hydrogen or methoxy, R [ deep] 2 alkenyl with 3 to 5 carbon atoms, benzoyl, furoyl, thienylcarbonyl, alkoxycarbonyl with 2 to 5 carbon atoms, alkenoxycarbonyl with 4 or 5 carbon atoms or (2-hydroxyalkoxy) carbonyl with 4 or 5 carbon atoms. When separated, R [deep] 3 is hydrogen and R [deep] 4 is -CH [deep] 2C [deep] 6H [deep] 4R [deep] 5, -COOHCH [deep] 2C [deep] 6H [deep] 4R [deep] 5, -COR [deep] 6, -COCF [deep] 3, -CHO or -COOR [deep] 6, and when present together, R [deep] 3 and R [deep] 4 together with the nitrogen atom, to which they are bound, a cyclic imido group, examples of such cyclic imido groups are the phthalimido, succinimido, maleimido and glutarimido groups as well as imido groups derived from cyclic dicarboxylic anhydrides, such as diglycol, thieglycol, cyclohexane-1,2 dicarboxylic acid, 4-bromophthalic acid, 3-nitzophthalic acid and methyl maleic anhydride. Preferred cyclic imido groups are phthalimido, succinimido and maleimido. R [deep] 5 is hydrogen, chlorine, bromine, methyl, methoxy or nitro, and R [deep] 6 is alkyl of 1 to 4 carbon atoms.

When the process of the invention is carried out according to method A, as shown in the above reaction scheme, it is advantageous to use compounds of the formula (III) in which X is chlorine or bromine, R [deep] 1 is hydrogen or methoxy and R [deep] 3 is hydrogen and

R [deep] 4 -CH [deep] 2C [deep] 6H [deep] 4R [deep] 5, where R [deep] 5 has the meaning given above, or where R [deep] 3 and R [deep] 4 together with the nitrogen atom to which they are attached form a phthalimido, maleimido or succinimido group. Such compounds of the formula (II) react with the compounds of the formula (III) described above to form intermediates of the formula (IV) or a hydrochloride or hydrobromide salt thereof. When such compounds of formula (IV) are desired, it is advantageous to carry out the reaction using approximately equimolar amounts of the reactants for reasons of economy and performance. However, this is not essential to the success of the reaction and there may be an excess of one of the reactants. The intermediate compound of formula (IV) can be conveniently isolated in the form of the hydrochloride salt or hydrobromide salt, each of which is generally insoluble in the reaction solvent and can be obtained by mere filtration and washing. On the other hand, the above-mentioned salts can be treated with an alkaline reagent such as sodium hydroxide, potassium hydroxide, potassium carbonate or sodium methoxide during the work-up of the reaction mixture, and then the free base can be dissolved in a water-immiscible solvent such as chloroform, dichloromethane or gasoline , extracted and the extractant evaporated to dryness. If desired, a compound of the formula (IV) or the salt thereof can be worked up further by standard methods, such as e.g. by crystallization or column chromatography. However, these compounds are often sufficiently pure for further conversion to compounds of the formula (I) without the need for further purification.

As mentioned above, the compound of formula (IV) or the hydrohalide salt thereof is further reacted to remove the 4-amino substituents, R [deep] 3 and R [deep] 4, to give the desired compound of formula (I) obtain. When a compound of the formula (IV) is used in which R [deep] 3 is hydrogen and R [deep] 4 is a benzyl group, -CH [deep] 2C [deep] 6H [deep] 4R [deep] 5, R is [deep] 2 preferably benzoyl, furoyl, thienylcarbonyl, alkoxycarbonyl with 2 to 5 carbon atoms and (2-hydroxyalkoxy) carbonyl with 4 or 5 carbon atoms. It is preferred to remove the benzyl group by catalytic hydrogenolysis. The term "catalytic hydrogenolysis" used here is known to the person skilled in the art of hydrogenation and is explained in the following examples.

Catalytic hydrogenolysis can be carried out by several methods known for this type of conversion, such as those discussed by Augustine in "Catalytic Hydrogenation", Marcel Dekker, Inc., New York, 1965, pages 139-142 . A particularly convenient method consists in that the compound of formula (IV), wherein R [deep] 3 is hydrogen and R [deep] 4 is -CHC [deep] 6H [deep] 4R [deep] 5, in a reaction-inert Solvent in the presence of a suitable catalyst at a at an appropriate temperature and pressure until hydrogenolysis is complete. The desired product of formula (I) can then be isolated by conventional methods, including removing the catalyst and recovering the product from the solvent.

As used herein, "reaction inert solvent" refers to any medium that is a solvent or suitable suspending agent for the reactant, is stable under hydrogenolysis conditions, and does not affect the effectiveness of the catalyst or does not react with the reactant or product. Polar organic solvents are generally suitable, and these include lower alkenols such as methanol, ethanol and butanol, cyclic and straight-chain water-soluble ethers such as dioxene, tetrahydrofuran, diethylene glycol monomethyl ether, 2-ethoxyethanol, the lower alkanoic acids such as acetic acid or propionic acid, aqueous media containing the above solvents and dilute aqueous hydrochloric acid. These and other solvents are commonly used in known hydrogenation techniques and are therefore not critical.

The temperature is no more critical than in other known hydrogenolysis reactions. Accordingly, a temperature of 0 ° to 100 ° C can be used with good results be applied. However, the preferred temperature range corresponds to 10 ° to 60 °, and room temperature is particularly preferred for the sake of simplicity. At temperatures below 0 ° C the reaction proceeds unusually slowly, while at temperatures above 100 ° C decomposition of the starting material can take place. The higher the temperature, the faster the reaction rate. However, the reaction is generally completed in 1 to 24 hours.

Suitable catalysts for achieving the desired products of the formula (I) in the hydrogenolysis reaction are platinum, palladium, rhenium, rhodium and ruthenium, either of the carrier type or of the non-carrier type, and also in the form of the catalytic compounds thereof, such as oxides or chlorides . Examples of suitable catalyst supports are carbon, silica and barium sulfate. Palladium is particularly preferred for reasons of economy and performance.

The catalyst is usually used in an amount of 10 to 100% by weight based on the starting compound of the formula (IV).

The pressure used during hydrogenolysis is not critical and, for example, satisfactory results can be obtained at pressures ranging from normal pressure to 100 atmospheres.

When using the compounds of the formula (IV) in which R [deep] 3 and R [deep] 4 together with the nitrogen atom to which they are bonded are one of the above-mentioned cyclic imido groups, these compounds (IV) are by hydrolysis or reacted further with hydrazine to form the desired products of the formula (I). This hydrolysis can be 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, hydriodic acid, dichloroacetic acid and trifluoroacetic acid. It has been found that hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid can be used in a particularly simple and effective manner to hydrolyze the preferred cyclic imido compounds of formula (IV). It is advantageous to carry out the hydrolysis with one of these acids at a temperature in the range from 0 ° to 100 ° C., a particularly preferred range for such a hydrolysis corresponding to 20 ° to 50 °. At temperatures below 0 ° C the rate of hydrolysis is unusually slow. Excessive amounts of decomposition products can be formed at temperatures above 100 ° C.

The molar ratio of the above acids to the compound of the formula (IV) can vary within a wide range, and molar ratios from 1: 1 to 200: 1 can be used with satisfactory results. The one to achieve The time required for practically complete hydrolysis depends on the reaction temperature and is usually only a few minutes when carried out at 100 ° C, and up to 24 hours may be required to achieve complete hydrolysis when carried out at 0 ° C. The hydrolysis can be carried out in an aqueous medium or an aqueous-organic medium using a water-immiscible organic solvent such as chloroform, methylene dichloride, benzene or toluene. After the hydrolysis is complete, which can be determined by thin layer chromatography on silica using, for example, a 95: 5 ethyl acetate / diethylamine solvent system, the desired product of formula (I) can be isolated as the salt of the acid used in the hydrolysis using known methods . However, it is generally easier to adjust the reaction mixture to an alkaline pH value by adding, for example, sodium hydroxide, potassium hydroxide or sodium carbonate and then the compound of the formula (I) in the form of the free base using, for example, one of the organic solvents mentioned above, which may have been used in the hydrolysis.

On the other hand, as mentioned above, the intermediate of formula (IV) wherein R [deep] 3 and R [deep] 4 together with the nitrogen atom to which they are attached can be any of Form cyclic imido groups, are further reacted with hydrazine to give the end product of the formula (I). The use of hydrazine to remove the phthaloy group from phthalimido acids or the corresponding lower alkyl esters is known, see, for example, Boissannas, Advances in Org. Chem., 3, 179-183 (1963) and Sheehan et al., Jour.Amer.Chem.Soc. , 76, 6329 (1954). It has now been found that the above intermediates of the formula (IV) which contain one of the above-mentioned cyclic imido groups, and in particular those containing the phthalimido, maleimido or succinimido group, also result in the desired products of the formula (I ) implemented. The reaction is carried out in the presence of an inert organic solvent. Examples of organic solvents which can be used in this reaction are lower alkanols such as ethanol, propanol, isopropanol, butanol and isoamyl alcohol, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, diethylene glycol dimethyl ether and diethylene glycol monoethyl ether. The hydrazine used can be essentially pure hydrazine or can be a derivative such as hydrazine hydrate, hydrazine hydrochloride or hydrazine sulfate. If the acid addition salts are used, the hydrazine is formed in situ by adding a suitable base to neutralize the acid. Examples of such suitable bases are sodium methoxide, potassium carbonate, triethylamine, triethanolamine and sodium hydroxide. Although a molar excess of up to 5 moles per mole

Intermediate (IV) can be used successfully in the reaction, it is advantageous to use an equimolar amount of hydrazine in order to limit possible side reactions to a minimum, and for reasons of economy. It is advantageous to carry out the reaction with hydrazine at temperatures from 0 ° to 100 °. A particularly preferred temperature range corresponds to 20 ° to 50 ° C. At temperatures above 100 ° C, undesirable side reactions occur, while at temperatures below 0 ° C the reaction rate is exceptionally slow.

The time required to achieve virtually complete reaction will of course vary with temperature and the precise nature of the reactants and solvent. In general, however, the reaction with hydrazine to give the end product of the formula (I) is essentially complete in 1 to 48 hours. The reaction of hydrazine with the above cyclic imido compounds also results in the formation of a cyclic hydrazide by-product, such as phthaloyhydrazide in the case of the phthalimido intermediates. The reaction mixture can be freed from the cyclic hydrazide occurring as a by-product by methods known in this field and the desired product of the formula (I) can be isolated by known methods, such as, for example, by evaporation in vacuo to dryness, trituration of the residue with dilute strong mineral acid, such as hydrochloric acid or sulfuric acid, wherein the cyclic hydrazite generally dissolves only slightly, filtering and adjusting the filtrate to an alkaline pH, whereupon the desired product is then isolated by extraction or filtration.

When a compound of the formula (II) in which R [deep] 1 is hydrogen or methyl, R [deep] 3 is hydrogen and R [deep] 4 -COOCHCH [deep] 2C [deep] 6H [deep] 4R [deep] 5, -COR [deep] 6, -COCF [deep] 3, -CHO or -COOR [deep] 6, wherein R [deep] 5 and R [deep] 6 have the meaning given above, with a 1-substituted one Piperazine of formula (III) is reacted in the process of the invention, the reaction leads directly to the desired product of formula (I) as shown by method B in the reaction scheme above. Accordingly, the 1-substituted piperazine (III) reacts with such a compound of the formula (III) at both the 2-position of the quinazoline (II) replacing the halogen atom, X, (X = Cl or Br) and removing the R. [deep] 4 group, when R [deep] 3 is hydrogen and R [deep] 4 is one of the above carbonyl-containing groups, with formation of a compound of the formula (I) in a single process step.

Although Method B can conveniently be carried out using molar ratios of compound (II) to compound (III) of 1: 1 or 3: 1 or higher, it is advantageous to combine the compound of formula (II) with the compound of formula ( III) to be implemented in a molar ratio of 2: 1 for reasons of economy and effectiveness.

When the reaction is carried out according to method B, the desired product of formula (I) is easily isolated by standard methods either in the form of the hydrochloride salt (when X is chlorine), the hydrobromide salt (when X is bromine) or as the free base. For example, when a compound of formula (II) where X is the most preferred chlorine is reacted with 2 moles of a compound of formula (III), the hydrochloride salt of compound (I) is generally obtained by merely filtering the reaction mixture and washing the product obtain. If the free base of the product of formula (I) is desired, the reaction mixture is treated with an excess of an aqueous solution of a strong alkaline reagent such as sodium hydroxide, potassium hydroxide or sodium carbonate and the free base with one immiscible with water after the reaction has ended Solvents such as chloroform, methylene chloride, 1,2-dichloroethane or benzene, extracted. The product can then be obtained, for example, by evaporating the solvent and, if desired, further purified.

Although intermediates of the formula (II) in which R [deep] 1 is hydrogen, R [deep] 3 is hydrogen and R [deep] 4 is benzyl are described in US Pat. No. 3,511,836 and intermediates of the formula (IV) Certain other compounds of the formulas ( II) and (IV) new compounds. The new intermediate compounds falling under the formula (II) are those of the formula (V) as indicated above.

The new intermediates falling under the formula (IV) are those of the formula (VI), as indicated above.

The new intermediates of the formulas (V) and (VI) differ in a patentable manner from the previous compounds of the formulas (II) and (IV) with regard to the above-mentioned differences in the methods by which the R [deep] 3- and R [deep] 4 groups are removed to obtain the desired compounds of formula (I). That is to say, the previous compounds of the formula (II) in which R [deep] 3 is hydrogen and R [deep] 4 is benzyl, react with compounds of the formula (III) to form the corresponding known compounds of the formula (IV) in which R [ deep] 3 is hydrogen and R [deep] 4 is benzyl. To remove the benzyl group, the compound of formula (IV) is subjected to hydrogenolysis, as discussed above. In contrast, react the new compounds of formula (V) in which R [deep] 30 is hydrogen and R [deep] 40 -COOCH [deep] 2C [deep] 6H [deep] 4R [deep] 5, -COR [deep ] 6,

-COCF [deep] 3, -CHO or COOR [deep] 6 and R [deep] 5 and R [deep] 6 have the meaning given above, with compounds of the formula (III) with direct formation of the desired products of the formula ( I). The compounds of the formula (V) in which R [deep] 30 and R [deep] 40 together with the nitrogen atom to which they are bonded form a phthalimido, maleimido or succinimido group, react with the compounds of the formula (III) with formation of the new intermediates of the formula (VI), which in turn give the desired compounds of the formula (I) by hydrolysis or reaction with hydrazine, as indicated above.

The above-described intermediates of formulas (II) and (V) are prepared from the appropriate 2,4-dihalo-6,7-dimethoxyquinazolines or 2,4-dihalo-6,7,8-trimethoxyquinazolines, in which halogen is chlorine or bromine, manufactured. The preparation of these dihalo compounds is described in U.S. Patents 3,511,836 and 3,669,968 and by Curd et al. Jour. Chem. Soc. (London), 777 (1947) and loc. Cit., 1759 (1948).

To prepare the new intermediates of the formula (V), one of the above 2,4-dihaloquinazolines is combined with a suitable cyclic imide, primary amide or urethane in an inert organic solvent 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 implemented. After the reaction is essentially complete, the compound of formula (V) is isolated by standard methods known in the art, such as by quenching the reaction mixture in excess water or dilute acid and filtering, washing and drying to recover this product. Dilute acid quenching is preferred when said amide or urethane is used.

Examples of suitable cyclic imides are the above-mentioned, preferred cyclic imides are phthalimide, maleimide and succinimide. Preferred primary amides are formamide, trifluoroacetamide and those of the formula R [deep] 6CONH [deep] 2, in which R [deep] 6 is alkyl having 1 to 6 carbon atoms or C [deep] 6H [deep] 4R [deep] 5, in which R [deep] 5 is hydrogen, chlorine, bromine, methyl, methoxy or nitro. Preferred urethanes are those of the formulas R [deep] 5C [deep] 6H [deep] 4CH [deep] 2OCONH [deep] 2 and R [deep] 6OCONH [deep] 2, where R [deep] 5 and R [deep] 6 have the meaning given above.

Examples of reaction-inert organic solvents which can be used are N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, ethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dimethyl sulfoxide, toluene and benzene. Preferred organic solvents which are inert to the reaction are N, N-dimethylformamide and tetrahydrofuran.

A charge of 2.65 g of benzylamine was added and heating continued for one hour after which time an additional 2.68 g of benzylamine was added. The mixture was for
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In carrying out the reaction to form the new intermediates of formula (V), the preferred strong base is sodium hydride for reasons of economy and performance. A molar ratio of said strong base to said 2,4-dihaloquinazoline of about at least 1: 1 is usually employed and molar ratios of 1: 1 to 2: 1 are preferred.

Although the above reaction can be carried out within a wide temperature range, a temperature range of from 0 ° to 150 ° C, and particularly from 65 ° to 100 ° C, is preferred. The reaction proceeds unusually slowly below 0 ° C, while excessive amounts of undesirable by-products are obtained at temperatures above 150 ° C. The rate of reaction is faster at higher temperatures and the time required to complete the reaction will vary with the temperature and the particular nature of the reactants and solvent. However, the reaction is generally completed in 2 to 24 hours.

The following examples illustrate the invention.

example 1

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

6.48 g (0.025 mol) of 2,4-dichloro-6,7-dimethoxyquinazoline and 104 ml of tetrahydrofuran were added to a 200 ml three-necked round bottom flask. The flask was with a at 70 ° C heated oil bath held. Then, 2.68 g (0.025 mol) of benzylamine was added to the flask, and the resulting mixture was heated with stirring for one hour. Another charge of 2.65 grams of benzylamine was added and heating continued for one hour after which time another 2.68 grams of benzylamine was added. The mixture was heated for an additional 2 hours, then filtered while it was still warm to remove precipitated benzylamine hydrochloride. The filtrate was concentrated to half volume, 2 volumes of hexane were added, and the resulting mixture was slowly stirred for 30 minutes to cause grain formation. After filtering off and drying, 6.0 g (73%) of the compound named in the title of this example were obtained, mp 190-195 ° C. The structure was confirmed by NMR and mass spectroscopy.

Example 2

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

66 ml of isoamyl alcohol and 6.0 g (0.018 mol) of 4-benzylamino-2-chloro-6,7-dimethoxyquinazoline were added to a 200 ml three-necked round bottom flask equipped with a thermometer, condenser and drying tube. A solution of 3.6 g (0.020 mol) of 1- (2-furoyl) piperazine in 50 ml of isoamyl alcohol was added. The resulting mixture was heated to reflux (130 ° C) for 4 hours, cooled to 20 ° C, filtered, washed with ethyl ether, and air dried, and it became the hydrochloride salt of the title of this example mentioned connection received. This was done by dissolving in 150 ml of hot methanol, adding 1.3 g of sodium methoxide, stirring at 50 ° C. for 10 minutes, cooling to 20 ° C., adding 100 ml of water and then extracting with two 100 ml portions of chloroform in the free base is transferred. After concentrating the extracts to dryness, 6.0 g (70%) of the title compound was obtained, mp 220-225 ° C.

When the above procedure was carried out at 80 ° C for 24 hours, the results obtained were essentially unchanged.

When the reaction was carried out using carbitol (diethylene glycol monomethyl ether) as a solvent and heating either at 200 ° C for 20 minutes or at 50 ° C for 48 hours, the title compound was also obtained.

Example 3

2- [4- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline (prazosin)

1.0 g (2.1 mmol) of 2- [4- (2-furoyl) -piperazin-1-yl] -4-benzylamino-6,7-dimethoxyquinazoline and 15 ml of ethanol were added to a Paar kettle. Water (about 5 ml) was added to the cloud point and then 400 mg palladium on carbon (50% wetting) catalyst was added. The obtained mixture was in a Paar hydrogenator shaken at 3.5 kg / cm [high] 2 for 18 hours, filtered, and the filtrate was slurried with 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 of this example, mp 263-265 ° C, identified by thin layer chromatography a silica gel plate (ethyl acetate / diethylamine 95: 5 solvent system) and comparing the infrared spectrum with that of an authentic sample of prazosin.

Example 4

The procedures of Examples 1 and 2 were repeated, but using the appropriately substituted benzylamine in each case in place of the benzylamine used in Example 1, to give the following compounds similarly.

R [deep] 5 R [deep] 5

4-NO [deep] 2 2-Br-

2-NO [deep] 2- 4-Br-

2-Cl- 2-CH [deep] 3-

3-Cl- 3-CH [deep] 3-

4-Cl- 4-CH [deep] 3-

R [deep] 5

3-CH [deep] 3O-

4-CH [deep] 3-O-

Example 5

The process of Example 3 was repeated, but using one of the compounds obtained in Example 4 instead of 2- [4- (2-furoyl) piperazin-1-yl] -4-benzylamino-6,7-dimethoxy-1- yl] -4-amino-6,7-dimethoxyquinazoline.

Example 6

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

50 ml of N, N-dimethylformamide, 1.47 g (0.010 mol) of phthalimide and 0.48 g (0.010 mol) of 50% (wt. / Wt.) Sodium hydride entered. After stirring at room temperature for 30 minutes, a clear solution was obtained. Thereto, 2.59 g (0.010 mol) of 2,4-dichloro-6,7-dimethoxyquinazoline was then added, 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 in vacuo. 3.1 g of the compound named in the title of this example were obtained, mp 255 ° C. The structure was confirmed by the NMR and mass spectroscopic data. Yield: 84%.

Example 7

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

In a 35 ml, single neck, round bottom flask equipped with a condenser and drying tube, 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) 1- (2-furoyl) -piperazine added. The resulting mixture was heated at 130 ° 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 isolated by filtration and dried. There was obtained 0.70 g (47%) of the hydrochloride salt of the compound identified in the title of this example. The purified free base was obtained from the salt by silica gel chromatography on a 5.1 x 30.5 cm column, eluting with ethyl acetate / diethylamine (90:10). The purified product melted at 305 ° C.

When the above procedure was repeated but using the indicated solvents in place of isoamyl alcohol and using the indicated temperature and reaction time, the title compound was also obtained.

Solvent reaction temperature, ° C reaction time, h

Isobunatol 50 ° 48

1,2-dimethoxyethane 80 ° 30

Diethylene glycol mono-

ethyl ether 200 ° 1

Example 8

A solution of 95 mg (0.185 mmol) of 2- [4- (2-furoyl) -piperazin-1-yl] -4-phthalimido-6,7-dimethoxyquinazoline in 2.0 ml of concentrated hydrochloric acid was added at room temperature for 2 hours touched. Then 4.0 ml of chloroform was added and the mixture was adjusted to pH 10 by adding sodium carbonate solution. The chloroform layer was separated and 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 comparison of the infrared spectrum with that of an authentic sample and by thin layer chromatography on silica gel using a 95: 5 ethyl acetate / diethylamine solvent system.

Example 9

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 to dissolve and 0.55 g (0.011 mol) of hydrazine hydrate was added. The resulting solution was kept at 20 ° C. for 18 hours and then evaporated to dryness under reduced pressure. The residue was filtered to remove the precipitated phthalhydrazide. The filtrate was made alkaline (pH 10) with sodium hydroxide solution and extracted with chloroform, and the extracts were concentrated to dryness to give 2- [4- (2-furoyl) -piperazin-1-yl] -4-amino-6, 7-dimethoxyquinazoline.

Example 10

The procedures of Examples 1 and 6 were repeated, but using the appropriate starting materials in each case, to obtain the following compounds of formula (II).

Example 11

The procedures of Examples 2 and 7 were repeated, but in each case using the appropriate compound of formula (II) from the compounds obtained in Example 10 and the appropriate 1-substituted piperazine as starting materials, the following compounds of formula (IV ) were obtained.

Example 12

Using the catalytic hydrogenolysis process described in Example 3, but with the indicated starting material, which in each case is obtained from the compounds of the formula (I) prepared according to Example 11.

Example 13

When a suitable compound of formula (IV) selected from the compounds prepared according to Example 11 was hydrolyzed by the method of Example 8, but using an equimolar amount of the specified acid and carrying out the hydrolysis at the specified temperature for the specified Duration, the following compounds of the formula (I) were obtained in the same manner.

Example 14

If the appropriate compound of formula (IV) selected from the compounds prepared according to Example 11, instead of the

2- [4- (2-Furoyl) -piperazin-1-yl] -4-phthalimido-6,7-dimethoxyquinazoline was used in the procedure of Example 9 under the indicated conditions, the following end products of formula (I) were obtained .

* N, N-dimethylformamide

+ Diethylene glycol dimethyl ether

Example 15

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

In a 100 ml three-necked round bottom flask equipped with a reflux condenser, thermometer and drying tube, 32 ml of dry tetrahydrofuran, 10 ml of dry N, N-dimethylformamide, 6.48 g (0.025 mol) of 2,4-dichloro-6.7 -dimethoxyquinazoline [prepared by the method of Curd et al., J. Chem. Soc., 1759 (1948)], 3.03 g (0.025 mol) of benzamide and 2.4 g (0.051 mol) of 50% (wt. /Weight-) sodium hydride entered, the hydride being added as the last component. The resulting mixture was heated to reflux for 24 hours, cooled to room temperature and filtered, washed with tetrahydrofuran to give 6.0 g (66%) of the sodium salt of the title compound of this example, mp 315 ° C .

After slurrying 1.0 g of the sodium salt in 20 ml of water, acidifying to pH 3 to 4 with 2N hydrochloric acid, stirring for 15 minutes at 20 to 25 ° C, filtering and drying overnight, 0.67 g of the Get the connection given under the heading of this example. M.p. 235-240 ° C. After recrystallization from isoamyl alcohol, the compound melted at 236-238 ° C. The mass spectrum showed maxima at 342 and 344.

Example 16

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

To a 200 ml reaction kettle were 6.48 g (0.025 mol) of 2,4-dichloro-6,7-dimethoxyquinazoline, 1.5 g (0.025 mol) of acetamide, 32 ml of dry N, N-dimethylformamide and 2.4 g (0.050 mol) of 50% sodium hydride entered.

After heating to 40 ° C., an exothermic reaction began and the temperature rose very quickly to 120 ° C. with considerable foaming of the reaction mixture. During this exothermic period the reaction mixture turned purple and then red. The mixture was cooled to 90 ° C. and held at this temperature for 2 hours. The mixture was then cooled to room temperature, poured into 150 ml of water, washed with two 100 ml portions of chloroform, and the aqueous phase was adjusted to pH 2 by adding concentrated hydrochloric acid. The precipitated product was filtered off and dried, and the compound given in the title of this example was obtained in a yield of 86%, mp 275 ° C. Only one spot was obtained by thin layer chromatography on silica gel eluting with 95: 5 ethyl acetate / diethylamine. The mass spectrum showed one molecular ion at M / e 281.

Example 17

The procedures of Examples 15 and 16 were repeated, but with an equimolar amount of the appropriate alkyl amide or aryl amide in place of the amides used therein, and in those cases where R [deep] 1 was methoxy, using an equimolar amount of 2,4- Dichloro-6,7,8-trimethoxyquinazoline obtained by the method of U.S. Patent 3,669,968 in place of 2,4-dichloro-6,7-dimethoxyquinazoline. The following compounds were obtained.

Example 18

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

2,4 dichloro-6,7-dimethoxyquinazoline (6.48 g, 0.025 mol), 32 ml tetrahydrofuran, ethyl carbamate (2.23 g, 0.025 mol) and 50% sodium hydride (2.4 g, 0.050 mol) were added in added a 100 ml reaction flask equipped with a thermometer, reflux condenser and drying tube. The reaction mixture was refluxed for 2 hours and then 70 ml of methanol were slowly added, after which the mixture was heated to 60 ° C. and filtered while warm. The filtrate was concentrated to a thick slurry which was isolated by filtration solid substance was washed with 5 ml of chloroform and 5.4 g (7/4) of the compound named in the title of this example was obtained. A sample melted after recrystallization from a mixture of tetrahydrofuran and hexane (2: 3) at 212 ° C.

Analysis: Calculated for C [low] 13H [low] 14N [low] 3O [low] 4Cl (%): C, 50.09;

H, 4.53; N, 13.48

Found: C, 49.95; H, 4.46; N, 13.54.

Example 19

4-phenoxycarbonylamino-2-chloro-6,7,8-trimethoxyquinazoline

25.4 g (0.10 mol) of 2,4-dichloro-6,7,8-trimethoxyquinazoline, prepared according to the information in US Pat. No. 3,669,968, 13.7 g (0 , 10 mol) of phenyl carbamate (Aldrich Chemical Co), 130 ml of tetrahydrofuran and 9.6 g (0.20 mol) of a 50% strength sodium hydride dispersion were added. The resulting mixture was refluxed for 4 hours, cooled to room temperature, mixed with 250 ml of methanol and heated to 60 ° C. and filtered. The filtrate was concentrated to a thick slurry, the solid substance isolated by filtration was washed with chloroform and was the compound given in the title of this example.

When 2,4-dibromo-6,7,8-trimethoxyquinazoline was used in place of 2,4-dichloro-6,7,8-trimethoxyquinazoline in the above procedure, the same was used in the above procedure

How to obtain 4-phenoxycarbonylamino-2-bromo-6,7,8-trimethoxyquinazoline.

Example 20

When the procedures of Examples 18 and 19 were repeated but using the appropriate starting materials in each case, the following compounds were similarly obtained.

Example 21

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

160 mg (0.66 mmol) of 4-benzoylamino-2-chloro-6,7-dimethoxyquinazoline, prepared according to the procedure of Example 15, 244, were placed in a 50 ml flask equipped with a stirrer, reflux condenser and drying tube , 2 mg (1.32 mmol) 1- (2-furoyl) -piperazine and 4 ml isoamyl alcohol added. The resulting mixture was heated at 100 ° C. for 4 hours, then cooled to room temperature. The precipitated solid substance was isolated by filtration and dried, and 60 mg of the crude product was obtained. This was identified as 2- [4- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline by silica gel thin layer chromatography (ethyl acetate / diethylamine 90:10). The crude material was purified on 1.27 cm x 22.85 cm silica gel eluting with benzene / acetone / formic acid / water (100: 100: 20: 5 by volume) to give 35 mg, M.p. 275 ° C. When the above procedure was repeated but using the indicated solvent in place of isoamyl alcohol and carrying out the reaction at the indicated temperature for the indicated time, the compound indicated in the title of this example was also obtained.

Solvent reaction temperature, ° C reaction time, h

2-butanol 50 ° 50

2-methoxyethanol 80 ° 18

2-methyl-2-pentanol 130 ° 2

Diethylene glycol 200 ° 0.25

Example 22

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

4-Ethoxycaronylamino-2-chloro-6,7-dimethoxyquinazoline (2.0 g, 0.0064 mol) and 23 ml of isoamyl alcohol were combined in a reaction flask. A solution of 1- (2-furoyl) piperazine (2.54 g, 0.014 mol) in 18 ml of isoamyl alcohol was added and the mixture was heated at 130 ° C for 4 hours. The precipitated solid substance was isolated by filtration, washed with isoamyl alcohol and then stirred with 100 ml of 10% strength aqueous sodium hydroxide solution. An equal volume of chloroform was added and the mixture was stirred for 15 minutes. The organic layer was separated, concentrated to about 25 ml, and 50 ml of tetrahydrofuran was added. The solid substance was isolated by filtration and then further purified by chromatography on a silica gel column (2.54 x 45.72 cm) eluting first with ethyl acetate and then with methanol. The fractions containing the compound identified in the title of this example were combined and evaporated to dryness. The residue was taken up in 10 ml of chloroform, hexane was added to the cloud point, the mixture was stirred for 15 minutes and the crystals were isolated by filtration, mp 265 ° C., yield 900 mg (37 4).

When the above reaction was repeated at 80 ° C for 18 hours, the results were practically unchanged.

Example 23

2- (4-Benzoyl-1-piperazinyl) -4-amino-6,7-dimethoxyquinazoline hydrochloride

4-Aletamino-2-chloro-6,7-dimethoxyquinazoline (28.2 g, 0.10 mol) 1-Benzoylpiperazine (38.0 g, 0.20 mol) and 750 ml of isoamyl alcohol were combined. The resulting mixture was refluxed for 3 hours and then cooled to room temperature. The precipitated product was filtered off, washed with ethyl acetate, then washed with ether and air dried to give the product indicated in the title of this example.

Example 24

2- [4- (2-Hydroxy-2-methylprop-1-yloxycarbonyl) -piperazin-1-yl] -4-amino-6,7,8-trimethoxyquinazoline

4-phenoxycarbonylamino-2-chloro-6,7,8-trimethoxyquinazoline (19.5 g, 0.05 mol), 1- (2-hydroxy-2-methylprop-1-yloxycarbonyl) piperazine (20.2 g, 0.10 mol) and 500 ml of diethylene glycol dimethyl ether were heated at 125 ° C. for 2 hours. The reaction mixture was concentrated in vacuo to about 200 ml and an equal volume of ethyl ether was added. The precipitated hydrochloride salt was filtered off, washed with ether and then stirred with 200 ml of saturated aqueous sodium carbonate solution. The liberated base was extracted with three 200 ml portions of chloroform and the extracts concentrated up to about 150 ml. Diisopropyl ether, about 100 ml, was added and the mixture was allowed to stand overnight, then filtered and it became that in the title connection given in this example.

Example 25

When the compounds obtained according to Examples 17 and 20 were reacted with the appropriate substituted piperazines of the formula (III) according to the procedures of Examples 21 to 24, the following compounds of the formula (I) were obtained in a corresponding manner.

<Table>

Claims (19)

1. Process for the preparation of a compound of the formula or a hydrochloride or hydrobromic acid addition salt thereof, characterized in that one mole of a first reactant of the formula with one to two moles of a second reactant of the formula in a reaction-inert organic solvent at a temperature of 50 ° to 200 ° C, wherein R [deep] 1 is hydrogen or methoxy, R [deep] 2 is alkenyl with 3 to 5 carbon atoms, benzoyl, furoyl, thienylcarbonyl, alkoxycarbonyl with 2 to 5 carbon atoms, Is alkenyloxycarbonyl of 4 or 5 carbon atoms or (2-hydroxyalkoxy) carbonyl of 4 to 5 carbon atoms, X is chlorine or bromine, R [deep] 3 is hydrogen and R [deep] 4 is -CH [deep] 2C [deep] 6H [deep] 4R [deep] 5, -COOCH [deep] 2C [deep] 6H [deep] 4R [deep] 5, -COR [deep] 6, -COCF [deep] 3, CHO or COOR [deep] 6 , or R [deep] 3 and R [deep] 4 together with the nitrogen atom to which they are attached form a cyclic imido group, R [deep] 5 is hydrogen, chlorine, bromine, methyl, methoxy or nitro and R [deep ] 6 is alkyl of 1 to 4 carbon atoms or -C [deep] 6H [deep] 4R [deep] 5. 2. The method according to claim 1, characterized in that in the compound of formula II R [deep] 3 and R [deep] 4 together with the nitrogen atom to which they are bonded form a phthalimido, maleimido or succinimido group. 3. The method according to claim 1 or 2, characterized in that the reaction is carried out at a temperature of 80 ° to 130 ° C. 4. The method according to claim 1, characterized in that when R [deep] 2 is benzoyl, furoyl, thienylcarbonyl, alkoxycarbonyl with 2 to 5 carbon atoms or (2-hydroxyalkoxy) carbonyl with 4 or 5 carbon atoms, R [deep] 3 is hydrogen and R [low] 4 -CH [low] 2C [low] 6H [low] 4R [low] 5 is equimolar amounts of the reactants of formulas (II) and (III) to form an intermediate of formula and this intermediate product is then further converted by catalytic hydrogenolysis to give the desired end product of the formula (I). 5. The method according to claim 4, characterized in that the catalytic hydrogenolysis is carried out in the presence of a palladium catalyst. 6. The method according to claim 1, characterized in that if R [deep] 3 and R [deep] 4 together with the nitrogen atom to which they are bonded form a cyclic imido group, equimolar amounts of the reactants of the formulas (II) and (III) to an intermediate of the formula converts, wherein R [deep] 1, R [deep] 2, R [deep] 3 and R [deep] 4 have the meaning given in claim 1, and then this intermediate product at a temperature of 0 ° to 100 ° C in addition End product of formula (I) either a. by hydrolysis or b. by reaction with an equimolar amount of hydrazine in the presence of an inert organic solvent. 7. The method according to claim 6, characterized in that the cyclic imido group is a phthalimido, maleimido or succinimido group. 8. The method according to claim 6 or 7, characterized in that the hydrolysis of process step a. in the presence of hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. 9. The method according to any one of claims 6 to 8, characterized in that the further reaction of the intermediate product is carried out at a temperature of 20 ° to 50 ° C. 10. The method according to claim 1, characterized in that when R [deep] 3 is hydrogen and R [deep] 4 -COOCH [deep] 2C [deep] 6H [deep] 4R [deep] 5, -COR [deep ] 6, COCF [deep] 3, CHO or COOR [deep] 6, converts one mole of said first reactant and two moles of said second reactant directly to the end product of formula (I). 11. The method according to any one of the preceding claims, characterized in that R [deep] 1 is hydrogen and R [deep] 2 is 2-furoyl. 12. The method according to any one of claims 1 to 10, characterized in that R [deep] 1 is methoxy and R [deep] 2 is 2-methyl-2-hydroxyprop-1-yloxycarbonyl. 13. The method according to any one of claims 1 to 10, characterized in that R [deep] 1 is methoxy and R [deep] 2 is 2-methylprop-2-enyloxycarbonyl. 14. The method according to any one of the preceding claims, characterized in that X is chlorine. 15. An intermediate compound suitable for the preparation of antihypertensive agents, characterized by the formula wherein X and R [deep] 1 have the meaning given in claim 1, R [deep] 30 is hydrogen and R [deep] 40 -COOCH [deep] 2C [deep] 6H [deep] 4R [deep] 5, - COR [deep] 6, -COCF [deep] 3, -CHO or -COOR [deep] 6 or R [deep] 30 and R [deep] 40 together with the nitrogen atom to which they are attached form a cyclic imido group , and R [deep] 5 and R [deep] 6 have the meaning given in claim 1, and the acid addition salts thereof. 16. A compound according to claim 15, characterized in that the cyclic imido group is a phthalimido, maleimido or succimido group. 17. A compound according to claim 15 or 16, characterized in that X is chlorine. 18. For the preparation of antihypertensive agents suitable intermediate compound, characterized by the formula wherein R [deep] 1 and R [deep] 2 have the meaning given in claim 1 and R [deep] 31 and R [deep] 41 together with the nitrogen atom to which they are bonded form a cyclic imido group, and the Acid addition salts thereof. 19. A compound according to claim 18, characterized in that the cyclic imido group is a phthalimido, maleimido or succinimido group.