DK146510B - 2- (4- (2-FUROYL) PIPERAZIN-1-YL) -4-PHTHALIMIDO-6,7-DIMETHOXYQUINAZOLINE USED AS INTERMEDIATE IN THE PREPARATION OF 2- (4- (2-FUROYL) PIPERAZIN-1-YL) - 4-amino-6,7-dimethoxyquinazoline - Google Patents

Description

(19) DENMARK

|| j „g PUBLICATION MANUAL od 146510 B

DIRECTORATE OF THE PATENT 06 BRAND

(21) Patent Application No. 4415/80 (51) Int.CI.3: C 07 D 405/14 (22) Filing Date: 17 Oct 1980 (24) Running Date: 01 Jun 1977 (41) Aim. available: 17 Oct 1980 (44) Submitted: 24 Oct 1983 (86) International Application No :-(62) Stock Application No .: 2408/77 (30) Priority: 15 Jun 1976 US 696201 (71) Applicant: 'PFIZER INC .; New York, US.

(72) Inventor: Philip Dietrich 'Hammen; US.

(74) Agent: Hofman-Bang & Boutard Patent Office (54) 2- (4- (2-furoyl) piperazin-1-yl) -4-phthalimido-6-7-dimethoxyquinazoline for use as an intermediate in the preparation of 2- {4 - {2-furoyl) pi-piperazin-1-yl} -4-amlno-6I7-dimethoxy-quinazoline

This invention relates to the novel compound 2- [4- (2-furoyl) piperazin-1-yl] -4-phthalimido-6,7-dimethoxyquinazoline for use as an intermediate in the preparation of 2- [4- (2-furoyl) ) piperazine-1-D-yl] -4-amino-6,7-dimethoxyquinazoline, called prazosin. The compound of the invention is characterized in that it has the formula (VI) of the claim Λ or is an acid addition salt thereof, Q 2 -piperazino-4-aminoquinazoline derivatives of the general formula: R1 2 146510 π2 ch3ct Y "nh2 Wherein R is hydrogen or methoxy and R is alkenyl of 3 to 5 carbon atoms, benzoyl, furoyl, thienylcarbonyl, alkoxycarbonyl of 2 to 5 carbon atoms, alkenyloxycarbonyl of 4 or 5 carbon atoms or (2-hydroxyalkoxy) carbonyl of 4 or 5 carbon atoms , are known chemical compounds which are valuable because of 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 -dimethoxyquinazolines and 2- (4-substituted-piperazin-1-yl) -4-amino-6,7,8-trimethoxyquinazolines disclosed in U.S. Patent Nos. 3,511,836 and 3,669,968.

U.S. Patent No. 3,111,836 discloses several processes for preparing 2- (4-subs tituated-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) -4Tamino-6,7-dimethoxyquinazoline. U.S. Patent No. 3,669,968 discloses the preparation of 2- (4-substituted-piperazin-1-yl) -4-amino-6,7,8-trimethoxyquinazolines by reaction of 2-chloro-4-amino-6.7,8-trimethoxyquinazoline with the appropriate 1-substituted piperazine.

U.S. Patent No. 3,935,213 discloses the preparation of 2- (4-substituted-piperazin-1-yl) -4-amino-6,7-dimethoxyquinazolines and the corresponding 6,7,8-trimethoxyquinazolines in the process comprising either (1) reacting the appropriate 4,5-dimethoxy-substituted or 3µ-4,5-trimethoxy-substituted 2-aminobenzonitrile with certain 1,4-disubstituted piperazines, or (2) reacting the appropriate 4 , 5-dimethoxy- or 3,4,5-trimethoxy-substituted 2-aminobenzamidine with the same 1,4-disubstituted piperazines.

3 146510

Compounds of the formulas: CEoO Cl CH, 0 µl / \

3V ^ V NY

T li * ° s T li * \ / CH3CT ^ V ^ N ^ - ch30 ^^ s> ^^ n ^ NHCH2C6H5 NHCH2C6H5 (II) (IV) wherein Y means hydrogen, alkyl of 1-5 carbon atoms, hydroxyalkyl of 2- 5 carbon atoms, alkanoyl of 2-7 carbon atoms, allyl, propargyl, 2-methallyl, phenyl, benzyl, benzoyl, chlorobenzoyl, bromobenzoyl, trifluoromethyl, methoxyphenyl, methylphenyl, methylbenzoyl, trifluoromethylbenzoyl, furoyl, benzofuroyl, pyridine arbonyl, 3,4-trimethoxybenzoyl, carboxylic acid alkyl ester wherein alkyl has 1-6 carbon atoms, and carboxylic acid alkenyl ester wherein alkenyl has 3-6 carbon atoms are disclosed in U.S. Patent No. 3,511,836.

A particularly valuable compound of formula I, namely 2- [4- (2-fluoroyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline, known by the name of prazosin, has recently been reported to have therapeutic utility in humans (Cohen, Journal of Clinical Pharmacology, 10, 408 [1970]; De Guia, et al., Current Therapeutic Research, 15, 339 [1973]).

The method of U.S. Patent No. 3,511,836 is the only method exemplified in the prior art for the preparation of prazosin; and this example requires 4 steps to prepare the desired compound from the commercially available starting material, 2,4-dichloro-6,7-dimethoxyquinazoline. No yield is indicated for this reaction sequence. In principle, however, prazos .n may also be prepared via the known intermediate of formula (IV) wherein Y is 2-furoyl.

The novel compound of the invention of formula (VI) differs substantially from the known compound of formula (IV) in view of the differences in the methods by which the 4-amino protecting groups are removed to obtain the desired compound prazosin. To remove the benzyl group, the compound of formula (IV) must be subjected to catalytic hydrogenolysis. In contrast, the compound of formula (VI) gives the desired compound prazosin by hydrolysis or reaction with hydrazine as described below.

The utility of the compound of the invention of formula (VI) as an intermediate lies in a process for the preparation of the desired compound prazosin, whereby a compound of formula: CH, O ... (V) o o wherein X represents chlorine or bromine is reacted with an approximately equimolar amount of 1- (2-furoyl) piperazine of formula OO (III) in a reaction inert organic solvent at a temperature of 50-200 ° C, preferably 80-130 ° C to form the intermediate of the invention of formula (VI ), after which it is further reacted at a temperature of 0 - 100 ° C, preferably 20 - 50 ° C, to form the final product, prazosin, either (a) by hydrolysis or (b) by reaction with an equimolar amount of hydrazine in the presence of a reaction inert organic solvent.

When hydrolysis is used, it is preferred that it be carried out in the presence of hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.

5 U6510

The reaction of the compounds of formulas (V) and (III) is carried out as mentioned in the presence of a suitable reaction-inert organic solvent. A suitable solvent is one which will serve to substantially dissolve the reactants and will not adversely affect the reactants or products in the reaction. 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 monoethyl ether, 1,2-dimethoxyethane and diethylene glycol dimethyl ether, tertiary amides such as Ν, Ν-dimethylformamide, Ν, Ν-diethylacetamide and N-methylpyrrolidone, dimethylsulfoxide and pyridine. Although the reaction can be carried out over a wide temperature range, a temperature in the range of 50-200 C is preferred. A particularly preferred temperature range is 80-130 ° C. The time required for the process to reach substantial completion varies according to several factors, such as the reaction temperature, the reactivity of the particular starting materials used, and the concentration of the reactants. At lower temperatures, longer reaction times are required, while the reaction at higher temperatures completes in a shorter time. A reaction time of from 15 minutes to 50 hours is generally satisfactory.

As mentioned, in the compounds of formula (V), X is chlorine or bromine, and particularly preferred are compounds wherein X is chlorine. It is preferred to carry out the reaction to form the intermediate of formula (VI) or the hydrochloride or hydrobromide salt thereof using approximately equimolar amounts of the reactants (V) and (III) for economy and efficiency. However, this is not necessary for the reaction to be carried out and an excess of one or the other reactant may be present. The intermediate of formula (VI) may conveniently be isolated in the form of the hydrochloride salt or hydrobromide salt, both of which are generally insoluble in the reaction solvent and thus obtainable only by filtration and washing. Alternatively, the above-mentioned salts may be treated with an alkaline reagent, e.g. sodium hydroxide, potassium hydroxide, potassium carbonate or sodium methoxide, followed by extraction of the free base into a water-immiscible solvent, such as chloroform, dichloromethane or benzene, and evaporation to dryness. If desired, either the compound of formula (VI) or its salt can be further purified by standard methods such as crystallization or column chromatography. However, they are often sufficiently pure for further reaction to form prazosin without any further purification.

As mentioned above, the compound of formula (VI) or the hydrohalide salt thereof is further reacted to cleave the 4-amino-protecting phthalimido group by hydrolysis or with hydrazine to give the desired product, prazosin. Said 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 such suitable acids are hydrochloric, hydrobromic, sulfuric, phosphoric, hydroiodic, dichloroacetic and trifluoroacetic. For hydrolysis of the intermediates of formula (VI), it has been found to be particularly convenient and effective to use hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. It is preferred to carry out the hydrolysis with one of these acids at a temperature in the range of 0-100 ° C, with a particularly preferred temperature range for the hydrolysis being 20-50 ° C. At temperatures below 0 ° C, the rate of hydrolysis is disproportionately low. At temperatures above 100 ° C, excessive amounts of degradation products are formed.

The mole ratio of the above acid to the compound of formula (VI) may vary over a wide range and thus mole ratios of from 1: 1 to 200: 1 can be used with satisfactory results. The time required for substantial completion of the hydrolysis will vary according to the reaction temperature, and livis worked at 100 ° C is usually sufficient for a few minutes, and if worked at 0 ° C, up to 24 hours may be required. to reach completion. The hydrolysis may be carried out in an aqueous medium or an aqueous-organic medium using a water-immiscible organic solvent such as e.g. chloroform, methylene dichloride, benzene or toluene. Upon completion of the hydrolysis, which can be readily determined by thin layer chromatography on silica gel using a solution system of, for example, 95-5 ethyl acetate / diethylamine, the desired product, prazosin, can be isolated as a salt of the acid used in the hydrolysis. using methods well known in the art. However, it is generally more convenient to adjust the reaction mixture to an alkaline pH by adding, for example, sodium hydroxide, potassium hydroxide or sodium carbonate, followed by extraction of the prazosin as the free base, with, for example, one of the above-mentioned organic solvents, optionally could be used in the hydrolysis. The product is then easily isolated by evaporation.

Alternatively, as mentioned above, the intermediate of formula (VI) may be further reacted with hydrazine to form the final product, prazosin. The use of hydrazine to remove the phthaloyl 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., 7_6, 6329 (1954). It has now been found that the above intermediate of formula (VI) also reacts to form the desired product prazosin. The reaction is carried out in the presence of a reaction inert organic solvent. Examples of organic solvents which may be used in this reaction are the 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 may be substantially pure hydrazine or a derivative such as hydrazine hydrate, hydrazine hydrochloride or. · Hydrazine sulfate. When the acid addition salts are used, the hydrazine is produced in situ by the addition of 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 hydrazine of up to 5 moles per mole can be used successfully. in this reaction, it is preferable to use an equimolar amount of hydrazine to reduce any side reactions and for economic reasons. It is preferred to carry out the reaction with hydrazine at temperatures of 0 to 100 ° C. A particularly preferred temperature range is 20-50 ° C. At temperatures above 100 ° C, undesirable side reactions occur, while the reaction rate at temperatures below 0 ° C is disproportionately low.

Of course, the time required for substantial completion of the reaction will vary with the temperature and the exact nature of the reactants and the solvent. Generally, however, the reaction with hydrazine to form the final product prazosin 8 will be substantially complete within 1-48 hours. The reaction of hydrazine with the above-mentioned phthalimido compound also forms a cyclic hydrazide by-product, phthaloylhydrazide. The reaction mixture can be liberated from this by-product and the desired product, prazosin, can be isolated by methods well known in the art, such as evaporation to dryness in vacuo, tearing off the residue with dilute strong mineral acid such as hydrochloric acid or sulfuric acid wherein cyclic hydrazide is usually only soluble, filtering and adjusting the filtrate to an alkaline pH at which the desired product is isolated by extraction or filtration.

The intermediates of formula (V) described above are prepared from the appropriate 2,4-dihalo-6,7-dimethoxyquinazolines wherein the halogen is chlorine or bromine. The preparation of said dihalogen compounds is previously described in U.S. Pat.

3,511,836 and 3,669,968 and by Curd et al. Jour. Chem. Soc. (London), 777, (1947); ibid., 1759 (1948).

To prepare the novel intermediates of formula (V), one of the aforementioned 2,4-dihaloquinazolines is reacted with phthalimide in a reaction-inert organic solvent and in the presence of a strong base, e.g. sodium hydride, potassium hydride, calcium hydride, sodium methoxide, potassium ethoxide, lithium butoxide or butyllithium, under anhydrous conditions. After the reaction is substantially complete, the compound of formula (V) is isolated by standard methods, e.g. by quenching the reaction mixture in excess water or dilute acid and filtering, washing and drying to obtain the product.

Examples of reaction-inert organic solvents which may be used are Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, N-methyl-pyrrolidone, ethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, di-. methyl sulfoxide, toluene and benzene. Eoracted reaction-inert organic solvents are Ν, Ν-dimethylformamide and tetrahydrofuran.

In carrying out the reaction to prepare the novel intermediates of formula (V), the preferred strong base for economy and efficiency is sodium hydride. Used.

Generally, a mole ratio of this strong base to 2,4-dihydroquinazoline of at least 1: 1 and mole ratio of 1: 1 to 2: 1 is preferred.

Although the above reaction can be carried out over a wide temperature range, a temperature in the range of 0 150 ° C is preferred.

and especially in the range of 65-100 ° C. At below 0 ° C the reaction is disproportionately slow, while at temperatures above 150 ° C excessive amounts of unwanted by-products are obtained. The reaction rate is faster at higher temperatures and the time required for completion will vary with the temperature as well as with the exact nature of the reactants and solvent. However, the reaction is usually completed in 2-24 hours.

The following examples serve to illustrate the invention, in which Example 1 illustrates the preparation of the intermediate of the invention of formula (VI) and Examples 2 and 3 illustrate its use in the preparation of the desired final product prazosin.

EXAMPLE 1 2-Chloro-4-phthalimido-6,7-dimethoxyquinazoline In a 100 ml three-necked round bottom flask fitted with a thermometer, stirrer and dryer tube, 50 ml of Ν, Ν-dimethylformamide, 1.47 · g (0.010 mol ) phthalimide and 0.48 g (0.010 mol) of 50 wt% sodium hydride. After stirring at room temperature for 50 minutes. a clear solution was obtained. To this was added 2.59 g (0.010 mole) of 2,4-dichloro-6,7-dimethoxyquinazoline and the resulting mixture was cooled to room temperature, then 150 ml of water was added and the precipitated product was isolated by filtration and dried. in vacuo to give 3.1 g of the above. • standing compound, mp: 255 ° C. The structure was confirmed by NMR and mass spectral data. Yield: 84 pot.

2- [4- (2-Euroyl) piperazinyl] yl2-4-phthalimido-6A7-methoxyguinazoline In a 35 ml single-necked round bottom flask, provided with reflux and 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 to 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 collected by filtration and dried to give 0.70 g (47 f) of the hydrochloride salt of the above compound. The purified free base was obtained from the salt by silica gel chromatography on a 5 x 30 cm column eluting with ethyl acetate / diethylamine (90:10). The purified product melted at 305 ° C.

Similarly, when the above procedure is repeated but using the indicated solvent instead of isoamyl alcohol and the indicated temperature and reaction time, the above compound is obtained.

Solvent Sealing temperature, ° G Reaction time, hours

Isobutanol 50 48 - 1,2-Dimethoxyethane 80 50

Diethylene glycol monoethyl acetate 200-1 EXAMPLE 2

A solution of 95 mg (0.185 millimole) of 2- [4- (2-furoyl) piperazin-1-yl] -4-phthalimido-6,7-dimethoxyquinazoline in 2.0 ml of concentrated hydrochloric acid was stirred at room temperature for 2 hours. Then 4 »0 ml of chloroform was added and the mixture was adjusted to pH 10 by the addition of sodium carbonate solution. The chloroform layer was separated and evaporated to dryness to give 55 mg (77.6 f) of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxy-quinazoline mp: 270 ° C. The structure was confirmed by the combination.

equating the infrared spectrum with the spectrum of an authentic sample and by thin layer chromatography on silica gel using 95: 5 ethyl acetate / diethylamine as the solution system.

EXAMPLE 3

A suspension of 5.14 g (0.01 mole) of 2- [4- (2-furoyl) piperazin-1-yl] -4-phthalimido-6,7-dimethoxyquinazoline in 200 ml of isoamyl alcohol is heated to give solution, and 0.55 g (0.011 mol) of hydrazine hydrate is added. The resulting solution is stored at 20 ° for 18 hours and then evaporated to dryness under reduced pressure. The residue is triturated with 30 ml of 0.5N hydrochloric acid and maintained at 4 ° C for 2 hours. The solution is filtered to remove the precipitated phthalhydrazide. The filtrate is made alkaline (pH 10) with sodium hydroxide solution, extracted with chloroform, and the extracts are concentrated to dryness to give 2- [4- (2-furoyl) piperazine. zin-l-yl] -4-amino-6,7-dimethoxyquinazoline. The structure was confirmed in the same way as in Example 2.