FI66853C - MELLAN PRODUCTS FOR ANALYZING THE HYPOTENSIVE 2- (4- (2-FUROYL) PIPERAZIN-1-YL) -6,7-DIMETOXYQUINAZOLINE - Google Patents

Description

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Patent · oeh rsgisterstyrslsan ("> 31.08.84 (32X33X31) Aiming to" wont— " ) Philip Dietrich Hammen, East Lyme, Connecticut, USA (74) Oy Kolster Ab (54) Antihypertensive 2- [V (2-furoyl 1 i) pi perats i n-1-yy 1 ί / -6, Intermediate used in the preparation of 7 "-dimethoxyquinazole -Mellan product for the preparation of hypotensive 2- / 4- (2-furoyl) piperazine n-1-y 1, / - 6 Jd imethoxyquinazole in

The invention relates to novel 2-halo-4- (protected amino) -6,7-dimethoxyquinazoline derivatives and their acid addition salts which are useful as intermediates in the preparation of known antihypertensive 2- [4- (2-furoyl) piperazin-1-yl] -4 -amino-6,7-dimethoxyquinazoline of the formula ch3 ° y ^ vn ^ rNs »ir-A </ | \ _ / o ii

YY

CH..0 nh2 and is called prazosin. Antihypertensive 2- (4-substituted piperazin-1-yl) -4-amino-6,7-dimethoxyquinazolines are described in U.S. Patent 3,511,886.

66853

Said U.S. Patent describes several methods for preparing 2- (4-substituted piperazin-1-yl) -4-amino-6,7-dimethoxyquinazolines. They can be prepared, for example, by reacting 2-chloro-4-amino-6,7-dimethoxyquinazoline with a suitable 1-substituted piperazine or by reacting piperazin-1-yl) -4-chloro-6,7-dimethoxyquinazoline with ammonia or by alkylation, alkanoylation. , by aroylation or alkoxylation of 2- (1-piperazinyl) -4-amino-6,7-dimethoxyquinazoline.

U.S. Patent No. 3,935,213 describes the preparation of 2- (4-substituted piperazin-1-yl) -4-amino-6,7-dimethoxyquinazolines by methods in which 1) a suitable 4,5-dimethoxy-substituted 2-aminobeconitrile is reacted with certain 1 , With 4-disubstituted piperazines, or 2) the appropriate 4,5-dimethoxy-substituted 2-aminobenzamidine is reacted with the same 1,4-disubstituted piperazines.

U.S. Patent No. 3,511,836 discloses a compound of the formula ch3o NHCH-CcHr-2 6 5

The present invention relates to the use of an intermediate 2-halo-4- (protected amino) in the preparation of the antihypertensive 2 / 4- (2-furoyl) piperazin-1-yl-4-amino-6,7-dimethoxyquinazoline of formula II. 6,7-dimethoxyquinazoline derivative of the formula y jr y ch i Y *

R1 V

II

3 66853 1 2 3 1?

wherein Y is chlorine or bromine, R is hydrogen and R is -COOR or R and R

together with the nitrogen atom to which they are attached form 3 phthalimido groups, and R is alkyl having 1 to 4 carbon atoms, and an acid addition salt thereof.

To prepare a compound of formula II, one mole of an intermediate of formula I is reacted with two moles of a compound of formula i HN N - C-k „/ \ / Il 111

O

in a reaction-inert solvent at a temperature of 50 to 200 ° C. A particularly preferred temperature range is 80-130 ° C.

When the process is carried out using compounds of formula I in which R and R together with the nitrogen atom to which they are attached form a phthalimido group, equimolar amounts of starting materials can also be advantageously used to give an intermediate of formula jj ϊ ν'1! N * f -Il) 3 i I \ _ / h Λχ ^ iva

° CH 3 ^ X

0 </ CO

Ö

The resulting intermediate is converted at 0-100 ° C to the final product of formula II by (a) hydrolysis or (b) reaction with an equimolar amount of hydrazine in the presence of a reaction inert solvent. A particularly preferred temperature range for converting an intermediate of formula IVa to a final product of formula II by hydrolysis or hydrazine is 20-50 ° C. The hydrolysis is preferably carried out in the presence of hydrochloric, hydrobromic, sulfuric or phosphoric acid.

When a compound of formula I wherein R 1 is hydrogen and R 3 is -COOR wherein R is alkyl of 1 to 4 carbon atoms is used, the compound of formula II or a hydrochloride or hydrobromide salt thereof is directly formed. In this case, it is preferred to bring one mole of the compound of the formula I with two moles of the compound of the formula III.

As mentioned above, the novel compounds are useful intermediates in the preparation of the antihypertensive 2- [4- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline or prazosin of formula II. Prazosin has been reported to have therapeutic use in humans (Cohen, Journal of Clinical Pharmacology, 10, 488 (1970); De Guiam et al., Current Therapeutic Research 15, 339 (1973)).

As indicated above, a compound of formula II or a hydrochloride or hydrobromic acid addition salt thereof can be prepared by reacting a compound of formula I with a compound of formula III.

In certain cases, which are described in detail below, an intermediate of formula (IV) or an acid addition salt thereof is initially obtained, which is further reacted to give a compound of formula II. The reaction of the compounds of the formulas I and III is carried out in the presence of a suitable reaction-inert organic solvent. A suitable solvent is a solvent whose main function is to dissolve the starting materials and which does not adversely affect the starting materials or reaction products. Examples of such solvents include 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 N, N-dimethylformamide, Ν, Ν-diethylacetamide and N-methylpyrrolidone; dimethyl sulfoxide and pyridine. The reaction can be carried out over a wide temperature range, e.g. about 50-200 ° C. A particularly preferred temperature range is 80-130 ° C. The time required for the process to be substantially complete varies depending on several factors, such as the reaction temperature, the reactivity of the starting materials used, and the concentration of the starting materials. At lower temperatures longer reaction times are required, while at higher temperatures the reaction is completed in a shorter time. A reaction time of 15 minutes to 50 hours is generally sufficient.

In certain cases, the reaction of a compound of formula I with a compound of formula III forms an intermediate of formula IV, which is then further reacted to give a compound of formula II. Thus, the preparation can be carried out by either of two methods, designated Method A and Method B, as shown in the following reaction scheme:

"VYV. ./->. -O

/ \ III R1 / XR2 T K1 a2 /

/ IV

\ ^ Method B

ch3o N ^ \ / N "C

ch3o j nh2

II

The methods use a compound of formula I wherein Y is 1 2 chlorine or bromine, preferably chlorine, and R and R are as defined above.

τ ~ - 66853

When the compound of formula II is prepared according to Method A as described in the above reaction scheme, it is preferable to use a compound of formula I wherein Y is chlorine or bromine and R and R together with the nitrogen atom to which they are attached form a phthalimido group. Such compounds of formula I react with the compounds of formula III described above to give an intermediate of formula IV or a hydrochloride or hydrobromide salt thereof. The intermediate of formula IV can be conveniently isolated in the form of a hydrochloride salt or a hydrobromide salt, both of which are insoluble in the reaction solvent and can thus be obtained only by filtration and washing. Alternatively, the above salts may be treated with an alkaline reagent such as sodium hydroxide, potassium hydroxide, potassium carbonate or sodium methoxide while stirring the reaction mixture, followed by extraction of the free base with a water-immiscible solvent such as chloroform or dichloromethane; as well as evaporation to dryness. If desired, either the compound of formula IV or a salt thereof can be further purified by standard methods such as crystallization or column chromatography. However, they are often pure enough for further reaction to form compounds of formula II without such further purification.

As mentioned above, the compound of formula IV or a hydrohalide salt thereof is further reacted to remove the 4-amino substituents R 2 and R to give the desired compound of formula II.

When a compound of formula IV is used in which R and R together with the nitrogen atom to which they are attached form a phthalimido group, the compound is hydrolysed or reacted with hydrazine to give a compound of formula II.

The hydrolysis can be carried out under basic conditions, for example in the presence of 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 acids. For the hydrolysis of the phthalimido compound of the formula IV, it has been found particularly suitable and effective to use hydrochloric, hydrobromic, sulfuric or phosphoric acid. It is preferred to carry out the hydrolysis with one of these acids at a temperature of 0 to 100 ° C, with a particularly preferred temperature range for such hydrolysis being 20 to 50 ° C. At temperatures below 0 ° C, the rate of hydrolysis is unreasonably slow. Excessive decomposition products develop at temperatures above 100 ° C.

The molar ratio of the above-mentioned acids to the compound of formula IV can vary over a wide range, so that molar ratios of from 1: 1 to 200: 1 can be used with satisfactory results. The time required to achieve substantially complete hydrolysis varies depending on the reaction temperature, and usually when hydrolysis occurs at 100 ° C, only a few minutes is sufficient, and when it occurs at 0 ° C, up to 24 hours are required. The hydrolysis can be carried out in an aqueous medium or in an aqueous organic medium using a water-immiscible organic solvent such as chloroform, methylene dichloride, benzene or toluene. When the hydrolysis is complete, which can be readily determined by thin layer chromatography using silica gel and, for example, a 95: 5 ethyl acetate / diethylamine solvent system, the desired compound of formula II can be isolated as a salt of the acid used in the hydrolysis using methods well known in the art. However, it is usually more convenient to adjust the pH of the reaction mixture to a base by adding, for example, sodium hydroxide, potassium hydroxide or sodium carbonate, followed by extraction of the compound of formula II as the free base using, for example, one of the above organic solvents. The product is then easily isolated by evaporation.

Alternatively, as mentioned above, the formula IV can be used

An intermediate according to 1 2, wherein R 3a R together with the nitrogen atom to which they are attached form a phthalimido group, is further reacted with hydrazine to give the final product of formula II. The use of hydrazine to remove a phthaloyl group from phthalimide acids or similar lower alkyl esters is known in the art, cf. e.g., Boissannas, Advances in Org. Chem., 3, 179-183 (1963) and Sheenan et al., Jour. Amer. Chem. Soc., 76, 6329 (1954). The reaction is carried out in the presence of a reaction-inert organic solvent. Examples of organic solvents useful for this reaction include lower alkanols such as ethanol, propanol, isopropanol, butanol and isoamyl alcohol; N, N-dimethylformamide, Ν, Ν-dimethylacetamide, dimethyl sulfoxide, diethylene glycol dimethyl ether and diethylene glycol monoethyl ether.

__ - τ ~ 66853 The hydrazine used may be substantially pure hydrazine or a derivative such as hydrazine hydrate, hydrazine hydrochloride or hydrazine sulfate. When acid addition salts are used, hydrazine is formed in situ by the addition of a suitable base to neutralize the acid. Examples of suitable bases are sodium methoxide, potassium carbonate, triethylamine, triethanolamine and sodium hydroxide. Although up to 5 moles of excess hydrazine per mole of intermediate IV can be successfully used in this reaction, it is preferable to use an equimolar amount of hydrazine to reduce possible side reactions as well as for economic reasons. It is preferred to carry out the reaction with hydrazine at a temperature of 0 to 100 ° C. A particularly preferred temperature range is 20-50 ° C. Unexpected side reactions occur at temperatures above 100 ° C, while at temperatures below 0 ° C the reaction rate is unreasonably slow.

The time required to achieve a substantially complete reaction will, of course, vary with the temperature and the nature of the starting materials and solvent. Usually, however, the reaction with hydrazine to form the final product of formula II is substantially complete in 1 to 48 hours. The reaction between hydrazine and the phthalimido compound also produces phthaloyl hydrazide. The reaction mixture can be liberated from the phthaloyl hydrazide by-product and the desired product of formula II can be isolated by methods well known in the art, such as evaporation to dryness in vacuo, trituration of the residue with a dilute strong mineral acid such as hydrochloric acid, or sulfuric acid. the pH of the filtrate is basic, after which the desired product is isolated by extraction or filtration.

1 2 3

When a compound of formula I wherein R is hydrogen and R is -COOR, 3

wherein R is as defined above is reacted with 1-substituted piperazine III, the reaction directly yields a compound of formula II, as shown in the reaction schemes above. Thus, when such a compound of formula I is used, 1-substituted piperazine III reacts with both quinazoline I

2 in the 2-position to replace the halogen atom Y (Y = Cl or Br) and to remove the R group, whereby the compound of formula I is obtained in a single step.

9 66853

While Method B may be carried out using suitably molar ratios of Compound I to Compound III of 1: 1 to 3: 1 or greater, it is preferred to react a compound of Formula I with a compound of Formula III in a molar ratio of 2: 1 for reasons of efficiency and economy.

When the reaction process is carried out according to Method B, the compound of formula II is readily isolated by standard methods in the form of either the hydrochloride salt (when Y is chlorine), the hydrobromide salt (when Y is bromine) or the free base. For example, when a compound of formula I wherein Y is particularly preferably chlorine is reacted with two moles of a compound of formula III, the hydrochloride salt of compound II is usually obtained by filtration of the reaction mixture alone and washing of the product. When the free base of a compound of formula II is desired, the reaction mixture, after completion of the reaction, is treated with an excess of a strongly alkaline reagent such as sodium hydroxide, potassium hydroxide or sodium carbonate and the free base is extracted with a water-immiscible solvent such as chloroform, methylene With 1,2-dichloroethane or benzene. The product is then obtained, for example, by evaporation of the solvent and then further purified, if desired.

The novel intermediates of the formula I also differ from the known analogous compounds described, for example, in U.S. Pat. No. 3,511,836, also in terms of use.

Known compounds wherein R 1 is hydrogen and is benzyl react with a compound of formula III to give the corresponding known compounds of formula IV wherein R 1 is benzyl and R 1 is hydrogen. To remove the benzyl group, a compound of formula IV is hydrogenated. In contrast, the novel compounds of the formula I in which R is hydrogen and R is 3 -COOR in which R is as defined above react directly to the compound of the formula II. A compound of formula I, wherein R and R together with the nitrogen atom to which they are attached form a phthalimido group, reacts with a compound of formula III to give a new intermediate of formula IV which forms a compound of formula II by hydrolysis or reaction with hydrates. as described above.

Intermediates I according to the invention are prepared from the appropriate 2,4-dihalo-6,7-dimethoxyquinazolines, the halogen being chlorine 66853 or bromine. The preparation of these dihalogen compounds has been previously described in U.S. Patents 3,511,836 and 3,669,968 to Curd et al. in Jour. Chem. Soc. (London), 777 (1947); ibid., 1759 (1948).

In the preparation of new intermediates of formula I, 2,4-dihaloquinazoline is reacted with a phthalimide or a suitable urethane of formula R 1 OCON 1 in an inert organic solvent and a strong base such as sodium hydride, potassium hydride, calcium butoxide, calcium methoxide, sodium methoxide, sodium methoxide in the presence of butyllithium, under anhydrous conditions. After the reaction is substantially complete, the compound of formula I is isolated by known standard methods, for example by immersing the reaction mixture in excess water or dilute acid, and filtering, washing and drying to obtain the desired product. Immersion in dilute acid is preferred when using said urethane.

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

The preferred strong base to be used in the reaction is sodium hydride for reasons of economy and efficiency. The molar ratio of this strong base to 2,4-dihaloquinazoline is usually at least 1: 1 and molar ratios between 1: 1 and 2: 1 are preferred.

The reaction can be carried out over a wide range of temperatures, but 0 to 150 ° C, and especially 65 to 100 ° C, is preferred.

Below C ° C, the reaction is unreasonably slow, while at temperatures above 150 ° C too much unwanted by-products are obtained. The reaction rate is higher at higher temperatures and the time required to complete the reaction varies depending on the temperature as well as the starting materials and solvent. However, the reaction is usually complete in 2-24 hours.

The following examples illustrate the invention. Examples 1 and 5 describe the preparation of an intermediate according to the invention and Examples 2, 3, 4 and 6 describe the preparation of the final product.

Il 66853 11

Example 1 2-Chloro-4-phthalimide-6,7-dimethoxyquinazoline In a 100 ml three-necked round bottom flask equipped with a thermometer, stirrer and drying tube was placed 50 ml of N, N-dimethylformamide, 1.47 g (0.010 g). moles) of phthalimide and 0.48 g (0.010 moles) of 50% w / w sodium hydride. After stirring for 30 minutes at room temperature, a clear solution was obtained. To this was then added 2.59 g (0.010 mol) of 2,4-dichloro-6,7-dimethoxyquinazoline, and the resulting mixture was heated at 100 ° C for 5 hours. The reaction mixture was cooled to room temperature, 150 ml of water were added and the precipitated product was isolated by filtration and dried in vacuo to give 3.1 g of the title compound, m.p. 255 ° C. The structure was confirmed by NMR and mass spectrum values. 84% in the hall.

Example 2 2- [4- (2-Furoyl) piperazin-1-yl] -4-phthalimide-6,7-dimethoxyquinazoline was placed in a 35 ml one-necked, round-bottomed flask equipped with a reflux condenser and a drying tube. 1.0 g (0.0027 mol) of 2-chloro-4-phthalimide-6,7-dimethoxyquinazoline, 10 ml of isoamyl alcohol and a solution of 0.550 g (0.003 mol) of 1- (2-furoyl) piperazine. the mixture was heated at 130 ° C for 4 hours and then cooled to room temperature 35 ml of hexane was added to the reaction mixture, and the precipitated product was collected by filtration and dried to give 0.70 g (47%) of the hydrochloride salt of the title compound, purified from the salt using silica gel chromatography. On a 5 x 30 cm column, eluting with ethyl acetate / diethylamine (90:10) The purified product melted at 305 ° C.

When the above procedure is repeated, but using the solvent mentioned below instead of isoamyl alcohol and the temperature and reaction time mentioned below, the title compound is obtained in the same manner.

Solvent__Reaction temperature ° C Reaction time one hour

Isobutanol 50 48 1,2-dimethoxyethane 80 30

Diethylene glycol monoethyl ether 200 1 - Γ 12 66853

Example 3

A solution of 95 mg (0.185 mmol) of 2- [4- (2-furoyl) piperazin-1-yl] -4-phthalimide-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 adding sodium 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 comparing the infrared spectrum with that of an authentic sample and using thin layer chromatography on silica gel using 95: 5-ethyl acetate / diethylamine as the solvent system.

Example 4

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

Example 5 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) was placed in a 100 mL reaction flask equipped with a thermometer, reflux condenser and drying tube. The reaction mixture was heated to reflux for 2 hours, after which 70 ml of methanol was slowly added, the resulting mixture was heated to 60 ° C and filtered hot. The filtrate was evaporated to a thick slurry, the solid was collected by filtration and washed with 5 ml of chloroform to give 5.4 g (70%) of the title compound. After recrystallization from a mixture of tetrahydrofuran and hexane (2: 3), a sample melted at 212 ° C.

66853 13

Analysis:

Calculated for C 13 H 14 N 3 O 4 Cl%: C, 50.09; H, 4.53; N, 13.48 Found: C, 49.95; H, 4.46; N, 13.54

Example 6 2- [4- (2-Furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline 4-Ethoxycarbonylamino-2-chloro-6,7-dimethoxyquinazoline (2.0 g, 0, 0064 moles) 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 solids were collected on a filter funnel, washed with isoamyl alcohol and then mechanically stirred with 100 ml of 10% aqueous sodium hydroxide. An equal volume of chloroform was added and the mixture was stirred for 15 minutes. The organic layer was separated, evaporated to about 25 ml and 50 ml of tetrahydrofuran were added. The solids were collected by filtration and further purified by chromatography on a silica gel column (2.5 x 45 cm) eluting first with ethyl acetate and then with methanol. The fractions containing the title compound were combined and evaporated to dryness. The residue was collected in 10 ml of chloroform, hexane was added to the cloud point, stirred for 15 minutes, and the crystals were collected by filtration, m.p. 265 ° C, yield 900 mg (37%).

When the reaction described above is repeated at 80 ° C for 18 hours, the results are essentially unchanged.

Claims (1)

The intermediate used in the preparation of the antihypertensive 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline as an intermediate 2-halo-4- (protected amino) -6 , 7-dimethoxyquinazoline derivative or an acid addition salt thereof, characterized in that it has the formula ch3 °> v ^: sn ^ nw y ^ IV ch3o> ^ Yn, Ai R1 R 1 2 3 1? wherein Y is chlorine or bromine, R is hydrogen and R is -COOR or R and R together with the nitrogen atom to which they are attached form 3 phthalimido groups, and R is alkyl of 1 to 4 carbon atoms.