SE439162B - A 2- (4- (HALOGEN-SUBSTITUTED 2-FUROYL) -PIPERAZIN-1-YL) -4-AMINO-6,7-DIMETOXICINAZOLINE FOR USE AS INTERMEDIATE AND PREPARED TO PREPARE THIS - Google Patents

Abstract

Novel compounds of the general formula II in which X represents a chlorine, bromine or iodine atom, and n denotes an integer from 1 to 3, are obtained by reacting a 6,7-dimethoxyquinazoline with a halogen-substituted furan. The compounds obtained can then be reacted at a temperature from 0 DEG to 150 DEG C with hydrogen in the presence of a catalytic amount of a dehalogenating catalyst and in the presence of a solvent which is inert to the reaction. The compound 2-[4-(2-furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxy-quinazoline which can be prepared according to the invention is in general useful on account of its ability to lower the blood pressure in mammals having high blood pressure.

Description

8203583-3 P.ans. 7707472-2 discloses a novel process for the preparation of 2- [N- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline or a hydrochloride, hydrobromide or hydroiodide salt thereof, which process comprises reacting a compound having the formula | ïï fi ë - (x) n / _ \ _ CHBO ° C330 ... II with hydrogen in the presence of a catalytic amount of a dehalogenating catalyst, consisting of supported or unsupported palladium, copper, cobalt or nickel or a mixture of palladium with platinum, ruthenium or rhodium, in the presence of a reaction-inert solvent at a temperature from about 0 ° C to 150 ° C and optionally in the presence of an acid acceptor, in which formula X represents chloro, bromo or iodo and n is a whole numbers from 1 to 3.

A particularly preferred embodiment of the above process is that carried out using a compound having the formula II, wherein n is 1 and X is chloro or bromo, at a temperature of from 25 to 10 ° C, in the presence of at least nl mol of an acid acceptor having a pKb value of 7 or less and in the presence of a catalyst consisting of palladium or palladium on carbon or a mixture containing from 98 to 99.9 parts by weight of palladium and 0.1 to 2 parts by weight of platinum, ruthenium or rhodium.

Most particularly preferred is a process wherein the compound of formula II is 2- [N- (5-bromo-2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline, the catalyst is palladium and the reaction is carried out in the presence of at least one equivalent of triethylamine as the acid acceptor.

The above process is useful for the preparation of 2- [α- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline, which is known as prazosin. Prazosin has been shown to have therapeutic utility in humans; compare Cohen, Journal of Clinical Pharmacology, lg, 408 (1970).

According to the present invention there are provided new and useful starting materials for the above process, having the formula II above, wherein X is chloro, bromo or iodo and n is an integer from 1 to 3. A particularly preferred starting material is 2- [- (5-bromo -2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline.

The above procedure for the preparation of the valuable hypotensive agent, 2- [α- (2-furoyl) -piperazin-1-yl} 4-amino-6,7-dimethoxyquinazoline (I), by catalytic dehalogenation of compounds of the formula (II) can be represented by the following reaction scheme: C330 1-1 fi ql fl n CH3O \ NJ 'Nwn N-Ü 0 / Hg / cat. The process is carried out in such a way as to cause the compound having the formula (II) to react with hydrogen in the presence of the defined dehalogenation catalyst. The term "dehalogenation catalyst" "refers to a catalyst which promotes selective replacement of halogen with hydrogen under the process conditions for the formation of product (I) without significant hydrogenation or hydrogenolysis of the furan and quinazoline moieties in the starting material and the product. The dehalogenation catalyst used in the above process may be applied to a or not and consists of palladium, copper, cobalt or nickel or a mixture of palladium with platinum, ruthenium or rhodium.Examples of suitable catalyst supports include carbon, barium oxide, calcium carbonate and barium sulphate.These catalysts can be prepared in situ by pre-reduction of a corresponding oxide or a corresponding salt of the catalytic compound.The pre-reduction is simply carried out in such a way that the catalyst precursor compound is suspended in the hydrogenation medium, after which it is hydrogenated and the substrate is added and the hydrogenation is started. Alternatively, all components can be added at once and hydrogenation started. The former process has the advantage of allowing the quantity of hydrogen absorbed during the pre-reduction of the catalyst and during the hydrogenation phase to be determined separately. The degree of hydrogenation can then be easily regulated.

Among the suitable dehalogenation catalysts which can be used in the above process are finely divided metals such as cobalt, nickel and copper. The preparation and use of such catalysts are disclosed in Freifelder, "Practical Catalytic Hydrogenation", John Wiley and Sons, Inc., New York, 1997, and in the references cited therein.

The catalysts in the above process are palladium, copper, cobalt, nickel and mixtures of palladium with platinum, ruthenium or rhodium. While any of the mentioned mixtures containing palladium and one of the other metals in which the weight ratio of palladium to platinum, ruthenium or rhodium varies within a wide range, are useful in the process according to the invention, particularly preferred mixtures containing from 98-99, 9 parts by weight of palladium and 0.1 - 2 parts by weight of platinum, ruthenium or rhodium.

The catalysts are used in the process in "catalytic amounts", a term well known to those skilled in the art of hydrogenation, and such amounts are illustrated in the working examples below.

Also compare Freifelder, loc. cit .; pages 79-81. Generally, however, it is preferred to use from 1 to 40% by weight of catalyst, based on the weight of starting material of formula (II).

The above procedure is carried out in the presence of a reaction-inert solvent. A suitable solvent is one which serves to substantially dissolve or disperse the reactants and does not react adversely with the reactants, products or catalysts. Examples of such solvents are the lower alkanols, such as methanol, ethanol, isopropanol, n-butanol, isobutanol and isoamyl alcohol; cyclic and straight-chain water-soluble ethers such as dioxane, tetrahydrofuran, diethylene glycol monomethyl ether, 2-ethoxyethanol, N, N-dimethylformamide and N, N-dimethyllacetamide, as well as mixtures of such solvents with water.

The hydrogen pressure used to perform the above procedure is not critical and depends primarily on the equipment used.

In general, pressures from atmospheric pressure up to about 140 kp / cm 2 are preferred. As is well known, hydrogenation at atmospheric pressure is generally carried out in an apparatus in which a certain volume of hydrogen is present in a container connected to a manometer in order to be able to measure the volume of hydrogen consumed. Alternatively, a magnesium citrate bottle (Parr vessel) and mechanical shaker can be used with a calibrated pressure gauge such as a Parr hydrogenation apparatus or a high pressure autoclave equipped with a stirrer or shaker.

The dehalogenation process is carried out at a temperature in the range from about 0 ° to 150 ° C. A particularly preferred range for the temperature is from 25 to 100 ° C.

When the process is carried out with a compound of formula (II) alone, the product initially formed is the hydrogen halide addition salt of the compound (I). This can be isolated as such or converted to the free base by treatment with aqueous alkali such as sodium hydroxide or potassium hydroxide followed by filtration of the base or extraction by a water-immiscible solvent such as ethyl ether, chloroform or methylene chloride. Alternatively, the process can be carried out in the presence of an acid acceptor so as to directly obtain the free base of the compound (I) and the halide salt of the acid acceptor. By the term "acid acceptor" is meant a basic compound which, when added to the reaction mixture and used in the process of the invention, selectively reacts with liberated hydrogen halide to form a halide salt without causing significant by-product formation by further reaction with the reactant or products and In order to be able to successfully compete with the hydrogen halide formed during the process, the acid acceptor must be a stronger base than the reactant of formula (II) or the product (I), ie it must be a base with a pKb value of 7 or less.

Examples of suitable acid acceptors are amines such as triethylamine, N-methylpyrrolidine, triethanolamine, n-butylamine, benzylamine, isoamylamine, morpholine and piperidine; ammonia, hydrazine and alkali metal and alkaline earth metal oxides and hydroxides such as those of sodium, potassium, magnesium, calcium and barium. Particularly preferred as the acid acceptor is triethylamine due to its readiness, economy and efficiency.

The acid acceptor is preferably used in an amount at least sufficient to neutralize n-1 mole of hydrogen halide per mole of compound (II), wherein n is the number of atoms of halogen per mole of starting material of formula (II), i.e. n is an integer from 1 to 3. When the amount of acid acceptor is at least equivalent to the amount of hydrogen halide formed, the product is the free base of formula (I). In such cases, an excess of the acid acceptor can be used if desired. Alternatively, when n-1 equivalents of the acid acceptor per mole of compound (II) is used, the product formed is the hydrogen halide salt of the compound of formula (I). When, for example, in the starting material of formula (II) X is chloro, n is 3 and 2 equivalents of acid acceptor per mole of compound of formula (II) are used, the product obtained is the hydrochloride salt of compound (I).

When it is desired to use an acid acceptor in the above procedure, it is preferred that at least one equivalent of acid acceptor be used per mole of compound of formula (II).

The time required for the dehalogenation process to be substantially complete varies with factors such as temperature, catalyst and the exact nature of the starting material of formula (II). Usually, however, the dehalogenation is substantially complete after about 0.5 to 24 hours.

As mentioned above, the product of the above process may be either the free base of formula (I) or a hydrochloride, hydrobromide or hydroiodide salt thereof. Any of these products can be isolated and further purified if desired according to methods well known to those skilled in the art. For example, the free base can often be isolated only by evaporation of the solvent after removal of the catalyst by filtration, whereby the product precipitates, or it can be made to precipitate by the addition of a non-solvent such as hexane or heptane. The free base can be further purified by methods such as, for example, recrystallization or column chromatography on silica gel. When the product obtained in the above process is one of the above-mentioned hydrohalide salts of the compound (I), it may be converted into the free base and isolated as described above, or the hydrohalide salt may be isolated by heating the reaction mixture to ensure dissolution of the said the hydrogen halide salt, after which the reaction mixture is filtered to remove the catalyst and the filtrate can then be concentrated to a small volume and cooled, after which the desired product is usually precipitated. This can be further purified if desired, for example by recrystallization. The starting compounds of formula (II) above, wherein X is chloro, bromo or iodo and n is an integer from 1 to 3, are new compounds. They can be prepared according to any of the prior art methods described above for the preparation of 2- [N- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline by use of suitable halogen-substituted starting materials in any case. The preferred methods for preparing the compounds of formula (II) are those set forth below as Method A and Method B.

Method A c1¶3o NY) 0 / N + HFN _fi_ loj (mn-aux) 3 NH2 ... III '___IV CH MetOd B cH3o N / \ (xnfq-: ï ___-__.) (II) Wim + \ o coA N / Cao 3 NH 2 ... V ... VI In each of the compounds of formulas (III) and (VI), A is chlorine or bromo and (X) n has the meaning given above. The compounds of formulas (III) and (V) are available according to methods described in U.S. Patent No. 3,511,836.

The acyl halides of formula (VI) are prepared from the corresponding halogenated-2-furonic acids according to well known methods, for example by reacting the acids with an excess of thionyl chloride sznzsss-3 or thionyl bromide followed by evaporation of the reaction mixture. Of the halogenated furanecarboxylic acids from which the compounds (VI) are derived, 5-bromo-2-furanecarboxylic acid is commercially available. The remaining chloro- and bromofuranecarboxylic acids are prepared according to methods described by Shepard et al., Jour. Amer. Chem. Soc., Âå, 2083 (1930) and Gilman et al., Ibid., Eel, ll46 (1935) and the references cited therein. The iodofurancarboxylic acids are prepared from the corresponding iodofurfurals by oxidation with alkaline peroxide according to the method given by Borisova et al., Chem. Abstr., Lay, 35l34f (1970) or according to the method set forth by Sornay et al., Bull. Soc. Chem., France, 990 (1971).

When Method A is used, the 1-substituted piperazine of formula (IV), which can be prepared from the above-described acid halides of formula (VI) and an equimolar amount of piperazine, is reacted in approximately equimolar amounts in the presence of a reaction-inert organic solvent. The reaction can be carried out over a wide temperature range, but a temperature in the range of 50 ° to 100 ° C is preferred. The reaction is usually complete in 1-24 hours. The product can be isolated in the form of the hydrochloride or hydrobromide salt and then converted to the free base of formula (II) according to standardized methods. Alternatively, the reaction mixture can be made alkaline, for example with sodium hydroxide or potassium hydroxide, and the free base is isolated by extraction and evaporation of the solvent. Examples of suitable reaction-inert solvents for this process are alkanols such as ethanol, n-butanol, isoamyl alcohol, n-hexanol or cyclohexanol; N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, diethylene glycol diethyl ether, ethylene glycol-n-butyl ether, chloroform or methylene chloride.

When Method B is used, the compound of formula (V) is reacted with an equimolar amount of compound of formula (VI) in the presence of a suitable reaction-inert organic solvent.

The reaction is preferably carried out at a temperature of from -20 ° C to 10 ° C. Examples of suitable solvents for use in this process are those set forth above for Method A.

The reaction is usually complete within a few minutes to 10 hours. The desired product is isolated by standard methods such as adjusting the reaction mixture to an alkaline pH by adding an aqueous base, for example sodium hydroxide, potassium hydroxide or sodium carbonate, extracting the product with a water-immiscible solvent such as chloroform or methylene chloride. - riding and evaporation of the solvent.

For economic reasons and efficiency reasons, particularly preferred compounds of formula (II) are those wherein n is 1 and X is chloro or bromo. Most preferred is 2- [N- (5-bromo-2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline.

The following non-limiting examples further illustrate the invention.

Example 1 (a) illustrates the preparation of the novel intermediate compound of formula (II) and Example 1 (b) illustrates a process for the use of the novel intermediate of the invention for the preparation of the compound of formula (I).

Example 1 (a) 2-LA- (5-bromo-2-furoyl) -piperazin-ly;] - 4-amino-6,7-dimethoxyquinazoline A flask containing 19.1 g (0.1 mol) -bromo-2-furancarboxylic acid in 10 ml of chloroform was added with 20 g of thionyl chloride and the resulting mixture was stirred at room temperature for two hours and then allowed to stand overnight. The volatile components were then evaporated in vacuo to give 5-bromo--2-furoyl chloride. This was dissolved in 50 ml of methylene chloride and the solution was added dropwise at 25 ° C to a solution of 8.6 g (0.1 mol) of piperazine in 50 ml of the same solvent. The addition required about 30 minutes. The resulting mixture was stirred for an additional hour and then made alkaline by the addition of 2N sodium hydroxide solution. The organic layer was separated and the aqueous layer was re-extracted with methylene chloride. The organic layers were dried over anhydrous potassium carbonate and then evaporated to dryness to give 23 g of 1- (5-bromo-2-furoyl) -piperazine. A portion was recrystallized from methylene chloride / ethyl acetate, mp 113-115 ° C.

Analysis; Calculated for C 9 H 11 O 2 N 2 Br C 41.72 H 4.28 N 10.81 Br 30.84 Found: C 41.44 H 4.35 N 10.66 Br 30.49 In a reaction vessel 9.55 g (0.04 mol 4-Amino-2-chloro-6,7-dimethoxyquinazoline, prepared according to U.S. Patent 3,511,836, 200 ml of isoamyl alcohol and 20.7 g (0.08 mol) of 1- (5-bromo-2-furoyl) -piperazine obtained as above. The resulting suspension was heated at reflux for 90 minutes, then cooled and filtered and washed with ethanol to give 21.8 g of crude hydrochloride salt of the title compound, melting with decomposition at 276-27800.

This was slurried in 200 ml of ethanol and 2N sodium hydroxide solution was added thereto to effect dissolution. The solution was concentrated to a small volume by evaporation in vacuo, cooled, filtered, washed with water and dried to give 18.8 g of product, m.p. 206-209 ° C. This was dissolved in a mixture of chloroform and methanol, dried over sodium sulfate, treated with carbon and the solvent was replaced with ethyl acetate. After recrystallization, 9.8 g (53%) of purified product were obtained, m.p. 213-215 ° C-Analysis; Calculated for C 19 H 20 N 5 O 4 Br: C 49.36 H 4.36 N 15.15 Br 17.28 Found: C 48.70 H 4.36 N 14.87 Br 16.87 (b) In a pressure vessel according to Parr 1.0 was introduced g (2.16 mmol) 2- [4- (5-bromo-2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline, 10 ml methanol, 1.0 ml triethylamine and 0.4 g 5% Pd on carbon (50% wet). The vessel was placed in a Parr shaker and set under hydrogen pressure to 3.5 kp / cm 2 at room temperature. After shaking for 18 hours, the theoretical amount of hydrogen had been absorbed. The mixture of catalyst and precipitated product was filtered and the solids were slurried in 25 ml of chloroform and filtered again to remove catalyst. To the filtrate was added 50 ml of hexane, the mixture was stirred for 10 minutes and then filtered to give a crude product, which was purified in a 450 x 75 mm column of silica gel, eluting with ethyl acetate / diethylamine (90: 10 calculated on volume) to obtain 300 mg of 2 - [α- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline, m.p. 266 ° C, which was identified by comparing the IR spectrum in chloroform with it for an authentic sample and thin layer chromatography on silica gel.

Claims (3)

8203583-3 13 PATENT REQUIREMENTS 1. A 2- [N- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline, which is halogen substituted in the furoyl group, for use as an intermediate in the preparation of 2- [N- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline, which has the formula i ... I F - (X) n cn 30 N \ / N \ fl d / N'ä I 0 / CH 0 -. ~ II wherein X is chloro, bromo or iodo and n is an integer 1, 2 or 3. 2- [N- (5-bromo-2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline. 3. A process for the preparation of a compound having the formula (II) in claim 1, characterized in that a 6,7-dimethoxyquinazoline having the formula szussss-3 '' NYN / CH 3 O NH 2 is reacted with a halofuran, which has the formula -_- (X) n zE __1, \ oj ß 'wherein, when either Y or Z is -N NH, the other is chloro or bromo and X and n have the meaning given in claim 1.