DK144475B - In the FUROYL GROUP HALOGEN-SUBSTITUTED 2- (4- (2-FUROYL) PIPERAZIN-1-YL) -4-AMINO-6,7-DIMETHOXYQUINAZOLINES USED AS INTERMEDIATES IN THE PREPARATION OF 2- (4- (2-FURO)) -1-YL) -4-AMINO-6,7-DIMATHOXYQUINAZOLINE OR THE HYDROCHLORIDE HYDROBROMIDE OR THE HYDROIODIDE THEREOF - Google Patents

Description

(19) DENMARK tjj | Li;

W (12) PUBLICATION OF 141 + (+ 75 B)

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 5974/80 (51) lnt.CI.3 C 07 D 405/12 (22) Submission date 19 · s ep. 1 g80 (24) Running day l4. Christmas. 1977 (41) Aim. available Sep 19 1 g80 (44) Presented 1 5 · mat1. 1 g82 (86) International application no. - (86) International filing day (85) Transfer day - (62) Master application no. 3200/77

(30) Priority Aug. 6 1976, 712277, US

(71) Applicant EFIZER INC., New York, US.

(72) Inventor Philip Dietrich Hammen, US.

(74) The Patent Office of Hofman-Bang & Boutard.

(54) in the furoyl group halogen-substituted 2- (4- (2-furoyl) piperazin-1-yl) -4-amino-6,7-dimetho = xyquinazolines for use as intermediates in the preparation of 2 - (4- (2-furoyl) -piperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline or the hydrochloride, hydrobromide or hydroiodide thereof.

The invention relates to novel, in the furoyl group halogen substances [v. used 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazolines for use as intermediates in a particular process _3 to prepare 2- [4- (2- furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline or the hydrochloride, hydrobromide or γ / hydroiodide thereof, which are valuable drugs because of their ability to lower blood pressure in hypertensive mammals. , and the use of which is set forth in U.S. Patent No. 3,511,836.

2- [4- (2- oy 1) -p ip is az in 1-yl] -4-amino-6,7-dimethoxyquinazoline is known in the pharmaceutical industry as prazosin. Prazosin has been shown to have therapeutic utility in humans: see Cohen, Journal of Clinical Pharmacalogy, 1Cl, 408 (1970).

U.S. Patent No. 3,511,836 discloses several methods for preparing 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline. For example, by reacting 2-chloro-4-amino-6,7-dimethoxyquinozoline with 1- (2-furoyl) -piperazine, by reacting 2- [4- (2-furoyl) piperazin-1-yl] -4 -chloro-6,7-dimethoxy-quinazoline with ammonia or by acylation of 2- (1-piperazinyl) -4-amino-6,7-dimethoxyquinazoline, for example with 2-furoyl chloride.

U.S. Patent No. 3,935,213 discloses methods wherein 2- (4-substituted-piperazin-1-yl) -4-amino-6,7-dimethoxy-quinazolines, including 2- [4- (2-furoyl)] -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline is prepared either (1) by reaction of 4,5-dimethoxy-2-aminohenzonitrile with corresponding 1,4-disubstituted piperazines or (2) by reaction of 4,5-dimethoxy-2-aminobenzamide with the same 1,4-disubstituted piperazines.

A special process has now been found whereby 2- [4- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline can be obtained in greater yield than by the above-mentioned known methods.

This process consists in the catalytic hydrogenation of the novel compounds of the invention, which are characterized in that they have the formula II as defined in claim 1.

A particularly preferred compound of the invention is 2- [4- (5-bromo-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline.

A particularly preferred embodiment of said process is carried out using a compound of formula II wherein n is 1 and X is chlorine or bromine at a temperature of 25-100 ° C in the presence of at least n-1 mole of an acid binding agent. agent having a pK of 7 or less and in the presence of a catalyst which is palladium or palladium on coal or a mixture of 98 - 99.9 parts by weight of palladium and 0.1 - 2 parts by weight of platinum, ruthenium or rhodium . Most preferred is a process wherein the compound of formula II is 2- [4- (5-bromo-2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline, the catalyst being palladium, and the reaction. is carried out in the presence of at least one equivalent of triethylamine as an acid binding agent.

The process for preparing the valuable agent, 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline (I), by catalytically dehalogenating the compounds of the formula (II) can be illustrated by the following reaction scheme: CH 3 O,,, / Λ-. JpHxln ^ / ΥϋΠ

YV yv / jwY YW

ch3o T CK3O 7

,., ΙΙ ... I

wherein X is chlorine, bromine or iodine and n is 1, 2 or 3. The process is carried out by reacting the compound of formula (II) with hydrogen in the presence of a dehalogenation catalyst.

By the term "dehalogenation catalyst" is meant a catalyst which will promote selective replacement of halogen with hydrogen under the process conditions to form the product (I) without substantial hydrogenation or hydrogenolysis of the furan and quinazoline moieties of the starting material and product.

The dehalogenation catalyst used in the process can be of the supported or unsupported type 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 sulfate. These catalysts can be prepared in advance or formed in situ by prior reduction of a suitable oxide or salt of the catalytic compound. Pre-reduction is performed simply by suspending the catalyst precursor in the hydrogenation medium, hydrogenating it, adding the substrate and continuing the hydrogenation. Alternatively, all the components can be incorporated at once and hydrogenation is started. The former procedure has the advantage of allowing the technician to separately determine the amount of hydrogen absorbed during the catalyst pre-reduction and hydrogenation phase. The degree of hydrogenation can thus be easily controlled.

Among the suitable dehalogenation catalysts which can be used in the process are finely divided metals such as cobalt, nickel or copper. The preparation and use of such catalysts are disclosed in Freifelder, "Practical Catalytic Hydrogenation", John Wiley and Sons, Inc., New York, 1971 and references cited therein.

The catalysts for use in the process are palladium, copper, cobalt, nickel and mixtures of palladium with platinum, ruthenium or rhodium. Although any of the mentioned palladium containing mixtures and any of the other metals in which the palladium to platinum, ruthenium or rhodium weight ratios vary over a wide range are useful, mixtures consisting of 98 - 99.9 parts by weight of palladium and 0 are preferred. , 1 - 2 parts by weight of platinum, ruthenium or rhodium.

The catalysts are used in "catalytic amounts", a term understood by those skilled in the hydrogenation technique and are illustrated in the following examples; see also Freifelder, loc. cit., pages 79-81. However, it is generally preferred to use 1 to 40% by weight of catalyst, based on the weight of the starting compound of formula (II).

The process is carried out in the presence of a reaction inert solvent. A suitable solvent is one which will serve to substantially dissolve or disperse the reactants and will not adversely affect the reactants, product or catalyst. 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, -dimethylformamide and N, N-dimethylacetamide as well as mixtures of such solvents with water.

The hydrogen pressure used in the catalytic dehalogenation is not critical, but depends primarily on the apparatus used. In general, atmospheric pressure is preferred to about 140 kp / cm. As is well known, hydrogenation at atmospheric pressure is generally carried out in equipment in which a measured volume of hydrogen contained in a reservoir is connected to a pressure gauge to determine the volume of hydrogen consumed. Alternatively, a magnesia citrate bottle (Parr bottle) and mechanical shaker may be used with a calibrated pressure sensor such as a Parr hydrogenation apparatus or a high pressure agitated or shaken type autoclave.

The dehalogenation is carried out at a temperature in the range 0 - 150 ° C. A particularly preferred temperature range is 25-100 ° C.

When carried out with a compound of formula (II) alone, the first formed product is the hydrohalide addition salt of compound (i). This can be isolated as such or can be 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 into a water immiscible solvent such as ethyl ether, chloroform or methylene chloride. Alternatively, the process may be carried out in the presence of an acid-binding agent to directly provide the free base of the compound (I) and the halide salt of the acid-binding agent.

By the term "acid binding agent" is meant a basic compound which, when added to the reaction mixture, reacts selectively with the released hydrogen halide to form a halide salt without producing substantial by-product formation upon further reaction with the reactant or product and having little or no reaction. no detrimental effect on the catalyst used. In order to successfully compete for the silica halide formed during the process, the acid binding agent must be a stronger base than both the reactant of formula (II) and product (I), i.e. it must be a base with pKfe of 7 or less.

144475 6

Examples of suitable acid binding agents are arnins 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, e.g. of sodium, potassium, magnesium, calcium and barium. Especially preferred as an acid binding agent for convenience, economy and efficiency is triethylamine.

The acid binding agent is preferably used in an amount that is at least sufficient to neutralize n-1 mole of hydrogen halide per liter. m is the number of halogen atoms per mole of the compound (II), where n moles of starting material of formula (II), i. n is 1, 2 or 3. When the amount of the acid binding agent is at least equivalent to the amount of hydrogen halide formed, the product is the free base of formula (I). In such cases, if desired, an excess of acid binding agent may be used. Alternatively, when n-1 equivalents of the acid binding agent are used per day. mole of compound (II), the product obtained is the hydrogen halide salt of the compound of formula (I). For example, if in the starting material of formula (II) X is chlorine, n is 3 and two equivalents of acid binding agent are used. mole of compound (II), the product obtained is the hydrochloride salt of compound (i).

If one wishes to use an acid binding agent in the process, it is preferred that at least one equivalent of acid binding agent is used per day. mole of compound (II).

The time required for the dehalogenation to substantially complete will vary with factors such as temperature, catalyst and the precise nature of the starting material of formula (II). Generally, however, the dehalogenation will be substantially complete in about 0.5 to about 24 hours.

As mentioned above, the final product of the process may be either the free base of formula (I) or the hydrochloride, hydrobromide or hydroiodide thereof. Any of these products, if desired, can be further isolated and purified by methods well known to those skilled in the art. For example, the free base can often only be isolated by evaporation of the solvent, after removal of the catalyst by filtration, upon which the product precipitates or can be precipitated by the addition of a non-solvent such as hexane or heptane. The free base can be further purified by methods such as recrystallization or column chromatography on silica gel. If the product obtained is one of the above hydrohalide salts of compound (i), it can be converted to the free base and isolated as described above, or the hydrohalide salt can be isolated by heating the reaction mixture to dissolve the hydrogen halide, the reaction mixture is filtered to remove the catalyst. and the filtrate is then concentrated to a small volume and cooled, whereupon the desired product is usually precipitated. If desired, it can be further purified, e.g. by recrystallization.

The compounds of the invention of formula (II) can be prepared analogously to any of the known methods described above for the preparation of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxy-quinazoline using the corresponding halogen-substituted starting material in each case. The preferred methods for preparing the compounds of formula (II) are those illustrated below as Method A and Method B.

METHOD A

OH ° yyV + / "“ \ ιτ ^ ίΗ'η - ^ 1 »l ir hn» - CH-, 0 3 NH2 tv

... III

MET0DE_B

ch3PyvOkh + * (II)

ch3 ° I

J nh2 ... v ±

..V

In each of the compounds of formulas (III) and (Vi), A is chlorine or bromine, X is chlorine, bromine or iodine and n is 1, 2 or 3. The compounds of formulas (III) and (V) can be prepared by methods described in U.S. Patent No. 3,511,836. The acyl halides of formula (VI) are prepared from the corresponding halogenated 2-furancarboxylic acids by well known methods, e.g. by reacting the acids with an excess of thionyl chloride or thionyl bromide, followed by evaporation of the reaction mixture. From the halogenated furancarboxylic acids from which the compounds (VI) are derived, 5-bromo-2-furancarboxylic acid is commercially available. The remaining chloro and bromfuran carboxylic acids are prepared by methods described by Shepard et. al., J. Am.Chem.

Soc., 52, 2083 (1930) and Gilman et al., Ibid., 5Ί, 1146 (1935) and references cited therein. The iodofurancarboxylic acids are prepared from the corresponding iodofurfurals by oxidation with alkaline peroxide by the method described by Borisova et al.

Chem. Abstr., 73, 3513f (1970), or by the method described 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 a quimolar amount of piperazine, is reacted with the compound of formula (III) in approximately quimolar amounts in the presence of of a reaction inert organic solvent. The reaction can be carried out over a wide range of temperatures, but a temperature in the range of 50-150 ° C is preferred. The reaction is usually carried out 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) by standard methods. Alternatively, the reaction may be carried out alkaline, e.g. 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 method are alkanols such as ethanol, n-butanol, isoamyl alcohol, n-hexanol or cyclohexanol, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, diethyl-englycol 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 the compound of formula (VI) in the presence of a reaction inert organic solvent.

The reaction is usually carried out at a temperature of between -20 and 100 ° C. Examples of suitable solvents for use in this method are those set forth above for method A. The reaction is usually completed in a few minutes to 10 hours. The desired product is isolated by standard methods, e.g. adjusting the reaction mixture to an alkaline pH by adding an aqueous base, e.g. sodium hydroxide, potassium hydroxide or sodium carbonate, extraction of the product with a water-immiscible solvent such as chloroform or methylene chloride, and evaporation of the solvent.

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

The following examples serve to illustrate the invention. Example 1 illustrates the preparation of the novel intermediates of formula (II), and Example 2 illustrates their catalytic dehalogenation to form the midicinally valuable end products of formula (I).

EXAMPLE 1 [11: 5-bromo-2-furoyl] piperazin-1-yl] = 4-amino-6,7-dimethoxy-2-quinazoline

To a flask containing 19.1 g (0.10 mol) of 5-brcm-2-furanecarboxylic acid in 100 ml of chloroform was added 20 g of thionyl chloride and the resulting mixture was stirred at room temperature for 2 hours and then allowed to stand overnight. The volatiles 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 (0.10 mol) of piperazine in 50 ml of the same solvent. The addition required about 30 minutes. The resulting mixture was stirred at room temperature for an additional 1 hour and then made alkaline by the addition of 2N sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted again 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 crystallized from methylene chloride / ethyl acetate, mp: 113 - 115 ° C.

Analysis calculated for CgHH₂ 2₂W₂Br: - - -> - 72 - H 4.28 - N 10.81 -

Br, 30.84 found: C, 41.44; H, 4.35; N, 10.66 -

Br, 30.49.

Into a reaction vessel was placed 9.55 g (0.04 mole) of 4-amino-2-chloro-6,7-dimethoxyquinazoline prepared by the procedure of U.S. Patent No. 3,511,836, 200 ml of isoamyl alcohol and 20.7 g (0 (08-mol) of the 1- (5-bromo-2-furoyl) piperazine prepared above.

The resulting suspension was heated at reflux for 90 minutes, then cooled, filtered and washed with ethanol to give 21.8 g of crude hydrochloride salt of the above compound, which melted during decomposition at 276-278 ° C.

This was suspended in 200 ml of ethanol and 2N sodium hydroxide solution was added to dissolve the substance. 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, mp: 206-209 ° C. This was dissolved in a mixture of chloroform and methanol, dried over sodium sulfate, treated with charcoal, and the solvent replaced with ethyl acetate. Crystallization yielded 9.8 g (53%) of purified product, mp: 213 - 215 ° C.

Calcd. For C, qH-β ^ uO, 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 Example 2 Into a Parr pressure flask is placed 1.0 g (2.16 nmol) of 2- [4- (5-bromo-2-furoyl) piperazin-1-yl] -4-amino-6, 7-dimethoxyquinazoline, 10 ml of methanol, 1.0 ml of triethylamine and 0.4 g of 5% Pd-on-charcoal (50% humid). The bottle was placed in a Parr shaker and placed un- 2.

that pressurized with hydrogen to 3.5 kp / cm at room temperature. After shaking for 18 hours, the theoretical amount of hydrogen was absorbed. The mixture of catalyst and precipitated product was filtered off, the solid suspended in 25 ml of chloroform and filtered again to remove the 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 on a 41.5 x 7.6 cm column of silica gel and eluted with ethyl acetate / diethylamine (volume ratio 90 : 10) to give 300 mg of 2- [4- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoin, m.p. 266 ° C which was identified by comparing the infrared spectrum in chloroform with the spectrum of an authentic sample and by thin-layer chromatography on silica gel.