CS202074B2 - Method of producing 2-/4-/2-furoyl/piperazin-1-yl/-amino-6,7-dimethoxy-quinazoline - Google Patents

Abstract

Novel compounds of the general formula II <IMAGE> 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

The present invention relates to a novel process for the preparation of 2 '- {4-72-furolyl-piperazin-1-yl] -4-amino-6,7-dimethooyl-quinoline which is valuable because of its ability to lower the blood pressure of hypertensive mammals. U.S. Patent No. 3,511,836]. Furthermore, the invention discloses certain novel menodines, such as 2 ', 4' - (halogeno-2-fluoroyl) -piperazin-1-yl] -4-amino-1,7-dimerhooylCinaaoliay, which are useful as starting materials for work according to the invention.

U.S. Pat. No. 3,511 1,836 discloses several processes for the preparation of 2- [4- (2-furlyl) trans-1-yl-2,4-amo-1,7-dimethoxyquinazoline, such as the reaction of 2-chloro-4 '. amino-6,7-dimethoyychiMzolinu with ^1- / ^{2-f i} urlylip ^{peaazi.eem, the} rea tion ^{of 2} - [4 · 7 ² - urlyl ^{F /} i ⁱ ieraoio- ¹ -yl ^ -chter ^{-6, 7} - dimethyloquinazoline with ammonia or acylation of 2- (1-fluorooloyl) -4-amino-1,7-dimethoxyquinazoline, for example 2-furlyl chloride.

U.S. Pat. No. 3,935,213 describes methods in which 2- / 4-subst. piitraoyoyl-1-yl] -4-amino-6,7-dimethoxyquinoaolines, including 2- [4 '(2-furlyl) -thiazol-1-yl]] 4-amino-1,7-dimethooyquinazoline, manufactured by bud

1) reaction of 4,5-dimethoxy-2-aminoOeroonitrile with certain 1,4,4-disubstituted prazines, or

2) by the reaction of 4,5-dimethylamino-2-amino-benzoamido with the same 1,4-disubstituted aminoazines.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of 2- [4- (2-furlyl) trans-1-yl] -4-amino-1,7-dimethoxycarbonyl.

/ 1 /,

NHg or its hydrochloride, hydrobromide or hydroiodide, characterized in that the compound of formula (II)

.....

NH ₂ .

in which .

X is chlorine, bromine or iodine, reacted with hydrogen in the presence of a catalytic amount of a dehalogenation catalyst, optionally supported on a noosilane selected from the group consisting of palladium, copper, cobbat, nickel and palladium-8 platinum, ruthenium or rhodium, in the presence of an inert solvent at a temperature of from 0 to 150 ° C and optionally in the presence of an acid binding agent.

In contrast to the processes known in the art, the process of the invention has the main advantage that it provides considerably higher yields of the desired product. *

A particularly preferred embodiment of the process according to the invention consists in:. If the starting material used is a compound of the above formula (II) in which X represents - chlorine or bromine, the reaction is carried out at a temperature of from 25 to 100 ° C, optionally in the presence of at least 1 mol of an acid acceptor and in the presence of a palladium or palladium-on-catalyst catalyst, or a mixture comprising 98 to 99.9 parts by weight of palladium and 0.1 to 2 parts by weight of platinum, ruthenium or rhodium. According to a particularly preferred embodiment, 2- [4- (5-bromo-2-furoyl) piperazin-1-yl] -4-amino-4-methyl-4-quinazoline is used as the starting material of the formula II The palladium and the reaction is carried out in the presence of at least one equivalent of trielhylammonium as an acid acceptor.

The process according to the invention is suitable for the preparation of 2- [4- (2-furyl) piperazin-1-yl] -4-amias-6,7-trimethoxycinazoline, known under the designation prazos. It has been shown that prazosin can be used therapeutically in human meedcin [see Cohan, Journal of Pharmacology, J_0, 408/197 ^ //].

The invention also includes novel useful starting materials of formula II wherein X is as defined above. A particularly preferred starting material is 2- [4- (5-bromo-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxycilalazo.

The process is carried out by treating a compound of formula II with hydrogen to form a dehalosilane catalyst and as defined herein. The term dehalogenation catalyst refers to a catalyst which affects the selective replacement of halogen with hydrogen under the conditions of the process to produce a compound of formula (I) without hydrogenating or hydrogenolyzing the furan or illinic portion of the parent compound and the product.

The dehalogenation catalyst used in the process of the present invention may be unsupported or supported, and may be palladium. copper, cobbat or nickel, or a mixture of palladium with platinum, ruthenium or rhodium. Examples of suitable catalyst carriers include potassium, barium oxide, calcium and calcium, and barium sulfate. These catalysts may be prepared in advance or may be prepared in situ prior to reduction of a suitable oxide or salt of the catalyst compound. This pre-reduction is effected simply by suspending the catalyst compound in a hydrogenation medium, with the addition of a carrier, and continuing hydrogenation. Otherwise, all 3 components can be added all at once and hydrogenated. The foregoing process has the advantage that it allows the worker to separately identify the ammunition of hydrogen that has been absorbed during the preparation of the catalyst and many times. of hydrogen of its own phase hydrogenated. The extent of hydrogenation can then be easily controlled,

Suitable dehalogenation catalysts useful in the process of the present invention include metals such as coball, nickel, methane, and mixtures thereof, in bulk. The preparation and use of such catalysts is described in Freifelder ' s Working Chemical Caecaltic Hydcogenaion, J. Wiley &amp; Sons, New York, 1971, and references therein to other work.

Catalysts for carrying out the process of kobaat, nickel and palladium / platinum mixtures, any of said mixtures comprising a palladium to platinum ratio of ruthenium or rhod of a preferred composition containing 98 to nia or rhodium by weight.

The catalysts used in the process, which is well known to those skilled in the art, Freifelder, the above-mentioned book, pages 79 to 1-40 of the catalyst, calculated according to the invention, are mainly palladium, honey, ruthenium or rhodium. Although one of the other metals mentioned can be used where the mass may bite in a wide range,

99.9 parts of paiadium; 2 parts of platinum according to the invention in catalytic capacities and is exemplified in the appended examples. See also 81. In general, however, it is preferred to use. by weight of the starting compound of formula (II).

The process according to the invention is carried out under an inert solvent under the reaction conditions. A suitable solvent is any one that substantially expands or disperses the reactants without reacting undesirably with them, without reacting with the products or catalyst formed. Examples of usable solvents include lower alcohols such as 1, 2-propanol, ethanol, 2-propanol, 1-n-butanol, isobutanol and isoamides, as well as cyclic and acyclic ethers when soluble in water. such as dioxane, tetrahydrofuran, diethylene glycol methyl ether, 2-methoxyethanol, N, N-dimethylformamide and Ν, Ν-dimethylacetamide, and mixtures of such solvents with water.

The pressure offered by the hydrogenation of the present invention is not particularly important, and is primarily dependent on the equipment used. In general, pressures from atmospheric up to 13.73 MPa may be used as preferred. hydrogenation at atmospheric pressure generally in a device where the measured volume of hydrogen contained in the reservoir is connected to a pressure gauge to measure the volume of hydrogen consumed, otherwise a citrate or magnesium flask (Parr flask) or mechanical shaker can be used. The apparatus 8 may be calibrated by a pressure scale such as a Parr hydrogenation apparatus or may be operated in a high-pressure autoclave with stirring or shaking.

Dehalogenation procedure of the invention. is carried out at a temperature ranging from 0 to 150 ^o C. A particularly preferred dimension ^: ne temperature ranges from 25 to. 100 ° C.

When the process of this invention is carried out with the compound of formula IX as such, then the acid salt of the compound of formula 18 is obtained as the product. The salt may be isolated as such or may be converted into the free base by treatment with an aqueous solution of an inorganic base such as sodium hydroxide or potassium hydroxide with the following. or by extracting the base into a solvent immiscible with water, such as ethyl ether, chloroform or carbon tetrachloride. Alternatively, the process of the present invention can be carried out with an acid-binding agent, thereby directly isolating the free base of formula (I), and the salt of the halo-hydronic acid and the substance used to bind the acid. The acid is a base compound which is added to the reaction mixture and used in the process of the present invention, reacting selectively with the hydrogen halide which is used in the reaction. and to form a salt. Further, the reaction of the reactants or products takes place without any significant formation of by-products, furthermore the added substance has little or no effect on the catalyst used. In view of the perfect bonding of the hydrogen halide formed in the reaction according to the invention, the stronger base is to be used as the acid-binding substance. than a compound of formula II or the product of formula I, I know ^ i ^ and _F that Torn be based on the value of the pK ^ 7 or less.

Examples of suitable acid binding agents include amines such as triethylamine,

N-methylpyrrolidine, triethanolamine, n-butylamine, benzylamine, isoammonium, morpholine and piperidine, as well as ammonia, hydrazine and oxides or hydroxides of alkali or alkaline earth metals such as oxygen or sodium hydroxide, potassium, magnesium, calcium and barium.

In terms of efficiency, economy and efficacy, triethylamine is a particularly preferred acid binding agent. .

Thus, when an acid-leaching agent is used in the reaction of the present invention, at least in an equivalent amount relative to the amount of hydrogen halide formed, the compound of formula Г is obtained as the free base. When working in the absence of an acid binder, a salt of the compound of formula I with a hydrohalogenic acid is formed as the product.

Thus, for example, starting from a compound of formula (II) in which X is chlorine and working in the absence of an acid acceptor, the hydrochloride of the compound of formula (1) is obtained as the product.

If it is desired to work in the presence of an acid acceptor, at least one equivalent of the acid acceptor is preferably used for each mole of the compound of formula II.

The reaction time required for the virtually complete process of the dehalogenation according to the invention varies depending on various factors, such as the reaction temperature, the catalyst and the nature of the starting material of formula II. Usually, however, dehairgenation is virtually complete in about 0.5 to 24 hours.

As mentioned above, the reaction according to the invention can be produced as a product of the compound of formula (I) in the form of a free base or in the form of a hydroquinone, hydrobromide or hydroiodide. Any of these products. they can be isolated and optionally further purified in a known manner. For example, the free base can often be isolated by mere evaporation of the solvent (after filtering off the catalyst) after which the product is precipitated, or the free base can be precipitated from the reaction mixture by addition of a substance in which the product is n-shredded, such as hexane or heptane. The free base can be further purified by various methods, such as recrystallization or silica gel column chromatography. If any of the above-mentioned hydrogenic compounds of the formula I are formed in the reaction according to the invention, it can be converted to the free base and then recovered in the manner described above, or the hydrogenic acid can be isolated by heating the reaction mixture so that The filtrate is concentrated to a small volume and cooled, whereupon the desired product usually precipitates. Optionally, the resulting hydrohalogenide can be further purified, for example by recrystallization.

The starting materials of the formula - II, in which X is as defined above, are novel compounds. These compounds may be prepared by any of the known methods described above for the preparation of 2- (4- (2-furoyl) piperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline using the appropriate hair-starting compounds. . Preferred methods for preparing the compounds of formula (II) are described below as A, respectively. B,

After step A

NHa (III) (iv) (II)

Procedure В

nh ₂

-in

СОА (V) (VI) (и)

In the compounds of formulas III and VI, A is chlorine or bromine. X is as defined above. Compounds of formulas III and V may be prepared by the methods described in U.S. Patent No. 3,511,836. Acyl halides of formula VI are prepared from the corresponding halogenated 2-furoic acids by known methods, for example by reacting such acids with an excess of thionylyl chloride or thionyl bromide with The 5-bromo-2-furoic acid is commercially available from the halogenated furoic acids from which the compound of formula (VI) is prepared, the other chlorinated and thrombinated furoic acid derivatives are added according to the procedures described by Shepard et al. in J. Arnmr. Chem. Soc.

·. 5. 2,083 (1930) and GUman et al., J. Amme, Chem. Soc. 5 7, 1146 (1935); other references are cited there. Iodinated furoic acid derivatives are prepared from the corresponding iodinated furfural derivatives by oxidation with an alkali metal peroxide using the procedures described by Boris et al., Chem. Abstr. 73, 35, 34f (1970) or by the procedure of Sornay et al., Vol.

Soc. Chim. France, 1971, 990.

when process A, the 1-sulfated piperazine derivative of formula IV, which can be prepared from the above acid halide of formula VI and equimolar piperazine, is treated with a compound of formula III in about ЬЬ. The reaction is carried out in the presence of an organic solvent inert to the reaction conditions. The reaction can be carried out over a wide temperature range, but a temperature range of 50 to 150 ° C is preferred. The reaction is usually complete in 1 to 24 hours, and the product can be isolated in the form of the hydrochloride or hydrobromide, and then the isolated salt is converted to the free base of formula (II) using conventional procedures. Alternatively, the reaction mixture may be alkali. For example, sodium or potassium hydroxide may be added, and then the free base is isolated by extraction into a solvent and separating it. Examples of suitable solvents which are inert under the reaction conditions include, for example, alkanols such as ethanol, n-butylalcohol, isoamyl alcohol, n-hexyl alcohol or cyclohexanone, furthermore N, N-dimethylformamide, N, Nd imetohols, di-6-sulfosulfoxide, diethyl ether of di-cyclohexyl, n-butylithirethylene glycol, chloroform or MeOH.

When procedure B was followed, the compound of formula V was treated with an equal amount of the compound of formula VI in the presence of a suitable organic solvent inert to the reaction conditions. The reaction is preferably carried out at a temperature of from -20 ° C to 100 ° C, and examples of suitable solvents for this process include the same solvents as described above for Process A. The reaction is usually completed in a few minutes to 10 minutes. · Hours. The expected reaction product is isolated using conventional procedures such as adjusting the pH of the reaction mixture to an alkaline region by adding an aqueous solution of a base such as sodium hydroxide, potassium hydroxide or sodium carbonate, and then extracting the product into a water-immiscible solvent. such as chloroform or belhhleenChori.d, and the solvent is distilled off.

For reasons of economy and efficacy, compounds of formula II are particularly preferred where X is chlorine or bromine. A particularly preferred compound is 2- [4- (5-Srob-2-fluoro) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline.

Other examples, which are not intended to limit the scope of the invention in any way, describe and illustrate in more detail the process of the invention. Examples 1 and 2 describe the preparation of the novel intermediates of formula (II) and describe examples 3 to 6. the process of the invention.

EXAMPLE 1 ^{2 '(4/5-Bromo-2- f} urρyl / iiizrazín-1-yl] -4-aminp-6, ^7-d ime thoKychinazolin

To a solution of 19.1 g (0.10 md) of 5-bromo-4-furoic acid in 100 ml of chloroform was added 20 g of thipnyl chloride, and the resulting reaction mixture was stirred at room temperature for 2 hours. let it stand overnight. The volatiles were then separated in vacuo to give 5-bromo-2-furoyl chloride. This was dissolved in 50 ml of methylene chloride, and at 25 ° C, this solution was added dropwise to a solution of 8.6 g (0.10 moo) piperazine in 50 ml of the same solvent. It takes about 30 minutes. The reaction mixture was stirred for an additional hour, added with 2N sodium hydroxide solution, the organic layer was separated and the aqueous solution was extracted again with methylene chloride. After drying the solution in an organic solvent with anhydrous potassium carbonate and filtration, the solvent is distilled off to dryness, and 23 g of 1- (5-bromo-2-furoyl) -piperazine are obtained as a residue. A portion of this material was recrystallized from a mixture of methyl methacrylate and ethyl acetate; mp 113-115 ° C.

Andl / za:

for C 8 H 10 O 2 N 2 Br calculated: 41.72% C, 4.28 7 H, 10.81 N, 30.84% Br; Found: 41.44 7. C, 4.35% · H, 10.66 7 N, 30.49 7. Br.

A mixture of 9.55 g / 0.04 mol 1/4-amino-D-2-chloro-6,7-dimethoxyquinine prepared from the procedure of U.S. Pat. No. 3,551,836, 200 ml of isoamylae 20, 7 g (0.08 mol) of (1- (5-bromo-4-furo) -4-piperazine, as prepared above, are heated in the suspension for 90 minutes at reflux, whereupon the reaction mixture is estimated The precipitate was filtered and washed with ethanol to give 21.8 g of crude hydrate (1: 1) of the title compound, which melted at 276 DEG-278 DEG C. with decomposition and stirred in 200 ml of ethanol. and, by adding 2 N sodium hydroxide solution, the suspension is brought into solution, the solution is vacuum-fed to a small volume, the residue is <2 h 1 ad i, the solid is filtered off, and washed with water followed by drying to give 18, 8 g of product, m.p. 206 DEG-209 DEG C. This is dissolved in a mixture of chloroform and methanol, dried over anhydrous sodium sulphate and, after decolourisation with activated carbon, dissolves. The product is replaced by ethyl acetate and 9.8 g (53%) of pure product is isolated from m.p. 213-215 ° C.

AAdysis:

for C 19 H 20 N 5 _O 4 Br calculated: 49.36 7 C, 4.36 7 H, 15.15 7 N, 17 7.28 7 Br; found: 48.70% C, 4.36 ZH, 14.87 ZN, 16.87 Z Br.

P Pikl a d 2

2-O4- (3-Chloro-2-phenyl) piperazinyl} -amino-6'-diethyloxyhinooolil

The reaction of 3-chlorofuran-2-carboxylic acid, prepared according to the procedure of Shepard et al., Is carried out with an excess of toluene at room temperature, and further concentration of the solvent in vacuo yields the acid chloride residue.

To a solution of 28.9 g (0.10 mh) of 2- (1-piperazinyl) -4-ailo-6,7-diolomethyl-cinnamoline prepared according to U.S. Pat. No. 3,511 1,836 in 300 ml of methanol is added during 30 minutes with vigorous stirring 16.5 g (0.10 mol) of the above acid chloride, and the resulting reaction mixture is stirred for an additional 3 hours at a temperature of тоШ. The solvent was removed in vacuo, and the residue was stirred in an aqueous solution of 2 N sodium hydroxide, the organic layer was separated, dried over sodium sulfate and concentrated to dryness to give the title compound, m.p. the composition is given in the title. .

When thionyl bromide is used instead of thionyl chloride in the above procedure, and the prepared acid bromide is reacted with 2- (1-piperazinyl) -4-amino-6,7-dimethoxyquinazoline, the results are essentially the same.

Example 3 '

1.0 g (2.16 mmoo) 2- 4- / 5-bromo-2-furoul / piperazin- is mixed in a Parr shaker.

1-yl-4-amine-6,7-dimethoxyquinazoline, 10 ml of methanol, 1.0 ml of triethylamine and 0.4 g of 5% palladium on carbon (50% moisture). Place the flask in a Parr shaker, pressurize the hydrogen to 0.34 MPp. The theoretically calculated amount of hydrogen is consumed after 18 hours, then the catalyst / precipitated product is filtered off, the solids are taken up in 25 ml of chloroform, and the catalyst solution is removed from the product solution, 50 ml of the filtrate are added. hexane, the mixture is stirred for 10 minutes, then the crude reaction product is isolated by filtration, which is purified by chromatography on a silica gel column 45 x 7.5 cm eluting with ethyl acetate / diethylamine (90:10 by volume); 300 mg of 2- [4- (2-furyl) piperazin-1-yl-4-amino-6,7-dimethoxychanazoline, mp 266 ° C, was identified by comparing the infrared spectrum in chloroform with the spectrum of the authentic sample as well as by thin layer chromatography on silica gel.

Example 4

In a vessel for hydrogenation at atmospheric pressure, 4.18 g (.0.01) moo / 2- (4- / 3-

- (1 - (- 2 -) - piperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline, 75 ml 95% ethanol, 0.50 g / 0.10 moo The reaction mixture was cooled to 0 [deg.] C. and concentrated for 4 hours at atmospheric pressure, then the catalyst was filtered off from the reaction mixture, and the filtrate was concentrated in vacuo. The organic layer was dried over sodium sulfate, and concentrated to dryness to give 2- [4- (2-fluoro) -piperazin-1-ene-4a-cyclo-6,7-dimethoxyquinazoline]. which is purified by column chromatography on silica gel.

Again, but using 0.5 g of catalyst containing at least 99.9 parts of paliadium and 0.1 parts of platinum, the results are essentially the same,

^In auto PříkladS ^monastery vu 500 ml at ^{9.24 g} ííti ^ ^{/ 0} ° ^{for 2} m ^ ^/ ^^ - M-bromo-furo ^ ^ erazto Vp ^-

1-yl] -6-amino-4-dimethoxycyclohexene, 2.0 g of 50% wet R-nickel nickel and 200 ml of 70% ethanol (ethanol / water 7: 3 by volume). The reaction mixture is maintained at 100 ° C for 30 minutes under a hydrogen pressure of 1, 373 MPp; After cooling to the temperature of methanol, the catalyst is filtered off, the filtrate is filtered off with ethanol, the concentrate is taken up in potassium carbonate and the product is extracted into chloroform, whereupon the chloroform extracts are concentrated to dryness to give 2- ( The product may be further purified by column chromatography on silica gel (4- (2-fluoroyl) -piperazin-1-yl) -4,7-dimethyl-6,7-dimethoxycarbonyl.

EXAMPLE 6

4.18 g (0.0 1 moo) was placed in the hydrogenation apparatus at the atoooeric pressure.

2- [4- [4-Chloro-2-iurlyl] piperazin-1-yl] -4a-yno-6,7 &quot; phenoxycycloalzoline, 200 ml isoaoylCaltool and 0.20 g of powdered catalyst containing 99.9 parts of palladium and 0; , 1 part rhodium / holocot /. The reaction mixture was hydrogenated with vigorous stirring for 2 hours at atmospheric pressure; during this time, the theoretical amount of hydrogen is consumed, after which the mixture is poured from the apparatus itself, heated to boiling and the catalyst is filtered off while hot. The filtrate was cooled in ice, and the precipitated 2- (2-furocyl) -piperazolin-1-yl] -4-oxo-6,7-dihydro-oxycanazoline was separated by filtration.

When repeat the above procedure, but using 0.01 mol of 2- [4- / 5-bromo-2-furoyl / piperazin-1 l У1] 1 4-Amino ° 6, ⁷ instead of dimethyl thoxychinazoli.nu ppoíci da ^ í. 4-chloro him ^{about ri2-furo} ylideirí ^the carboxylate, is isolated: 2- [4- / 2lfuroy1 / aiaerazin-l-yl-6,7 i4iamino "dimethoxyquinazoline similar way

Claims (5)

SUBJECT OF THE INVENTION 1. A process for the preparation of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline of the formula I nh ₂ (1), or its hydrochloride, hydrobromide or hydroiodides, is characterized by reacting a compound of formula II nh ₂ (II) in which X is chlorine, bromine or iodine with hydrogen in the presence of Uatalyti. show the use of a dehalogenated catalyst, optionally supported on a catalyst selected from the group of palladium, copper, cobalt, nickel and mixture i paladium with platinum, ruthenium or rhodium, in the inert solvent at temperature from 0 to 150 ° C and optionally in an amount of acetic acid. 2. Mp 100 ° C. The method of item 1 characterized in that the reaction is carried out at a temperature of from 25 to 25 ° C 3. pK _b is; The method of item 1 1 or less. or 2, as indicated wherein an acid acceptor is used 4. Method according to point 3 , you from nn learn by that at least one equivalent of accep- of acid of each mole of the compound of formula II. 5. A process according to any one of claims 1 to 4, wherein the catalyst is palladium or palladium on carbon. 6. The process according to any one of claims 1 to 4, wherein the catalyst is a mixture comprising 98 to 99.9 parts by weight of palladium and 0.1 to 2 parts by weight of platinum. ruthenia or rhod ia. 7. A process according to any one of claims 1 to 6, wherein X is chlorine or bromine. 8. A process according to any one of Claims 1 to 7, wherein at least 1 equivalent of trielhylamine is used as the acid acceptor.