KR810001414B1 - Process for preparing 2-(4-(2-furoyl)piperazine-1-yl)-4-amino-6,7-dimethoxy quinazoline - Google Patents

Abstract

2-[4-(2-FUROYL)PIPERAZIN-1-YL -D-amino-6,7-dimethoxyquinazoline (I) or its HCL, HBr or Hi salts are prepd. by contacting (II) with H2 in the presence of a dehalogenation catalyst. X is Cl, Br or I and n is 1-3. Pref. the catalyst is Pd, Cu, Co, Ni, Pd/Pt, Pd/Ru or Pd/Rh and reaction is at 0-150, esp. 25-100oC, in an inert solvent. (I) is a known hypotensive agent (prazosin).

Description

Method for preparing 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxy quinazoline

The present invention relates to a novel process for the preparation of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazolin. This compound is used to lower blood pressure in hypertensive mammals and its use is known.

The invention also provides a novel starting product 2- [4- (halogenated-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxy, which is a useful starting material for the process of the invention. It relates to quinazolines.

Various methods are known for the preparation of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazolin.

For example, 2-chloro-4-amino-6,7-dimethoxyquinazolin can be reacted with 1- (2-furoyl) -piperazine, or 2- [4- (2-furoyl) piperazine -1-yl] -4-chloro-6,7-dimethoxyquinazoline with ammonia or 2- (1-piperazinyl) -4-amino-6,7-dimethoxyquinazoline 2- There is a method of reacting with something like furoyl chloride.

The methods are known in US Pat. No. 3,935,213, so that 2- (4-substituted with 2- [4- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-methoxymethoxyazolin -Piperazin-1-yl] -4-amino-6,7-dimethoxyquinazolins are produced by one of the following: (1) 1,4 to 4,5-dimethoxy-2-aminobenzonitrile -Disubstituted piperazines or (2) 4,5-dimethoxy-2-aminobenzamidine can be prepared by reacting with the same 1,4-disubstituted piperazines.

The present invention provides a compound of formula (III) in the presence of a dehalogenation catalyst such as a mixture of hydrogen and a catalytic amount of supported or unsupported palladium, copper, cobalt, or nickel or palladium angle platinum, ruthenium or rhodium, 2- [4- (2-furoyl) piperazin-1-yl] -4-amino- consisting of reacted in the presence of an inert solvent and, if desired, in the presence of an acid acceptor at a temperature of about 0 ° to 150 ° C. A novel method for the preparation of 6,7-dimethoxyquinazolin or its hydrogen chloride, hydrogen bromide or hydrochloride iodide is provided.

Where X is chlorine, bromine or iodine, and n is an integer from 1 to 3. When expressing this invention especially preferably specifically, In the formula (II), using a compound whose n is 1 and X is chlorine or bromine, at least n-1 mol of PKb 7 or its at 25 degreeC-100 degreeC It is carried out in the presence of an acid acceptor having the following and a catalyst such as palladium or palladium on carbon or a mixture of 98 to 99.9 parts by weight of palladium and 0.1 to 2 parts by weight of platinum, ruthenium or rhodium. Most preferred method is a compound wherein the formula (II) is 2- [4- (5-bromo-2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazolin, catalyst Is palladium, and the reaction is carried out in the presence of at least one equivalent of an acid acceptor of triethylamine.

The process of the present invention is useful for the preparation of 2- [4- (2-proyl) piperazin-1yl] -4-amino-6,7-dimethoxyquinazoline known as prazosin. Prazosin is known to be useful for the treatment of humans.

The present invention also provides novel and useful starting materials for the process wherein X in formula (II) is chlorine, bromine or iodine and n is an integer from 1 to 3. Particularly preferred starting materials are 2- [4- (5-bromo-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazolin.

A valuable blood pressure lowering agent, 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxy quinazoline (I), is catalyzed by the compound of formula (II) The scheme of the present invention for preparation by dehalogenation is as follows.

The method is carried out by reacting a compound of formula II with hydrogen in the presence of a dehalogenation catalyst as defined herein.

The term 'dehalogenation catalyst' means that halogen is selected as hydrogen, substantially without hydrogenation or hydrocracking of the furan and quinazoline components of the starting materials and products under the conditions of the process for providing product (I). It refers to a catalyst for substitution.

The dehalogenation catalyst used in the process of the present invention is of supported or unsupported type and is a mixture of palladium, copper, cobalt or nickel, or palladium with platinum, ruthenium or rhodium. Examples of suitable catalyst supports include carbon, barium oxide, calcium carbonate and barium sulfate. Such catalysts can be formed in situ by preforming or preliminarily reducing the appropriate oxide or salt of the catalyst compound. Preliminary reduction simply suspends the catalyst precursor in a hydrogenation medium, which is established by hydrogenation, substrate addition and continued hydrogenation. Alternately, all components are mixed temporarily and hydrogenation begins.

The previous process has the advantage of helping the technician determine the amount of hydrogen absorbed, respectively, during catalyst pre-reduction and hydrogenation. The limits of hydrogenation can then be easily adjusted. Among the suitable dehalogenation catalysts used in the process of this process are finely divided metals such as cobalt, nickel, copper and mixtures thereof. The preparation and use of such catalysts is known.

Catalysts for the process of the present invention are palladium, copper, cobalt nickel and a mixture of palladium with platinum, ruthenium or rhodium and the like.

Any of the above mixtures containing palladium and other metals mentioned above, varying over a wide range of weight ratios of palladium to platinum, ruthenium or rhodium, are useful in the process of the present invention, but 98 to 99.9 parts by weight of palladium and 0.1 to Particular preference is given to mixtures containing 2 parts by weight of platinum, ruthenium or rhodium. In the process of the invention, the catalyst is used by the 'catalyst amount'.

The 'catalyst amount' is well understood by those skilled in the art of hydrogenation and is described in the examples presented herein. Usually, however, the use of from 1 to 40% by weight of catalyst based on the weight of the starting compound of formula (II) is preferred.

The process of the invention is carried out in the presence of a reaction inert solvent. Suitable solvents are those which dissolve or disperse into the reactants and conversely do not react with the reactants, products or catalysts. Examples of such solvents are lower alkanols such as methanol, ethanol, isopropanol, n-butanol, isobutanol and isoamyl alcohol: converted and straight-chained water soluble ethers such as dioxane, tetra hydrofuran, diethylene glycol monomethyl ether, 2-ethoxyethanol, N, N-dimethylformamide and N, N-dimethylacetamide: and mixtures of such solvents and water.

The hydrogen pressure used to carry out the process of the invention is not critical and depends on the apparatus used. Generally, a pressure of atmospheric pressure to about 2000 p · s · i is preferred. As is known, hydrogenation at atmospheric pressure is generally carried out in such a device in which the measured capacity of hydrogen contained in the reservoir is added to the pressure gauge to measure the consumed hydrogen capacity. Alternatively, a mechanical shaker with a magnesium citrate bottle and a calibrated pressure gauge, such as a parhydrogenation device, or a high pressure autoclave with a stirrer or shaker can be used.

The dehalogenation process of the present invention is carried out at a temperature in the range of 0 ° to 150 ° C. Especially preferable temperature range is 25 degreeC-100 degreeC.

When the process is carried out alone with a mixture of formula (II), the first compound (I) formed is a hydrogen halide addition salt. It is either isolated or treated with a water soluble alkali such as sodium or potassium hydroxide to be converted into a free base and the base is filtered or extracted in a solvent which is immiscible in water such as ethyl ether, chloroform or methylene chloride. Alternately, the method is carried out in the presence of an acid acceptor to immediately produce a free base of compound (I) and a halogenated salt of the acid acceptor.

The term 'acid acceptor', when added to the reaction mixture or used in the process of the present invention, no longer reacts with the reactants or products to produce by-products, and optionally reacts with the liberated hydrogen halide to form halogenated salts. It refers to such basic compounds which do not have any detrimental effect on the catalyst used. In order to successfully compete for the hydrogen halide formed during the process, the acid acceptor must be a stronger base than the reactant or product of formula (II). That is, a base having a PKb of 7 or less.

Examples of suitable acid acceptors include salts such as triethylamine, N-methylpyrrolidine, triethanolamine, n-butylamine, benzylamine, isoamylamine, morpholine and piperidine, ammonia, hydrazine and sodium, potassium, magnesium , Alkali and alkali metal oxides and hydroxides of calcium and barium.

Particularly preferred as an acid acceptor, which is convenient, economical and effective, is triethyl amine. The acid acceptor is preferably used in an amount at least sufficient to neutralize n-1 mol of hydrogen halide per mol of compound (II), where n is the number of halogen atoms per mol of starting material of formula (II). That is, n is an integer of 1-3. The product is the free base of formula (I) when the amount of acid acceptor is at least equal to the amount of hydrogen halide formed. In such a case, if necessary, an excess acid acceptor may be used. Alternately, when the acid acceptor n-1 equivalent per mole of compound (II) is used, the obtained product is the halogenated hydrochloride of the compound of formula (I). For example, in the starting material of formula (II), when X is chlorine, n is 3, and 2 equivalents of acid acceptor per mole of compound (II), the obtained product is the hydrochloride of compound (I).

When it is desired to use an acid acceptor in the method of the present invention, it is preferable to use an acid acceptor having at least one equivalent per mole of compound (II).

The time required to really complete the dehalogenation process of the present invention depends on factors such as temperature, catalyst and the exact nature of the starting material of formula (II). Usually, but dehalogenation is really finished in around 0.5 ~ 24 hours. As mentioned above, the product of the process of the present invention is the free base of formula (I) or hydrochloric acid, hydrobromic acid or hydroiodide thereof. If such products are desired, they can be isolated and further purified by methods well known to those skilled in the art.

For example, after filtration to remove the catalyst, the free base can sometimes be isolated by only evaporating the solvent, and as a result the product can precipitate or induce precipitation by adding 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. When the product obtained by the process of the invention is one of the halogenated hydrochlorides of compound (I) mentioned above, it can be converted to a free base and isolated as described above, and the reaction mixture is warmed to isolate the halogenated hydrochloride. The halogenated hydrochloride solution can be protected and the reaction mixture can be filtered to remove the catalyst and the filtrate can be concentrated and cooled to a small volume to precipitate the desired product. If desired, it can be further purified into crystalline.

Starting compounds of the formula (II) wherein X is chlorine, bromine or iodine and n is an integer from 1 to 3 are novel compounds. It is described above for the preparation of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxy quinazoline each time using a suitable halogen-substituted starting material. By the method. Preferred methods for the preparation of compounds of formula (II) are described below in Methods A and B.

Method A

In the compounds of the formulas (III) and (IV), A is chlorine or bromine and (X) n is as described above.

Compounds of formulas (III) and (V) are useful in the methods described in US Pat. No. 3,511,836. The halogenated acyls of formula (VI) are prepared by well known methods from the corresponding halogenated-2-furo acids, for example by reaction with an acid described above with an excess of thionyl chloride or thionyl bromide to evaporate the reaction mixture.

Of the halogenated furoic acids from which compound (VI) is derived, 5-bromo-2-furoic acid is commercially useful. The remaining chloride or bromic acid is prepared by known methods. Iodide furoic acid is prepared from the oxidation of the corresponding iodide furfural with an alkaline peroxide, of known methods.

When using method A, the molar amount of piperazine of 1-substituted piperazine of formula (IV) prepared from the acid halide of formula (VI) described above is reacted in the presence of a reaction-inert organic solvent. The reaction may be carried out at a wide range of temperatures but is preferably in the range of 50 ° to 150 ° C. The reaction is usually completed in 1 to 24 hours. The product can be isolated in the form of hydrogen chloride or hydrobromide and subsequently converted to the free base of formula (II) by standard methods. Alternately, the reaction can be made alkaline with sodium or potassium hydroxide and the free base can be isolated by extraction and evaporation of the solvent. Examples of suitable inert solvents for this method include alkanols such as ethanol, n-butanol, isoamyl alcohol, n-hexanol or cyclohexanol: N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide And ethylene 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 the compound of formula (VI) in the presence of a suitable reaction-inert organic solvent. The reaction is preferably carried out at a temperature of -20 ° ~ 100 ° C. Examples of suitable solvents used in the present method are the same as those in the above method A. The reaction is usually completed in a few minutes to 10 hours. The desired products are added in a standard manner, for example by adding a water soluble base such as sodium hydroxide, potassium hydroxide or sodium carbonate to adjust the reaction mixture to alkaline pH and extracting the product with a solvent which is incompatible with water such as chloroform or methylene chloride to evaporate the solvent. Isolate. Economically and effectively preferred compounds of formula (II) are those wherein n is 1 and X is chlorine or bromine.

Especially most preferred are 2- [4- (5-bromo-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxy quinazoline.

The following examples will illustrate the invention in more detail. Examples 1-3 illustrate the preparation of novel intermediate products which are compounds of formula (II) and Examples 4-8 illustrate the process of the invention.

Example 1

2- [4- (5-bromo-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxy quinazoline

20 g of thionyl chloride was added to a flask containing 19.1 g (0.10 mol) of 5-bromo-2-furoic acid in 100 ml of chloroform and the resulting mixture was stirred at room temperature for 2 hours and left overnight. The volatile components were evaporated in vacuo to afford 5-bromo-2-furoyl chloride. This was dissolved in 50 ml of methylene chloride and the solution was added dropwise to a solution of 8.6 g (0.10 mol) of piperazine in 50 ml of the same solvent at 25 ° C. It took 30 minutes to add. The resulting mixture was stirred for another 1 hour and added alkali with 2N sodium hydroxide solution. The organic layer was separated and the aqueous layer was extracted again with methylene chloride. The organic layer was dried over anhydrous potassium carbonate and evaporated to dryness to yield 23 g of 1- (5-bromo-2-furoyl) piperazine. Some were determined from methylene chloride-ethyl acetate.

Melting point 113 ° ~ 115 ℃

Anal: calcd (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) of 4-amino-2-chloro-6,7-dimethoxy quinazoline prepared by US Pat. No. 3,511,836, 200 ml of isoamyl alcohol and 1- (5-bromo- obtained above) 20.7 g (0.08 mol) of 2-furoyl) piperazine was added. The resulting suspension was refluxed for 90 minutes, heated, cooled, filtered and washed with ethanol to give 21.8 g of crude hydrochloride of the title compound which dissolved and decomposed at 276 ° -278 ° C. It was mixed into 200 ml of ethanol and 2N sodium hydroxide solution was added to make a solution.

The solution was concentrated in a small volume by evaporation in vacuo, then cooled, filtered, washed with water and dried to give 18.8 g of product having a melting point of 206-209 ° C. This was dissolved in a mixture of chloroform and methanol, dried over sodium sulfate, carburized, and the solvent was replaced with ethyl acetate.

Crystallization gave 9.8 g (53%) of purified product having a melting point of 213-215 캜.

Anal: calcd (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

Example 2

2- [4- (3-chloro-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline

3-chlorofuran-2-carboxylic acid prepared by the method of Shepard was reacted with an excess of thionyl chloride at room temperature and evaporated in vacuo to give an acid chloride as a residue. 16.5 g (0.10 mole) of the above acid chloride in a 28.9 g (0.10 mole) 2- (1-piperazinyl) -4-amino-6,7-dimethoxy quinazoline solution in 300 ml of methanol, prepared as known Was added with vigorous stirring over 30 minutes and the resulting mixture was stirred for another 3 hours at room temperature. The solvent was removed in vacuo and the residue was mixed with methylene chloride and alkalined with 2N sodium hydroxide solution. The organic layer was separated, dried over sodium sulfate and evaporated to dryness to afford the title compound. The same is true when the acid bromide obtained by using thionyl bromide instead of thionyl chloride in the above process is reacted with 2- (1-piperazinyl) -4-amino-6,7-dimethoxyquinazolin.

Example 3

Repeating the process of Example 1 or Example 2 with the acid chloride used in place of the appropriate halo-2-furoyl collide halo-2-furoyl bromide yields similar compounds.

2-furoyl chloride or bromide is prepared from the corresponding halo-2-furoic acid. Chloro or bromofuroic acid is prepared by known methods by J. S. Amer. Chem. Soc., 52, 2083 (1930) and Gilman et al. (Ibid., 57, 1146 (1935)). Urinary furoic acid is oxidized to the corresponding urethralfurfural with alkaline peroxides by the method by Chem. Abstr., 73, 35134f (1970) or by Bulli Soc. Chem. France 990 (1971). It is manufactured from what was done.

Example 4

1.0 g (2.16 mmol) 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 (50% moisture) in carbon.

The bottle was placed in a Parr shaker and pressurized with hydrogen up to 50 p.s.i at room temperature. After shaking for 18 hours, the theoretical amount of hydrogen was picked up. The mixture of catalyst and precipitated product was filtered and the solids were mixed in 25 ml of chloroform and filtered again to remove the catalyst. 50 ml of hexane was added to the filtrate, and the mixture was stirred for 10 minutes to obtain a crude product. The mixture was eluted with ethyl acetate-diethylamine (volume ratio 90:10) and purified on an 18 × 3 inch silica gel column to obtain 300 mg of a melting point of 266 ° C. Obtaining 2- [4- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazolin and comparing the infrared and infrared spectra to a reliable sample in chloroform, and It was confirmed by thin layer chromatography on silica gel.

Example 5

4.18 g (0.01 mol) of 2- [4- (3-chloro-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxy quinazoline, 95 in an air hydration flask Add 0.5 g of a catalyst containing 75 ml of% ethanol, 0.05 g (0.10 mol) hydrazine hydrate and 98 parts by weight of palladium and 2 parts by weight of platinum. The resulting mixture is cooled to 0 ° C. and exposed to hydrogen at atmospheric pressure for 4 hours. The mixture is filtered to remove the catalyst and the filtrate is concentrated to dryness in vacuo and then partitioned between methylene chloride and water. The organic layer was dried over sodium sulfate and evaporated to dryness to afford 2- [4- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxy quinazoline, by silica gel column chromatography. Purify. Repeating the process with 0.5 g of catalyst containing 99.9 parts by weight of palladium and 0.1 part by weight of platinum results in essentially no change.

Example 6

9.24 g (0.02 mole) of 2- [4- (4-bromo-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline in 500 ml autoclave, 2.0 g of water 50% Raney nickel catalyst and 200 ml of 70% ethanol (weight ratio 7: 3 ethanol / mol) are added. The mixture is held at 100 ° C. at about 200 p.s.i hydrogen pressure for 30 minutes and then cooled at room temperature. The catalyst is filtered off, the filtrate is concentrated to remove ethanol, the concentrate is alkaline with potassium carbonate, extracted with chloroform and the extract is concentrated to dryness to 2- [4- (2-furoyl) piperazin-1-yl] 4-amino-6,7-dimethoxyquinazoline was obtained. The product can be further purified by silica gel column chromatography.

Example 7

4.18 g (0.01 mol) of 2- [4- (4-chloro-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxy quinazoline, isoamyl alcohol in an atmospheric hydrogenation flask Add 0.20 g of powdered catalyst containing 200 ml and 99.9 parts by weight of palladium and 0.1 part by weight of rhodium. The resulting mixture is hydrogenated under vigorous stirring for 2 hours at atmospheric pressure. The theoretical amount of hydrogen was consumed. The mixture is removed from the apparatus and heated to boiling and filtered while hot to remove the catalyst. The filtrate was cooled on ice and then filtered to afford 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazolin hydrochloride.

This process is followed by 0.01 mole of 2- [4- (5-bromo-2-furoyl) piperazin-1-yl] -4-amino instead of the corresponding 4-chloro-2-furoyl analog used above. 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline hydrobromide when repeated with -6,7-dimethoxyquinazoline This is obtained similarly.

Example 8

When the indicated halogen-containing starting material selected from the products obtained in Examples 1 to 3 is reacted under the conditions shown in the table below, 2- [4- (2-furoyl) piperazine- in the form of a free base or the indicated halogenated hydrochloride salt 1-yl] -4-amino-6,7-dimethoxy quinazoline was obtained.

* THF is terahydrofuran, DMF is N, N-dimethylformamide.

TEA is triethylamine.

Claims (1)

The compound of formula II is reacted with hydrogen in the presence of a catalytic amount of supported or unsupported palladium, copper, cobalt, or nickel or a dehalogenation catalyst which is a mixture of palladium with platinum, ruthenium or rhodium 2- [4- (2-furoyl) piperazin-1-yl] -4-, characterized in that it is reacted at a temperature of about 0 ° to 150 ° C in the presence of an inert solvent or in the presence of an acid acceptor. A method for producing amino-6,7-dimethoxyquinazoline or its hydrogen chloride, hydrogen bromide, and hydrochloride iodide.

X is chlorine, bromine or iodine, n is an integer of 1-3.