FI65999B - PROCEDURE FOR THE FRAMSTATION OF AV 2- (4- (2-FUROYL) PIPERAZIN-1-YL) -4-AMINO-6,7-DIMETOXYQUINAZOLINE AND ANIMAL PRODUCTS FOR ANALYSIS OF FOOD - Google Patents

Description

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Patent · och regictentytelaen '7 Ameka utiagd o <± utUkrifuo pubiicmd 30 - 04.84 (32) (33) (31) Requested «yields» —Baglrd prioHtat 06.08.76 USA 712277 (71) Pfizer Inc., 235 East 42nd Street, New York, NY, USA (72) Philip Dietrich Hammen, East Lyme, Connecticut, USA (74) Oy Kolster Ab (5 * 0 Method 2- / 4- (2-furoyl) piperazine Intermediate used in the preparation of 1-y1-L7-4-amino-6,7-dimethoxy-quinazoline - Process for the preparation of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7 ~ Dimethoxyquinazoline and an additional product for use in the preparation

The invention relates to a new process for the preparation of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazolyl of the formula I or its hydrochloride, hydrobromide or hydroiodide salt. , ___ k | -------- PH o ^ / A jl 11 v-d'Y'7'k · "

Ch'0''V ^ \ /

• 3 I

NH 2

The compound of formula I known as prazosin has antihypertensive activity (U.S. Pat. No. 3,311,836) and has been shown to have therapeutic use (Cohen, Journal of Clinical Pharmacology, 10, 408 (1970)).

2 65999

The process according to the invention is characterized in that the compound of formula r'H 0 Λ \ c [ί ί - (X) n $ V 11 cii..ou-v, d'Xa 'z wherein X is chlorine, bromine or iodine and n are an integer from 1 to 3, are reacted with hydrogen in the presence of a catalytic amount of a dehalogenation catalyst which is palladium, copper, cobalt or nickel or a mixture of palladium of platinum, ruthenium or the like. with rhodium, with or without a support, in the presence of a reaction-inert solvent at a temperature of about 0-15 ° C and, if desired, in the presence of an acid acceptor.

The invention also relates to an intermediate of formula II for use in the process.

U.S. Patent 3,511,836 describes several methods for preparing 2-Z4- (2-furoyl) piperazin-1-yl-4-amino-6,7-dimethoxyquinazoline. Of these, mention should be made. Reaction of 2-chloro-U-amino-6,7-dimethoxyquinazoline with 1- (2-furoyl) piperazine, 2-N- (2-furoyl) piperazine -! reaction of -yl--4-chloro-6,7-dimethoxyquinazoline with ammonia and acylation of 2- (1-piperazinyl) -4-amino-6,7-dimethoxyquinazoline with e.g. 2-furoyl chloride.

U.S. Patent No. 3,935,213 describes methods in which 2- (4-substituted-piperazin-1-yl) -4-amino-6,7-dimethoxy-quinazine and, int. 2-N- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline, prepared either by: (1) reacting 4,5-dimethoxy-2-aminobenzonitrile With certain 1,4-disubstituted piperazines; or (?) reacting 4,5-dimethoxy-2-aminoberizamidine with the same 1,4-disubstituted piperazines.

What is new and surprising in the process for the preparation of prazosin according to the invention is that only the dehalogenation of the intermediate of formula II takes place in the reaction. In addition, the the intermediate is easily synthesized.

65999

No yields are reported in the aforementioned U.S. Patent 3,511,836, so it can be assumed that the desired compound is obtained by the process of the invention in significantly better yields. The prior art closest to the present invention is disclosed in Dunlop, The Furans, 1953, pp. 709-710, which describes the dehalogenation of certain 2,5-diphenylhalofurans.

However, the compounds in question are not ordinary furans because the furan ring is stabilized with phenyl groups at positions 2 and .5.

U.S. Patent 3,083,236 and Heterocyclic Compounds, 1973, p. 1010 show that an unprotected furan ring can be readily reduced to tetrahydrofuran and cleaved to the acyclic compound. Thus, it is known to dehalogenate halofuran compounds having a furan ring protected by aromatic substituents. When using unprotected furans, the the reaction results, based on the prior art, in the formation of a saturated ring and / or ring cleavage. It was therefore surprising that when a new intermediate according to the invention is used, only dehalogenation takes place.

According to a preferred embodiment, a compound of formula II is used in which n is 1 and X is chlorine or bromine at a temperature of 25-100 ° C in the presence of at least n-1 moles of an acid acceptor with a pK i of 7 or lower, and a catalyst which is palladium / lithium or palladium / carbon or a mixture containing 98 to 99.9 parts by weight of palladium and 0.1 to 2 parts by weight of platinum, ruthenium or rhodium. In a particularly preferred form of mixing, the compound of formula II is 2- [1- (5-bromo-2-furoyl) -piperazin-1-yl] -N-yl. - 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 an acid acceptor.

The process according to the invention can be described by the following reaction scheme: CH n Γ ~ \ „| 5 - (X) CH „0 λ„ -.

: 1 X ----- 'Ä H0,. \ / | 0 0 I 1 w 'o CH3 ° ί NH2 CH3Ci] nh2 “65999

A support may be used in connection with the dehalogenated catalyst used in the process of the invention. Examples of suitable catalyst supports are carbon, barium oxide, calcium carbonate and barium sulphate. The catalyst may be preformed or formed in situ by pre-reducing the appropriate oxide or salt of the catalyst compound. The 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 ingredients can be combined and hydrogenation begins at the same time. The above procedure has the advantage that the amount of hydrogen absorbed during the pre-reduction and hydrogenation step of the catalyst can be determined separately. The degree of hydrogenation can then be easily adjusted.

The preparation and use of catalysts for use in the process of the invention have been described by Freifelder, "Practical Catalytic Hydrogenation", John Wiley and Sons, Inc., New York, 1971.

The catalysts used are palladium, copper, cobalt, nickel and mixtures of palladium with platinum, ruthenium and rhodium.

Particularly preferred catalyst mixtures are those containing 98 to 99.9 parts by weight of palladium and 0.1 to 2 parts by weight of platinum, ruthenium or rhodium. The catalyst is used in the process of the invention as "catalytic amount", a term well understood by those skilled in the art of hydrogenation (see also Freifelder, loc.cit .; pp. 79-81). However, it is usually 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 that substantially dissolves or disperses the reactants and does not adversely affect the reactants, the final product, or the catalyst. Examples of such solvents include 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, M-dimethylformamide and N, N-dimethylacetamide, and mixtures of such solvents and water.

5 65999 The hydrogen pressure used is not critical and depends primarily on the equipment used. In general, pressures from atmospheric pressure to about 135 atm are preferred. As is known, hydrogenation at atmospheric pressure is generally carried out in an apparatus in which a measured volume of hydrogen in a tank is connected to a manometer to measure the volume of hydrogen consumed. Alternatively, a magnesium oxide citrate bottle (Parr bottle) and a mechanical stirrer as well as a calibrated pressure gauge such as a Parr hydrogenator or a high pressure autoclave of the stirring or shaking type can be used.

The dehalogenation process is carried out at a temperature of about C-150 ° C. A particularly preferred temperature is 25-100 ° C.

When the process is carried out without an acid acceptor, a hydrogen halide addition salt of the compound (I) of the formula I is obtained. This can be isolated as such or converted to the free base by treatment with an aqueous alkali such as sodium hydroxide or potassium hydroxide, followed by filtration or extraction of the base in a water-immiscible solvent such as ethyl ether, chloroform or methylene chloride. Alternatively, the process may be performed in the presence of an acid acceptor to directly obtain the free base of the compound of formula I and the halide salt of the acid acceptor. The term "acid acceptor" refers to a basic compound that, when added to a reaction mixture, selectively reacts with liberated hydrogen halide to form a halide salt without causing substantial by-product formation by further reacting with the reactant or product and has little or no detrimental effect on the catalyst used. In order to successfully bind the hydrogen halide formed during the process, the acid acceptor should have a stronger base than the compounds of formulas (II) and I, i.e. it should have a base with a pK i of 7 or less.

Examples of suitable acid acceptors include 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 oxides and hydroxides of sodium, potassium, magnesium, calcium and barium. A particularly preferred acid acceptor is triethylamine.

6 65999

The acid acceptor is preferably used in an amount at least sufficient to neutralize n-1 moles of hydrogen halide per mole of the compound of formula II, where n is the number of halogen atoms per mole of the 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 compound of formula I is obtained as the free base. In such cases, an excess of acid acceptor may be used if desired. Alternatively, when n-1 equivalents of acid acceptor per mole of compound of formula TI are used, the compound is obtained as the halogen-hydrogen salt. For example, when in the starting material of formula (II) X is chlorine, n is 3 and 2 equivalents of acid acceptor per mole of the compound of formula II are used, the compound of formula I is obtained as the hydrochloride salt.

When it is desired to use an acid acceptor in the method of this invention, it is preferred to use at least 1 equivalent of acid acceptor per mole of the compound of formula II.

The time required for the dehalogenation process to be substantially complete will vary depending on various factors such as the temperature, the catalyst and the starting material of formula (II). Usually, however, the dehalogenation is substantially complete in about 0.5-24 hours.

As mentioned above, the obtained compound may be in the form of a free base or a hydrochloride, hydrobromide or hydroiodide salt. Any of these products can be further isolated and purified, if desired, by methods known per se. For example, the free base can often be isolated simply by evaporating the solvent after the catalyst has been removed by filtration, after which the product precipitates or may be precipitated by the addition of an e.i-1 solvent such as hexane or heptane. The free base can be further purified by various methods, such as recrystallization or column chromatography using silica gel. The halogen-hydrogen salt can be converted to the free base and isolated as described above, or it can be isolated by heating the reaction mixture to ensure dissolution of the halogen-hydrogen salt, filtering the reaction mixture to remove the catalyst, and then evaporating the filtrate to a small volume and cooling. It can be further purified, if desired, for example by recrystallization.

7 65999

The intermediates of formula II are novel compounds.

They can be prepared by methods previously used to prepare 2-A- (2-furoyl) piperazin-1-yl-1- + amino-6,7-dimethoxyquinazoline using a suitable halogen-substituted starting material. Preferred methods for preparing compounds of formula (II) are Methods A and B described below.

Method A

CH3 ° \ -.A

f I J * / \ I— CHJ f \ ____ / i NH?

... III ... IV

Method B

CH 3? -V / N. ® _, J \ __ / + (X) n — j— j -> (II) ^ OA /

CELO I

3 I - NH2

. . .V ... VI

In the compounds of formulas (III) and (VI), A is chlorine or bromine and (X) has the same meaning as above. Compounds of formulas (III) and (V) are obtained by the methods described in U.S. Patent 3,511,836. The acyl halides of formula (VI) are prepared from the corresponding halogenated 2-furanoic acids by known methods, for example by reacting these acids with an excess of thionyl chloride or thionyl bromide. followed by evaporation of the reaction mixture. Of the halogenated furanoic acids from which the compounds of formula VI are derived, 5-bromo-2-furanoic acid is commercially available. Chloro and bromofuranic acids are prepared by the methods described in Jour. Amer. Chem.

Soc., 52, 2083 (1930) and Gilman et. et al., Ibid., 57, 1146 (1935) and references therein. Iodifuranoic acids are prepared from the corresponding iodofurals by oxidation with alkaline peroxide Boriso-van et. al. by the method of Chem. Abstr., 73, 30134f (1970) or Sor-Nayn et al. method, Bull. doc. Chem., France, 990 (1971).

Using Method A, a 1-substituted piperazine of formula (IV), which can be prepared from the acid halides of formula (VI) described above, and an equimolar amount of piperazine are reacted in about equimolar amounts in the presence of a reaction-inert organic solvent. The reaction can be carried out over a wide range of temperatures, however, a temperature of 50 to 150 ° C is preferred. The reaction is usually complete in 1/4 hour. 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 made alkaline, for example with sodium hydroxide or potassium hydroxide, and the free base isolated by extraction and evaporation of the solvent. Examples of suitable reaction-inert solvents include alkanols such as ethanol, n-butanol, isoamyl alcohol, n-hexanol and cyclohexanol; N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, diethylene glycol diethyl ether, ethylene glycol n-butyl ether, chloroform and methylene chloride.

Using Method B, a compound of formula (V) and an equimolar amount of a compound of formula (VI) are reacted in the presence of a suitable reaction-inert organic solvent. The reaction is preferably carried out at a temperature of -0 ° -100 ° C. Examples of suitable solvents for use in this method are set forth above for Method A. The reaction is usually complete in about 5 minutes to 10 hours. The desired product is isolated by standard methods, such as adjusting the pH of the reaction mixture to an alkaline value 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 and evaporating the solution.

Particularly preferred compounds of formula (II) are those wherein n is 1 and X is chlorine or bromine. Very particularly preferred is 2- [4- (S-bromo-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline.

65999 p

The following examples illustrate the invention. Examples 1-3 illustrate the preparation of an intermediate of the invention and Examples 4-8 illustrate a process of the invention.

Example 1 2- [4- (5-Bromo-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline

To a flask containing 19.1 g (0.10 mol) of 5-bromo-2-furanoic 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 allowed to stand over night. 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 took about 30 minutes. The resulting mixture was stirred for another hour, 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 give 23 g of 1- (5-bromo-2-furoyl) piperazine. A portion was crystallized from methylene chloride / ethyl acetate, m.p. 113-115 ° C.

Analysis:

Calcd for C 9 H 11 N 2 O 2: 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.

9.55 g (0.04 moles) of 4-amino-2-chloro-6,7-dimethoxyquinazoline prepared by the method of U.S. Patent 3,511,836, 200 ml of isoamyl alcohol and 20.7 g (0.04 moles) of .08 moles) of 1- (5-bromo-2-furoyl) piperazine obtained above. The resulting suspension was refluxed for 90 minutes, then cooled, filtered and washed with ethanol to give 21.8 g of the crude hydrochloride salt of the title compound, which melted with decomposition at 276-278 ° C. This was slurried in 200 ml of ethanol and 2N sodium hydroxide solution was added to effect dissolution. The solution was concentrated to a small volume by evaporation in vacuo, cooled, filtered, washed with water and dried to give 18.9 g of product, m.p. 206-209 ° C. This was dissolved in a mixture of chloroform and methanol, dried over sodium sulfate, treated with charcoal and the solvent was replaced with ethyl acetate. After crystallization, 9.8 g (53%) of pure product were obtained, m.p. 213-215 ° C.

Analysis i:

Calculated for C H 2 H 5 O 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-methoxyquinazoline 3-Chlorofuran-2-carboxylic acid prepared by Shep- by the method of ardin et al., is reacted at room temperature with an excess of thionyl chloride, followed by evaporation in vacuo to give the acid chloride as a residue.

To a solution of 28.9 g (0.10 moles) of 2- (piperazinyl) -4-amino-6,7-dimethoxyquinazoline prepared as described in U.S. Patent 3,511,836 in 300 mL of methanol is vigorously added with stirring 16.5 g (0.1 mol) of the acid chloride obtained above over 30 minutes and the resulting mixture is stirred for a further 3 hours at room temperature. The solvent is removed in vacuo and the residue is slurried in methylene chloride and made alkaline with 2N sodium hydroxide solution. The organic layer is separated, dried over sodium sulfate and evaporated to give the title compound.

When thionyl bromide is used instead of thionyl chloride in the above method and the resulting acid bromide is reacted with 2- (1-p i p e r a t s i n y y 1 i) - 4 - a m i n o - 6,7 - d dimeth k k i i. N a t s o in, the results are essentially the same.

Example 3

When the procedure of Example 1 or Example 2 is repeated, but replacing the acid chloride used therein with a suitable halo-2-furoyl chloride or halo-2-furoyl bromide, the following compounds are obtained in the following manner: __ .. ^ (X) n ™ 3 °. , »/» O-c-t; r r r "^ o ° -CH ^ ΐ 11 65999 3__4 (.

Example No. C | i Π

Method 5 '3' Chloro-2-furoyl 1,4-chloro-2-furoyl 1,3,4-dichloro-2-furoyl 2 3,4,5-trichloro-2-furoyl 2 3- bromo-2-furoyl 2,4-bromo-2-furoyl 2,5-bromo-2-furoyl 1,5-dibromo-2-furoyl 1,5-iodo-2-furoyl 2,4-iodo-2-furoyl 2-furoyl chlorides or bromides are prepared from the corresponding halo-2-furanoic acids. Chloro and bromofuranic acids are prepared by the methods described by Shepard et al., Jour.Amer.Chem.

Soc., 52, 2083 (1930) and Gilman et al., Ibid., 57, 1146 (1935) and references therein. Iodifuranoic acids are prepared from the corresponding iodifurfural by oxidation with an alkaline peroxide according to the method of Borisovan et al., Chem. Abstr., 73, 35134f (1970) or Sornay et al. method, Bull. Soc. Chem., France, 990 (1971).

Example 4

1.0 g (2.16 mmol) of 2-N- (5-bromo-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazate are charged to a pressure flask. and 10 ml of methanol, 1.0 ml of triethylamine and 0.4 g of 5% Pd / carbon (50% moist). The flask was placed on a Paar shaker and pressurized with hydrogen to 3.4 atm at room temperature. After 18 minutes of shaking, the theoretical amount of hydrogen had been taken up. The mixture of catalyst and precipitated product was filtered and the precipitate was slurried in 25 ml of chloroform and refiltered to remove the catalyst. To filter, 50 mL of hexane was added, the mixture was stirred for 10 minutes, then filtered to give the crude product which was purified on a 46 x 7.6 cm silica gel column eluting with ethyl acetate-diethylamine (90:10 by volume) to give 300 mg of 2- / 4- (2 -furoyl) -piperazin-1-yl-4-amino-6,7-dimethoxyquinazoline, m.p. was 266 ° C and was identified by comparing the infrared spectrum in chloroform to that of an authentic sample, and by thin layer chromatography on silica gel.

65999 E r; ; m e r 'kki 5

4.18 g (U, U1 moles) of 2- [4- (3-chloro-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline, 75 ml, are placed in a flask of an atmospheric hydrogenator. . 95% ethanol, 0.50 g (0.10 mol) of hydrazine hydrate and 0.5 g of catalyst containing 38 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 puffs. The mixture is then filtered to remove the catalyst, the filtrate is concentrated in vacuo and then partitioned between methylene chloride and water. The organic layer is dried over sodium sulfate and evaporated to give 2- [4- (2-furoyl) -piperazin-1-yl] -4- amino- 6,7-dimethylene zoline, which is purified by chromatography on a silica gel column. .

When the above procedure is repeated, but using 0.5 g of a catalyst containing 39.9 parts by weight of palladium and 0.1 part by weight of platinum, the results remain essentially unchanged.

Example 6 9.2 g (0.02 moles) of 2- [4- (4-bromo-2-furoyl) piperazin-1-yl] -4- (4-amino) -6,7 are added to a 500 ml autoclave. -dimethoxyquinazoline, 2.0 g of a 50% moisture Raney nickel catalyst and 200 ml of 70% ethanol (7: 3 ethanol / water, by weight). The mixture is maintained at 100 ° C and 13.0 atm under hydrogen pressure for 30 minutes and then cooled to room temperature. The catalyst is removed by filtration and the filtrate is concentrated to remove ethanol, concentrated for a while with potassium carbonate, extracted with chloroform and the extracts evaporated to dryness to give 2- [4- (2-furoyl) -piperazin-1-yl] -4-air, in-6-7-7- dimethoxy.nazoline. The product can be further purified by chromium t ogra f 1s e s 11 picylic acid ge e1ik o1o n n i s s o.

Example 7

4.18 g (0.01 mol) of 2- [14- (4-chloro-2-furoyl) piperazin-1-yl] -4-amino-G,7-dimethoxyquinazoline, 200 ml of isoamyl alcohol are placed in an atmospheric hydrogenation flask. and 0.20 g of a finely divided catalyst containing 99.9 parts by weight of palladium and 0.1 part by weight of rhodium. The resulting mixture is hydrogenated at atmospheric pressure for 2 hours with vigorous stirring. The theoretical amount of hydrogen consumed. The mixture is then disconnected from the apparatus, heated to boiling and filtered while still hot to remove the catalyst. The filtrate is cooled on ice, then filtered to give 2-Zh- (2-furoyl) piperazin-1-yl / -4-amino-6,7-dimethoxyquinazoline hydrochloride.

When the above procedure is repeated, but using 0.01 mol of 2- [4- (5-bromo-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline of the same kind of 4- in place of chloro-2-furoyl used above, 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline hydrobromide is obtained in a similar manner.

Example 8

When the halogen-containing starting material shown in the table selected from the products obtained in Examples 1-3 is subjected to the conditions shown in the following table, 2- [4- (2-furoyl) -p] piperazin-1-yl] -4- amino-6,7-dimethoxyquinazoline either as the free base or as the indicated hydrohalide salt.

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Claims (10)

16 Claims 6 5 9 9 9 Process for the preparation of 2- [1- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline or its hydrochloride, hydrobromide or hydroiodide salt, characterized in that the compound of formula (x CH3NH2 wherein X is chlorine, bromine or iodine and n is an integer from 1 to 3 is reacted with hydrogen in the presence of a catalytic amount of a dehaloogenation catalyst which is palladium, copper, cobalt or nickel or a mixture of palladium with platinum, ruthenium or rhodium, with or without a support, in the presence of a reaction-inert solvent at a temperature of about 0 to 150 ° C, and, if desired, in the presence of an acid acceptor. Process according to Claim 1, characterized in that the reaction is carried out at a temperature of about 25 to 100 ° C. Method according to Claim 1 or 2, characterized in that the acid acceptor has a pK i of 7 or less. Process according to Claim 3, characterized in that at least 1 equivalent of acid acceptor per mole of compound of the formula (II) is used. Process according to one of the preceding claims, characterized in that the catalyst is palladium tax carbon. Process according to one of Claims 1 to 4, characterized in that the catalyst is an inner compound containing 98 to 99.9 parts by weight of palladium and 0.1 to 2 parts by weight of platinum, ruthenium or rhodium. Process according to one of the preceding claims, characterized in that n is 1 and X is chlorine or bromine. 17 65999 Process according to one of the preceding claims, characterized in that at least 1 equivalent of triethylamine is used as the acid acceptor. 9. A compound used as an intermediate in the preparation of 2- [1- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline, characterized in that it has the formula Οι-ί. ix) CH 3 O nh 2 wherein X is chlorine, bromine or iodine and n is an integer from 1 to 3. Intermediate according to Claim 9, characterized in that it is 2- [1- (5-bromo-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline. 18 6 5 9 9 9