CH633794A5 - Process for the preparation of novel 2-[4-(halogenated 2-furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxyquinazolines - Google Patents

Description

The present invention relates to a process for the preparation of new 2- [4- (halogenated-2-furoyl) piperazin-l-yl] -4-amino-6,7-dimethoxyquinazolines. The invention further relates to a process for the preparation of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline.

(2) Reaction of 4,5-dimethoxy-2-aminobenzamidine with the same 1,4-disubstituted piperazines.

25th

The process according to the invention for the preparation of a new compound of the general formula II

rA

(X) n

(ii)

ch3o in which X represents a chlorine, bromine or iodine atom, and n a 40 in which either Y or Z represents a radical of the formula integer from 1 to 3, is characterized in that

that a 6,7-dimethoxyquinazoline of the general formula ch3o

45

H

/ ~ \

N liso with a halogen-substituted furan of the general formula

Z-C

55

means, and the other radical each represents a chlorine or bromine atom, and X and n have the meaning given above, is reacted.

60 The new compounds of general formula II

633794

4th

where X represents a chlorine, bromine or iodine atom, and n represents an integer from 1 to 3, can be used to prepare 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6 , 7-dimethoxy-quinazoline of the formula I.

CH, 0

15

20th

(ii

25th

30th

or its hydrochloride, hydrobromide or hydroiodide salt can be used by dehalogenation.

A particularly preferred embodiment of the dehalogenation is used in that a compound of the general formula II, in which n has the value 1 and X represents a chlorine or bromine atom, at a temperature of 25 ° to 100 ° C. in the presence of at least n-1 moles an acid acceptor with a pKü value of 7 or less and in the presence of a catalyst which is palladium or Palla35

dium-on-carbon or a mixture with 98 to 99.9 parts by weight of palladium and 0.1 to 2 parts by weight of platinum, ruthenium or rhodium is used. Particularly preferred is a process in which the compound of the general formula II is 2- [4- (5-bromo-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline, the catalyst Is palladium and the reaction is carried out in the presence of at least one equivalent of triethylamine as an acid acceptor.

The compounds of the formula II are suitable for the preparation of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dime-thoxyquinazoline, which is known to the person skilled in the art as prazosin. Prazosin has shown therapeutic effectiveness in humans, cf. Cohen, Journal of Clinical Pharmacology, Volume 10, page 408, (1970).

The invention also provides new and suitable starting substances for the above-mentioned process, which have the above-mentioned formula II, in which X represents a chlorine, bromine or iodine atom and n represents an integer from 1 to 3. A particularly preferred starting substance is 2- [4- (5-bromo-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline.

A preferred process for the preparation of the valuable hypotensive, 2- [4- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline (I) by catalytic dehalogenation of compounds of the general formula II can be seen from of the following reaction scheme:

I +

The process is preferably carried out by reacting the compound of the general formula II with hydrogen in the presence of one of the dehalogenation catalysts described. The term “dehalogenation catalyst” denotes a catalyst which supports the selective replacement of halogen atoms by hydrogen atoms under the conditions according to the process. As a result, a product of the general formula I is obtained in general without substantial hydrogenation or hydrogenolytic cleavage of the furan and quinazoline components of the starting substance and of the end product.

The dehalogenation catalyst used in the dehalogenation process can be used with or without a carrier and is preferably palladium, copper, cobalt or nickel or a mixture of palladium with piatin, ruthenium or rhodium. Examples of suitable catalyst supports are carbon, barium oxide, calcium carbonate and barium sulfate. These catalysts can be preformed or formed in situ by previously reducing an appropriate oxide or salt of the catalytic compound. The foregoing reduction is usually carried out simply by suspending the catalyst precursor in a hydrogenation medium, being hydrogenated, subsequently adding the substrate and continuing the hydrogenation. 60 As an alternative to this procedure, all components can be entered at the same time and hydrogenolysis can be started. The method has the advantage, for example, that the operator is able to separately determine the amount of hydrogen which is absorbed during the pre-reduction of the catalyst and during the hydrogenation phase. The extent of the hydrogenation can then be easily controlled.

Among those suitable for the dehalogenation process

Dehalogenation catalysts are preferably the finely divided metals, such as cobalt, nickel, copper and mixtures thereof. The production and use of these catalysts is known, for example, from Free Fields, "Practical Catalytic Hydrogenation", John Wiley and Sons, Inc., New York, 1971, and from the literature references mentioned therein.

The catalysts for the dehalogenation process are preferably palladium, copper, cobalt, nickel and mixtures of palladium with platinum, ruthenium or rhodium. Any of the mixtures mentioned with palladium and one of the other metals mentioned, in which the weight ratio of palladium to platinum, ruthenium or rhodium varies over a wide range, can be used in the dehalogenation process. Mixtures which contain 98 to 99.9 parts by weight of palladium and 0.1 to 2 parts by weight of platinum, ruthenium or rhodium are particularly preferred.

The catalysts are used in the dehalogenation process in “catalytic amounts”. This term is generally familiar to the person skilled in the art in the field of hydrogenation and is further explained in the examples below. In addition, reference is made, for example, to the above-mentioned literature from Freifelder, pages 79 to 81. In general, however, it is preferred to use 1 to 40% by weight of catalyst, based on the weight of the starting compound of the general formula II.

The preferred process for the preparation of the compound of formula I is carried out in the presence of an inert solvent. The suitable solvents essentially dissolve or disperse the reactants and normally do not show any adverse interaction with the reactants, products or the catalyst. Examples of such solvents are the lower alcohols, such as, for example, methanol, ethanol, isopropanol, n-butanol, isobutanol and isoamyl alcohol, the cyclic and straight-chain, water-soluble ethers, such as, for example, dioxane, tetrahydrofuran, diethylene glycol monomethyl ether, 2-ethoxyethanol , N-dimethylforamide and N, N-dimethylacetamide and their mixtures with water.

The hydrogen pressure used to carry out the dehalogenation process is generally not critical and depends primarily on the plant used. Generally, pressures between atmospheric and about 140.6 at are preferred. As is known, hydrogenation at atmospheric pressure is generally carried out in a device in which the measured volume of hydrogen is in a storage container which is connected to a pressure gauge in order to measure the volume of the hydrogen consumed. Alternatively, a citrate in a magnesia bottle (Parr bottle) and a mechanical shaker with a calibrated pressure gauge, such as a Parrian hydrogenation apparatus or a high pressure autoclave of the stirred or shaken unit, can be used.

The dehalogenation process is preferably carried out at temperatures in the range from 0 ° to 150 ° C. A particularly preferred temperature range is between 25 ° and 100 ° C.

If the dehalogenation process is carried out only with a compound of the general formula II, the first product formed is the hydrogen halide addition salt of the general formula I. This can be isolated as such or can be converted into the free base by treatment with an aqueous alkali solution , such as, for example, sodium hydroxide or potassium hydroxide, and subsequent filtration of the base or extraction into a water-immiscible solvent, such as, for example, ethyl 5 633794

ether, chloroform or methylene chloride. Alternatively, the process can be carried out in the presence of an acid acceptor to directly obtain the free base of the compound of general formula I and the halogen salt of the acid acceptor. The term “acid acceptor” means a basic compound which, when added to the reaction mixture and used in the process according to the invention, selectively reacts with the released hydrogen halide to form a halogen salt, without essential by-products being formed by further reaction with the Reactants or the products, and has no or no adverse effect on the catalyst used. In order to successfully compete for the hydrogen halide formed in the underlying process, the acid acceptor should generally be a stronger base than the reactant of general formula II and the product of general formula I, ie it should be a base with a pKβ of 7 or be less.

Examples of suitable acid acceptors are amines, such as, for example, triethylamine, N-methylpyrrolidine, triethanolamine, n-butylamine, benzylamine, isoamylamine, morpholine and piperidine, ammonia, hydrazine and alkali metal and alkaline earth metal oxides and hydroxides, such as those of Sodium, potassium, magnesium, calcium and barium. 25 The most preferred acid acceptor is triethylamine for ease of use, price and efficiency.

The acid acceptor is preferably added in an amount which is at least sufficient to neutralize n-1 moles of halo-30 hydrogen per mole of compound II, where n is the number of halogen atoms per mole of the starting substance of formula II, ie, n is one Integer from 1 to 3. If the amount of the acid acceptor is at least 35 equivalent to the amount of hydrogen halide formed, the product is usually the free base of the general formula I. In such cases, an excess of acid acceptor can optionally be used. If, on the other hand, n-1 equivalents of the acid acceptor are used per mole of the compound of the general formula II, the product obtained is usually the hydrogen halide salt of the compound of the general formula I. If, for example, X in the starting substance of the general formula II denotes a chlorine atom , n has the value 3 and 2 equivalents of the acid acceptor are used per mole of the compound of the general formula II, the product obtained is the hydrochloride salt of the compound of the general formula I.

If it is desired to use an acid acceptor in the dehalogenation process, it is preferred to use at least one equivalent of the acid acceptor per mole of the compound of the general formula II.

The time it takes to substantially complete the dehalogenation process of the invention is normally dependent on such factors as temperature, catalyst and the exact appearance of the starting substance of general formula II. In general, however, the dehalogenation process becomes essentially within a period of 0.5 to 24 hours.

As mentioned above, the product of the dehalogenation process is either the free base of general formula I or its hydrochloride, hydrobromide or hydroiodide salt. Alternatively, each of these products can be isolated and further purified using methods known to those skilled in the art. E.g. the free base 65 can often be isolated only by evaporating the solvent after the catalyst has been removed by filtration, whereupon the product precipitates or by adding a non-solvent, such as, for example, hexane or heptane,

633794

is made to fail. The free base can be further purified by methods such as recrystallization or column chromatography on silica gel. If the product obtained in the dehalogenation process is one of the aforementioned hydrogen halide salts of the compound of the general formula I, it can be converted into the free base and isolated as described above. The hydrogen halide salt can also be isolated by heating the reaction mixture to ensure a solution of said hydrogen halide salt, then filtering the reaction mixture to remove the catalyst and then concentrating the filtrate to a small volume and finally cooling, whereupon the desired product usually fails. If necessary, it can be cleaned, for example by recrystallization.

The compounds of the general formula II which can be prepared according to the invention, in which X represents a chlorine, bromine or 5 iodine atom and n denotes an integer from 1 to 3, are new compounds. They can 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-dimethoxy-quinazoline by using the appropriate halogen-substituted starting material be represented in any case. The methods for preparing the compounds of the general formula II are described in more detail below as Method A and Method B.

Method A

CH-0

(x) ^ (n)

... III

. . .IV

CH-Q

CH-, 0

"\

w

NH +

(II)

. . .VI

In each of the compounds of the general formula III and VI, A represents a chlorine or bromine atom and (X) n has the meaning given above. The compounds of general formulas III and V can be obtained, for example, by methods described in US Pat. No. 3,511,836. The acrylic halides of the general formula VI are normally obtained by reacting the corresponding halogenated 2-furoic acids by known methods, for example by reacting the acids mentioned with an excess of thionyl chloride or thionyl bromide and subsequently evaporating the reaction mixture. Of the halogenated furoic acids from which the compounds of the general formula VI are obtained, 5-bromo-2-furoic acid is normally commercially available. The remaining chloro and bromofuroic acids are prepared, for example, by methods described by Shepard et al., Jour. Amer. Chem. Soc., Vol. 52, page 2083 (1930) and Gilman et al., Journ. Amer. Chem. Soc., Volume 57, page 1146 (1935) and in the literature citations listed therein. The iodofuroic acids are usually obtained from the corresponding iodine fururals by oxidation with alkaline peroxide by methods described by Borisova et al., Chem. Abstr., Volume 73, page 35 134 f (1970) or by the method Sornay et al., Bull. Soc. Chem., France, page 990, (1971).

When using method A, the 1-substituted piperazine of the general formula IV, which can be prepared from the acid halides of the general formula VI described above, and an equimolar amount of piperazine are preferably in approximately equimolar amounts in the presence of an inert organic solvent implemented. The reaction can be carried out in a wide range of temperatures, but the temperature range from 50 ° to 150 ° C. is preferred. The reaction is usually complete in 1 to 24 hours. The product can be isolated in the form of the hydrochloride or hydrobromide and subsequently converted into the free base of the general formula II by standard methods. Alternatively, the reaction can be carried out in an alkaline manner, for example with sodium hydroxide or potassium hydroxide, and the free base can be isolated by extraction and evaporation of the solvent. Examples of suitable 60 inert solvents for this process are alkanols, such as, for example, ethanol, n-butanol, isoamyl alcohol, n-hexanol or cyclohexanol, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, diethylene glycol, diethyl ether, ethylene glycol-n -butyl ether, chloroform and 65 methylene chloride.

When using method B, a compound of general formula II and an equimolar amount of a compound of general formula VI are preferably in counter

7

633794

were implemented a suitable reaction-inert solvent. The reaction is preferably carried out at a temperature of from -20 ° to 100 ° C. Examples of suitable solvents in this process are the same as described for Method A above. The reaction is usually completed in a few minutes to 10 hours. The desired product is usually isolated by standard methods, such as adjusting the reaction mixture to an alkaline pH by adding an aqueous alkali such as sodium hydroxide, potassium hydroxide or sodium carbonate, and then extracting the product with a water-immiscible solvent , such as chloroform or methylene chloride and then evaporating the solvent.

For economic reasons and for reasons of efficiency, particular preference is given to the compounds of the general formula II in which n is 1 and X is a chlorine or bromine atom. The 2- [4- (5-bromo-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline is particularly preferred. 20th

The following non-limiting examples are preferably presented to further illustrate the invention. Examples 1 to 3 illustrate the preparation of the new compounds of general formula II and Examples 4 to 8 explain the dehalogenation process.

evaporated to a small volume by evaporation under reduced pressure, cooled, filtered, washed with water and dried. 18.8 g of the product with a melting point of 206 to 209 ° C. were obtained. This was dissolved in a mixture of chloroform and methanol, dried over sodium sulfate, treated with carbon and then the solvent was replaced by ethyl acetate. After crystallization, 9.8 g (53%) of the purified product with a melting point of 213 to 215 ° C. were obtained.

Analysis: Calculated for C19H20N5O4

Analysis: Calculated for C9H11O2N2

Calc: C 41.72 Found: C 41.44

H 4.28 H 4.35

N 10.81 N 10.66

Ber. 30.84 calc. 30.49

Example 1 (continued)

In a reaction vessel, 9.55 g (0.04 mol) of 4-amino-2-chloro-6,7-dimethoxyquinazoline, which had been prepared by the process of US Pat. No. 3,511,836, 200 ml of isoamyl alcohol and 20.7 g (0.08 mol) of the l- (5-bromo-2-furoyl) piperazine obtained as described above. The suspension obtained was heated under reflux for 90 minutes, then cooled, filtered and washed with ethanol. 21.8 g of the crude hydrochloride salt of the title compound were obtained, which melted at 276 to 278 ° C. with decomposition. This was slurried in 200 ml of ethanol and 2N sodium hydroxide solution was added to obtain a solution. The solution was

Calc .: C 49.36 Found: C 48.70

H 4.36 H 4.36

N N

15.15; 14.87;

Ber. Ber.

17.28 16.87

example 1

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

In a flask containing 19.1 g (0.10 mol) of 5-bromo-2-furoic acid in 100 ml of chloroform, 20 g of thionyl chloride were added and the mixture obtained was stirred at room temperature for 2 hours. Then it was left overnight. The volatiles were subsequently evaporated under reduced pressure to obtain the 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 allowed to stir for an additional hour and then made alkaline by adding a 2N sodium hydroxide solution. The organic layer was separated and the aqueous layer was repeatedly extracted with methylene chloride. The organic layers were dried over anhydrous potassium carbonate and subsequently evaporated to dryness. 23 g of l- (5-bromo-2-furoyl) piperazine were obtained. A portion was crystallized from methylene chloride-ethyl acetate, melting point 113 to 115 ° C.

25th

30th

35

40

45

EXAMPLE

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

3-chlorofuran-2-carboxylic acid was prepared according to the method of Shepard et al. shown and reacted at room temperature with an excess of thionyl chloride. Subsequent evaporation under reduced pressure gave the acid chloride as a residue.

A solution of 28.9 g (0.10 mol) of 2- (1-piperazinyl) -4-amino-6,7-dimethoxyquinazoline, which had been prepared according to the process of US Pat. No. 3,511,836, in 300 ml Methanol was mixed with 16.5 g (0.10 mol) of the above acid chloride with vigorous stirring in 30 minutes and the resulting mixture was stirred for a further 3 hours at room temperature. The solvent was removed under reduced pressure and the residue slurried with methylene chloride and made alkaline with a 2N sodium hydroxide solution. The organic layer was separated, dried over sodium sulfate and evaporated to dryness to give the title compound.

If thionyl bromide was used instead of thionyl chloride in the process described above and the acid bromide obtained was reacted with 2- (l-piperazinyl) -4-amino-6,7-dimethoxyquinazoline, essentially the same results were achieved.

Example 3

When the procedure of Example 1 or Example 2 was repeated using the appropriate halo-2-furoyl chloride or halo-2-furoyl bromide in place of the acid chlorides, the following compounds were obtained in a similar manner.

50

60

<X).

65

c

II

0

rr v crs

Process according to Example No. 1 3-chloro-2-furoyl 1 4-chloro-2-furoyl

633 794

8th

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 4,5-dibromo-2-furoyl

1 5-iodo-2-furoyl

2 4-iodo-2-furoyl

The 2-furoyl chlorides or bromides are made from the corresponding halogen-2-furoic acids. The chlorine and bromofuroic acids are made according to the methods of She-pard et al., Journ. Amer. Chem. Soc., Vol. 52, page 2083 (1930) and Gilman et al., Jour. Amer. Chem. So., Volume 57,

Page 1146 (1935) and according to the methods of the literature references cited there. The iodofuroic acids are prepared from the corresponding iodine fururals by oxidation with alkali peroxide according to the method of Borisova et al, Chem. Abstr. Volume 73, page 35134 f (1970) or according to the method of Sorney et al, Bull, Soc. Chem., 20 France, page 990 (1971).

Example 4

1.0 g (2.15 mmol) of 2- [4- (5-bromo-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxy-25 quinazoline are placed in a Parr pressure bromine , 10 ml of methanol, 1.0 ml of triethylamine and 0.4 g of a 5% Pd on carbon (50% wet). The pressure bottle was placed in a Parr shaker and a hydrogen pressure of 3.5 atm at room temperature was applied. After stirring for 18 hours, the theoretical amount of hydrogen was taken up. The mixture of catalyst and precipitated product was filtered and the solids were slurried in 25 ml of chloroform and filtered again to remove the catalyst. 50 ml of hexane were added to the filtrate, the mixture was stirred for 10 minutes and then filtered. The crude product was obtained, which was purified over a 45.7 cm × 7.6 cm silica gel column, eluting with ethyl acetate-diethylamine (90:10 parts by volume). 300 mg of 2- [4- (2-furoyl) piperazin-l-yl] - 40 4-amino-6,7-dimethoxyquinazoline with a melting point of 266 ° C. were obtained. The product was identified by comparing the infrared spectrum in chloroform with the infrared spectrum of an authentic sample and by thin layer chromatography on silica gel. 4S

Example 5

4.18 g (0.10 mol) of 2- [4- (3-chloro-2-furoyl) piperazin-l-yl] -4-amino-6,7-dimethoxyquinazoline were placed in a flask for hydrogenation at atmospheric pressure. 75 ml of 95% so ethanol, 0.50 g (0.10 mol) of hydrazine hydrate and 0.5 g of a catalyst which contained 98 parts by weight of palladium and 2 platinum. The resulting mixture was cooled to 0 ° C and exposed to hydrogen gas at atmospheric pressure for 4 hours. The mixture 55 was then filtered to remove the catalyst, subsequently concentrated to dryness under reduced pressure and finally distributed between methylene chloride and water. The organic layer was dried over sodium sulfate and evaporated to dryness to give the 2- [4- (2-furoyl) piperazin-l-yl] -4-amino-6,7-dimethoxyquinazoline which was purified by column chromatography on silica gel has been.

When the above procedure is repeated using 0.5 g of a catalyst containing 99.9 parts by weight of palladium and 0.1 part by weight of platinum, the results are essentially unchanged.

Example 6

9.24 "g (0.02 mol) of 2- [4- (4-bromo-2-furoyl) piperazin-l-yl] -4-amino-6,7-dimethoxyquinazoline, are placed in a 500 ml autoclave. 2.0 g of a 50% wet Raney nickel catalyst and 200 ml of 70% ethanol (7: 3 ethanol / water in parts by weight) were added and the mixture was kept at 100 ° C and 14.1 at hydrogen pressure for 30 minutes and then The catalyst was removed by filtration and the filtrate was concentrated to remove the ethanol. The concentrate was made alkaline with potassium carbonate, extracted with chloroform and the extracts concentrated to dryness. The 2- [4- (2-furoyl) -piperazin-l-yl] -4-amino-6,7-dimethoxyquinazoline The product can be further purified by column chromatography on silica gel.

Example 7

4.18 g (0.10 mol of 2- [4- (4-chloro-2-furoyl) piperazin-l-yl] -4-amino-6,7-dimethoxyquinazoline, 200 were placed in a flask for hydrogenation at atmospheric pressure ml of isoamyl alcohol and 0.20 g of a powdery catalyst containing 99.9 parts by weight of palladium and 0.1 part by weight of rhodium were added The mixture obtained was hydrogenated under atmospheric pressure for 2 hours with vigorous stirring and the theoretical amount of hydrogen was consumed The mixture was then removed from the device, heated to boiling and filtered hot to remove the catalyst, the filtrate was cooled in ice and then filtered to give 2- [4- (2-furoyl) piperazin-l-yl ] -4-amino-6,7-dimethoxyquinazoline hydrochloride obtained.

Repeating the above procedure using 0.01 mole of 2- [4- (5-bromo-2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline in place of the corresponding related 4- Chloro-2-furoyl compounds used above similarly gave 2- [4- (2-furoyl) piperazin-l-yl] -4-amino-6,7-dimethoxyquinazoline hydrobromide .

Example 8

When the specified halogen-containing starting substances, which were obtained from the products according to Examples 1 to 3, were subjected to the conditions listed below, the 2- [4- (2-furoyl) piperazin-l-yl] -4-amino- Obtained 6,7-dimethoxyquinazoline either as the free base or as the said hydrohalide salt.

Starting substance

Reaction conditions

Isolated product

Mol

catalyst

temperature

time

Solvent"

Acid-

Hydrogen-

(° C)

(Hours)

acceptor "1"

Pressure (at)

3,4-dichloro-2-

5% Pd / C (2)

O O

O

3rd

Dioxane

TEA (0.10)

1.1

HCl salt furoyl 0.10

3,4,5-trichloro-2-

10% Pd / C (0.8)

150 °

2nd

Isoamyl alcohol

TEA (0.15)

7.0

Free base furoyl 0.05

9 633794

Example 8 (continued)

Starting substance

Reaction conditions

Isolated product

Mol

catalyst

Temperature (° C)

time

(Hours)

Solvent*

Acid acceptor +

Hydrogen pressure (at)

3-bromo-2-

99.9% palladium,

45 °

10th

Ethanol water

MgO (0.05)

3.5

Free base furoyl

0.05

0.1% ruthenium

7: 3 (w / w)

(w / w) (0.2)

5-bromo-2-

99.9% palladium 1%

25 °

12th

Methanol

ammonia

1.1

Free base furoyl

0.10

Rhodium (w / w) (0.5)

(0.20)

4,5-dibromo-2

Copper powder (1)

50 °

4th

Methanol

Ba (OH) (0.20) 2

1.1

Free base furoyl

0.05

5-iodine-2-

Raney cobalt

25 °

6

n-butanol

1.1

HJ salt furoyl

0.02

50% (1)

4-iodine-2-

Pd / ru 98: 2 (w / w)

25 °

5

THF

N-methylpyr

1.1

Free base furoyl

0.01

(0.1)

rolidine (0.02)

5-iodine-2-

Pd / Rh 98: 2 (w / w)

25 °

6

Ethanol

7.0

HJ salt furoyl

0.01

(0.1)

5-bromo-2-

5% Pd / C (1.5)

25 °

10th

DMF-H2O (8: 2)

CaO (0.05)

140.6

Free base furoyl

0.10

(f / f)

5-chloro-2-

Raney Cobalt Raney 25 °

8th

Ethanol water

NaOH (0.10)

1.1

Free base furoyl

0.10

Copper 1: 1 (w / w) (1.0)

7: 3 (w / w)

"THF = tetrahydrofuran, DMF = N, N-dimethylformamide + TEA = triethylamine

B

Claims (13)

633794 2nd PATENT CLAIMS 1. Process for the preparation of a new compound of general formula II CH-, 0 Y \ - /! (II) in which X represents a chlorine, bromine or iodine atom, and n is one in which either Y or Z represents a radical of the formula integer from 1 to 3, characterized in that that a 6,7-dimethoxyquinazoline of the general formula CHjO with a halogen-substituted furan of the general formula 20th 25th 30th / "A Yv1 means, and the other radical each represents a chlorine or bromine atom, and X and n have the meaning given above, is reacted. 2. Use of the new compounds of general 35 formula II wherein X represents a chlorine, bromine or iodine atom, and n represents an integer from 1 to 3, for the preparation of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7 dimethoxyquinazoline of the formula I. CH, 0 (I) or its hydrochloride, hydrobromide or hydroiodide salt by dehalogenation. 3. Use according to claim 2, characterized in that compounds of the formula II are reacted with hydrogen in the presence of a catalytic amount of a dehalogenation catalyst and in the presence of an inert solvent at a temperature of 0 ° to 150 ° C. 4. Use according to claim 3, characterized in that the dehalogenation catalyst on little- 55 at least one carrier material is applied. 5. Use according to one of claims 3 to 4, characterized in that the dehalogenation catalyst is palladium, copper, cobalt or nickel or a mixture of palladium with platinum, ruthenium or rho- Is 60 dium. 6. Use according to one of claims 3 to 5, characterized in that the dehalogenation takes place in the presence of an acid acceptor. 7. Use according to claim 6, characterized in 65 that the acid acceptor has a pKa of 7 or less. 8. Use according to any one of claims 6 to 7, characterized in that at least one equivalent of the acid 3rd 633794 is used per mole of the compound of general formula II. 9. Use according to claim 6, characterized in that at least one equivalent of triethylamine is used as the acid acceptor. 10. Use according to claim 3, characterized in that the dehalogenation reaction is carried out at a temperature of 25 ° C to 100 ° C. 11. Use according to claim 3, characterized in that the catalyst is palladium or palladium-on-carbon. 12. Use according to claim 3, characterized in that the catalyst consists of a mixture which contains 98 to 99.9 parts by weight of palladium and 0.1 to 2 parts by weight of platinum, ruthenium or rhodium. 13. Use according to claim 3, characterized in that n has the value 1 and X represents a chlorine or bromine atom. This compound is generally valuable due to its ability to lower blood pressure in hypertensive mammals. This use is known from US Pat. No. 511,836. s Various processes for the preparation of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline are known from US Pat. No. 511,836. An example is the reaction of 2-chloro-4-amino-6,7-dimethoxyquinazoline with 1- (2-furoyl) piperazine or the reaction of 2- [4- (2- lo furoyl) -piperazin-l-yl] -4-chloro-6,7-dimethoxyquinazoline with ammonia or finally the acylation of 2- (l-piperazinyl) -4-amino-6,7-dimethoxyquinazoline with e.g. 2-furoyl chloride. Methods are known from US Pat. No. 3,935,213, by which is 2- (4-substituted-piperazin-1-yl) -4-amino-6,7-dimethoxyquinazolines including 2- [4- (2-furoyl ) -piperazin-l-yl] -4-amino-6,7-dimethoxyquinazoline can be prepared by: 20 (1) reaction of 4,5-dimethoxy-2-aminobenzonitrile with certain 1,4-disubstituted piperazines or