DK146625B - 2-HALOGEN-4- (PROTECTED AMINO) QUINAZOLINE DERIVATIVES USED AS INTERMEDIATES IN THE PREPARATION OF 2- (4- (2-FUROYL) PIPERAZIN-1-YL) -4-AMINO-6,7-DIMETHOXYQUINAZINE - Google Patents

Description

Mf! | P

(19) DENMARK

t (i2) PUBLICATION MANUAL (n) 146625 B

DIRECTORATE OF THE PATENT-00 TRADE MARKET

(21) Patent Application No. 2408/77 (51) Intel.3: C 07 D 239/95. . C 07 D 403/04 (22) Notice: 01 Jun 1977 // C07D 405/12 (41) Aim. available: 16 Dec 1977 (44) Submitted: 21 Nov 1983 (86) International Application No: - (30) Priority: 15Jun1976US696201 (71) Applicant: * PFIZER INC .; New York, US.

(72) Inventor: Philip Dietrich 'Hammen; US.

(74) Fluid: Hofman-Bang & Boutard Patent Office (54) 2-Halogen-4- (protected-amino) quinazoline derivatives for use as intermediates in the preparation of 2- {4- {2-furoyl) piperazine-1 yl) -4-amino-6,7-dimethoxyquinazoline

This invention relates to novel 2-halogen-4- (protected-amino) -quinazoline derivatives for use as intermediates in the preparation of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxy - 'quinazoline, called prazosin.

2-Piperazino-4-aminoquinazoline derivatives of the general formula

ISLAND ISLAND

in Ri CM. j "v I" 'VVv'w I 1 □ Xv / xv *

CH3 ° I

Wherein R is hydrogen or methoxy and R is alkenyl of 3-5 carbon atoms, benzoyl, furoyl, thienylcarbonyl, alkoxy carbonyl of 2-5 carbon atoms, alkenyloxycarbonyl of 4 or 5 carbon atoms or (2-hydroxyalkoxy) carbonyl with 4 or 5 carbon atoms, are known chemical compounds which are valuable because of their ability to lower blood pressure in hypertensive mammals.

More specifically, these hypotensive compounds are certain 2- (4-substituted-piperazin-1-yl) -4-amino-6,7-dimethoxyquinazolines and 2- (4-substituted-piperazin-1-yl) -4-amino-6 , 7,8-trimethoxyquinazolines disclosed in U.S. Patent Nos. 3,511,836 and 3,669,968.

U.S. Patent No. 3,511,836 discloses several processes for preparing 2- (4-substituted-piperazin-1-yl) -4-amino-6,7-dimethoxyquinazolines, for example, by reacting 2-chloro-4-amino 6,7-dimethoxyquinazoline with the appropriate 1-substituted piperazine, by reacting a 2- (4-substituted-piperazin-1-yl) -4-chloro-6,7-dimethoxyquinazoline with ammonia or by alkylation, alkanoylation, aroylation or alkoxylation of 2- (1-piperazinyl) -4-ramino-6,7-dimethoxyquinazoline. U.S. Patent No. 3,669,968 discloses the preparation of 2- (4-substituted-piperazin-1-yl) -4-amino-6,7,8-trimethoxyquinazolines by reaction of 2-chloro-4-amino-6.7,8-trimethoxyquinazoline with the appropriate 1-substituted piperazine.

U.S. Patent No. 3,935,213 discloses the preparation of 2- (4-substituted-piperazin-1-yl) -4-amino-6,7-dimethoxyquinazolines and the corresponding 6,7,8-trimethoxyquinazolines in the process comprising either (1) reacting the appropriate 4,5-dimethoxy-substituted or 3,4,5-trimethoxy-substituted 2-aminobenzonitrile with certain 1,4-disubstituted piperazines, or (2) reacting the appropriate 4, 5-dimethoxy- or 3,4,5-trimethoxy-substituted 2-aminobenzamidine with the same 1,4-disubstituted piperazines.

Compounds of Formulas: CH-ϊΟ Cl 2 CH, 0 ^ .N / \ V VK Η-Ϊ XJLJ ° e Xjflw ch3o ch3 ° NHCH2CgH5 NHCH2CgH5 (II) (IV) 3 146625 wherein Y means hydrogen, alkyl of 1-5 carbon atoms , hydroxyalkyl of 2-5 carbon atoms, alkanoyl of 2-7 carbon atoms, allyl, proparyl, 2-methallyl, phenyl, benzyl, benzoyl, chlorobenzoyl, bromobenzyl, trifluoromethyl, methoxyphenyl, methylphenyl, methylbenzoyl, trofluoromethylbenzoyl, furoyl, benzof , thenoyl, pyridinecarbonyl, 3,4,5-trimethoxybenzoyl, carboxylic acid alkyl ester wherein alkyl has 1-6 carbon atoms and carboxylic acid alkenyl ester where alkenyl has 3-6 carbon atoms are disclosed as intermediates in U.S. Patent No. 3,511,836 .

A particularly valuable compound of formula I, namely 2- [4- (2-furoyl) piperazine-1-yl] - <-amino-6,7-dimethoxyquinazoline, has recently been reported to have therapeutic utility in humans (Cohen, Journal of Clinical Pharmacology, 10, 408 (1970);

De Guia, et al., Current Therapeutic Research, L5, 339 (1973)).

The method of U.S. Patent No. 3,511,836 is the only method exemplified in the prior art for the preparation of prazosin; and the reactions involved are illustrated in the following Reaction Scheme A: A.

»3raVYV C1 H0C ° 2Et -, W ΊΓ, ^ Ψ æ” H3C0 ^^ V / N NCO-Et HCO. ) 111 i T j h? °, Tii i H rnA / V1 "(3) r XJU® H3C0 I H3CO y nh2 nh2 furoyl chloride 3 c —nn— * ΓΤ T ^ i 0

H 3> ^ VN

nh2 4 146625

It will be seen that this prior art requires 4 steps to prepare the desired compound from the commercially available starting material, 2,4-dichloro-6,7-dimethoxyquinazoline. No yield is indicated for this reaction sequence.

It has been found that the use of novel compounds of the formula ^ VvV1 1 x 1 ch3ct \ ^^ \ ^ ... (V) λ n. . D30,,,,, n, and R means -COCH, -CO, HI- or wherein R means hydrogen '3' 6 5 nnnn 11. "i / fei allows to produce -COOC, Η,. , as intermediate 3 s * · „. -. ,. step from the same starting mate the desired compound in two. ,,,,,, 4. the following Scheme B: needles, as illustrated by the 1 6.

“3 \ yVC1. W

h3co ^^ Y'k 7 »* h3C0 / O- ^ in NHCCLEt

Cl Z

1- (2-Furoyl) piperazine, cf (2> 1 * 0)

37% n3c0 I

NH 2 µ x 37 _ 26

Total Yield: When R 2 and in the formula (V) together with the nitrogen atom to which they are attached form a phthalimido group, the desired compound can be prepared in three steps as explained below, wherein the last step is a simple hydrolysis or cleavage with hydrazine which can be carried out with high yield.

Accordingly, the compounds of the invention are characterized in that they have the formula (V) specified in the characterizing part of the claim or are acid addition salts thereof.

These compounds are useful as intermediates in a process for the preparation of prazosin, wherein the compounds (V) are reacted with 1-2 moles of 1- (2-furoyl) piperazine of the formula ΛΛ J ~ \, HN NCf> (III) When the process is carried out with a first reactant of formula (V) wherein R R and R ^ together with the nitrogen atom to which they are attached form a phthalimido group, it is preferred to use equimolar amounts of the reactants. to form an intermediate of formula (VI)

CH3o J

γγγ w \

OC CO

& 6 148625

Said intermediate is further reacted at a temperature of 0-100 ° C to form the final product prazosin: (a) by hydrolysis or (b) by reaction with an equimolar amount of hydrazine in the presence of a reaction-inert organic solvent.

A particularly preferred temperature for the further reaction of the intermediate of formula (VI) by hydrolysis or with hydrazine is 20-50 ° C.

When hydrolysis is used, it is preferred that it be carried out in the presence of hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.

When the process is carried out with a compound of formula (V) wherein R R is hydrogen and R40 er is COCH₂, -COCgHg or -CCKX ^Hg, the desired compound, prazosin, or the hydrochloride or hydrobromide acid addition salt is obtained directly. thereof. In the latter case, it is preferred to react one mole of the first reactant of formula (V) with 2 moles of 1- (2-phenyl) piperazine (III).

The reaction of the compounds of formulas (V) and (III) is carried out in the presence of a suitable reaction-inert organic solvent. A suitable solvent is one which will serve to substantially dissolve the reactants and will not adversely affect the reactants or products in the reaction. Examples of such solvents are alkanols such as isopropanol, butanol, isobutanol, isoamyl alcohol 2-methyl-2-pentanol and 3,3-dimethyl-1-butanol, glycols such as ethylene glycol and diethylene glycol, glycol ethers such as ethylene glycol monomethyl ether, diethylene glycol monoethyl , 1,2-dimethoxyethane and diethylene glycol dimethyl ether, tertiary amides such as N, N-dimethylformamide, Ν, Ν-diethylacetamide and N-methylpyrrolidone, dimethylsulfoxide and pyridine. Although the reaction can be carried out over a wide temperature range, a temperature in the range of 50-200 ° C is preferred. A particularly preferred temperature range is 80-130 ° C.

The time required for the process to reach substantial completion varies according to several factors, such as the reaction temperature, the reactivity of the particular starting materials used, and the concentration of the reactants. At lower temperatures, longer reaction times are required, while the reaction at higher temperatures is completed in a shorter time. A reaction time of from 15 minutes to 50 hours is generally satisfactory.

In some cases, by reacting a compound of formula (V) with 1- (2-furoyl) piperazine (III), an intermediate of formula (VI) which is then further reacted to obtain the desired compound is formed prazosin. Thus, the process can be carried out either in one or two steps as shown in the following 2 reaction scheme wherein R stands for 2-furoyl and where in the case of methods A R30 and R40 together with the nitrogen atom to which they are attached form a phthalimido group, and in the case of method B R30 is hydrogen and R40 is COCH ,, COC, Hc o 6 5 or -COOC ^.

CH, 0 M rl _ CH, 0 ^ „/ \ r_R2

YW ·. * YYY W

N (III) I

R30 "V ° / / N \" (V) / \ y

\ / O

(VI) ΛΆ 2 n h-r

CH 3 O ^ S ^ S ^ N

™ 2 (I) 146625 δ When the reaction is carried out in two steps, as shown by method A of the above reaction scheme, as shown compounds of formula (V) wherein R R and O40 together with the nitrogen atom to which they are attached are used. Such compounds of formula (V) react as mentioned with 1- (2-furoyl) piperazine (III) to form an intermediate of formula (VI) or hydrochloride or hydrobromide salts thereof. It is preferred to carry out the reaction using approximately equimolar amounts of the reactants for economy and efficiency, however, this is not necessary for the reaction to be carried out and an excess of one or the other reactant may be present. The intermediate of formula (VI) may be suitably isolated in form of the hydrochloride salt or hydrobromide salt, both of which are generally insoluble in the reaction solvent and thus obtainable only by filtration and washing. during the reprocessing of the reaction mixture is treated with an alkaline reagent, e.g. sodium hydroxide, potassium hydroxide, potassium carbonate or sodium methoxide, followed by extraction of the free base into a water-immiscible solvent, such as chloroform, dichloromethane or benzene, and evaporation to dryness. If desired, either the compound of formula (VI) or its salt can be further purified by standard methods such as crystallization or column chromatography. However, they are often sufficiently pure for further reaction to form prazosin without any further purification.

As mentioned above, the compound of formula (VI) or its hydrohalide salt is further reacted to remove the phthalimido group by hydrolysis or with hydrazine to give the desired compound, prazosin.

Said hydrolysis can be carried out under alkaline conditions in the presence of e.g. sodium hydroxide or potassium hydroxide, or under acidic conditions using a suitable acid. Examples of such suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, hydrogen iodic acid, dichloroacetic acid and trifluoroacetic acid. It has been found to be particularly convenient and effective to use hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. It is preferred to carry out the hydrolysis with one of these acids at a temperature in the range of 0-100 ° C, with a particularly preferred temperature range for the hydrolysis being 20-50 ° C. At temperatures below 0 ° C, the rate of hydrolysis is disproportionately low.

At temperatures above 100 ° C, excessive amounts of degradation products are formed.

The mole ratio of the above acid to the compound of formula (VI) may vary over a wide range and thus mole ratios of from 1: 1 to 200: 1 can be used with satisfactory results. The time required for substantial completion of the hydrolysis will vary according to the reaction temperature, and if worked at 100 ° C, a few minutes are usually sufficient and if worked at 0 ° C, up to 24 hours may be required to reach completion. The hydrolysis may be carried out in an aqueous medium or an aqueous-organic medium using a water-immiscible organic solvent such as e.g. chloroform, methylene dichloride, benzene or toluene. Upon completion of the hydrolysis, which can be readily determined by thin layer chromatography on silica gel using a solution system of e.g.

95-5 ethyl acetate / diethylamine, the prazosin can be isolated as a salt of the acid used in the hydrolysis using methods well known in the art. However, it is generally more convenient to adjust the reaction mixture to an alkaline pH by adding e.g. sodium hydroxide, potassium hydroxide or sodium carbonate, followed by extraction of the prazosin as the free base, with e.g. one of the above-mentioned organic solvents which could possibly be used in the hydrolysis. The product is then easily isolated by evaporation.

10 146625

Alternatively, as mentioned above, the intermediate of formula (VI) may be further reacted with hydrazine to form the final product, prazosin. The use of hydrazine to remove the phthaloyl group from phthalimido acids or the corresponding lower alkyl esters is known, see e.g. Boissannas, Advances in Org. Chem., 3, 179-183 (1963) and Sheehan et al., Jour. Amer. Chem. Soc., 76, 6329 (1954). It has now been found that the above intermediate of formula (VI) also reacts to form the desired product, prazosin. The reaction is carried out in the presence of a reaction inert organic solvent. Examples of organic solvents which may be used in this reaction are the lower alkanols such as ethanol, propanol, isopropanol, butanol and isoamyl alcohol; Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, dimethyl sulfoxide, diethylene glycol dimethyl ether and diethylene glycol monoethyl ether.

Bet hydrazine used may be substantially pure hydrazine or a derivative such as hydrazine hydrate, hydrazine hydrochloride or hydrazine sulfate. When the acid addition salts are used, the hydrazine is produced in situ by the addition of a suitable base to neutralize the acid. Examples of such suitable bases are sodium methoxide, potassium carbonate, triethylamine, triethanolamine and sodium hydroxide. Although a molar excess of hydrazine of up to 5 moles per mole can be used successfully. mole of intermediate (Vi) in this reaction, it is preferred to use an equimolar amount of hydrazine to reduce any side reactions and for economic reasons. Bet is preferred to carry out the reaction with hydrazine at temperatures of 0 to 100 ° C. A particularly preferred temperature range is 20-50 ° C. At temperatures above 100 ° C, undesirable side reactions occur, while the reaction rate at temperatures below 0 ° C is disproportionately low.

The time required for substantial completion of the reaction will, of course, vary with the temperature and the exact nature of the reactants and the solvent. Generally, however, the reaction with hydrazine to form the final product prazosin will be substantially complete within 1-48 hours. The reaction of hydrazine with the above-mentioned phthalimido compound (VI) also forms a cyclic hydrazide by-product, phthaloylhydrazide. The reaction mixture can be freed from this cyclic hydrazide by-product, and the desired product, prazosin, can be isolated by methods well known in the art, such as e.g. evaporation to dryness in vacuo, tearing off the residue with dilute strong mineral acid such as hydrochloric or sulfuric acid, wherein the cyclic hydrazide is usually only soluble, filtering and adjusting the filtrate to an alkaline pH and then isolating the desired product by extraction or filtration.

When a compound of formula (V) wherein R 2 is hydrogen and R 40 is -COCH 2 -COC 2 H 4 or -COOC 2 H 2, is reacted with 1- (2-furoyl-piperazine of formula (III)), the reaction takes place directly to form the desired compound prazosin in a step as shown by method B. of the above reaction scheme. Thus, with such a compound of formula (V), the 1-substituted piperazine (III) reacts both in the 2-position of the quinazoline (V) 40 to replace the chlorine atom and during removal of the R group when R R is hydrogen and R ^ is one of the above carbonyl-containing groups to form prazosin in a single step.

Although the one-step process can conveniently be carried out using molar ratios of compound (V) to compound (III) of from 1: 1 to 3: 1 or greater, it is preferred to react the compound of formula (V) with the compound of formula (III) in a molar ratio of 2: 1 for efficiency and economy.

The desired product, prazosin, is readily isolated by standard methods, either in the form of the hydrochloride salt or in the form of the free base. For example, the compound of formula (V) is reacted with 2 moles of the compound of formula (III), the hydrochloride set of prazosin is usually easily obtained by filtration of the reaction mixture and washing of the product. If the free prazosin base is desired, upon completion of the reaction, the reaction mixture is treated with an excess of an aqueous solution of a highly alkaline reagent such as sodium hydroxide, potassium hydroxide or sodium carbonate, and the free base is extracted with a water-immiscible solvent such as chloroform, methylene chloride, 1,2-dichloroethane or benzene. The product can then e.g. obtained by evaporation of the solvent, if desired, further purified.

The novel intermediates of formula (V) are patentably different from the known corresponding compound of formula (II) in view of the aforementioned differences in the methods by which the protecting groups are removed to obtain the desired compounds of formula (I). The known compound having the formula (II) corresponding to (V) wherein R 1 is hydrogen and R is benzyl reacts with the compound of formula (III) to give the known compounds of formula (IV). To remove the benzyl group, this compound is subjected to hydrogenolysis. In contrast, the novel compounds of formula (V) wherein R 1 is hydrogen and R 2 is -COCH 2, -CO 2 H 2 or -CO 2 H 2, react with the compound of formula (III) to give the desired product, prazosin, directly .

The compound of formula (V) wherein and R 1 together with the nitrogen atom to which they are attached form a phthalimido group reacts with the compound of formula (III) to form the novel intermediate of formula (IV) which in turn yields the desired compound prazosin by hydrolysis or reaction with hydrazine as described above.

The compounds of the invention of general formula (V) are prepared from the appropriate 2,4-dihalo-6,7-dimethoxyquinazolines wherein the halogen is chlorine or bromine. The preparation of said dihalogen compounds is previously described in U.S. Patents Nos. 3,511,386 and 3,669,968 and by Curd et al.

Jour. Chem. Soc. (London), 777 (1947); ibid., 1759 (1948).

In the preparation of the novel compound of formula (V) wherein R R and R ^ together with the nitrogen atom to which they are attached form a phthalimi dog group, one of the 2,4-dihaloquinazolines mentioned above is reacted with phthalimide in an reaction-inert organic solvent and in the presence of a strong base, such as sodium hydride, potassium hydride, calcium hydride, sodium methoxide, potassium ethoxide, lithium butoxide or butyllithium, under anhydrous conditions. the formula (V) by standard methods, for example by quenching the reaction mixture in excess of water or dilute acid and filtering, washing and drying to obtain the product, dilution in dilute acid is preferred when the amide or urethane is used.

Examples of reaction-inert organic solvents which may be used are N, N-dimethylformamide, Ν, Ν-dimethylacetamide, N-methyl-pyrrolidone, ethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dimethyl sulfide oxide, toluene and benzene. Preferred reaction-inert organic solvents are Ν, Ν-dimethylformamide and tetrahydrofuran.

The preferred base is sodium hydride for economy and efficiency. Generally, a molar ratio of the strong base to 2,4-dihaloquinazoline of at least 1: 1 is used, and molar ratios of 1: 1 to 2: 1 are preferred.

Although the above reaction can be carried out over a wide temperature range, a temperature in the range of 0-150 ° C and especially in the range of 65-100 ° C is preferred. At below 0 ° C the reaction is disproportionately slow, while at temperatures above 150 ° C excessive amounts of unwanted by-products are obtained. The rate of reaction is faster at higher temperatures and the time required for completion will vary with temperature as well as with the exact nature of the reactants and solvent. However, the reaction is usually completed in 2-24 hours.

The following examples serve to illustrate the invention, Examples 1-4 illustrating the preparation of the compounds of formula (V) and Examples 5-7 illustrating their use as intermediates in the preparation of prazosin.

EXAMPLE 1 2-Chloro-4-pctthalimido-6,7-flimethoxy-quina2oline In a 100 ml three-necked round bottom flask, fitted with a thermometer, stirrer and dryer tube, put 50 ml of Ν, Ν-dimethylformamide, 1.47 g ( 0.010 mol) phthalimide and 0.48 g (0.010 mol) 50% sodium hydride. After stirring at room temperature for 30 minutes, a clear solution was obtained, to which was added 2.59 g (0.010 mol) of 2,4-dichloro-6,7-dimethoxycinazoline and the resulting mixture was cooled to room temperature, then 150 ml of water were added and the precipitated product was isolated by filtration and dried in vacuo to give 3.1 g of the above compound, mp: 255 ° 0. The structure was confirmed by NMR and mass spectral data. Yield: 84 per cent.

EXAMPLE 2 4-Genzoglamino-2-chloro-6A7-dimethoxyquinazoline In a 100 ml three-necked round bottom flask fitted with reflux, thermometer and dryer, 32 ml of dry tetrahydrofuran, 10 ml of dry N, W-dimethylformamide, 6.48 g (0.025 mol) 2,4-dichloro-6,7-dimethoxyquinazoline [prepared according to Curd et al., J. Chem. Soc., 1759 (1948)], 3.03 g (0.025 mole) of benzamide and 2.4 g (0.050 mole) of 50 wt.% Sodium hydride, the hydride being added last.

The resulting mixture was heated at reflux for 24 hours, cooled to room temperature, filtered and washed with tetrahydride of uranium to give 6.0 g (66 f) of the sodium salt of the above compound, mp: 315 ° C.

After slurrying 1.0 g of the sodium salt in 20 ml of water, acidifying to pH 3-4 with 2N hydrochloric acid, stirring for 15 minutes at 20-25 ° C, filtering and drying overnight, 0.67 g of the above was obtained. compound, mp: 235-240 ° C. After recrystallization from isoamyl alcohol, the melting point was 236 - 238 ° C. The mass spectrum showed maxima at M / e 342 and 344.

EXAMPLE 3 Example 2 S 2 S 2 S 2 S 2 S 2 S 2 S 2 S 2 S 2 S 2 S 2 S 2 S 2 S 2 S 2 In a 100 ml reaction vessel 6.48 g (0.025 mol) of 2,4-dichloro-6.7 dimethoxyquinazoline, 1.5 g (0.025 mol) of acetamide, 32 ml of dry N, N-dimethylformamide and 2.4 g (0.050 mol) of 50 µm sodium hydride. After heating to 40 °, an exothermic reaction began and the temperature rose rapidly to 120 ° C with considerable foaming. During this exothermic period, the reaction mixture turned purple and then red. The mixture was cooled to 90 ° C and kept at this temperature for 2 hours. The mixture was then cooled to room temperature, poured into 150 ml of water, washed with two 100 ml portions of chloroform, and the aqueous phase was adjusted to pH 2 by the addition of concentrated hydrochloric acid. The precipitated product was collected by filtration and dried to give an 86 F yield of the above compound, mp: 275 ° C. Only one spot was obtained by thin layer chromatography on silica gel eluting with 95: 5 ethyl acetate / diethylamine. The mass spectrum showed a molecular ion at M / e 281.

EXAMPLE 4 1ζ5ί ^ 22Ζ22ΐΪ222ϊ§5ΐΒ2 ^2 ^ Ζ2- £ ιΖζ £ Ϊΐ2Ϊΐ25Σ22ΐ-22ii 2,4-Dichloro-6,7-dimethoxyquinazoline (6.48 g, 0.025 mol), 32 ml tetrahydrofuran, ethyl carbamate (2.23 g, 0.025 mole) and 50 µl sodium hydride (2.4 g, 0.050 mole) are placed in a 100 ml reaction flask equipped with a thermometer, reflux and drying tube. The reaction mixture was heated under reflux for 2 hours, then 70 ml of methanol was slowly added. The resulting mixture was warmed to 60 ° C and filtered hot, the filtrate was concentrated to a thick slurry, the solid was collected by filtration and washed with 5 ml of chloroform to give 5.4 g (70 f) of the the above connection. A sample, recrystallized from a mixture of tetrahydrofuran and hexane (2: 3), melted at 212 °.

Analysis calculated for C C HH ^ NN ClCl (fo): 0 50.09 - H 4.53 - N 13.48 found: 0 49.95 - H 4.46 - N 13.54.

Example 5 16 2-66 4- [4- (2-Eurogl) giperagin-1-yl] -4-phthalimido do-6,7-dimethoxyquinazoline In a 35 ml single-necked round-bottom flask, provided with reflux and drying tube, 1.0 g (0.0027 mol) of 2-chloro-4-phthalimido - 6,7-dimethoxyquinazoline, 10 ml of isoamyl alcohol and a solution of 0.550 g (0.003 mol) of 1- (2-furoyl) piperazine were added. The resulting mixture was heated to 130 ° C for 4 hours and then cooled to room temperature. To the reaction mixture was added 35 ml of hexane and the precipitated product was collected by filtration and dried to give 0.70 g (47 l of) of the hydrochloride salt of the above compound. The purified free base was obtained from the salt by silica gel chromatography on a 5 x 30 cm column eluting with ethyl acetate / diethylamine (90:10). The purified product melted at 305 ° C.

Similarly, when the above procedure is repeated but using the indicated solvent instead of isoamyl alcohol and the indicated temperature and reaction time, the above compound is obtained.

Solvent Reaction temperature, u0 Reaction time, hours

Isobutanol 50 48 1,2-Dimethboxyethane 80 30

Diethyleneglycone 1- monoethyl ether 200 [2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline by hydrolysis

A solution of 95 mg (0.185 millimole) of 2- [4- (2-furoyl) piperazin-1-yl] -4-phthalimido-6,7-dimethoxyquinazoline in 2.0 ml of concentrated hydrochloric acid was stirred at room temperature for 2 hours. Then 4.0 ml of chloroform was added and the mixture was adjusted to pH 10 by the addition of sodium carbonate solution. The chloroform layer was separated and evaporated to dryness to give 55 mg (77.6 fo) of 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline, m.p. : 270 ° 0. The structure was confirmed by comparing the infrared spectrum with the spectrum of an authentic sample and by thin layer chromatography on silica gel using 95: 5 ethyl acetate / diethylamine as the solution system.

2- [4- (2-Furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline by reaction with hydrazine ____________________________________________

A suspension of 5.14 g (0.01 mole) of 2- [4- (2-furoyl) piperazin-1-yl] -4-phthalimido-6,7-dimethoxyquinazoline in 200 ml of isoamyl alcohol is heated to give solution, and 0.55 g (0.011 mol) of hydrazine hydrate is added, and the resulting solution is stored at 20 ° C for 18 hours and then evaporated to dryness under reduced pressure. The residue is triturated with 30 ml of 0.5N hydrochloric acid and kept at 4 ° C for 2 hours. The solution is filtered to remove the precipitated phthalhydrazide. The filtrate is made alkaline (pH 10) with sodium hydroxide solution, extracted with chloroform and the extracts concentrated to dryness to give 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7- dimethoxyquinazolin.

EXAMPLE 6 2- [4- (1-6,6-7-dimethoxyquinazoline) In a 50 ml flask, provided with a stirrer, reflux and drying tube, was placed 160 mg (0.66 mol) of 4- "benzoylamino-2-chloro-6," 7-Dimethoxyquinazoline, prepared by the procedure of Example 2, 244.2 mg (1.32 mmol) of 1- (2-furoyl) piperazine and 4 ml of isoamyl alcohol, the resulting mixture was heated to 100 ° C for 4 hours and then cooled to room temperature. room temperature, hot precipitated solid was collected by filtration and dried to give 60 mg of crude product, hot identified as 2- [4- (2-furoyl) -piperazin-1-yl] -4-amino -6,7-dimethoxyquinazoline by silica gel thin layer chromatography (ethyl acetate / diethylamine 90: 100). The crude material was purified on a 1.3 x 23 cm column of silica gel eluting with benzene / acetone / formic acid / water (volume ratio 100: 100: 20: 5) to give 35 mg, mp: 275 ° C.

Similarly, when the above procedure is repeated but using the indicated solvent instead of isoamyl alcohol and carrying out the reaction using the indicated temperature and time period in each case, the above compound is similarly obtained.

18 146625

Solution ™ part Reaction temperature, ° G Reaction time, hours 2-Butanol 50 50 2-Methoxyethanol 80 18 2-Methyl-2-pentanol 130 2

Riethylene Glycol 200 0.25 EXAMPLE 7 2- [4- (2-Furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline 4-Ethoxycarbonylamino-2-chloro-6,7-dimethoxycinazoline (2 , 0 g, 0.0064 mol) and 23 ml of isoamyl alcohol were combined in a reaction flask.

A solution of 1- (2-furoyl) -piperazine 2.54 g (0.014 mol) in 18 ml of isoamyl alcohol was added and the mixture was heated to 130 ° C for 4 hours. Straight precipitated solids were collected on a filter funnel, washed with isoamyl alcohol and then stirred with 100 ml of 10 µl aqueous sodium hydroxide solution. An equal volume of chloroform was added and stirred for 15 minutes. Purely organic layers were separated, concentrated to about 25 ml, and 50 ml of tetrahydrofuran was added. Purified solid was collected by filtration and then further purified by chromatography on a silica gel column (2.5 x 46 cm) eluting first with ethyl acetate and then with methanol, the fractions containing the above compound were combined and evaporated to dryness. The residue was taken up in 10 ml of chloroform, added hexane to the cloud point, stirred for 15 minutes, and the precipitated crystals were collected by filtration, mp: 265 °, yield 900 mg (37 $).

When the above reaction is repeated at 80 ° C for 18 hours, the results are essentially unchanged.