CA1065317A - Catalytic dehalogenation process for preparing 2-(4- (2- furoyl) piperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
2-[4-(2-Furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxy-quinazoline or certain hydrohalide salts thereof are prepared by a novel catalytic dehalogenation process from certain novel 2-[4-(halogenated-2-furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxy-quinazoline intermediates. The product is a known hypotensive agent.

Description

lO~iS31~

The invention relates to a novel process for the preparation of 2-~4-(2-furoyl)piperazin-1-yl~-4-amino-6,7-dimethoxyquinazoline, valuable in the art by virtue of its ability to lower blood pressure in hypertensive mammals~ use of which is taught in United States patent 3,511,836~ The inven-tion also relates to certain novel intermediate 2-[4-(halogenated-

2-furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxyquinazolines which are useful starting materials for the process of the invention.
United States Patent 3,511,836 discloses several processes for preparing 2-[4-(2-furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline. For example r hy reaction of 2-chloro-4-amino-6,7-dimethoxyquinazoline with 1-(2-furoyl)-piperazine, by reaction of 2-[4-~2-furoyl)piperazine-1-yl]-4-chloro-6,7-dimethoxyquinazoline with ammonia or by acylation of 2-(1-piper-az$nyl)-4-amino-6,7-dimethoxyquinazoline, e.g., with 2-furoyl chloride.
In United States Patent 3,935,213 processes are dis-closed whereby 2-~4-substituted-piperzin-1-yl)-4-amino-6,7-dimethoxyquinazolines including 2-[4-(2-furoyl)-piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline are produced by either:
(1) reaction of 4,5-dimethoxy-2-aminobenzonitrile with certain 1,4-disubstituted piperazines; or ~2) reaction of 4,5-dimethoxy-2-aminobenzamidine with the same 1,4-disubstituted piperazines.
The present invention provides a novel process for preparing 2-[4-(2-furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxy-10~5317 quinazoline or a hydrochloride, hydrobromide or hydroiodide salt thereof which comprises reacting a compound of the formula CH3 ~ ~ ~ - ~ (X)n CH3 ~
~H2 ...II
with hydrogen in the presence of a catalytic amound of a dehalo-genation cataly~t which is supported or unsupported palladium, copper, cobalt, or nickel or a mixture of palladium with platinum, ruthenium or rhodium, in the presence of a reaction inert solvent at a temperature of from ahout 0 to 150C., and, if desired, in the presence of an acid acceptor, wherein X is chloro, bromo or iodo and n is an integer from one to three.
An especially preferred embodiment of the invention is that carried out employing a compound of Formula II wherein n i9 one and X i~ chloro or bromo, at a temperature of from 25 to 1~C., in the presence of at least n-l moles of an acid acceptor having a PKb of 7 or less an~ in the presence of a catalyst which i8 palladium or palladium-on-carbon or a mixture containing from 98 to 99.9 parts by weight of palladium and 0.1 to 2 parts by weight of platinum, ruthenium or rhodium.
Most particularly preferred i9 a process wherein the compc~und of Formula II is 2-[4-(5-bromo-2-furo~l)-piperazin-1-yl]-~;-amino-6,7-dimethoxyquina201ine, the catalyst is palladium and t~e re-action is carried out in the presence of at least one equivalent of triethylamine as acid acceptor.
The process of the present invention is useful for the preparation of 2-[4-(2-furoyl)-piperazin-1-yl]-4-amino-6,7-~ 0~;5317 dimethoxyquinazoline, known in the art as prazosin. Prazosin has been shown to have therapeutic utility in man; ~ee Cohen, Journal of Clinical Pharmacology, 10, 408 (1970).
The invention also provides the novel and useful ~tart-S ing materials for the above ~oce~s, having the above Formula II
wherein X i9 chloro, bromo or iodo and n is an integer from one to three. A particularly preferred starting material is 2-[4-~5-bromo-2-furoyl)piperazin-1-yll-4-amino-6,7-dimethoxy-~uinazoline.
The process of the invention for the preparation of the valuable hypotensive agent, 2-[4-(2-furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline (I) by catalytic dehalogenation of compounds of Formula ~II) may he represented by the following reaction scheme:

)n CH O A h ~33 ~ ; ~

~H2 ~H2 ... II ... I
The process i9 carried out by reacting the compound of Formula (II) with hydrogen $n the presence of a dehalogenation catalyst as herein defined. By the term "dehalogenation catalyst" is meant a catalyst which will promote selective replacement of halogen with hydrogen under the conditions of the process to provide the product (I) without substantial hydrogenation or hydrogenolysis of the furan and quinazoline moieties of the starting material and product.

The dehalogenation catalyst used in the proce~ of ;S317 the invention may be of the supported or unsupported type and is palladium, copper, cobalt or nickel or a mixture of palladium with platinum, ruthenium or rhodium, Examples of suitable catalyst supports înclude carbon, barium oxide, calcium carbonate and barium sulfate. These catalysts may he preformed or formed in ~i~l by prereduction of an appropriate oxide or salt of the cata-lytic compound. Prereduction i9 accomplished simply by suspending the catalyst precursor in the hydrogenation medium, hydrogenating it, adding the substrate and continuing the hydrogenation.
Alternatively, all of the components may be incorporated at once and hydrogenation commenced. The former procedure has the ad-~antage of permitting the operator to separately determine the quantity of hydrogen absorbed during the catalyst prereduction and hydrogenation phase. The extent of hydrogenation then may be readily controlled.
Among the suitable dehalogenation catalysts to be used in the process of the invention are finely divided metals - such as cobalt, nickel, copper and mixtures thereof. Preparation and use of such catalysts is taught in Freifelder~ "Practical Catalytic Hydrogenation", John Wiley and Sons, Inc., New York, 1971, and references cited thereln.
The catalysts fox the process of the invention are palIadium, copper, cobalt, nickel and mixtures of palladium with platinum, ruthenium or rhodium. Whlle any of the said mixtures containing palladium and one of the said other metals in which the weight ratio of palladium to platinum, ruthenium or rhodium varies over a wide range is useful in the process of the in-VentiOn, especially preferred are mixtures containing from 98 to 99.9 parts by weight of palladium and 0.1 to 2 parts by weight of platinum, ruthenium or rhodium.

31 ~

The catalyst~ are employed in the proce~s of the in-vention in "catalytic amounts", an expression well understood by those skilled in the art of hydrogenation and is illustrated in the examples appearing herein. See also, Freifelder, loc. cit.;
S pp. 7~-81. Ordinarily, however, it is preferred to employ from 1 to 40% by weight of catalyst based on the weight of starting compound of Formula (II).
The process of the inventlon is carrled out in the presence of a reaction inert solvent. An appropriate solvent is one which wlll serve to substantlally dissolve or disperse the reactants and will not adversely interact with the reactants, products or catalyst. Examples of such solvents are the lower alkanols, such as methanol, ethanol, isopropanol, _-butanol, isobutanol and isoamyl alcohol; cyclic and straight chain water-soluble ethers such as dioxane, tetrahydrofuran, diethylene glycol monomethylether, 2-ethoxyethanol, N r N-dimethylformamide, and N,N,-dimethylacetamide, as well as mixtures of such solvents with water.
The hydrogen pressure employed to carry out the process of the invention is not crltical and i9 prlmarily dependent upon the apparatus utilized. In general, pressures of from atmospheric to about 2000 p.s.i. are preferred. As is known, hydrogenation at atmospheric pressure is generally carried out in e~uipment wherein a measured volume of hydrogen contained in a reservoir is attached to a manometer in order to measure the volume of hydrogen consumed. Alternatively, a citrate of magnesia bottle ~Parr bottle) and mechanical shaker with a calibrated pressure gauge, such a a Parr hydrogenatlon apparatus, or a high pressure autoclave of the stirred or shaken variety may be employed.
The dehalogenation process of the invention is carried 11)~531'7 out at a temperature in the range of from 0 to 150C. An e~pecially preferred range of temperature i~ from 25 to 100C.
When the process of the invention is carried out with a compound of Formula (II) alone, the initial product formed is the hydrogen halide addition salt of compound (I). This may be isolated a such or may be converted to the free base by treat-ment with aqueous alkali such as sodium hydroxide or potassium hydroxide followed by filtration of the base or extraction into a water immiscible solvent such as ethyl ether, chloroform or methylene chloride. Alternatively, the process may he carried out in the presence of an acid acceptor to directly provide the free base of compound (I) and the halide salt of the acid acceptor.
By the term "acid acceptor" is meant a basic compound which, when added to the reaction mixture and employed in the process of the invention, selectively reacts with the hydrogen halide released to form a halide salt without causing substantial by-product formation by further reacting with the reactant or products, and has little or no detrimental effect upon the catalyst employed. In order to successfully compete for the hydrogen halide formed during the instant process, the acid acceptor should be a stronger hase than either the reactant of Formula (II) or the product (I), i~e., it ~hould be a base Of PKb of 7 or less.
Examples of suitable acid acceptors are amines such as triethylamlne, N-methylpyrrolidine, triethanolamine, _-butyl-amine, benzylamine, isoamylamine, morpholine and piperidine;
ammonia, hydrazine and alkali metal and alkaline earth oxides and hydroxides such as those of sodium, potassium, magnesium, calcium and barium. Especially preferred as the acid acceptor 0 for reasons of convenience, economy and efficiency is tri-1(3~S3~'7 ethylamine.
The acid acceptor i9 preferably employed in an amount at least sufflcient to neutralize n-l mole~ of hydrogen halide per mole of compound (II) where n i8 the number of atoms of halogen per mole of starting material of Formula (II), i.e., n $8 an integer from one to three. When the amount of acid acceptor is at least equivalent to the amount of hydrogen halide formed, the product is the free hase of Formula (I). In such case~ an exces of acid acceptor may be employed if desired.
Alternatively, when n-1 equivalents of the acid acceptor per mole of compound (II) are employed, the product obtained i8 the hydrogen halide salt of the compound of Formula (I). For example, when in the starting material of Formula (II), X is chloro, n is 3, and 2 equivalents of acid acceptor per mole of said compound (II) is employed, the product obtained i~ the hydrochloride salt of compound (I).
When lt is desired to utilized an acid acceptor in the process of the invention it i9 preferred that at least one equivalent of acid acceptor per mole of the compound ~II) is employed.
~ he time required for the dehalogenation proce~s of the invention to reach substantial completion will vary according to factors such a8 temperature, catalyst, and the precise nature of the ~tarting material of Formula (II). Ordinarily, however, the dehalogenation will be substantially complete in from about 0.5 to 24 hours.
As mentioned above the product of the process of the invention may be either the free ba~e of Formula (I) or a hydrochloride, hydrobromide or hydroiodide salt thereof. Any of these product~ may be isolated and further purified, if desired, 10~;5317 by methods well known to tho~e skilled in the art. For example, the free base may be isolated often merely by evaporation of solvent, after removing the catalyst by filtration, whereupon the product precipitate~ or may be caused to precipitated by addition of a nonsolvent such as hexane or heptane. The free base may be further purified by methods such as, for example, recrystallization or column chromatography on silica gel. When the product obtained by the process of the invention i8 one of the above mentioned hydrohalide salts of compound (I), lt may be converted to the free base and isolated a~ described above, or the hydrohalide salt may be l~olated by warmlng the reactlon mixture to ensure solution of the said hydrogen halid salt, the reaction mixture filtered to remove catalyst~ and the filtrate then may be concentrated to a ~mall volume and cooled whereupon the desired product ordinarily precipitates. It may be further purifled, l de~ired, for example, by recrystallization.
The ~tarting compounds o~ Formula (II), above~ wherein X is chloro, bromo or iodo and n is an integer from one to three are novel compounds. They may be prepared by any of the prior art methods described above for the preparation of 2-t4-(2-furoyl)plperazine-1-yl]-4-amino-fi,7-dimethoxyquinazoline by employing the appropriate halogen-sub~tituted ~tarting material in each case. The preferred methods for preparing the compound~ of Formula (II) are tho~e depicted below a~ Method A
and Method B.

10~;5317 Method A

CH O

p~`f + ~?, ~(X)n~(II) ... III ... IV

Method B

CH~ ~ NH

NH2 .VI
. . .V
In each o the compounds of Formulae (III) and (VI), A i8 chloro or bromo, and (X)n i9 as described above. The compounds of Formulae (III) and (V) are available by methods described in United State~ Patent No. 3,511,836. The acyl halide~ of Formula (VI) are prepared from the corre~ponding halogenated-2-furoic acids by well-known methods, for example, by reactlng the said acid~ with an excess of thionyl chloride or thionyl bromide followed by evaporation of the reaction mixture. Of the halogenated furoic acids from which the compounds (VI) are derived, 5-bromo-2-furoic acid is commercially available, The remalning chloro and bromofuroic acids are prepared by method~
described by Shepard et. al., Jour. Amer. Chem. Soc., 52, 2083 (1930) and Gllman et al., lbid.,~57~ 1146 (1935) and reference lOtiS31'7 cited therein. The iodofuroic acids are prepared from the corresponding iodofurfurals by oxidation with alkaline peroxide by the method of Borisova et al., Chem. Abstr., 73, 35134f (1970) or by the method of Sornay et al., Bull. Soc. Chem., France, 990 (1971).
When Method A i~ employed, the l-substituted piperazine of Formula ~IV), which may be prepared from the above-descrlbed acid halides of Formula lVI) and an equimolar amount of plper-azine, are reacted in approximately equimolar amounts in the pre~ence of a reaction-inert organic solvent. The reaction may be carried ou~ over a wide range of temperature, however, a temperature in the range of 50 to 150C. is preferred. ~he reaction is ordinarily complete in from 1 to 24 hours. The product may be isolated in the form of the hydrochloride or hydrobromide salt and subsequently converted to the free base of Formula ~II) by standard methods. Alternatively, the re-action can be made alkaline, for example, with sodium hydroxide or potassium hydroxide and the free base isolated by extraction and evaporation of solvent. Examples of suitable reactlon-inert solvents for thi3 method are alkanols such as ethanol, n-butanol, isoamyl alcohol, n-hexanol or cyclohexanol; N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, diethyleneglycol diethyl ether, ethyleneglycol-n-butyl ether, chloroform or methylene chloride.
When Method B i~ employed the compound of Formula (V) and an e~uimolar amount of compound of Formula (VI) are reacted in the presence of a suitable reaction-inert organic solvent.
The reaction i8 preferably carried out at a temperature of from -20 to 100C. Examples of ~uitable solvents for use in this method are those set forth above for Method A. The reaction i9 i5317 ordinarily complete in from a few minute~ to ten hour~. The desired product i~ i~olated by standard method~, such a~, for example, ad~usting the reaction mixture to an alkaline pH by additlon of an agueou~ base, for example, sodlum hydroxide, S pota~ium hydroxide or sodium carbonate, extracting the product wlth a water-lmmlsclble solvent such a~ chloroform or methyl-ene chloride and evaporation of the solvent.
For rea~ons of economy and efficiency e~pecially preferred compounds of Formula ~II) are those wherein n i~
one and X 1~ chloro or bromo. Most partlcularly preferred 1~
2-~4-(5-bromo-2-~uroyl)plperazin-1-yl]-4-amlno-6~7-dimethoxy-qulnazollne.
~ he ~ollowlng non-llmlting Example~ are provlded to further lllustrate the inventlon~ Examples 1 to 3 lllustrato the prepara~ion of the novel intormediat- compound~
of Formula (II) and Example~ 4 to 3 lllustrat~ the proce~
of the lnventlon~

iO6~3~7 ':
, EXAMPLE 1 2-[4-(5-Bromo-2-furoyl)piperazin-1-yll-4-amino-_, _ 6,7-dimethoxyquinazoline !
I' ~
~ To a flask containing 19.1 g. (0.10 mole) of 5-bromo-2-furoic acid 5, ln 100 ml. of chloroform wag added 20 g. of thionyl chloride and the resultlng ~' mis~ure was stirred a~ room temperature for 2 hours then allowed to stand l, overnight. The volatile components were then e~apo-rated in vacuo to obtain ', 5-bromo-2-furoyl chloride. This was dissolved in 50 ml. of ~ethylene chloride ;
, and the solution added dropwise at 25 C. to a solution of 8.6 g. (0.10 mole) -!j , 101, of piperazine in S0 ml. of the same solvent. The addition required about 30 ll minutes. The resulting mixture was allowed to stir for another hour then made ! alkaline by atdition of 2N sodium hydroxide solution. The organic layer was lliseparated and the aqueouis layer wais extracted again with methylene chloride.
,I The organ~c layers were dr~ed over anhydrous potassium carbonate then evaporated 15~1 to dryness to obtain 23 g. of 1-(5-bromo-2-furoyl)piperazine. A portion was !i crystalllzed fro~ m~thylene chloride-ethyl acetate,M.P. 113-115' C.
Anal. Calc'd. for CgH1102N2Br: C, 41.72; H, 4.28; N, 10.81; Br. 30.8 Foo~d: C, 41.44 H, 4.35; N, 10.66 ~r, 30.49 , ;, ' , . . , .

lO~S3~7 EXAMYLE I (Contlnued) In a reaction vessel was placed, 9.55 g. (0.04 mole) of 4-amino-2-, chloro-6,7-dimethoxyquinazoline, prepared by the procedure of U.S. 3,511,836, 200 ml. of isoamyl alcohol and 20.7 g. (0.08 mole) of the 1-(5-bromo-2-furoyl)-, plperazine obtained above. The resulting suspension wag heated at reflux for 90 minutes, then cooled, filtered and waYhed with ethanol to obtain 21.8 g. of crude hydrochlorlde salt of the tltle compound which melted wlth decomposition at 276-278 C. This wag slurried in 200 ml. of ethanol and ZN sodlum hydroxide l solutiou was added to effect solution. Th2 solution was concentrated to a ! small volume by evaporation in vacuo chilled, filtered, washet with water 10 ! and dried to obtain 18.8 g. of product, M.P. 206-209 C. Ihis was dissolved ! in a mixture of chloroform and methanol, dried over sodium sulfate, carbon treated and the solvent replaced with ethyl acetate. Upon crystallization 9.~8 g. (53%) of purified prcduct was obtained, M.P. 213-215 C.
l~ Anal- Calc'd for C19~20NsO4Br C~ 49-36; H, 4.36; N, 15.15; Br, 17.28 15 ~ Yound: C, 48.70; H, 4.36; N, 14.87; Br, 16.87 , ; -14-531~

~ EXAMPLE 2 !~ 2-[~-(3-Chloro-2-furoyl)piperazin-1-ylj-4-amino-6,7-dimethoxyquinazoline .; i ~' 3-chlorofuran-2-carboxylic acid, prepared by the ~ethod of 5 i Shepard et al., is reacted at room eemperature with excess thionyl chloride iifollowed by evaporation in vacuo to obtain the acid chlorite as a residue.
To a solution of 28.9 g. (0.10 mole) of 2-(1-plperazinyl)-4-amino-6,7-dimethoxyquinazo}ine, preparet as describet ln U.S. 3,511,836, in 300 ml.
i f methanol ls added with vigorous stirring, 16.5 g. (0.10 ~ole) of the above 10 l acld chloride over 30 minutes and the resulting mixture stlrred for an l,additional three hours at room temperature. The solvent is removed in vacuo t and the residue i~ slurried with methylene chloride and made alkaline with ¦,2N sodium hydroxide ~olution. The organic layer is separated, dried over ll~odium sulfate and evaporated to dryne~s to obtain the title compound.

15 i' When thionyl bromide ls employed ~n place of thionyl chloride li j in the above procedure and the acid bromide obtained i8 reacted with 2-(1-!~ piperazinyl)-4-amino-6,7-dimethoxyquinazoline, the res~lts are substantially ;S3~'7 i' EXAMPLE 3 . When the procedure of Example 1 or Example 2 is repeated but with Il the acld chloride used therein replaced with the appropriste halo-2-furoyl !' chloride or halo-2-furoyl bromide, the following co~pounds are si~llarly 5 l~ obtained.
1. . . .

3 ~ ~ ~ C-~ ~

, i', ', . I

¦'. 3 4 ,~K)n ii ' -C ~
¦ Proceture of ,, O 5 Example No. n ;
. i 3-chloro-2-furoyl j, 1 4-chloro-2-furoyl 10 l¦ 1 3,4-dichloro-2-furoyl 2 3,4,5-trichloro-2-furoyl 2 3-bro -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-ioto-2-furoyl ',; , ~ 53~t~

EXAMPLE 3 tContinued) , The 2-furoyl chlorites or bromides are prepared fro~ the correspontlng halo-2-furoic acits. The chloro ant bromofuroic acids are pr~pared by methots I described by Sheparet et al., Jour. Amer. Chem. Soc., 52, 2083 (1930) and !~ Gilman et al., ibid., 57, 1146 (1935) and reference therein. The lodofuroic 5 'i acids are prepared from the corresponding iodofurfural by o~itatlon with ,~ alkaline peroxide by the method of Borisova et al., Chem. Ab~tr., 73, 35134f l~ (1970) or by the method of Sornay et al., Bull. Soc. Chem.~ France, 990 (1971).

!l j 1 ~ , , t t' I ' .

. ~i ~ l-o~js;~l7 '! In a Paar pressure bottle i8 placed 1.0 g. (2.16 mmole) of 2-[4-i~ (5-bromo-2-furoyl)piperazin-l-yl]-4-amino-5,7-dimethoxyquinazoline, 10 ml.
I of methanol l.0 ml. of triethylamine and 0.4 g. of 5% Pd-on-carbon (50% wet).
5 ii The bottle was placed in a Paar shaker and pressurized with hydrogen to I, 50 p.s.i. at room temperature. After shaking for 18 hours the theoretical ! &mount of hydroge~ was taken up. The mixture of catalyst and precipitated !
,~ product was filtered and the solids were slurried ln 25 ml. of chloroform and ! ' filtered again to remove catalyst. To the filtrate was atded 50 ml. of hexane, lO ¦' the mixture stlrred for ten minutes then filtered to obtain a crude product !~ which was purified on an 18 x 3 inch column of silica gel, eluting with ethyl ~, acetate-diethylamine (90:10 by volume) to obtain 300 mg. of 2-14-(2-furoyl)-!' piperazin-l-yl]-4-amlno-6,7-dimethoxyquinazoline, M.P.`266 C. which was ll itentified by comparison of the infrared spectrum in chlorofor~ with that of 1~ aD suthentic sample, and by thi~ layer chro= tography on slllca gel.

-, .
. I' .

,, --1 ~--lO~S31 7 In an atmosphe~eic hydrogenation apparatus flask ls placed 4.18 g.
(0.01 le) of 2-[4-(3-chlorc-2-furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxy-quinazolinè, 75 ml. of 95% ethanol, 0.50 g. (0.10 mole) of hytrazine hydrate , and 0.5 g. of a catalyst containing 98 parts by weight of palladlum and 2 S ,~ parts by welght of platinum. The result~ng mixture i9 cooled to 0 C. and i exposed to hydrogen at atmospherlc pressure for 4 hours. The mixture is then filtered to remove catalyst, the filtrate concentrated in vacuo to dryness then ~, psrtitioned between methylene chloride and water. The organlc layer is dried ' over sodium sulfate and evaporated to dryness to obtaln the 2-[4-(2-furoyl)-i' .
10 1 piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline which i9 purified by silica gel column chromatography.
When the above procedure is repeated but e~ploying 0.5 g. of Il catalyst containing 99.9 parts by weight of palladium and 0.1 part by weight 'l, of platinum, the results are essentially unchanged.
15 1~ EXAMPLE 6 i In a 500 ml. autoclave is placed 9.24 g. (0.02 mole) of 2-[4-(4-jlbromo-2-furoyl)piperazln-l-yl]-4-amino-6~7-dimethoxyquinazoline~ 2.0 g. of 50Z
!~ wet Raney nlckel catalyst and 200 ml. of 70% ethanol (7:3 ethanol/water, by 1Iweight). The mixture is maintained at 100 C. and 200 p.9.1. hydrogen pressure 20 ! for 30 minutes then cooled to room temperature. The catalyst is removed by filtration and the filtrate concentrated to remove ethanol, the concentrate ' i8 made alkaline with potassium carbonate, extracted with chloroform and the extracts concentrated to dryness to obtain 2-[4-(2-furoyl)piperazin-1-yl]-

4-amino-6,7-dimethoxyquinazoline. The product can be purifled further by silica gel column chromatography.

, . --19--1~;531~

In an at spheric hydrogenatlon flask is placed 4.18 g. (0.01 le) of 2-[4-(4`chloro-2-furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline ,' 200 ml. of isoamyl alcohol and 0.20 grams of a powdered catalyst containing

5 l 99.9 parts of palladium and 0.1 part of rhodium by weight. The resulting mixture is hydrogenatet at atmospheric pressure for 2 hours with vigorous , stirring. The theoretlcal a unt of hydrogen is consumet. The mixture ls ! thèn disconnected from the apparatus~ heated to bolling and filtered while !~ ho~ to remove the catalyst. The flltrate is cooled in ice, then filtered to N ! obtain 2-[4-(2-furoyl)piperizin-1-yl]-4-~m~no-6,7-dimethoxyquinazoline j hydrochloride.
i When the above procedure is repeated, but employing 0.01 le of 1 2-[4-(5-bromo-2-furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline ln -l,place of the corresponding 4-chloro-2-furoyl congener used above, 2-[4-(2-furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline hydrobromide i~
~ aimllarb obealDed.

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Claims (11)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound of the formula:

...II
wherein X is chloro, bromo or iodo and n is an integer from one to three which comprises reacting a 6,7-dimethoxy-quinazoline of the formula:

with a halofuran of the formula:

wherein when either Y or Z is then the other is chloro or bromo and X and n are as defined above.

2. A compound of the formula:

wherein X is chloro, bromo or iodo and n is an integer from one to three, whenever prepared by a process according to claim 1.

3. 2-[4-(5-Bromo-2-furoyl)-piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline, whenever prepared by a process according to claim 1.

4. A process for preparing 2-[4-(2-furoyl)-piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline or the hydrochloride, hydrobromide or hydroiodide salt thereof, which comprises reacting a 6,7-dimethoxyquinazoline of the formula:

with a halofuran of the formula:

wherein, when either Y or Z is then the other is chlolo or bromo, X is chloro, bromo or iodo and n is an integer from one to three to provide a compound of the formula:

(II) wherein X and n are as defined above, and then reacting the resultant compound of formula (II) with hydrogen in the presence of a catalytic amount of dehalogenation catalyst which is supported or unsupported palladium, copper, cobalt, or nickel or a mixture of palladium with platinum, ruthenium or rhodium, in the presence of a reaction inert solvent at a temperature of from about 0° to 150°C., and, if desired, in the presence of an acid acceptor.

5. A process according to claim 4, wherein the dehalogenation reaction is carried out at a temperature of from about 25° to 100 C.

6. A process according to claim 4, wherein the said acid acceptor has a pKb of 7 or less.

7. A process according to claim 6, wherein at least one equivalent of the said acid acceptor per mole of said compound of formula (II) is employed.

8. A process according to claim 4, wherein the said catalyst is palladium or palladium-on-carbon.

9. A process according to claim 4, wherein the said catalyst is a mixture containing from 98 to 99.9 parts by weight of palladium and 0.1 or 2 parts by weight of platinum, ruthenium or rhodium.

10. A process according to claim 4, wherein n is one and X is chloro or bromo.

11. A process according to claim 4, wherein at least one equivalent of triethylamine is used as acid acceptor.