Note: Descriptions are shown in the official language in which they were submitted.
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-
-2-
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-
--3--
~ 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 ~ ; ~
CH3 CH
~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
--4--
;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.
--5--
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
--6--
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-
--7--
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,
--8--
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)
H2
... III ... IV
Method B
CH~ ~ NH
CH3
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
--10--
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
--11--
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~
-12-
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
, ;,
'
,
--13--
. . ,
.
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
-15-
;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-~ ~
1
,
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
',; ,
-16-
~ 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
-17-
~ l-o~js;~l7
EXAMPLE 4
'! 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
EXAMPLE 5
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~
EXAMPLE 7
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.
.
-20-
~)tiS317
~1 ~ I ~ ~
O ~ b _~ 8 u~
:~
~ ~ O . .~
~I O . y O ~C ~0 ~ ~0 0=~o' 0
o ~ .. ~ c e
'~ 5 9 ~ _, 1~ _ .
_ S C ~ C ~ b~, C e
li ~I b U Cl~ C~ ~ Q 1~ 3 r~ ~ ~ I
~ ~ ~ .. ~
i, Jl --I .0 E~ ~ e~
c SQ ~ ~ o o ~ ~ o
1 e ,' ,s, c~ ~~ c ~ " ~ ~,
~- C o ~ ~ _ ~ ,,; o ~ o
o '9 ~ . ~ c~ ~n ~ ~ 3 D E~ ~ =' 3 3 _ ~ -~
o ~ ~ ~ o O , 0~ ~0
C U 3 ~ o o o o o o
D~ _~ _.__ _
. ~ NO b O
21-
` lOt~ 1'7
U ~ ~ U
~ ~ ~u ~ ~ ~ ~
. 2 ~ ~ ~
,. . - ~c~
o Ul o o
I; l ~o ~ ,
,. . 0 ~c ~ ô e o ô ~ -I '
g ~ ~ ~ o g ~o
! ~ ~
C ~' ~ E~ ,C, '~OC~ ~C~rl
' ~, æ ~ s
il ~ E~ ~ u~ ~ o c
i.i' ~ . . . .. - ..
'. ~ C~ O O O O
~" . g
. P~ ~ ~ 3_ ~ 3 ô ~
1~ ~ x ~.a:~ ~-- & o ta o - ~
C~ ~ a~
. z
~ o
c ~ 2 2 , --
o~.7 ~o o
I ,
--22--
