Note: Descriptions are shown in the official language in which they were submitted.
.:
6~
~. ---.. .
This invention relates to a novel process for prepar
ing substituted aminoquina~oline derivatives and intermediates
thereforO The final products produced by the process of the
invention are known chemical compounds, valuable in the ar~ by
virtue of their abillty to lower blood pressure in hypertensive
mammals. More specifically, these hypotensive compounds are
certain 2-(4-substituted piperazin-1-yl)-4~amino-6,7-dimethoxy-
quinazolines and 2-l4 substituted piperazin-1-yll-4-amino-6t7,8-
trimethoxyquinazolines, which are disolosed in United State~
Patent Speci~ications No. 3,511,836 and 3,669,968. The inven-
tion also relates to certain 2-halo-6,7-dimethoxy-4~substituted ~ -
amino~quinazolines; 2-halo-6,7,8-trimethoxy-4-(substituted amino)-
quinazolines and the corresponding compounds in which the 2-halo
substituent is replaced by certain 4- ubstituted piperazinyl
group~, which are novel intermediates.
~, .
United States Patent Specification No. 3,511,836 dis-
closes several processes or the preparation o 2-¢4-substituted
: ., .
piperazin-l-yll-4-amino-6,7-dimethoxyquinazolines. For example,
by the reaotion of 2-ahloro-4-amlno-6,7-dimethoxyquinazoline
with the appropriate l-substituted piperazine, by reaction o$ a
2-~4-substituted piperazin-1-yll4-chloro-6,7-dimethoxyquinazoline
with ammonia or by alkylation, alkanoylation, aroylation or
alkoxylation o 2-~1-piperazlnyl~-4-amino-6,7-dimethoxyquinazol-
ine. United States Patent Specification No. 3,669,968 discloses
the preparation of 2-~4-sub~tituted piperazin-1-yl)-4-amino- ;
-2-
-,, ~', , ' ' ' , ' ' '
o~,
~6~6~
6,7~8-trimethoxyquinazolines by the reaction of 2-chloro-4-
amino-6~7l8-trimethoxy~uinazoline with the appropriate 1-9ub-
stituted piperazine.
United States Patent Specification No. 3,935,213
discloses the preparation of 2-l4-substituted piperazin-1-yl)4- -~
amino-6,7-dimethoxyquinazolines and ~he corresponding 6,7,8-
trimethoxyquinazolines by proaesses which comprise eithero
(1) reaction of the appropriate 4,5-dimethoxy substituted or
3,4,5-tximethoxy-substituted 2-aminobenzonitrile with certain
1,4-disubsti~uted piperazines; or ~2~ reaction of the appropriate
4,5-dimethoxy or 3,4,5-trimethoxy substituted 2-aminobenzamidine
with the same 1,4-disubstituted piperazines.
Compounds of the formulae:
CH30 N Cl CH30 N
~ ~ and ~ ~ N N~
CH30 ~ CH30 ~
NHCH2C6H5 NHCH2C6H5 ~-
where Y is hydrogen, alkyl having from 1 to 5 carbon atoms,
hydroxyalkyl having from 2 to 5 carbon atoms, alkanoyl having
2 to 7 carbon atoms, allyl propargyl, 2-methallyl, phenyl,
benzyl, benzoyl, chlorobenzoyl, bromobenzoyl, trifluoromethyl,
methoxyphenyl, methylphenyl, methylbenzoyl, tri1uoromethyl-
benzoyl, furoyl, benzofuroyl, thenoyl, pyridinecarbonyl, 3,4,5-
trimethoxybenzoyl, carboxylic acid alkyl ester where alkyl hasfrom 1 to 6 carbon atoms and carboxylic acid alkenyl ester where
alkenyl has from 3 to 6 carbon atoms, are disclosed in United
State~ Patent Specification No. 3,511,836. However, other
intermediates, useful in the proces3 o the present invention, ~:.
are novel compound~.
In accordance with the present invention there i8 pro-
-3-
-- .. , '' . , :
~ . ., ~ ,. . . .
" ,
. , . . - . ,
:: , .
- : .
'
~ 6~369~3
vided a process for the preparation o~ a compound having the
formu~a~
IRl
CH30~ ~ y ~ ;
CH30 ~ ... I
NH2
which comprises reacting one mole o a first reactant having the . -~
formula: ~
Rl ;- : . :
CH30 ~ N q / X
CH30 ~ .
N
/ \ ... II : .
R3 R4
with from one to two moles of a second reactant having the -.;.
: . .
formula:
. .
~~'\ ,
H~ ~-R2
/
..III
in a reaction-inert organic solvent at a temperature from 50
to 200C.; wherein Rl is hydrogen or methoxy; R2 is alkenyl
having from three to five carbon atoms, benzoyl, furoyl, thienyl-
carbonyl, alkoxycarbonyl having from two to five aarbon atoms,
alkenyloxycarbonyl having four or five carbon atoms or ¢2-hydr- ~ ~ ~
oxyalkoxy)carbonyl having four or five oarbon atomis; X is :. -
chlorine or bromine; R3 is hydrogen and R4 is -C~2C6H4R5, -
-COOCH2C6H4R5, -COR6, -COCF3, -CHO or -COOR6, or R3 and R4
together with the nitrogen atom to which they are attaahed orm
a ayclic imido group, preferably a phthalimido, maleimido or
; ~ , ", , , ": : :,, ,,, " ;, " ~ ,, ,", ,,", ",, "", , , ;" , , , , ,, , , "
r~ ` 10686~3
succinimido group; R5 is hydrogen, ahlorine, bromine, methyl,
methoxy or nitro; and R6 is alkyl having from one to four
carbon atoms or -C6H4R5.
An especially preferred range of temperature is from
80 to 130C.
When the above process is carried out with reactants
~ and ~ wherein R2 is benzoyl, furoyl, thienylcarbonyl,
alkoxycarbonyl having from two to five carbon atoms or (2-hydr-
oxyalkoxy)carbonyl having four or five carbon atoms; R3 is
hydrogen and R4 is CH2C6H4R5 it is preferred to react equi-
molaramounts of said reactants. An intermediate compound having
the formula~
Rl ~ . .
CH30~N ~I-R~
~N
R3 R4 . . o IV
wherein Rl, R2, R3 and R4 are as defined above, is obtained and
this intermediate compound is further reacted by catalytic hydro-
genolysis to form the flnal product of formula (I). An
~ especially preferred aatalyst for the hydrogenolysis is palIadium.
: When the process of the invention is carried out with a
first reactant of formula (II) wherein R3 and R4 together with
the nitrogen atom to which they are attached form a phthalimido,
maleimido or succinimido group, it is also preferred to employ
an equimolar amount of each reaatant to form an intermediate of
formula (IV~. In which case, the said intermediate is further
reacted at a temperature from 0 to 100C. to form the inal
25 product o formula ~ ta~ by hydrolysis, or ~) by reaction
-5-
,:
, ' , ,, " , ~'. ' .,.,, ' ' .
. ' - . ' ' ' ' ' ' ,
,' ''' ,' " ' ''' ~ ~,
'' ,, "
'' ' , ' ',
-~ ~L068698
with an equimolar amount of hydraæine in the presence of a re- :
action inert organic ~olvent.
... ~.
An especially preferred temperature for further re- ~ :
acting the intermediate of formula ¢IV) by hydrolysis or with ~ ~
S hydrazine is from 20 to 50C. . : : :
When hydrolysis is employed it is preferred that it
be carried out in the presence of hydrochloric, hydrobromic,
sulfuric or phosphoric acid.
When the process of the inv2ntion is carried ou~ with :
a compound of formula (II) wherein R3 is hydrogen and R4 is .
COOCH2C6H4R5, -COR6, COCF3, -CHO or -COOR6 wherein R5 and R6
: are as previously defined, the desired compound of formula ~I),
or the hydrochloride or hydrobromide addition salt thereof, is :
directly provided In the latter case it is preferred to react
one mole of the first reactant of formula ~II) with two moles
of the seaGnd reactant of formula ~III).
Whereas the process of the present invention is u~eful
for the preparation of the said, known, ~ypotensive agents of
formula I, it is especially useful for the preparation of two ::
: 20 particularly valuable compounds of formula I, namely, 2-[4-12- .
furoyl~piperazin-l~yl~-4-amino-6,7-dimethoxyquinazoline and
2-[4-~2-hydroxy-2-methylprop-1-yloxyaarbonyl~-piperazin-1-yl]-
4-amino-6,7,8-~rimethoxyquinazoline, ~nown in the art as
pra~o~in and trimazo~in. 2-~4- ~-Methylprop-2-enyloxycarbonyl)-
piperazin-1-yl~-4-amino-6,7,8 trimethoxyquinazoline i~ a vaIu-
able starting material for the production of trimazosin ¢United
States Patent No. 3,669,968). Prazosin and trimazosin have - :
recently been reported to have therapeutia utility in man ~Cohon,
~ , 10, 408 ~1970~; De Guia, et al.,
; 30 ~ , 15, 339 [1973]).
-6- . : ~.
;~
., .: . , ., . . ,, ~
. . ., , . , , , , , , ,, . - , , , .. : . :
.. , , . . , , ~ , , .
-- ~06~369~3
The invention also provides novel and useful inter-
mediate compounds of formula ~V)~
Rl ;
C 300
R30 40 ..OV
: ~ wherein X and Rl are as previously defined, R30 is hydrogen and
R40 is -COOCH2C6H4R5, -COR6, -COCF3, -CHO or -COOR6 or R30 and
R40 together with the nitrogen atom to which they are attached
form a:cvclic imido group, preferably a phthalimido, maleimido
or succinimido group; and R5 and R6 are as defined above.
The invention further provides useful lntermediate
: 10 compounds of formula ¢VI)
l A
C 30~N~i-R
R31 R41 ...VI
wherein Rl and R2 are as previously defined and R31 and R41
together with the nitrogen atom to which they are attached form
~ a cy¢lic imide group, preferably a phthalimido, maleimido or
succinimido group.
~he present invention provides a proae~s for the
preparation o a compound of the formula ~I~ above, or a hydro-
chloride or hydrobromide acid addition salt thereof, by reacting
a compound of the formula (II) with a compound of formula III.
In certain ca~es, described in detail below, an
-7-
:: . '';, .' ' , ' . ' ' i ' " '' ' ' :
: , f
,, ' '.',, .,'. , ~ ~ , I
,', ,'' ' '
06~36~8
intermediate compound of formula ~IV~, or acid addition salt
thereof, is initially obtained which is further reacted to
obtain a compound of formula ~I) The reaction of compounds
of the formulae ~I and III~ is carried out in the presence of
an appropriate reaction inert oxganic solvent. An appropriate
sol~ent is one which will serve to substantially dissolve the
reactants, and will not adversely interact with reactants or
products of 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
ethyleneglycol monomethyl ether, diethylene glycol monoethyl
ether, 1,2-dimethoxyethane, and diethylene glycol dimethyl ether;
tertiary amides such as N,N-dimethylformamide~ N,N-diethylacet-
amide and N-methylpyrrolidone; dimethylsulfoxide and pyridine.
While the reaction may be carried out over a wide range of
temperature, a temperature in the range of 50 to 200C. i pre-
ferredr An especially preferred range of temperature is from
80 to 130C. The time required for the process to reach sub-
stantial completion varies according to several factors, suchas, for example, the reaction temperature, reactivity of the
partiaular starting materials employed and the concentration o
reactants. At lower temperatures longer reaction times are ,!,1' '~
needed, while at higher temperatures the reaction is completed
in a shorter time~ A reaction time of from 15 minutes to 50
hours is generally suficient~
In certain cases the reaction of a compound of formula
~II) with a compound of formula ~III) forms an intermediate com-
pound of formula ~V) which is then urther reacted to obtain
the desired compound of formula (I). Thus, the process of the
-8-
- . . . .
,, . :,
6~3691!3
invention may be carried out by either of two methods, designat-
ed as Method A and Method B, as shown in the following reaction
scheme~ -
CH30 ~ X CH3O I N A--R~
~ ~ ~ ~ ~1 A Methsd A ` ~ ~ ~ \
CH30 ~ ~ 3
/ N ~III) / N
R3 R4 / R3 4
OV)
C~3o ~ ~ N ~ -~
CH30 ~ ::
NH2
(I~
The compounds o formulae ~II) and ~III) employed as
reactants in the process of the invention are those wherein X
is chlorine or bromine and particularly preferred are compounds
wherein X is chlorine; Rl is hydrogen or methoxy; R~ is alkenyl
having from three .to five carbon atoms, benzoyl, furoyl, thienyl-
carbonyl, alkoxycarbonyl having ~rom two to five carbon atoms,
alkenoxycarbonyl having four or five aarbon atoms or (2-hydroxy-
alkoxy~aarbonyl having four or five carbon atoms~ When taken
separately, R3 is hydrogen and R4 is -CH2C6H4R5, -COOCH2C6H4R5,
-COR6, -COCF3, -CHO or -COOR6 and when taken together with the
nitrogen atom to which they are attached R3 and R4 form a
cyclic imido group. Examples of such cyclic imido groups are
_g_
.. . . .
; .
, . , . .. , ,,, - . ; , . :-
~' .
, .
:'.
-`` 106~6~
phthalimido, succinimido, maleimido, glutarimido, and imido
groups derived from other cyclic diaarboxylic acid anhydrides
such as diglycolic, thioglycolic, cyclohexane-1,2-dicarboxylic,
4-bromophthalic, 3-nitrophthalic and methylmaleic acid anhydride.
Preferred cyclic imido groups are phthalimido, succinimido and
maleimidoO R5 is hydrogen~ chlorine, bromine, methyl, methoxy
or nitro; and R6 is alkyl having from one to four carbon atoms
or -C6H4R5.
When the process of the invention is carried out accord-
ing to Method A, as depicted in the above reaction scheme, it is
preferred to employ compounds of the formula (II) wherein X is
chlorine or bromine; Rl is hydrogen or methoxy, and R3 is hydro-
gen and R4 is -CH2C6H4R5 wherein R5 is as previously defined,
or R3 and R4, together with the nitrogen atom to which they are
attached, form a phthalimido, maleimido or succinimido group.
Such compounds of formula ~II) react with the above described
,
compounds of formula ~II) to obtain intermediates of formula : --
~IV), a hydrochloride or hydrobromide salt thereof~ When such
compounds of formula ~IV) are desired it is preferred to carry
out the reaction employing approximately equimolar amounts of :
the reactants for reasons of economy and efficienay. However, ;
this is not essential to the suacess of the reaction, and an
excess of either reactant may be presen O The intermediate com-
pound of formula ~IV~ conveniently may be isolated in the form
~5 of the hydrochloride salt or hydrobromide salt each o~ which is
ordinarily insoluble in khe reaction solvent and thus may be
obtained merely by filtration and washing. Alternatively, the
above mentioned salts can be treated during workup of the reac-
tion mixture with an alkaline reagent such as, for example,
sodium hydroxide, potassium hydroxide, po~assium carbonate, or
--10--
. .
, ' ':'. ' . . : ; , ' ; -
,. , , . ~.,.
. .
106~6g~
sodium methoxide, ~ollowed by e~traction of the free base into
a water immiscible solvent such as, for example, chloroform,
dichloromethane or benzene; and evaporation to dryness. When
desired, either the compound of formula (IV) or the salt there-
o~ may be further puri~ied by standard methods such as crystal-
lization or column chromatographyO However, they are often of
sufficient purity for further reaction to form compounds of
formula ~I~ without such further purificationO
As mentioned above, the compound of formula (IV) or
10 the hydrohalide salt thereof is further reacted to remove the
4-amino substituents, R3 and R4, to obtain the desired compound
of formula ~. When employing a compound of formula ~IV)
wherein R3 is hydrogen and R4 is a benzyl group, -CH2C6H4R5, the
pre~erred values of R2 are benzoyl, furoyl, thienylcarbonyl,
15 alkoxycarbonyl having from two to five carbon atoms and ~2-
hydroxyalkoxy)carbonyl having four or five carbon atomsO It is
preferred to remove the benzyl group by catalytic hydrogenolysis.
The term "catalytic hydrogenolysis" as used herein i6 well
underskood by those skilled in the art of hydrogenation, and is
20 illustrated in the Examples appearing hereinafter.
The catalytic hydrogenolysis may be carried out by a
variety of procedures well known in the art for this type of
transformation, such as tho~e discussed by Augustine in
"Catalytic Hydrogenation", Marcel Dekker, Inc., New York, 1965,
25 ppO 139 to 142. A particularly convenient procedure comprises
contacting the compound o~ ~ormula (IV), wherein R3 i9 hydrogen
and R4 is -CH2C6H4R5, with hydrogen, in a reaction inert solvent
medium and in the presence of a suitable catalyst at an appro-
pria~e temperature and pressure until hydrogenolysis is complete.
30 Thereafter the desired product o~ formula tI) may be recovered
,,, .,,...................................... "' ' ' .
~` ~068698
by conventional methods involving catalyst removal and recovery
of the product from the solvent mediumD
As used herein "reaction inert solvent medium" refers
to any medium which is a solvent or suitable suspending agent
for the reactant~ is stable under the hydrogenolysis conditions
and does not interfere with the effectiveness o the catalyst
or interact with the reactant or product Polar organic solvents
are generally suitable and include the lower alkanols such as
methanol, ~thanol and butanol, cyclic and straight chain water
soluble ethers such as dioxane~ tetrahydrofuran, diethylene
glycol monomethylether, 2-ethoxyethanol, the lower alkanoic ;~
acids such as acetic acid or propionic acid~ aqueous media in-
cluding the foregoing solvents, and dilute aqueous hydrochloric -
acid. These solvents and others are conventional in known hydro-
genation techniques and hence are not criticalO --~
The temperature is no more critical than it is in
other known hydrogenolysis reactions Thus, a temperature of
from 0 to 100Co may be employed with good results. The
preferred range of temperature, however, is from 10 to 60C~
and room temperature is especially pre~erred for reasons of -
convenience O At temperatures below 0C~ the reaction is in-
ordinately slow whereas at temperatures above 100C~, decomposi-
tion o the starting material may occur. The higher the tempera-
ture, the faster the reaction rate~ However, the reaction,
ordinarily~ is complete in 1 to 24 hoursO
Suitable catalysts for obtaining the desired products
of formula ~I3 in the hydrogenolysis reaction are platinum,
palladium, rhenium, rhodium and ruthenium, either o the
supported or non-supported type, as well as catalytic compound
thereof such as the oxides or chlorides1 Examples of suitable
-12-
. .
~ ' ' ' ' " , . " ' ' ,. , ' , . ' ' ' ' ' ~ ' , ' ' ' '; ~
''.' ,''. ".' '. "', ' "~' ' " '','' """"'"".,, .' .'''1,.'''. " , ,, "' . ',,',, ' ' . '," ", ''' " ' '' ' ,.. ..
' . , ', ., ' ,' '' "' '''','.".' ' .' ' '"','' "' ~ ' ~.",, ' ''',' "."',"",
69~3
catalyst supports are carbon, silica and barium sulfate.
Especially preferred as catalyst is palladium for reasons of
economy and e~ficienc~
The catalyst is ordinarily employed in an amount of ``
rom 10% to 100~ by ~eight based o~ the said starting compound
of ormula ~IV~o
The pressure employed during hydrogenolysis is not
critical, for example, satisfactory results may be obtained at
pressures var~ing from ambient pressure to 100 atmospheres.
When employing the compounds of formula ~IV) wherein
R3 and R4 together with the nitrogen atom to which they are
attached form one of the above mentioned cyclic imido groups,
: ~he said aompounds ~V) are further reacted by hydrolysis or
with hydrazine to provide the desired products of formula tI).
: lS The said hydrolysis may be carried out under alkaline conditions
in the presence of, for example, sodium hydroxide or potassium
hydroxide, or under acidic conditions employing a suitable acid.
Examples of such suitable acids are hydrochloric, hydrobromic, :
sulfuric, phosphoric, hydroiodi~, dichloroacetic and trifluoro-
ace~ic acidsO For hydrolysis of the preferred cyclic imido
compounds of formula ~IV) it has been found to be particularly
convenient and efficient to employ hvdrochloric, hydrobromic,
suluric or phosphoria acid It is preferred to carry out the
hydrolysis with one of these acids at a temperature in the
range of 0 to lOO~C , a particularly preerred range of tempera-
ture for such hydrolysis is from 20 to 50C~ At temperatures
below 0C., ~he hydrolysis rate is inordinately slow, At
temperatures above lOO~Co ~ excessive amounts o~ decompositio~ .
products are generated~
The mole ratio of the above acids to the compound of
-13-
': '` .
. , . ~:,. .,,. .,. , . , , . , . ; ~.. :: .
.. : .. - .: . ., ,: ., ., ... , : ,:, . , .. ,, . : . ... .
.: ,., : : .. , , .. . : ,'~ ' ` i .' : , ': ; ' : : ` ~ ' ' '
~ 36~69t3
formula ~IV) may vary over a wide range, thus mole ratios of
from 1:1 to 200:1 may be employed with satisfactory results.
The time required to reach substantial completion of the hydro-
lysis will vary according to the reaction temperature, and
ordinarily when carried out at 100C. only a few minutes is ;
sufficient and when carried out at 0C. 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 employing a
water immiscible organic solvent su~h as, for example, chloro-
form, methylene dichloride, benzene, or toluene. Upon comple-
tion of the hydrolysis, which may be determined readily by
thin-layer chromatography on silica gel employing, for example,
a 95 5 ethyl acetate/diethylamine solvent system, the desired
product of formula ~Ii may be isolated as a salt of the acid
used in the hydrolysis, employing methods well known in the art.
However, it is ordinarily more conuenient to adjust the reaction
mixture to an alk`aline pH by addition of, for example, sodium
hydroxide, potassium hydroxide or sodium carbonate, followed by
extraction o the compound of formula ~I) as the free base,
employing, for example, one of the above mentioned organic
solvents optionally employed in the hydroly6is. The product is
then readily isolated by evapo~ation.
Alternatively, as mention~d above, the intermediate of
~ormula ~IV) wherein R3 and R4 together with the nitrogen atom
to which they are attached form one of the cyclic imido group~,
may be urther reacted with hydrazine to provide the final
product o formula ¢I~. The use of hydrazine to remove the
phthaloyl group from phthalimido acids or the corresponding
lower alkyl esters is known in the art, see, for example,
~30 Boissannas, A ~ , 3, 179-133 ~1963) and
-14-
. , , . ~ - , ,. - .. " , . -:, ........... ,; .... ,.. : : :,
:, ., - , :. , ,: ~: :,
~ 68698
Sheehan et al., Jour. Amer. Chem. Soc., 76, 6329 (1954). It
__ _
has now been found that the above intermediates of formula (IV)
containing one of the previously mentioned cyclic imido groups
and especially those containing the phthalimido, maleimido or
sucoinimido group also react to provide the desired products
of formula ~I~. The reaction is carried out in the presence of
a reaction inert organic solvent. Examples of organic solvents
which may be employed for this reaction are the lower alkanols
such as ethanol, propanol, isopropanol, butanol, and isoamyl
alcohol; N,N-dime~hylformamide, N,N-dimethylacetamide~ dimethyl-
sulfoxide, diethyleneglycol dimethylether and diethyleneglycol
monoethylether.
The hydrazine employed may be substantially pure
hydrazine or a derivative such as hydra~ine hydrate, hydrazine
hydrochloride or hydrazine sulfate. When the acid addition salts
are employed the hydrazine is generated ln situ by addition of a
suitable base to neutralize the acid. Examples of such suitable
bases are sodium methoxide, potassium carbonate, triethylamine,
triethanolamine, and sodium hydroxide. While a molar excess of
hydrazine up to five moles per mole of intermediate ~IV) may be
successfully emploved in this reaction, it is preferred to employ
an equimolar amount of hydrazine to minimize possible side re-
actions and for reasons of economy. It is preferred to carry out
the reaction with hydrazine at temperatures from 0 to 100C.
A particulaxly preferred range of temperature is from 20 to
50C. At temperatures above 100C. unwanted side reactions
occur, while at temperatures below 0C. the reaction rate is
inordinately slow.
The time re~uired to reach substantial completion of
reaction will, of cour3e, vary with the temperature and the
:
-15-
:, ~, ;
.. , . : : . , . . . . , ~ : . . .
`~ ~L06~365~
prec~se nature of the reactants and solvent~ Ordinarily, how-
ever, the reaction with hy~razine to form the final product of
formula ~I) will be suhstantially complete in from 1 to 48
hours. ~he reactlon of hydrazine with the above cyclic imido
compounds also forms a cyclic hydrazide by~product, such as, for
example, phthaloylhydrazide in the case of the phthalimido
intermediates. ~he reaction mixture may be freed from the by-
product cyclic hydrazide and the desired product of formula ~
may be isolated by methods well known in the art such as, for ~-
example, evaporation ln vacuo to dryness, trituration of the
residue with dilute strong mineral acid such as hydrochloric, or
sulfuric acid in which the cyclic hydrazide is usually only
sparingly soluble, filtering and adjusting the filtrate to an
alkaline pH~ whereupon the desired product is isolated by extrac-
tion or filtration.
When a compound of the formula (II) wherein Rl is
hydrogen or methyl, R3 is hydrogen and R4 is -COOCH2C6H4R5,
-COR6, -COCF3, ~CHO or -COOR6 wherein R5 and R6 are as previous-
ly defined is reacted with a l-substituted piperazine of formula
(III3 in the process of the invention, the reaction proceeds
directly to provide the desired compound of formula ~I) as
indicated by Method B in the above reaction scheme. Thus, with
such a compound of formula ~II), the 1-subs~ituted piperazine
~ reacts at both the 2-position of the quinazoline (II) to
displace the halogen atom, X, (X = Cl or Br) and to remove the
R4 group when R3 i~ hydrogen and R4 is one of the above carbonyl
containing groups, to obtain a compound of formula ~I) in a
single step.
While Method B may be carried out conveniently employ- ~
iny molar ratios of compound ~II) to compound (III) from 1:1 to -
-16-
.. , . , . : , . , .. " . . .. . .
, ' :'', ' ' "' ' ' . ,,' ~' , ' ' ~ .' : .
"
- , '.' '' . ' : ' , .:
:" ,: ,: , ......... . ..
.. .. . . .
-~-` lOG8698
3:1 or higher, it is preferred to react the compound o~ ~ormula
~ with the compound of formula (III) in a molar ratio of 2:1
for reasons of efficiency and economy.
When the process of the reaction is carried out
according to Method B, the desired produc~ of formula ~I) i9
readily isolated by standard methods either in the form of the
hydrochloride salt ~when X is chlorine~, the hydrobromide salt
(.when X is bromine) or as the free baseO For example, when a
compound of the formula (II) wherein X is the especially pre-
ferred chlo~ine is reacted with two moles of a compound o
formula ~III), the hydrochloride salt of compound (I) is
rdinarily obtained merely by filtration of th~ reaction mix-
ture an~ washing the product~ When the free base of the product
of formula ~I) is de~ired, the reaction mixture, upon completion
of the reaction, is treated with an excess of an aqueous solution
o~ a strongly alkaline reagent such as sodium hydroxide, potassium
hydroxide or sodium carbonate and the free base extracted with a
water immiscible solvent such as chloroform, methylene chloride,
1,2-dichloroethane, or benzeneO The product may then be obtain-
ed, for example, by evaporation of solvent and further purified
if desiredO - :
While intermediates o the formula ~II) wherein Rl is
hydrogen; R3 is hydrogen and R4 is benzyl are disalosed in .:
United States Patent Specification NoO 3,511,836 and inter-
mediates of ormula ~IV~. having the same values or Rl, R3 and .;~ . :R4 and R2 is as previously described are claimed therein, certai~ ; ;
of the remaining compounds o ormulae (II) and (IV) are novel ~ .:
compound~D The nov~l intermediates falling within formula
are those of the formula ~V) as defined hereinabove. .~
-~ 30 The novel intermediates falling within.formula ~IV) ~ ;
-17- : .
, ,. . ., j .. . . . . . .
::" ,., '~' ", '. ., ' , ,. ' ~,. , ,'"' . .' . ' '' . ' `' .: . ' ' " ' " ' ' '"' ' ' '
' ' ' ', '''' ', ' ', . ''', ."" ,' ' ,', '' .'" ' "," '', , ~ ' ""'"" " ""' "' ' ' ,' '' ''. ' ' " ' ' '. ;. ~ ' '' ' . . ~ ' '
,'", ',"''" ,, '''' ''''','' ", ''' '"' ' '. " "" ," '' "', ', "' ' ,' " ~' "' " ' ''
~196~36~1
,` ,~
are those of the ormula ~VI) as defined hereinabove.
The novel intermediate~ of formulae (V) and ~VI) are
patentably distinc-t from the prior art compounds of formula (II)
and ~IV) in view of the above mentioned differences in the methods
by which the R3 and R4 groups are removed to provide the desired
compounds of formula ~I~. That is, the prior art compounds of
formula ~I) wherein R3 is hydrogen and R4 is benzyl react with
the compounds of formula ~ to provide the corresponding known
compounds of formula ~IV~ where R3 is hydrogen and R4 is benzyl.
In order to remove the benzyl group, the compound of formula (IV)
is subjected to hydrogenolysis as discussed above. By contrast,
the novel compounds of formula (V) wherein R30 is hydrogen and
R40 is -COOCH~C6H4R5, -COR6, -COCF3, CHO or -COOR6 and R5 and
R6 are as deflned above, react with compounds of formula ~III) to
provide the desired products of formula ~I), directly. The com-
pounds of formula ~V) wherein R30 and R40 together with the
nitrogen atom to which they are attached form a phthalimido,
maleimido or succinimido group react with the compounds of
formula ~III) to provide the novel intermediates of formula ~VI)
which, in turn, provide the desired compounds of formula ~I) by
hydrol~sis or reaction with hydrazine as described previously.
The above described intermediates of formulae ~II) and
~V) are prepared from the appropriate 2,4-dihalo-6,7-dimethoxy-
quinazolines or 2,4-dihalo-6~7,8-trimethoxyquina~olines, where
halo is chloro or bromo. Preparation of said dihalo compounds
are previou~ly described in United States Patent Specification~
No. 3,511,836, and 3,669,963 and by Curd et al., Jour. Chem.
, 777 ~1947); ibid., 1759 ~1948).
In the preparation of the novel intermediates o~
j30 formula ~V) one of the above 2~4-dihaloquinazolines is reacted
-18-
.. -. . : . . . .
,
S16~8
with an appropriate cyclic imide, primary amide or urethan in
a xeaction inert organic solvent and in the presence o a strong
base such as, for example, sodium hydride, potassium hydride,
calcium hydride, sodium methoxide, potassium ethoxide, lithium
butoxide or butyl lithium, under anhydrous conditions. ~fter
the reaction is substantially complete, the compound of formula
(V) is isolated by standard methods known in the art, for example,
by quenching the reaction mixture in an excess of water or
dilute acid and filtering, washing and drying to obtain said
product. Quenching in dilute acid is preferred when said amide
or urethan is employedO
Examples of appropriate cyalic imides are any of those
previously mentioned; preferred cyclic imides are phthalimide,
maleimide and succinimide. Preferred primary amides are form-
amide, trifluoroacetamide and those of the formula R6CONHwhere R6 is alkyl having from one to six carbon atoms or
-C~H4R5 wherein R5 is hydrogen, chlorine, bromine, methyl,
methoxy or nitroO Preferred urethans are those of the formulae
R5C6H4CH20CONH2, and R60CONH2 whérein R5 and R6 are as previous-
. .
~ 20 ly definedO ~ ~
:. .: :.
Examples of reaction inert organic solvents which may
be employed are N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidone, ethyl ether, tetrahydrofuran, 1,2-dimeth-
oxyethane, dimethylsulfoxide, toluene and benzene. Preferred ~-
~5 reaction inert organic solvent are N,N-dimethylformamide and
tetrahydrofuran, -
In carrying out the reaction to provide the novel
intermediates of formula ¢V) the preferred strong base for
reasons of economy and eficiency is sodium hydride. A mole
ratio of said strong base to said 2,4-dihaloquinazoline o~ at
--19--
~L~61~698
', ,,
least 1:1 is ordlnarily employed and mole ratios of from 1:1 to
2:1 are preferred.
Whil2 the above reaction may be carried out over a
wide range of temperature, a temperature in the range of from
0 to 150Co and especially f.rom 65 to 100C. is preferred.
Below 0C. the reaction is inordinately slow while at tempera-
tures above 150 C ~ ~ excessive amounts of undesired by-products
are obtained~ The reaction rate is faster at higher temperatures
and the time required to reach completion will vary with the
temperature as well as the specific nature of the reactants and
solvent. Eowever, the reaction is ordinarily complete in from
2 to 24 hoursO
The following Bxamples illustrate the invention.
:, ' ' .
-20- ~-
.. .
.
.
.. . . . . ..
- ' ' ~ - ' ' ' ;
- , ' . '.
. . :
~C)6136~8
`:~
EXAMPLE 1
.
In a 200 ml. three-necked round bottomed flask was placed 6.48 g.
(0.025 mole~ 2,4-dichloro-6,7-dimethoxyquinazoline and 104 ml. of tetrahydro-
furan. The flask was heated by means of an oil bath held at 70C. To the
flask was then added 2.68 g. (0.025 mole) of benzylamine and the resulting
mixture heated with stirring for one hour. An additional charge of 2.68 g.
benzylamine was added and heating continued for one hour, after which another
2.68 g. of benzylamine was added. The mixture was heated for an additional ~ ~ -
2 hours, then filtered while still hot to remove precipitated benzylamine
hydrochloride. The filtrate was concentrated to half volume, two volumes of
hexane was added and the resulting mixture was stirred slowly for thirty
minutes to effect granulation. Upon filtering and drying 6.0 g. (73~) of the
title compound was obtained, M.P. 190-195C. The structure was verified by
means of nuclear magnetic resonance spectroscopy (NMR) and mass spectroscopy.
' " ';
.. ~ .
. ,,
,:
-21-
" ": , ., , : . , . , , ,, : . . , :. ". . - :::
.. . , . - , - - -,: - ~ .. . ::: : .,,, . : . . :
~06~698
,. ,
~X~MPI.~ 2
2-[4-(2-Furoyl)piperazin-l-yl]-4-bell~ylamino-
6,7-dimethoxyquinazoline
¦ In a 200 ml., three-necked, round bottom flask fitted with therm~-
5 ¦ meter, condenser and drying tube was placed 66 ml. of isoamyl alcohol and
6.0 g. (0.018 mole) of 4-ben~ylamino-2-chloro-6,7-dimethoxyquinazoline. To
this was added a solution of 3.6 g. (0.020 mole) 1-(2-furoyl)piperazine in
50 ml. of isoamyl alcohol. The resulting mixture was heated at reflux (130 C)
~for 4 hours, cooled to 20 C;, filtered, washed with ethyl ether and air dried
to obtain the hydrochloride salt of the title compound. This was converted
to the free base by dissolvinz in 150 ml. hot methanol, addihg 1.3 g. of
sodium methoxide, stirring at 50 C. for tcn minutes, cooling to 20 C., addin~
100 ml. of water, followed by extraction with two 100 ml. portions of chloro-
I form. After concentration of the extracts to dryness 6.0 g. (70%) of the
I . ~ :
15 ~ title compound, M.P. 220-225 C., was obtained.
~ When tnè above procedure is carried out at 80- C. for twenty four
; hours the results are substantially unchanged.
When the reaction is repeated using carbitol (diethyleneglycol
¦ momoeehyl ether) as solvent and heating at either 200 C. for 20 minutes or
20 ~ at 5~ . for 48 h~-r:, tle .itle cmmpo~ d i8 ~imilarly obtaln~d.
~ ,
', , .
. ,~ , .
I ~ -22-
;.:. ~ ' :
, . , - . . : . . . .
. ~ :: ' ' ' ' - ' ' ' ' ' : '
.
,",............... .... ..... ..
10613698
EXAMI~.~ 3
2-[4-(2-~uroyl)piperazin-1-yl]-4-arllino-6,7-dimethoxy-
_ q~nazoline~Prazosin)~
I In a Paar bottle was placed 1.0 g. (2.1 millimoles) of 2-[4-(2-
furoyl)piperazin-1-yl]-4-benzylamino-6,7-dimethoxyquinazoline and 15 ml. of -
ethanol. I~ater (about 5 ml.) was added to the cloud point, then 400 mg. of
palladium-on-carbon (50% wet) catalyst~ The resulting mixture was shaken in
e Paar hydrogenation apparatus at SO p.s.i. for 18 hours, filtered and the
~filtrate was ~slurried with 50 ml. of chloroform and filtered a8ain. The
10 filtrate was concentrated in vacuo to 10 ml., granulated ~or 15 minutes and -
filtered to obtain 450 mg. (56%) of the title compound, M.P. 263-265 C. 9
identified by thin-layer chromatography o~ a silicn gel plate (ethyl acetate/
¦ dieChylamine 95:5 solvent system) and by comparison of the infrared spectrum
with that obtained on an authentic sample of prazosin. ;~
';
. , . ~-: "
! . . . . ., ' ` '
.
I :
. .~ . .
. , `~
.. , .. ~ .. .
. . . ,, , . : :'-'
-23- i
' ~ ` ~(1 686~8
EXAMPLE 4 ~ .
' .
. When the procedures of Examples 1 and 2 are repeated but employing : .
........................ . ; .
the appropriately substituted benzylamine in each case in place of the benzyl-
amine employed in Example 1, the followin~ compounds are similarly obtained.
. . :
. ' ': - '
;~ 5
t : 4-N02- 2-Br-
2-N02- 4-Br-
. 2-Cl- 2-CH3-
3-Cl- 3-CH3- : . :
10 ¦ . 4-Cl- 4-CH3-
. 3-CH30- ! '~
4-CH30- ¦
~, , I ' . '' I '- .,
' I .' '
~: I EXAMPLE 5
.I~en the procedure of Example 3 is repeated, but with any of the
lS I compounds obtained in Example 4 in place of 2-[4-(2-furoy')piperazin-1-yl]-
: I 4-benzylamino-6,7-dlmethoxyquinaizoline, 2-[4-(2-furoyl)piperazin-1-yl]-4-amino-
. I ~,7-dlmet xyqoinazoline i~ cbtained in like manner.
I . .
~ '
. , . ' , .
' : '
~ -24- :
', ~ ', ', '- - - . . ,
.
". :; . . , - , : . :
:. . .
., : ~: . .
,
,' ' '
1(:~6l~69~ , : ~
: . ! ~ . ~ :
EX~MPLE 6 ;
2-Chloro-4 ~hthalimido-6,7=dimethoxyquinazoline
To a 100 ml. three-necked, round bottomed flask fieted with thermo-
meter, stirrer and drying tube ~as charged 50 ml. of N,N-dimethylformamide, -
1.47 g. (0.010 mole~ phthalimide and 0.48 g. (0.010 mole) o~ 50~ w/w sodium
hydride. After stirring at room temperature for thirty minutes a clear
solution was obtained. To this was then added 2.59 g. (0.010 mole) of 2,4-
dichloro-6,7-dimethoxyquinazoline and the resulting mixture ~as heated at
100 C. for 5 hours. The reaction mixture wa. cooied to room temperature, -
150 ml. of water added and the precipitated product isolated'by filtration
and dried jin vacuo to obtain 3.1 g. of thc title compound, M.P. 255 C. The
I~ ~u~e~ e ~s ~ ~fle~ by NUR and = ~s s ec~ral ~ ta. Yie~d, 84X.
1, ~ I .. , I ~
.. . ' ' '' .
~'
. .
, .
-25- - I
.:' ' ' ' "` '' '
'~'' ''
. , ~ .. , ,.: . , . ... ,. . . ., , . . . . , ;. . . . . . .
1¦ iO6B698
,~..;
, ! .
X~MPL~ 7
2~[4-(2-Furoyl)pipera~in~l-yl]~4-phthalimido~
_ 6~7-dimethoxyquinazolinc~
. ' ' , I ~ :.
To a 35 ml., one necked, round bottomed flask fitted with con~ ¦
denser and drying tube was placed 1.0 g. (0.0027 mole) 2~chloro~4~phthalimido~
6,7~dimethoxyquina~oline, lO ml. isoamyl alcohol and a solution of 0.550 g.
,~ (0.003 mole) 1~(2~furoyl)piperazine. The resulting mixture was heated at
130 C. for 4 hours, then cooled to room temperature. To the reaction mlxture ,
~ 35 ml. of hexarje was added and the precipitated product collected by filtra~
tion and dried to obtain 0.70 g. (47%) of the hydrochloride salt of the title
compound. The purified free base was obtained from the salt by silica gel
. . .,.:
chromatography on a 2 inch x 12 inch colun~l, eluting with ethyl acetatc/
diethylamine (90:10). The purified product melted at 305 C. r
¦ When the above procedure is repeated but employing ~he indicat~ed
, . -
solvent in place of isoamyl alcohol and the indicated temperature and reactior
ti~e, the title compound is likewise obtained. ¦
I' l i
SolventReaction Reaction
TemperaLure, C Time, Hours
Isobutanol50~ 48
1,2-Dimethoxy~
I ethane 80 30
¦ Diethyleneglycol
monoethyl ether 200
,, , .~, . :~'
. '' '' ' . .
. . ..
., ~ ,~ , . .
~ -26- .
,. - . .'` , ' .
.
. . - ~. , - , . , , ,.. ~:~
.
,. :. . . .
,. . . . .
~::" ~(~61~6~8 ' I
XAM ~ 8
. ' , . .i :.. ' . ' ' '- ':
A solution of 95 milligrams (0.185 millimole) of 2-[4-(2-
furoyl)piparazin-l-yl]-4-phthalimido-6,7-dimethoxyquinazoline in 2.0 ml. of -~ -
concentrated hydrochloric acid was stirred at room temperature for two hours.
Then 4.0 ml. of chloroform was added and the mixture adjusted to pH 10 by
addition of sodium carbonate solution. The chloroform layer was separated
and evaporated to dryness to obtain 55 mg. (77.6X) of 2-[4-(2-furoyl)piperazin-
l-yl]-4-amino-6,7-dimethoxyquinazoline, M.P. 270 C. The structure was
verified by com~arison of the infrared spectrum with that of an authentic
sample, and by thin-layer chromatography on silica gel using,a 95t'5 ethyl
', , ' `'. ,':'';:,
-? , .
-27- .
.. : . ., ~ , ' . , ' ,' ~. :
. 106869~3 ~
EX~n~LE 9
A suspension of 5.14 g. tO.Ol mole) of 2-[4-(2-furoyl)piperazin-1-
yl]-4-phthalimido-6,7-dimethoxyquinazoline in 200 ml. of isoamyl alcohol is
heated to effect solution and 0.55 g. (0.011 mole) of hydrazine hydrate is
added. The resulting solution is stored at 20 C. fo~ 18 hours then evapo-
rated to dryness under reduced pressure. The residue is triturated with 30 ml. ~-
of 0.5 N hydrochloric acid and stored at 4 C. for two hours. The solution
was filtered to remove the precipitated phthalhydrazide. The filtrate is made
alkaline(pl~ 10) 'with sodium hydroxide solution extracted with chloroform and
the extracts concentrated to dryness to afford 2-14-(2-furoyl)piperazin-1-yl]-
4-a~ino- ,7 dimethoxyqui==zoline.
.
!, ~:
.
., , . .' , '. ,'.
. , ". ..
.~'' . .
.' ' . ' , , .
~ -28-
.. . . . . .
. . .
. . .
' ' ' .; -.".,'. ' " ,: ,
,. ' ' , ' ' ' , ' ' . ' ' '
. . .
j 10613698 '
:. ¦ ! .
. . _AMPJ,E ~0
When the procedures of Example 1 and F,xample 6 are repea~ed but
¦ using the appxopriate starting material~ in each case the following compounds
of formula (II) are obtained. ::
X : .
C3(1~
. , R3 R4 :
` , ' ~ : ''' ' ~' ' .
X Rl R3 P~4 ~
. _ _ , . ..
- : ~ Cl 11- succinimido
. Br H- maleimido
Cl CH30- phthalimido - . -
I Br CH30 succinimido
10 ¦ . . . Cl CH30- maleimido -
Br H-- H 4-CH30C6H4CH2- ~ . :
Cl C~d30- H 2-BrC6H4CH2- .
~:: Cl CH30- H C6H5C~l2
Cl CH30- H 4-N02C6H4CH2
15 ¦ Cl H- H 4-ClC6~14CH2-
Br C~130- H 3-CH3C61~4CH2-
Br H-- phthaiimido . .~.
I Br H-- .H C6H5CH2- : ~
! Br H-- 2 6 4 2 `: :
20 ¦ Cl CH30- H ~ 2 6 4 2
~ Br U-- 11 3-ClC6H4C1l2-
,1 , , .
11 .. . ,. ,
. . ,~' .'
,.,. ~ -29- , , .::
I . . ':'. ': :
I . ll '... .
" , , ' ;: ' ' ., ' ',:' ~ ' " ':, ' , : . ., ' ,
. - . , . , .................. , , ~ . , ;:
- ~ . . , ~ ,
: . -' : ' . , ~ ' ", : , .'
. :::, ~ . : . .
... . .. . . . . ..
_ ~61~698 ~
EXAMPLE 11 :~ :
When the procedures of Examples 2 and 7 are repeated but in each
case employing the appropriate compound of Formula II selected from those
provided in Example 10 and -the appropriate l-substituted piperazine as
starting materials, the following compounds of Formula (IV) are obtained.
CH3 ~ ~ R R R (IV)
N
R R
3 4 ..
Rl R2 3
R- -CH2CH=CH2 phthalimido
H- -CH2CH=CHCH2CH3 succinimido
-CH2CH=C(CH3)2 maleimido
: 10 H- -COC6H5 H 3 6 5 2
3-furoyl H r 6 4 2
H- 3-thienylcarbonyl phthalimido
CH30- 2-thienylcarbonyl H 2 6 4 2
. H- -COOCH3 H 4-ClC6H4CH2-
CH30- -COOCH2CH3 H 3-cH3c6H4cH
CH30- -COOCH2CH(CH3)2 phthalimido
: H- -coocH2cH(oH)cH3 H C6H5CH2-
CH30- -COOCH2CHCH3 H C6H5CH2-
CH3
3 , -CcH21c(cH3)~2 succinimido
. OH
H -COOCH21CHCH3 H 4-N02C6H4CH2-
OH
CH30- -COOCH2CHCH2CH3 maleimido
bH
-30-
.. . . . . .
. :.. . ..
. . :. .
,
,, . , , ~ , . . ;
:: . :
, :. : ' :
.: ,. . ; :
,
1al6~698
,. . .
EXAMPLE II~(Continued)
R2 R3 R4 _ _
H- -COC6H5 phthalimido
CH30- 2-thienylcarbonyl phthalimido
CH30- 3-thienylcarbonyl H 2 N2C6H4CH2
H- -CH2CH=C(CH3~2 H 3-Clc6H4cH2~
CH30- CCH21C CH2 phthalimido
H COOCH2CH CH2 succinimido
H -COOCH3 maleimido
"
: ,
', ' '':
' .
, '
;
~'' ''' ' ~ ~'
,
:, . ,
:":
-31-
,,
"' ' ~',,",' ,'' . ~ " ,, ' ',",' '. ' ~ ' ''.,,., ' '': " '
- , , , . . . :"
..
- . : , . . .
, ~ , . . ~, .. . .
-`` 1(;~68698
EX~MPLE 12
Employing the catalytic hydrogenolysis procedure described in
Example 3, but with the indicated start;ng material in each
case selected from those provided in Example 11, the following compounds of
Formula (I) are obtained.
CH3~ _R~2
N ~ ~ NH2
R~ 4-CH30c6H4cH2-
CH30- 3-furoyl 2-BrC6H4CH2-
CH3 2-thienylcarbonyl 4-N02C6H4cH2-
H- -COOCH3 4-clc6H4cH2-
CH3 -COOCH2CH3 3 CH3C6 4 2
H- ' -COOcH2cH(OH)cH3 C6H5CH2-
CH30- COOC 21 3 C6H5CH2-
H3
: ~ ~ H- -coocH28HcH3 4-N02C6H4CH2-
H
: 15 CH30- 3-thien~lcarbonyl 2 N02C6 4 2
H- -CH2CH-C(CH332 3-C1C6H4CH2
:
, .
-32-
~ . . . . . . . .. .
. . .
.. . . . . . .. .
,. , ~ ... .. . . .
,. . . :
. ,. ,- . . , ,., , ~. , . , ;., ~, :.,
: . , , :, . . . ... .
. : ' , ' , ',"' ' ' ' . ,- ' ' ,' , ' ' ~ . ': :: : ' ' . .' " . .: , ,:
369~3
, :
EXAMPLE 13
~ hen the appropriate compound of Formula (IV), selected from thoseprovided in Example ll, is hydrolyzed by the procedure of Example 8~ bUt
employing an equivalent amount of the indicated acid and carrying out the
5 hydrolysis at the indicated temperature for the indicated time, the followin~ :
compounds of Formula (I) are similarly obtained. .,
3 ~ ~ 0 2 2 ~ ~ ~ N-R2
CH3 ~ ~R .
N (IV) (I) NH2 :
/ \ "~
R3 R4 . . Time
R~ R2 R3 + R~ Acid TC Hours
-
:~ H-CH CH CH phthalimido 48% hydrobromic 50 l : :
H--CH2CH=CHCH2CH3 succinimido 96% sulfuric 0 6
CH30-CH2CH=C(CH3)2. maleimido 85% phosphoric 100 / 0.25
CH30--COOCH2CH(CH3)2 phthalimido37% hydrochloric. 20 2
CH30--CcH2lc(cH3)2 succinimido 48% hydrobromic
H -:
3 21 2 3 chloric . 10 4
: 15 H COC~ 5 phthalim~do, 37% hydrochloric 20 2 ~:
CH30- 2-thienyl- phthalimido , 37% hydrochl~ric20~ 2
carbonyl :
H 3-thienyl- phthalimido ,37% hydrochloric 50 0.75
carbonyl
CH30 -C008H2=CH2 phthalimido 37% hydrochloric 25 2
H3 ` .
H -COOCH3 maleimido 80% 9ulfuric 25 2
~t
-33-
' ,'. `, ' ' ' " ... ' ' ' . ' ' ', . ' ,~ ~' " ' ' ', '
.. .. . . . . . . . . .
' ' '''', "~'' ''.'. ,'' '"., ,,',''," .''".","'. '' '.' ',,, ,' ' ;' ~;' ', : '' ,
061~698
EXAMPLE 14
When the appropriate compound of Formula (IV), selected from those
provided in Example 11 is employed in place of 2-~4-(2-furoyl)piperazin-1-yl]-
~-phthalimido-6,i-dimethoxyquinazoline in the procedure of Example-9 under
the indicated conditions, the following final products of Formula (I) are
also obtained. Rl
3 ~ ~ ~ N 3 _R2 3 ~ ~ ~ -R
CH3
~ N ~ CH30 ~H2
R3 R4
~IV) ~I)
::
- -34- : .
:' ' ~ :,,
: . . .,. : . .. . . i .. . : .. , : :: ., ,., .. ,, . : , : . " . .
:, . , . : : , .. ,. . , , .: , .
:: ., : , . . , , . :
''' ' ' , :, . : . .. . . . . ..
~(~681i98
EXAMPLE 14 - (Cont'd)
Time
~L_ R? R3 -~ R4 SolYent TC Hours
H- -CH2CH-CHCH2CH3 succinimidoisoamyl alcohol100 1 .
H- -COC6H5- phthalimido ethanol 50 4
CH30- 2-thienyl- phthalimido n-butanol 0 48
carbonyl '
CH30- -CcH2cH~cH3)2 phthalimido DMF* 100 0.5
CH30- -COOCH2CtCH3)2 succinimido di~lyme~ 25 20
1H -
CH30- -COOCH2CHCH2CH3- maleimidoethanol20 24 . ~ :
H
CH30- -COOCH2C~ CH2 phthalimidodiglyme 20 18 ~:
H 3-thlenyl- phthalimidoisoamyl alcohol50 4 .-
carbonyl : .
H -CH2CH=CH2 phthalimidO ethanol 20 18
2 2 succinimido DMF* 100 1 ~:
H -COOCH3 maleimido ethanol oo 48
*N,N-Dimethylformamide ~ .
~Diethyleneglycol dimethylether
:.
~ '
.
..
.
--35--
, . - .. :- . . . , . - , . , . . ,, .. ... ,.. :. :.. - .,:, .:
68698
EXAMPLE L5 _
, '' .
4-BenzoYlamino-2-chloro-6,?-dime~hoxyquinazoline
. ' ' ' , .
In a 100 ml. three-necked, round bottomed flask fitting witll reflux
condenser, thermometer and drying tube were placed 32 ml. oi~ dry tetr~lhydro-
5 furan, 10 ml. of dry N,N-dimethylformamide, 6.48 g. ~0.025 mole) 294-llichloro-
6,7-dimethoxyquinazoline [prepared by the procedure of Curd et al., J. Chem.
Soc., 1759 (1948)],3.03 g. (0.025 mole) of benzamide and 2.4 g. (0.051) mole)
of 50% w/w sodium! hydride, the hydride being added last. The resultil~g mixture
was heated at reflux for 24 hours, cooled to room temperature and fil,~ered,
10 washing with tetrahydrofuran, to obtain 6.0 g. (66~) of the sodium saLt of the
title compound, M.P. 315 C.
Upon slurrying 1.0 g. of t~le sodium salt in 20 ml. of water,
acidifying to p~l 3 4 with 2N hydrochloric acid, stirring for 15 minut!~s at
~ 20-25 C, filtering and drying overnight, 0.67 g. of the title compoulld was
15 obtained. ~I.P. 235-240 C. Upon recrystallization from isoamyl alcoh!~l, it
~elted t .6-23a~ c. h- mas~ spectrum ~ ~wea peak6 at Y/e 34 and ~44.
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061~i698
EXI~'LE l6
4-l~cetylamino-2-cllloro-6,7-diillothoxyquina~ollne
In a 100 ml. reaction vessel were placed, 6.48 g. ~0.025 mole)
1 2~4-dichloro-6,7-dimethoxyquinazoline, 1~5 g. (0.025 mole) acetamide, 32 ml. ~;
5 ¦ of dry N,N-dimethylformamide and 2.4 g. (0.050 mole) of 50~ sodium hydride.
Upon warming to 40 C., an exothermic reaction commenccd and the temperature
rapidly increased to 120D C. with considerable foaming. During this exothermi
period the reaction mixture turned purple, then red. The mixture was cooled
to 90 C. and maintained at this temperature for two hours. The mixture was
10 ! then cooled to room temperature, poured into 150 ml. of water, washed with
j two l00 ml. portions of cTlloroform and ~hc aqueous phase adj usted to pH 2 ~; ;
¦ by addition of concentrated hydrochloric acid. 'rhe precipitated product was
¦ coilected by filtration and dried to obtain an 86~ yield of the title compound,~ -
li M.P. 275 C. Only one spot was obtained on thin-layer chromatography on
151i silica gel, eluting with 95:5 ethyl acetate/diethylamine. The mass spectrum
il showed a molecular ion at M/e 281.
I
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06t369~
E ~IPLE 17 . '
I . , , . '~ .
. I ~hen the procedures of Examples 15 and l6 are repeated but with
an equimolar amount of the appropri.ate alkylamide or arylamide in place of.the :~
amides employed therein, and in those cases where Rl is methoxy, employing
5I an equimolar amount of 2,4-dichloro-6,7,8-trimethoxyquinazoline, obtained bythe procedure of ~.S. 3,669,968, in place of 2,4-dichloro-6,7-dimethoxy-
~ui=azoIine, ~he foIIo~ing compoonds are prep~re~. ¦
11, ' .
,. ........ , .. " ,., .. , , ,.. .... ..... .... ,.... . .. ~; ,, ..... ... , .. ~` .,. .- . . . .
.. .. , .. " . ... .... ... , .. ,. . .. , . . .. . ., ~, ...... ., . . . . , ; , , . ; . . .
.,. ,, .......... , . .... " . ", .,.. , .. , , .,. .,... ., ., ... - ~. .. . . . . .. .. .. ...
..... ., ., . ,.. ,, . - .......... . . ,.,", . ,, ;....... ., :.. .: . .
.... ., .......... ,. ..... , . .. , . ,, . .... , , ,,., . . . .... , ;. . ... .
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~ ; 106~i6~8 ~ I ~
EXAPfPLE 17 (Con' t) '
.- . .
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C~I~C~
. ............ , , . ','~.,
. ." , .
.,
~ ~ , .
: 1 4 1 . 4
. H- HC0- G1130- HC0-
l C 3CH2C0 3 C113C0 .
:~ . H CH3C~12CH2cO- 3 ( 3)2 . I .
5 1 ( 3)2CHC~2C0C1130 - C113(C~12)3C0
. H- 4-ClC6H4C- 3 3 6 4C
H- 2-BrC6H4C0- CH30- 4-N02C6H4cO- ¦ ¦
H- 3-N02C61~4CO- CH30 3 ClC6 4
H 4 C 30C6M4C0 3 C6H5C
H- C~3Co_ CH30 3
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. 1~6i~698
: .,` . . ':
EXI~LE 18
4-Ethoxyc~rbonylamino-2-chloro-6,7-dimethoxyquinazoline
2,4-dichloro-6,7-dimethoxyquinazoline (6.48 g., 0.025 mole), 32 ml.
tetrahydrofuran, ethylcarbamate t2.23 g., 0.025 mole) and 50% sodium hydride
(2.4 g~, O.OS0 mole) was placed in a 100 ml. reaction flask fitted with therm-
ometer reflux condenser and drying tube. The reaction mixture was refluxed
for two hours after which 70 ml. of methanol was slowly added, the resulting
mixture heated to 60 C. and filtered while hot. The filtrate was concentrate
¦ to a thick slurr!y, the solid collected by filtration washed with 5 ml.
10¦ chloroform to obtain 5.4 g. (70%) of t',^~e title compound. A samp~e ~pon
recrystallization from a mixture of tetr~hydrofuran and hexane (2:3) melted
at 212 C.
., I
Anal- Calc~d for C13H14N3O4Cl (percent): C, 50.09; H, 4.53; N, 13.4
~o~nd: C, 49.95; 1{, 4.46; N, 13.54
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:- ~ 1068698 ~ ~
EXAMPL~ 19 . .
4-PhenoxYcarbonylamino~2-chloro-6,7,8-trin,ethoxyquinazoline
In a 500 ml. flask i9 pl~ced 25.S g. (0.10 mole) 2,4-dichloro-
6,7,8-trimethoxyquinazoline prepared as described in U.S. 3,669,968, 13.7 g.
S (0.10 mole) phenylcarbamate (Aldrich Chemical Co.), 130 ml. tetrahydrofuran
and 9.6 ~. (0.20 mole) of a 50~ dispersion of sodium hydride. The resulting
mixture is refluxed for 4 hours~ cooled to room temperatare, 250 ml. of
methanol is added and the mixture warmed to 60 C. and filtered. The filtrate
is concentrated,to a thick slurry, the solid collected by filtration and
washed with chloroform to obtain the title compound.
When 2,4-dibromo-6,7,8-trimethoxyquinazoline is employed in the
above procedure in place of 2,4-dichloro-6,7,8-dimethoxyquinazoline, 4-phenoxy -
carbonylamino-2-bromo-6,7,8-trimethoxyquinaæoline is similarly obtained.
. ~ '
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When the procedures of Examples 18 and 19 are repeated~ but
e~ploying the appropriate starting materials in each case~ the following
. compounds are likewise obtained.
. .
Rl
CH30 ~ N ~_ Cl
. C~30 ~ ~
: ' NHR4
Il ' , . ,~ ,, -
., 11 ` ' ,, ' ' . ';.':':
Rl R4 1 4 1 ~ ~
.. . ._._ ...
~1 ~130C0- C~130_ C113CIl20C0-
¦l H (CH3)3cOcO- CH30- (CH3j2
ll H C6H50C0- 3 3t 2)3
: ¦I H 4-Clc6H40co- CH30- 4-BrC6H40co-
10 ¦¦ H 2-BrC6H40C0- CH30- 3-CH3C6H40C0-
!I H 3-CH30C6~40Co-CH30- 4-N02C6H40Co-
¦~ ~ H 4 ~2C6~4c CH30- C6H5C~l20co- , . : ~:
¦¦ H 4-ClC6~14c~20cO- CH30- 4-BrC6~l4cH20co-
1¦ H 2-CH3C6H4cH2oco- CH30- 2-C~130C6H4CH20C0~ ~ . :
15 ¦ :i 2-NOzC6114Cii2oCo~ Cil30- 4 ClC6H4C
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_XA~PL~ 21
2 [4-(2-furoyl)piperazirl-l-yl]-4-amino-6~7-
_ _ dimeLlloxyquin?zo].ine __
To a 50 ml. flask fitted with stirrer, reflux condenser and
dryin~ tube was added 160 mg. (0.66 mmole) 4-benzoylamino-2-chloro-6,7-
dimethoxyquinazoline prepared by the procedure of Examples 15, 244.2 mg.
(1.32 mmole) 1-(2-furoyl)piperazine and 4 ml. of isoamyl alcohol. The
~esulting mixture was heated at 100 C. for ~ hours then cooled to room
- lO ~temperature. The precipitated solid was collected by filtration and dried,
to obtain 60 mg. of crude product. It was identified as 2-[4-(2-furoyl)- ¦ -piperazin-l-yl]-~ amino-6~7-dimethoxyqulnazoline by silica gel thin-layer
chromatography (etllylacetatc/diethylamine 90:10). The crude material was
purified on a O.5 inch x 9 inch column of silica gel, eluting with benzene/
acetone/formic acid/water (100:100:20:5, by volume) to provide 35 mg.,
M.P. 275 C. -
~hen the above procedure is repeated but employing the
indicated solvent in place of isoamyl alcohol and carrying out the reaction
¦ employing the tabulated temperatyre and time in each case, the title compound
¦ is obtained in like manner.
I . : .
I . - ' '' .
Solvent Reaction Reaction
Temperature, C. Time, Hours
_ _ . .__ _
2-Butanol 50 50 I -
2-Methoxyethanol 80 18 1,
2-Methyl-2-pentanol 130- 2
Diethyleneglycol 200 0.25 ,
. . . .
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EX~ E 22
2-[4-(2-~uroyl)pi~erazin-1-yl]-4-amino-
6,7-dimct!loxyquina~oline _ _
- 4-Ethoxycarbonylamino-2-chloro-6,7-dimethoxyquinazoline,
(2.0 g., 0.0064 mole) and 23 ml. of isoamyl alcohol were combined in a
reaction flask. A solueion of 1-(2-furoyl)piperazine (2.54 g., 0.014 mole)
in 18 ml. of isoamyl alcohol was added and the mixture heated at 130 C.
for 4 hours. The precipitated solids were collected on a filter funnel,
~ashed with isoamyl alcohol then stirred with 100 ml. of 10% aqueous sodium
hYdroxide~ ~n equal volume of chlorofo-;m was added and the mixture stirred
for 15 minutes. The organic layer was separated, concentrated to about
25 ml. and 50 ml. of tetrahydrofuran added. The solids were collected by
filtration then ~urther purified by chromatography on a silica gel column
11 x 18 inches) eluting first with ethylacetate, then with methanol. The ¦ ~
151 fractions containing the title compound were com~ined and evaporated to ¦ - ;
I ! dryness. The residue was taken up in 10 ml. of chloroform, hexane added to ~ ;
the cloud point, stirred 15 minutes and the crystals collected by filtration, ¦ -
! M-P- 265 C., yield 900 mg. (37%).
~¦ When the above reaction is repeated at 80 C. for 18 hours, the
20¦ resu~s are substantially unchanged. ,
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~061~98
EX~MrLE 23
2-(4-~enzoyl-1-piperazlnyl)-4-amino-
¦ 6,7-dimethoxyquinazoline hydrocllloride
4-Acetylamino-2-chloro-6,7-dimethoxyquinazoline (28.2 g., o.lb
mole), l-benzoylpiperazine (38.0 g.) 0.20 mole) and 750 ml. o~ isoamyl alcohol
are combined. The resulting mixture is refluxed for three hours then cooled
to room temperature. The precipitated product was filtered, washed with
¦ ethYlacetate~ then with ether and air dried to obtain the title compound.
¦ I EX~MPLE 24
10 ¦ 2-[4-(2-Hydroxy-2-methylprop-l~yloxycarbonyl)-
piperazin-l-yll-4-am-ino-6~7~8-trime~hoxyquinazolinc
4-Phenoxycarbonylamino-2-chloro-6,7,8-trimethoxyquinazoline
¦ (19.5 g., 0.05 mole), 1-(2-hydroxy-2-methylprop-1-yloxycarbonyl)piperazine
I ¦ (20.2 g., 0.10 mole) and 500 ml. of diethyleneglycol dimethylether are
heated at 125 C. for two hours. The reaction mixture is concentrated
. in vacuo to about 200 ml. and an equal volume of ethyl ether is added. The
I ~ precipitated hydrachloride salt is filtered, washed with ether then stirred
with 200 ml. of saturated aqueous sodium carbonate solution. ~he liberated I --
base is extracted with 3 x 200 ml. portions of chloroform and the extracts
~20~ concentrated to about 150 ml. Diisopropyl ether, about 100 ml., is added
and the mixture set aside overnight, then filtered $o yield the crystalline
¦ title compound. ;
When the above procedure is repeated with an equimolar amount of
4-phenoxycarbonylamino-2-bromo-6,7,8 tximethoxyquinazoline in place of the
corresponding 2-chloro compound and the reaction mixture is main~ained at
50 C. for 40 hours, at 80 C. for 15 hour's, or at 200 C. in a high pressure
reactor for 25 minutes the title compound is obtaincd in the same manner.
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368~.;98
Ex~ E 25 ,
When ~he compounds obtained in E~amples 17 and 20 are xeactedwith the appropriately ~ubstituted pipera~ines of fo~mula tIII) by the pro-
cedures of E.~amples 21 through 24, the following compounds of formula (I)
5¦~ ~re ~ rly obCl m ed.
¦ 3 ~ , N~ Cl ~ CN30 ~
¦ C~30 NHR4 12 CH30 NH
I , ,
1 (III) (I)
I . , ' ' .
l 4 ~2
. H~ ~CO- . -CH2CH=CH2
H- CH3CH2CO- CH2CtCH3)=CH2
1 . H- CH3CH2CH2CO- -CU2C(CH3)=CHCH3
lO1 H- (C113)2CHCH2CO- -COC6H5
! H- 4-ClC6114CO- 2-furoyl
jl H- 6 4 3-furoyl
I¦ ~_ 3-N02C6114CO- 2-thienylcarbonyl
l H- 4-CH30C6H4co- 3-~hi~nylcarbonyl
15 1 C}130- ~CO- -COOcl13
CH30- C1l3CO- -COOC112C113
C~130- (CH3)2CHCO- -C00~12(CH2)2CH3
l C~130- C~13~C112)~C- , -coocll2c~l=cll2
1 1 CH30- 4-C11 C H CO- -Cooc~2ctcH3)=cH2
3 4 2C6H~co -COOC1t2CH=C11CH3
3- 3 ClC6114CO- . -C00~12C(0;-1)(C1~3~2
CH30- C6~15C- -COOC312C11(OH)C~13
. ~1- C1130CO- ~Coocll2cllto~l)cl~3
H- CF3CO- 2-fur~yl /
.~ -46- '
.. . . . . ..
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...
.
,
06~36~8 ,
l EXl~l:PLE 2~S (Continu~d) . ~ I
. . ' ' "' '
. , . : ,
Rl R4 R2 ._ ..
, ~
H- ( 3)2COCO -cOOC~l2c(OH) (CH3~2
H- C6H5C- -COOCH2c(cil3)=cH2
l H- 4-clc6H4()co- 2CH CH2
5 1 H- 2-BrC6H40Co- -COOCH2CH (CH3) 2
¦ .! H- 4-No2c6H4oco- -COOCH (CH3) 2
I H- 4 ClC6H4C~120C -COOCH3
. H- 2-cH3c6~l4cll2oco- 2-thienylcarbonyl
. H- 2 6 4 2 2-f uroyl
C~30- CH3CH20C- 3-furoyl . ~:
¦ CH30-(CH3)2C110CO- 2-furoyl , .
CH 0-C113~ Ii2l 30CO- C 2 2
CH30- 4-BrC6H40co- 2 ( 3) CH2 . : :
~: CH30- 3-C~13C6HbC- CH2C(CH3)=CH2
C1130- 4-N02C6~140CO- 6 5
3 C6H5cll2oco -COOCH2CII-CE12 :~
CH30- 4-BrC6H4cH20co- -COOCH2C(CH3)=CH
3 3 6 4CH20CO -COOCH3 ~ ::
C1130- 4-clc6H4cH2oco- -COOCH2CH3~ ~ :
20 ~11 CH30-- OE3CO -COCcl~2c~cii3~-~i2
,
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