Note: Descriptions are shown in the official language in which they were submitted.
~(~83~5~
THERAPEUTIC AGENTS
. .
This invention relates -to certain 2~phenyl-5-
(5-lH-tetrazolyl)pyrimidin-4(3H)-one derivatives and to
their use as inhibi-tors of allergic reactions.
Various medicinal agents have been employed in
the treatment of allergic reactions such as bronchial asthma
and allergic rhinitis which are believed to result mainly
from antigen-antibody interaction. With respect to bronchial
asthma, one of -the most serious of these allergically-
mediated diseases, bronchodilators such as theophylline,isoprotereno., epinephrine and atropine are used primarily
in providing symptomatic relief. These agents, however, have
undesirable side effects, e.g. cardiac stimula-tion and ~ -
gastrointestinal distress.
'' , ~,'
With the recent introduction of disodium cromo-
glycate described by J.S.G. Cox, et al. in Adv. in Drug. Res.,
5, 115-196 (1970), the physician has been provided with an ~
agent which, when administered to asthmatic patients prior ~ -
to inhalation of specific antigens, inhibits the release
of mediators, e.g. histamine and SRS-A (slow-reacting-substance
of anaphylaxis), believed to be responsible for the
asthmatic response. While making possible a propyl-
latic treatment for bronchial asthma without cardiovascular
' '
-- 1 --
':' '
'' ' ' '
~0~3~5;2
side effects and thus representing a significant advance,
disodium cromoglycate suffers from a major clisadvantage in
that i-t is not orally absorbed and must be administered by
inhalation.
With respect of the 2-phenyl-5-(5-lH-tetrazolyl)-
pyr.imidin-4(3H)-one derivatives of the present invention,
the following references illustrate structurally related
compounds known in the art.
l. Preparation of the unsubstituted acid and ester
of the formula
Hl~ C2
' ~
where R is hydrogen or ethyl is disclosed by -;
S. Ruhemann in Ber., 30, 821 (1897).
2. The p-methylphenyl and p-me-thoxyphenyl sub-
stituted esters and acids of the formula
... .
5;~
~ / 2
HIN
~ ~ ~ N
X '~
where R is hydrogen or ethyl and X is methyl
or methoxy are disclosed by Mitter, et al. in
J. Chem. Soc., 123, 2179 (1923) and Quart._J.
Indian Chem. Soc., 2, 61 (1925). ~
, .
3. Shen, et al. in U.S. Patents 3,660,403 and ~;~
3,745,161 disclose compounds of the general
formula
' ' '. . ` .:
OY . ", , '
R { Ar ~ ~ COX ~ ~ ~
.
': : ~ '"
where R ~ Ar3 may inter alia be substituted phenyl,
¦ Y may be hydrogen and X is any of various substi~
tuents including hydroxy, alkoxy or N-heterocyclo.
The reference compounds are disclosed as having
antiinflammatory, antipyretic and analgesic
activity, and no mention is made of any utility
as antiallergy agents.
- 3 -
' ''':i' , ,
:. . . :
., ., :
~83~52
4. U.SO Pa-tent 3,883,653 discloses antiallergy
compounds of the formula
HO
H2 C~
N ~
(CH2)m-Ar
where m is an integer of 0 or 1 and AR is
pyridyl, thienyl~ furyl, phenyl or phenyl
substituted by hydroxy, methyl, methoxy, nitro~
chloro, fluoro, 3,4-dimethoxy, 3,4,5-trimethoxy
or alkanoylamino.
5. U.S. Patent 3,44~,107 discloses lipid regulating
agents of the formula
X2 , , .
N ~
~ J (CH2~n ~ H
X ~ N
.' ' '~
where Xl and x2 may be various substituents
includiny hydroxy, phenyl, p-chlorophenyl, p- .
methylphenyl and p aminophenyl and n may be -
0 to 4. No disclosure is made of applicants'
compounds where in the above formula n is 0 and
where the pyrimidinyl ring system is substituted
,. .
;, ,
,~ .
~8315~:
at the 4-position by hydroxy and at the 2-
position by substituted pheny].
Summary of the Invention ~
This invention relates to new therapeutically use- ;
ful 2-(substituted)phenyl-5-(5-lH-tetrazolyl)pyrimidin-4-
(3H)-one derivatives, to processes for their preparation,
to pharmaceutical compositions containing them and to methods
for treating allergically-mediated diseases in mammals by
administration of such derivatives or pharmaceutical
compositions thereof. The compounds and compositions
provided by the present invention are particularly valuable -
in the prophylactic treatment of allergic bronchial asthma
by oral administration.
The antiallergy agents of the present invention -~
may be represented by the formula
; , ~
N -~ N
Rl 3 ~N~\~ N/N
~ N
R2 ~ l 1
R I
wherein Rl, R2 and R3 which may be the same or different
, ... . . .
'-.- ~ : ''
. .
52
are each hydro~en, halogen, ~lower)alkyl, (lower)alkenyl,
(lower)alkoxy, -O-(lower)alkenyl, -O-(CH2)m-C~ CH2)n in
which m is 0 or an integer from 1 to 6 and n is an integer
, CH2(CH2)xO(CH2)yCH3 in which x is 0 or an
integer from 1 to 6 and y is 0 or an integer from 1 to 6.
CF3, -OCF3, -OCH2CF3, hydroxy, ~lower)alkylthio, amino, nitro,
-N ~ CH2)r in which r is 4 or 5, -w O , (lower)alkylamino,
di~lower)alkylamino, carboxyl, -CO2-(lower)alkyl, -O(CH2)uCO2Ra
in which u is an integer from 1 to 6 and Ra is hydrogen or
(lower)alkyl, acyl, acylamino, acyloxy, -O-C-NHRb in which
Rb is ~lower)alkyl, -O(CH2)kOH in which k is an integer from
2 1 CH20H, OCH2-1CH-CH20CH3 or CH2c6H ~ and
OH H
pharmaceutically acceptable salts thereof, with the proviso
that Rl, R and R3 may not all be alike except in the case
where they represent (lower)alkoxy.
The Rl, R2 and R3 substituents mentioned above
may be located at any of the available positions of the
phenyl ring, i.e., at the 2-6 positions. The substituents
may be alike or different, but the only compounds included
within the scope of the invention where Rl - R2 = R3 are those
in which Rl, R and R3 are all (lower)alkoxy. The substituent
groups disclosed ab~ve may be further deiined as iollcws:
; 6
.'
,, .
~083~S;2
(a) Halogen includes chlorine, bromine, fluorine and iodine.
Preferred halogen substituents are chlorine and fluorine;
(b) (Lower)alkyl includes both straight and branched chain
saturated aliphatic hydrocarbon radicals having from 1-10
carbon atoms inclusive, e.g. methyl, ethyl, n-propyl, iso-
propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
Preferred substituents are those having from 1-6 carbon atoms
and most preferred are Cl-C4 alkyl radicals;
(c) (Lower)alkenyl includes straight or branched chain un-
saturated aliphatic hydrocarbon radicals containing one
double bond and having from 2-10 carbon atoms inclusive,
e.g. vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-
butenyl. Preferred groups are C2-C6 alkenyl radicals;
(d) (Lower)alkoxy includes Cl C10 alkoxy radicals, the
alkyl portion of such radicals being defined as in (b)
above. Examples include methoxy, ethoxy, n-propoxy, iso-
propoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentyloxy, iso-
pentyloxy, n-hexyloxy, etc. Preferred groups are Cl-C6
alkoxy and most preferred are Cl-C4 alkoxy radicals;
(e) -O-(Lower)alkenyl groups include radicals in which the
alkenyl portion is as defined above in (c), e.g. vinyloxy,
.. :
10~3~.5~
allyloxy or isopropenyloxy. A mos-t preEerred group is
allyloxy;
(f) -O-(CH2)m-C~ ~CH3)n includes cyclo(lower)alkyloxy and
cyclo(lower)alkyl-(Cl-C6)alkyloxy groups in which the cyclo-
alkyl ring contains from 3 to 8 carbon atoms, preferably
3-6 carbon atoms. Examples of such groups are cyclopropyl-
oxy, cyclobutyloxy~ cyclopentyloxy, cyclohexyloxy, cycloheptyl-
oxy, cyclopropylmethyloxy, cyclopropylethyloxy, cyclobutyl-
methyloxy, cyclobutylethyloxy, cyclopentylmethyloxy, cyclohexyl-
methyloxy, cyclohexylethyloxy and cyclohexylpropyloxy;
(g) -O-CH2(CH2)XO(CH2)yCH3 includes radicals such as
2 3 2 2OCH3, -OCH2CH2OCH2CH3, -OCH OCH CH d
-OCH2cH2cH2OcH2cH3;
(h) (Lower)alkylthio includes Cl-C10 alkylthio radicals in
which the alkyl portion is as defined above ln (b). Examples
of such groups are methylthio, ethylthio, propylthio and
butylthio;
(i) (Lower)alkylamino includes Cl-C10 alkylamino radicals
in which alkyl is as defined as in (b). Examples of such
groups are methylamino, ethylamino, propylamino and butylamino;
(j) Di(lower)alkylamino includes di Cl-C10 alkylamino radicals
in which alkyl is as defined above in (b). Examples of such
' ', ', ' ' '
,
15Z
groups are dimethylamino and diethylamino;
(k) -CO2-Lower)alkyl includes ester radicals in which the
alkyl moiety is as defined above in (b), e.g. carbomethoxy,
carbethoxy, carbopropoxy and carbobutoxy.
(1) ~-O(CH2)uCO2R r~presents radicals in which R is as
defined in (b) above such as -OCH2CO2H, -OCH~CH2CO2H,
CH CH CO H -CH2c2cH3' -CH2c2c2 5' 2 2 2
and CH2cH2c2c2HS;
:, :
(m) Acyl includes radicals of the type RC-CO- where Rc is ~i
; 10 an aliphatic, cycloaliphatic, aromatic or araliphatic hydro- ~ -
carbon radical or a heterocyclic or heterocyclic-aliphatic
radical~ e-g- CH3CO-, C2H5C-~ C3H7CO-, C6H5Co-l C6H5cH2cO_,
~ CH2CO- and CH2 - CH-CO-. Preferred acyl groups
are those in which Rc is alkyl as defined in (b);
(n) Acylamino includes radicals of the type R -CO-NH- where
Rc is as defined above in connection with acyl and is pre-
ferably C1-C10 alkyl. Examples of such groups are CH3CONH-,
C2H5CONH- and C6H5CONH-;
(o) Acyloxy includes radicals of the type R -COO- in which
Rc is as defined above in connection with acyl and is prefer-
` ably C1-C10 alkyl. Examples are CE13COO-, C2~5COO-, C3H7COO-,
C6H5CH2COO- and C6H5COO-;
,, ~ ,.
(p) -N~__/CH2)r includes pyrrolidino and piperidino; and
- g _
, . . . ..... .
.
: "
~L~1!33~5Z
(q) -O-C-NHRb includes (lower)alkyl carbamoyloxy radicals
in which the (lower)alkyl portion is as defined above in
(b). Examples of such substituents include -OCONHCH3,
-ocoNHc2Hs and -OCONHC3H7-
A preferred embodiment of the present inventioncomprises the compounds of the formula
R2 ~U ~ :
Rl
I~
wherein Rl and R2 which may be the same or difEerent are
as defîned above in connection with the compounds of general
formula I, with the proviso that Rl may never by hydrogen,
and the pharmaceutically acceptable salts of said compounds
of formula I'.
Preferred compounds and salts oE formula I' are
those in which Rl is (lower)alkoxy, i.e. straight or branched
chain Cl-C10 alkoxy, -O~(lower)alkenyl or -O-(CH2)m -CE ~ CH2)n
in which m is O or an integer from 1 to 6 and n is an integer
from 2 to 7. Within this group, preferred sub-groups are
those compounds and salts of formula I' in which:
.
. ~' :
i2
(a~ Rl is -O-Cl-C6 alkyl, most preferably methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, isobutoxy or sec-butoxyi
(b) Rl is -O-C2-C6 alkenyl, most preferably allyloxy; and
"
(c) R is -O-(CH2)m-CH (CH2)n in which m is O or an integer
from 1 to 4 and n is an integer from 2 to 5, most prefer-
ably cyclopropylmethoxy. The preferred R2 substituents for
the compounds of formula I' are hydrogen, (lower)alkoxy,
-O-(lower)alkenyl, -O (CH2)m-CH ~ CH2)n in which m is
O or an integer from 1 to 6 and n is an integer from
2 to 7, nitro, amino or di(lower)alkylamino. Most -~
preferred R substituents are hydrogen, (lower)alkoxy,
nitro, amino or di(lower)alkylamino.
A more preferred embodiment of the present inven-
tion comprises the compound of the formula
1 , "'
N N ;~
NH ~ N
\ ~ ~ N
IL
~! wherein Rl and R2 which may be the same or different are
as defined above in connection with the compounds of general
formula I, with the proviso that Rl is never hydrogen, and
the pharmaceutically acceptable salts of said compounds of
formula I".
., .
-- 11 --
. , .
:, ...... . . . .
: ~ .
3~S;~:
Preferred compounds and salts of formula I" are
those in which R1 is (lower)alkoxy, -O-(lower)alkenyl or
O (CH2)m CH ~ H2)n in which m is O or an in-teger from 1 to
6 and n is an integer from 2 to 7. Within this group, pre~
ferred sub-groups are those compounds and salts of formula
I" in which:
(a) Rl is -O-Cl-C6 alkyl, mos-t preferably methoxy, ethoxy,
n propoxy, isopropoxy, n-butoxy, isobutoxy or sec-butoxy;
(b) Rl is -O-C2-C6 alkenyl, most preferably allyloxy; and
~ ,~ '
(c) R is -O-(CHz)m-CH (CH2)n in which m is O or an integer
from 1 to 4 and n is an integer from 2 to 5, most prefer-
ably cyclopropylmethoxy. The preferred R substituents for
the compounds of formula I" are hydrogen, (lower)alkoxy,
-o-(lower)alkenYl~ ~~(CH2)m~cH 3 C~l2)n
O or an integer from 1 to 6 and n is an integer from 2
to 7, nitro, amino or di(lower)alkylamino. Most pre- ~ ~
ferred R2 substituents are hydrogen, (lower)alkoxy, ~ ~ ~
nitro, amino or di(lower)alkylamino. -
Particularly preferred compounds and salts of
formula I" are those in which Rl is methoxy, ethoxy, n-
propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,
allyloxy or cyclopropylmethoxy and R2 is methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,
a:lyloxy, cyclopropylmethoxy, nitro, amino or dimethylamino.
- 12 -
: , . , ':
, -:
~331~
Another more preferred embodimen-t of the present
invention comprises the compounds of the formula
HN
~`~ J :
R1 I"'
wherein Rl is halogen, (lower)alkyl, (lower)alkenyl, (lower)-
alkoxy, -O-(lower)alkenyl, -O-(CH2)m-CH (CH~)n in whieh m ~.
is 0 or an integer from 1 to 6 and n is an integer from 2
to 7, -OCH2(CH2)xO(CH2)yCH3 in which x is 0 or an integer
from 1 to 6 and y is 0 or an integer from 1 to 6, CF3, -OCF3,
-OCH2CF3, hydroxy, (lower)alkylthio, amino,
-N ~ CH2)r in whieh r is 4 or 5, -N O , (lower)alkylamino,
di(lower)alkylamino, earboxyl, -CO2-(lower)alkyl,
-O(CH2)uCO2R in which u is an integer from 1 to
6 and Ra is hydrogen or (lower)alkyl, acyl (pre:ferably
RC-CO- in whieh Rc is (lower)alkyl), aeyl.ami.no (preferably
R -CO-NH- in whieh Re is (lower)alkyl), acyloxy (prefer-
ably RC-COO- in whieh Re is (lower)alkyl), -O-C=NHRb in
whieh Rb is (lower)alkyl, -O(CH2)kOH in which k is an
integer from 2 to 6, -OCH2-CH-CEI20H, -OCH21CH-CH20CH3 or
OH OH
-OCE12C6H5, and pharmaceutically acceptable salts thereof.
.',
- 13 -
1~i83~SZ
A preferred group of compounds wlthin the
scope of formula I''' comprises those compounds of
formula I''' wherein R is (lower)alkoxy,
-O-(lower)alkenYl, -O-(CH2)m-CH (CH2)n in which m is 0 or
an integer from 1 to 6 and n is an integer from 2 to 7,
-OCH2(CH2)XO(CH2)yCH3 in which x is 0 or an integer from
1 to 6 and y is 0 or an integer from 1 to 6, -OCF3, -OCH2CF3,
hydroxy, (lower)alkylthio, amino, (lower)alkylamino, di(lower)-
alkylamino, -O-(CH2)uCO2Ra in which u is an integer from 1 to
6 and Ra is hydrogen or (lower)alkyl, -O(CH2)kOH in which k
: is an integer from 2 to 6t ~OCH2-CIH-CH2OH, -OCH2-clH-cH2OcH3
OH OH
or -OCH2C6H5, or a pharmaceutically acceptab].e salt thereof.
Within this group, those compounds wherein Rl is (lower)-
~~, . .
alkoxy, -O-(lower)alkenyl, -O-(CH2)m-CH (~H2)n ln whlch
m is 0 or an integer from 1 to 6 and n is an integer
, CH2(CH2)XO(CH2)yCH3 in which x is 0 or
an integer from 1 to 6 and y is 0 or an integer from
`~ 1 to 6 -OCF3, -OCH2CF3, hydroxY, -(C~2)uc
u is an integer from 1 to 6 and Ra is hydrogen or (lower)-
alkyl, -O(CH2)kOH in which k is an integer from 2 to 6,
2 1 zOH, OCH2-1CH-CH2OCH3 or -OCH C H or
OH OH : .
pharmacuetically acceptable salts thereof, are preferred.
, ~ ~
;' ,',
~ .
,, :
~t33~5;2
O-ther preferred compounds and salts of formula I'''
are those in which Rl is (lower)alkoxy, -O-(lower)alkenyl
or -O-(CFI2)m-CH (CH2)n in which m is 0 or an integer ~rom
1 to 6 and n is an integer from 2 to 7.
More preferred compounds and salts of formula I"'
are those in which Rl is ~O-Cl-C6 alkyl, most preferably
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,
or sec-butoxy; -O-C2-C6 alkenyl, most preferably allyloxy;
or -O-(CH2)m -CH~__/CH2)n in which m is 0 or an integer from
1 to 4 and n is an integer from 2 to 5, most preferably
cyclopropylmethoxy.
Most preferred compounds and salts of formula
I''' are those in which Rl is methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, isobutoxy, sec-butoxy, allyloxy or
cyclopropylmethoxy.
Since the compounds of this invention are amphoteric
in nature, they can be converted to salts of either acids
or bases by treating said compounds with a substantially
equimolar amount of a chosen acid or base in an aqueous
solution or in a suitable organic solvent such as methanol
or ethanol. When such salts are to be used for human
33~lSZ
consumption, the acids or basec3 which are used to prepare
the pharmaceutically acceptable salts must, of course, be
those which necessarily form non-toxic salts. Examples of
suitable acids include hydrochloric, hydrobromic, hydroiodic,
nitric, sulfuric, phosphoric, acetic, lactic, citric, tar-
taric, oxalic, succinic, ma!leic, gluconic, ascorbic and p-
toluene sulfonic. Pharmaceutically acceptable salts may
be formed from such bases as ammonia, organic amines and
metal salts, e.g. metal salts containing sodium, potassium,
calcium, magnesium, barium and aluminum cations. Represen-
tative of such bases are ammonia, primary amines such as
n propylamine, n-butylamine, ethanolamine, ethylenediamine,
cyclohexylamine, benzylamine, ethylamine, octylamine or
tris(hydroxymethyl)aminomethane, secondary amines such as -~
diethanolamine, tertiary amines such as triethanolamine, :.
N-methylpyrrolidine, N-methylmorpholine or 1,5-diazabicyclo-
[4,3,0~-5-nonene and metal compounds such as sodium hydroxide,
potassium hydroxide, ammonium hydroxide, sodium ethoxide,
potassium methoxide, magnesium hydroxide, calcium hydroxide
or aluminum hydroxide.
Those skilled in the art will appreciate that the
compounds represented by formula I contain two tautomeric
hydrogen atoms, and the compounds are thus capable of ..
existing in the forms 1-6 shown below. All the forms may
be present to a greater or lesser degree and are in a state
- 16 -
:'`',", . ' - ~ ' .
~ . ,' . . .
~a~83~5Z
of dynamic equilibrium with each other. This invention
en~races all such forms, but for the sake of convenien~e
structure 1 has been arbitrarily used herein to described
the present compounds.
N- -- -N
R~ ~ ¦ R ~ ~
1 / 2
-
R2 R2 ~ ~
N. ---N N _ N
R2 N
- 17 -
.... .
,:: ':;, , ~ ' '
~t33152
The compounds of the presen-t invention may be
prepared by several alternative methods. One preferred
method ls disclosed by W. G. Finnegan, et al. in
J. Am. Chem. Soc., 80, 3908 (1958) and comprises reacting
an appropriate nitrile of the formula
~ CN
H,N ~
Rl I ¦¦
R2 ~ ~N J
R3 ;~
(wherein Rl, R2 and R3 are defined as above in reference
to formula I) with an azide salt selected from the group
consisting of ammonium, substituted ammonium, sodium
and lithium azide in an inert organic solvent. The
nitrile II and azide salt may be used in approximately
equimolar amounts. Examples of suitable azide salts are
provided by Finnegan i~the above-mentioned reference
and include azides such as NaN3, LiN3, NH4N3, (n-C4Hg)2NH2N3,
C6H5NH3N3, and (CH3)4NN3. The azide salt may be added
directly or may be generated ln situ, e.g. by double de-
composition reactions of sodium azide and an appropriate
chloride salt such as LiCl, NH4Cl, (CH3)4NCl, etc.
While the condensation reaction proceeds over a wide
temperature range, it is preferred in order to minimize
reaction times to use elevated temperatures, e.g., from about
100C wp to the reflux temperature of the solvent system.
- 18 -
' -
;
: . .
~3~iiZ
The inert organic solvent may in general be any solvent having
good solvent power for the azide salt and which is chemically
inert. Examples of preferred solvents are dimethylformamide,
dimethylacetamide, dimethylsulfoxide and he~amethylphosphor-
amide. The most preferred solvent is dimethylformamide. The
condensation reaction is found to be subject to general acid
catalysis and yields are improved by addition of such reagents
as hydrazoic acid, amine hydroazides and Lewis acids such as
BF3 to the sodium azide. At the completion of the reaction,
the tetrazole product may be recovered from the reaction
mixture by removing the solvent, diluting the residue with
water and then acidifying the mixture to give the desired
compound of formula I. The product may be further purified
by recrystallization, e.g., from glacial acetic acid, and
optionally converted to a pharmaceutically acceptable salt
thereof as described above. Following condensation, pro-
ducts of formula I may if desired be further reacted by
methods known per se to convert one or more R , R , or R
substituent groups to other substituent groups within the
scope of formula I. Thus, for example, a compound of
formula I where R , R or R is nitro may be subjected to
catalytic hydrogenation to give the corresponding amino-
substituted compound or a compound where Rl, R2 or R3 is
amino may be alkylated to give the corresponding (lower)
alkylamino- or di(lower)alkylamino-substituted compound.
An alternative variation of the above procedure
involves condensing the nitrile starting material II with
aluminium azide in tetrahydrofuran followed by an acid-
ification recovery step as described above~ The reaction
......
. ~- ,
3~;iZ
may convenien-tly be carried out hy reactincJ nitrile II
with aluminum chloride and sodium azide in molar proportions
of about 1:1:3, respectively. While the temperature for
the reaction is not critical, advantageous results have
been obtained at reflux temperature.
Another alternative method for preparing the com-
pounds of formula I comprises heating the desired nitrile
compound of formula II with either hydrazoic acid in an inert
organic solvent such as benzene, xylene or toluene or with
sodium azide and acetic acid in butanol. In this procedure
an acidification step is not required to recover the desired
end-product.
Yet another alternative and preferred procedure
for preparing the compounds of formula I comprises reacting
an acrylate intermediate of the formula
C2H5O2C \ / CN
N ~
R2 ~ ¦¦ ~
R3
(wherein Rl, R2 and R3 are as defined above in reference to
Formula I) with sodium azide and ammonium chJoride in an
inert organic solvent. The preferred reaction conditions,
i.e. molar ratios, temperature range and solvents, are des-
cribed above in connection with the NaN3/NH4Cl condensation
procedure. The product of formula I may be conveniently xe-
covered from the reaction mixture by addition of sufficient
water followed by acidification to effect precipitation of the
desired compound I.
- 20 -
.. . . . . .
.. , ~ .
,, ~
3~52
A most preferred procedure for preparing the
compounds of formula I comprises reacting a substituted
benzamidine of the formula
Rl ~ .
~ NH
R2~ 11 .
~ '.
R3
VII
(wherein Rl, R2 and R3 are as defined above in reference to
formula I) and ethyl ethoxymethylene cyanoacetate of the
formula
C2H52C~ / CN
Il . ~ '
C2H5 / H
in an inert organic solvent with sodium azide and ammonium
chloride. Approximately equimolar quantities of the four
reactants are used in an organic solvent which is reaction-
10inert and which possesses good solvent power for the sodium
azide. Suitable solvents include dimethylformamide, dimethyl-
acetamide, dimethylsulfoxide and hexamethylphosphoramide.
The most preferred solvent is dimethylformamide. For best
results the reaction is carried out with heating, preferably
at temperatures from about 100C. up to the reflux temperature
of the solvent system. At the conclusion of the reaction,
the desired product can be recovered by addition of sufficient
water followed by acidification to precipitate compound I
from the reaction mixture.
.~, .
8315Z
The above process is a most preferred embodiment
of the presen~ invention since it enables compound I to be
prepared directly from the basic ben2amidine and ethyl ethoxy-
methylenecyanoacetate starting materials in one step without
the necessity of first preparlng the isolating one or more
intermediates required for the alternative methods described
above. The advantages in overall yield and simplicity of
operation will be apparent from examining the illustratlve
examples below.
The nitrile starting materials of formula II may
be prepared by various known reaction routes. One preferred
method [J. Heterocycl. Chem., 8, 715-719(1971)] involves
dehydration as with phosphorus oxychloride of the corre-
sponding amide of formula III according to the following
reaction sequence: C1
NE12
POC13 H20
R > R >
III IV
RI 3 ~ ~
~R
3~
II
The dehydration step is accomplished at elevated temperatures,
most preferably under reflux conditions.
Amide compounds of formula III may be obtained by
treatment of the corresponding esters of the formula
, - 22 -
" ,~ .
. , , , . - , .
. . ., . - . . . . .
' , ' '~' ', ' , '' ~ ' .'' ' ,. ` '
~1~83~1Lrj2
HN ~ ,~ C02R
Rl I ¦l .
~ ~ N
R V
wherein R is Cl-C6 alkyl with liquid ammonia, ammonium
hydroxide or a solution of ammonia in a (lower~alkanol (e.g.
methanol or ethanol) containing an excess of sodium methoxide.
The reaction is conveniently carried out in a sealed vessel
at steam bath temperature. When concentrated ammonium
hydroxide is used, good results have also been achieved by ~ ;
reaction at room temperature for two to three days without
the necessity of either heat or a sealed vessel.
The ester intermediates of formula V may be
prepared by condensation of a substituted benzamidine of
the formula
Rl NH2
R2 ~ N~l
3 ~ J
R
VII
where Rl, R and R3 are as defined above (in connection
with compounds of formula I), or an acid addition salt
thereof, with a compound of the formula
'.
- 23 -
' '-'. ' ' . ' ~ ' '
~ ~ -' - ''' ' : '
!33~2
:
C
/c\
y H
VIII
wherein Rl is Cl-C6 alkyl, X is carb-(lower)alkoxy and Y is
a suitable leavin~ group such as -OC2H5, -CH(COOC2H5)2,
~ or ~ in an inert organic solvent and in the
presence of a condensing agent.
The condensation of reactants VII and VIII is
carried out in an inert organic solvent, e.g. a Cl-C6 alcohol, ~`
acetonitrile or tetrahydrofuran, and, advantageously, at
elevated temperatures. Good results have been obtained when
the reactants are refluxed in ethanol.
Compounds VII and VIII are generally reacted together -
in the presence of from at least a catalytic amount up to a
several-fold molar excess of a suitable condensing agent.
Alkali metal alkoxides (commonly prepared ln situ by addition
of the alkali metal to a C1-C6 alcohol) such as sodium meth-
oxide are preferred condensing agents. When the benzamidine
or benzamidine salt is condensed with diethyl ethoxymethylene- ;-
malonate, the alkali metal alkoxide condensing agent may be re-
placed by alkali metal carbonates or may even be eliminated
as shown in the examples below.
::
' -'
'' ' .' ' ',
-' ~
24
, .. , - . . .
' ,, ,' ' . :, , ~ ,: .
,',' ,' ~ "' ,,'.' ' .' ' .
3~iZ
Benæamidine starti.ng material VII may be used either
as the free base or as a salt thereof, e.g. -the hydrochloride,
fluorosulfonate or methyl sulfate salts. When the free base
is employed, a molar equivalent or slight excess thereof of
the alkali metal alkoxide is preferably used. If a benza-
midine salt is used, two moles of alkoxide per mole of
compound VII are found to provide advantageous results. A
preferred condensation procedure involves condensing
the benzamidine or benzamidine salt (e.g. the methyl sulfate)
with diethyl ethoxymethylenemalonate in an inert organic
solvent (preferably ethanol) in the presence of about one
mole of potassium carbonate per mole of benzamidine or salt
thereof with heating, preferably at reflux temperature.
¦ Good results have also been obtained in the above procedure
when the benzamidine free base is condensed with the diethyl
ethoxymethylenemalonate in the absence of a condensing agent.
Compounds VII and VIII are employed in appro~imately
equimolar amounts. Schemes I-III below illustrate condensa- ~`
tion reaction procedures which are embodiments of the
general process described ao~,ve.
:
;
.
, ~
- 25 -
`:~
1~83~5~2
Scheme I
A substituted benzamidine may be condensed
with an alkyl dicarboxyglutaconate by the general method
of S. Ruhemann in Ber. 30, 821 (1897). Illustrative of
this procedure is the reaction
NH2 C2H500C \ / COOC2 5
~ ~ (C2~1500C)2C~
C2 5
~, ~;.'
O
H ~ C2C2H5
1- NaC2H5
~ ~ ~ N /
~ OC2~s ~
- , .
Scheme II
The substituted benzamidine VII is reacted with a ~ ; -
dialkyl ethoxymethylenemalonate according to the general
method described by P.C. Mitter, et al. in J. Chem._Soc.,
123, 2179 (1923) and Quart. ~. Indian Chem. Soc., 2, 61-
70 (1925). Typifying this procedure is the sequence
..... - , .
,:. . . . .
,. . . .. . .
:,, . . . , ,: : '
.
.' . ; , ~ ' ~ ,
~33:~52~
NH2 C2H500C \ / COOC2 5
`~`NH C2H50 H
OC2H5
HN ~ ~ 2 2 5
] ~ N J
OC2H5 ::
Reaction scheme II is illustrative of the preferred process
for preparing the intermediates V of the present invention.
As described above another preferred procedure involves the
reaction
'
~' ,,.
''
: 1 0
:' ' , '' . :
~3~L5Z
NH2 NH2 ' HOS03CH3 :~
C2~ 5 ~ ~r
C;2H52c~/c2c2 5
/ C 2 3
C2H50 H C2H50H -:
2- ~130~ ~
O ''~
.. .
OC H
~.~.....
Scheme III
A third condensation procedure de~cribed by
Santilli, et al. in J. Med. Chem., 7, 68 (1964) involves
condensing the benzamidine with a dialkyl morpholinomethylene- -
malonate or a dialkyl piperidinomethylenemalonate. An example
of this procedure is the reaction '
: ,:
-- 28 --
: :
: `:
.:
. . ..
~ ~.
~83~S;~
NH2 C2H502C ~ 2 2 5
/~NII G ' `
C2H502C ~ f 02C2 5
or / C 1. NaOC2H5
f~N H 2- 30
O :~
C02C2~5
1w
OC2 5 ..
Use of an alkali metal condensing agent, e.g.
K2C03 or NaOC2H5, in the above procedures results in forma-
tion of a soluble alkali metal salt. Acidification of the ~ -
reaction mi~ture with a mineral acid or an organic acid such
as acetic acid will cause the desired ester to precipitate
out of solution.
'
-- 29 --
il3:~5Z
Starting materials VII and VIII are either known
or are prepared by methods known in the art. A preferred
method of preparation of substituted benzamidines may be
represented by the reaction sequence ~illustrated for the
case where R = -OC2H5)
~( (C2H5)30+BF4 ;5
BF4 ~-
1. NH3 in C2H50H
2 i~
2. NaOH ¦ - ,
~ ~ ,:''`,.'.~,'"'.
~ OC2H5 -; ~
,' ',.
In this procedure which is described in U.S. Patent 3,819,631
and J. Org. Chem., 33, 1679 (1968), the triethyloxonium fluoro-
borate reactant mentioned above may be replaced by alkyl fluoro~
sulfonates (e.g. methyl fluorosulfonate), dimethyl sulfate or
10by other alkyloxonium fluoroborates. A most preferred procedure '~
involves use of the relatively inexpensive dimethyl sulfate
, [(CH30)2S02] as the alkylating agent in place of the more costly
alkyl fluorosulfonates and triethyloxonium fluoroborate. This
procedure which is outlined below result6 in formation of a
benzamidine methyl sulfate salt.
- 30 -
~, , ., ~: : ,
.. . .
:
.: . .
., .
~0~315Z
CONH2 3
3~~ HOSO3CH3
C2H5 reflux 2 5
NH2
~ 3 3 ;~
NH3, C2HsH ~
> 2 5
.' .
An alternative procedure for preparing benzamidine
compound of formula VII comprises the reaction (illustrated
for the case where R = -OC2H5) ~. -
NHOH .~ ~ .
CN .
~( NH20H HCl ~ NH
2 . ~ . : .
catalytic hydrogenation,
~/ NH
e.g. H2/Raney nickel ~ 2 5 ~:
An alternative method for preparing the nitriles
of formula II comprises (a) condensing a substituted
benzamidine VII with an equimolar amount of ethoxymethylene
cyanoacetate of the formula
.
~ 31 -
,,,
.
-
~3~52
C2H502C\ /CN
/
C2H5 H
in an inert organic solvent, e.g. a Cl-C6 alcohol (prefer-
ably ethanol) or dimethylformamide, preferably with cooling
to temperatures o~ about 0C., to produce an acrylate ~ ~
intermediate VI of the formula `
' "~ ' ' ''. .
C2H502C , . . .. ..
\ / CN
Rl Nl 2 11 ~ '
~ ~ ~ CH
R ~ ~ ;~
R VI -~
and
(b) cyclizing intermediate VI by heating (at temperatures
ranging from-slightly above room temperature to the reflux
temperature of the solvent) in an inert organic solvent,
e.g. dimethylsulfoxide, toluene or dimethylformamide, to
produce the desired nitrile II. The general process of
preparing the intermediates of formula VI is disclosed by ~ `
Nishigashi et al. in Chem. Pharm. Bull., 18, 1003 (1970)
for the case in which Rl, R2 and R3 are all hydrogen.
The above-mentioned process has been found to be
much superior to the base catalyzed condensation of ~ '
benzamidines with ethyl ethoxymethylenecyanoacetate de-
scribed in Quart. J. Indian Chem. Soc., 2, 61 (1925)
and in U.S. Patent 3,660,403 which produces a mixture of
both the desired nitrile II and the unwanted amino ester of
the formula
- 32 -
31~
~ / C2C2 5
Rl N
~ ~ N
R
The acrylate intermediate VI produced above may
also be converted directly to the desired product of formula
I by reaction with sodium azide and ammonium chloride in an
inert organic solvent.
A still further method which can be used for
. .
preparation of the nitrile compounds of formula II is dis-
closed by Hromatka in U.S. Patent 2,235,638. The Hromatka
procedure involves the reaction sequence
R ~ N N / -
~ CN
R II
In preparing compounds of formula I in which
R , R or R contain free hydroxy, amino or carboxyl
groups, it is of course understood that such groups will
be protected by suitable known pro~ecting groups during ~ ~
the reaction steps beginning with the benzamide starting
materials through the formation of the final tetrazoles.
-,
- 33 -
. . j . . .
.. .. . . .
,
~0~33~S;~
The protec-ting group(s) may then be removed by methods
known per se to give the desired products having the un-
protected substituent groups. In preparing compounds
of formula I where R , R or R are (lower)alkylamino or
di(lower)alkylamino, the corresponding amino-substituted
compound may first be prepared and then alkylated by methods
known per se. Alternatively, the dialkylamino-substituted
compounds can be prepared directly from the appropriate
benzamide starting material.
As noted previously, the compounds of formula I
have been found to inhibit the release of toxic products,
i.e. mediators, which arise from the combination of certain -~
types of antibody and specific antigen. They are of particu-
lar value in preventing the symptons of allergic bronchial
asthma in mammalian subjects by administering to such subject
a mediator-inhibiting dose of a compound of formula I.
The compounds may also be useful for the relief and
prophylaxis of other allergic reactions such as allergic
rhinitis.
The compounds of the present invention may be
administered either as individual therapeutic agents or
as mixtures with other therapeutic agents. They may be
administered alone but are generally administered in the
form of pharmaceutical compositions, i.e. mixtures of the
active agents with suitable pharmaceutical carriers or
diluents. Examples of such compositions include tablets,
lozenges, capsules, powders, aerosol sprays, aqueous or
oily suspensions, syrups, elixers and aqueous solutions
for injection. The compounds are most preferably adminis-
3- tered in oral dosage forms.
- 34 -
'
.
1~3~52
The nature of the pharmaceutical composition
and the pharmaceutical carrier or diluent will, of course,
depend on the desired route of administration, i.e. orally,
parenterally or by inhalation. Oral compositions may be
in the form of tablets or capsules and may contain con-
ventional excipients such as binding agents (e.g. syrup,
acacia, gelatin, sorbitol, tragacanth or polyvinylpyrroli-
done), fillers (e.g. lactose, sugar, maize-starch, calcium
phosphate, sorbital or glycine), lubricants (e.g. magnesium
stearate, talc, polyethylene glycol, or silica), disinte-
grants (e.g. starch) or wetting agents (e.y. sodium lauryl
sulfate). Oral liquid preparations may be in the form of
aqueous or oily suspensions, solutions, emulsions, syrups,
elîxers, etc. or may be presented as a dry product for
reconstitution with water or other suitable vehicle before
use. Such liquid preparations may contain conventional
additives such as suspending agents, flavoring agents,
diluents or emulsifying agents. For parenteral adminis-
tration or inhalation, solutions or suspensions of a
compound of formula I with conventional pharmaceutical
vehicles may be employed, e.g. as an aerosol spray for
inhalation, as an aqueous solution for intravenous injec-
tion or as an oily suspension for intramuscular injectlon.
The compounds may also be administered by means of inhalers
or other devices which permit the active compounds in hte
form of dry powders to come into direct contact with the lungs.
~. .
:i :
' .
: :.
'~
.. .~ , . ,
''"'~ ' ' ' ;' ,' ' .
: . ~ '' , , -' ' ' .
' ' ' : ` '
The compounds of -the present invention or pharma-
ceutical composition thereof may be administered to human
asthmatic patients in single oral doses of approximately
1-500 mg. of active ingredient and multiple oral doses -
totalling up to about 1000 mg./day of active ingredient.
When administered by inhalation, lower doses are generally
given, i.e. on the order of abou-t 0.1 of the normal oral
dosage for the particular compound in question. These
values are illustrative only, however, and the physician
of cource will ultimately determine the dosage most suitable
for a particular patient on the basis of factors such as age,
weight, severity of the symptons and the particular agent
to be administered.
The in vivo animal model studies described below
indicate that the compounds of formula I are highly potent
antiallergy agents.
Biological Activity Data
The reagin-mediated rat Passive Cutaneous ~naphy-
laxis (PCA) sc~eening test used to evaluate the present
compounds is generally regarded as one of the bes-t animal
models for use in predictin~ the antialler~y activity oi test
, . .
- 36 -
~ .
:' "' ' ' .. ' " ,,
-- .
1~33~5~
compounds in man. Briefly, the method consists of passive
sensitization of s~in sites on the test animals with
reaginic antibodies followed after 24 hours by administra-
tion of the test drug and antigen challenge. The allergic
response is measured by use of Evans' blue dye and is evalu-
ated by the spot diameter at the injection site. Details of ~ -
the test are provided below.
Materials
, ~ ....
Ovalbumin (5 times crystalline) ~ -
Dinitrobenzene sulfonic acid, Na salt
Bordetella pertussis vaccine - phase I
10-20 x 109 killed organisms/ml.
Aluminum hydroxide gel - 10 mg./ml.
Potassium carbonate
Male Sp~ague-Dawley (S/D) ~ats - 200 gms.
Female Sprague-Dawley Rats - 100 gms.
Tris Buffered Saline (TBS) - 0.02 M 2-amino-2-
hydroxymethyl-1,3-propanediol (Tris), 0.15 M ~
NaC1, pH 8.2 ~ ;
- 37 -
.
, ~ ..
,
~)83~5;~ ~ :
Antigen Preparation - DNP-d EA
A substituted ovalbumin antigen is used both as
immunogen and challenging antigen. The antigen is prepared
as follows: 500 mg. ovalbumin (EA) and 500 mg. K2CO3 are
dissolved in 25 ml. distilled H2O and stirred a-t room
temperature for 5 minutes. Five hundred (500)mg. dinitro-
benzene sulfonic acid, Na+ salt, (previously recrystallized
from hot absolute ethanol) is then added slowly with con-
tinued stirring. The reaction mixture is then immediately
placed in the dark and allowed to proceed for 2 hours with
constant stirring. A~ter 2 hours the mixture is placed in
suitable dialysis tubing and dialyzed against 5 changes
(4 liters each) of distilled H2O at 5C. After dialysis
the product is lyophilized and stored at room temperature
in a brown or amber container. The antigen obtained will
appear as a light yellow, amorphous solid which is very
soluble in water or saline. It is designated as DNP
denatured ovalbumin (DNP-d EA).
Immunization Method for IgE Production
.
Adult, male Sprague-Dawley rats are used as a
source of reagin-rich antisera for the PCA model~ Immuni-
,~ ....
,
.,
~ - 38 -
33~
za~ion is by a combination of DNP-d EA on Al(OH)3 gel and
B. pertussis vaccine. Preparation of the Dl~P-d EA ~ gel
immunogen i5 as follows: Dissolve the DNP-d EA in TBS so
as to give a concentration of 10 mg./ml. Slowly add 1 ml.
of this solution to 10 ml. Al(OH)3 gel (10 mg. solids/ml.)
with constant stirring at room temperature. Stir the mix-
ture an additional 30 minutes to insure a uniform adsorption
of antigen on gel.
The resulting preparation is then used in com-
bination with phase I Bo pertussis vaccine to immunize
male S/D rats as follows: For each rat administer 0.1 ml.
DNP-d EA - gel suspension intramuscularly in each hind
leg (200 ~g DNP-d EA and 2 mg. gel total dose). Follow
these injections by the intraperitoneal administration of
1.0 ml. B. pertussis vaccine (10-20 x 109 organisms). The
use of light ether an~sthesia during this procedure is
recommended to insure proper intramuscular and intraperitoneal
lnjections. Nine days following immunization (but no longer
than 10) the animals are exsanguinated by cardiac puncture
or abdominal aorta cannulation under ether or pentobarbital
anesthesia. The collected whole blood is allowed to clot, the
serum separated by centrifugation and the individual serum
samples stored frozen until assayed for IgE content.
- 39 -
33~jiZ
Selection of_Hi~h Titered
Serum Samples for Pooling
Individual serum samples should be screened for
reaginic antibody concentration before being pooled with
other sera, as not all rats respond to immunization pro-
cedures with reagin production. A 1:50 saline dilution
of~serum from each immunized rat is used for this purpose.
Intradermal injections of 0.05 ml. of the diluted sera are
made in the shaven backs of two small female recipient
rats 100-120 gms. Several serum samples can be tested -
slmultaneously in recipient animals. After a 24 to 4~ hour
latent period antigen challenge is accomplished by intra-
venous administration to each rat of 1 mg. DNP-d EA in 0.5
ml. 0.5% Evans' blue dye in saline. Sera which show positive
PCA reactions at the 1:50 dilution, as measured 20 to 30
minutes post-challenge are pooled, dispensed in small
aliquots and stored at -70C. or lower until used. Nega-
tive sera may be discarded.
.. ..
The IgE titer of the antisera pool should then
be determined. Serial two-fold dilutions (1:5 to 1:160)
of unheated sera and sera heated at 56C. for 1 hour are
prepared in saline and 0.05 ml. of each dilution injected
intradermally on the backs of female recipient rats. At
least four animals should be used for both the heated and
- 40 -
.
-
~8315Z
unheated serum titrations. After a 24-hour latent period
each group is challenged with 1 mg. ~NP-d EA in 0.5 ml.
0.5~ Evans' blue dye. Reactions are read by reflecting
the skin 20 to 30 minutes post-challenge. Intensity (blueing)
and spot diameter should be measured and recorded. The pool
titer is defined as the reciprocal of the greatest dilution
of unheated serum which yields a measurable PCA response
(~6 mm. diameter) in at least half of the recipient ani-
mals. Antiserum pools having a titer of 50 or greater are
acceptable for the PCA screen. These pools should be
; sterile-filtered and stored at -70C. or lower until use.
Lyophilization in small aliquots may be used as an alternate.
PCA Screening Method
'
1. Animals - Young female Spraque-Dawley rats,
90-110 grns. should be used. The rats should be conditioned
(acclimatized) for at least five days prior to use r with
food and water ad lib.
2. Passive Sensitization - The test animals are
prepared for passive sensitization by carefully shaving
areas on each side of the back with a fine toothed clipper.
Using a 27 gauge 5/8" needle mounted on a 1 ml. tuberculin
syringe make intradermal injections of saline dilutions of
the antiserum pool. ~our dilutions (two on ei~her side)
~ ,
';
'~
- 41 -
~983~Z
of antiserum are used. The exact dllutions used depend on
the titer of the pool. For example, if the antiserum pool
has a titer of 50, then dilutions of l:lO, 1:20, 1:30 and
1:40 are used; if the pool titers at 100, then the dilu-
tions would be 1:20, 1:40, 1:60 and 1:80. The sequence of
placement of each dilution should be either clockwise or
counter-clockwise to facilitate ease in scoxing. The
latent period should be at least 24 but no more than 48 hours.
3. Drug Administration-Standard and Unknowns -
Four animals are used for each test compound. Disodiumcromoglycate (DSCG), solubilized in saline, is administered
by intravenous (i.v.) route at the time of antigen challengeO
The tetrazole test compounds are solubilized in aqueous
sodium bicarbonate. The test compounds are administered
i.v. or per os (p.o.) either 1-5 or 10 minutes, respectively,
prior to antigen challenge.
4. Antigen Challenge and Reaction Evaluation -
Elicitation of the PCA response is accomplished by intravenous
administration of l mg. DNP-d EA in 0.5 ml. 0.5~ Evans' blue
dye in saline to each test rat. PCA reactions are maximal
twenty to thirty minutes post-challenge. Reactions should
be scored visually for color intensity and the average diameter
of the spots measured at each antiserum dilution site. Both
operations should be done by reflecting the skin. For
- 42 -
'',~,, ' '
':
3~5~2
comparative purposes the numbers in the con-trol group
(untreated) should be at least 5% and usually 10%, of
the total animals tested on a particular day.
Observed drug inhibition is reported as percent
reduction in effective antiserum titer in treated versus
control groups.
Results
Test results for certain of the preferred compounds
of the present invention by i.v. and p.o. routes of adminis~
tration are shown below in Table I along with data for DSCG.
The results are given in terms of the ID50 value, i.e. the ;~
dose of compound tùat inhibits 50% of the responss.
~` ' . ,
- 43 -
-.
~,, . :
,' . . ; . , .i ': ., '; , . .... .
'', ' : ~. . ;
:' ' ' . '. :
33~5%
Table I
Rat PCA Screening Data ~or ~-Phenyl-5-
.,. ~
~5-lH-tetr~zolyl)pyrim din-4(3Hl one~
Compo~d
N--N
~\ . ,N
' Example 1 2 ID50 in ng./k~3
No- R R iv. ~ ~
6 OCH3 H _ ~O.1
OC2H5 H O . 02 0 . 09
~, 2 H2 2 3 ~ _ O o4
(CH3~2 H - ~0.04
OCH2cE2c~2cH3 H - ~ 0.07
OCH(CH~ )CH2CX3 H - 0 .05
7 0CH2C~(cH~)2 H _ ~ 0.1 : .
8 OCH2-CH=CI12 H _ 0.24
9 OCH2~ H ~ O . 07
OCH2CH2CH~ OCE~3 - 3
14 OCH2 CH2 CH3 NO 2 5
: 15 OCH2CH2CH3 NH2 ~ 0.1
16 OCH2CHzCE3 N(C~3)2 ~ ^~ 4
DSCG
,` , :
- 9 4 -
~.,,
. ~,,,
3~lSZ
The following examples are provided solely for
the purpose of illustrating preparation of the starting
materials and compounds of the present invention and are
not to be construed as limitations of the invention. All
temperatures referred to below are in degrees Centrigrade.
"Skellysolve B" is a petroleum ether fractlon of b.p.
60-68C. consisting essentially of n-hexane (trade name
of Skelly Oil Co.).
Preparation of Starting Materials
'~
The substituted benzamidine (or benzamidine salt
starting materials may be prepared according to the pro-
cedures illustrated below.
' '
Preparation 1: 2-Etho_ybenzamidlne hydrochloride
To a cooled (ice-water) solution of triethyloxonium
fluoroborate (100 g., 0.53 mole) in 226 ml. of methylene
chloride was added all at once a suspension of 2-ethoxy-
benzamide (87 g., 0.53 mole) in 915 ml. of methylene
chloride. The resulting solution was stirred at room
temperature for 36 hours. The solution was concentrated
to one-third volume and diluted with about 600 ml. of
diethyl ether, thereby precipitating the crude ethyl 2-
ethoxybenzimidate fluoroborate (130 g., m.p. 116-133).
.
: :
- 45 -
: ~- '''
. . - .
3~52
The above salt was suspendecl in 500 ml. of cold
10% ethanolic ammonia and the solution stirred at room
temperature for 36 hours. The solution was reduced to
dryness and the residue partitioned between ethyl acetate
and 5N NaOH. The ethyl acetate layer was dried to give
a viscous oil. About 200 ml. of acetonitrile was added
to the oil whereupon a solid separated and was recovered
to yield 36 g. of material, melting at 180-183. The
solid was dissolved in about 60 ml. of methanol and acidi-
fied with hydrogen chloride. Addition of about 1 literof dry ether precipitated the desired hydrochloride salt
(31.2 g., m.p. 198-199). ~
'. ~ ;~'''.' '
Preparation 2: 2-Ethoxybenæamidine hydrochloride
(alternate procedure) `
Methyl Eluorosulfonate (14.5 g., 0.127 mole) was added to
a solution of 2-ethoxybenzamide (20.0 g., 0.121 mole) in
methylene chloride (324 ml.). After three hours the solvent ~-
was removed under reduced pressure. The residue was tri- ~ ~
turated with diethyl ether and the mixture filtered. The ~ ~ ;
collected crude ethyl 2-ethoxyben~imidate fluorosulfonate
(28.5 g.), m.p. 83-110, was added to saturated ammoniacal
ethanol (120 ml.). The mixture was stirred at room tempera-
ture for four days. The mixture was filterecl and the filtrate
concentrated. The residue was triturated with 2N sodium
' ,.: .
., ,
~ 46 -
- , . .
,"~' , ' ' ' ,
.: :
3L;~3~3~
hydroxide and the resulting mix~ure extracted with ethyl
acetate. The extract was dried over sodium sulfate and then
concentrated. A solution of the residual oil in acetonitrile
(50 ml.) was treated with hydrogen chloride. Addition of
diethyl ether (700 ml.) precipitated 2-ethoxybenzamidine
hydrochloride (11.0 g., m.p. 193-196).
Preparation 3: 2-Ethoxybenzamidine
To a solution of 2-ethoxybenzamide (13.0 g., 0.0785 mole)
in 34 ml. of dry methylene chloride was added all at once a
suspension of triethyloxonium fluoroborate (15.0 g.,
0.0785 mole) in 137 ml. of methylene chloride. The solution
which formed immediately upon addition of the fluoroborate
was stirred for 19 hours at room temperature. The solution
was concentrated to about one-third volume and diluted with
about 100 ml. of diethyl ether to precipitate the ethyl 2-
ethoxybenzimidate fluoroborate which, when collected and dried,
weighed 19.2 g., m.p. 113-116.
The above imidate fluoroborate was then added
to 100 ml. of ethanol containing 1.4 g. of NH3. The resulting
solution was stirred for 78 hours at room temperature while
keeping the flask tightly stoppered. The solvent was re-
moved under reduced pressure to give a colorless solid which
was dissolved in a small volume of water and basified with
6N NaOH. After extraction with ethyl acetate, the solvent
extract was dried to yield 7.4 g. of title product, m.p.
78-84.
- 47 -
,:
;.
.
1~133152
Replacement oE the 2-ethoxybenzamide used above
by an equimolar amount of 2-isopropoxybenzamide or 2-n-
propoxybenzamide gives 2-isopxopoxybenzamidine and 2-n-
propoxybenzamidine, respectively.
Preparation 4: 2-Ethoxybenzamidine fluorosulfonate (Method ~)
To a suspension of 2-ethoxybenzamide (500 g., 3.03 moles) in
dry methylene chloride ~8 1.) was added methyl fluorosulfonate
; (256 ml., 3.17 moles). The resulting solution was stirred at
room temperature for 3 hours. The solvent was removed under
vacuum. The residue was triturated with diethyl ether and
the mixture filtered. The collected solid was washed with
ether and then added to a cold (ice-water) solution of ammonia ~ '
' (500 g.) in ethanol (3 1.). The mixture was stirred in the
! cold for 0.5 hour and then at room temperature for 16 hours.
The solution was concentrated and the residue crystallized
from 1,2~dichloroethane to give 2-ethoxybenzamidine fluoro-
sulfonate (517 g., 65%), m.p. 98-99.
Anal. CalcdO for CgH12N2O-HFSO3: C, 40.90, H, 4.96; N, 10.60.
Found: C, 40.95; H, 4.83; N, 10.73.
. .
Preparation 5: 2-Ethoxybenza~idine fluorosulfonate (Method B)
... . .. ......... . . _ _
To a suspension of 2-ethoxybenzamide (1 kg., 6.05 moles) in
methylene chloride (12.5 1.) was added methyl fluorosulfonate
.~ .
. ~ .
- 48 -
'
il~8315~
(538 ml., 6.66 moles). The mixture was stirred at room
temperature for 18.5 hours. Ammonia gas was -then bubbled
- into this mixture for 8 hours while the temperature of the
mixture was maintained below 26. The mixture was stirred
for an additional 16 hours at room temperature. The solvent
was removed under vacuum to leave crude 2-ethoxybenzamidine
fluorosulfonate (1.7 kg.).
Preparation 6: 2-Ethoxybenzamidine methyl sulfate
A solution of 2-ethoxybenzamide (16.5 g., 0.1 mole) and
dimethyl sulfate (19.0 ml., 0.2 mole) in 1,2-dichloroethane
(~0 ml.) was heated under reflux for 17 hours with stirring.
The solvent was removed under reduced pressure. The residual
oil was stirred for 0.5 hour with diethyl ether (200 ml.).
The methyl 2-ethoxybenzimidate methyl sulfate was collected
by filtration, dried, and then added to stirred, saturated
ethanolic ammonia (150 ml.). The solution was allowed to
stand at room temperature for 18 hours. The solution was `
filtered and the filtrate concentrated. The residue was
triturated with diethyl ether after which the 2-ethoxybenzami-
dine methyl sulfate (19.9 g., 72% based on 2-ethoxybenzamide)
was collected by filtration.
~'' .
~repar~ 7: 2-n-Propoxybenzamidine hydrochloride
,~
,~
~ ,~
- 49 -
', .
~83~
A. Ethyl 2-n-Propoxybenzimidate fluoroborate -
A solution of triethyloxonium fluoroborate (33.0 g., 0.175
mole) in methylene chloride (75 ml.) was added during 10
minutes to a stirred solution of 2-n-propoxybenzamide (31.3
g., 0.175 mole) in methylene chloride (150 ml.). The solu-
tion was stirred for an additional 18 hours at room temperature.
The solution was concentrated to about one-fifth volume and
was diluted with diethyl ether to precipitate the ether 2-n~
propoxybenzimidate fluoroborate (44.0 g., 85% yield), m.p. ~ ~
108-112. ~ ~ -
B. -n-Propoxybenzamidine hydrochloride -
Ethanol (100 ml.) containing 6.5 g. of ammonia was added
during five minutes to a stirred suspension of ethyl 2- ~;n-propoxybenzimidate fluoroborate (44.0 g.) in ethanol
(25 ml.). The resulting solution was stirred at 25 for
20 hours. The solution was reduced to dryness and the ~ -
residue partitioned between diethyl ether and 5N sodium
hydroxide. The ether layer was washed with brine, dried
over sodium sulfate, and concentrated. A solution of the
residue in ether (500 ml.) and ethanol (50 ml.) was
treated with hydrogen chloride to precipitate 2-n-propoxy-
benzamidine hydrochloride (28.8 g., 76.6% yield), m.p.
184-186.5.
. .
-,
; - 50 -
:: ,
:.
~33~
Preparation 8: _-n-Propoxybenzamidine methyl sulfate
To a warm, s-tirred solution of 2~n-propoxybenzamide (896 y.,
5.0 moles) in 1,2-dichloroethane (5 1) was added dimethyl
sulfate (950 ml., 10.0 moles) over a period of about 0.5 hour.
The mixture was stirred and heated under reflux for 17 hours.
The solvent was removed. The residual oily solid was collected
by filtration, washed with e-thyl acetate and dried to give
methyl 2-n-propoxybenzimidate methyl sulfate ~403 g.), m.p.
79-82. The combined filtrate and washlngs were stored at 0
for 18 hours and gave a second crop (503 g.) of benzimidate,
m.p. 81-83. A slurry of the methyl 2-n-propoxybenzimidate
methyl sulfa-te (906 g.) in ethanol (1 1) was added to ethanol
(4 1) which had previously been saturated with gaseous ammonia.
The mixture was stored at room temperature for 17 hours. The
mixture was filtered. The filtrate was evaporated to dryness
to give 2-n-propoxybenzamidine methyl sulfate (872 g., 60
m.p. 86-88.
'.
Preparation 9: 2-Isopropoxybenzamidine hydrochloride
A solution of triethyloxonium fluoroborate (38.4 g., 0.202
~20 mole) in rnethylene chloride (75 ml.) was added during 15
; minutes to a stirred solution of 2-isopropoxybenzamide (36.2 g.,
0.202 mole) in methylene chloride (100 ml.). The mixture was
stirred for 18 hours at room temperature. The solution was
concentrated to about one-fifth volume and was diluted with
diethyl ether to precipitate colorless crystals (60 g.,
m.p. 90-110) of crude ethyl 2-isopropoxybenzimidate fluoro-
borate. Recrystallization of this material from methylene
chloride-diethyl ether gave 55 g. of colorless material,
m.p. 114-120.
,
,~
', ~'' ' " - ' " ,
~ . . . .
~ ' ' , . :'
.
~L(31531S;Z
To a stirred suspension of the above fluoroborate
(55 g.) in ethanol (50 ml.) was added 150 ml. of 8% ethanolic
NH3. The mixture was stirred for 64 hours at 25. The
solution was reduced to dryness and the residue made basic
with 100 ml. of S N NaOH. The basic mixture was extracted
with ether and the ethereal extract dried. A solution of
the residue in ether (500 ml.) and ethanol (50 ml.) was
treated with hydrogen chloride to precipitate 24.1 g. of
colorless 2-isopropoxybenzamidine hydrochloride, m.p.
162-164.
Preparation 10- 2-n-Butoxybenzamidine hydrochloride
. .
A solution of triethyloxonium fluoroborate (32.4 g., 0.171 mole)
in methylene chloride (75 ml.) was added to a stirred solution
of 2-n-butoxybenzamide [J. Pharm. Pharmacol., 4, 872 (1952)~
(33.0 g., 0.171 mole) in methylene chloride (200 ml.) at ;
25. The mixture was stirred at 25 for 20 hours. The
solution was concentrated to about one fifth of the original
volume and then diluted with diethyl ether. The precipitated
- solid was recrystallized from methylene chloride-diethyl
ether to give ethyl 2-n-butoxybenzimidate fluoroborate
(28.7 g.), m.p. 82-88. To a stirred, cooled (ice-water)
suspension of the fluoroborate (28.7 g.) in ethanol (75 ml.)
was added 8% ethanolic ammonia (150 ml.). The mixture was
stirred at 25 for 20 hours. The ethanol was removed and
,: . .
:~ the residue partitioned between ether and 5N sodium hydroxide
.~; .
,~ .
~ - 52 -
.. . . .
' ~ ' ,' ' '
" . ,
~.~83:~L52
(lO0 ml.). The ether layer was washed with brine, dried
over sodium sulfate, and then concentrated. A solu-tion of
the residual oil in ether was treated with hydrogen chloride
to precipitate the title compound (16.8 g.~, m.p. 150-155.
Preparation 11: (+~-2-sec-Butoxybenzamidine hydrochloride
In a manner similar to that described for the preparation
of 2-n-butoxybenzamidine hydrochloride in Preparation lO
above, (~)-2-sec-butoxybenzamidine hydrochloride, m.p.
142-144, was prepared from (+)-2-sec-butoxybenzamide which
itself is disclosed in J. Pharm. Pharmacol., 9, 855 (1957).
- ..
Preparation 12: 2-Isobutoxybenzamidine
A cold (ice-water) solution of 2-isobutoxybenzamide -
(70.1 g., 0.363 mole) in methylene chloride (800 ml.)
was added to a cold solution of triethyloxonium fluoro-
borate (69.0 g., 0.363 mole) in methylene chloride (175 ml.).
The resulting solution was stirred at room temperature for
16 hours. Approximately two thirds of the solvent was
; removed and the residue diluted with diethyl ether (500 ml.).
The mixture was filtered; The collected ethyl 2-isobutoxy-
- 20 benzimidate fluoroborate (76.5 g.), m.p. 110-112, was added
to ethanol (350 ml.) saturated with gaseous ammonia. After
67 hours at room temperature the solution was evaporated
to dryness. The residue was treated with 5N sodium hydrox-
ide (160 ml.). The mixture was extracted with methylene
chloride (3 x 200 ml.) and the combined extracts were
washed with water, dried (sodium sulfate) and concentrated.
'' '
- 53 -
.~ . . . .
~ , : ' ' .
iL5Z
The residue was recrystallized from cyclohexane to give 2-
isobutoxybenzamidinel ~42.9 g., 61.5% overall), m.p. 49-51.
Anal- Calcd. for Cl1H16N2O: C, 68.72; H, 8.39; N, 14.57.
Found: C, 68.60; H, 8.42; N, 14.28.
Reference
.
1. B.J. Broughton, B.J. Large, S.M. Marshall, D.L. Pain and
K.R.H. Wooldridge, U.S. Patent 3,819,631 (1974).
Preparation 13: 2-Isobutoxybenzamidine fluorosulfonate
.. . _ _ ... _ . _ . ... ~ . .
Methyl fluorosulfonate (5.65 g., 0.0495 mole) was added to a
stirred solution of 2-isobutoxybenzamidel (8.6 g., 0.0445
~; mole) in methylene chloride (100 ml.) under nitrogen. The
solution was stirred at room temperature for 18 hours.
Ammonia gas was then bubbled through the solution for 3
hours with stirring. The solution was concentrated and
the residue recrystallized from 1,2-dichloroethane to give
the title compound (1.1 g., 8.5% yield).
Reference
:, '
1. B.J. Broughton, B.J. Large, S.M. Marshall, D.L. Pain
and K.R.H. Wooldridge, U.S. Patent 3,819,631 (1974).
,, . ~,
Preparation 14: 2-Ethoxy-5-methoxybenzamidine hydrochloride
A: 2-Ethoxy-5-methoxybenzamide
5-Methoxysalicylamide (41.8 g., 0.250 mole) was dissolved
in a solution of sodium (6.37 g., 0.277 g-atom) in ethanol
(250 ml.). To the resulting cooled (ice-water) solution was
- 54 -
:
:
. . .
33~Z
added iodethane (38.9 g., 0.250 mole) over a period of 20
minutes. The reaction mixture was allowed to warm to room
temperature over 0.75 hour and then was hea-ted under reflux
for 19 hours. The mixture was concentrated and the residue
triturated with water. The mixture was filtered and the
collected solid recrystallized from acetonitrile to give 2-
ethoxy-5-methoxybenæamide (34.5 g., 70.7%), m.p. 128-130.
Anal. Calcd. for CloH13NO3: C, 61.52; ~I, 6.71; N, 7.18~
Found: C, 61.45; H, 6.51; N, 6.93.
-:,
B. 2-Ethoxy-5-methoxybenzamidine hydrochloride
~ethyl fluorosulfonate (28.4 g., 0.248 mole) was added to a
cooled (ice-water) solution of 2-ethoxy-5-methoxybenzamide
(33.5 g., 0.172 mole) in methylene chloride (450 ml.) over
a period of 20 minutes. The mixture was stirred at room
temperature for 4 hours. Two thirds of the solvent was re-
' moved and the residue diluted with diethyl ether. The pre-
cipitated crude methyl 2-ethoxy-5-methoxybenzimidate fluoro-
sulfonate (50.0 g.), m.p. 144-152 was dissolved in cold
ethanol (300 ml.) which had been saturated with ammonia.
The mixture was stirred with cooling (ice-water) for 2 hours
followed by 17 hours at room temperature. The ethanol was
removed under reduced pressure to give a semi-solid which
was treated with 5N sodium hydroxide (200 ml.). The mixture
was extracted with ethyl acetate. The extract was dried
., ~
(sodium sulfate) and concentrated. A solution of the residue
in acetonitrile-acetone (2:5) was treated with hydrogen ~;~
chloride gas to precipitate 2-ethoxy-5-methoxybenzamidine
hydro~hloride (10.5 g., 26.5%), m.p. 166-167.
- 55 -
~198315~
Preparation 15: 5-Carbomethoxy-2-ethoxybenzamidine
A: 5-Carbomethoxy-2-etho~ybenzamide
5-Carbomethoxy-2-ethoxybenzamide (m.p. 159-161) was prepared
from 5-carbomethoxysalicylamide, iodethaner and sodium
methoxide in methanol in a manner analogous to that described
for the preparation of 2-ethoxy-5-methoxybenzamide in
Preparation 14A.
B: 5-Carbomethoxy-2-ethoxybenzamidine
5-Carbomethoxy-2-ethoxybenzamidine, m.p. 133-135, was pre-
~10 pared from 5-carbomethoxy-2-ethoxybenzamide in a manner ,~
; similar to that described for the preparation of 2-isobutoxy-
benzamidine in Preparation 12.
Preparation 16: 5-Chloro-2-ethoxybenzamidine hydrochloride
A: 5-Chloro-2-ethoxybenzamide
.; ,-
A mixture of 5-chlorosalicylamide (16.0 g., 0.093 mole),
iodoethane (31.8 g., 0.204 mole), and potassium carbonate
(13.1 g., 0.095 mole) in ethanol (225 ml.) was heated under
reflux for 20 hours. The hot mixture was filtered. I'he
filtrate was reduced to dryness. The residue was triturated
~;20 with water. The mixture was filtered and the collected solid
recrystallized from acetonitrile to give 5 chloro-2-ethoxy-
benzamide ~6.8 g., 36.6%) m.p. 136-139.
~: ,
'
.
- 56 -
~3~2
Anal. Calcd- for CgHloClNO2
C, 54.15; H, 5.05; Cl, 17.76; N, 7.02.
Found:
C, 54.25; H, 4.85; Cl, 17.42; N, 6.89.
B: 5-Chloro-2-ethoxybenzamidine hydrochloride
If the procedure of Preparation 10 is repeated with the 2-
n-butoxybenzamide used therein replaced by an equimolar amount
or 5-chloro-2-ethoxybenzamide, there is produc0d the title
product, m.p. 227 wi-th decomposition. ~ ;
Anal. Calcd. for CgHllClN2O HCl:
C, 45.97; H, 5.15; N, 11.91.
Found:
C, 46.23; H, 5.20; N, 11.87.
' ~ ~
Preparation 17: 2,5-Dimethoxybenzamidine hydrochloride
If the procedure of Preparation 10 is repeated with the 2-
n-butoxybenzamide used therein replaced by an equimolar
amount of 2,5-dimethoxybenzamide, there is produced the --
title product, m.p. 170-172.
Preparation 18: 2-Cyclopropylmethoxybenzamidine hydrochloride
A: 2-Cyclopropylmethoxybenzamide
A stirred mixture of salicylamide (10.02 g., 0.074 mole),
- potassium carbonate (10.24 g.~ 0.074 mole) and bromomethyl- ~-
. .
;' ,'.
' , .
- 57 -
:
,
. ' , , ' , ~ ~ '
'
~3833LSi2
cyclopropane (10.0 g., 0.074 mole) in ethanol (15 ml.) was
heated under reflux for 19 hours. The mixture was concen-
trated and the residue treated with water. The mixture was
filtered and the collected solid recrystallized from benzene-
Skellysolve B to give 2-cyclopropylmethoxybenzamide (10.0 g.,
71.6%), m.p. 102-105.
s: 2-Cyclopropylmethoxybenzamidine hydrochloride
A solution of triethyloxonium fluoroborate (99.1 g., 0.522
mole) in methylene chloride (225 ml.) was added to a stirred
solution of 2-cyclopropylmethoxybenzamide (99.2., 0.518
mole) in methylene chloride (450 ml.). The mixture was stirred
at 22 for 18 hours. The solution was concentrated to about
one-fifth volume and then diluted with diethyl ether. The
precipitated solid was recrystallized from methylene chloride
diethyl ether to give ethyl 2-cyclopropylmethoxybenzimidate
~` fluoroborate (104.7 g., 65.7%), m.p. 120-121. To a stirred,
cooled (ice-water) mixture of the fluoroborate (104.7 g.) in
~, ethanol (100 ml.) was added 400 ml. of 6% ethanolic ammonia.
The mixture was stirred for 18 hours at 20. The mixture was
~` 20 concentrated and the residue partitioned between diethyl
ether and 3N sodium hydroxide. The ether layer was washed
~' with brine and dried over sodium sulfate. The dried solution
,,''i
-~ was treated with hydrogen chloride. The precipitate was
recrystallized from methylene chloride-diethyl ether to give
~ .;.................................................................... .
... .
.
.
~.,''
:, .
- 58 -
3~5;~
2-cyclopropylmethoxybenæamidine hydrochloride (71.5 g., 92.5%
~rom fluoroborate), m.p. 166-171.
Preparation 19: 5-Methox~-2-n-~propoxy~enzamidine hydrochloride
A: 5-Methoxy-2-n-propoxybenzamide
5-Methoxysalicyiamide (56.0 g., 0.335 mole) was added to a
cooled, stirred solution of sodium (8.55 g., 0.372 g-atom)
in ethanol (335 ml.). To the resulting suspension was added
1-bromopropane (41.3 g., 0.335 mole) dropwise over 20 minutes.
The mixture was stirred at room temperature for one hour, then
was heated under reflux for 19 hours. The solvent was removed
under reduced pressure. The residue was treated with cold
water (500 ml.). The solid was collected by filtra-tion and
recrystallized from acetonitrile to give 5-methoxy-2-n-pro-
poxybenzamide (29.0 g., 41.4~), m.p. 83-87.
~nal- Calcd- for CllH15NO3: C, 63-14; H, 7.23; N, 6.69.
Found: C, 63.28; H, 7.43; N, 6.47.
B: 5-Methoxy-2-n-propoxybenzamidine hydrochloride
: . '
To a solution of 5-me-thoxy-2-n-propoxybenzamide (29.0 g.,
0.139 mole) in methylene chloride (200 ml.) at 5 was added
methyl fluorosulfonate 15.8 g., 0.139 mole). The solution
was stirred at room temperature for 5 hours. Most of the
solvent was removed and the residual solution diluted with
diethyl ether (500 ml.). The precipitated me-thyl 5-methoxy-
;
~.
; - 59 -
.... . .
. . - : . : . ~. :
. .
.
:., ' ', ' ~ . .
1~3~S;Z:
2-n-propoxybenzimida-te fluorosulfonate (35.4 g., m.p. 117-
126) was collected and added to cold, saturated ethanolic
ammonia (220 ml.). The mixture was stirred at room tempera-
ture ~or 19 hours. The solution was concentrated and the
residual oil dissolved in a mixture of acetonitrile and
ether. The resulting solution was treated with hydrogen
chloride to precipitate 5-methoxy-2-n-propoxybenzamidine
hydrochloride (31.5 g.) as an oil, whlch was separated by
decantation of the solvents.
Preparation 20-1: 2-Methoxybenzamidine hydrochloride
In a manner similar to that described for the preparation of
2-n-propoxybenzamidine hydrochloride in Preparation 7, 2-
methoxybenzamidine hydrochloride, m.p. 150-152 was
prepared from 2-methoxybenzamide. -~
'
Preparation 20-2: 2-Ethylthiobenzamidine hydrochloride
_ . . . . _ _ ..
A. 2-Ethylthiobenzamidoxime
_ . . _ _ . .,
A solution of 2-ethylthiobenzonitrile (29.0 g., 0.178
mole) [disclosed by K. Brand et al. in J. Prakt. Chem.,
108, 19 (1924)] in ethanol (284 ml.) was added over a
30 minute period to a solution of hydroxylamine hydro-
chloride (4.47 g., 0.64 mole) and sodium carbonate (31.2 g./
0.29 mole) in water (474 ml.). The mixture was heated
under reflux for 1.75 hours. The cooled mixture was re-
duced to one third volume. The residue was partitioned
between diethyl ether and lN hydrochloric ac~d. The
ether and aqueous layers were separated. The ether layer
'
- 60 -
. . . .. . .
-,: :
. ~ .,
. - : ,-
1~831~
waS extracted twice with fresh lN HCl. The combined aqueous
layers were adjusted ~o pH 5.5 with sodium bicaxbonate.
The mixture was extracted with ether (3 x 200 ml.). The
combined ether extracts were dried (sodium sulfate) and
concentrated ~o give 2-ethylthiobenzamidoxime (12.5 g.,
; 36%), m.p. 72-78. Recrystallization from 2-propanol-
ether gave analytical material, m.p. 79-83.
Anal. Calcd. for CgH12N2OS: C, 55.09; H, 6~17; N, 14.2~.
Found: C, 54.92; H, 6.27; N, 14.08.
B. 2-Ethylthiobenzamine hydrochloride
Raney nickel was added to a solution of 2-ethylthiobenzamidoxime
(6.0 g., 30.6 mmoles) in ethanol (200 ml.) and the mixture
shaken for 3 hours in an atmosphere of hydrogen at an
initial pressure of 3.5 kg./cm2. The mixture was filtered
and the filtrate concentrated. The residual oil was dis-
solved in a mixture of ethanol (30 ml.) and diethyl ether
(400 ml.). The solution was treated with hydrogen
chloride. The precipitated 2-ethylthiobenzamidine hydro-
chloride, m.p. 290-291 (2.4 g., 36.2%), was recrystallized
from 2-propanol-ether to give analytical material, m.p.
296-297.
The 1,6-dihydro-6-oxo-2-phenyl-pyrimidine-5-
carboxylate esters (general formula V) may be prepared as
follows:
Preparation 21: Ethyl 1,6-dihydro-6-oxo-2-(2-ethoxyphenyl)-
~ - pyrimidine-5-carboxylate (illustrates use of benzamidine
- free base)
To a cooled solution of sodium (1.04 g., 0.045 g -atom) in 35
ml. of ethanol was added all at once 2-ethoxybenzamidine (7.4 g.,
45 mmole). There was then added to this suspension over a 5
- 61 -
: . .
'
:~831SZ
minute period a solution of diethyl ethoxymethylenemalonate
(9.7 g., 45 ~nole) in 20 ml. of ethanol whereupon a pale yellow
precipitate soon formed. An additional 25 ml. of ethanol was
added to the reaction mixture which was then heated under reflux
for 2 1/4 hours, The cooled solution was poured into about
500 ml. of ice-water and acidified with 6N HCl to produce a
pale yellow solid. The solid was dried to give 10.2 g., m.p.
144-149, of title product. Recrystallization from acetonitrile
gave 9.8 g., m.p. 147-150, of purified product.
.
Anal- Calcd- for C15H16N24 C, 62-49; H~ 5-60; N~ 9-72-
Found: C, 62.23; H, 5.57; N, 9.63.
Preparation 22: Ethyl 1~6-dihydro-6-oxo-2-(2-ethoxyp-henyl)- ~ -
pyrimidine-5-carboxylate (lllustrates use of benzamidine
hydrochloride salt)
To a cooled solution of sodium (8.2 g., 0.356 g-atom) in
300 ml. of ethanol was added all at once 2-e-thoxybenzamidine
- hydrochloride (35.7 g., 0.178 mole). A solution of diethyl
ethoxymethylenemalonate (38.4 g., 0.178 mole) in 80 ml. of
ethanol was added to the suspension and the mix-ture was heated
under reflux for 2 1/4 hours. The cooled solution was added
to about 2800 ml. of ice-water and the mixture was acidified
to pH 5 with glacial acetic acid. The precipitated ti-tle
product was dried to give 47 g. of an off-white solid, m.p.
147-150.
'
Preparation 23: Ethyl 1,6-dihydro-6-oxo-2-(2-ethoxyphenyl)-
pyrimidine-5-carboxylate (illustrates use of benzamidine
fluorosulfonate)
To a solution of sodium ethoxide at 18 prepared from sodium
(41 g., 1.78 g-atoms) in ethanol (1 1.), was added a solution
- 62 -
3~lS~
of 2-ethoxybenzamidine fluorosulfonate (206.5 g., 0.78 mole)
in ethanol (500 ml.~. The resulting soluticn was cooled
to 13 and then treated with a solution of diethyl ethoxy-
meth~lenemalonate (180 ml., O.89 mole~ in ethanol (400 ml.).
The mixture was heated under reflux for 2.25 hours. The
mixture was cooled to 10 and then poured into cold water
(5 1.) with good stirring. Ice was added as necessary to
keep the temperature of the mixture below 20. The mixture
was acidified to pH 5 with glacial acetic acid. The solid `~
material was collected by filtration, washed with water, ~ ~-
and dried to give the title compound (218.7 g., 97%).
Recrystallization from acetronitrile gave product with m.p.
144-1~7.
,:
Preparation 24: Ethyl 1,6-dihydro-6-oxo-2-(2-ethoxyphenyl)-
pyrimidine-S-carboxylate (illustrates most preferred procedure
~
using benzamidine methyl sulfate)
2-Ethoxybenzamidine methyl sulfate (19.9 g., 0.072 mole~
followed by diethyl ethoxymethylenemalonate (17.0 g.,
0.079 mole) were added to a stirred solution of sodium
(3.3 g., 0.144 g-atom) in ethanol (150 ml.). The mixture
was heated under reflux for 2.25 hours. The cooled mixture
was poured into ice-water (250 ml.) which was then acidified
with glacial acetic acid. The title compound was collected
by filtration, washed with water and dried. The product
(16.0 g., 77~), had mOp. 138-140.
.
,
- 63 -
:.,,, " , , ' :
. .' , ~' '" " ' .
~33~
Preparation 25: Ethyl 1,6-dlhydro-6-oxo-2-(2-n-propoxyphenyl)-
pyrimidine-5-carboxylate (benzamidine hydrochloride)
2-n-Propoxybenzamidine hydrochloride (12.0 g., ~.0558 mole)
was added to a stirred, cooled (ice-water) solu-tion of
sodium (2.57 g., 0.112 g-atom) in ethanol (50 ml.). To
this cooled, stirred solution was added a solution of
diethyl ethoxymethylenemalonate (12.1 g., 0.0558 mole) in
ethanol (50 ml.) during 10 minutes. The mi~-ture was heated
under reflux for 2.5 hours. The cooled solution was poured
onto ice and acidified with 6N hydrochloric acid. The pre-
cipitated ethyl 1,6-dihydro-6-oxo-2-(2-n-propoxyphenyl)-
~; pyrimidine-5-carboxylate (16.2 g., 96% yield) had m.p. 111-
113. Two recrystallizations from cyclohexane gave title
product with m.p. 112-113.
Anal- Calcd- for C16H18N24 C, 63-56; H~ 6-00; N~ 9-270
Found: C, 63.59; H, 6.15; N, 9.47.
,
Preparation 26: Ethyl 1,6-Dihydro-6-oxo-2-(2-n-propoxyphenyl)-
pyrimidine-5-carboxylate (benzamidine methyl sulfate with
sodium ethoxide
To a warm solution of sodium (181.7 g., 7.9 y-atoms) in
~, ethanol (5 1) was added with stirring a slurry o~ 2-n-propoxy-
, benzamidine methyl sulfate (1146.7 g., 3.95 moles) in ethanol
`, 1.6 1). After 2-3 minutes diethyl ethoxymethylenemalonate
; 854 g., 3O95 moles) was added and the mixture stirred and
heated under reflux for 2.25 hours. The mixture was cooled
and then added to cold water (13 1). The mixture was acidified
to pH 5-6 with glacial acetic acid. The solid was collected
by filtration, washed with water, and dried to give the
.:
- title compound (937.8 g.), m.p. 102-104 . An additional
64 -
,
. . ' . ,
3~ii2
crop of product (101.6 g., m.p. 105-107, was obtained frorn
the filtra-te and washings. Total yield of product, 1039 4 g.
(87%).
;''~
Preparation 27: Ethyl 1,6-dihydro-6-oxo-2-(2-n-propoxyphenyl)-
pyrimidine-5-carboxylate (benzamidine methyl sulfate with
X2C3 )
A mixture of 2-n-propoxybenzamidine methyl sulfate (7.4 g.,
0.0255 mole), potassium carbonate (3.53 g~, 0.025 mole),
and diethyl ethoxymethylenemalonate (5.99 g., 0.0277 mole)
in ethanol (80 ml.) was heated under reflu~ with stirring
for 17 hours. The cooled mixture was added to ice-water
(160 ml.) which was then acidified with glacial acetic acid.
The precipitate was collected by filtration, washed with
water, and dried to give the title compound (6.55 g., 89%),
m.p. 106-107.
Preparation 28: Ethyl 1,6-dihydro-6-oxo-2-(2-isopropoxyphenyl)-
- pyrimidine-5-carboxylate (benzamidine hydrochloride)
:
2~Isopropoxybenzamidine hydrochloride (10.0 g., 0O0465 mole)
was added to a stirred, cooled (ice-water~ solution of
sodium (2.14 g., O.Og3 g-atom) in ethanol (100 ml.). To
this cooled, stirred solution was added dropwise a solution
, of diethyl ethoxymethylenemalonate (10.1 g., 0.0465 mole)
-~ in ethanol (30 ml.) over a 10 minute period. The mixture
was refluxed for 2 hours and stored at 22 for 18 hours.
The mixture was then poured onto ice-water containing
acetic acid (10 ml.) and concentrated HCl (10 ml.) to
precipitate the desired product. The precipitate was
', :'
. : :
,--, .. .
'- .
. - f : , .,
:; . ' . ~
. .
,' .~ ' '"'., ' ''' '.,, '"'. ' ' ' ' , '
3~LS~
washed and dried to give 15.5 g. o~ -the title product,
m.p. 123-124. Recrystallizations from ethyl acetate and
then cyclohexane gave colorless crystals o~ the ester,
m.p. 128-130.
Anal- Calcd- for C16H18N24 C~ 63-56; H~ 6-00; N~ 9-27-
Found: C, 63.60, H, 5.93; N, 9.29.
Preparation 29: Ethyl 1,6-dihydro-6-oxo-2-(2-allyloxyphenyl)-
:
pyrimidine-5-carboxylate (benzamidine hydrochloride
2-Allyloxybenzamidine hydrochloridel (19.07 g., 0.0896 mole)
was added to a cooled (ice-water), stirred solution of
sodium ethoxide (12.25 g., 0.18 mole) in ethanol (100 ml.).
To this cooled, stirred mixture was added a solution
of diethyl ethoxymethylenemalonate (19.4 g.; 0.0896 mole)
in ethanol (15 ml.). ~he mixture was heated under reflux
for 2.5 hours and then allowed to stand at room temperature
~or 18 hours. The mixture was poured into ice-water containing
acetic acid. The solid was collected and recrystallized from
cyclohexane to give the title compound (24.0 g., 89~), m.p.
118-120. Recrystallization from cyclohexane gave product
with m.p. 118.5-120.5.
Anal~ Calcd- for C16H16N24 C~ 63-99; H~ 5-37; N~ 9-33-
~ Found: C, 63.93; H, 5.42; N, 9.36.
.:''
1. U.S. Patent 3,819,631.
- 66 -
, - ,
L5Z
Preparation 30: Eth 1 1 6-dih dro-6-oxo~2-(2-n butox phen 1)-
Y ~ .Y _ Y Y
pyri dine-5-carboxylate (benzamidine hydrochloride)
The procedure of Preparation 29 was repeated except that
the 2-allyloxybenzamidine hydrochloride used therein was
replaced with an equimolar amount of 2-n-butoxybenzamidine
hydrochloride. There was produced the title product, m.p.
123-125.
Anal. Calcd. for C17H20N2O4
Found: C, 64.41; H, 6.23; N, 9.07.
Preparation 31: Ethyl(~)-1,6-dihydro-6-oxo-2-(2-sec-butoxy-
henyl)pyrimidine-5-caroboxylate (benzamidine hydrochloride)
.
In a manner similar to that described for the preparation
of ethyl 1,6-dihydro-6-oxo-2-(2-n-butoxyphenyl)pyrimidine
-5-carboxylate in Preparation 30, ethyl (+)-1,6-dihydro-
; 6-oxo-2-(2-sec-butoxyphenyl)pyrimidine-5-carboxylate, m.p.
134-136, was prepared from (+)-2-sec-butoxybenzamidine
hydrochloride.
~' '
Anal. Calcd. for C17H20N2O4
Found: C, 64.31; H, 6.12; N, 8.82.
'
Preparation 32: Ethyl l,6-dihvdro-6-oxo-2-(2-isobutoxyphenYl)- -
, _ ~ , ~
pyrimidine-5-carboxylate (benzamidine free base)
To a stirred solution of sodium (3.15 g., 0.137 g-atom) in
ethanol (250 ml.) was added 2-isobutoxybenzamidine (26.3 g.,
0.137 mole) followed by diethyl ethoxymethylenemalonate
,,
(29.6 g., 0.137 mole). The mixture was heated under reflux
for 3 hours. The cooled mixture was added to ice-water
(300 ml.) which was then acidified to pH 5 with glacial
;
, ' . .
- 67 -
~ . . . . . . . .
,.-. ,. , .. , - ' , ~ , .
~ . , - . .
~lO~3~5~
- ace-tic acid. The crystalline product (36.4 g., 85%) m.p.
89-91, which formed on cooling was collected and a portion
recrystallized from 50~ aqueous ethanol to give the title
compound, m.p. 92-93.
Anal. Calcd- fo Cl7 20 2 4
Found: C, 64.66; H, 6.64; N, 8.69.
Preparation 33: Ethyl 1,6-dihydro-6-oxo-2-t2-isobutoxyphenyl)
pyrimidine-5-carboxylate ~benzamidine fluorosulfonate)
To a solution of sodium (161 mg., 7 mg-atoms) in ethanol
(10 ml.) was added 2-isobutoxybenzamidine fluorosulfonate
(1.02 g., 3.5 mmole). The mixture was warmed to give a clear
solution to which was added a solution of diethyl
ethoxymethylenemalonate (756 mg., 3.5 mmole) in ethanol (2 ml.).
The solution was heated under reflux for 3 hours. The cooled
mixture was added to ice-water (50 ml.~ and was acidified to
pH 5 with glacial acetic acid. After brief stirring, the
solid was collected by filtration, washed with water, and
~` dried to give the title compound (0.94 g., 86%), m.p. 90-91.
..~
Preparation 34: Ethyl 1,6-dihydro-6-oxo-2-(2~isobutoxyphenyl)-
pyrimidine-5-carboxylate (use of K2CO3 in place of alkali
~ metal alkoxide
- Diethyl ethoxymethylenemalonate (6.42 g., 0.03 mole) was
added to a s-tirred mixture of 2-isobutoxybenzamidine (5.76 g.,
0.03 mole) and potassium carbonate (4.14 g., 0.03 mole) in
ethanol (70 ml.). The mixture was heated under reflux for
: :.
~ 4 hours. The cooled mixture was added to water (100 ml.)
; which was then acidified to pH 8 with 6N hydrochloric
~- acid and then to pH 5 with glacial acetic acid. The title
- 68 -
;~
. `~
. ` ,
~0~3~Si;2
compound was collected by Eil-tration, washed with water,
and dried. The product (6.76 g., 71~) had m.p. 88-90.
Preparation 35: Ethyl 1,6-dihydro-6-oxo-2-~2-isobutoxyphenyl)-
pyrimidine-5-carboxylate (coupling reac~ion without use of
base condensing agent
The experiment described above in Preparation 35 was repeated,
but this time without the potassium carbona~e. The title
product was obtained in 69% yield, m.p. 89-91.
Preparation 36:
The following ethyl 1,6-dihydro-6~oxo-2-phenyl-pyrimidine-5-
carboxylates were prepared from the corresponding benzamidine
hydrochlorides according to the general method of Preparation ~ -
29.
A. Ethyl 1,6-dihydro-6-oxo-2-(2,5-dimethoxyphenyl)pyrimidine-
5-carboxylate m.p. 149-150.
...
Anal- Calcd- for C15H16N25 C~ 59-20; H~ 5-30; N~ 9-21-
Found: C, 59.07; H, 5.27; M, 9.23.
B. Ethyl 1,6-di:~ r 5-chloro-2-ethoxyphenyl)-
; pyrimidine-5-carboxylate, m.p. 209-212
",;
Anal. Calcd. for C15H15ClN2O4: C, 55-82; H~ 4-68;
Cl, 10.99; N, 8.68.
~` Found: C, S5.66; H, 4.76; `
Cl, 10.87; N, 8.78.
.: .
- C. Ethyl 1,6-dihydro-6-oxo-2-(2-ethoxy-5 mekhoxyphenyl-
pyrimidine-5-carboxylate, m.p. 149-152.
' ';'~
Anal. Calcd- for C16 18 2 5
~ Found: C, 60.31; H, 5.68; N, 9.09.
.. .
- 69 -
:,, . ' '
.
: , .
. ~83J 5~
D. Ethyl 1,6~dihyclro-6-oxo-2-(2-methoxy~--nyl)p ~ e-
5-carboxylate, m.p. 148-150.
s .
Anal. Calcd. for C14H14N2O4: C, 61.31; H, 5.14; N, 10-21-
Found: C, 61.38; H, 5.05; N, 10.23.
s
E. Ethyl 1,6-dihydro-6-oxo-2-(2-chlorophenyl)pyrimidine-
1 5-carboxylate, m.p. 139-141.
i Anal.Calcd. for C13HllClN2O3: C, 56.02; H, 3-98; Cl, 12-72;
N, 10.05.
Found: C, 55.90; H, 3.83; Cl, 12.34;
10N, 10.16.
F. Ethyl 1,6-dihydro-6-oxo-2-(3-methoxyphenyl?pyrimidine-
5-carboxylate, m.p. 169-170.
Anal- Calcd- for C14H14N24 C~ 61-31; H~ 5-14; N~ 10-21-
Found: C, 60.96; H, 5.13; N, 10.16.
G. Ethyl 1,6-dihydro-6-oxo-2-~3-trifluoromethylphenyl)-
pyrimidine-5-carboxylate, m.p~ 151-152.
`~
, ::
-~ Anal. Calcd. for C14~IllF3N2O3: C, 53.85; H, 3.55; N, 8.97.
Found: C, 53.84; H, 3.70; N, 8.71.
H. Ethyl 1,6-dihydro-6-oxo-2-(4-methoxyphenyl)pyrimidine-
205-carboxylate, m.p. 230-232.
.
I. Ethyl 1,6-dihydro-6-oxo-2-(4-chlorophenyl)pyrimidine-5-
carboxylate, m.p. 245-247.
Anal- Calcd- for C13HllClN23 C~ 56-02; H~ 3-98; Cl~ 12-72;
N, 10.05.
Found: C, 55.94; H, 4.06; Cl, 12.A6;
~ N, 9.86.
`-~J. Ethyl 1,6-dihydro-6-oxo-2-(4-trifuloromethylphenyl)-
pyrimidine-5-carboxylate, m.p. 225-226.5.
- 70 -
i
~83~
Anal. Calcd. for C14HllF3N2O3: C, 53.85; ~T, 3-55; N~ ~-97
Found: C, 54.00; El, 3.62; N, 9.05.
Preparation 37: Ethyl 1,6-dihydro-6-oxo-2-(5-carbethoxy-2-
Diethyl ethoxymethylenemalonate (1.18 g., 5.45 mmoles) was
added to a cold, stirred mixture of sodium e-thoxide (0.37 g.,
5.45 mmoles) and 5-carbomethoxy-2-ethoxy-benzamidine (1.21 g.,
5.45 mmoles) in ethanol (15 ml.). The mixture was heated under ~ ;
reflux for 0.5 hours. The cooled mixture was poured onto ice-
; 10 water and acidified with acetic acid. The precipitate was
recrystallized from ethanol to give the title compound (1.49 g.,
76%) as colorless crystals, m.p. 180-181.5.
-~
Note that during the coupling reaction between the
carbomethoxybenzamidine and the ethoxymethylenemalonate, ester
exchange occurs (under the influence of the NaOC2H5/C2H5OH)
resulting in the 5'-carbethoxy product.
- ..... :~ . ,
Preparation 38: Ethyl 1,6-dihydro-6-oxo-2-(5-amino-2-ethoxy-
phenyl)pyrimidine-5-carboxylate
.. . .
A. Ethyl 1,6-dihydro-6-oxo-2-(2-ethoxy-5-nitrophenyl)-
pyrimidine-5-carboxylate
Ethyl 1,6-dihydro-6-oxo-2-(2-ethoxyphenyl)pyrimidine-5-carboxy-
- late (1.0 g., 3.46 mmoles) was added over a -twenty minute
;~ period to a cooled (ice-water), stirred mixture of 70% nitric ~;
,,~ acid (1.7 ml., d=1.42) and 96% sulfuric acid (0.29 ml., d=1.84).
~ ~.
The mixture was stirred at room temperature for 19 hours. The
solution was poured into ice-water (300 ml.). The mixture was
,.. .
triturated and then filtered. The collected solid was recrystal-
.
lized from acetonitrile to give the title compound (0.64 g.,
55~), m.p. 222-224.
'' '
-~ 30 Anal. Calcd. for C15H15N3O6: C, 54.05; ~1, 4.54; N, 12.61.
Found: C, 54.32; H, 4.71; N, 12.56.
- 71 -
-
~' ,
~'';
.
~83~52
B. Ethyl 1,6-dihydro-6-oxo-2-(5-amino-2-ethoxyphenyl)-
imidine-5-carboxylate
A mixture of ethyl 1,6-dihydro-6-oxo-2-~2-ethoxy-5-
nitrophenyl)pyrimidine-5-carboxylate (0.42 ~., 1.26 mmoles)
. and 10% palladium on carbon (0.07 g.) in ethanol (200 ml.)
was treated with hydrogen at a pressure o about 3.5 kg./cm2
~, until uptake of hydrogen ceased. The mixture was filtered
and the filtrate reduced to dryness. The residue was
recrystallized from water followed by aqueous ethanol to
give the title compound (0.12 g., 31.6%), m.p. 107-110.
- Anal. Calcd. for C15H17N3O4-H2O:
- C, 56.07; H, 5.96; N, 13.08; H2O, 5.62.
Found:
C, 56.37; H, 5.70; N, 13.32; H2O, 5.82.
~ . .
- Preparation 39: Ethyl 1,6-dl y_ro-6-oxo-2-(2-cyclopropylmethoxy-
~; phenyl)-pyrimidine-5-carboxylate
.~
~ The title compound was prepared from 2-cyclopropylmethoxy-
: .
- benzamidine hydrochloride in a manner similar to that
described for the preparation of ethyl 1,6-dihydro-6-oxo-2-
(2-allyloxyphenyl)pyrimidine-5-carboxylate in Preparation 29.
The product had m.p. 104-105.
'. . ' .
Anal. Calcd. for C17H18N2O4: C, 64.95; H, 5.77; N, 8~91.
F~und: C, 64.66; H, 5.93; N, 8.87.
,,
,' '
- 72 -
1~3~iiZ
,.
Preparation 40: Ethyl 1,6-dihydro-6-oxo-2-(5-methoxy-2-n-
-- _
propoxyphenyl)pyrimidine-5-carboxylate
The title compound was prepared from 5-methoxy-2-n-
propoxybenzamidine hydrochloride in a manner similar to
tha-t described for the preparation of ethyl 1, 6-dihydro-6-
oxo-2-(2-allyloxyphenyl)pyrimidine-5-carboxyla-te in Preparation
29. The produc-t had m.p. 124-126.
Preparation 41: Ethyl 1,6-dihydro-6-oxo-2-(2,4-dimethoxy-
phenyl)pyrimidine-5-carboxylate
A solution of diethyl ethoxymethylenemalonate (8.4 g.,
0.0388 mole) in ethanol (20 ml.) was added dropwise to a
cooled (ice-water) stirred mixture of 2,4-dimethoxybenzamidine
~- (7.0 g., 0.0388 mole) in ethanol (50 ml.) containing sodium
(0.89 g., 0.0388 g-atom). The mixture was heated under
. ,: .
reflux for two hours. The cooled mixture was poured into
ice-water and acidified with dilute hydrochloric acid. The
~` precipitate was recrystallized from 95% ethanol to give ethyl
1,6-dihydro-6-oxo-2-(2,4-dimethoxyphenyl)pyrimidine-5-
; carboxylate (9.0 g., 63.5% yield), m.p. 190-192.
..I,,
15 16 2 5 C, 59 0; , 5.30; N, 9.21.
; Found: C, 59.15; H, 5.22; N, 9.19.
:,'', :
-~ Preparation 42-1:
The following ethyl 1,6-dihydro-6-oxo-2-phenyl-pyrimidine-
5-carboxylates were prepared from the reaction of the
~ .
appropriate benzamidine with diethyl ethoxymethylenemalanate
according to the general procedure of Preparation 41.
' '',: '
.''~
- 73 -
.
10~ 5Z
Ethyl 1,6-dihydro-6-oxo-2-~2-fluorophenyl)pxrlmid ne-5-
carboxylate, m.p. 151-153.
. ~ _
Anal- Calcd- for C13H~lFN23 C, 59.54; H~ 4-23; N~ 10-68-
Found: C, 59.69; H, 4.15; N, 11.05.
Ethyl 1,6-dihydro-6-oxo-2-(2-benzyloxyphenyl3pyrimidine-5-
: `
carboxylate, m.p. 156.5-157.5
Anal- Calcd- for C20H18N24 C, 63-56; H~ 5-18; N~ 8-00-
Found: C, 68.27; H, 4.99; N, 8.01.
~ Preparation 42-2: Ethyl 1,6-Dihydro-6-oxo-2-(2-ethylthiophenyl)-
;~ 10 pyrimidine-5-carboxylate
2-Ethylthiobenzamidine hydrochloride (2.12 g., 10.0 mrnoles)
~;~ was added to a cooled ~ice-water) solution of sodium (0.46 g.,
,
20 mg.-atoms) in ethanol (12 ml.)O To this mixture was
added a solution of diethyl ethoxymethylenemalonate (2.16 g.,
` 10.0 mmoles) in ethanol (4 ml.). The mixture was heated ~ -
under reflux for 3.5 hours. The cooled mixture was poured
into ice-water (400 ml.) and acidified to p~ 6 with glacial
acetic acid. The precipitate was collected and recrystallized
from acetonitrile to give the title cornpound (2.04 g., 64.6~),
m.p. 117-120.
Anal. Calcd. for C15H16N2O3S: C, 59.19; H, 5.30; N, 9.20.
Found: C, 59.42; H, 5.31; N, 9.37. ~ -
~: `'
Preparation 42-3: Ethyl 1,6=Dihydro-6-oxo-2-(2-methylthiophenyl)-
pyrimidine-5-carboxylate
In a manner similar to that described in Preparation 42-2,
the title compound was prepared from 2-methylthiobenzamidine
hydrochloride (disclosed in U.S. Patent 3,819, 631). Af-ter,
recrystallization from benzene, the produc-t had a m.p. 155-156.
- 74 -
,
, ~ , .. .
1~8;~LSZ
Anal- Calcd. for C14H14N2O3S: C, 57.92; N, 4.86; N, 9.65;
S, 11.04.
Found: C, 57.93; H, 4.76; N, 9.71;
S, 11. 01.
Preparation 42-4: Ethyl 1,6-Dihydro-6-oxo-2-(2-nitrophen~l)-
pyrimidine-5-carboxylate
Diethyl ethoxymethylenemalonate (0.73 g., 3.44 mmoles),
potassium carbonate (0.95 g., 6.88 mmoles), and ethanol
(11 ml.) were added to 2-nitrobenzamidine hydrochloride
(0.69 g., 3.44 mmoles) (prepared according to general
method disclosed in U.S. 2,450,386). The mixture was
heated under reflux for 3.5 hours. The cooled mixture
-~ .
; was filtered. The filtrate was poured into ice-water
.~ ~, , .
(150 ml.) and the pH adjusted to 6.0 with acetic acid.
The precipitate was collected and dried to give the
title compound (0.20 g., 20.2~), m.p. 171-175.
Recrystallization from acetonitrile gave analytical
material, m.p. 175-177.
Anal- Calcd- for C13HllN35 C~ 53-98; H~ 3-83; N~ 14-53-
- 20 Found: C, 53.62; H, 3.90; N, 14.35.
,' ':
Preparation 42-5: Ethyl 1,6-Dihydro-6-oxo-2-(2-aminophenyl)-
pyrimidine-5-carboxy_ate
--~
A mixture of ethyl 1,6-dihydro 6-oxo-2-(2-nitrophenyl)pyrimidine-
5-carboxylate (0.91 g., 3.14 mmoles), 10~ palladium on carbon
- (0.34 g.) and ethanol (200 ml.) was shaken in an atmosphere of
hydrogen at an initial pressure of 3.5 kg./cm2. After hydrogen
uptake ceased, the mixture was filtered and the fil-trate
- 75 -
1~33~52
concentrated. The residue was recrystallized from
acetonitrile to gi~re the title compo~nd (0.445 g.,
54.5%), m.p. 228-230 ~decomp.).
Anal. Calcd. for C13Hl;3N30~: C, 60.22; H, 5.05; N, 16-21-
Found: C, 59.89; H, 4.38; N, 16~.51.
The 1,6-dihydro-6-oxo-2-phenylpyrimidine~5-carb~xamides
(general formula III) may be prepared as follows:
~: 1,6-Dihydro-6-oxo-2-(2-ethox~hen~ æmidine
-
-5-carboxamide
A mixture of ethyl 1,6-dih~dro-6-oxo-2-(2~e~hoxypherLyl)pyrimidine
-5~carboxylate (10~0 g.) and aqueous a~monia (120 ~., d 2 ~.9o)
was heated in a sealed vessel on a steam bath for 4.5 hours~
The solution was partially evaporated and then acidified
to pH 3 with 6N hydrochloric acid. The collected solid
was washed with water, dried, and recrystallizsd from N,N-
dimethylformamide to give the title compo~d (6~93 g~, 77
yield), m.p. 236-238.
~al- Calcd- for C13H13~3~: C~ 60.22; ~, 5.05; N, 16.21.
Fou~d: C, 60,15; H, 5.11; N, 1~.77.
Preparation 44-
The following carboxamides were prepared ~rom the corr~spondin~;
ethyl l,~-dihydro-6~oxo-2-phenylpyrimidine-5-carboxylates b~y
the procedure described ln Preparation 43 above.
1~331~2
4 1,6-dihYdro-6 o o-2-(2-n-~o_oxyphenyl~2rimldine-5-
carboxamide, mOp. 225-226.
Anal. Calcd.for C14H15N303: C, 61.53; H, 5.53; ~7 15-380
Fo~nd: C~ 61.76; ~, 5.56; N, lS.14.
B. 1,6-dihydro-6-oxo-2-~2-metho ~ - ~ -
S-carboxamide, m.p. 218-219.
Anal. CalcdO for C12HllN303: C, 58,77; H, 4.52; N, ~7-14-
Found: C, 59.17; H, 4.48~ N, 16.~7
C. 1~6-dihydro-6-oxQ-2-~2-isopropoxy~henyl~pyrimidine-5
carboxamide, m.p. 200-201.
Anal. Calcd. for C14H15N303: C, 61.53; H, 5.53; N, i5.38. ~ .
Found. C, 61.42; H, 5.53; N, 14~9.
D. 1.6-dlhydro-6-oY~o-2-~2-n-butoxy-phe-n~pyr-im-idine
5-carboxa~nide, m.p. 1~1-183.
Anal. Calcd. for C15H17~303: C, 62.7G; H, 5.96; N~ 14~3.
Found: C, 62.71; H, 5.94; M, 14.61.
Preparat~on 45~ 9:59~93~ n.3l-
p!~lrimid e-5-carboxa_ide
A steel bomb containing ethyl (~)-1,6-dihydro-6- oxo-2~
(2-sec-bufoxyphenyl)~yrimidine-5-car~oxy~.ate (3.76 g.) and
liquid ammonia (ca. ~5 ml,~ was heat0d on a s~eam bath for
our hours. The ~mmonia was removed. A solution o~ the
residue in ice-water was acidi~ied with conrentrated
-77-
~831SZ
hydrochloric acid. The precipitatc Jras rscrystallized from
methanol to give the title comp~und (2.99 g~, 87.7~ yleld),
m.p. 183-185.
d- for C15~17N3 ~ : C~ 62-70; H, 5.96; N, 14.63
Found: C, 62037; ~, 5.95, N~ 14.50.
.
6 Dihydro-6-oxo-2 (2-isobutoxy~hen~
midine-5-carboxamide
~ .. .~
A ml~ture of ethyl 1,6-dihydro-6-oxo-2-(2-~sobutoxyphenyl)-
pyrimidine-5-carboxylate (10.0 g., 0.0316 mole) and ammon~um
hydroxide (110 ml., d-0.9) was heated in a sealed steel bom~
for 4.5 hours. The solutlon was partially evaporated and the
residue acidified with 6N hydrochloric acid. The mixture
was filtered and the collected solid recryst~llized from -
N~N -dimethylformamide to give the title compound (7.5 g.,
83~ yield), m.p. 230-231.
C15H17N303: C, 62.70; H, 5.96; N, 1~ 63 i
Found: C, 62.58; H~ 5.91; N3 14.23.
~ : ~ ro~_yphen~l)
pyrlmidine-5-carboxamide (illustrates u~e of NH40H at room
temperature
To a slurry of ethyl 1,6~dihydro-6-oxo-2-(2-n-propoxyphenyl~-
pyrimidine-5-carboxylate ~811.4 g.) in ammonium hydroxi~e (12 1,
d=0.9) was added tetrahydrofuran (800 ml.). The solution
was stored at room temperature for 64 hours. Partial
evaporation of the solvents under reduced pressure ga~e a
thick slurry which was cooled and acidi~led to pH~ with 6
hydrochloric acid~ The solid was collected by filtration~
washed with water, dried, and recr~stallized from N,N-dimethyl-
~ormamide to gi~e the title co~pound (11~07.7 g.~ 86~), m~p. 227
2~9
-78-
~33~S'~
P9~: ,
Following the general procedures of Preparat~ons 4~-47 abo~r~
there rnay be prepared ~rorn the appropriate ethyl 1,6-dih~dro-
6 oxo-2-phenylpyr~nidine-5-carboxylates the following
carboxamides:
A . 1, 6-dihydro-6-oxo-2 -(2-chlorophengl)pyrimid~ne~5-carboxamide;
B. 1,6-dihydro-o-oxo-2-(3-methoxyphenyl)pyrimidine-5-
carboxamide;
C. 1,6-dihydro-6-oxo-2-(3 trifluoro-,nethyl)pyrimidine-
5-earboxamide;
7 1,6-dihydro-6-oxo-2-(4-methoxyph2nyl)pyrimidine-
5-carboxamide;
E- 1,6-dihydro 6-oxo-2-~4-trifluoromethyl)pyrimidin~-
5-carboxamide; -
F. 1,6-dihydro-~-oxo-2~(2,4-dimetho7cyDhenyl)pyrimidine-
S-carboxamide;
G. 1,6-dihydro-6-oxo-2~ fluorophenyl)pyrimidine-
5-carboxamide;
H~ 1,6-dihydro-6-oxo-2~(2-benzyloxphenyl~pyrimidine-
5-carboxamide;
I. 1,6-dihydro-6-oxo-2-(2-ethylthlophen1Jl)pyrlmldine-
5-carbsxamid e;
J. 1,6-dih~rdro-6-oxo-2-(2-methylthiophenyl)pyrimidlne-5-
c~-rboxamide; and
K. l~o-dihydro-o-oxo-2-(2-a;~inophenyl)pyrimidine-5 -carbox~rnide.
-79-
- - ~
~ ~3315~
Preparation 49: ox ~ -
pyrimidine-5-carboxamide
A mixture of ~thyl 1,6-dihydro-6-oxo 2 (~-allyloxyphenyl)-
pyrimidine-5-carboxylate (5.0 ~.) and liquid ammonia (50 mlO)
in a steel bo~b was kept at 25 ~or 18 hours and then heated
on a steam bath for 2.5 hours. The ammonia wa~ removed. T~e
residue was dissol~ed in water and the solution acidified with
acetic acid~ The prec~pitated title compound (4.4 g. J 97~,
m.p. 202-204 with resolidiflcation and remelting at 275-
280, was recrystallized from ethanol to give analytical
material, m.p. 205-207
Anal. Calcd. for Cl~Hl3N3 ~ : C, 61.98; X~ 4.83; N~ 15.~9.
Found: C, 61.97; H, 4.79; N, 15.~0
: 1?6-Dihydro-6-oxo-2~(2-c,~clopropy:lmet ~ nyl)
dine-5-carboxamide.
.
In a manner similar to that described ~or the prep~ration o~
1,6-dihydro-6~oxo-2-(2~allyloxyphenyl~pyrimidinew5-carboxamide
in Preparation ~9, khe title compound was prepared fro~
ethyl 1,6-dihydro-6-oxo-2-(2-cyclopropylmethoxyphenyl)pyrimidine~
5-carboxylate. The product ~lO0~) had m.~. 215-217 (recrys-
tallization from ethanol).
Anal. Calcd. for Cl5Hl5N~03: C, 63.15; H, 5.30; N, 14~7~.
Found: C, 63.00; EI, 5~6; N~ 14.62.
Preparation 51:
~imidine-5-carboxamide
A mixture of ethyl 1,6-dihydro-6~oxo-~-(5-methoxy-2-n-propoxy-
phenyl)pyrimidine-5-carboxylate ~lO.0 g.) and concentrated
ammonium hydroxide (100 ml.) was heated in a sealed steel bomb
-80-
3~5~ :
on a steam Dath ~or 4.5 ho1~s. The reaction m~xture-wa
concentrated and then aci.dified to pX 3 with 6N hydrochloric
acid. The collected solid wa3 partially dried and recrys-
tallized f`rom acetonitrile to give the title compound (3.8 g.,
41.6~ .p. 206-207.
C15~17N304: C, 59.~9; H~ 5,~5; ~3 13.86
Found: C, 59.17; ~, 5.81; N~ 1~o69
~ .
The 1,6-dihydro-6-oxo-2-phenylp~r~midine-5-carbonitriles
(genPral formula II) may be prepared accordinæ to the methods
illustrated below.
Preparation 52: 1,6-Dihydro-6-oxo-?-(2-ethoxy~henyl~pyrlmidine-
A solution of 1,6-dihydro~6-oxo-2-~2-ethoxyphenyl)pyrimidine-
~-carboxamide (5.5 g.) in phosphorus ox~chloride (16a ml.)
was heated under re~lux for 3.5 hours, The solution was
evaporated under reduced pressure to ~ thick o~l which was
treated wlth water (150 ml.) with vigorous stirring~ The
mi~ture was filtered. The collected solid was washed with
water, dried, and recrystallized f'rom glacial acetic aci.d
to give the title co~pound (3.48 g., 68~ yield), m.p. 186-
187~
Anal- Calcd- for C13HllN32 C~ 64-72; H~ 4-60; ~? 17.~2.
Found: C~ 65.og; H, 4.84, H~ 17.75.
-81-
~83~S2
~re~aration 53~ ~
.
The following carbonitriles were prepared ~rom th~
correspond~ng 1,6-dihydro-6-oxo-2~phanylpyrim~dine-5~
carboxamides by the procedure de9cribed in Preparation
52 above.
A. ~ ~æ~ din~-
5-ca~bonitrile, m.p. 171~172.
Anal. Calcd. ~or C14~13N302: ,
Found: C3 65082~ HJ 5.22,
B. ~ _
5~carbonitrile, m~p. 245-246~.
Anal. Calcd. ~or C12HgN302 C, 63.43; H, 3.99, N, 18.49~
Found: C9 63.09; H, 4.09; N, 18.22.
C. 1,6 dihydro-6-oxo-2- ~ ro~oxy~ ~ -5-
carbonitrile, m.p. 174 175.
r
Anal. Calcd for Cl~H13N302:
Found: N, 16.53~
D. 1,6-dihvdro-6-oxo-2-(2-n-butoxyDhenyl)~yrimidine-
5-carbonitrile, m,p. 171.5-173,5.
Anal. Calcd. for C15H15N302: C, 66.90; H, 5.61; N, 15.~1
Found: C, 66.58; H, S,62; N, 15.46,
E, ~ 6-dih~dro~6 oxo-2-(2-sec-bute~e~yll:2~ ne~
5-carbonitr_ e, m.p. 152-158.
Anal. Calcd. ~or C15~15N32 ~ 66-90; H~ 5-61; N~ 15-6~-
Found: C, 65.S9; H, 5.43; N, 15.77.
-82-
~ID83~5~
Preparation 54: 1,6-Dihydro-6-oxo-2-(2-isobutoxyphe~
p rimidine-5-carbonitrile
Y _
A mixture of 1,6-dihydro-6-oxo-2-(2-isobutoxyphenyl)pyrimidine-
5-carboxamide (7.4 g.) and phosphorus oxychloride (150 ml.)
was heated under reflux for 3.5 hours. Excess phosphorus
oxychloride was removed under reduced pressure. The residue
was treated with water (150 ml.). The mixture was stirred
briefly, cooled, and filtered. The collected solid was re-
crystallized from 50% aqueous acetic acid to give the title
compound (3.9 g., 58% yield), m.p. 186-187.
Preparation 55:
Following the general procedures of Preparations 52-54 above,
there may be produced from the appropriate 1,6-dihydro-6-oxo-
2-phenylpyrimidine-5-carboxamides the following carbonitriles:
A. 1,6-dihydro-6-oxo-2-(2-chlorophenyl)pyrimidine-5-
carbonitrile;
B. 1,6-dihydro-6-oxo-2-(3-methoxyphenyl)pyrimidine-
5-carbonitrile;
; C. 1,6-dihydro-6-oxo-2-(3-trifluoromethylphenyl)-
pyrimidine-5-carbonitrile;
D. 1,6-dihydro-6-oxo-2-(4-methoxyphenyl)pyrimidine-
5-carbonitrile;
F. 1,6-dihydro-6-oxo-2-(4-trifluoromethyl)pyrimidine-
5-carbonitrile;
-' ~
'
- 83 -
1(~8315Z
F~ 1,6-dihydro-6-oxo-2-(2,4-dimethoxyphenyl)~yrimidine-
5-carbonitrile;
G, 1,6-dihydro-6-oxo-2-(2-fluorophenyl)pyrimidine-
5-carbonitrile; - ~
H. 1~6-dihydro-6-oxo-~-(2-benzyloxyphenyl)pyrimidine-
5-carbonitrile;
I~ 1,6-dihydro~6-oxo-2-(2-ethylthiophenyl)pyrimidine-
5-carbonitrile;
J. 1,6-dihydro~6~oxo-2-(2-methylthiophenyl)pyrimidine-
5-carbonitrile; and ~i
K. 1,6-dihydro-6-oxo-2 (2-aminophenyl)pyrimidine-5-
carbonitrile.
Preparation 56: ~ -all/lo~l~h ~lle,~lmidine~
5-carbonitrile
A solution o~ 1,6-dihydro~6 oxo-2-(2~allyloxyphenyl)pyrimidine-
5-carboxamide (3~58 g.) in phosphorus oxychloride (60 ml.) was
heated under reflux for 2 hours. The solution was evaporated
to dr~ness. The residue was cooled ~n ice and then treated
cautiously with ice-water. The mixture was ~rarmed to 25 and ~.
then heated on a steam bath for 15 minutes. The solid was
collected~ washed with cold water, and recrystalliz~d .~rom
benzene-Skellysolve B to give the title compound (2.3 g., 69~),
~.p~ 162-164.
nal. Calcd. for C14HllN32 C~ 66-~9; H~ 4-38; N~ 16-59-
~ound: C, 66~36; H, 4.45; N, 16.5~.
-~4
1~33~2
Pre~aratlon ~7~
~ imid~ne-5-carbonitrile
1,6-Dihydro-6-oxo-2-(2-c~cloprop~lmethoxyphenyl)pyrimidine-5~
carboxamide (13.6 g., o.o476 mole) wa5 added to a stirred~ cold
solution o~ py~idine ~1809 g., 0.24 mole) in phosphorus oxy-
chloride (136 ml.), and the mixture hèated ~nder re~lux-~or
15 minut~s. The mixture was evapor~ted to dryness and ~he
residue added to a mixture of ice and methylene chloride.
The mlxture was neutralized with sodium bicarbonate~ TAe
methylene chloride layer was dried (sodium sulfate) and
concentrated. To the residual oil was added lN sodium
hydroxide (15 ml.) and tetrahydrofuran (10 ml.). The mixture
was allowed to stand at 25 for 18 hours. The mixture was
washed wlth diethyl ether, filt2r~d, and the ~iltrate
acidified with acetic acid. The precipitate was recrystallized
from toluene to give the title eompound (7.6 g., 59.6%), m~p.
188-190. Two recrystallizations from ethyl acetate gave
analytical material, mOp. l87-l8go.
Anal. Calcd- ~or Cls~l~N~02 9
Found: C, 67.oo; H, 4.96; N, 15.50.
Preparation ~ ~
~ e
The title compound (82.5~), m.p. 192-194, recrystallized from
2-propanol, was prepared ~rom 1,6-dihydro~6-oxo-2-(5-methoxy-
2-n-propoxyphenyl)pyrimid~ne-5-carboxamide in a manner similar
to that descrlbed ln Preparation 56
C15H15rJ33: C, ~3.15; H, 5.30; N, 14 73
Found: C, 62.87; H, 5.28; N, 14.74.
-85-
".
~33~5%
Pre~ration 59: 1~6-Dih~dro~6-ox ~ -
~yrimidine-5-carbonitrile
A solution of ethyl 2-cyano-3-~2-isopropoxybenzamidino)acrylate
(o.60 g.3 1.99 mmoles) (prepared accord~ng to Preparation 60)
in dimethyl sul~oxide (15 ml.) was heated by means of an oil
bath maintained at 100~ for 18 hours. The cooled mixture was
poured into ice-w~ter (~00 ml.). Th~ mixture was filtered
to give the title compound (0.40 g., 78.7~), m.p. 182-184.
When the above procedure wa~ repeated ~ith tolue~e
substituted for the dimethyl sulfoxide used therein, ther~
was obtained the crud~ title product in 81.7% yield.
When the above procedure was repeated with N,N-
dimethylformamide ~ubst~tut~d for the dimethyl sul~oxide used
there~n, there was obtained the title product, m.p. 184-188,
in 74~ yield.
__ _
The acrylate intermediates of general form~la VI may be pre-
pared as ~ollows:
: _h~l 2-c~ano~3-(2-isoprop_ ~benzamidino)-
acr~ te
Ethyl ethox~me~hylenecyanoace~a~e (0.95 g., 5.61 ~moles) was
added to an ice~cold solution o~ 2-isopropoxybenzamidLne (1.0 g4
5.61 mmoles) in ethanol (7.1 ml.). The mixtura was stirred at
5 ~or 1.5 hours. The mixture was filtered to ~i~e the title
compound (1 2 g., 71~), m.p. 118-122. An analykical sample
had m.p. 123-12~ (decomp).
r C16HlgN33 C~ 63-77; H, 6 36; N, 13 95
Found: C, 63.57; H, 6.25; N~ 14.02.
-8~-
~ 8 ~ 5 ~
In a similar manner, but substltuting N~N-
dimethylformamide ~or ethancl ln the procedure ~bove, sthyl
2-cyano~3-(2-isopropoxybenzamidino)acrylate, m.p~ 118-120,
was prepared in 76.2~ yield.
-87-
331~2
Example 1
2-~2-Ethoxyphenyl)-5-(5-lH-
- - ~
; tetrazolyl)pyrimidin-4-(3H)-one
A mixture of 1,6-dihydro-6-oxo-2-(2-ethoxyphenyl)-
pyrimidine-5-carbonitrile (2.17 g., 9.0 mmole), sodium
azide (0.645 g., 9.9 mmole), and ammonium chloride (0.53
g., 9.9 mmole) in dry N,N-dimethylormamide (18 ml.) was
stirred at 125 for 16 hours. The solvent was removed
under reduced pressure. The residue was treated with water
and the resulting slurry acidified with 1_ hydrochloric
acid. The mixture was filtered. The collected solid was
washed with water, dried, and recrystallized from glacial
acetic acid to give the title compound (1.28 g., 50~ yield).
An analytical sample had m.p. 289-290 with decomposition.
. Calcd. for C13H12N6O2: C, 54.92; H, 4-26; N, 29.57.
Found: C, 55.09; H, 4.32; N, 29.29. ~
~- Example 2 -
.,- - :
2-(2-n-Propoxyphenyl)-5-(5-lH-
~,,. ~ '
tetrazolyl)pyrimldin-4(3H)-one
~`'~ 1 .
~ 20 The procedure o Example 1 is repeated except
`~ that an equimolar amount of 1,6-dihydro-6-oxo-2-(2-n-pro-
~ poxyphenyl)pyrimidine-5-carbonitrile is used in place of the ;
: "'
1,6-dihydro-6-oxo-2-(2-ethoxyphenyl)pyrimidine-5-carbo-
.", ~ :
. .
- 88 -
'
;
.: ': . ",, . , ~ ' ~: , ., ' .
,: . . . .:
:., . ~ . .
,
, ~, . . .
~3~1LSX~
nitrile used therein. ~hs~r~ i3 pr~e~d the title product,
m.p. 247-248.
Anal. Calcd. for C14H14N6 2
Found: N, 28.27.
Example 3
2-(2-Isopropoxyphenyl)-5-(5-lH-
; tetrazolyl)pyrimidin-4(3H)-one
The procedure of Example 1 is repeated except that
an equimolar amount of 1,6-dihydro-6-oxo-2-(2-isopropoxyphenyl)-
pyrimidine-5-carbonitrile is used in place of the 1,6-dihydro-
-6-oxo-2-(2-ethoxyphenyl)pyrimidine-5-carbonitrile used
:
therein. There is produced the title product, m.p. 275-
276 with decomposition.
Anal- Calcd- for C14H14N62 C~ 56-37; H~ 4-73; N~ 28-17-
Found: C, 56.22; H, 4.75; N, 28.13.
`, .- .
Example 4
2-~2-n-Butoxyphenyl)-5-(5-lH-
tetrazolyl)pyrimidin-4(3H)-one
~, ,
The procedure of Example 1 is repeated except that
an equimolar amount of 1,6-dihydro-6-oxo-2-(2-n-butoxyphenyl)-
,
,.~i, .1
;,'
,
.,
~ - 89 -
",
s .
i, . - - .
'~...... . .: .
.~ ,. . .
,
13~i2
pyrimidine-5-carbonitrile is used in place of the 1,6-
dihydro-6-oxo-2-(2 ethoxyphenyl)pyrimidine-5-carbonitrile
used therein. These is produced the title product, m.p.
244-247 with decomposition.
~nal- Calcd- for C15H16N62 C~ 57-68; H~ 5-16; N~ 26-91-
Found: C, 57.41; H, 5.13; N, 27.09. -~
Example 5
(+)-2-(2-sec-Butoxyphenyl)-5-(5-
lH-tetrazolyl)pyrimidin-4(3H)-one
The procedure of Example 1 is repeated except that
an equimolar amount of (+)-1,6-dihydro-6-oxo-2-(2-sec-butoxy-
phenyl)pyrimidine-5-carbonitrile is used in place of the
1,6-dihydro-6-oxo-2-(2-ethoxyphenyl)pyrimidine-5-carbonitrile
used therein. There is produced the title product, m.p.
240-242 with decomposition. It should be noted that the
product of this example contains an asymmetric carbon atom
and thus can exist as the racemate, i.e. equal mixtures of
the (+) and (-) optical isomers or, upon resolution by methods
known per se, as the individual (+) and (-) isomers.
Anal- Calcd- for C15H16N62 C~ 57-68; H~ 5-16; N~ 26-91-
Found: C, 57.49; H, 5.09; N, 26.66.
Example 6
- ~ .
; 2-(2-Methoxyphenyl)-5-(5-lH-
tetrazolyl)pyrimidin-4(3H)-one
,-
- 90 -
'.'.' , ' ' '
,
1~83~S~
Sodium azide (283 mg., 4.35 mmole) was added to a
solution of aluminum chloride (193 mg., 1.45 mmole~ in
tetrahydrofuran (8 ml.). The mixture was stirred under
reflux for 0.5 hours. 1,6-Dihydro-6-oxo-2-(2-methoxyphenyl)-
pyrimidine-5-carbonitrile (300 mg., 1.32 mmole) was then
added and the mixture stirred under reflux for 24 hours.
The cooled mixture was diluted with water (15 ml.) and
acidified with 6N hydrochloric acid. The mixture was filtered.
The collected solid was recrystallized from glacial acetic
acid to give the title compound (130 mg., 36.4% yield),
m.p. 282-283 with decomposition.
Anal. Calcd. for C12HloN6O2
Found: C, 53.20; H, 3.74; N, 31.50.
.
Example 7
-
2-(2-Isobutoxyphenyl)-5-(5-lH=
tetrazolyl)pyrimidin-4(3H)-one
A mixture of 1,6-dihydro-6-oxo-2-(2-isobutoxyphenyl)-
pyrimidine-5-carbonitrile (3.78 g., 0.014 mole), sodium
azide (1.0 g., 0.0154 mole), and ammonium chloride (0.824 g.,
0.0154 mole) in N,N-dimethylformamide was heated at 125 for
~i 19 hours with stirring. The solvent was removed under re-
duced pressure. The residue was treated with water (40 ml.).
` ,-'
,
~, , .,' .
~''.''~
:
~`: -- 91 --
,~
'~,' `~',''' -' ' - "' ' , ' ,
~ 33~
The mixture was acidified with 6N hydrochloric acid with
stirrlng. The mixture was filtered and the collected solid
recrystallized from glacial acetic acid -to give the title
compound (2.4 g., 55% yield), m.p. 230-231.
Anal- Calcd- for C15H16N62 C, 57-68; H~ 5-16; N~ 26-91-
Found: C, 57.52; H, 5.27; N, 26.72.
Example 8
2-(2-Allyloxyphenyl)-5-(5-lH-
tetrazolyl)pyrimidin-4(3H) one
Aluminum chloride (1.71 g., 0.0128 mole) followed
by sodium azide (2.5 g., 0.0384 mole) was cautiously added
to ice-cold, stirred tetrahydrofuran (100 ml.). The mixture
was heated under reflux for 0.5 hour. To the mixture was ~;
added 1,6-dihydro-6-oxo-2-(2-allyloxyphenyl)pyrimidine-5-carbo-
nitrile (3.23 g., 0.0128 mole) and refluxing was continued
for 18 hours. The cooled reaction mixture was diluted with
water and acidified with 6N hydrochloric acid. The precipitate
was collected and recrystallized from 95% ethanol to give
, - .
the title compound (1.4 g., 37%), m.p. 221-~25. Two re-
~' 20 crystallizations from acetic acid gave analtyical material,
~ m.p. 230.5-232 (decomp).
~;
Anal. Calcd. for C14H12N6O2: ,
~ Found: C, 56.71; H, 4.24; N, 28.40.
.'1~ . .
, :
:
:.
. ~, . .
.. .... .
~'' -''' .
~- - 92 -
:~.' :
~ .
',; ;~ ~:,
:, . . . ..
:. , . .; . ~ : . :
33:~L5;Z
ample g
2- ~ Cyclopro~ylmethoxyphen~l ~5-
(5-lH-tetrazolyl)~y~imidin-4(3~-or~e
A stirred mixture of 1,6~dihydrQ~6-oxo-2-(2-cyclopropyl~
methoxyphenyl)pyrimidine-5-carbonitrile (4.5 g~, 0~0168 mole~,
sodium azide (1~2 g~, 0.0184 mole) and ammonlum chloride (0.~9 gD~
0.0185 mole) in N,~-dimethyl~orm~mide (45 ml.) was heated b~
means o~ an oil bath maintained at 125 for 20 hours. The
mix~ure was concentrated. The residue was dilu~ed with water
~nd the mi~ture acidl~ied with concentrated hydrochlGric acld~
The precipitated title compound (4.7 g., 90~), m.p. 237~43
(decomp)9 was recrystallized from acetic acid ~ollowed by 2-
methoxyethanol to give analgtical material, m.p. 252-254 (d~omp).
Anal. Calcd- for ClsH14N602 3
Found: C, 58.16; H~ 4.66~ ~ 27.04.
--.
~ Example 10
. , .
2-(5-Methox~-2-n-Pr9.5~IL ~ ~9~
(5-lH-tetrazo~ pyrimidin~4(~H)-one
In a manner similar to that described ~or ~he preparation
o~ 2-(2-cyclopropylmethoxyphenyl)-5-(5-lH-tetra2O1~1)pyrimid~n-
4(~H~-one in Example 9, the title compound was prepared ~rom
~6-dihydro-6-oxo-2-(5~methox~J-2-n-propo*ypherl~l)pJrimidlrle-5
carbonitrile. The crude procluct was recrystallized ~rom 2-
methoxyethanol to give analytical materLal (65~o) ~ m.p. 257_260.
.,
~ -93
108~3~S;~
15 16N60~: C, 5~.87; H, 4.91; ~ 25 60
Found: C, 54.92, H, 4.90; N, 25~69.
Example 11
2-(2-Isopro ~ ~5-(5 lH-
~ H~~one
intermediate) _
To a solution of ethyl 2-cyano-3-(2-isopropoxybenz~mid~lo)~
acrylate (o~60 g., 1.99 mmoles) in N,M-dimethylformamide (15 ml.)
was added sodium azide (0.159 g., 2.44 mmoles) and ammonium
chloride ~0,131 g., 2.44 ~moles). The mixture was heated at
; 127 for 21 hours. The cooled mixture was poured into lce-
water (400 ml.) and acidi~ied to pH 2 with 6~ hydrochloric acld.
The mixture was ~iltered and the collected solid recrys-tallized
from 2-methoxyethanol to gi~e the tltle co~pound (o.o6 g., 10~),
m.p. 274_277.
Example 12
. '
-~: 2 ~2-n-ProE~ox~h n~ 5-~ tetrazolyl
pyr midin-~ ~ H)-one (illustrat,es sin~le
,, ~!~)
'' ': '
To a coDled (ice bath) solution o~ 2-.n-propoxybenzamidlne
(1.00 g., 5.61 r~noles) in dry N,N-dim~thyl~ormamide ~4 ml.) ~r~s
a~ded ethyl ethoxymethylenecyanoacetate (0.94 g., 5.61 m~oleR), .-
Twenty minute.s later sodl~n azide (0~447 g., 6.88 mmoles) and
ammonium chloride (o.368 g., 6.88 mmoles were added. The ice
-94-
i~ ~ 3~ Sz
bath was removed and the mixture hea1;ed by me~ns of an oil
bath maintained at 127 ~or 30 hours. The cooled mixture was
poured into ice-water (400 ml,) and ac1dified with 6N hydro-
chloric acid~ The collected solid (0.93 g.), m.p. 245-248
(decomp) wao recrystallized from 2-methoxyethanol to give
the title compound (o.69 g., 41~) ~ m.p. 256-257 (decomp).
2- ~ Isopropoxyphen~ 5-(5~1H
~le ~ ced ~
By replacing 2-n-propoxyben2amidine in Example 12 with
2-isopropoxybenzamidine, the tLtle compound was prepared i~
a similar manner. The recrystallized product (38~) had mlp~
282-283 (decomp).
.
ample 14
`:
~ ~ H
tetrazolyl)pyrirnidin ~(3~one . .
~ .
2-(2-n~Propoxyph~nyl)-5-(5-lH-tetrazolyl)pyri~idin-4(3X)-
one (1.03 g., 3.46 rnmoles) was added o~er a period o~ 20 minutes
to a cooled (5) mixture of 70~ nitric acid (1.7 mlO, 26.~ mmoles)
~nd concentrated sulfuric acld (2 ml.). The mi~ture was allowed
to stand at room temperature for 2 hoursl The mixtuxe was poured
onto ice-water (200 ml.). The precipitate was recrystallized
from 2-methoxyethanol to give the title compound ~0.73 g., 61,~
m.p. 251 Z52 (decomp~.
.~
-95-
3~ ~ ~
N70l~: C, 48.98; H, ~.82; N~ 28 56
Found: C, 48.76; H, ~.71; N, 28~47,
~ .
A mixture of 2-(5-nitro-2-n-propoxyphenyl)-5-(5~
tetrazolyl)pyrimidin-~(3H)-one ~5.0 g.) and 10~ palladium-on-
carbon (4.0 g.) in 2-methoxyethanol (900 ml.) was shaken in an
a~mosphere OL hydrogen at an ~nitial pre~sure o~ 3.5 kg./cm for
19 hours. The mixture was filtered and the ~ilt~ate ~vaporated
to dryness to give the title compound (3.6 g~, 79~), m.p. 250-
25~ (decomp). Recrystallization from 2-methoxyethanol gave
analytical material, m.p. 261-262.
Anal. Calcd. for Cll~H15N702 C~ 53-66~ H~ 4-8~-
;~ Found: C, 5~.92; H, 5.04
. .
a~ple 16
,:~
~' 2 ~
i ~ ,.
To a suspension o~ 2-(5 amino 2-n-propoxyphenyl)-5-
(5-lH-tetrazolyl)pyrimidin-4(3H)-one (0.50 g., 1.6 mmoles)
~n acetonitrile (40 ml.) was added 37~ ~orm~ldehyde in water
(1.~2 ml., 16.0 mmoles). Sodium cyanoborohydrid~ (O.~OZ g.,
4.8 mmoles) was then added ~ollo~Jed by ~lacial acetic acid (1.67
~). The suspension was stirred at room temperature ~or 15
-96-
-- , .
, .
~,
. .
~3315~Z
minutes and then heated under re~lux t'or ~ hours. The mixcuxe
was cooled in an icebath. The preclpitate was recr~stallized
from acetonitrile to give the title compound (0.19 g~, 35%)~
m.p. 258-259.
Anal- Calcd- for C16H19N72 C~ 56.29; H~ 5.61; N~ 28-73~
Found: C, 55.92j H, 5.1~2; N, 28.63,
Exa~ple 17
':~
Followlng the general procedures of Examples 1-16, the
following compounds may be prepared b~ use of the appropriate
nitrile starting material. The nitriles a~e either disclosed
in Preparations 52-59 above or are made follo~Ting the general
I methods illustrated therein.
.:
N ~ N
R 6 ~ N
5 ~ ~ N
R2 ~,~ 2
~'
~'
,, -97-
~L~8;3~LS;2
Rl R2 3
2-C1 7
3-OCH3 H H
3-CF3 - H ~-
4-OCH3 H
4-Cl H H
4-CF3 . H H
2-F H H
2-C~2C6H5 H ~1
?-OH El H
2-CH3 H ~ :
2-C2H5 H
2 -C 3M7 H H
2-~H 2CH_ CH2 H }1
2-CH= CH2 H ` H
2 -cyc lopropyloxy H H
2-OCH20CH3 H
,
2-OCH2CHzOCH3 H H
2-CF3 . H H
' 2-OCF3 H ~E
2-OCH2CF3 H H
2-SCH H H
. 2 SC2H5 H H
-N ~\O , H H
~J - H H
H H
....
--98--
','
lO~lSZ
2-NH2 H H
~-~THCH3 H H
2-NHC2H5 H a
2 -N (CH3) 2 ~ ~1
2-COOH H H
2-C02CH3 H ~I
2 2 5 H
CH2c2H H H
2 2 3 H H
O
~ I H H
2 " H H
O
2-C-C2X5 H H
2~ -C-CH3 H H
~0~
2~ C-C6H5 H
2-O-C-CH3 H H
2-O-C~CH2C j,H5 H H
O
2 O C C H H H
,~
2-CH2CH2H H H
2-OCH2-CH-GH~OH H H
: OH
2 2 ~ 2 3 H H
OH
2-OCH2CH2CH20H H H
:
;;'' '
_ 9 9 _
-
~33~iZ
2-OCH3 4-OCH3 M
3-CH3 4-CH3
2 -C 1 5 -C 1 H
2-F 5-F H
3-OCH3 3
2-O-n-C3H7 5-Cl H
5-F }I
.~ 5-~H3 H
: 5 -C 2H5 H . . .
5-CH2CH_ CH2 H
5-CH- C~l H
5-OC2H5 H ~ :
;-O-n-C3H7 H : :.
.~ 5 -OC~ (CH3~ 2 H
5 -OCH2CH = CHz H
. ~ 5-OCH ~CH20C~I3 H
5 -CF3
5-OCF3 H
. 5 H2CF3
5-OH H
,: 5-SCH3 ~1
~ 1 \ / 5 -NHCH3 H
~ .
;f. /~
, 5-N ~O H
' ~ 5-N~ H
, 5-~O H
1 0 0-
r
,~
~383~5;~
2 -O -n-C3H7 5 -NHC ~
S-COOH H
5-CO2cH3 H
S c2C2H5 H
5-OCH2co2H H
~-oCH2C02CH3
5-O-C-~HCH3 H
5-C-CH3 H
. O
' ~ ~ S-C-C2H5 ,
O
,, . 5-NH-C-~6H5
.,., O
:': 5-~:)-C-(~83 ~I
O
5-O-C-CH2C6H5 H
,.' 5-0-C-C6H5
~'. 5-OCH2CH20H
~',1 5-OCH2-CH-C~120
,.~ OH
,. / 5-OCH2-CH-C}I~OCH3 H
', OH
.,
~';
~, .
'`''' -101-.
~;~
.~..... . .
~33:~5~
2 O-CEI(CH3)2 5-OCH3
5-OC2H5 H
5-O-n-C H H
5-OCH(CH3)2 H
OC 2 CH2 H
\ / 5-CF3 H
2-OC2H5 5-OCEI3 H
2-OC2H5 5-OC2H5 H
2-OC2H5 5-O-n-C H H
2-OC2H5 5-OCH(CH3)2 H
2-O-n-C4H9 5-OC2H5 H
2-O-n-c4~9 5-O-n-C H H
2-O-n-C4H9 5-OCH(CH3)2 H
3-OCH3 4-OCH3 5-OCH3 ~ ;
.1 .
! : :
;' Example 18
2-(2-n-Propoxyphenyl)-5-(5-lH-
tetrazolyl?pyrimidin-4(3H)~one Sodium Salt
~;~ A slurry of 2-(2-n-propoxyphenyl)-5-(5-lH-tetrazolyl)-
pyrimidin-4(3H)-one (298 mg., 1 mmole) in water (10 ml.)
was treated with lN sodium hydroxide (1 ml.). The resulting
solution was filtered. The filtrate was reduced in volume
7j and treated with acetone. The slurry was stirred for 20
minutes. The sodium salt was collec-ted by filtration, ~'
washed with acetone, dried, and allowed to stand exposed
; to the atmosphere for 1 week.
, - 102 -
s~ : "
' . :
:~ "
, . ... .
~ ,: , .
iL5;~
Anal. Calcd. for C14H13N6NaO2 2H20: C, 47.19; H, 4.81;
N, 23.59; H20, 10.11.
Found: C, 47.37; H, 4.55;
N, 24 54; H20, 11.70.
Replacement of the 2-(2-n-propoxyphenyl)-5-(5-lH-
tetrazolyl)pyrimidin-4-(3H)-one in the above procedure with
an equimolar weight of the other 5-~5-lH-tetrazolyl)pyrimidin-
4(3H)-one co~pounds prepared in Examples 1, 3-11, and 13-17
above gives the correspondin~ sodium salts for each of the
named compounds.
Replacement of the sodium hydroxide in the above
procedure with other bases, e.g. KOH, Ca(OH)2, Mg(OH)2, or
NH40H, gives the corresponding base addition salts.
The 5-(5-lH-tetrazolyl)pyrimidin-4(3H)-one com-
pounds prepared in Examples 1-17 may be converted to their
;` acid addition salts by addition of a stoichiometric equi- ~ -
valent of a suitable acid, e.g. HCl, HBr, HI, CH3COOH or H3P04,
; to a methanolic solution of the desired pyrimidin-4(3H)-
~, one compound.
_ample 19
Ethanolamine Monohydrate Salt of 2-(2-n-
Propoxyphenyl)-5-(5-lE-tetrazolyl)pyrimidin-
4(3H)-one
Freshly distilled ethanolamine (141.6 g., 2.32 moles)
Z,'~l
was added to a stirred suspension of micropulverized 2~(2-n-
propoxyphenyl)-5-(5-lH-tetrazolyl)pyrimidin-4(3H)-one (671.4 g.,
, 2/25 moles) in distilled water (7 1). Stirring was continued
at 40 to effect almost total solution. The mixture was
' - 103 -
':
.
Z'', ~' ~.' ' '
~, ~' " :,, ' ~ . , . '
,
33~52
Eiltered and the filtrate lyophilized ~o leave the title
compound (831.4 g., 98%), m.p. 145-148.
14 14N6O2 C2H7NO-H2O: C, 50.92; H, 6.14;
N, 25.98; H2O, 4.77.
Found: C, 50.71; H, 6.09;
N, 26.18; H2O, 5.64.
" , ~ ,' :
Example 20 ~ -
Ethylenediamine Dihy _a e Salt of 2-(2~n-
Propoxyphenyl)-5-(5-lH-tetrazolyl)pyrimidin
104(3H)-one
; Ethylenediamine (0.625 g., 0.0104 mole) was added
to a stirred suspension of 2-(2-n-propoxyphenyl)-5-(5-lH-
tetrazolyl)pyrimidin-4(3H)-one (2.98 g., 0.010 mole) in water
- (30 ml.). Total solution was obtained upon gentle warming.
The solution was lyophilized to leave a quantitative yield
of the title compound m.p. 177 180~, which was allowed to
equilibrate with atmospheric moisture for one month.
Anal. Calcd. For C14H14N6O2 C2H8N2 2
N, 28.41; H2O, 9.13.
Found: C, 48.98; H, 6.21;
N, 29.25; H2O, 8.75.
Example 21
Following the general procedures of Example 19,
... .
but substituting diethanolamine, triethanolamine and tris-
(hydroxymethyl)aminomethane for the ethanolamine used therein,
~.
`the following water soluble salts of 2-(2-n~propoxyphenyl)-5-
,:1
(5-lH-tetrazolyl)pyrimidin-4(3H)-one were prepared;
- 104 ~
,, ~ . . ,
. .
,
83~LSZ
diethanolamine salt~ C14H14N62 C4 11 2
triethanolamine salt, C14H14N6O2 C6H15N 3, p
tris(hydroxymethyl)-
aminomethane salt, cl4G14N6O2 C4H11 3'
Replacement of the 2-(2-n propoxyphenyl)-5-(5-lH-
tetrazolyl)pyrimidin-4(3H)-one in the procedures of Examples
19-21 with an equimolar weight of the other 5-(5-lH-tetrazolyl)-
pyrimidin-4(3H)-one compounds prepared in Examples 1,3-11, and
13-17 gives the corresponding salts for each of the named
compounds.
' ' ~
' .
. ~, .
.'`, ' .
.
. :
5' ~ :
~ 105
i~ :
i~ .
`
- , ' ' , ~:
5 :
,, .. :
~,,
