Note: Descriptions are shown in the official language in which they were submitted.
CYANOCARBOXAMIDINES AND QU:[NAZOLINE PROCESS
I. Description:
TECHNICAL FIELD
This invention relates to new and useful N-cyano-
N'-phenylcarboxamidines and to their chemical method of
preparation. More particularly, the instant invention is
concerned with use of the novel carboxamidine compounds as
starting material for a one-step synthesis of antihypertensive
agents such as the various 4-amino-2-(4-substituted
piperazine-l-yl)quinazolines described in U.S. Patents
3,511,836; 3,669,968; 4,001,237; 4,001,238; and 4,101,548; and
the 2-(4-substituted homopiperazino)-4-amino-6,7-dimethoxy-
quinazolines of U.S. Patent 3,920,636.
BACKGROUND OF PRIOR ART
F. H. S. Curd, et al., J. Chem. Soc. 1759 (1948)
describes a procedure for the preparation of 2,4-dichloroquina-
zolines. As illustrated below, the Curd, et al. process
involves cyclization of an ortho-ureido derivative (1) of
various aromatic acids, amides, nitriles and esters with
aqueous base or acid to form a 2,4-(lH,3H) quinazolinedione
(2) which is chlorinated to the 2,4-dichloroquinazoline (3).
3 ~ " ~ CH3 ~ N ~
NHCNH2 / H
(1) Cl ~ (2)
CH30 N
C 3 ~N /J\ C~
(3)
The foregoing procedure of Curd, et al. had been employed in
the preparation of various quinazolines disclosed in Hess,
U.S. Patents 3,511,836 and 3,669,568; Cronin, U.S. Patent
3,517,005; Partyka, et al., U.S. Patents 4,001,237; 4,001,238;
and 4,060,615.
Hess U.S. Patent 3,935,213 describes a process for
preparing quinazolines illustrated by formula (6) which
involves the use of compounds of formulas (4) and (5) as set
forth below.
CH3O ~ / Q A-N
3 ~ NH2
R (5)
NH2
,J` '-- /~ V
(6)
- 2 -
8 1 7'
-3-
German Patent 2,261,739 (1974) (See Chem. Abs. 81,
84394q (1974)) discloses the following synthesis of
quinazolin-2,4-dlones:
R~ ~ NHR2 + ClCNC0 ~~~~ ~ ~
Z. Budesinsky, et al., Coll. Czech. Chem. Commun., 37,
2779 (1972) report that treatment of 1-aryl-3-acylureas (7) with
polyphosphoric acid yields 4-aroyl (or alkyl)-2-(lH)-quin-
azolinones (8). R2
RL~`~CNHCR~ > ~
(7) (8)
W. Ried, et al., Chem. Ber., 109, 2706 (1976) (Chem. Abs.
(1976)) describes the reaction of chloroformamidines of
formula (9) with cyanamide derivatives of formula (10) to
yield 4-amidino-quinazolines of formula (11).
N-C-NH.
R - ¢ . ~ . _~ R
(~) (10) (11)
17'
--4--
The process of the instant invention for preparing
quinazolines characterized by formula (I) below and the Ried,
et al. procedure set forth above differ sisnificantly in a
number of respects. In the Ried, et al. procedure, the cyano
nitrogen in the cyanamide derivative (10) becomes part of the
quinazoline ring (i.e., the number 3 position) whereas in the
instant invention, the cyano nitrogen of cyanamide becomes
the 4-amino group attached to the quinazoline ring.
BRIEF SUMMARY OF INVENTION
Broadly described, this invention is concerned with a new
process for the preparation of antihypertensive quinazolines
generally typified by formula I
A NH~
~. ,f J ~ I - R~ (I)
The instant process involves a one-step conversion of novel
piperazinyl substituted N-cyano-N'-phenylcarboxamidines to
formula I quinazoline products.
DETAILED DESCRIPTION OF INVENTION
As indicated hereinabove, one aspect of the instant
invention is concerned with a process for preparing quinazoline
compound of formula I
8117
--5--
A NH,
~\~--R,
(CH2) n
wherein
n is equat to 2 or 3;
A is hydrogen or lower alkoxy of 1 to 4 carbon atoms
inclusive;
8 and C are independently selected from the group consisting
of lower alkoxy of 1 to 4 carbon atoms inclusive;
Rl is selected from the group consisting of lower alkyl of
from 1 to 6 carbon atoms inclusive; R2CO in which R2 is
cycloalkenyl, cycloalkyl, methylcycloalkyl in which
cycloalkyl and cycloalkenyl are from 3 to 8 carbon atoms
inclusive; hydroxyalkoxy from 2 to 6 carbon atoms
inclusive or phenyl; and ZC=O in which I is a hetero-
cyclic radical selected from the group consisting of
Ra
t ~d
' ~} Re and ~ Re
in which X is either oxygen or sulfur, Ra is lower
alkyl of 1 to 6 carbon atoms inclusive, Rb is
selected from the group consisting of hydrogen,
11~1817
--6--
amino, lower alkyl of 1 to 4 carbon atoms inclusive
and NHC02Rc in which Rc i~i lower alkyl of 1 to 4
carbon atoms inclusive, R~ and Re are independently
selected from the group consisting of hydrogen,
lower alkyl of 1 to 6 carbon atoms inclusive, lower
'! alkoxy of 1 to 6 carbon atoms inclusive, and lower
alkylthio of 1 to 6 carbon atoms inclusive
which comprises cyclizing a cyanocarboxamidine of formula II
B 1~ (Cl~ n
wherein the symbols "A, B, C, n and Rl are as recited above.
Preferred embodiments of the foregoing process for the
preparation of compounds characterized by formula I are those
wherein;
(a) The compound of formula II employed in 4-methyl-
piperazine-l-~N-cyano-N'-(3,4-dimethoxyphenyl)]-
carboxamidine;
(b) The compound of formula II employed is 4-(2-furoyl)-
p;peraz;ne-l-~N-cyano-N'-(3,4-dimethoxyphenyl)~-
carboxamidine;
(c) The compound of formula II employed is 4-(5-methylthio-
1,3,4-oxadiazole-2-carbonyl)piperazine-1-[N-cyano-N'-
~3,4-dimethoxyphenyl)]carboxamidine;
(d) The cyclization process is carried out by treating
the compound of formula II with phosphorus trichloride
or phosphorus pentachloride in a solvent amount of
phosphorus oxychloride;
(e) The cyclization process is carried out by treating the
co~pound of formula II with phosphorus tribromide or
phosphorus pentabromide in a solvent amount of
phosphorus oxybromide;
(f) The cyclization process is carried out by treating
the compound of formula II with aqueous hydrochloric
acid;
(g) The cyclization process is carried out by treating
the compound of formula II with hydrogen chloride
in phosphorus oxychloride;
(h) The cyclization process is carried out by treating
the compound of formula II with a Lewis acid catalyst;
(i) The cyclization process is carried out at a temperature
of 25-125;
(j) The cyclization process is carried out at a temperature
of 70-100;
(k) The cyclization process is carried out for a period of
1 to 3 hours at a temperature ;n the range of 70-100.
A preferred embodiment of the present invention is a process
for the preparation of a quinazoline of formula Ia
N~2
CH30 ~A ~ ~Ia)
C~130 N ~/N-C
11'~1~1 7
which comprises cyclizing a cyanocarboxamidine having formula IIa
CX30 ~ NC-NH ~ 0 ~ (Ila)
CH30 ~ N=C- N-C - 0
Another preferred embodiment of the present invention is
the process for the preparation of a quinazoline of formula Ib
N~
CH30 ~ ~ ~ -C ~ 0 ~ -CH3
which comprises cyclizing a cyanocarboxamidine having formula
S IIb
CH30 ~ NC-NH o r ~ (IIb)
CH,0 ~ N-C - ~ -C o ~ S-CH3
Another preferred embodiment of the present invention is
a process for the preparation of a quinazoline of for~ula Ic
NH~
CH30 ~ ~0~ r 1 (Ic)
CH30 ~ ~ ~ -C ~
~ L8~7
which comprises cyclizing a cyanocarboxamidine having formula IIC
CH30~ NC-NH ~\ O
CH30--~!LN=C~ C~ (IIc)
Another preferred embodiment of the present invention is the
process for the preparation of a quinazoline of formula Id
~1
Cd 3 ~N O OH
CH30~ J{~-COCHZC(CH3), (Id)
OCH3
which comprises cyclizing a cyanocarboxamidine having formula IId
CH,O~ NC-NH O OH
CH,O~LN-C-N/~I-COCH~ C(CH,) z (lId)
OCH3
Preferred groups of compounds contemplated within the class
of cyanocarboxamidines of formula II are those wherein:
(a) the A, B and C substituted phenyl radical is 3,4-
dimethoxyphenyl, n is 2, or 3 and Rl is selected
from the group consisting of methyl, cyclopentyl,
2-furoyl, 5-methylthio-l,3,4-oxadiazole-2-carbonyl,
2-methyl-2-hydroxypropoxycarbonyl;
(b) The A, B and C substituted phenyl radical is 2,3,4-
trimethoxyphenyl, n is 2 or 3 and Rl is selected
from the group consisting of methyl, cyclopentyl,
1~1817
--1 o--
2-furoyl, 5-methylthio-1,3,4-oxadiazole-2-carbonyl,
2-methyl-2-hydroxypropoxycarbonyl.
Particularly prepared cyanocarboxamidines of formula II are:
4-methylpiperazine-1-[N-cyano-N'-(3,4-dimethoxyphenyl)]-
carboxamidine;
4-(2-furoyl)piperazine-1-[N-cyano-N'-(3,4-dimethoxy-
phenyl)]carboxamidine;
4-(5-methylthio-1,3,4-oxadiazole-2-carbonyl)piperazine-1-
[N-cyano-N'-(3,4-dimethoxyphenyl)]carboxamidine;
4-(2-methyl-2-hydroxypropoxycarbonyl)piperazine-1-[N-cyano-
N'-(2,3,4-trimethoxyphenyl)]carboxamidinei
4-(cyclopentylcarbonyl)piperazine-1-[N-cyano-N'-(3,4-
dimethoxyphenyl)]carboxamidine;
4-(2-furoyl)homopiperazine-1-[N-cyano-N'-(3,4-dimethoxy-
phenyl]carboxamidine
It is to be understood that the term "cycloalkyl" as used herein
includes cycloalkyl radicals containing 3 to 8 ring carbon atoms
inclusive and encompasses such groups as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The
term "methylcycloalkyl" refers to the aforementioned cycloalkyl
radicals containing from 3 to 8 ring carbons inclusive having
a methyl substituent and encompasses such groups as l-methyl-
cyclopropyl, l-methylcyclopentyl, 2-methylcyclopentyl, 3-
methylcyclopentyl, l-methylcyclohexyl, 2-methylcycloheptyl,
4-methylcyclohexyl, and the like. By the term "cycloalkenyl",
it is intended to refer to those having from 4 to 8 ring carbon
atoms inclusive containing a single ring carbon-carbon double
bond encompassing such groups as l-cyclobutenyl, l-cyclopentenyl,
2-cyclopentenyl, 3-cyclopentenyl, l-cyclohexenyl, 2-cyclohexenyl,
and the like.
It is also to be understood that by the terms "lower
alkyl" and "lower alkoxy", as used herein, it ;s meant that
the carbon chain which comprises these groups include both
straight and branched carbon radicals of the designated number
of carbon atoms inclusive. Exemplary of carbon chain radicals
have 1 to 4 carbon atoms inclusive are methyl, ethyl, propyl,
isopropyl, l-methylpropyl, 2-methylpropyl, and tert.-butyl.
By the term "independently selected", as used herein, it
is meant that the recited substituents such as A, B, C, Rd and
! Re may or may not be identical.
Conversion of formula II carboxamidines to quinazolines of
formula I is carried out by treating the formula II carboxamidines
with cyclizing reagents such as phosphorus trichloride or
phosphorus pentachloride in a solvent amount of phosphorus
oxychloride. Other phosphorus halides and phosphorus
oxyhalides such as phosphorus tribromide and phosphorus
pentabromide in a solvent amount phosphorus oxybromide may be
employed. Ring closure of the carboxamidines of formula II to
the quinazoline compounds of formula I is acid catalyzed with
reagents such as aqueous hydrochloric acid, hydrogen chloride
in phosphorus oxychlor;de, trichloroacetic acid or Lewis acid
catalyst such as ZnC12, FeC13, AlC13, AlBr3, and the like.
With respect to carrying out the reaction with phosphorus
halides, approximately equimolar portions of the formula II
carboxamidines and phosphorus halides are employed with a
convenient solvent amount of phosphorus oxyhalide relative to
the amount of carboxamidine starting material. The ter~
"solvent amount" used herein, refers to a quantity of phosphorus
oxychloride or phosphorus oxybromide sufficient to provide
good mixing and handling characteristics with respect to the
reaction mixtures. For this purpose, a ratio of from about
2 to 15 ml. of the phosphorus halide for each gram of the
carboxamidine reactant of formula II is generally preferred.
Commonly used temperatures for carrying out the cyclization
reaction range from about 25-125 with a particularly preferred
temperature range of from about 70-100. As will be appreciated
17
-12-
by those skilled in the art, reaction tlme and conditions
required for cyclization of the compounds of formula II and
formation of the compounds of formula I vary according to several
factors such as temperatures and reaction times. For instance,
at lower temperatures, long reaction periods are needed,
while at higher temperatures, the cyclization reaction is
completed in a shorter time. Reaction periods from about 0.5
to 24 hrs. can be used with a period of 1.0 to 3.0 hrs. preferred
at a temperature in the range of about 70-100 .
During the cyclization reaction of the formula II carbox-
amidines, the cyano carbon acts as a carbonium ion forming a
carbon-carbon bond with the benzene nucleus thereby establishing
the quinazoline ring while the cyano nitrogen becomes the
quinazoline 4-amino group.
The carboxamidines of formula II used as starting materials
in the instant process for preparation of quinazoline compounds
of formula I are themselves new compounds which are prepared
by
(a) treating the corresponding urea or thiourea of
formula III
NH-C~ i-R, (III)
C CH2);,
wherein the symbols "A, B, C, n, and Rl'' are as
recited above and Y is sulfur or oxygen with an
R-X alkylating reagent in which R is lower alkyl
ll'~i817
--1 3--
of 1 to 4 carbon atoms inclusive or an aryl
derivative containing electron withdrawing
groups (e.g., 2,4-dinitrophenyl), X is halogen
(e.g., Cl, Br, and I), lower alkyl S04 of 1 to 4
carbon atoms inclusive, phenyl S03, F3CS03, and the
`! like to provide a hydrohalide intermediate of formula IV
A~
C NR~C - N/ ~ -~ (Iv)
wherein the symbols "A, B, C, n, R, Rl, X and Y"
are as recited above, and then
(b) reacting the halide intermediate IV with cyanamide
to provide carboxamidines of formula II.
Alkylation of urea and thiourea starting materials of
formula III and subsequent reaction with cyanamide is normally
carried out in a reaction inert organic solvent. Suitable
solvents include dioxane, tetrahydrofuran, dimethyl sulfoxide,
diethyl sulfoxide, and alkanol solvents such as methanol,
ethanol, or isoamyl alcohol. The reaction can be conducted
at temperatures vary;ng within the range of from about 25 to
100C. for a period of about 0.5 to 24 hrs.
In addition to the above process, alternate methods for
preparing carboxamidines of formula II can be employed as
depicted in the reaction schemes below.
317
,~
Method A
A
~,
3--t
--NH2 + (CH3S) 2C-~C~ 7
, C
(V)
A ~ N-Rl
B ~L " For~ula Il
(VI)
Method B
r~ '
}~N-Rl I (CH3S) 2C=NCN
(VII)
A>~::~
B ~LH2
.lC-N ~
Fo~mula I I
, \_J
(VIII)
3~ 7
-15-
Thus, reaction of (CH3S)2C=NCN or chemical equivalents thereof
with formula V anilides or formula VII piperazines wherein the
symbols "A, B, C, n and Rl" are as previously defined provide
cyano intermediates VI and VIII, respectively. Treating the
cyano intermediate VI with a piperazine of Formula VII or
the cyano intermediate VIII with an aniline of Formula V
affords the formula II carboxamidines.
The formula III urea and thioureas are obtained by reacting
appropriately substituted phenylisocyanates and phenyl-
isothiocyanates with N-substituted piperazines and homopiperazines
in an inert reaction solvent such as ethanol. Required piperazine
and homopiperazine starting material is obtained by conventional
procedures; e.g. acylation of piperazine or homopiperazine with
o
ZCCl wherein Z is as previously defined.
In addition to being useful intermediates in the preparation
of the compounds of formula I, the carboxamidines of formula II
are also valuable for their anti-ulcer properties, for instance,
4-~2-furoyl)piperazine-l-[N-cyano-N'-(3,4-dimethoxyphenyl)]-
carboxamidine and 4-(5-methylthio-1,3,4-oxadiazole-2-carbonyl)-
piperazine-l-~N-cyano-N'-3,4-diméthoxyphenyl]carboxamidine at
a subcutaneous dose of lO mg/kg and 3 mg/kg body weight,
respectively, inhibit acid secretion in the pylorus ligated
rat model of Shray, Gastroenterology, 5, 43 (1946).
The following examples further illustrate the present
invention and will enable others skilled in the art to understand
it more completely. It is to be understood that the invention
is not limited solely to the particular examples given below.
All temperatures expressed herein are in degrees centrigrade.
~ L8 1 7
Example I
4-Methylpiperazine-l-[N-cyano-N'-(3,4-dimethoxyphenyl)]-
carboxamidine
CH 30 ~_ NC-~"d
CH30-- ~=C `;~I-C-~3
(a) A solution of 3,4-dimethoxyphenyl isothiocyanate
(6.8 g., 34.8 mmoles) obtained according to the procedure of
G. M. Dyson, et al., J. Chem. Soc., 436 (1927) in 34 ml. of
absolute ethanol is added to a stirred solution of N-methyl-
piperaz;ne (3.49 9., 30.8 mmoles) in 100 ml. of absolute
ethanol. After heating the solution of reflux for a 2 hr.
period, the solvent is removed under reduced pressure. The
semi-solid residue thus obtained is first crystallized from
toluene to provide 8.95 9. (87% yield), m.p. 156-159.5 of
the carbothioamide intermediate. Crystallization of this
material from nitromethane affords analytically pure 4-
methylpiperazine-1-(N-3,4-dimethoxyphenyl) carbothioamide,
m.p. 158-161.
Anal. Calcd. for C14H21N302S: C, 56.92; H, 7-16; N, 14-23;
S, 10.85. Found: C, 56.74; H, 7.38; N, 14.40; S, 10.90.
(b) Methyl iodide (1.2 9., 0.0303 mole) is added to a
suspension of 4-methylpiperazine-1-(N-3,4-dimethoxyphenyl)-
carbothioamide (8.95 9., 0.0303 mole) in 125 ml. of methanol.
The reaction mixture is then stirred at reflux temperature
for a period of 2 hr. and cooled to 25. Cyanamide (8.7 g.,
0.27 mole) is added to the cooled solution and reflux continued
31 7
-17-
for an additional 16 hr. period. After the solvent is removed
under reduced pressure, residual oil is made strongly basic
with acqueous 4.0 N sodium hydroxide and then extracted with
chloroform. The chloroform extracts are washed with water,
saturated brine solution and dried. Concentration of the
~! dried solution affords a residual gum which when rubbed under
cold toluene provides 4.46 g., (49~ yield) of crystalline
material, m.p. 155-158. Recrystallization from toluene
affords analytically pure 4-methylpiperazine-1-[N-cyano-N'-
(3,4-dimethoxyphenyl)]-carboxamidine, m.p. l60-l63.
Anal- Calcd- for C15H2lN32 C~ 59-3 ;
Found: C, 58.95; H, 6.83; N, 22.35.
(c) Following the procedure of Example l(a), but employing
an equimolar amount of 3,4-dimethoxyphenylisocyanate in place of
lS 3,4-dimethoxyphenylisothiocyanate, there is produced N-(3,4-
dimethoxyphenyl)-4-methyl-l-piperazinecarboxamide. The
carboxamide treated with methyl iodide and then with cyanamide
according to the procedure of Example l(b) provides 4-methyl-
piperazine-l-[N-cyano-N'-(3,4-dimethoxyphenyl)]carboxamidine.
Example 2
4-(2-Furoyl)piperazine-l-[N-cyano-N'-(3,4-dimethoxyphenyl)~-
carboxamidine
CH30--~ NC-NH- 0
CEI30~L N=C~
8 1 7
-18-
(a) A solution of 3,4-dimethoxyphenyl isothiocyanate (3,21 9.,
16.4 mmoles) in 10 ml. of absolute ethanol is added to a stirred
solution of 1-(2-furoyl)piperazine (2.96 9., 16.4 mmoles) prepared
according to the procedure of M. Desai, et al., Org. Prep. Proced.
Int., 8, 85 (1976) in 35 ml. of absolute ethanol and the reaction
solution refluxed for a period of 2.5 hr. Concentration of the
reaction mixture under reduced pressure provides a dark yellow gum
which rubbed under cold ethanol affords 5.39 9., (87% yield) of
yellow solid material, m.p. 183-187. Crystallization of this
material from acetonitrile affords analytically pure 4-(2-furoyl)-
piperazine-l-(N-3,4-dimethoxyphenyl)-carbothioamide, m.p. 185-188.
Anal. Calcd. for C18H21N3045: C, 57.59; H, 5.64; N, 11-19;
S, 8.54. Found: C, 57.23; H, 5.48; N, 11.53; S, 8.54.
(b) To a suspension of 4-(2-furoyl)piperazine-1-(N-3,4-dimethoxy-
phenyl)carbothioamide (22.0 9., 0.0586 mole) in 400 ml. of methanol
is added methyl iodide (8.32 9., 0.0586 mole). The mixture is
stirred and rèfluxed for a per;od of 2.5 hr. and then cooled to 20.
Cyanamide (18.7 9., 0.445 mole) is added to the cooled solution, and
the mixture refluxed for an additional period of 16 hr. and the
solvent evaporated under reduced pressure to provide an oily residuewhich is made strongly basic with aqueous 4.0 N sodium hydroxide.
The basic mixture is extracted with chloroform and the chloroform
extracts washed first with water and then with saturated brine
solution. After drying, the chloroform extract is concentrated
under reduced pressure providing a residual gum which is crystallized
by rubbing under cold ethanol to afford 11.1 9. (49% yield) of
white solid, m.p. 181-183.5. Crystallization of this material from
ethanol provides analytically pure 4-(2-furoyl)piperazine-1-[N-cyano-
N'-(3,4-dimethoxyphenyl)]carboxamidine, m.p. 186.5-188.5.
Anal- Calcd- for C19H21N54 C~ 59-52; H~ 5-52; N~ 18-27-
Found: C, 59.13; H, 5.40; N, 18.07.
(c) Following the procedure of Example 2(a), but employing
equimolar amount of 3,4-dimethoxyphenylisocyanate in place of 3,4-
l7
_19_
dimethoxyphenylisothiocyanate, there is obtained N-(3,4-dimethoxy-
phenyl)-4-(2-furoyl)-1-piperazinecarboxamide. Reaction of the
carboxamide with methyl iodide and then with cyanamide according to
the procedure of Example 2(b) provides 4-(2-furoyl)piperazine-1-[N-
cyano-N'-(3,4-dimethoxyphenyl)]carboxamidine.
!
Example 3
4-(5-Methylthio-1,3,4-oxadiazole-2-carbonyl)piperazine-1-
[N-cyano-N'-(3,4-dimethoxyphenyl)]carboxamidine
CH,O ~ NC-NH O
CH30 ~ ~ =C~ C ~ ~ S-C~I3
(a) 1-(5-Methylthio-1,3,4-oxadiazole-2-carbonyl)p;perazine
hydrochloride (5.29 9., 0.02 mole) is first added to a stirred
solution of triethylamine (2.02 9., 0.02 mole) in 50 ml. of absolute
ethanol followed in 5 min. by a solution of 3,4-dimethoxyphenyl
isothiocyanate (3.90 9., 0.02 mole) in 15 ml. of absolute ethanol
to provide a pale yellow gummy precipitate. The reaction mixture
is heated to reflux (during which time the gum crystallizes), diluted
with 28 ml. of absolute ethanol, refluxed for an addit;onal 3 hr.
period and filtered. The collected material is washed with absolute
ethanol and crystallized from methanol to provide 4.41 9. (52Yo yield)
of 4-(5-methylthio-1,3,4-oxadiazole-2-carbonyl)piperazine-1-(N-3,4-
dimethoxyphenyl)carbothioamide, m.p. 143.5-147.
Anal- Calcd- for C17H21N54S2 C, 48.21; H~ 5-00, N~ 16-54i
S, 15.14. Found: C, 48.28; H, 4.90; N, 16.46; S, 15.19.
(b) Methyl iodide (1.06 g., 7.44 mmoles) is added to a
suspension of 4-(5-methylth;o-1,3,4-oxadiazole-2-carbonyl)-
piperazine-1-(N-3,4-dimethoxyphenyl)carbothioamide (3.15 9.,
7.44 mmoles) in 100 ml. of methanol. The mixture is st;rred at
reflux temperature for a period of 2.5 hr. and the resulting
-20-
solution concentrated under reduced pressure to a wlume of about
60 ml. where a precipitate begins. The mixture is chilled at 0
and filtered to yield 2.93 9. (70%) yield) of 1-~methylthio-EN-(3,4-
dimethoxyphenyl)[iminocarbonyl]-4-(5-methylthio-1,3,4-oxadiazole-2-
carbonyl)-piperazine hydroiodide, m.p. 180.5-185 (dec.). Crystal-
lization from ethanol provided analytically pure hydroiodide inter-
mediate, m.p. 184-187 (dec.).
Anal Calcd. for C18H23N50452 HI: C, 38.24i H, 4-28; N~ 12-39-
Found: 38.49; H, 4.44; N, 12.01.
(c) Cyanamide (0.66 g., 15.7 mmoles) is added to l-Emethylthio-
[N-(3,4-dimethoxyphenyl)]iminocarbonyl]-4-(5-methylthio-1,3,4-oxa-
diazole-2-carbonyl)piperazine (2.44 9., 5.58 mmoles) free base in
35 ml. of absolute ethanol. The mixture is stirred at reflux tem-
perature for a period of 20 hr., cooled in an ice bath and filtered
to provide 1.12 g. (49% yield) of off-white solid, m.p. 175-181.
Crystallization of this material from methanol affords analyt;cally
pure 4-(5-methylthio-1,3,4-oxadiazole-2-carbonyl)piperazine-1-EN-
cyano-N'-(3,4-dimethoxyphenyl)]carboxamidine, m.p. 174-178.
Anal. Calcd. for C18H21N704S: C, 50.12i H, 4-90; N~ 22-73-
Found: C, 50.08; H, 4.73; N, 22.57.
(d) Following the procedure of Example 3(a), but employing
an equimolar amount of 3,4-dimethoxyphenylisocyanate in place of
3,4-dimethoxyphenylisothiocyanate, there is obtained N-(3,4-
dimethoxyphenyl)-4-(5-methylthio-1,3,4-oxadiazole-2-carbonyl)-1-
piperazine carboxamide. Reaction of the carboxamide with methyliodide and then with cyanamide according to the procedures of
Examptes 3(b) and 3(c), respectively, provides 4-(5-methylthio-1,3,4-
oxadiazole-2-carbonyl)piperazine-1-[N-cyano-N'-3,4-dimethoxyphenyl)]-
carboxamidine.
-21-
Example 4
4-(2-Methyl-2-hydroxvpropoxycarbonyl)p;perazine-1-[N-cyano-
N'-2,3,4-trimethoxyphenyl]carboxamidine
CH30 ~ NC-NH ~ OH
CH30 ~ C--101- OCH~C(CH3) 2
OCH3 . ~
Reaction of 2,3,4-trimethoxyphenylisothiocyanate with 1-(2-
methyl-2-hydroxypropoxycarbonyl)piperazine according to the procedure
of Example l(b) provides 4-(2-methyl-2-hydroxypropoxycarbonyl)-
piperazine-l-(N-2,3,4-trimethoxyphenyl)carbothioamide. Subsequent
reaction of the carbothioamide with methyl iodide and then with
cyanamide according to the procedure of Example l(b) accords 4-(2-
methyl-2-hydroxypropoxycarbonyl)piperazine-1-~N-cyano-N'-2,3,4-
trimethoxyphenyl]carboxamidine.
Example 5
4-(Cyclopentylcarbonyl)piperazine-1-~N-cyano-N'-(3,4-
dimethoxyphenyl)]carboxamidine
CH30 ~C~LNC- IH o~--C{l
Following the procedure of Example l(a) but employing an
equimolar amount of N-(cyclopentylcarbonyl)piperazine in place of
N-methylpiperazine, there is produced 4-(cyclopentylcarbonyl)-
piperazine-l-(N-3,4-dimethoxyphenyl)carbothioamide. Reaction of
the carbothioamide with methyl iodide and then with cyanamide
according to the procedure of Example l(b) affords 4-(cyclopentyl-
3~ 7
-22-
carbonyl)piperazine-l-[N-cyano-N'-(3,4-dimethoxyphenyl]carboxamidine.
Example 6
4-(2-Furoyl)homopiperazine-l-[N-cyano-N'-(3,4-dimethoxyphenyl]-
, carboxamidine
C~30 ~ N c---N ~ - c ~
Followin~ the procedure of Example l(a-b) but substituting
1-(2-furoyl)homopiperazine for 1-(2-furoyl)piperazine, the title
compound is obtained.
Example 7
4-Amino-6,7-dimethoxy-2-(4-methylpiperazine-1-yl)quinazoline
dihydrochloride
Phosphorus pentachloride (0.31 9., 1.48 mmoles) is added with
stirring to 10 ml. of phosphorus oxychloride followed in 5 min.
by 4-methylpiperazine-1-[N-cyano-N'-(3,4-dimethoxyphenyl)]-
carboxamidine of Example 1 (0.45 9., 1.48 mmoles). The reaction
mixture is heated at 95-98 for a period of 2.5 hr. during which
time a yellow gum forms and changes to a suspended sol;d by the end
of the heating period. The reaction mixture is then cooled to 30
and excess phosphorus oxychloride removed under reduced pressure to
provide a residual material which is treated cautiously with ice/
water. The aqueous phase is filtered and the filtrate concentrated
under reduced pressure to provide a brown oil which is crystallized
by rubbing under cold acetone. Insoluble material is collected
and crystallized from methanol to afford 0.175 9., 31% yield of
4-amino-6,7-dimethoxy-2-(4-methylpiperazine-1-yl)-quinazoline
dihydrochloride, m.p. 280-282 (dec) identical with the sample
-23-
prepared according to the procedure clescribed in U.S. Patent
3,511,836.
Example 8
4-Amino-6,7-dimethoxy-2-[4-(2-furoyl)piperazine-1-yl]quinazoline
! 5 hydrochloride
Hydrogen chloride gas is bubbled for a period of 8 min. into a
cold, stirred mixture of 4-(2-furoyl)piperazine-1-[N-cyano-N'-
(3,4-dimethoxyphenyl)]carboxamidine of Example 2 (3.0 9., 7.82 mmoles)
in 45 ml. of phosphorus oxychloride. After addition of the hydrogen
chloride gas, the reaction mixture is stirred at 25-30 for 10 min.
and then heated at 70-75 for a period of 75 min. during which time
a gummy solid separates. The reaction mixture is cooled to 30, the
excess phosphorus oxychloride removed under reduced pressure and
residual material rubbed under ice/water to provide a solid. The
sol;d is collected to afford 2.76 9. (84% yield) of 4-amino-6,7-
dimethoxy-2-[4-(2-furoyl)piperazine-1-yl~quinazoline hydrochloride
identical with a sample prepared according to the procedure of U.S.
3,511,836.
Example 9
4-Amino-6,7-dimethoxy-2-14-(5-methylthio-1,3,4-oxadiazole-
carbonyl]piperazine-l-yl]quinazoline hydrochloride
Hydrogen chloride gas is bubbled for a period of 4 min. into
a cold, stirred mixture of 4-(5-methylthio-1,3,4-oxadia7O1e-2-
carbonyl)piperazine-l-[N-cyano-N'-(3,4-dimethoxyphenyl)~carboxamidine
of Example 3 (0.16 9., 0.37 mmoles) in 6 ml. of phosphorus oxychloride
and the mixture then stirred at 25-30 for an additional 8 min.
period and finally heated to 72-75 for a period of 75 min. during
which time a pale yellow solid precipitates. After the heating period,
the mixture is cooled to 30, excess phosphorus oxychloride removed
-24-
under reduced pressure and residual solid rubbed under ice/water
and collected to provide 4-amino-6,7-dimethoxy-2-[4-(5-methylthio-
l,3,4-oxadiazole-2-carbonyl]piperazine-l-yl]quinazoline hydrochloride
in 95% yield identical to a sample prepared according to the pro-
cedure of U.S. Patent 4,00l,238.
Example lO
The cyclization procedure illustrated in Examples l-3 is
repeated with the following cyanocarboxamides:
4-(2-methyl-2-hydroxypropoxycarbonyl)piperazine-l-
[N-cyano-N'-(2,3,4-trimethoxyphenyl)]carboxamidine,
4-(cyclopentylcarbonyl)piperazine-l-[N-cyano-N'-(3,4-
dimethoxyphenyl)]carboxamidine,
4-~2-furoyl)homopiperazine-l-[N-cyano-N'-(3,4-dimethoxy-
phenyl)]carboxamidine,
to produce respectively,
(a) 4-amino-6,7,8-trimethoxy-2-[4-(2-methyl-2-hydroxy-
propoxycarbonyl)piperazine-l-yl]quinazoline,
(b) 4-amino-6,7-dimethoxy-2-[4-cyclopentylcarbonyl)-
piperazine-l-yl]quinazoline,
(c) 4-amino-6,7-dimethoxy-2-[4-(2-furoylhomopiperazine-l-
yl)]quinazoline.
STATEMENT OF INDUSTRIAL APPLICATION
The novel N-cyano-N'-phenylcarboxamidine compounds of this
invention are particularly valuable as intermediates in the pre-
paration of antihypertensive 4-amino-2-(4-substituted-piperazine-
l-yl)-quinazolines. The invention includes the method of preparation
.817
-25-
of the novel N-cyano-N'-phenylcarboxamidines as well as the one step
synthesis of the aforesaid antihypertensive compounds utilizing the
novel N-cyano-N'-phenylcarboxamidines of the invention.
The novel N-cyano-N'-phenylcarboxamidine compounds are also
! 5 valuable in the treatment of ulcers.
