Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
09~l7
The present invention relates to a novel process for producing
6,7-dimethoxy-4-a~lno-2-~4-(2-furoyl)-1-piperazinyl] quinazoline, a con~iound
having an antihypertensive effect.
This co~ound, which is known as prazosine, is known to have a
strong antih~pertensive effect (Cohen, Journal of Clinieal Pharmacology,
0 (1970) ) ~ e formula of the comp~und is
3 ~ ~rN N - C
N H2
I
Several proeesses have been disclosed in U.S. Patent 3 511 836 for
producing 6,7~dimethoxy-4~amino-2-~4-substituted)-1-piperazinyl] ~uinazo-
lines. One of these processes for pr~ducing pra~osine is to cause 6,7-di-
methoxy-4-amino-2-ehloro_quinazoline to react with (2-fry~yl)-1-piperazine
aeeording to the reaction fornLla below:
)~ + H-N~ - OC ~ ~ pr~ osine
:~ 20 2
:~ .
Duteh Patent 7206067 discloses another process for producing,
among other things, prazosine, and aecording to this proeess 3,4-dimetho~y-
6-aminobenzonitrile is caused to reaet with l-eyano-4-~2 furoyl)-piperazine
according to ~he reaction fornNla below:
G 3 ~ H2 ~ O
3 ~ NC - N N - OC ~ ~ prazos ne
-2-
117
One prior art process for producing prazosine is illustrated
by the reactin ~ormula below:
C 30 ~ ~ ~ ~ ~rdZoS~e
NH NH NH NH
where Q = CN or C and A = CN, C ~ ~ C\ or C
2 NH2 OR SR
in which case R = an alkyl with 1-6 carbon atoms; however,
when Q is CN, A is c~NH or C~'NH
~ OR ~ SR
An object of a principal aspect of the present invention is to
provide a new process for producing prazosine, differing from previously
known processes Ln the resEeot that the formation of the quin201ine ring
occurs within the ~lecule to form the final oo~po,und ana not, as in kncwn
processes, in a reaction between two different m~lecules.
The proce~s accor,ding ~o a broad aspect of this Lnvention for ErO-
ducing prazosine9 6,7-dimetho~y-4-amino-2- r4- (2-furoyl)-1-piFerazinyl~
zollne, ~ rises: re~ct ~ 3,4 ~ imet ~ -6-~4-~2-furoyl)-1-piperazinyl-
thiocarbanido~benzonitrile, having the formLla
. .
CH30~NH ~ N ~ OC
CH30 CN II
with methyl iodide~ to fonm methyl N-(3~4-dimethlxy-6-cyanophenyl)-~4-(2-
furoyl)-l-pip~razinyl]-thioformamidate, having the ~ornNla
-- 3 --
~0Y~Z~l~
~,
CH3~N=~--.'\1 N - O
CH3 o CN
III,
and cyclizing such compound (III) by heating it, together with ammonia, in
a polar solvent in the presence of alkali metal amide.
By one variant of this process, the reaction of the compound hav-
ing formula (II) with methyl iodide is performed in formamide, in N,N-
dimethyl formamide, in bis-methoxyethyl ether (diglyme), or in a mixture
of such solvents, at 50-100C.
By another variant, the cyclization is performed in formamide or
in N,N-dimethyl formamide at 100-150C, using 1-3 equivalents of an alkali
metal amide.
By yet another variant, the reaction of the compound having for-
mula II with methyl iodide and the cyclization of the compound having
formula III is performed continuously in one and the same solvent without
separating the intermediate products.
The compound 3,4-dimethoxy-6-E4-(2-furoyl)-1-piperazinyl-thio-
carbamido]benzonitrile (II) used as the initial substance is a new com-
pound; Processes for the production of this compound having formula (II)20
are disclosed and claimed in copending Canadian application Serial No.
293,066 filed Dec. 14, 1977. However, in summary, such compound can be
prepared starting from 3,4-di-methoxy-6-aminobenzonitrile and 1-(2-furoyl)
piperazine, using the processes illustrated by the reaction formulas
below:
-- 4 --
~z~
Cll 30~ CS C 12 3 ~ NCS
CH30 CN C~13~) CN
IV V
.~ V I I V I
r~ ~
CH30~NH- I - N N - OC
CH30 CN
II
HN~I--OC ~ ~ Cl-~-N~I OC
VI VII
~ ccording to the first alternative, 3,4~dimethQxy-6-amino-benzoni-
trile tIV) is first allowed to react with thiophosgene to fonm 3,4-dimethQxy-
6-isothiocyanatobenzonitrile ~l), an~ then further with 1-(2-furoyl) pipera-
zine ~I) to form 3,4-dimethoxy-6-~4--(2-furoyl)-1-piperazinylthiocarbamido]
benzonitrile ~II). Alternatively, oQ~pound II can be produced by allowing
1-(2-furoyl~pip2razine ~VI) to react first with thiophosgene to form acid
chloride VII, and thereafter with 3,4-d~methcxy-6-amunobenzonitrile (IV~.
As disclosed above the prccess according to one aspect of the in-
vention can also be carried out so that the production o~ prazosine starting
fm m 3,4-dimetho~y-6-~4-~2-furoyl)-1-piperazinylthiocarb~mido]benzanitrile
(II), (even starting from 3,4-di~methcxy-6-isothiocyanato~enzonitrile ~V)),
can be perfoLmed continuously in one and the same reaction vessel and in cne
' - ~ a,
~Zl~IL7
in one and~the sc~me solvent, e.g. Eormamide, without separatiny the inter-
mediate products.
me followin~ examples will illustrate various a~pects of the
invention.
- 4 b -
1[39Z~7
r`xamp:Le 1
a) 3,4-dimethoxy-6-isothiocyanatoben7Onitri:Le (V)
27,0 ~ (0.15 mo:Le) o~ 3,4-~i~nethoxy-6-~tlinol-x~n%onitr:ile (IV) is
dissolved in 150 ml of 1,2-dichloroethane~ anrl added cJradually
at 0-5C to a rnixture which contains 23.0 g (0.2 mvle) of
thiophosc3ene, 100 ml of 1,2-dichloroethane, 20.0 cJ (0.2 mole)
of calcium carbonate, and 200 ml oE water. After this addition,
the mixture is stirred for 1 hour at 0-5C, thereafter for 16
hours a-t 20C, and finally Eor 1 hour at 35C. The reaction
mixture is ~ tered and the dichloroethane layer separa-ted,
washed with dilute hydrochloric acid and wa-ter, and dried with
MqSO~. The solvent is removed in vacuum, and the crystalline
residue (m.p. 126-127C) is used as such for the nex-t s-tage. The
yield is 31.0 g (94~ of the -theoretical) of 3,9-dimethoxy-6-
isothiocyanatobenzonitrile.
C10I~8N22S calc. C = 54.53 Obs. C = 53.43
El = 3.66 l-l = 3.78
N = 12.72 N = 12.18
S = 14.56 S = 13.79
b) 3,4-dimethoxy-6-i4-(2-furoyl)-1-piperazinylt}liocarbamidol-
benzonitrile (II)
11.2 g (0.051 mole) of 3,4-dimethoxy-6-isothiocyanatobenzonitrile
(V) is dissolved in 65 Ml of ethyl acetate and added ~radually,
while stirring , at 0C to a solution which contains 9.2 g
(0.051 mole) of 1-(2-furoyl)-piperazine in 65 ml of ethyl
ace-tate. The solution is allowed to stand overnight at -25C,
whereby the product crys-tallizes. It is filtered and the crys-tals
are washed wi-th cold ethyl acetate and dried. The yield is 16~3 g
(80~ of the theoretical) of 3,4-dimethoxy-6-14-(2-furoyl)-
l-piperazinylthiocarbamidolbenzonitrile. M.p. 178-180C.
19 20N4O4S Calc. C = 56.99 Obs. C = 57.41
H = 5.03 H = 5.39
N = 13.99 N = 14.14
S = 8.01 S = 7.68
. ~
092~
_ample 2
3~4-dimethoxy-6-l4-(2-Euroyl)-]-piperaz:inylth:iocar~amido~benzo-
nitrile (IL)
5.0 C3 (0.02~ moJe) of 1-(2-Euroyl)piE)erLlzirle (VI) and 2.33 ~3
(0.028 mole) of triethylamine are dissolvecl in 60 ml of
dichlorometlla1le. 'rhis solution is addecl, while stirrinc3 , at
approx. 0C to a mixture which contains 3.~ g (0.0336 Mole)
of thiophoscJene in 50 mJ of dichloromethane. After this addition,
the mixture is stirr~d for Z hours at 0C and for 3 hours at
room -temperature. The triethylamine hydroch]oride is filtered
off, and the solution is completely evaporated in a vacuum. The
residue, 9-(2-furoyl)piperazinyl-thiocarbonyl chloride (VII),
is redissolved in 50 ml of dichloromet}lane and added, while
aqitating, at 0C to a solution which contains 4.98 g (0.028 mole)
of 3,4-dime-thoxy-6-aminobenzonitrile (IV) and 2.83 ~ (0.028
mole) of triethylamine in 60 ml of dichloromethane. The mixture
is~agitatecl for 2 hours a-t 0C and thereaE-ter for 2 3 hours
at room tempera-ture. The triethylamine hydrochloride is filtered
off, and the solution is washed with water, dried with M~SO4,
and completely evaporated in a vacuum. ~thyl acetate is added,
the mix-ture is cooled -to -25C and filtered. I'he yield is 6.2 g
(55% of the theore-tical) of 3,4-dimethoxy-6-[4-(2-furoyl)-1-
piperazinylthiocarbamidoJbenzonitrile. M.p. 175-178C.
Exam~le 3
a) Methyl N-(3,4-dimethoxy-6-cyanophenyl)-14-(2-furoyl)-1-
piperazinyl~thioformamidate hydrolodide (III-HI)
20;0 C3 (0.05 mole) of 3,4-dimethoxy-6-l4-(2-furoyl)~l-
piperazinylthiocarbamido~benzonitrile is dissolved in 200 ml of
bis-methoxyethyl ether (diglyme), and 14.2 ~3 (0.1 mole) of
methyl iodide is added. The mixture is refluxed for
9 hours at 60C. The solution is cooled to room
temperature and filtered. The crys-talline reac-tion product is
washed with ether al-d dried. The yield is 24.6 c3 (90~ of the
theoretical) of methyl N~(3,4-dimethoxy-6-cyanopllenyl)-l4-(2-
furoyl)-l-piperazinyll-thioformami-:late hyclroioclide. M.p. 163C.
~09Z~i7
C20H23IN404S Calc. C - 44.29 Obs C = 44.25
H = '~.27 ~ ~ 4.26
I = 23.39 I = 22.93
N = 10,33 N = 9.61
S = 5.91 S = 5.58
b) Methyl N~(3l4~dimethoxy-6-cyanophenyl~r4~(2~furoyl)-l~piperazinyl]thio-
formamidate (III)
62.0 g (0.114 mole) of methyl N-(3,4~dimethoxy~6~cyanophenyl)~[4-(2-
furoyl)~l~piperazinyl]thioformamidate hydroiodide i9 dissolved at 0~5C
in 350 ml of methanol, and 186 ml of a 25 % ammonia solution is added,
while stirring. The mixture is agitated for 2 hours at 0C, filtered, and
washed with ether. The yield is 42,7 g (90 of the theoretical) of
methyl N-(3,4~dimethoxy~6~cyanophenyl)~r4~(2-furoyl)~l~piperazinyl]~
thioformamidate. M.p. 105~107C. ,
20 22N44S Calc. C = 57.95 Obs. C = 58.01
H = 5.36 H = 5.54
N = 13.52 N = 13.73
S = 7.73 S = 7.53
c) 6,7-dimethoxy-4~amino~2 [4~(2~furoyl)-l~piperazinyl]~quinazoline (I)
7.0 g (0.017 mole) of methyl N~(3,4~dimethoxy-6-dyanophenyl)~~4-(2-furoyl)-
l~pipera~inyl]thioformamidate is dissolved in 100 ml of formamide, and
2.0 g (0.051 mole) of sodium amide is addedO The solution is saturated
wlth NH3 gas at 0C. The temperature of the solution is rised slowly to
120 C, and it is heated for 24 more hours at this temperature, in th~ stream
of NH3 gas. The cooled reaction mixture is poured into 100 ml of ice
water and extracted 6~7 times with 50 ml of chloroform. The chloroform
extract is washed 4 times with 50 ml of water, dried, and completely
evaporated in a vacuum. The product is crystallized from an ethanol~
water mixture (50:15). The product is 6,7-dimethoxy-4-amino~2-[4~(2-
2~L~iL7
furoyl)-l-piperazinyl.]-qu:Lnazollne, M.p. 262-264C. The IR and NMR
spectra of the product are identical ~7ith the spectra of the compound
produced by processes prevlously described in literature.
- 7 a -
Z~l~
19 21 5 4 Ca]c. C = 59.52 Obs. C = 59.28
Il = 5.52 ll = 5.88
N = 18.27 N = 17.99
Example 4
6,7-dimethoxy-4-amino-2-14-(2-furoyl)-1-piperazlnyllquinazoline
(Ij
9.7 g (0.044 mole) of 3,4-dimethoxy-6-iso-thiocyanatobenzonitrile
(V) is suspellded in :100 ml oE formamide, and to this suspension
is added CJI. adually, while stirring, at room temperature
7.9 y (0.044 mole) of 1-(2-furoyl)piperazine (VI) dissolved in
65 ml of formamide. After this addition, the stirring is
continued at room temperature until all of -the 3,4-dimethoxy-
6-isothiocyanatobenzonitrile is dissolved (3-4 hours). There-
after 12.5 g (0.088 mole) of methyl iodide is added to the
mixture and the mixture is heated for 9 hours at 60C. Excess
methyl iodide is removed by evaporating and the solution is
satura~ted with Nl13 gas at 0C, and 6.9 g (0.176 mole) of
sodium amide is added to the solu-tion. The ternperature is
rised to 120-l90C, and the so]ution ls heated for 24 hours
at this-te~lr~erature, in ~le stream of NE13 cJas. The cooled reaction
mixture is poured into ice water (approx. 150 ml) and extracted
using chloroform (8 x 50 ml). The chloroform extract is washed
with water, treated wi-th activa-ted carbon, dried, and completely
evaporated in a vacuum. The resiclue is crystallized from an
ethanol-water mixture (50:15). The product is
6,7-dimethoxy-4-amino-2-14-(2-furoyl)-1-piperazinyl]quinazoline.
M.p. 263-265C.
-- 8 --
