Note: Descriptions are shown in the official language in which they were submitted.
33;~
The present invention relates to a process for preparing 3,4-
dimethoxy-6-[4~(2-furoyl)-1-piperazinyl thiocarbamide] benzon-ltrile and to
the 3,4-dimethoxy-6-[4-(2-furoyl)-l-piperazinyl thiocarbamide] benzonitrile
so formed. Such 3,4-dimethoxy-6-[4-(2-furoyl)-l-piperazinyl thiocarbamide]
benzonitrile is an intermediate product for the production of 6,7-dimethoxy-
4-amino 2-[4-(2-furoyl)-1-piperazinyl]quinazoline (prazosine).
Prazo`sine, whi~h has the formula
;~13 ~r /--\l OC ~~
(I)
is known to have a strong antihypertensive effect (Cohen, Journal of Clini-
cal Pharmacology, 10 (1970).
Several processes for producing~prazosine and compounds of the
same group are now well known in the art. Some of these processes are
described in U.S. Patent 3 511 836, Dutch Pstent 7206067, and German Paten~
Application 2457911. What these processes all have in common is that the -
quinazoline ring is~formed in a reaction between two diferent lecules.
An object of a principal aspect of the present lnvention is to
provide an intermediate produc~t which is suitable for the production of
prazosine and, when started from this product, the formation of the quinazo-
line ring occurs within the molecule, producing the final compound; this pro-
cedure is diferent from prior known process.
The intermediate product according to one aspect of this inven-
tion is 3,4-dimethoxy-6-[4-(2-~uroyl)-l-piperazinylthiocarbamido]benzoni-
trile having the formula
Cll3O ~ ,~ C ~ OC
Cll3O CN
~, `
~ (II)
,~
~ '
3~
The production of prazosine (I) starting from the intermediate
pxoduct ~II) according to an aspect of the present invention can be performed
accordIng to an aspect of this invention disclosed and clai~ed in copending
applicati~n Serial No. 293,065 filed on December 14, 1977,
by causing 3,4-~imethoxy-6-[4-(2 furoyl)-l-piperazinylthiocarkamido]-benzoni-
trile to react with methyl iodide to fo~n methyl N-(3,4-dimethoxy-6-cyano-
phenyl)-[4-(2-furoyl)-1-piperazinyl]-thioeor~amidate having the form~la
C 3 ~ N - C - N ~1 - OC
C1130 `CN
(III)
and this compound is cyclized by hea~lg it, together with amnonia, in a
polar solvent in the presence of an alkali metal amide.
When the starting point is inbermeliate product II according to an
aspect of the present invention,~ it is also possible to prnduce prazosine
oontinuously in one and the same solvent without separatin;g the intermediate
products, which greatly simplifies the production.
The present invention in another aspect also relates to a process
for the p~oduction of the intermediate product II. The process according ;
:
to one variant of this aspect of the invention comprises reacting 3,4-dimeth-
oxy-6-amanobenzonitrile,;havlng the for~la
3 ~ 2
CH30 CN
(IV)
with thiophosgene to fonm 3,4-dimethoxy 6-isothiocyanatobenzonitrile having
the formula
- 3 -
.~,~
i, . . - , ,
, ~ - -, . . .
: : : , ,
... .
:' ' ' ' ' ' ' ': ~' ' '
'
, ".: .. ..
Z3~
CH30 ~ NCS
CH30 ~ ~ CN
(V)
and then reacting thls compound (V) with 1-(2-furoyl)piperazine having
the formula
~ O
H ~ OC
(Vl)
By another variant of this aspect of the invention 1-(2-furoyl3
piperazine according to Formula VI is caused to react with thiophosgene
to form 4-(2-furoyl)piperazinylthiocarbony chloride having the formula
Cl - C~ OC ~ :
~ ~ (VII)
and then this compound (~II3 is caused to react with 3,4-dimetho~y-6-
aminobenzonitrile according to Formula IV.
By one variant~of this process, 3,4-dimethoxy-o-aminobenzonitrile
is reacted with thiophosgene in a solvent comprising 1,2-dichlorothane,
thereby to form 3,4-dimethoxy-6-i60thiocyanatobenzonitrile, and then react-
ing said 3,4-dimethoxy-6-isothiocyanto-benzonitrile with 1-(2-furoyl)pi-
perszine in a solvent comprising ethyl acetate, thereby to form 3,4-dime-
,
thoxy-6-[4-(2-furoyl)-1-piperazinylthiocarbamido]benzonirrile.
By another variant of this process, 1-(2-furoyl)piperazine is
reacted with thiophosgene in a solvent comprising dichlorothane, thereby
to form 4-(2-furoyl)piperazinylthiocarbonyl chloride, and then reacting the
4-(2-furoyl)piperazinylthiocarbonyl chloride with 3,4-dimethoxy-6-amino-
benzinitrile in a solvent comprising dichloromethane, thereby to form 3,4-
~1 -.
-- 4 -- .
~: . -, :
:
LQ~33~
dimethoxy-6- L 4-(2-furoyl)-1-piperazinylthiocarbamido~benzonitrile.
The following examples are given to illustrate various aspects
of this invention.
_ample 1
a) 3,4-dimethoxy-6-isothiocyanatobenzonitrile (V)
27.0 g (0.15 mole) of 3,4-dimethoxy-6-aminobenzonitrile (IV)
is dissolved in 150 ml of 1,2-dichloroethane and added gradually at 0-5C
to a mixture containing 23.0 g (0.2 mole) of thiophosgene, 100 ml of l,Z-
dichloroethane, 20.0 g (0,2 mole) of dal~i~m carbonate and 200 ml of water.
After this addition, the mixture is stirred for 1 hour at 0-5C, thereafter
for 16 hours at 20C, and finally for~ 1 hour at 35C. The reaction mixture
~ ~ ,
; '
'' ;~ '
. ~:
X _ 5 _
, ' .
is filtered and the dichloroethane layer is separated, washed with dilute
hydrochloric acid and water, and dried with MgSo4. The solvent is removed
in a vacuum, and the crystalline residue (m.p. 126-127C) as such is used
for the next state. The yield is 31.0 g (94% of the theoretical) of 3,4-
dimethoxy-6-isothiocyanatobenzonitrile.
ClOH8N22S Calc. C = 54.53 Obs. C = 53.43
H = 3.66 H ~ 3.78
N = 12.72 N = 12~72
S = 14.56 S = 13.79
b) 3,4-dimethoxy-6-[4-(2-furoyl)-1-piperazinylthiocarbamido]-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 gradually, while agitating,
at 0C to a solution which contains 9.2 g ~0.051 mole) of 1-(2-furoyl)
piperazine in 65 ml of ethyl acetate. The solution is allowed to stand
overnight at -25C, whereby the prodoct crystallizee. The~solution ie fil-
tered and the crystals are washed with co~ld ethyl acetate and dried. The
yield is 16.3 g (80% of the theoretical) of 3,4-dimethoxy-6-[4-(2-furoyl)-
l-piperazinylthiocarbamido]benzonitrile. M.p. 178-180C. ~ ~
C19H20N44 Calc. C = 56.99 Obs. C = 5i.41
H = ~5.03 H = 5.39 :
N = 13.99 N = 14.14
S = 8.01 S = 7.68
Example 2
3,4-dimethoxy-6-[4-(2-furoyl)-l~piperazinylt-niocarbamido]-benzonitrile (II)
5.0 g (0.028 mole) of 1-(2-furoyl) piperazine (VI) and 2.83 g (0.028 mole)
of triethylamine are dissolved in 60 ml of dichloromethene. This solution
is added, while agitating, at approx. 0C to a mixture containing 3,86 g
(0.0336 mole) of thiophosgene in 50 ml of dichloromethane. After this
-- 6 --
, ' ' ' ~ ~
- : . :
3~
addition, the mixture i9 stirrad for 2 hours at 0C and for 3 hours at room
temperature, the triethylamine hydroc,hloride is removed by filterlng and
the solution is completely evaporated in a vacuum. The residue, 4-(2-
furoyl)piperazinylthiocarbonyl chloride (VII)
~: ~
`:
~:
.,
/f. - 6a -
-.~
.,~, ~
,: - ' ' ':,
:
,~ ,
,
3Z
is redlssolved in 50 ml of dichloromethane and added, while agitating, at
0C to a solution which contains 4.93 g (0.028 mole) of 3,4-dimethoxy-6-
aminobenzonitrile (IV) and 2.83 g (0 028 mole) of triethylamine in 60 ml
of dichloromethane. This mixture is agitated for 2 hours at 0C and there-
after for 2-3 hours at room temperature. The triethylamine hydrochloride
is removed by filtering, alld the solution is washed with water, dried with
MgSO4, and completely evaporated in vacuum. Ethyl acetate is added, the
mixture is cooled to -25C and filtered. The yield is 6.2 g (55% of the
theoretical) of 3,4-dimethoxy-6-[4-(2-furoyl)-1-piperazinylthiocarbamido]
10 benzonitrile. M.P. 175-178C.
Prazosine can ~e produced from the intermediate product according to one
aspect of this invention in the following manner.
Example 3
a) Methyl N-(3j4-dimethoxy-6-cyanophenyl)-[4-(2-furoyl)-l-piperazinyl]thio-
formamidate hydroiodide (III.HI)
20:0 g (0.05 mole) of 3,4-dimethoxy-6-[4-(2-furoyl~-1-piperazinyl-
- thiocarbamido]benzonitrile is dissolved in 200 ml of bis-methoxy-
ethyl ether (diglyme), and 14.2 g (Ool mole) oE methyl iodide is added.
The mixture is refluxed----------------------------------------------------
hours at 60C. The solution is c-oled to room temperature and filtered.
The crystalline reaction product is washed with ether and dried. The
yield is 24.6 g (90% of the theoretical) of methyl N-(3,4-dimetho~y-6-
cyanophenyl)-[4-(2-furoyl)-1-piperazinyl]thioformamidate hydroiodide.
M.P. 163C.
':
3~Z
C20H23IN404S Calc. C = 44.29 Obs. C = 44.25
H = 4.27 H = 4.26
I = 23.39 I = 22.93
N = 10.33 N = 9.61
S = 5.91 S = 5.58
b) Methyl N-(3,4-dimethoxy-6-cyanophenyl~[4-(2-furoyl)-1-piperazlnyl]thio-
formamidate (III)
62.0 g (0.114 mole) of methyl N-(3,4-dimethoxy-6-cyanophenyl)-[4-(2-
furoyl~-l-piperazinyl]thioformamidate hydroiodide is
.
,,, ~.
;
- -
:
: : : : ~ :: `
~: : : : :
. .~
.,
~ . 7 a -
.
. :, ~ , . , ~ ~ ::
:, , : ~ : : :
:: . :' ' ': ' : .
. , ,
33;~:
dissolved at 0-5C in 350 m~ of methanol, and 186 ml of a 25-% ammonia
solution i8 added, while stirring. The mixture is a8itated 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)-[4-(2-furoyl)-1-
piperazinyl~thioformamidate. M.P. 105-107C.
C20H22N44S Calc. C = 57.96 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)-1-piperazinyl]-quinazoline (I)
7.0 g (0.017 mole) of methyl N-(3,4-dimethoxy-6-cyanophenyl~-[4-(2-furoyl)-
l-piperazinyl]thioformamidate is dissolved in lOO ml of formamide, and
2.0 g (0.051 mole) of sodium amide is added. The solution is saturated
with NH3 gas at 0C. The temperature of the solution is raised gradually
to 120C, and it is heated for 24 hours at this temperature in the stream
NH3 gas. The cooled reaction mixture is poured into 100 ml of ice water
and extra~ted 6-7 times wlth 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-furoyl)-1-piperazinyl]quina-
zoline. M.P. 262-264~C. The IR and NMR spectra of the prodllct are identical
with the spectra of the compound produced according to processes previously
described in literature.
Cl9H21N54 Calc. C = 59.52 Obs. C = 59.28
H = 5.52 H = 5.88
N = 18.27 N = 17.99
~! - 8-
. ' , ., ~ ,
32
Example 4
6,7-dimPthoxy-4-amino-2-[4-(2-furoyl)-1-pipera~inyl]quinazoline (I)
17.6 g (0.044 mole) of 374-dimethoxy-6-[4-(2-furoyl)-l-piperazinyl~
thiocarbamido]benzonitrile is dissolved in 100 ml of formamide,
~' '
,
. :
:
:: :
: ~
.
:: :
.-.
~ . :
' ~
:
- 8a -
,
.
,
~ Z33~
12.5 g (0.088 mole) of methyl iodide is added, and this mixture is heated
for 9 hours at 60C. Excess methyl iodide ls evaporated off, the solution
is saturated with NH3 gas at 0C, and 6.9 g (0.176 mole) of sodium amide is
added to thc solution. The temperature is raised to 120-140C, and the
solution is heated for 24 hours at this temperature, in the stream NH3 gas.
The cooled reaction mixture is poured into ice water (150 ml) and extracted
with chloroform (8 x 50 ml). The chloroform extract is washed with water,
treated with activated carbon, dried, and completely evaporated in a vacuum.
The residue is crystallized from an ethanol-water mixture (50:15). The pro-
duct is 6,7-dimethoxy-4-amino-2-[4-(2-furoyl)-1-piperazinyl]quinazoline, m.p.
263-265C.
:
_ g --
,
.
, ' ", , ' , ~ ' , ' ' :
, ~
