Note: Descriptions are shown in the official language in which they were submitted.
This invention relates ~o a process for preparing
derivatives of quinoxaline and quinazoline which are described
and claimed in British Patent No. 1,381,979.
According to the invention there is provided an
improved process for preparing a compound of the formula:
~ NH-Q (I)
where Q represants a group of the formula:
~ ~ ~ or ~ 2
(Rl)X (~l)x
in which the free valence may be in any ona of the 5-, 6-,
:1:0 7- or 8- positions in the quinoxaline or quinazoline
nucleus; : :
(Rl)X represents up to 3 optional substituents in
~.
any of the remaining 5-, 6-, 7- or 8- positions,
each Rl being a halogen atom or a lower alkyl,
lower alkoxy.or triflu~oromethyl group and x being
O to 3;
and R2 represents an optional substituent in either of
the 2- or 3-, or 2- or 4- positions of the quin-
- oxaline or quinazoline nucleus, respectively, R :
-2~ ~
~4~`7~
being a hydrogen atom or a lower alkyl or lower alkoxy group:
by reac'cing the corresponding i~othiocyanate of the formula
Q-NCS, with ethylane diamine to form a ~ -aminoethyl thio-
ureido compound of the formula Q-NH~CS.NHCH2CH2NH2, cyclizing
the ~ -aminoethyl-thioureido compound to form the compound
of the formula (I), recovering the latter a~ the product, and
optionally, converting the,product into a pharmaceutically
acceptable acid addition salt. the improvement which comprise~
preparing said isothiocyanate by heatlng a t~oureido compound
of the formula Q-NHCSNH2, wherein Q is as defined above.
The thioureido compounds of the formula Q-NHCSNH2
may be prepared a3 described in the aforesaid
British patent , preferably by reacting the corre-
sponding amine of the formula Q-NH2 with ~enzoyl isothiocyanate
to form the corresponding N-benzoyl thioureido compound, fol- ~-
lowed by hydrolysis to the thioureido compound. The benzoyl
isothiocyanate may be prepared in situ from benzoyl chloride
and ammonium isothiocyanate.
The process of the invention may be represented as
follows:
(1)
Q-NHcsNH2 > Q-~CS
~ (2)
Q-NH ~ / ( _ Q-NH.CS.NHCH2CH2NH2
~. . ' :.
~ (3)
In step ~1) the reaction may be carried out by -
heating the thioureido compound in a suitable inert organic
solvent. High temperatures are generally nicessary, prefer-
ably temperature~ of from 130 to 170C. The reaction is
--3--
-'-.
~ 3~
typically carried out by refluxing the thioureido compound for
a period of up to about 20 hours in a high-boiling organic
solvent in which the isothiocyanate is soluble, preferably
chlorobenzene or bromobenzene. It has been found that in
general improved yields of the desired product of the formula
(I) are obtained when the isothiocyanate intermediate is not
isolated, but, if desired, the isothiocyanate can be isolated
by e.g. evaporation of the solvent to dryness or by partial
evaporation of the solvent followed by allowing the compound
to crystallize on cooling.
In step (2) the isothiocyanate is reacted with an
excess (e.g. 5 moles) of ethylene diamine in a suitable
solvent~ e.g. a lower alkanol such as methanol, ethanol, or
iso-propanol in which the ~-aminoethyl compound is formed
in solution. The reaction is preferably carried out by adding
a hot solution of the isothiocyanate in chloro- or bromo-
benzene to a hot, preferably refluxing, solution of ethylene ~ ~ -
diamine in the lower alkanol. Under these conditions the
~ -aminoethyl-thioureido compound automatically cyclizes to
give the desired product of the formula (I), i.e. steps (2)
and (3) may be carried out in one operation, viz., by adding
a solution of the isothiocyanate in chloro- or bromo- benzene
to a solution of ethylene diamine in a lower alkanol and
heating preferably under reflux for up to about 24 hours.
In order to improve the yield of the final product, it may
be necessary to carry out the cyclization in the presence of
a mercuric or cupric oxide catalyst, or in the presence of
an organic mercuric or cupric salt soluble in the solvent
medium, as described in the aforesaid patent.
0 In the case of the preparation of the preferred compound,
-4-
'
viz. 5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline, no
catalys t has been found to be necessary.
If it is desired to isolate the ~ -aminoethyl-
thioureido compound~ then step (2) may be carried out by
reacting the isothiocyanate with ethylene diamine at room tem-
perature for up to a few hours in a solvent such as diethyl
ether, benzene, chloroform or dioxan from which the compound
precipitates and may be recovered by filtration, the cycliza-
tion of step ~3) then being carried out by refluxing the -
isolated ~ -aminoethyl-thioureido compound in a lower alkanol.
Typically, the product of formula (I) is recovered
by allowing the reaction mixture to cool and stirring, the -~
product precipitating from the reaction mixture. It may how-
ever be necessary to partially evaporate the solvent before
crystallization will occur, or even to completely evaporate
the reaction mixture ln vacuo to obtain the desired product. `
When a cyalization catalyst is usled, the reaction mixture
should be fiItered prior to crystallization or evaporation to
.
remove any mercuric or cupric sulphide formed as a by-product.
:
The product may be recrystallized as the free base
or c~nverted to an acid addition salt by reaction with a
~uitable acid by conventional means.
; ~ Preferred compounds of the formula (I) preparable ` ~ ;~
by the method of the present invention include those whereln
25 (Rl)X includes a halogen atomr more preferably a bromine atom, ;
and/or those wherein the 2-imidazolin-2-ylamino group is in -
the 6- or 7-po ition in the qulnoxaline or quinazoline nucleus.
More preferably, when the 2-imidazolin-2-ylamino group i9 in
the 6 -position, (Rl)X is a single halogen in the S- position,
and when the imidazolin group is in the 7- position, (Rl)X i8
-5-
.
. . ' ~ .
:. , ' ,. . .. ' - ' ,, :
a single halogen atom in the 8- position.
As previously stated, the most preferred compound of
the formula (I) is 5-bromo-6[2-imidazolin-2-ylamino]quinoxaline.
As stated in the aforementioned patent,
S the compounds of the formula (I) are of value as antihyper~
tensive agents.
The method of the invention is illustrated by the
following Example, in which all temperatures are given in C.
EXAMPLE
Part A
Preparation of 5-~romo-6-thioureidoquinoxal_ne.
A mixture of 6-amino-5~bromoquinoxaline hydrobromide -
(2.09 kg.) and deionized water (14 1.) was stirred at 50,
filtered warm, and thff solids washed with warm water (2 x 3.45
l.) and discarded. Anhydrous sodium acetate (g.843 kg.) was
then added to the combined filtrate and washings and the
cooled mixture was extracted with methylene chloride (5 x
15 1.). The combined methylene chloride extracts were
evaporated to dryness and the residual 6-amino-5-bromo-
quinoxaline was dissolve~ in acetone (22 1.).
A mixture of benzoyl chloride (0.950 kg.), ammonium
thiocyanate (0.565 kg.) and acetone (13 l.) was stirred under
reflux for 15 minutes. The mixture was cooled slightly and ~ ;
stirred as the acetone solution of 6-amino-5-bro~oquinoxaline ~ -~
was added over 20 minutes. The resulting suspension was heat-
ed under reflux for 45 minutes and the acetone was then distil-
10d off as deionized water (35 1.) was added. The aqueous
~uspension was chilled to 10C. and the solids were filtered
and washed with water (lO 1).
The collected solids were stirred with a mixture
-6-
.:,, . . ,:
- ` :
of 40~ aqueous sodium hydroxide solution (2.95 1.) and de-
ionized water (27 1.), and heated at 90 for 30 minutes. The ;
reaction solution was chilled, adjusted to pH 8 with concen~
trated hydrochloric acid, and stirred at 10~ for 30 minutes
to ensure complete prPcipitatîon of the product. Filtration
and washing with water (2 x 3 lo ) gave 5-bromo-6-thioureido-
quinoxaline (1.59 kg., 82.0~) as a yellow solid m.p. 193-
197 (decomp.).
Analysis:
Found: C, 38.22; H, 2.55; N, 20.00%;
Required for CgH7BrN4S C, 38.18; H, 2.49; N, 19.79%
Part B
Preparation of 5-Bromo-6-[2-imidazolin-2-ylamino]quinoxaline.
A suspension of 5-bromo 6-thioureidoquinoxaline
(50 g.) prepared as in Part A in bromobenzene (500 ml.) was
re~luxed for 2 hours and cooled to ambient temperature. The
mix~ure was then filtered and the filtrate was added over 40
minutes to a refluxing solution o ethylene diamine (42.5 g.)
in ethanol (300 ml.). The mixture was refluxed for 2 hours
and then distilled at atmospheric pressure to remove the
ethanol. S~irring of the residual solution at 10 for 30
minutes followed by filtration and washing with ethanol
(50 ml.), gave 5-bromo-6-[2-imidazolin-2-ylamino]quinoxaline
(39.Q8 g., 75.8~) as yellow crystals, m.p. 252.
Part C
Preparation of 5-Bromo-6-[2-imidazolin-2-ylamino]~uinoxaline
tartrate.
A mixture of 5-bromo-6-[2-imidazolin-2-ylamino~-
quinoxaline ~65.4 g.) prepared as in Part B~ tartaric acid
(33.59 g.), charcoal (6.54 g.) and deionized water (280 ml.)
--7--
'7~
was heated at 95 for 50 minutes. The mixture was then filter-
ed hot and the solids were washed with hot water (47 ml.) and
discarded. The combined filtrate and washings were stirred
and heated as acetone (1308 ml.) was added at a rate which
maintained a gentle reflux. The mixture was cooled and
stirred at 10C. to ensure complete precipitation of the
product. Filtration and washing with acetone (2 x 125 ml.)
gave 5~bromo-6~2-imidazolin-2-ylamino]quinoxaline tartrate
(92.80 g., 93.7%) as white crystals m.p. 207.5.
~
Found: C, 40.56; H, 3.60; N, 16.14%;
Required for C15H16BrN506 C, 40.74; H, 3.65; N, 15.84%
'
" ':'
,.:
