Note: Descriptions are shown in the official language in which they were submitted.
10~3B059
¦ The invention relates to therapeutic agents which are
novel derivatives of 4-amino-2-(piper~zin-1-yl or homopiperazin-
l-yl)quinazoline. Such compounds are useful as regulators of the
cardiovascular system, and, in particular, in the treatment of
hypertension.
The novel compounds according to the invention are
those having the general formula:
R
lR)~ (C32)J O R~ ~ --- (I)
NH2
. ..
wherein (R)r represents 6,7-di(lower alkoxy) or 6,7,8-tri(lower
alkoxy);
m is 1 or 2;
X represents -CHR - or -CH2CH2-;
each R , which may be the same or different; represents
hydrogen or lower alkyl;
and R and R , which may be the same or different, each
represent hydrogen, lower alkyl, lower alkoxy, halogen,
lower alkanoyl, l.ower alkoxycarbonyl or a group of the
: (PLC. 272)
. , : .::. : .
., ~ . : . .
- . : :
.
:: ,,.. , :
..-,
13059
formula -CoNR4R5 or -So2NR4R5 wherein R4 and R5,
which may be the same or different, each represent
hydrogen or lower alkyl;
and the pharmaceutically acceptable acid addition salts thereof~
In this specification, "halogen" means fluorine, chlorine,
bromine or iodine. The term "lower" applied to an alkyl or alkoxy group
indicates that such a straight or branched chain group contains from 1
to 6 carbon atoms. Preferably such groups contain from 1 to 4 carbon atomsO
The term "lower" applied to an alkanoyl group means that such a straight
or branched chain group contains from 2 to 6 carbon atomsO Preferably such
groups contain from 2 to 4 carbon atoms.
Pharmaceutically acceptable acid addition salts of the compounds
of the invention are those formed from acids which form non-toxic acid
addition salts containing pharmaceutically acceptable anions, such as the
hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acid phos-
phate, acetate, maleate, fumarate, succinate, lactate, tartrate, citrate,
gluconate, saccharate and p-toluene sulphonate saltsO
One preferred group of compounds has the formula:
7 N ~ N N -C ~ (IA)
= 3 Rl R3
NH2
:: . - ... , .:
:- : . . : . ,
: ~ . ::.. : . : :.... ..
:,:: : . . .
:: : . :.
-: :- .: , .
059
-- 4 --
i
wherein (R) represents 6,7-di(lower alkoxy) or 6,7,8-tri(lower
alkoxy);
R represents hydrogen or lower alkyl;
and R and R3, which may be the same or different, each
S represent hydrogen, lower alkyl, lower alkoxy, halogen,
lower alkanoyl or a group of the formula -CONR R or
-So2NR4R5 wherein R4 and R5, which may be the same or
different, each represent hydrogen or lower alkyl;
and the pharmaceutically acceptable acid addition salts thereof.
Another preferred group of compounds has the formula
~I) wherein (R)n is 6,7-dimethoxy, 6,7-diethoxy or 6,7,8-trimethoxy;
m is 1 or 2; each R is independently H or CH3; and R and R are
each independently hydrogen, lower alkyl, lower alkoxy, halogen,
lower alkanoyl, lower alkoxycarbonyl, -CONH2 or SO2N(CH3)2.
The most preferred compounds have the formula:
~ IB)
3 ~ ~ ~ O R3
3 ~ N ..
NH2
wherein R is H or CH3 and R and R3 are hydrogen, lower alkyl,
lower alkoxy, halogen or lower alkanoyl.
(PLC. 272)
1.~
. . : .: . .~ :
- :: . :.
, . . . . . . ~: ~ , -.. -:
~ - , ' , ; ~, ~, '.
la~r~30ss
The most preferred individual compound is 4-amino-2-
[4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7-dimethoxy-
quinazoline.
The compounds of the invention containing one or more
asymmetric centres will exist as one or more pairs of enantiomers,
and such pairs or individual isomers may be separable by physical
methods, e.g. by fractional crystallisation of suitable salts. The
invention includes the separated pairs as well as mixtures thereof,
as racemic mixtures or as separated d- and 1- optically-active
lo isomeric formsO
When X represents -CHRl- wherein Rl is lower alkyl, then
cis- and trans-isomerism is possible, and both isomers ~and mixtures
thereof) are within the scope of the inventionO
According to the invention, the new compounds of formula
(I) are prepared by either of two reactions, as set out below~
(a) The new compounds are prepared by reacting a
quinazoline of the formula:
(R)n = ~ --- (II)
NH2
wherein (R)n is as defined above and Q represents a facile leaving
group, such as chloro, bromo, iodo, lower alkoxy or (lower alkyl)
thio, with a piperazine or homopiperazine of the formula:
- :, : - . , ~ .: . .: : ,
- : ,,.
-i : , : , . - :.
,
~31~Q59
HN\ N_ C~ ~R3 ~~~ (III)
(CH ~/ R
2 m
with resultant elimination of HQ. Q is preferably chloro or bromo.
The reaction is typically carried out by heating the
reactants, e.g. at a temperature of from 80 to 150 C, e.g.
under reflux, in an inert organic solvent, e.g. n-butanol. When
the reaction is substantially complete, the product may be isolated
and purified by conventional procedures. For example, in a typical
procedure the reaction mixture is cooled, and the resulting crude
solid product collected, washed with e.g. cold n-butanol, and
dried. The crude product may be purified in a typical procedure
by dissolving it in hot aqueous dimethylformamide, filtering and
concentrating the filtered solution, e.g. in vacuo. The solution
is then cooled and ether added to precipitate the pure product,
which may be filtered and washed with ether. ~-
The intermediates of the formulae (II) and (III) are
either known compounds or may be prepared by methods analogous to
those of the prior art. For example, the intermediate~ of the
formula (III) may be prepared according to the following reaction
procedure:
(PLC. 272)
. -: : - :, ~ ,: . . .
)59
1 R Rl R2
R X~
/ \ ¦ l -~HN N-C ~ ~ J
HNNH + Cl - C --~ , ~ ~ \ / " ~ O ~
~ \ o' ~ (CH2 ~ ] ~1 ~ R3
(CH2)m o Rl R3
(IV) (V) (III)
The intermediates of the formula (IV) and (V) are either known
compounds or may be prepared by conventional proceduresO When X is -CHRl-
wherein Rl is lower alkyl J then cis- and trans- isomers of compound (V) are
possibleO A mixture of these isomers may be used but if a mainly cis or trans
end product is desired then the appropriate cis or trans starting material
may generally be prepared by an appropriate chromatographic technique on the
corresponding methyl or ethyl ester, followed by conversion to the acid
chlorideO
(b) The new compounds are also prepared by acylating a quinazoline
of the formula:
R
/~
N\ NH
N~ ~ (CH2) ~---(VI)
NH2
with a carboxylic acid of the formula:
., , . ;. , , .;.
.......
- - : . . . . . :,: . ,. , :- .,: ~.,
059
\
~ ~ COOH --- (VII)
R3 Rl
or with an acylating derivative thereof, eOgo an acid chloride or
bromide, "activated" ester, or mixed anhydride of the compound of
the formula (VII).
The acid chloride or bromides may be prepared by conven-
tional procedures, e.gO by reacting the free acid with, respectively,
thionyl chloride or bromide~
The preferred "activated ester" is the succinimido
ester of the formula:
R
~ ~ --- (Vlll)
R3 Rl
O
which again may be prepared by conventional procedures, e.gO by
reacting the free acid with N-hydroxysuccinimide in the presence
of a dehydrating agent, e.g. dicyclohexylcarbodiimide~ After pre-
ferred "activated ester" is the phthalimido esterO
Suitable mixed anhydrides have the formula:
C - O - C - Y (IX)
~ ~3 R
: - 8
, :
: ~ , ,~ . :: . .
059
wherein Y is a lower alkyl or lower alkoxy group, most preferably
a t-butyl or iso-butoxy group. They may be prepared by conventional
procedures, e.g. by reacting the free acid with the appropriate
lower alkanoyl chloride or lower alkyl chloroformate, respectively,
e.g. pivaloyl chloride or iso-butylchloroformate, in the presence
of a base such as triethylamine. t
When the free acid form of compound (VII) is used, the
reaction should generally be carried out in the presence of a dehy-
drating agent such as dicyclohexylcarbodiimide.
(PLC. 272)
.
:: : :. ., :.. :
.: ~ :.... .~ .: , -: : :. ::
.. , :- -~ .:.
'1~ 059
- 10- '
Preferably, the compounds of the formula (VII) are
reacted in the form of their acid chlorides or bromides.
In a typical procedure using an acid chloride of (VII),
the acid chloride in a suitable solvent, e.g. methylene chloride,
is added dropwise to a stirred suspension of the quinazoline (VI)
in a suitable solvent, e.g. methylene chloride. The mixture may
then be stirred for a few hours at room temperature, and the
resulting solid then filtered off and purified by conventional
techniques.
When X is -CHR - wherein R1 is lower alkyl, then cis-
trans isomerism will be possible as mentioned in route (1).
The intermediates of the formula tVI) and (VII) may be
prepared bv conventional procedures.
The pharmaceutically acceptable acid addition salts of
the compounds of the invention may be prepared by conventional
procedures, e.g. by reacting the free base with the appropriate
acid in an inert organic solvent, and collecting the resulting
precipitate of the salt by filtration. If necessary, the product
may then be recrystallised to purify it. Often, however, the
product obtai.ned by routes (1) and (2) will be in an acid-addition
salt form.
The invention also includes the pharmaceutically
acceptable bioprecursors of the compounds of the formula (I) and
said salts thereof.
(PLC. 272)
- - - - ~ , :,. :: . -
.: . . .
::: , , ~ :, . ...
~ 59
The term "pharmaceutically acceptable bioprecursor"
requires some explanation. It is of course, common practice in
pharmaceutical chemistry to overcome some undesirable physical
~ or chemical property of a drug by converting the drug into a
t S chemical derivative which does not suffer from that undesirable
property, but which, upon administration to an animal or human
being, is converted back to the parent drug. For example, if the
I drug is not well absorbed when given to the animal or patient,
-¦ by the oral route, it may be possible to convert the drug into a
chemical derivative which is well absorbed and which in the serum
or tissues is reconverted to the parent drug. Again, if a drug
is unstable in solution, it may be possible to prepare a chemical
derivative of the drug which is stable and may be administered in
solution, but which is reconverted in the body to give the parent
drug. The pharmaceutical ch~nist is well aware of the possibility
¦ of Overcoming intrinsic deficiencies in a drug by chemical modifi-
¦ cations which are only temporary and are reversible up~n adminis-
tration to the animal or patient.
For the purpose of this specification the term "pharma-
ceutically acceptable bioprecursor" of a compound of the formula ~I)
means a compound having a structural formula different from the
compounds of the formula ~I) but which nonetheless, upon adminis-
tration to an animal or human being, is converted in the patient's
body to a compound of the formula ~I).
..,~
'' :'
~PLC. 272)
.
;
:' :' :: ~ :. ': :
:: : . ~ - . :. , -, :
:
: . . : : :
: ~ :- :~ : ; .: ~ .
S9
-12-
¦ The antihypertensive activity of the compounds of the
' invention is shown by their ability to lower the blood pressure of
concious spontaneously hypertensive rats and conscious renally
hypertensive dogs, when administered orally at doses of up to
mg/kg.
The compounds of the invention can be administered alone,
but will generally be administered in admixture with a pharmaceutical
carrier selected with regard to the intended route of administration
and standard pharmaceutical practice. For example, they may be
administered orally in the form of tablets containing such
excipients as starch or lactose, or in capsules either alone or in
admixture with excipients, or in the form of elixirs or suspensions
containing flavouring or colouring agents. They may be injected
parenterally, for example, intramuscularly, intravenously or sub-
cutaneously. For parenteral administration, they are best used in
, the form of a sterile aqueous solution which may contain other
solutes, for example, enough salt or glucose to make the solution
¦ isotonic.
Thus the invention also provides a pharmaceutical
composition comprising.a compound of the formula (I) or pharma-
ceutically acceptable acid addition salt thereof together with a
pharmaceutically acceptable diluent or carrier.
,, :
,
(PLC. 272)
,:
. : -
- ~ ..: : ..
.:
: - - . - :
: ~ :; . : - : ` . . . , :
;~ :
os9
_ 13_
The compounds of the invention can be administered to
humans for the treatment of hypertension by either the oral or
parenteral routes, and may be administered orally at dosage levels
approximately within the range 1 to 20 mg/day for an average adult
patient (70 kg), given in a single dose or up to 3 divided doses.
Intravenous dosage levels would be expected to be about -5th to1-oth
of the daily oral dose. Thus for an average adult patient,
individual oral doses in tablet or capsule form will be approxi-
mately in the range from 1 to 50 mg of the active compound.
Variations will necessarily occur depending on the weight and
condition of the subject being treated and the particular route of
administration chosen as will be known to those skilled in the art.
The invention yet further provides a method of treating
an animal, including a human being, having hypertension, which
comprises administering to the animal an antihypertensive amount of
a compound of the formula (I) or pharmaceutically acceptable acid
addition salt thereof or pharmaceutical composition as deflned
above. ~-
The following Examples illustrate the invention:-
~.
(PLC. 272)
.. . . .. . .. .. . . . .. .. . ..
.
: ~: . , ~
-. : ,: . . ; .
: ,
~ ::
.. . . ..
- ~:
OS9
EX~MPLE 1
4-Amino-2-/4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl7-
6,7-dimethoxyquinazoline
C~3 ~ Cl ~ ~ ~ X ~ ~ + 3C1
CH3 + HN ~ CH3
4-Amino-2-chloro-6,7-dimethoxyquinazoline (140 g) and
N-(1,4-benzodioxan-2-carbonyl)piperazine (150 g) were stirred
together under reflux in n-butanol (2 l) for 3~ hours. The mixture
was then cooled to 80 C, the solid product collected, washed with -
cold n-butanol (2 x 250 ml), and dried. The crude product was
10 dissolved in hot (80 C) dimethylformamide (530 ml) and water (130 ml),
filtered, concentrated in vacuo to about 300 ml, then cooled and
ether (1.8 l) added. The solid so obtained was collec~ed and
washed with ether to give 4-amino-2-/4-(1,4-benzodioxan-2-carbo~yl)
piperazin-1-yl7-6,7-dimethoxyquinazoline hydrochloride (215 g),
15 m.p. 289 - 290C.
Analysis ~:-
Found: C, 56.9; H, 5.4; N, 14.4
Calculated for C23H25N5O5.HCl: C, 56.6; H, 5.4; N, 14.4.
.
(PLC. 272)
::
. . . :: , : .
59
EXAMPLE 2
4-Amino-2-/4-(1,4-benæodioxan-2-carbonyl)piperazin-1-yl7-
_
4-Amino-2-chloro-6,7,8-trimethoxyquinazoline (1 g) and
N-(1,4-benzodioxan-2-carbonyl)piperazine (1.168 g) were heated
under reflux in n-butanol (67 ml) with triethylamine (1.87 g) for
24 hours. Further N-(1,4-benzodioxan-2-carbonyl)piperazine (0.026 g)
was then added and the mixture heated under reflux for an additional
30 hours. Butanol was then removed in vacuo and the residue
partitioned between aqueous sodium carbonate solution and chloro-
form. The combined chloroform extracts were washed with water,
dried (Na2SO4) and evaporated in vacuo to leave a solid (3.4 g)
which was taken up in the minimum quantity of dimethylformamide
then set aside at 0 C overnight. Ether was then added and the
cloudy solution further cooled to yield 4-amino-2-/4-(1,4-benzo-
dioxan-2-carbonyl)piperazin-1 -yl7- 6,7,8-trimethoxyquinazoline
(0.58 g), m.p. 269 - 271C.
Analysis %:-
Found: C, 59.3; H, 5.6; N, 14.1
Calculated for C24H27N5O6: C, 59.9; H, 5.7; N, 14.6.
(PLC. 272)
,
,. :.
.: : ~,: .: , ~
... , . ` , . , , . , . ........................ ,. ~ .. ~ .. , ., ,.. , .. , . .... ~ 1
~3B059
-16-
EXAMPLE 3
4-Amino-2-/4-(1,4-benzodioxan-2-car~onyl)piperazin-1-yl7-6,7-
diethoxyquinazoline
4-Amino-2-chloro-6,7-diethoxyquinazoline (0.33 g) and
N-(1,4-benzodioxan-2-carbonyl)piperazine (0.32 g) were heated
under reflux in n-butanol (30 ml) overnight. The mixture was then
evaporated ln vacuo and the residue partitioned between sodium
carbonate solution and chloroform. The combined chloroform
extracts were washed with water, dried (Na2SO4), evaporated in vacuo .
and the residue chromatographed on silica gel (70 g) using chloro-
form/methanol (0-5%) as eluent. Similar fractions were combined~ ;
evaporated in vacuo then redissolved in chloroform/methanol and
treated with ethereal hydrogen chloride. The solution was then
evaporated in vacuo and the residue recrystallised from isopropanol
to give 4-amino-2-/4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl7-
6,7-diethoxyquinazoline hydrochloride. 2~ hydrate ~0.19 g),
m.p. 180 - 184 C (decomp.).
Analysis %:-
Found: C, 53.3; H, 5.6; N, 12.2
Calculated for C25H29N505-HCl 2~ H2O C, 53.5; H, 6.3; N, 12.5.
(PLC. 272)
, . ~ :
;:
.
059
-- 17--
EXAMPLE 4
4-Amino-2-/4-(1,4-benæodioxan-2-carbonyl)homopiperazin-1-yl7-
6,7-dimethoxyqulnazoline
4-Amino-2-chloro-6,7-dimethoxyquinazoline (1.58 g) and
N-(1,4-benzodioxan-2-carbonyl)homopiperazine (2.0 g) were heated
under reflux in n-butanol (114 ml) for 60 hours. The mixture was
then cooled, butanol removed in vacuo and the solid residue
triturated with ether, taken up in hot methanol, filtered and
cooled. The solid product was collected, then the residual solution
was evaporated in vacuo and the residue taken up in hot isopropanol,
cooled, filtered, then re-evaporated in vacuo. The residue was
combined with the original solid product, treated with cold methanol,
and recrystallised from ethanol to give 4-amino-2-/4-(1,4-benzodioxan
-2-carbonyl)homopiperazin-1-yl7-6,7-dimethoxyquinazoline hydro-
chloride (0.57 g), m.p. 250 - 251C.
Analysis %:-
Found: C, 57.2; H, 5.4; N, 13.8
Cslculated for C24H27N55 HCl C, 57.4; H, 5.6; N, 14Ø
(PLC. 272)
:: .... . .
- ,. ~ .
: , - : . . . :., ,: :
~ - : ~ , .
., . : .. . :
059
-18 ~
EXAMPLE 5
4-Amino-2-/4-(6-methoxy-1,4-benzodioxan-2-carbonyL)piperazin-1-yl/
6,7-dimethoxyquinazoline
t ` .
33J~,~ rl N~ f3
¦CH3 CH3 N
N82 2
;1 5 A solution of 6-methoxy-1,4-benzodioxan-2-carbonyl chloride
(2.17 g)(prepared from the acid and thionyl chloride) in dichloro-
1 methane (25 ml) was added dropwise to a stirred suspension of 4-
1 amino-2-piperazin-1-yl-6,7-dimethoxy-quinazoline (2.48 g) in
methylene chloride (50 ml) at room temperature. After the addition
, .
was complete, the mixture was stirred at room temperature for 4
hours, then fi:Ltered and the solid suspended in aqueous potassium
carbonate solution and extracted with chloroform. The combined
extracts were washed with water, dried (Na2SO4) and evaporated
I in vacuo to leave a solid residue (4.15 g) which was chromatographed
on silica (160 g) and eluted with chloroform then chloroform-
methanol (2~%).
(PLC. 272)
i: -
:. : : . . ,
1(~3i3059 -- '
-19- .'
Similar fractions (t.l.c.) were combined, evaporated in vacuo then
the residue taken up in ethyl acetate-methanol and treated with
ethereal hydrogen chloride. Addition of further ether
followed by cooling yielded a solid which was collected and
recrystallised from methanol to give 4-amino-2-/4-(6-methoxy-1,
4-benzodioxan-2-carbonyl)piperazin-1-yl/-6,7-dimethoxyquinazoline
hydrochloride hydrate (0.95 g), m.p. 220 - 222C.
Analysis ~:-
Found: C, 53.3; H, 5.5; N, 13.4
`t'r" 10 Calculated for C24H27N56 HCl ~2 C, 53.8; H, 5.6; N, 13.1.
EXAMPLES 6-24
The following compounds were prepared similarly to
Example 5, starting from 4-amino-2-piperazin-1-yl(or 2-/3-methyl-
piperazin-1-yl7)-6,7-dimethoxy-quinazoline and the appropriate
15 carbonyl chloride.
(PLC. 272)
,, , :, " . . ,. :, . : : , :-
-: , -.: : . , :: : : ., :
"` lO~)S9
_ __
_ Z ~ ~ ~ ô ~ ~
..=
~P~
~1 ~ ~ ~ ~ OD ~0 ..
~ u~u~ ~D u~9
o
E~ O ~ ~ O ~ Lr) N
, _ ~D ~9 C~) ~` Ul 1`
.
, ~ O ~ ~0 ~ ~0 ~ ~0
~-- ,1 ~ O ,1 ~ o ,~ ~ CO
., , ~0 ~ O ~ ~ O ,~ ~ ~ ~ ~
- t~ N~1 . ~ ~ I ~ ,~ I ~ I
~ 1 ~ .,~ ~ __ ~
~r~
(PLC. 272)
- . . ::~
:; ,. ~ ' . : . .
. .
:: ; :': '. , '~ - ., - :
15~
- 21 - .
~_
~ . _-~
d~
~ ~ i 'u7 U~ ~ ~ o~ ~
~. ~ ~In ~ ~r
h _ _ N C~
. ~ ___ _
O ~ ~ O .~ 4 a) N
~; ~ H . ~ ~ I O ~ . H 1~ 1
. ~ >~ oe ~ ~ ~-- ~ ~ o
',, . ~Z~ o ~ ~ ~ '' ~ C ~ ~ ~ ~
~ j_ N . i'q r :~
<~ . ~
~ ~
~ t)~ ~ I
~0 0~ o ~ ~ '
~ _ _
` a~ o
... __ - . __ .
~PLC. 272)
'
.. - :i i ::: :, : :: ' . . . . !
-: ' - ,. " ' . ' "'" .' ' ' '.: ;' :, ' .: :: ' '
5.~ 59
_ z ~ h~ .~ ~
. . ~ ~ ~ ~r ~r
'............................. d~,4
U~ ~ ~ ~ ~D ~r ~ ~
u~u~
.
E`~ ~,) Ul N Il-) ~C) C`l
~_ 11') Ll~ Il~ Ll') 11
Y _ _
~0~ ' ~0~ ~00 ~ ~0~9 ^
0 _ ~ ~r ~ O
K N H . ~ ,C q~ rl .C I + ~
O ~3 ~ I 1.) a~ o ~
E; ~ O 1` 11 dP O a~ 11 dP
Z ~ 14 ~a N 5 ~ p~
~:~æ _,~ _ ~
S~ . . ~
. C~ O l +
1~
o, <o oyo oyo
(PLC. 272)
' - '~' ~': ` . ' ' ` 1
59
-- 23 --
.
_ _ r
." . _ ~ ~ 1~0-
,t . Z ~) r~ ~
' ~15
'~
3 ~ ~ u~ ao ~ ~ ~ o
~ ~ In U~ , U~ U~ Ul~D
~3
:~ ~
o o~r o~r 0~9
E~ O ~ u7 ~ ~r n
... .~
~ ôC' ~ 00 ~ ~ a~o
~ -- h ~ ~r O ~ ~ O ~ _~
_, O~ a~ r ~ ~ ~ N ~! 'a
t~ N ~ . . ~ V ~) I V ~ I
~_ o ~ ~ r t~ 3 ~r
. ~ ~ ~q
~æ~
~ ~ _~ m .
~ . .
~q ~ .~
~
- ~ ~ -~
In ' ~D ~`
~ z -l ~ -~
:
(PLC. 272)
59
-- 24--
::Z ~_ ~,. .~
~ ~ r~) ~ ~ ~ ~
~: _.~ _,~ ~
m ~r, t~ ~r t~l n
v n n Ln Ln Ln n
E~ O ~D ~ ~ ~r co
_ Ln n Ln n
n n Ln n
0 _ .~ 1~ ~
E3 O N O ~ O ~ ~ I
E~ O ~ ~ o .,1 O ~
$ ~, S ~ m S _ __
~ Ç R,r`,'
\~ C~ \~ Y
.
13 -- -- N
~PLC . 27 2 )
. : ~ . : i
,
59
~ 25--
_ U-î- __ ~ô
. Z~1 ~1 N N ~ ~
P~
_1 ~ U~ Ln ~9 ~ Lr~
S~
E~ ~ ~ o ~ ~ ao ~
_ CO ~ U~ ~ ~
~r~
.
~ ~r o ~ o u~
O ' r-l Id N O ~1 ~) ~J N la _I
u~ ~ ,5~ ,r:: ~ ~ ` o
1~ N ~1 . t)~a I ra u ~ ~, ~ ~,
>~ ~ ~ ~1 ,~:: -- h
,,:~Z ~ O ~: ~ N ~ ~ N
~ ~ :~ m c, ~J
~Z ~
z>o ZN --~~ r~ ~
r~7 N r~
I ~
~ ~ N N N
~ _
(PLC. 272)
-. : .
::-: .. :. ::.:. .':. :: '
`$~059
--. 26--
'~
.
_
~J ô O ~ ~ ~
~ _~ ~ o
G g~ ~ 1
~ '
(PLC. 272)
: .
:~ : . ,. , . :, .~ :
193~059
- 27 ~
EX~MPLE 25
4-Amino-6,7-dimetho~y-2-/4-(a mixture of 6- and 7-carbamoyl-1,
4-benzodioxan-2-carbonyl)piperazino7quinazoline hydrochloride
Dicyclohexylcarbodiimide (2.06 g) and N-hydroxysuccinimide
(1.15 g) were added to a stirred solution of a mixture of 6- and 7-
cæbamoyl-1,4-benzodioxan-2-carboxylic acid (2.23 g) in dimethyl-
formamide (70 ml) at 0C. The mixture was stirred at 0 for 1 hourO
then 4-amino-6,7-dimethoxy-2-piperazino-quinazoline (2.8 g) was
added and the resultant mixture was stirred at room temperature
overnight. The reaction was then filtered, the filtrate diluted
with ether (500 ml) and the resulting oily precipitate collected.
The product was partitioned between chloroform/isopropanol/sodium
bicarbonate solution, the chloroform layer separated, washed with
water and evaporated in vacuo. The residue was chromatographed on
silica and elution with chloroform-methanol (3%) gave a crude
product which on treatment with ethereal hydrogen chloride solution
and recrystallisation from methanol/water/ether/dimethyl formamlde
followed by methanol/water/dimethylformamide yielded 4-amino-6,7-
dimethoxy-2-/4-(6- and 7-(mixture)-carbamoyl~1,4-benzodioxan-2-
carbonyl)piperazino7quinazoline hydrochloride hydrate, m.p. 228 -
235 C (dec.).
Further recrystallisation provided an analytical sample,
mOp. 245 - 248C.
(PLC. 272)
.
- .. :, :~ : -;
: . -: : : -
.:: : - - -: , ::
s9
.
- 28 ~
Analysis %:-
Found: C, 52.6; H, 5.5; N, 14.6
Calc 24 26 6 6 2 C, 5205 H, 5.3; N, 15.3.
High pressure liquid chromatographic analysis indicated
that the product was a mixture of 6- and 7- isomers in the ratio
of 7:3.
(PLC. 272)
-- : .. ,.. , : ,. .. .. .
,: : ,: . . , .: .,, . - . - :,:.
: ,:: , - - .. .-. , . .: .. , . . :
:. . - - : . , : :
)59
- 29-
The following illustrates the preparation of certain
of the starting materials:-
Preparation 1
(A) N~(l~4-Benzodioxan-2-carbonyl)piperazine
~N ~ t C ~ O ~ ~ ~ + ~Cl
A suspension of piperazine (11.88 g) and sodium acetate
(20.30 g) in a mixture of water (70 ml) and acetone (95 ml) was
stirred at 10 - 15C, then concentrated hydrochloric acid was added
(about 35 ml) until the pH of the solution reached 1.5. 1,4-
Benzodioxan-2-carbonyl chloride (31.0 g) and sodium hydroxide (5N, about
45 ml) were then added portionwise whilst maintaining the temperature
at 10 - 15C, the sodium hydroxide maintaining the pH at 1.7 -
2.2. After the addition was complete, the pH was adjusted to
2.0 by the addition of sodium hydroxide, and the suspension was
stlrred for a further 30 minutes. Water was then added until a
homogen~oussolution resulted, the acetone removed in vacuo, and
the aqueous residue extracted with chloroform (3 x 200 ml). The
aqueous phase was basified to pH 8 - 9 with sodium hydroxide (5N),
re-extracted with chloroform (3 x 200 ml) and the extracts washed
with water, dried (MgSO4) and evaporated in vacuo.
(PLC. 272)
.. . ..
: . . .- . :
: , - : ~ ~
:: ... . . .
1~'3~0:~9
--30 --
The oily residue was dissolved in ethyl acetate, treated with
ethereal hydrogen chloride, evaporated in vacuo and the solid
residue triturated with ether, followed by recrystallisation from
methanol to qive N-(1,4-benzodioxan-2-carbonyl)piperazine hydro-
chloride (4.85 g), m.p. 265 - 267C.
Analysis ~6:-
Found: C, 54.6; H, 5.5; N, 9.7
Calculated for C13H16N2O3-HCl C, 54.8; H, 6.0; N, 9.8
Preparation 2
.
6-Methoxy-1,4-benzodioxan-2-carboxylic acid
O C 2 ~ o ~ CO2E~
.CH3~O~/ ~0 J
Finely ground potassium permanganate (5.02 g) was added
in four portions to a stirred suspension of 2-hydroxymethyl-6-
methoxy-1,4-benzodioxan (4.52 g) in potassium hydroxide solution
(1.47 g, in 42 ml water) at 5 C. During the reaction, the
temperature was maintained at 5 - 15C then after addition was
complete, stirring was continued at room temperature for 4 hours
then the reaction set aside overnight.
Manganese dioxide was removed by filtration, the solid
washed with water and the combined aqueous phase acidified (pH 1)
with concentrated hydrochloric acid, cooled, then extracted with
chloroform.
(PLC.- 272)
' , ' '', ~ ' ". ,,' ~ ; .;
., ~,'.
, ~,. .. '
B~59
- 31-
The combined chloroform extracts were washed with sodium hydroxide
solution (5N, 2 x 40 ml) then the basic phase further washed with
chloroform, cooled, acidified (pH 1) with concentrated hydrochloric
acid and re-extracted with chloroform. This latter chloroform
solution was washed with water, dried (Na2SO4) and evaporated to
leave a crude residue of 6-methoxy-1,4-benzodioxan-2-carboxylic acid
(2.33 g). A sample was recrystallised from water, m.p. 120 - 121 C
Analysis ~:-
Found: C, 57.1; H, 4.8
calculated for C1oH10O5: C, 57.1; H, 4.8.
Preparation 3
8- and 5-(mixture)-Isopropyl-1,4-benzodioxan-2-carboxylic acid
~A) A stirred solution of 3-isopropyl catechol (23 g ) in
acetone (250 ml) was heated under reflux then potassium carbonate
(28 g) added. The heterogeneous mixture wasrefluxed for a further
15 minutes followed by the dropwise addition of methyl 2,3-
dibromopropionate (10 g). Three further batches of potassium
carbonate (28 g) and methyl 2,3-dibro~opropionate (10 g) were added
in a similar fashion then the mixture stirred under reflux for 12
hours. The mixture was then evaporated, the residue diluted with
water (700 ml), extracted with chloroform and the combined
extracts washed with water, dried (MgSO~) and evaporated. The
residual oil was distilled to give methyl 8(5)-isopropyl-1,4-
benzodioxan-2-carboxylate (29.3 g), b.p. 115 - 120 C/0.5 mm.
C n.m.r. spectroscopy confirmed the product was a mixture of
(PLC., 272)
.
. , ,, , ~
:~ .- ~ :: .
,~ , ., .: , :
-32 -
8-(71~) and 5-(29~) isomers.
(B) The above product (29.0 g) in sodium hydroxide solution
(160 ml, 2.5 N) was heated at 100 for ~ hour then the resulting
solution was cooled and acidified with concentrated hydrochloric
acid. The mixture was extracted with chloroform (3 x 200 ml), the
combined extracts dried(MgSO4) and evaporated in vacuo to leave
an oil (18 g) which solidified on standingO Recrystallisation from
methanol gave a mixture of 8- and 5-isopropyl-1,4-benzodioxan-2-
carboxylic acid, m.p. 86 - 88C.
Analysis %:-
Found: C, 64.7; H, 6.3
calculated for C12H14O4: C, 64.9; H, 6.3.
High pressure liquid chromatography indicated that the
product was a mixture of the 8- (86%) and 5- (13~) isomers. /Spectra
Physics 3,500 cs Machine; column, 1' x 4-" O.D. ~ Bondapak C-18;
eluant, acetonitrile (1)/0.15M potassium hydrogen phosphate buffer
pH 3.5 (2); flo~ rate, 14ml/min.; pressure 600 p.s.i 7.
Preparation 4
A mixture of 8- and 5-Methyl-1,4-benzodioxan-2-carboxylic acid
Potassium permanganate (23.15 g) was added in three
portions to a stirred suspension of a mixture of 8- and 5-methyl-
2-hydroxymethyl-1,4-benzodioxan (20 g) in potassium hydroxide
solution (6.5 g in 187 mlH2O) at 5 C.
.
~PLC. 272)
. . .
- ~ , : : : ., :: : .: .
-: : : .. :,
i ~O;~ S9
- 33-
The reaction temperature was maintained below 15 C and after the
addition was complete, the reaction was stirred at room temperature
for 4 hours. Manganese dioxide was removed by filtration, the
filtrate cooled, acidified with concentrated hydrochloric acid
and the oily product which separated on further cooling was extracted
I with chloroform. The chloroform extracts were washed with 5N
sodium hydroxide solution, the basic layer washed with chloroform
then acidified with concentrated hydrochloric acid to pH 1. The
acidic solution was extracted with chloroform, the combined extracts
washed with brine, dried (MgSO4) and evaporated in vacuo to leave
a mixture of 8- and 5-methyl-1,4-benzodioxan-2-carboxylic acid
(7.3 g) as a treacle-like residue with consistent spectroscopic
properties. A small sample was esterified with diazomethane and
was shown by gas chromatography to be a mixture of isomers (5:2). `
Preparation 5
6,7-Dimethyl-1,4-benzodioxan-2-carboxylic acid
CH3 CH3
CH3 ~ OH B ~ ~C~ ~ ~ 2 2 ~ ~ O2H
. CH3 OH r (a) ~ 3
~A) A stirred solution of 4,5-dimethylcatechol (7.0 g) in
dry acetone (45 ml) was heated under reflux, thenpotassium carbonate
(5 g) was added followed by the dropwise addition of ethyl dibromo-
propionate (3.5 g).
(PLC. 272)
:. , : ' , ' :',,' ', .. "' '' ''; '', . ' ' ' '' '.,.
;; , . ' . . " ~',, .'.','' , ' "' , ' ' ' '~. " ' ' . '' ' ' '
' : , "' ,': , . ~ .''`' ' I ' . ' '
-34 -
The addition procedure was repeated a further three times over
1- hours then the reaction was stirred under reflux for a further
34 hours. Aftcr cooling, the mixture was filtered, the solids
washed well with acetone then the combined filtrate concentrated
in vacuo. Water (35 ml) was added, the resulting solid collected,
washed with petrol then taken up in ether. The ethereal solution
was washed with water, dried (Na2SO4) and evaporated in vacuo to
give ethyl 6,7-dimethyl-1,4-benzodioxan-2-carboxylate (10.17 g),
m.p. 70 - 7I C.
10Analysis %:-
Found- C, 65.7; H, 6.8
Calculated for C13H16O4: -C, 66.1; H, 6.8.
(B) ~ydrolysis of the above ester (5.0 g) with sodium
hydroxide (10%, 13 ml) in ethanol (125 ml) as described for
related compounds (J.A.C.S., 77, 5374 (1956)) gave crude 6,7-
dimethyl-1,4-benzodioxan-2-carboxylic acid (4.04 g). A sample was
recrystallised from water, m.p. 150 - 151C.
Analysis ~:-
Found: C, 63.9; H, 6.0
Calculated for CllH12O4: C, 63.5; H, 5.8
(PLC. 272)
:. : ~ ;: .: ~ - . :.: .
::: . : :,. - , .: . :: .:
, ~. ,.: : : . .: : .
. - . :: :
,, , :-
059
~ 35--
reparation 6
6,7-Dichloro-1,4-benzodioxan-2-carboxylic acid
Hydrolysis of ethyl 6,7-dichloro-1,4-benzodioxan-2-
carboxylate (5.0 g) with sodium hydroxide (10%, 10.9 ml) in
ethanol (50 ml) gave 6,7-dichloro-1,4-benzodioxan-2-carboxylic
acid (3.4 g) m.p. 155 - 158C with a consistent n.m.r. spectrum
and identical Rf (t.l.c.) with an authentic sample.
Preparation 7
8-Methoxy-1,4-benzodioxan-2-carboxylic acid
8-Methoxy-1,4-benzodioxan-2-carboxamide (2.41 g) in
50g6 hydrochloric acid (35 ml) was stirred at 100 for 1 hour. The
resulting solution was cooled, diluted with water (200 ml),
extracted with chloroform (3 x 100 ml) then the extracts dried
(MgSO4) and evaporated in vacuo. The solid residue (-1.8 g) was
recrystallised from water (m.p. 75 - 78 ) then from ethyl acetate/
hexane to give 8-methoxy-1,4-benzodioxan-2-carboxylic acid, m.p.
131 - 132C.
Analysis %:-
Found: C, 56.9; H, 4.8
Calculated for C1oH10O5 C, 57.1; H, 4.8.
(PLC. 272)
- ~: : . -. :
: :~ . ~ ... , . .,,: , .
- : ~ . : - :: :,
: ,, :
- , : .
- :., . : : .
. :-: ,. .:.. ~ ~, : ,
:
S9
~ 36-- -
Preparation 8
5-Methoxy-1,4-benzodioxan-2-carboxylic acid
This compound was prepared by the method of Preparation
7 starting with 5-methoxy-1,4-benzodioxan-2-carboxamide. The
product was crystallised from water~ m.p. 85 - 87C~ then from
ethyl acetate-hexane to give 5-methoxy-1,4-benzodioxan-2-carboxylic
acid, m.p. 139 - 141C.
Analysis %:-
Found: C, 56.9; H, 4.8
Calculated for CloH1005: C, 57.1; H, 4.8.
Preparation 9
6-Acetyl-1!4-benzodioxan-2-carboxylic acid
Jones' reagent (11.6 ml) was added dropwise to a stirred
solution of 6-acetyl-2-hydroxymethyl-1,4-benzodioxan (4.0 g) in
acetone t70 ml) at 10 - 15 C. The reaction was stirred at room
temperature for 18 hours then diluted with isopropanol/water/
chloroform, the organic layer separated and evaporated in vacuo.
The residue was redissolved in chloroform, extracted with saturated
sodium carbonate solution (2 x 30 ml) then the basic phase washed
with chloroform, cooled and acidified to pH 1 with concentrated
hydrochloric acid.
(PLC. 272)
:- : : : .:: :, : ::
: - ~ - , .: ~. .:.,, :
.1)59
- 37-
The acidic solution was extracted with chloroform, the combined
extracts washed with saturated brine, dried tNa2SO4) and
evaporated in vacuo to give 6-acetyl-1,4-benzodioxan-2-carboxylic
acid (1.56 g), m.p. 159 - 162 . A sample was recrystallised from
ethanol/ethyl acetate, m.p. 174 - 17S.
Analysis %.-
-
Found: Cj 59.0; H, 4.8
Calculated for C11H10O5: C, 59.5; H, 4.5.
Preparation 10
7-Acetyl-1,4-benzodioxan-2-carboxylic acid
(A) A solution of methyl 2,3-dibromopropionate (13 ml) in
acetone (50 ml) was added dropwise over ~ hour, to a stirred
suspension of 3,4-dihydroxyacetophenone (15.1 g) ana anhydrous
potassium carbonate (28 g) in acetone (100 ml) heated under reflux.
The mixture was stirred under reflux for 4 hours, then evaporated
in vacuo and the residue partitioned between chloroform/water.
The chloroform extracts were washed with water, dried (MgSO4) and
evaporated to leave a mixture (18 g) of 6- and 7- acetyl-1,4-
benzodioxan-2-carboxylic acid methyl ester in the ratio of 2:1
as determined by C n.m.r. spectroscopy. A sample of this crude
product was recrystallised from isopropanol, m.p. 68 - 80 C.
Analysis ~:-
Found: C, 60.7; H, 4.9
Calculated for C12H12O5: C, 61.0; H, 5.1.
tPLC. 272)
. . .
. ~
,,: ~. .. '. .' ~ ~ : : .
~y~s9
- 38 ~
(B) Aqueous sodium hydroxide solution (1.2 g, in 5 ml water)
was added to a stirred solution of the product (7 g) from (~) in
ethanol (25 ml) at 15. The reaction temperature was maintained
I below 25 for ~ hour then the mixture evaporated ln vacuo, the
residue triturated with water, acidified with concentrated hydro-
chloric acid and extracted with chloroform. The ccmbined chloro- t
form extracts were dried (MgSO4), evaporated in vacuo and the
residue (1.46 g) recrystallised from ethyl acetate/methanol to
give 7-acetyl-1,4-benzodioxan-2-carboxylic acid, m.p. 167 - 168 C.
Analysis ~:-
Found: C, 59.0; H, 4.5
Calculated for CllHl0O5: C, 59.5; H, 4.5.
¦ High pressure liquid chromatography tHP~C) indicated
I isomeric purity of ~96%~Spectra Physics 3,500 CS Machine; column
¦ 15 1' x ~' O.D. ~-Bondapak C-18; eluant, acetonitrile (1)/0.05M
¦ potassium hydrogen phosphate buffer pH 4.5 (2); flow rate 0.6 ml/
I min.; pressure 780 p.s.i 7
I The acidic aqueous phase was evaporated in vacuo, the
residue extracted with methanol, the combined extracts evaporated
in vacuo and the producL (5.5 g) recrystallised from ethyl acetate/
methanol to give 6-acetyl-1,4-benzodioxan-2-carboxylic acid.
HPLC showed only one component which corresponded to an authentic
sample prepared by Preparation 9.
(PLC. 272)
.: : . . . : . : , :
.. : : , :: ., .. : - ::
, : :, : .
. : ~: . , : . . :, ,.: : , . . .:, ~ ;
59
39 ~
Preparation 11
tA) (+) l~4-Benzodioxan-2-carboxylic acid
lr4-Benzodioxan-2-carboxylic acid (21.6 g) and (~) dehydro-
abietylamine (34.26 g) were mixed together in hot industrial
methylated spirits(1000 ml) then allowed to stand at room temperature
for 24 hours. The precipitate which formed was collected (20 g)~
the filtrate concentrated to 600 ml and left for 48 hours when
further solid product (4 g) formed. The combined product (24 g,
m.p. 204 - 210 ) was repeatedly crystallised from industrial
methylated spirits-methanol to constant m.p. 229 - 230C (3.0 g)
then the mother liquors from the last two recrystallisations were
combined, reduced in volume and the solid product (5.6 g) collected.
~his salt was converted to the free carboxylic acid (5.5 g),
~ D + 60.1 (1% in chloroform) in the standard manner
then recrystallised twice from toluene to give (+)1,4-benzodioxan-
2-carboxylic acid (0.23 g), m.p. 98 - 99C, _CD = + 62.1 (1%
solution in chloroform).
Analysis %:-
Found: C, 60.3; H, 4.4
Calculated for CgH8O4 ' C, 60.0; H, 4.5.
(PLC. 272)
;
s9
(B) t~ 4-Benzodioxan-2-carboxylic acid
The initial mother liquors (600 ml) from the previous .
experiment were evaporated in vacuo and the oily residue was taken
up in acetone (250 ml) then set aside until crystallisation was
complete. The solid product (10.0 g) was collected, crystallised
from acetone then the salt (6.0 g) converted to the free acid in the
standard manner using dilute sulphuric acid. The crude product
was taken up in chloroform, chromatographed on silica gel (10 x
50 mm. column size) eluted with chloroform, evaporated in vacuo
then crystallised from toluene to give (-) 1,4-benzodioxan-2-carboxylic
acid (0.90 g), m.p. 98 - 99 C, C~D = -66.1 (1% solution in chloro-
form).
Analysis %:-
Found: C, 59.9; H, 4.5
Calculated for CgH8O4 C, 60.0; H, 4.5.
Preparation 12
N-(1,4-benzodioxan-2-carbonyl)homopiperazine
This compound was prepared as in Preparation 1 using
homopiperazine in place of piperazine. A sample of the hydro-
chloride salt was recrystallised from methanol, m.p. 189C.
Analysis %:-
._
Found: C, 56.2; H, 6.2; N, 9.3
Calculated for C14H18N23 HCl C, 56.3; H, 6.4; N, 9.4.
(PLC. 272)
: ~ ., ,:: : . :.-
,: .:: : .: . :: :: :
,; . : ::
.
59
.
Preparation 13
6- and 7-(mixture) Chloro-1,4-benzodioxan-2-carboxylic acid
(A) Chlorine gas was passed into a stirred ice cold solution
of methyl 1,4-benzodioxan-2-carboxylate (10 g) in chloroform (100
ml) in the presence of aluminium chloride (0.06 g). The reaction
was stopped after 20 minutes then the solution purged with nitrogen,
washed with water, sodium bicarbonate solution~then water again,
dried (Na2SO4) and evaporated in vacuo to leave a mixture (1:1 by
C13 n.m.r. spectrosco~y)of methyl 6- and 7-chloro-1,4-benzodioxan-
2-carboxylate (12.0 g).
(B) A sample of the above product (1.4 g) in ethanol (20 ml)
was treated with a solution of sodium hydroxide (0.25 g) in
; water (1 ml) at room temperature when a black colouration developed.After 48 hours at room temperature, the mixture was concentrated
in vacuo, dlluted with water, extracted with chloroform and the
chloroform layer discarded. The aqueous phase was acidified with
concentrated hydrochloric acid, extracted with chloroform, then
th6 combined extracts dried (MgSO4) and evaporated in vacuo to
give a mixture (1.0 g) of 6- and 7-chloro-1,4-benzodioxan-2-
carboxylic acid, m.p. 145 - 146C, with consistent spectroscopic
properties.
(PLC. 272)
: : . - : :.,~. .~,; :., ,
:~ - . ::.......... . .
~ s9
~ 42-
Preparation 14
2-Methyl-1,4-benzodioxan-2-carboxylic acid
Jones' reagent (33.3 ml) was added dropwise to a
¦ stirred solution of 2-hydroxymethyl-2-methyl-1,4-benzodioxan (5 g)
in acetone (300 ml) at 5C, then the reaction was allowed to
attain room temperature. Isopropanol (10 ml) was then added
followed by water (200 ml), the solution extracted with chloroform
and the extracts evaporated in vacuo. The residual oil was taken
up in chloroform (200 ml) then extracted with dilute sodium bicar-
bonate solution and the aqueous phase further washed with chloro-
form. The aqueous phase was then acidified with hydrochloric acid,
extracted with chloroform, the combined extracts washed with water,
dried (MgSO4) and evaporated in vacuo to give 2-methyl-1,4-
benzodioxan-2-carboxylic acid (1.7 g). A sample was recrystallised
from toluene, m.p. 133 - 134C.
Analysis ~:-
Found: C, 61.8; H, 5.2
Calculated for C1oH1004: C, 61.9; H, 5.2.
Preparation 15
6- and 7-~mixture)N,N-dimethylsulphamoyl-1,4-benzodioxan-2-
carboxylic acid
tA) Catechol (180 g) was added in portions to stirred sulphuric
acid (138.5 ml) so that the reaction temperature remained below 25C.
' - .
tPLC. 272)
: . : : . : .. ..
:. ,,: : . : : . .
:., .. : - . ' :. . . ' :.::: ~ : : ::,: ~ ::
- :; :. .~ , . .:. :
, :: :: :- ~
s9
- 43-
After addition was complete, the semi-solid mixture was heated at
45 C for 60 minutes then cooled to room temperature and poured
into ice-water (700 ml). The solution was neutralised with solid
barium carbonate, the barium sulphate collected, the filtrate
acidified to pH 1 with concentrated sulphuric acid then refiltered.
The filtrate wàs evaporated to leave crude 3,4-dihydroxybenzene-
sulphonic acid (182.40 g) which was used without purification.
(B) The above product (182.40 g) was acetylated in the standard
manner using acetic anhydride (300 ml) in pyridine (800 ml) and
the crude diacetoxy product (302.49 g) used directly.
(C) Phosphorous pentachloride (378 g) was added portionwise
to a stirred solution of the pyridinium salt of 3,4-diacetoxy-
benzene sulphonic acid (302.49 g) in chloroform (1000 ml) at 0C
so that the reaction temperature did not rise above 15C. After addition
temperatureovernight then
wascomplete, the reaction mixture was stirred atroo~ flltered, the chloro-
form solution evaporated in vacuo and the residual oil poured into ice
water. The aq~leous phase was extracted with chloroform, the
combined extracts dried (Na2SO4) and evaporated in vacuo to leave
a semi-solid residue which was recrystallised from carbon tetra-
chloride. This product (26.74 ~) was treated with aqueous dimethyl-
amine (265 ml, 15~ solution) at 20 C, the reaction left at room ;~`
temperature overnight then the solution evaporated in vacuo. The
dark residue was diluted with acetone (250 ml), then decanted,
the solution evaporated ln vacuo and the residual oil stirred with
an equal volume of sodium hydroxide solution at room temperature for2 hours.
(PLC. 272)
- : , ~ . '' . i:
: ~ .. . -: .,
:: .: : .
:,: . - ~- - :
s9
. ~ 44-
The solution was then acidified with concentrated hydrochloric acid
and the resulting product crystallised from water to give N,N-
dimethyl-3,4-dihydroxybenzene sulphonamide, m.p. 142C.
(D) A solution of sodium hydroxide (0.61 g) in water (5 ml)
was added dropwise to a stirred suspension of the above product
(3.0 gm) and epichlorohydrin (1.43 ml) in water (15 ml) then the
reaction was heated at 80 for 1~ hours. After cooling, the
reaction was extracted with methylene chloride, the combined
extracts washed with water, dried (Na2SO4) and evaporated to leave
a mixture of 6- and 7- N,N-dimethylsulphamoyl-2-hydroxymethyl-1,
4-benzodioxan (2.84 g) as a sticky oil with consistent spectroscopic
properties.
(E) Potassium permanganate.(2.15 g) was added in three
portions to a stirred suspension of the above alcohol (2.8 g) in
- 15 potassium hydroxide solution (0.59 g in 20 ml water) and acetone
(10 ml) at 5 C so that the reaction temperature did not rise above
10C. The reaction was left at room temperature for 3 hours then
the acetone evaporated and further potassium permanganate (1.5 g)
added followed by stirring overnight. Finally, more potassium
permanganate (3.0 g) was added and the reaction stirred at 35 -
40 C under nitrogen overnight. The resulting manganese dioxide
; was then collected, washed with water, the combined filtrates
acidified with concentrated hydrochloric acid and extracted with ~,
; chloroform.
t
. . - . I
(PLC. 272)
,1
:: , , .. ~ :
:: . -
: : . . :: : : :: ~: :: . . ~ , : , :, .
, :-:. . .. ::
:.:
.
$~ )59
~ 45 ~
The combined extracts were washed with sodium hydroxide solution
(5N 2 x 40 ml), the alkaline phase acidified with concentrated
hydrochloric acid, extracted with chloroform and the combined
extracts washed with water, dried (Na2SO4) and evaporated in vacuo.
The crude product (0.46 g) was combined with similar material
(0.21 g) obtained from re-extraction of the original manganese
dioxide to give a mixture of 6- and 7- N,N-dimethylsulphamoyl-1,
4-benzodioxan-2-carboxylic acid (0.67 g), m.p. 156 - 162C.
Analysis %:-
Found: C, 45.5; H, 4.6; N, 4.90
Calculated for C11H13NO6S: C, 46.0; H, 4.6; N, 4.9.
Preparation 16
cis and trans Ethyl 3-methyl-1,4-benzodioxan-2-carboxylate
These compounds were separated from each other by
15 preparative HPLC and were identified by n.m.r. spectroscopy
according to published data (see e.g. J. Med. Chem., 10, 880, 1967 ).
Each isomer was hydrolysed to the corresponding acid which was
converted to the acid chloride without further characterisation.
(PLC. 272)
- , : : .
: . : - - .. .. .
, . - ' ~ : ' . ' . ' : ~ : ,
. .. : : .
, . .
. . . , . : . ..
)59
46
Preparation 17
4-Amino-6,7-dimethoxy-2-(3-methylpiperazin -1-yl)quinazoline
4-Amino-2-chloro-6,7-dimethoxyquinazoline (8.05 g) and
2-methylpiperazine (10 g) were heated under rerlux in butanol for
15 hours. The reaction was then evaporated ln vacuo and the
residual oil was taken up in chloroform (200 ml), washed with
water (4 x 50 ml), dried (Na2SO4) and evaporated in vacuo. The
residual oil (13 g) was recrystallised from isopropanol to give
4-amino-6,7-dimethoxy-2-(3-methylpiperazin-1-yl) quinazoline hemi-
hydrate (3.0 g), m.p. 185 - 187C.
Analysis %:- ;
Found: C, 58.1; H, 6.8; N, 22.8
Calculated for C15E~21N5O2~H2 C, 57.7; H, 7.1; N, 22.4.
Preparation 1 a
Uixture of 6- and 7-carbethoxy-1,4-benzodioxan-2-carboxylic acid
(A) Sodium hydroxide solution (1.94 g in 16 ml water) was
added dropwise at room temperature to a stirred suspension of epi-
chlorohydrin (4.6 ml) and ethyl 3,4-dihydroxybenzoic acid (8 g)
when a solution resulted. The reaction was then heated at 80C
for 13~ hours, cooled and extracted with dichloromathane, the
extracts washed with water, dried (Na2SO4) and evaporated in vacuo
to leave a mixture of 6- and 7-carbethoxy-2-hydroxymethyl-1,4-
benzodioxan (10.87 g) as a sticky oil with consistent spectroscopic
properties.
(PL(. 272)
:';
. ::- . . . ... . .
. .
)S9
_ 47
(B) The above alcohol (5O0 g) was oxidised with Jones reagent
t12.3 ml) in acetone (70 ml) as described previously (Preparation 9)
to give a mixture (2:1 by HPLC) of 6- and 7-carbethoxy-1,4~benzo-
dioxan-2-carboxylic acid (1.78 g) with consistent spectroscopic
propertles.
Preparation 19
Mixture of 6- and 7-carbamoyl-1,4-benzodioxan-2-carboxylic acid
I
~A) A stirred suspension of potassium carbonate (5.6 g) and
4-cyanocatechol (2.7 g) in acetone (50 ml) was heated under reflux
for 4 hour then methyl 2,3-dibromopropionate (4.9 g) added dropwise.
The resulting mixture was heated under reflux for 48 hours, then
evaporated in vacuo, the residue diluted with water and extracted
with chloroform. The combined extracts were washed with water, .
dried (MgSO4) and evaporated in vacuo to give a mixture of methyl
6- and 7-cyano-1,4-benzodioxan-2-carboxylate ( 1.0 g). A sample
was recrystallised from isopropanol, m.p. 95 - 96 C.
Analysis ~
!
Found: C, 60.2; H, 4.2
Calculated for C11HgNO4: C, 60.25; H, 4.2.
HPLC analysis of the crude product mixture showed a
mixture of two components in the ratio of 5:2.
...
tPLC. 272)
.:, . .. .
:' ' : :. '
:- .:
59
- 48 -
~B) Sodium hydroxide solution (0.7 ml, 6N) and hydrogenperoxide (1 ml, 30%) were added dropwise to a stirred suspension
of the above cyano-ester (0.5 g) in ethanol (4 ml) at 15C. The
mixture was then heated at 40 - 50 C for 2 hours, cooled, acidified
with concentrated hydrochloric acid, the product collected and
recrystallised from methanol/ethanol/water to give a mixture of
6- and 7-carbamoyl-1,4-ben~odioxan-2-carboxylic acid, m.p. 258 -
260C.
Analysis ~;-
Found: C, 53.2; H, 4.1; N, 6.4
Calculated for C1oHgNO5: C, 53.8; H, 4.1; N, 6.3.
: ~PLC. 272)
.. . . : - . . : :
.
