Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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7~
sac~ und of the invention
In spite of the large number of known pharmaceutically-
active compounds for the treatment of inflammatory and
allergic condition~, as well as for the treatment of
ulcerous conditions of the gastro-intestinal tract, there
i9 a need for new compounds for treating these indications
which are less toxic than the known compounds and/or which
are more effective than the known compounds. It is an object
of the present invention to provide such new compounds.
Summary of the invention
Thus, the present invention provides new chalcone
derivatives of the general formulae:-
~ ~R3 (Ia)
and /CO
~ `~ CO - CH -~C~ ~ R3 (Ib)
wherein Rl is a hydroxyl, carboxylic acid or sulphonic acid
group or a carboxyalkoxy or sulphoalkoxy radical, the alkoxy
moieties of which contain up to 3 carbon atoms, R2 and R3,
which may be the same or different, are hydrogen or halogen
atoms, hydroxyl groups or alkoxy radicals containing up to 6
carbon atoms and R4 is an alkyl, hydroxyalkyl, alkoxy, car-
boxyalkoxy, sulphoalkoxy or carboxyalkylcarbonyloxyalkyl
radical, the alkyl and alkoxy moieties of which contain up
to 6 carbon atoms, or a carboxylic acid or sulphonic acid
group, with the proviso that the compounds of the general
formula (Ia) always contain at least one carboxylic acid or
sulphonic acid group; and the non-toxic inorganic and organic
salts of those compounds containing at least one carboxylic
acid or sulphonic acid group.
Detailed description of the invention
It is to be expected that the ethylenic double
bond of the new chalcone derivatives (Ia) is in the more
thermodynamically stable trans form.
Carboxyalkoxy radicals Rl and R4 are preferably of
the formula -O--~CH2 ~ COOH in which n is an inteyer e~ual
to or greater than 1 and is preferably 1 to 3.
-2-
~7~51~
The alkyl, hydroxyalXyl and alkoxy radicals con-
stituting or forming part of substituent~ in the new
compounds according to the present invention preferably
contain up to 6 carbon atoms and more prefera~ly contain
up to 3 carbon atoms~
The new compounds according to the present invention
can be prepared, for example, by condensi.ng an acetophenone
derivative of the general formula:-
1 ~ CO - C~ (II)
in which Rl and R2 have the same meanings as above, with
an aldehyde of the general formula:-
OHC ~ R3 (III)
R~
in which R3 and R4 have the same meaning~ a~ above.
This condensation reaction i~ prefera~ly carried outin the presence of a strong base, for ex~mple an alkali
metal hydroxide, in an aqueou3 or aqueou3 organic medium~
The reaction can be carried out at a temperature
between ambient temperature and the boiling point of the
reaction mixture~
When a product is obtained in which R4 i~ a Xydro~y-
alkyl radical, this can, if desired, be subsequently
reacted with an appropriate reacti~e derivative of an
alkane-dicarboxylic acid to give the corresponding carbvxy-
alkylcarbonyloxyalkyl compoundO
-3-
. . ~ . , .
7~
When R~ is a carboxyl group in the o-position, the
product can, if de~ired, be subsequently lactonised to
give a compound of general formula (Ib)o
Since the product obtained contain~ at leaRt one
free carboxylic or sulphontc acid group, this can, if
de~ired, be subRequently reacted with a non-toxic inorganic
or organic ba~e to give the corresponding salt~
The following Example~ are given for the purpo~e of
illustrating the present i~vention:-
Example 1.
a) 50 g. m Toluic acid were dis~olved in 750 ml.
methanol and 15 ml. concentxated sulphuric acid added
thereto. The reaction mixture was refluxQd for 3 hours,
whereafter thin layer chromatography (petroleum ether/
dichloromethane/acetone 6:3:1 v/v/v) showed esterification
to be complete. The solution wa3 reduced to 1/3 volume on
a rotary evaporator, diluted with water and extracted with
chloroform. The organic extract wa~ wa3hed with aqueous
sodium bicarbonate solution to remove any acid and then
with water until the aqueous washings wer~ neutral~ The
extract was then dried with anhydrou~ ~odium sulphateO
Removal of ~olvent ~ave an almo~t colourle~s o~il whlch wa~
distilled under water pump pre~ure to yield a major
fraction (b.p. 120 - 121C./14 mm.Hg)~ Yield 48~1 g.
methyl m-toluate~ The product was pure by thin layer
chromatography and the in~ra-red spectrum ~howed ester
absorption but no acid ab~orption.
b) 32.7 g. methyl m-toluate were placed in a 1 litre
7~
round bottomed flask equipped with a mechanical stirrer.
To this were added 340 ml. glacial acetic acid and then
339 ml. acetic anhydride, the reaction mixture ~eing
finally cooled to 0C. (ice/~alt bath). 51 ml. concentrated
sulphuric acid were add~d alowly, en3uring that the temp~r-
ature did ~ot exceed 6C., the addition taking approximat~ly
2 hour~. When all the acid had been ~dded, the x~action
mixture was again cooled to 0C. and 60 g. chromium trioxide
were added in small portion~, maXing ~ura that the temper-
ature did not ri~e above 5C. When addition wa~ complete,
the reaction mixture wa8 allowed to wa~m to 10C. for 10
minute3 and then poured into ~.5 litres ice-water~ Th~
re~ultant mixture ~as allowed to atand for 30 minute3,
then filtered, washed with water and pre~d dry to give
25.8 g. material after final drying. Thi8 crude product
was finely ground and thoroughly mixed with 200 ml. 2%
aqueous ~odium carbonate 301ution. ~he undi~solved
material wa~ filtered off, washed with water and dried in
a vacuum oven at 60C~ to give 20.8 g. 3-carbomethoxy~enzal-
diacetate which wa~ not further puri~ied. '~hin layer
chromatography indicated that the product had a purity
greater than 99%.
c) 23. a ~. 3-Carbomethoxyben~aldiacetate, 50 mlO
ethanol/ 50 ml. di~tilled water and ~ ml. concentrated
sulphuric acid were refluxed on a wat~r-bath for 1 hour.
The reaction mixture wa~ then diluted with 300 ml. water
and extracted with diethyl eth~r. The organic ~xtra~t
was washed with water, aqueou9 ~odium bicar~na~e ~ol~ltion
and finally with water until the washings were neutral.
The extract was dried with anhydroua ~odium sulphat~,
7~S~
filtered and the filtrate evaporated to give an almo~t
colourless oil. Thi~ wa~ dried in a vacuum desiccator
for a further 2 houra. Yield of methyl 3-formylbenzoate
11.40 g. The oil solidified ~n sta~di~g at ambient temp-
erature to give a white solid. Thi,n layer chromatography
(petroleum ether/dichloromethane/acetone 6:3:1 v/v/v)
~howed the product to be more than 99% pure. The material
had a melting point of 51 - 53C.
d) 20.5 g. 4-Hydroxyacetophenone, 25 g. methyl 3-
formylbenzoate, 250 ml. ethanol and 250 ml. 1~% aqueou~
~odium hydroxide qolution were ~tirred at 50C. for 4
hour~. Thin layer chromatography (9:1 chloroform/methanol
+ 1% acetic acid) then indicated that the condensation had
gone to completion. The reaction mixture wa~ allow~d to
cool and then left at ambient temperature overnight.
Careful acidification with concentrated hydrochloric acid
yielded a pale yellow solid which was filtered o~f, wa~had
well with water until the wa~hing~ were nautral and then
dried in a vacuum oven at 100C. Thiq yielded 22.9 g.
3-carboxy-4'-hydroxychalcon~. Thin layer chromatography
and ga~ liquid chromatography both indicated that the
material wa~ at lea~t 99% pure. The compound h~d a m~lti~g
point of 273 - 276C.
Example 2.
16.32 g. 4-Hydroxy^acetophenone (m.p. 111 - 113 C.1,
18.0 g. 4-carboxy benzaldehyde (m.p. 245 - 247C~), 180 ml.
ethanol and 180 ml. 1~ aqueous aodium hydroxide ~olution
were ~tirred at 60C. for 5 hoursO ~ reaction ml~tur~
wa,a allowed to cool and then left at ambient temperatur~
overnight. Care~ul acidification with concentrated hydro-
chloric acid yield~d a pa~e yellow solid which wasfiltered off, washed onc~ with ethanol and th~n with wat~r~
until the washings l~re neutral. The ~olid wa~ dried to
constant weight on a steam bath (yield 23.6 g.), dis~olv~d
in hot meth~nol/chloroform, filter~d and tha ~olution
boiled down to about 400 ml. and left to cool ovexnight~
~le resulting pale yellow ~olid was filtered, washed with
methànol and dried in a vactlum oven at 80 & . (yield 13.3 ~
Thin layer chromatography (chloroform/methanol/acetic acid
~9:10:1 v/v/v) and ga~ liquid chromatography (5' 1~ OV-17,
t = 240C.) both indicated ~he mat~rial to be at lea~t 99%
pure. The 4-carboxy-4'-hydro~y chalcone thus obtained had
a melting point of 300 - ~01~5C.
Example 3.
a) A solution of 8.8 ~. sodium hydroxide and 11.35 g.
chloroacetic acid (20~ exce~s~ in 110 ml. distilled water
was added to 13.6 g. 4 -hydro~y acetophenone and the r~ult-
ant solution was refluxed on an oil bath with magnetic
Qtirring ~or 8.5 hours. At regular intervalsl the pH was
measured and kept in the 8 - 9 ran~e by thè f urther
addition of aqueou~ ~odium hydroxide solution a~ nece~a~yO
Thin layer chromatography (petroleum ether/dichloromethane/
acetone 6:3:1 v~v/v) showed the reaction to be approximately --.
60% complete but refl~x was discontinued a8 no further
progress was being made. The hot reation mixture was
acidified with an exce~s of concentrat~d hydrochloric acid
and the white solid filtered off, washed with wat2r and
dried (yield - 12.45 g.~. This product wa~ dis~olved in
5% aqueous sodium carbonate solutlon and wa~hed sev~ral
times with ethyl acetate. Th~ aqueous layer wa~ then
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~7~5~
acidified with hydrochloric acid and the 301id filtered
off, washed with water and dried (yield = 10~2 g.)~ Thi~
mat~rial w~ cr~tallised from ethyl acetat~ to give 9.8 g.
of crys~alline ~-carboxymethoxy-acetophenone which w~8
~hown to be 99% pure by thin layer chromatography (chloro=
form/methanol/aceti~ acid 89:10,1 ~/~/v). The material
had a melting point of 1~3 - 185C.
b) 7.76 g. 4-Carboxymethoxy-acetophenonQ and 4~80 g.
m-tolualdehyde were placed ~n a 250 ml. round-bottom2d
fla~k equipped with a magnetic stirrer and a r2flux con-
den~er and heated on an oil bath. 50 ml. ethanol and
50 ml. aqueous 10% ~odium hydroxide ~olution w~re added
and the stirred mixture heated to 30C., whereupon the
mixture ~olidified. A ~hin layer chromatogram showed the
reaction to have proceeded about 70%~ 100 ml. ~thanol/
water (1:1) were added and the mixtur2 wa3 heated to 60C.
and thoroughly shaken for 15 minute~. Upon cooling,
crystalli~ation took place and the solid was filtered o~,
wa~hed with a littl~ water and sucked dry. mi~ wa~ then
cryqtalli~ed from methan~l containing 1~% of a 1~ aqueou~
~olution of sodium carbonate7 The white cry5talllne
needleæ were filtered of~, wa3hed with a littl~ water,
washed thoroughly with diethyl e~her and dried in a vacuum ; -
~at 70C. Yield 7.0 g~ A second ~rop of 1.6 g. ~a3
obtained from the mother liquor~. Thin layer chromatography
(n-butanol~ammonia 10:1 v/v) ~how~d th~ produc~ to b2 more
than 99~ pure. Gas chromatography (5' 1% OV-17 colu~n at
240C.) also showed better than 99% purity. The sodium
~alt o~ 4'-carboxymetho~y-3-methyl-chalcone thu~ obtained
had a meltin~ point of 315 - 318C.
..
L7~5~
Example ~.
15.52 g. ~-Carboxymethoxy acetophenone and 12.00 g.
4-carboxy-be~zald~hyd~ were di~olved in 70 ml. 10%
aqueou~ sodium hydrox~de solution and left at ambient
temperature for 16 hours. An equal volume of methanol was
added and the precipitated solid filtered off, washed
thoroughly with methanol and dried. ~(Yield ~ 23.8 gO).
Thi~ material wa~ di~solved in the minimum o~ hot water
(120 ml.) and an equal v~olume of methanol added. Cry~tall-
iqation took place and, when cold, the product was
filt~red off, wa hed thoroughly with ~ethanol and dried
to constant weight. Yield 13.8 ~. di~odium ~alt of 4-
carboxy-4'-car~oxymethoxy-chalcone. Thin layer chromato-
graphy (e~hyl acetate~methanol/30% tr~ethylamine 70~20:40
v/v/v) showed the material to be more than 99% pure, m.p.
360C,
A sample of the disodium salt was converted into the
free acid whic21 had a melting point of 313 - 314C.
Example 5.
a? To 24.4 g~ ~-hydroxy bsnzaldehyde w~s added a
Rolution of 17.6 g. ~odium hydroxide and 22.7 g~ chloro-
acetic acid in 150 ml. dis illed water and the resultan.
~olution was refluxed. After one hour, the pH of the
~olution had dropped,to 7 and a further 1 g. of sodium
hydroxide was added. After a further 2 hours reflu~jn~J,
another 1 g. of ~odium hydroxide wa~ added. Thin layer
chromatography (chloroform~methanol/acetic acid 89:10.1)
showed the reaction to be about 8~% co~plete ~o refluxin~
was continued for a further 2 hour~. Th~ hot ~olùtion wa~ ~;
acidified with concentrated hydrochloric acid and
~7~5~
cry~talli~ation took place upon cooling~ The 301id was
filtered off, washed with water and dried: yield 22.2 g.
Thi~ material wa~ crystalli~ed from ethyl acetatQ and then
from chloroform/methanol. YieLd 11.6 g. 4-carboxymethoxy-
benzaldehyde, which was more than 99% pure by thin layer
chromatography~ The product had a meltiny point of 203 -
204C.
b) 9.75 g. 4-Carboxymethoxy-ac~tophenone and 9.O g.
~-carboxymethoxy-benzaldehyde were di~solved in 100 ml.
5% aqueou~ sodium hydroxide solution and left for 16 hour8
at ambient temperature. A solid which had precipitated
wa~ filtered off, washed thoroughly with methanol and dried
to const~nt weight, yield 18.0 g. Thi8 material wa~
dis~olved in 230 ml. water, filtered off and an equal
volume of methanol added. Crystalli~ation took pla~e and
the solid wa~ filtered off, washed with methanol ~nd dried,
yield 14.0 g. Thi~ purification was repeated to give
11.8 g. material. Thin layer chromatography {ethyl acetat~/
methanol~30% triethylamine 70:20:40 v/v/v) ~howed the
product to be more than 99% pure. The disodium ~alt of
4,4'-ditcarboxymethox~ chalcone thu~ obtained had a
melting point of 275 - 276C.
Example 6.
15.52 g. 4-Carboxymethoxy acetophenone and 13.1 y.
methyl 3-formyl benzoate were di~301ved i n 80 ml. a~ou8
10% ~odium hydroxide solution, left at amb~ent t~mperature
for 16 hour~ and then heat~d to 50Co for 30 minute~. An
equal volume of m~thanol was added an~ the pracipit~t~d
~olid wa~ filtered off, wa~hed thoroughly with meth~nol
and dried, yield 18.4 g. This material was di~olved ln
-10-
,
7~5~
the minimum of hot water and the clear ~olution wa~
diluted to 200 ml. with methanol. Cxy~talli~ation took
place and, ~en cold, the product w~s filtered off, wa~hed
thoroughly with methanol and dried to con~tant weight
yield 12.1 g. Thin laye~ chromatography (ethyl acetate/
methanol/30% trimethylamine 70:20~40 v/v/v) ~howed the
material to be more than 99~ pure. The di~odium salt of
3-carboxy-4'-carboxymethoxy-chalcone thus obtained had a
melting point of > 360C. The water content was found to
be 4.9% (Karl Fischer) and a l:l compound/water molar ratio
would give a water content of 4.64~. Since further drying
at 110C. under water pump ~acuum did no~ reduco the water
content, the prod~ct probably contain~ one molecule of
~ater of cry~tallisation.
A sample of this di~odiu~ ~alt was converted into
the free acid. The melting point of the diacid was 296 -
298C. twith decomposi~ion).
Example 7.
a) A solution of 220 g~ ceric ammonium nit~ate
(technical grade) in 250 ml. di3tilled water waq prepared
at 38C. and one half thereof added to 27.6 g. finely
ground benzene-1,4-dimethanol and the mixture ~wirled~ :
A~ reaction occurred, ~he temperature ro~e to 57C. and
the dark colour di~appeared. 'rhe remainder of the oxidan~.
wa~ added in portion~, keeping the temperature ju~t b~low
60C, When the reaction wa~ complete, the reactlon mixture
was cooled, neutrali~ed with a~ueou~ 1~% ~odium hydroxid~
~olution and fil~ered. The solution Wa8 extracted with
two 125 ~1. portion~ oP petroleum ether ~b.p~ 60 - ~0CO~
diethyl ether (4:1) and the aqueou~ layer then extracted
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.,.. '! ' ' " . .:. .. ", ,,,, . . ~., .
~7~S~
with three portions of chloroform~ The chlorofonm extract~
were combined, washed once with a ~aturated aqueou~ 801uti~n
of sodium bicarbonate, dried over anhydrous sodium ~ulphat~,
filtered, evaporated in a rotary evaporator and dried
yield 18.5 g. This m~terial wa~ crystalli&ed from toluen~
in a refrigerat~r ~o giv~ 12 g~ of white crystals of 4-
formyl-benzyl alcohol, ~Yhich was shown to be 99% pure by
thin layer chromatography. The product had a ~elting
point of 39 - 41C.
b) To a mixture of 8.16 g. 4-formyl-benzyl alcohol
and 11.64 g. ~-carboxymethoxy acteoph~none wa~ added 150 m~0
aqueou~ 5% sodium hydroxide ~olution and the solution wa~ -
stirred at ambient temperature. A solid precipitated and
after 10 minutes the mixture became too thick to ~tir 30
a further 50 ml. of aqueous 5% sodium hydroxide ~olu~ion
were added. Ater ~tirring for 3 hours, the reaction
mixture wa~ left to ~tand overnight. The ~olid was
filtered off, wa3hed three times with aqueous 5% sodium
hydroxide ~olu~ion, boiled wi~h 300 ml. metllanol, filt~red
off, washed with methanol and dried; yield 180 0 g. Thi~
material was dissolve~ ~n 200 ml. hot water and the ~olution
was filtered, boiled down to about 140 ml. and allow~d to
cool. The ~olid obtained was filtered off, wa~hed with
methanol and dried yield 9.3 g. Thin layer chromatograp~y
(ethyl acetate/methanol/30% trimethylamine 7n2:4 v/v/v~
showed the material to be more than 99~ pureO The mono~
~odium salt of 4'-carboxyn~tho~y-4-hydro~ymethyl-chalcon~
thus obtained had a melting po~nt of > 360C. ~decot~po~ition
from a~out 326C.). The corre~pondin~ fre~ acid had a
melting point of 203 - 204C~
12-
51~
Exam~le 8.
a) ~0 g. 3-Fluoro~4-methoxyacetophenone were
di~;solved in 250 ml. dry benzene. In a separate ves~el,
a ~olution of 115 g. aluminium bromide in 350 ml. benzene
was prepared~ solution was filtered to re~ove ~ n801-
uble impuritie~ and then added to the above ~olution7
When the initial exothermic reaction had ce~sed, the
reaction mixture was refluxed :Eor 2 hour~ ter thi~
time, thin layer chromatography indicated that th~ reaction
was complete.
The reaction mixture was wor~d up hy pouring care-
fully, with ~tirring, into 300 ml. ice~'water. When all
the mixture had been quenched, the resultant two-layer
mixture wa~ poured into a ~eparating funnel and 200 mlO
ethyl acetate added thereto. The organic laye/r wa~ wa~hed
three ~ime~ with water, dried over anhydrous sodium
sulphate and evaporated in a rotary evaporator to give
20.8 g. of a pale yellow ~oli~. Thi~ solid wa~ di~-~olved
in the minimum amount of ethyl acetate and treated with
charcoal. Th~ 301ution thu~ obtained wa3 r~duced in
volume ta about 50 ml. ~y boiling, then 100 ml. b~nzene
were added thereto and the ~olution again reduced to 50 ml.
Upon cooling, the material cry~tallise~. It wa~ filtered
off ~ washed twice with benzene and dried in vacuo at 70C.
'co give 19 . 6 g~ of colourle~ cry~talline 3-fluoro-4-
hydroxyacetophenone, which was ~hown to be pure by thin
layer chromatography; m.p. 130 - 132C.
18 9. 3-Fluoro-4 hydroxyacetophenone were di~solv~d
in a solution of 11.5 g. ~odium hydroxide in 200 ml. water~
To the solution ~ere added 12.5 g. chlo~oacetic acid and
--13--
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7~D$~
the mixture ~hen refluxed. The reaction mixture wa~
allow~d to reflux for 2 hours, wherea~t~r thin layer
chromatography indicated that a 60% reacticn had tak~n
place. The pH of the 301utlon wa~ alao checked ~nd ~ound
to be low (about 7). 005 g. Sodium hydroxide wa~, there-
fore~ added to th~ reaction mixture and ref luxing continuQd
for 10 hours. min layer chromatography aftar this time
showed that the reaction had ~ill only proceeded to 60
50 the reaction mixture was worked up~
The reactio~ mixture wa~ cooled ~o ambient temperature
and extracted ~hree times with ethyl acetate to remov~
starting material for recycling. l~e aqueou~ layer was
acidified to pH 1 wi~h concentrated hydrochloric acid and
the precipitated ~olid collected, wa~hed thre~ times with
water and dried ln vacuo at 70C~ to give 14.05 g. of a
pale yellow solid which was ~hown by thin layer chromato~
graphy to be 96 - 97æ pure.
The material wa~ dis~olved in ethyl acetate, treated
with charcoal and filtered. Upon r~ducing the volume of
the filtrate~ cry~tallisation occurred~ ~he cry~tal3 ~re
filtered off, wa~hed with cold ethyl acetate and dried in
vacuo at 70Co to give 10 g. of a colourleAs~ cry~talline
solid which was shown to be more than 99% pure by thin
layer chromatography. The 3-fluoro-4-carboxymethoxy-
acetophenone ~hus obtained had a melting point of 170 -
172~C.
b) 10 9~ 3-Fluoro-4-carboxymethoxy acetophenone and
7.1 g. 4-carboxybenzaldehyde were d.i~solved in 1~ aqueou~
sodium hydroxide ~olution. Rapid solution wa~ aAsurod by
stirring vigorously and after a~ou~ 90 s~conds the reactio~
mixtuxe ~olidified.
-14-
5~
The 301id wa~ left to stand overnight and the
following day it was heated to 60C. for one hour. While
still hot, 200 ml~ methanol were added, with stirring, to
the reaction mi~ture and the re~ultant ~lurry allowed to
cool. When cool, the precipitatecl product was collected,
washed with methanol and dried in vacuo at 60C. to give
13.6 g. of a yellow solid.
m is ~olid was redis~olved in the minimum of water
and filtered. To the still hot solution wa~ then care-
fully added ~fficient methanol to precipitate all the
product (about four to five times the quantity of water).
When cool, the ~olid material was collected, wa~hed
with methanol and dried ln vacuo at 60C. to giv~ 10.1 g~
of a pale yellow crystalline material ~hich was ~hown to
be pure by thin layer chro~atography. The disodium sal~
of 4-carboxy-3'-fluoro-4'-carboxymetho~y chalcone thu~
obtained had a melting point of > 350Co
Example 9.
10 g. 3-Fluoro 4-hydroxyacetophenone and 9.4 g. 4-
carboxybenzaldehyde were di~solved in 120 ml. 10% aqueous
sodium hydroxide solution and dis~olved by vigorously -~
stirring. The reaction mixture was left overnight and on
the following morning heated to 60C. for 1 hour. The
reaction mixture wa~ then cooled and acidifi~d to pH 1
with concentrated hydrochloric acid. The prec~pikated
solid was collected, wa~hed well with water and dried in
vacuo at 70C. to give 15.1 g. of a pale yellow ~olidO
This solid was recry8tallised from chlorofonm/
methanol (1:4) to give a cry~talline, pale yellow product
which was washed with cold methanol and driad in vacuo at
60C, to give 10.1 g. 4-carboxy-3'-f1.uoro 4'-hydroxy-
chalcone.
Thi~ product ~a~ ~hown to be pure by th.in layer
chromatography; m.p. 272 - 274C. ~decomp.).
Example 10.
a) 16.3 g. 4'-Carboxymethoxy-~-hydroxymethyl
chalcone (see Example 7) and 6.27 ~. ~uccinic anhydrid~
were dis~olved in 50 ml. anhydrous pyridine and tha ~ol-
ution was heated on a water-bath for 90 minute~. A thin
layer chromatogram ~howed the reaction to be com~lete.
The cold reaction mixture was poured into ice-water/
hydrochloric acid ~exces~) and the precipitated solid ~as
filtered off, wa~hed with water until neutral ~nd dried;
yield = 21.0 g. Thi3 material wa~ charcoaled a~d
crystallised from chlorofonm/methanol and the filtered
solid wa~hed with methanol and dried, yield - 17.2 g.
Thin layer chromatography ~howed an impurity to be still
pre~ent which was not removed by further cry~talli~ations
~o column chromatography wa~ carried out a~ follow3:
16.5 g. of the material were di3~01ved in chloroform~
methanol, 33 g. silica gel 60 were added and the mixture
waR evaporated to dryne3s~ ~is wa~ placed on a dry ~ilica
column ~660 g~) and eluted with chlorofonm/metha~ol (8:2)
containing 1% acetic acid. q~e pure fraction~ were com~
bined, evaporated and dried. Yield = 14.7 g~ 4'-carbo~y-
methoxy-4-~-carboxypxopionyloxymethyl-chalcone, which h~d
a melting point of 190 - 192&~ Ga~ chromatography showed
the material to be more than 99% pure.
b) 12.44 g. 4'-Carboxymethoxy-4-~-carboxypropio~yl-
oxymethyl chalcone ~re finely ground and ~lurried with
-16-
.. ;, , i . ..."~,...
s~
20 ml~ distilled ~ater. Th~ ~uspension wa~ magnetically
~tirred and 30 mlO aqueou~ l~/o sodium carbonate solution
were added dropwise. ~he rate of addition wa~ ~lowed down
towards the end a~ the re~ction became slower. The cloudy
~olution obtained was filtered and acetone added until
precipitation wa~ complete. The solid wa~ filtered off,
washed with acetone and dried to con~tant ~eight yisld
12.2 g. ~hin layer chromatography show~d ~he material to
be more than 99% pure. The di~odium ~alt of 4'-carboxy-
methoxy-4~~-carboxypropionyloxymethyl-chalcone thus
obtained had a ~nelting point of > 360C. lwith decomposi~ion
from 333C.).
Example 11
a) 32.4 g. ~odium hydroxide and 41.9 g. chloroacetic
acid were di~solved in 368 ml. di~tilled water. Thi8
solution was added to 50 ~ 3 hydroxyacetophenone and the
resultant solution was refluxed on an oil bath. After a
reaction period of 3 hour~, the pH of the ~olutio~ was
found to be about 6. A further 2 g. of ~odium hydroxide
were added to bring the pH up to about 9 and the solution
then heated under reflux for a further 8 hours. ~hin
layer chromatography on the cooled reaction mixture (p~ 8)
indicated that about 80% reaction had occurred and the
reaction mixture was worked up in the followi~g manner:
The reheated reaction mixture wa~ acidified dropwi3e with
concentrated hydrochloric acid and the precipitated solid
filtered, wa~hed thoroughly with water ~nd dried in a
vacuum oven at 80Co ~ yield 54.9 g. The 801id was
di~solved in 5% aqueou3 sodium car~onate ~olution and
washed ~everal times with ethyl acetate. The aqueou~
-17-
. , , - , ~ ~ .. , . . . . .;
'' ~ 1.. 7a351!3
basic layer was acidified, washed with water and dried in
a vacuum oven at 80C., yield 46.8 g. The crude product
wa~ di~solved in hot ethyl acetate, ch~rcoaled, concentrated
and left to crystallise a~ 0C. A white crystalline solid
was obtained. Yield of 1st crop material 29.0 g., yield
of 2nd crop material 5.0 g. The 3-carboxymethoxyaceto-
phenone thu~ obtained had a melting point of 121 - 123C.
b) 15.52 g. ~-Carboxym~thoxyacetophenone, 13.1 gO
4-carboxybenzaldehyde and 80 ml. lOY~ aqueous ~odium
hydroxide ~olution were mixed in a 250 ml. conical flas~
and stirred at ambient temperature for 30 seconds. After
this very brief period, the reac~ion mix~ure had ~olidi~ied.
Thin layer chromatography of a sample indicated that
approximately 9~ reaction had occurred~ T~e reaction
product wa~ heated and stirred on a water ~ath for 5 minutes
and 100 ml. methanol added~ The mixture wa~ ~tirred and
heated for a further 10 minutes and then cooled. ~e solid
was filtered off, ~ashed with methanol and dried in a
vacuum oven to c0~3tant weight; yield 26.0 g. Thi~ wa~
then di~olved in a minimum volume of hot water (about
175 ml.), filtered through a ~o~44 paper and metha~ol added
(about 350 ml.) until precipitation occurred. The resultant
mixture was cooled ~o ambient temperature, with ~tixri~g,
and then kept at 0C. ovexnight. Filtration gave yellow
cry~tals which were wa~hed well with methanol and dried in
a vacuum oven to constant weight; yield o~ l~t crop
material 17.2 g. Thin layer chromatography indicated that
the product wa~ pure. The di~odium ~alt o~ 4-c~rboxy-3'~
carboxymethoxy-chalcone thu~ obtained had a melting poi~t
of > 360C.
-lB-
~ ~t~ 5
Example 12.
15~52 g~ ~-Carbo~ymetho~yacetophenone and 9060 g.
p-tolualdehyde were placed in a 500 ml' round-bottomed
flask equipped with a magnetic stirrer and reflux conden~erO
To this was added 100 ml. of a 5% aqueou~ sodiu~ hydroxide
solution and the resulting mixture was ~tirred at amblent
temperature until precipi~ation occurred~ A further 50 mla
of 5% aqueou~ sodium hydroxide ~olution were added and the
reaction mixture stirred for 2 hours at ambient temperature~
After this period of time, thin layer chromatography
indicated that an approximately 50Y0 reaction had taken
place. After the addition of a further 50 ml. o 5%
aqueous sodium hydroxide solution, the reaction mi~ture
was heated to 60C. for 30 minute~, whereafter a thin
layer chromatogram showed ~he complete absence of starting
material~. The reaction mixture wa~ finally cooled and
the precipitated ~olid wa3 filtered of~, wa~hed wlth w~ter
and pre~sed dry. The ~olid was dissolv~d in hot water/
methanol (2:1) containing 500 mg. ~odium carbonate and
filtered hot. Concentration and cooling yielded, after
filtration and washing with water, 14 g. of first crop
material a~ a white solid. ~hi~ was the mono~odium ~alt
of 4-methyl-4'-carboxymethoxy-chalcone. ~hin layer
chromato~raphy indicated that the produc~ wa~ more tha~
99% pure. The compound had a~melting point of ~ 360C.
The corresponding free acid had a melting poin~ of 196 -
197C
Example 13.
17.46 g. ~-Carboxy~ethoxy acetophenone and 13.5 g.
recrystalli~ed 2-carboxy-benzaldehyde w~re dis~ol~ed in
--lg--
'7~51!~
75 ml. 10% a~ueous sodium hydroxide solution, warming to
about 50Co bPing re~uired~ After 45 minute~ at ambient
temperature, a thin layer chromatogra~ ~howed incomplete
reaction. The reaction ~ixture wa~ warmed to 50C. ~or
4 hour~ and left at ambient temperatur~ overnight. The
precipitated product wa3 filtered off, wa~hed with a
little methanol,and then wa~hed thoroughly with I.M.S.
After drying in a vacuum oven at 80C., 20~1 g. of product
were obtained. Thin layer chromatography ~ho~d this
material to be 98% pure. It wa~ finely ground, slurried
with 30 ml. methanol containing 1 pellet of ~odium
hydroxide, filtered, thoroughly washed with I~M~So and
dried; yield 18.4 g. Thin layer chromatography show~d
thi~ material to be more than 99% pure. ~he pH of a 10%
aqueous solution was found to be 9.8. ~fter a further
I.M.S. wa~h, the pH of a 10% aqueous ~olution was found
to be 7.2. The product had a melting point of > 360C.
It was the expected disodium ~alt of 2-carbo~-4'-carboxy-
methoxy-chalcone.
Example 14.
a) To 24.4 g. ~-hydroxybenzaldehyde were added a
solution of 17.6 g. ~odium hydroxide and 220 7 g. chloro~
acetic acid in 150 ml. di~tilled water and the re3ultant
solution heated under reflux for 1 hour~ The pH of the ~-
solution wa~ mea~ured and found to be about 8 AO a furth~r
1 g. sodium hydroxide wa3 added. Reflu~ was continued
and the pH checked periodically, ~odium hydroxide being
added in 1 g. quantities when required. The total
reaction time was 8 hours, whereafter the p~ wa~ 9 and a
thin layer chrom~togram showed that about 80% reaction hsd
-20-
taken place. The reaction mixture wa~ left to cool over~
night and then washed with ethyl acetate to remove ~tart-
ing material until the wa~hings were colourle~s~ Careful
acidification with concentrated hydrochloric acid gave a
brownish coloured precipitate which wa~ filtered, washed
well with water and dried to c~n~tant weight in a vacuum
oven yield 21.6 g. of crude material.
The crude product was cry~tallised from ethyl acetatc
to ~ive 17.8 g. of 1st crop material in the fonm of pale
buff coloured crystal~. Thin layer chromatography
indicated that this material wa~ more than 99~ pure. The
product, which had a melting point of 124 - 126~C., was
3-carboxymethoxy-benzaldehyde.
b) To 10.8 g. 3-carboxymethoxybenzaldehyde and
11.64 g. 4-carboxymethoxyacetophenone were added, with
continual ~tirring, 60`ml. of 10% aqueous sodium hydroxide
solution. The reaction mixture waq ~tirred for 30 minutes
at ambient temperature and then left at ambient temperature
for 1 hour, during which time a yellow ~olid precipitated
out. Since a thin layer chromatogram indicated that there
wa~ only a very small quantity of starting material le~t,
the reaction mixture was worked up by diluting with 60 ml.
methanol, filtering, wa~hiny the filtered ~olid with
methanol and drying to con~tant weight in a vacuum oven.
Yi~ld 17 g. A second batch of material (7 g.) ~rom another
experiment and showing identical T.L.C. characteri~tic~
was combined with the above batch and the re~ulting batch
(24 g.) di~solved in 100 ml. hot water. 200 ml. methanol
were added and crystalli~ation occurred upon coolin~. ~he
crystals were filtered off, washed well with methanol and
-21-
... ~, .... ..
.7~5~
dried to constant weight in a vacuum ovenO Yield of 1st
crop material 13.3 g.
Thin layer chromatography indicat~d that the material
was more than g9% pure. The compound had a melt~ng point
Of ~ 350C. and a pH o~ 7 ~ 6 ( lOYo solution). ~he compound
was the expected di~odium salt of 3~4'-dicarb3~ymethoxy
chalcone.
Example lS.
15 g. of the di~odium salt of 2 carboxy-4'-car~oxy-
methoxy-chalcone ~see Example 13) were dissolved in 25G ml.
distilled ~ater, acidified with concentrated hydrochloric
acid to pH 1 and the resulting suspension heated to 60C.
on a water-bath for 30 minutes. The white precipitate
was washed ~everal time~ with water until the wa~hing~
were neutral and then drled in a vacuum oven at S0~.
Yield l ~o 39 g. Thi~ product was combined with the product
from a ~imilar lactonisation experiment to give a total
o~ 22.6 g.
The crud~ lactone was dissolved in 600 ml~ ethyl
acetate~methanol (2:1 v/v~ with ~tirring and heating.
The cloudy solution was filtered and concentrated until
crystalli~ation occurred. The whitc precipita~e w~
filtered off, washed with ethyl acetate and dried to
con~tant weight in a vacuum oven at 50C. Yield o~ 1st
crop material 20.5 g. Thin layer chromato~raphy indicated
that the first crop material was pure. An NMR spectrum
indicated that there was methanol present, probably as
solvent of crystallisation. Further dr~ing in a vacuum
oven at 110C. successfully removed this~
The product obtained, which wa~ 2-carbo~y-4'-carbo~y-
methoxy-chalcone ~-lactone, had a meltlng point of 184 -
186C.
'. , ' :: :
.
5~
Example 16.
15.52 ~. 4-Carboxymethoxyacetophenone and 10,88 g.
3-methoxybenzaldehyde were slurried in 40 rnl. methanol.
40 ml. 10~ aqueou~ ~odium hydroxids ~olution were added
thereto, with vigorou~ stirring, and stirring then con-
tinued until a clear solution w~s o~tained~
The reaction mixture was left to 3tand at ambient
temperature for 5 hours, whereafter thin layer chro~ato-
graphy showed that an approximately 70% reac~ion had
occur~ed. The reaction mixture was heated to 60C. to
redi~olve the precipitated solid and the mixture left
for a further 2 hours, after which time thin layer
chromatography ~howed that 8~ reaction had taken place.
The reaction mixture wa~ cooled and the solid
product filtered off, wa~hed twice with cold methanol and
dried to con~tant weight in a vacuum oven at 70C. 180
of a pale yellow amorphouq solid w~re obtained. This
solid was dissolved in 100 ml. water at 70 - 80~C.,
filtered and the filtrate left to coolO Cry~tallisakion
took place and the cryQtal~ were filtered off, wa~hed twice
with cold water and dried to constant w~ight in a vacuum
oven at 70C. 17.2 g~ of a pale yellow cry~talline ~olid
w~ obtained. Thi9 was the sodium ~alt of 3-methoxy-4'-
car~oxymethoxy chalcone: m.p. 283 - 285C. rhin layer
chromatography showed the product to be more than 99~ pur~.;
Example 17.
15.52 g. 4-Carkoxymethoxy-acetoph~none (~ee ~xam~le 3)
and 10.88 g. ~-anisaldehyde were m~xed with 85 ml~ methanol
and 85 ml. 10% aqueous ~odium hydroxide 301ution and the
reaction mixture heated und~r reflux for 3 hours~ Precipi-
-23-
tation occurred during the react.ion period but agitation
wa~ maintained by magnetic stirring. After khe reaction
period of 3 hours, thin layer chromatography (e~hyl acetate/
methanol/30% aqueou3 trimethylamine 702.4 v/v~v) indicated
that the reaction had proceeded to an extent of 7~/~. $he
reaction mixture was allowed to cool and the precipitated
solid was filtered off, wa~hed with cold watex and dried
in a vacuum oven at 60Co The solid was puril ied ~y
dis~olving in 600 ml. hot water, filte~ing and concentrat-
ing the ~olution to about 450 ml. It wa~ then left to
crystalli~e overnight. The cry~talline solid wa~ filter~d
off D wa~hed with cold water and dried to con~tant w~ight
in a vacuum oven a~ 70C. TherQ was obtained a fir~t crop
of 15.0 g. monosodium 4-methoxy-4'-carboxymethoxy-chalcone,
thin layer chromatography of which (ethyl acetate/methanol~
30% aqueous trimethylamine 7:2:4 v/v/v) showed .it to be
more than 99% pure; mOp. 342 - 343C.
A partion of the ~odium salt was converted into the
corre~ponding free acid for characterisation; m~pO 194 -
195C. The NMR spectrum confinmed the ~tructure of the
acid.
Example 18.
a) A ~olution of 26.4 g. ~odiu~ hydroxide and
34.05 g. (20% exce~s) chloroacetic acid in 330 ml.
di~tilled water wa~ added to 4908 g. 4-hydroxy-3-metho~y-
acetophenone and the re~ultant mixture was refluxed on an
oil bath for 9 hours, with magnetic ~tirr~ng. ~he pH wa~
monitored at regular interval~ and kept within th~ range
of 8 - 9 by adding further sodium hydroxide solution.
Thin layer chromatography (chloroform/methanol~acetic
-24~
7~5~
acid 94:5:1 v~v/v~ ~howed that the reaction wa~ then about
800~ complete~ Heating for a further 2 hour& did not
improve the yield. ~h~ rQaction mixture wa~ cooled,
tran3fer~ed to a separating funnel and wa~hed with ethyl
acetate -to remove unreac~ed ~tarting m~terial. The
~queous layer wa~ acidified wi~h hydrochloric acid and
the precipitate obtained was filtered off, washed with
water until the wa~hings were neutral and then dried in
a vacuum oven at 80C., the yield of crud~ product o~tained
being 39.89 g. It wa3 rec~ystallised from methanol/ethyl
acetate to give a first crop of ~2.0 g. of white crystal~
of 4-carkoxyme~hoxy-3-methoxyacetophenone. A second crop
of 7 g. wa~ obtained by further concentration.of the
mother~liquor. Thin layer chromatography ~howed that
the fir~t crop was more than 99% pure ~m.p. 153 - 155C.),
whereas the ~eoond crop contained about 5% of impuritia~0
b) 11.7 g. 4-Car~omethoxybenzaldehyde were di~solved
in 80 ml. 10% aqueou3 sodium hydroxide solution and
17.92 g. 4~carbo~ymetho~y 3-methoxyacetophenone added
thereto, while stirring magnetically. After stirring for
10 minute~ at a~bient temperature, a yellow ~olid precipi-
tated and thin layer chromatography showed about 5
reaction. A further 1 g. 4-carboxymethoxyben~,aldehyde wa~
added and the reaction mix ure furthex ~tirred for 2 hour~
at am~ient temperature, after l~hich time the reaction had
proceeded to an extent of about 60%. 100 mlO Methanol
were then added to the reaction mixture, with thorough
~tirring. The solid ~aterial was filtered off, w~hed
with methanol and dried to con~tant weight in a vacuum
oven at 80C~ to giv~ 1500 g. of a fir~t crop, m.p.
-2S-
> 300Co A _econd crop of 8 g. was obtained by adding
ethanol to ~he mother liquor. Thin layer chromatography
showed that the fir~t crop ~a~ more than 99~0 pure disodium
4-carboxy-4'-carboxymethoxy 3'-methoxychalcone, wherea3
the 3econd crop waq mainly impuritie~, identified as
terephthalic acid. ~r5~di~ S~t.
1 g. of the disodium ~alt was converted into the
corresponding free acid by dissolving in water and acid~
fying with hydr~chlori~ acid, m.p. 278 - 280C~ Thin
layer chroma~ography ~ethyl acetate/a~u~ou~ trimethylamlne/
methanol) showed the free acid to be more than 99% pure~
Example 19.
a) 15.2 g. 4-Hydro~y-3~-methoxybenzaldehyde, 19.4 g3
4-carboxymethoxyacetophenone (see Example 3) and 100 ml.
10% aqueou3 sodium hydroxide solution were heated at 70C.
under an atmosphere of nitrogen for 3 hours, thin layer
chromatography (ethyl acetate/water/30% trimethylamine/
e~hanol) then indicating that no further reaction was
taking place. A small amount of m~thanol, followed by
600 mlO ethanol was added to the reaction mixture to give
a precipitate which wa3 ~ilterèd off, washed with ethanol
and dried to give 9.4 g. of a fir~t crop. Further dil~tion
of the mother liquor with ethanol gave 705 ~. of a second
crop. Thin layer chromatography indicated that both CL'Op~
only contained a small amount of impurity. The product
thus obtained wa~ the deaired disodium 4~hydroxy-3-methoxy-
4'-carboxymethoxy chalcone, which had a brick-red cclourO
b) 12.0 g. of the di~odium salt w~re dissolved in
a minimum amount of water to give a deep red solution.
Dilute hydrochloric acid was slowly added the~-eto, with
~26-
L7~
~tirrlng, until the red colour of the ~olution had
changed to a pale orange-yellow colour. Any precipitated
diacid was filtered off and the filtrat~ wa~ concentrat~d
until crystallisation occurred. The fir3t crop of
material obtained was filtered off, wa~hed with e~hanol
and dried to constant weight in a vacuum oven at 100 C.~
~he yield being 10~4 g. Thin layer chromatography ~ethyl
acetate/methanol/30% ethanolic trimethylamine 702:~ v/v~v)
showed tha~ thi~ fir~ crop was pure. Th~ monosodium 4~
hydroxy-3-me~hoxy-4'-caxboxymethoxy~chalcone thu~ obtained
had a melting point of ~ 360Co
Exam~le 20.
a ) A mixture of 100 g. ~odium 4-hydroxy-butanoate
and 2 litre~ of 2% concentrated sulphuric acid in methanol
wa~ heated under reflux for 4 hour~ while stirring magnet~
ically. The reaction ~ixture wa3 cooled and, while
stirriny, sufficient Aodium bicarbonat~ was add~d to
increase the pH value to about 7 - 8. The precipi~a~ed
sodium salt~ were filtered off and washed with 500 ml.
diethyl ether, the wa~hings being add~d to the original
methanolic filtrate. The total organic liquid~ wsre con-
centrated, filtration being carried out whenever bumping
occurred. After al~ the 301vent had been remov~d, 65 ~.
of a clear pale yellow liquid remained, which wa~ kept
dry on Type 4A molecular sieve. The product wa~ methyl
4-hydroxybutanoate.
b) 25 g. Methyl 4-hydro~ybutanoate were mixed with
47.5 gO toluene-~ulphonyl chloride and 250 mlr dry pyridine
at 5C. and kept at thi~ temperature for 17 hour~, where~
after the reaction mixture wa3 poured into 2 litres ice
! 27
water. me oil thu~ fon~ed was extracted with diethyl
ether and the ethereal extract ~la~ ~ashed with 500 ml.
6N hydrochloric acid to remove exce~s pyridine, followed
by wa~hing with a saturated aqueou~ solution of ~odium
bicarbonate until neutral. Concentration of the organic
layer gave 32.5 g. of a yellow oil which was dissolved in
diethyl ether, treated with decoLorising charcoal, filtered
and the filtrate concentrated to give 30.5 g. of a pale
yellow oil which slowly crystalliaed at 5C. Thin layer
chromatography (petroleum ether/dichloromethane~acetone
6: 3 :1 v/v/v ) showed the product to b~ pure. The methyl
4~ oluene-~ulphonyl)-butanoate thus obtained had a
melting point of 23C~
c) 12 r 2 g~ 4-~ydroxyacetophenone wexe reacted under
anhydrou~ conditions wi~h 5.8 gu sodium hydride (5~% oil
di~per~ion) in 70 ml. dimethyl formamide which had been
dried over Type 4A molecular ~ieve. 24 g. Mathyl 4-t~-
toluene-~ulphonyl)-butanoate in 20 ml. dry dimethyl
formamide were added to the re~ultant ~olution over the
cour~e of 10 minute~. After the addition wa~ complete,
the reaction mixture wa~ heated at 60C. for 6 hours,
whereafter thin layer chromatography ~petroleum ether/
dichloromethane/acetone 6:3:1 ~/v/vj showed that the
reaction was about 80% complete. After cooliny, the pH
was adjusted to 1 by the careful addition of dilute hydro-
chloric acid, whereafter the reaction mixture wa~ extracted
wlth diethyl ether. The ethereal extract was washed with
a 10% a~ueou~ sodium hydroxide ~olution to remove ~ny
phenolic starting material. A~ter wa~hing wlth water to
remove any ba~ic material, the ethereal solution wa~ dried
-~8-
9~3
with anhydrouq sodium ~ulphate. Solvent was then removed
to ~ive 20.5 g. of a pale bro~ oil which waq hydrolysed
by heating at 60C~ for 30 minute~ with 30 ml. of a lOYo
aqueous sodium hydroxide solution and 30 ml. ethanol,
thin layer chromatography showing that hydroly~qis wa~
complete. The reaction mixture wa_ acidified with dilute
hydrochloric acid and the precipitated ~olid was filtered
off, waqhed with water and dried to con~tant w~ight in a
vacuum oven at 60C. to give 15.5 g. of product. Thi8
waq cry3tallised from ethyl acetate/ethanol to give pale
yellow cryqtalq which wer~ filtered off, washed with ethyl
acetate and dried in a vacuum oven at 60C. to give a
fir~t crop of 9.3 g. A ~econd crop of 3~2 g. o yellow
cry-~tal~ were obtained by concentration of the mother
liquors, thin layer chromatography (chloroform/methanol/
acetic acid 94:5:1 v/v/v) showing both crop~ to be more
than 99% pure. The 4-carboxy-propionoxyacetophenone thus
obtained had a melting point of 154 - 155C~
d) 12.2 g. 4-Carboxypropionoxyacetophenone wer~
suspended in 60 ml. of a 10% aqueou~ ~odium hydroxide
~olution and 8.24 g. 4-carboxybenzaldehyde added thereto.
The reaction mixture wa~ ~tirred for 1 hour at ambient
temperature and then diluted to 250 ml. with ethanol~
The precipitate obtained wa3 filtered off, waqhed well
with ethanol and then dried to constant weight in a vacuum
oven at 70C. 18.2 g. of pale yellow ~olid disodium 4
carboxy-4'-carboxypropionoxy chalcone were obtaine~, thin
layer chromatoyraphy ~howing the compound to be a~out 98%
pure. Thi~ amorphou~ di odium ~alt w~ dis~olved in ~
minimum amount of hot water, the ~olution wa~ filtered
-29-
~ ~ ~7~S~
and ethanol wa~ slowly added to the filtrate, with
swirling. The cry~talline Rolid formed was ~iltered off,
washe'd with ethanol and dried at 70C. in a vacuum o~en
to give 12.5 g. of the disodium salt, m.p. > 330C. (dec.).
Thin layer chromatography (ethyl acetate/methanol/30%
aq~eous trimethylamine) showed the product to be more than
99% pure.
The corresponding free acid was prepared ther~of in
the usual manner, m.p. 261 - 262C.
Exampl e ,?1-
a~ 9.O g~ 4-Carboxymethoxy-benzaldehyde ~ee
Example 5) and 8.2 ~. 4-acetylbenzoic acid were dis301ved
in 50 ml. 10% aqueou~ sodium hydroxide solution and the
~olution s~irred at ambient temperature for 2.25 hours.
150 ml. Ethanol were added and the 901id precipitate
obtained wa~ filtered off, washed with ethanol and dri~d
to give 16.9 g~ disodium 4'-carboxy-4'-carboxymethoxy
chalcone. This disodium salt was converted into the.acid
by dissolving in water, acidi~yin~ the solution with con-
centrated hydrochloric acid, filtering off the solid
obtained, wa~hing with water and drying, the yield being
15.1 g. Thin layer chromatography showed the presence of
about 7% of polar impurities, mo~t of which were removed
by refluxing the solid with methanol, filtering and drying
the undissolved solid, the yield being 11.9 g. Thin layer
chromatography then ~ho~ed the product to be about 98%
pure. The solid wa~ dissolved in dimethyl formamide and
the solution was filter~d and evaporated to a small volume~
200 ml. Methanol wa~ added and the solid pr~cipitat~
obtained ~a~ filtered off, washed with methanol and dried
-30-
......
7~
to give 8.0 g. of product, thin layer chromatography of
which showed it to be more than 99% pure. The 4'-carboxy-
4-carbo~meth~chalcone thu~ obtained had a melting point
of 312 - 314C.
b) 14.0 g. of the diacid obtained in a) above were
slurried with 20 ml. methanol ànd a solution of 3.435 g.
sodium hydroxide in 28 ml. di~tilled water added in ~mall
portions, with ~tirring. In order to prevent thickening
and to give a final ~olution, it waæ nece~ary to add a
fùrther 32 ml. of distilled water. 1~e solution was
filtered and`200 ml. methanol were added to the filtrate.
The precipitated solid obtained was filtered off, wa~hed
with methanol and dried to give a yield of 5.9 g. 500 ml~
Ethanol were added to the filtrate to give 6.6 gO of a
second crop of material which wa~ treated in the same way
as the first crop. Thin layer chromatography ~howed both
crops to be more than 99% pure. The product tllus obtained
wa~ disodium 4'-carboxy 4-carboxymethoxy-chalcone, which
had a melting point of 360C.
E.~ample 22.
a) 60 ~. Ethyl ~-toluene-sulphon~te ~ere plac~d in
a 1 litre round-bottomed three-necked fla~k and 320 ml.
acetic anhydride added theretou The ~olution obtained
was cooled to -5C. and 50 ml. concentrated sulphuric acid
910wly added thereto at ~uch a rate that the temperatur~
did not exceed 15C. When all the acid had been added,
the reaction mixture wa~ cooled to 5C. and a solution
of 65 ~. chromium trioxide in 300 ml. acetic anhydride
~lowly added at ~uch a rate that the temperature did not
rise abo~e 4C. After completion of the addition, the
-31-
reaction mixture wa~ left to stand for 30 minute~ at 5C.
and then poured, while stirring, i~to 4 litre~ of ice/
water. The green oily ~olution wa~ left to stand for
12 - 15 hours, during which time cry~talli~a~ion occurred.
The qolid waY filtered off, taken up in 300 ml. diethyl
ether and the solution wa~hed with a 2% a~ueou~ sodium
carbonate solution until no colour wa~ apparent in the
aqueou~ solution, three wa~he~ being necessary. The
ethereal solution wa~ dried o~er anhydrous sodium ~ulphate
and then evaporated to give 51.0 g. of cry~talline solid
which was ~hown to b~ pure by thin layer chromatography
(petroleum ether (b.p. 60 ~ 80C.)/dichloromethane/acetone
6:3:1 v/v/v). Thi~ product was 4-ethyl-~ulphonyl-ben~al
diacetate.
b) 12.64 g. 4-Ethyl sulphonyl-benzal diacetate wer~
placed in a 500 ml. round-bottomed fla~ and 100 ml.
ethanol and 100 ml. lO~o aqueou~ ~ulphuric acid added
thereto, followed by heatin~ for 45 minutes. The resulting
bro~ solution wa~ evaporated to about hal its volume,
whereafter 1~0 ml. 10% aqueou~ ~odium hydroxide solution
were added thereto. 4-Carbo~ymethoxyacetophenone was then
added to the basic ~olution and the mixture agitated to
ensure rapid solution. The reaction mixture was heated
on a steambath for 3 hour~, then cooled and 500 ml. methanol
added to precipitate the product~ The precipi~ate wa~
filtered off with ~uction, sucked dry and wa~hed fiv0 time~
with methanol, whereafter the filtrate wa~ clear. Upon
drying in vacuo at 110C., there w~re obtained 16.8 g. of
a pale yellow amorphou~ ~olid which was found to be about
90% pure by thin layer chromatography (ethyl acetate/
-32-
-
methanol/30% aqueous trimethylamlne 7:2:4 v/v/v). ~hi~
product wa~ dissolved in about 1 litre of hot water,
filtered and cooled, whereupon cry~tallisation occurred.
The cry~tals were filtered off, washed with cold water
and dried in a vacuum oven at 110C. to give 14.1 g. of
pale yellow cry~talline ~olid, thin layer chromatography
of which (ethyl acetat~methanol/30% trimethyl~mine 7:2:4
v/v/v) showed it to be more than 9g~ pure. Thi5 product
wa~ disodium 4'-carbox~methoxy-4-~ulphochalcone, ~hich
had a melting point of ~ 360C.
The corre~ponding diacid wa~ prepared by di~olving
the disodium salt in water, adding dilute hydrochloric
acid and filtering off the precipitated ~olid~ It was
wa~hed with water and dried in a vacuum oven at 100 C.
The diacid had a melting point of > 360C.
Example 23.
a) 30.4 ~. 3-Methoxy-~-hydroxybenzaldehyde were
dissolved in 120 ml. dimethyl formamide and 9.2 g. sodium
hydride (50/0 dispersion in oil) ~lowly added, wit~ ~tirring,
to the re~ultant solution, more dimethyl onmamide being
added to ~eep the reactants in solution. After cooling
the reaction mixture to ambient temperatur~, a aolution
of 24.6 ~. ethyl chloroacetate in dimethyl ~onmamide wa~
added and stirring cbn~inued at ambient temperature ~or
3 days, whereafter thin layer chromato~r~phy (petroleum
ether~b.p. 60 - aoc. ~/dichloro~ethane/acetone 6:3:1)
indicated that the reaction wa~ at lea~t 85% complete.
The reaction mixture was then acidified with dilute hyclro-
chloric acid, followed by extraction with diethyl ether.
The or~anic extract wa~ washed once with 500 ml. 10%
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aqueouq ~odium hydroxide ~ol~tion and 3 time~ with 300 ml.
amounts of distilled water, ~ollowed by drying over
anhydrous sodium sulphate. The 301vent waa removed and
the yellow solid obtained wa8 waahed with petroleum ether
to remove any oil from the sodium hydride dispersion. 'rhe
solid was then dried to co~tant weight in a vacuum
desiccator ~o give 22.4 g. 4-carbethoxymethoxy-3-methoxy-
benzaldehyde, m.p. 65 - 66.5C. Thin layer chromatography
indicated that the product was more than 99% pure~
b) 15.4 g. 4-Carbethoxymethoxy-3-methoxyben7aldehyde
and 56 ml. 10% aqueous ~odium hydroxide solution were mixed
and 15 ml. methanol added thereto. Water was then added
until a clear Qolution was obtained. 4-Carboxymethoxy-
acetophenone (~ee Example 3) was added to thi~ solution
and the reaction mixture left to stand overnight. A further
10 ml. 10% aqueous qodi~n hydroxide solution was added to
keep the reaction mixture al~aline. After a further 24
hours at ambient temperature, thin layer chromato~raphy
(ethyl acetate/methanol/3~% aqueous trimethylamine 7:2.4
v/v/v) ~howed that the reaction had proceeded to about 85%.
The reaction mixture wa~ then introduced into a conical
flask and diluted with ethanol until precipitation occurred.
The precipitate wa~ filtered off, wa~hed well with ethanol
and dried to constant weight in a vacuum oven, the yield
being 22.8 g. Thin layer chromatography indicated that
the product was about 95~ pure. It was crystalli~ed from
methanol/water to give a fir~t crop of 19, 5 g. o~ material
which was over 99~0 pure after dryin~ t~ ~on~tan~c weight in
a vacuum oven at 80C. The product had a mel tîng polnt o~
~ 360C. (decompo~ition from 240C.~. It was disodium
4,4'-di-( carboxymethoxy )-3-methoxychalcone.
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;. . ~
A sample of this disodium ~alt wa~ converted into
th~ corresponding diacid by acidifying an aqueous qolution
thereof with dilu~e hydrochloric acid, filtering off the
precipitate obtained, washing it with water ancl drying in
a vacuum oven at 80C. The diacid thus obtained had a
melting point of 210 - 211C. (decomp.).
The dl~odium salt was also converted into the
corresponding dimethyl ester in the following manner:
20 mg. of the di~odium ~alt and 2 drops of acetic acid
were mixed with 1 ml. dimethyl ~ulpho~ide and a solution
obtained by warmin~. After cooling, exces3 diazomethane
waq added and, after completion of the reaction, unreacted
diazomethane was destroyed by adding a drop of acetic acid.
The dimethyl ester obtained after working up the reaction
mixture wa~ found to be 99% pure.
Example 24
1.64 g. 4-Acetyl~enzoic acid and 1.50 g. 4-carboxy-
ben2aldehyde were added to a solution of 1. 0 g. sodium
hydroxide and 20 ml. 9~ aqueous ethanol. The reaction
mixture was stirred under reflux for 2 hours and the ~olid
was filtered off, washed thoroughly with ethanol and dried.
The yield wa~ 2.1 g. Thin layer chromatography (ethyl
acetate/methanol/30% aqueou3 trimethylamine 7:2:4 v~v/v)
~howed the material to be about 80Yo of the de~ired product.
This was purified by column chromatography through silica
gel to give 1~10 g. of disodium 4,4'-dicarboxychalcone o~
99% purity. It had a melting point greater than 360C.
A sample of this disodium ~alt wa~ converted in the
usual manner into the corresponding free acid, which al~o
had a melting point greater than 360C.
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The present invention also includes within its scope
pharmaceutical compo3itions containing at least one of
t~e new compounds according to the present invention, in
admixture with a 301id or liquid pharmaceutical carrier.
Solid composition~ for oral admini3tration include
compre~sed tablets, pills, dispersible powder~ and gran-
ules. In such solid composition~, one of the new compound~
is admixed with at least one inert diluent, such as calcium
carbonate, star~h, alginic acid or lactose~ The compos-
ition~ may al30 comprise, a~ is normal practice, additional
substances other than in~rt diluents, for example,
lubricating agent~, such as magne~ium stearate.
Liquid compo~itions for oral administration include
pharmaceutically acceptable emulsions~ solution~, su~pens-
ions, ~yrup~ and elixirs con~aining inert diluent~ co~nonly
u~ed in the art, such as water and liquid paraffin~
Be~ide~ inert diluents, -~uch composition~ may al~o compri~e
adjuvant~, such a~ wet~ing and suspen3ion agents, and
sweetening and flavouring agents.
The compositions according to the present inventio~,
for oral administration, include capcule~ of absorhable
material, such a~ gelatine, containing one of the new
derivatives, with or without th~ addition of diluents or
excipients~
Preparations according to the present invention for
parenteral administration include sterile aqueous or non-
aqueous solution~, ~u~pensions or emulsion3. Examples of
non-aqueous solvents or suqpending media include propylene
glycol, polyethylene glycol, vegetable oils, such as olive
oil, and iniectable or~anic e3ters, such as ~thyl oleate.
~36-
These compositions may also contain adjuvan~s, such a~
wetting, emul~ifying and di~per~ing agent~. They may be
qterilised, for example, by filtration through bacteria-
retaining filters, by incorporation into the compositions
of sterilising agen~s, by irradiation or by heating.
They may also be produced in the fonm of s~erile solid
compositions, which can be dissolved in sterile water or
some other sterile injectable medium immediately before
use.
The compositions accor~ing ~o the present invention
for topical application include lotions, creams, pastes,
ointments and liniments.
The percentage of active material in the composition~ ;
of the present invention may be varied, it being nece3sary
that it ~hould constitute a proportion uch that a suit-
able dosage for the desired therapeutic effect 3hall be
obtained. In general, the pr~parations o~ the present
invention should be administered orally or parenterally
to humans to give 1 to 1000 mg. and preferabLy 10 -
500 mg. o~ active substance per day.
The following Example~ illustrat~ pharmaceutical
composition~ according to the pre~ent invention:
Exame~ 25
250 mg. tablets are prepared containing:
3-carboxy-4'-hydroxychalcone50 mg.
~tarch 100 mg.
lactose 95 mg.
magnesium stearate 5 mgO
Example 26.
500 mg. tabletq are prepared containing:
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disodium 4,4'-dicarboxychalcone 100 mg.
starch 150 mg.
lactose 240 mg.
magnesium stearate 10 mg.
Example 27.
500 mg. tablets are prepared containing:
disodium 4-carboxy-3' -fluoro~4 ' -
carboxymethoxychalcone100 mg.
~tarch 190 mg.
lactose 200 mg.
magnesiu~ stearate 10 mg.
The compositions according to Examples 25 to 27
are intended for oral admini~tration to humans for
treating inflammat~ry and allergic conditions and for
treating ulcerous conditions of the gastro inte~tinal
tract.
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