CA1117958A - Chalcone derivatives - Google Patents

Abstract

ABSTRACT

New chalcone derivatives having the general formulae:

(Ia) and (Ib) in which R1 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 con-taining up to 6 carbon atoms and R4 is an alkyl, hydoxy-alkyl, alkoxy, carboxyalkoxy, sulphoalkoxy or carboxyalkyl-carbonyloxyalkyl 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, are prepared by condensing an acetophenone derivative of the general formula:

in which R1 and R2 have the aforesaid meanings, with an aldehyde of the general formula:

Description

-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 ~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 , 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 .,.. '! ' ' " . .:. .. ", ,,,, . . ~., .

~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~

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 ................ ....

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.

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 .. ;, , 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~

. , , - , ~ ~ .. , . . . . .;

'' ~ 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 -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 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 ... ~, .... ..

.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-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.

> 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 ~ ~ ~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 ......

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 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/

-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%

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.

;. . ~

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.

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:

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.

Claims (6)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. Process for the preparation of compounds of the general formulae:

(Ia) and (Ib) in which R1 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, carboxyalkoxy, 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 of the non-toxic inorganic and organic salts of those compounds containing at least one carboxylic acid or sulphonic acid group, wherein an aceto-phenone derivative of the general formula:

in which R1 and R2 have the same meanings as above, is con-densed with an aldehyde of the general formula:

in which R3 and R4 have the same meanings as above, whereafter, when a product is obtained containing a carboxyl group, this product is, if desired, subsequently lactonised and, if de-sired, the product obtained is reacted with a non-toxic orga-nic or inorganic base to give the corresponding salt.

2. Process according to claim 1, wherein the con-densation is carried out in the presence of a strong base.

3. Process according to claim 1 or 2, wherein the condensation is carried out in an aqueous or aqueous organic medium.

4. Process according to claim 1, wherein, when a product is obtained in which R4 is a hydroxyalkyl radical, this product is reacted with a reactive derivative of an alkane-dicarboxylic acid, the alkane moiety of which contains up to 6 carbon atoms, to give the corresponding carboxyalkyl-carbonyloxyalkyl compound.

5. The compounds of the general formulae:

(Ia) and (Ib) in which R1 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, carboxyalkoxy, 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, as well as the non-toxic inorganic and organic salts of those compounds containing at least one carboxylic acid or sulphonic acid group, whenever prepared by a process according to claim 1 or its obvious chemical equivalents.