NO791298L - PROCEDURE FOR THE PREPARATION OF CHROMON-2-CARBOXYLIC ACIDS - Google Patents

Description

Process for the production of chromone-2-carboxylic acids.

The present invention relates to a method for the production of chromone-2-carboxylic acids.

Chromone-2-carboxylic acids have usually been prepared from the corresponding o-hydroxyacetophenones.

Often, however, these output connections have not been

easily accessible, while one has had easier access to other derivatives, e.g. the corresponding o-hydroxycarboxylic acids. The present invention provides a method for producing chromone-2-carboxylic acids from such derivatives in a direct manner with very few intermediate steps.

The present invention provides

thus a method for the preparation of a chromone-2-carboxylic acid which involves reacting a 2'-hydroxy-2-alkylsulfinylacetophenone, provided that the alkyl group of this compound has no free hydrogen atom on the p-carbon atom (when present), or 2 '-hydroxy-2-phenylsulfinyl-acetof enone with glyoxylic acid in the presence of a base, whereby the desired compound is obtained.

The starting acetophenone compound may be substituted or unsubstituted as desired to obtain an appropriately substituted or unsubstituted chromone product. The starting products are preferably a 2'-hydroxy-2-methylsulfinylacetophenone. However, when using a 2-phenylsulfinylacetophenone, the 2-phenyl group is preferably unsubstituted, although it is possible, if desired, for the group to be substituted with one or more halogen atoms (e.g. chlorine) or a C1 to C4 alkyl group or alkoxy group (eg methyl or methoxy).

The base used is preferably an amine, especially a secondary amine, such as piperidine, morpholine or

dibutylarain.

The reaction can conveniently be carried out in a solvent or a suspending medium which is inert under the reaction conditions used, e.g. a high-boiling aromatic hydrocarbon, such as toluene. The reaction temperature is preferably from room temperature (10°C) to 160°C, more particularly from 60 to 130°C.

Compounds produced by the present method preferably have the following formula:

(where: (i) R represents hydrogen or hydroxy, 2 3 Æ R and Br together represent tetramethylene, and R^" represents n-propyl; or (ii) R 1 represents hydrogen, R 2 and RJ 3 together represent a group -COCH =C(COgHj-O-, and R^ represents n-propyl; or (iii)) R"*" represents a group of the formula:

and R , B<J>and Br all represent hydrogen).

To obtain compounds of formula

In (i), the starting acetophenone compound can have the following formula:

(where 'R''.represents alkyl without any free hydrogen atoms on the (3-carbon atom, when this is present, or phenyl which may be unsubstituted or substituted with one or more halogen atoms or C 1 to 4 alkyl or alkoxy groups, and X

either represents hydrogen to give a compound where R"<*>"represents hydrogen, which can then be converted, if desired, to the corresponding compound where R"<*>"represents hydroxy, or represents a blocked hydroxy group to, obtain the blocked hydroxy analogue of the compound where R"*" represents hydroxy, which can be treated afterwards to remove the blocking group). When it is desired to convert the product where R"<*>"represents hydrogen into the corresponding compound where R"<*>"represents hydroxy, this can be achieved e.g.

in the usual way by nitration/reduction/diazotization/hydrolysis. Removal of the blocking group where R 1 represents blocked hydroxy can be achieved in a conventional manner, for example by hydrolysis.

To prepare the compound of formula

In (ii), the starting acetophenone compound can have the following formula: (where R is as defined previously, and S and R 6 either together represent a chain -COCH-C(Y)-0- (where Y represents carboxy or esterified carboxy) or the groups respectively

and -OH where R is as defined previously).

To prepare a compound with formula 1 (iii), the starting acetophenone compound can have the following formula:

(where R, R; 5 and R 6 are as defined previously).

Where Y in any of the above formulas represents esterified carboxy, then the product is an ester which must be hydrolysed to give the phosphonic compound of formula I.

The compounds of formula II, III and IV are

per se new compounds, and the present invention also provides it as such.

The invention further provides a method for the preparation of compounds of formula I,

where a compound of formula II, III or IV is reacted with a glyoxylic acid ester in a suitable solvent and in the presence of a suitable catalyst, followed by a cyclisation, and in cases where the product is an ester, by a hydrolysis, whereby one obtains the claimed compound of formula I.

The condensation with glyoxylic acid esters is preferably catalyzed by a suitable Knoevenagel reaction catalyst, e.g. a base, such as sodium acetate or amine, e.g. piperidine, morpholine or triethylamine, and is preferably dissolved in a suitable solvent which is inert under the conditions used, i.e. pyridine or chloroform. The cyclization can also be acid catalyzed, e.g. of a Lewis acid, such as boron trifluoride.

The hydrolysis of the produced ester can conveniently be carried out with the aid of a base, e.g. an alkali metal base, such as sodium hydroxide, followed by an acidification,

or directly by means of an acid, such as hydrochloric acid or hydrobromic acid.

The aforementioned 2 1-hydroxy-2-alkylsulfinylacetophenones or the 2T<->hydroxy-2-phenylsulfinylacetophenone starting compound in all of the above-mentioned processes can be prepared by a process where the corresponding 2-alkoxycarbonylphenol is reacted under appropriate conditions with an anion of the formula ^CHgSOR (where R is as defined previously). Similar reactions have been described in the literature.

The compounds of formula II, III and IV can thus respectively be prepared from compounds of formula Ila, Illa and IVa:

(where X is as defined above, R^ represents alkyl with

r8 9

from 1 to o carbon atoms, and R and R^ either represent groups defined earlier for Ry S and R 6 or respectively represent groups -COOR7 1 and -OH where R<7>' is as defined earlier).

The compounds of formula Ila, Illa and IVa are in themselves either known compounds, or can be prepared by methods which are analogous to those known for the preparation of similar compounds.

The following examples illustrate the invention.

Example 1

4-- oxo- 4- H- l- benzopyran- 2- carboxylic acid

2.97 g of 2'-hydroxy-2-methylsulfinylacetophenone was suspended in 20 ml of toluene, and treated with 1.26 g of piperidine. 1.56 g of glyoxylic acid hydrate was then added, and the mixture was refluxed for 2 hours, then cooled and poured into 100 ml of ethyl acetate. The organic solution was washed with water and then extracted with a saturated sodium bicarbonate solution. The aqueous solution was then acidified and extracted with ethyl acetate. Drying and evaporation gave a sticky solid which

was treated with ether to give the precipitated product weighing 0.34 g. The structure was confirmed by mass spectroscopy and nuclear magnetic resonance spectroscopy.

Example 2

4-, 6- dioxo- 10- propyl- 4. H, 6H- benzo/ l, 2- b : 5, 4- b ' 7dipyran- 2, 8-dicarboxylic acid

(a) 1, 5- diacetyl- 2, 4- dimethoxy- 3- propylbenzene

236 g of 2,4-diacetyl-6-propylresorcinol was dissolved in 2 liters of dry dimethylformamide containing 276 g of suspended potassium carbonate, 0.5 g of potassium iodide and 355 g of methyl iodide. The mixture was stirred at room temperature for 84 hours and then poured into 10 liters of water and then extracted with ether. The ether solution was washed with 10% sodium hydroxide solution,

then with water and finally with sodium chloride solution.

Drying over magnesium sulfate and evaporation gave the sub-title compound weighing 231 g as a sticky oil. The structure was confirmed by NMR and mass spectroscopy.

(b) 2, 4- dimethoxy- 3- propylbenzene- 1, 5- dicarboxylic acid

87j5g of bromine was added to a solution of

88 g of sodium hydroxide in 364 ml of water cooled to 5°C, below

strong rowing. The temperature was raised slowly to 20°C, after which 22.05 g of 1,5-diacetyl-2,4-dimethoxy-3-propylbenzene were slowly added over the course of 5 minutes - with vigorous stirring. The stirring was continued for 3>5 hours while the temperature

was kept at 25°C, if necessary with cooling. The solution was then treated with an excess of sodium bisulphite solution

ning to remove unreacted hypobromite, and the basic solution was extracted into ether, which was then discarded. The aqueous phase was acidified and extracted with ethyl acetate.

Drying the organic solution and evaporation gave a

white solid weighing 9j7g>and its identity as the sub-title compound was confirmed by NMR and mass spectroscopy.

(c) Dimethyl 2,4-dihydroxy-3-propylbenzene 1,5-dicarboxylate

9.6 g of 2,4-dimethyl-3-propylbenzene-1,5-dicarboxylic acid was suspended in 100 ml of dry methanol, and saturated with dry hydrogen chloride gas by refluxing for 30 minutes. The methanol was removed in vacuo and the residue dissolved in

200 ml of chloroform. After cooling to -20°C, 25 ml of boron trichloride were slowly added while stirring. The reaction mixture was allowed to warm to room temperature over 18 hours,

and then poured into 1 liter of ice water. The water-chloroform mixture was vigorously stirred for one hour and the organic phase was separated, washed with saturated sodium bicarbonate solution and then with water and then dried. An evaporation of 5j4g of the sub-title compound as a white solid. The structure was confirmed by NMR spectroscopy.

(d) 2,4-dihydroxy-1,5-di(2-methylsulfinylacetyl)-3-propylbenzene

5.36 g of dimethyl-2,4-dihydroxy-3-propylbenzene-1,5-dicarboxylate was dissolved in a minimal volume of dry dimethyl sulfoxide, and then added a solution prepared by suspending 3>36 g of sodium hydride, free of oil, in 80 ml of dry dimethylsulfoxide and then heat the suspension to 70°C for one hour, and then to 30°C under nitrogen and vigorous stirring. The mixture was kept at 70°C for 18 hours under nitrogen and stirring, then cooled, and poured into 1 liter of ice and washed with diethyl ether.

The aqueous solution was acidified

pH6 with dilute hydrochloric acid, and the resulting precipitate was collected, washed with water and dried in vacuo. 3>6 g of the subtitle compound was identified by NMR spectroscopy.

(e) 4, 6- dioxo-10- propyl- 4H, 6H- benzo/ T, 2- b : 5, 4- b Vdipyran^ . 8-dicarboxylic acid

3.6 g of 2,4-dihydroxy-1,5-di-(2-methylsulfinylacetyl)-3-propylbenzene was suspended in 35 ml of toluene and treated with 2.52 g of piperidine. 3.12 g of glyoxylic acid hydrate were added, and the suspension heated under reflux for 12 hours, then cooled and poured into 200 ml of ethyl acetate. The organic solution was washed with dilute hydrochloric acid, then with water and then with sodium chloride solution. Extraction into a sodium bicarbonate solution and then acidification gave 0.72 g of a precipitate which, after drying, was identified as the sub-title compound by thin layer chromatography and an infra-red spectroscopic comparison with authentic material prepared by an alternative method.

Example 3 1« 3"- - bis (2- carboxychromon-5- yloxy)-2- hydroxypropane (a) 1, 3- bis( 3- hydroxy- 2- carbomethoxyphenoxy)- 2- hydroxypropane 168 g methyl 2, 6- dihydroxybenzoate was dissolved in 1 liter of methanol containing 23 g of sodium metal which had previously been dissolved. After stirring at 0°C for 1/2 hour, 46.25 g of epichlorohydrin was added, and the mixture was refluxed for 6 hours. After cooling the solution was saturated with dry hydrogen chloride gas, the precipitate was collected, washed with methanol and then discarded.The filtrate was concentrated to 100 ml and the resulting solid was collected and dried in vacuo to give 97.3 g of the subtitle compound.

The structure was confirmed by NMR spectroscopy.

(b) 1,3-bis-(3-hydroxy-2-(2-methylsulfinylacetyl)-phenoxy)-2-hydroxypropane

48 g of a ^0% oil dispersion of sodium hydride was washed free of oil with 3X300 mL dry ether under nitrogen at room temperature, and then covered with $00 mL dry dimethyl sulfoxide. The vigorously stirred suspension was heated under nitrogen to 70°C until no further evolution of hydrogen could be detected. The mixture was diluted with 50 ml of dry tetrahydrofuran and then cooled to 30°c. A solution of 56 g of 1,3-bis(3-hydroxy-2-methoxycarbonylphenoxy)-2-hydroxypropane in 250 ml of dry tetrahydrofuran was then added, and the mixture held

at 70°C for 18 hours.

The solution was poured into 3 liters of ice

and diluted with dilute hydrochloric acid to pH 5. The precipitated solid was collected and washed with diethyl ether to give 19.7 g of the sub-title compound which was identified by NMR spectroscopy.

(c) 1,3-bis(2-carboxychromon-'5-yloxy)-2-hydroxypropane

4.84 g of 1,3-bis(3-hydroxy-2-(2-methylsulfinylacetyl)phenoxy)-2-hydroxypropane was suspended in 40 ml of toluene and treated with 2.52 g of piperidine. 3.12 g of glyoxylic acid hydrate was then added, and the mixture refluxed for 5 hours, then cooled and poured into 200 ml of ethyl acetate. The organic solution was washed with water and then extracted into a sodium bicarbonate solution. The slurry of this solution left a gelatinous suspension which was centrifuged, and the aqueous overlying layer was poured off while the residue was washed with water (with centrifugation to separate the solid). Drying in vacuum gave 0.67 g of the product which was found to be identical by thin layer chromatography, NMR and IR spectroscopy to an authentic sample of the compound prepared by an alternative synthesis route.

Example 4

6, 7, 8, 9- tetrahydro- 4- oxo- 10- propyl- 4H- naphtho/ 2, 3- b7pyran- 2-carboxylic acid

(a) 3- acetyl- 5, 6, 7, 8- tetrahydro- 2- methoxy- propyl naphthalene

232 g of 3-acetyl-2-hydroxy-5,6,7,8-tetrahydro-1-propyl-naphthalene, 276 g of potassium carbonate, 200 g of methyl iodide and 1 liter of dimethylformamide were stirred on a steam bath for 36 hours, then

cooled and then completely poured into 6.5 liters of water. The precipitate was collected and washed with water. Drying in vacuo gives 229 g of the sub-title compound, and the structure was confirmed by NMR

and MS.

(b) 5, 6, 7, 8- tetrahydro- 3- methoxy- 4- propylnaphthalene- 2- carboxylic acid

875 g of bromine was added to a solution of 880 g of sodium hydroxide in 3.64 l of water cooled to 5°C with vigorous stirring. The temperature was allowed to rise to 20°C, after which 220 g of 3-acetyl-5,6,7,8-tetrahydro-2-methoxy-1-propylnaphthalene was added slowly over 5 minutes and with vigorous stirring. Stirring was continued for 4 l/2 hours while maintaining the temperature at 25°C,

by means of cooling if this was necessary.

The solution was treated with a profit

of a sodium bisulphite solution to remove hypobromide, and the aqueous solution was extracted into ether which was then discarded. The aqueous phase was acidified and the precipitated solid was collected and washed with water. Drying in vacuo gave 151 g of the sub-title compound which was characterized by NMR and MS.

(e) Methyl 5,6,7,8-tetrahydro-3-hydroxy-4-propylnaphthalene-2-carboxylate

157 g of the methoxy acid from step (b) was

added 500 ml of hydroiodic acid and kept at boiling under reflux

ran for 18 hours, after which the mixture was cooled and poured into 1 liter of ice water. The precipitated solid was collected,

washed with water and dried. It was then dissolved in 1 liter of dry methanol and saturated with dry hydrogen chloride gas under reflux for 1 hour. The solvent was removed in vacuo,

and 112.6 g of the residue was characterized as the sub-title compound by NMR and IR spectroscopy.

(d) 5- f 6, 7 , 8- tetrahydro- 3- hydroxy- 2- methylsulfinylacetyl- 4- propyl- naphthalene

18 g, sodium hydride free from oil was suspended

in 200 ml of dry dimethylsulfoxide and kept at 65-70°c for 2 hours under nitrogen. A solution of 62 g of the hydroxy ester from step (c) in 50 ml of dry dimethylsulfoxide was then added to the cooled solution of the sodium hydride at 30°C. The mixture was then kept at 70°C for 18 hours, cooled and poured into 1 liter of ice. The aqueous liquids were washed with ether and then acidified to pH6. The resulting precipitate was collected and washed with water. Drying in vacuo gave 29.7 g of the sub-title compound characterized by NMR and MS.

(e) 6, 7, 8, 9- tetrahydro- 4- oxo- 10- propyl- 4H- naphtho/ 2, 3- b7pyran-2- carboxylic acid

2.94 g 5,6,7,8-tetrahydro-3-hydroxy-2-methylsulfinylacetyl-4-propyl-naphthalene, 3.12 g glyoxylic acid hydrate,

2.52 g of piperidine and 40 ml of toluene were stirred and held

boiling under reflux for 4 1/2 hours. The mixture was cooled and poured into 200 ml of ethyl acetate, and the solution was washed with water, and then extracted into a sodium bicarbonate solution.

Acidification of this gave a precipitate which was collected and recrystallized from ethanol. 0.95 g of the product was identified as the title compound by comparison with authentic samples prepared by an alternative method.

Example 5

1, 3- bis( 2- carboxychromon- 5- yloxy)- 2- hydroxypropane (a) 1, 3- bis( 2- carboxychromon- 5- yloxy)- 2- hydroxypropane, di-n-butyl ester

4.84 g of 1,3-t>is(3-hydroxy-2-methylsulfinylacetyl-phenoxy)propan-2-ol in 100 ml of chloroform was treated with 4>4 g of butyl glyoxylate in the presence of a little sodium acetate for 4 hours. The solvent was removed and the residue purified by chromatography over silica gel with ether as eluent. The main component of the reaction product mixture, i.e. 2.03 g, was dissolved in 150 ml of dry benzene and then treated with 0.35 g of bDrtrifluoride etherate. After boiling for 3 hours, the mixture was cooled and poured into 500 ml of ice water. The two-phase mixture was stirred for 2 hours, the organic solution was separated, washed with sodium chloride solution, dried and evaporated to give 139 g of the title compound. The structure was confirmed by NMR and IR spectroscopy.

(b) 1, 3- bis( 2- carboxychrom- 5- yloxy)- 2- hydroxypropane

1.39 g of the diester, 1.4 g of sodium bicarbonate, 50 ml of water and 100 ml of ethanol were refluxed for 4 l/2 hours. The mixture was cooled and the ethanol removed in vacuo. Acidification of the aqueous solution gave a precipitate which was collected and dried, and 0.8 g was obtained. This product was identical to authentic material produced by an alternative method e.

Claims (12)

1. Process for the production of a chromone-2-carboxylic acid, characterized by reacting a 2'-hydroxy-2-alkylsulfinylacetophenone, provided that the alkyl group of the compound has no free hydrogen atoms on the (3-carbon atom (when such is present), or a 2'-hydroxy-2-phenylsulfinylacetophenone with glyoxylic acid in the presence of a base, thereby obtaining the desired compound. 2. Procedure according to claim 1, characterized in that the product manufactured by the method is a connection with the formula wherein: (i) R represents hydrogen or hydroxy; R 2 and R 3 together represent tetramethylene, and R 3 represents n-propyl; or (ii) R 1 represents hydrogen, R 2 and RJ 3 together represent a group -COCH=C(CO 2 H)-O-, and R^" represents n-propyl; or(iii) R"'" represents a group with the formula: 2 3 Æ and R 1 , R 1 , and R 1 , all represent hydrogen. 3. Method according to claim 2, characterized in that the product produced by the method is a compound defined under (i), and the acetophenone starting compound has the following formula: (where R represents alkyl without any free hydrogen atoms on the P carbon atom, when this is present, or phenyl which may be unsubstituted or substituted with one or more halogen atoms or Cl to C4 alkyl or alkoxy groups, and X represents hydrogen or blocked hydroxy) and where X represents blocked hydroxy, after which the product is treated to remove the blocking group. 4~ --■ Method according to claim 2, characterized in that the product produced by the method is a compound defined under (ii) and the acetophenone starting compound has the following formula: (where R is as defined in claim 3 and R? and R either together represent a chain -COCH=C(Y)0- where Y represents carboxy or restricted carboxy, or respectively the represen teres the group R-^-CHg-CO- and -OH), after which the product where Y represents esterified carboxy is hydrolyzed to the corresponding compound of formula I. 5- Method according to claim 2, characterized in that the product produced by the method is a compound as defined in (iii) and the acetophenone starting compound has the following formula: (. where R is as defined in claim 3> and R^ S and R 6 are as defined in claim 4)> after which the product where X represents esterified carboxy is then hydrolysed to the corresponding compound with formula I. 6. Method according to any one of claims 1 to 5, characterized in that the acetophenone starting compound is a 2,-hydroxy-2-methylsulfinylacetophenone. 7« Process according to any one of claims 1 to 6, characterized in that the base used is a secondary amine. 8. Method according to claim 7> characterized in that the secondary amine is piperidine. 9' Method for producing compounds of formula I as defined in claim 2, characterized in that a compound of formula II, III or IV as defined in claim 3, 4 or 5 is reacted with a glyoxylic acid ester in a suitable solvent and in presence of a suitable catalyst, followed by a cyclization and, if necessary, by a hydrolysis of any ester formed, thereby obtaining the desired compound of formula I. 10. Method according to claim 9, characterized in that the catalyst is a Knoevenagel reaction catalyst. 11. Method according to claim 10, characterized in that the catalyst is a base. 12. Method according to claim 11, characterized in that the base is sodium acetate or an amine. 13• Method according to any one of claims 9 to 12, characterized in that the solvent is pyridine or chloroform. 14• Method according to any one of claims 1 to 13, characterized in that the starting acetophenone compound itself is prepared by a method where the corresponding 2- alkoxycarbonylphenol is reacted under suitable conditions with an anion of the formula <Q> CHgSOR (where R is as defined in claim 3)«