NO761649L - - Google Patents

Description

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

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

According to the invention, a method is thus provided for the production of compounds with the formula:

where R^, RgjRy and Rg, which may be the same or different, are each hydrogen, hydroxy or alkyl, as well as pharmaceutically acceptable derivatives thereof, and this method is characterized by ring-closing a compound of the formula: where Rp., Rg, R ^ and Rg have the above meaning, R is a -COOH group or a group that can be hydrolyzed to this group, and Hal is a halogen atom, and if desired or necessary, the resulting compound is hydrolyzed to a compound of formula I and/ or the compound of formula I is converted into a pharmaceutically acceptable derivative thereof.

The R group can e.g. be an ester group -CORx

where Rx is a C 1-6 alkoxy group. The group Hal can be a bromine, chlorine, iodine or preferably a fluorine atom.

The reaction can be carried out in a solvent which is inert under the reaction conditions, preferably a high-boiling polar solvent, e.g. pyridine, dimethylformamide or hexamethylphosphoramide. The reaction is preferably carried out using a strong base which can remove a proton from the -COCHgCOR group (or its enol tautomer) in the compound of formula II; e.g. lithium, sodium or potassium hydride, a hydroxide, alkoxide (eg ethoxide), aryl oxide (eg phenoxide), aryl (eg phenyl) or alkyl (eg butyl). The reaction is preferably carried out at a temperature from approx. 80-200°C. Furthermore, the reaction is preferably carried out in the absence of free oxygen,

e.g. in an inert atmosphere such as nitrogen.

Compounds of formula II can be prepared by reacting a compound of the formula:

where R^, Rg, , Rg and Hal have the above meaning, with a mono- or di-alkyl oxalate, e.g. diethyl oxalate or potassium ethyl oxalate, in a manner known per se.

The compounds of formula I and the intermediates for obtaining these compounds can be recovered from the reaction media in which they are prepared using conventional techniques.

The compounds of formula III are either known or can be prepared from known compounds using known techniques.

When one or more of R,-, Rg, R^ and Rg are alkyl, it is preferred that the alkyl group contains 1-5 carbon atoms, inclusive, e.g. is ethyl or t-butyl. Furthermore, it is preferred that Rp- is hydrogen or hydroxy, Rg and Rg are alkyl and that R 7 is hydrogen.

The compounds of formula I and pharmaceutically acceptable derivatives thereof have pharmacological activity in animals, and they are particularly useful because they inhibit the release and/or action of pharmacological mediators resulting from the combination in vivo of certain types of antibody with specific antigen, e.g. . the combination of reaginic antibody with specific antigen, as in the passive putan anaphylaxis test in rats. The compounds and especially the 5-hydroxy-6,8-diethyl compound are therefore used in the treatment of allergic asthma. The 6,8-di-t-butyl compound is also useful as a uricosuric agent.

Pharmaceutically acceptable derivatives of the compounds of formula I comprise pharmaceutically acceptable salts, esters and amides thereof, particularly preferred are the pharmaceutically acceptable salts, e.g. the sodium salt.

In the following, the invention will be further illustrated with reference to the examples below.

Example 1

Ethyl-4-oxo-4H-1-benzopyran-2-carboxylate

(a) Ethyl 4-(2-bromophenyl)-2,4-dioxobutanoate

o-bromoacetophenone (5g) in dry dimethylformamide (20ml) was added to a suspension of sodium hydride (2.4g 50% mineral oil dispersion) in dry dimethylformamide (100ml) containing diethyl oxalate (13.7ml). The reaction mixture was stirred at room temperature under a dry nitrogen atmosphere for 3 days and then poured into dilute acetic acid and extracted with ethyl acetate. After washing with sodium bicarbonate solution, the extracts were dried and evaporated.

The remaining oil was subjected to fractional distillation which gave the product as a yellow oil (4.2 g), b.p. 200°C (air bath), 10.5 mm Hg, and the product showed the following characteristics:

Thin layer chromatography:

One stain in 10 solvent systems. Infrared absorption (film):

Y max.: 1735 (s), l600 (s) cm<-1.>

Ultraviolet absorption:

X ethanol max.: 320 nm. (e max. 10,589)-

NMR spectrum (CDCl^):

h: 2.5 (4H,m)

3.1 (lH,s)

5.65 (2H,q)

8.6 (3H,h)

Microanalysis:

Found: C 48.6, H 3.7, Br 26.4. C-^H^BrO^ requires C 48.2, H 3.7, Br 26.8%.

(b) Ethyl- 4- oxo- 4H- I- benzopyran- 2- carboxylate

The diketone product from step (a) (2.0 g) was added to a suspension of sodium hydride (0.321 g 50% mineral oil dispersion) in dry dimethylformamide (50 ml) and the resulting solution was stirred at 130°C in a nitrogen atmosphere for 3 hours.

Acidification of the cooled reaction mixture with dilute hydrochloric acid liberated the product which was extracted with ethyl acetate and washed with sodium bicarbonate solution and then dried.

Evaporation gave a solid which crystallized from petroleum ether (b.p. 60-80°C) to a material (0.36 g) m.p. 72-73°C.

Thin layer chromatography:

One stain in 10 solvent systems.

Infrared absorption (KBr disk)

Y max.: 1730 (s), 1640 (s) cm"<1>

Mass spectrum:

m/e 218

NMR spectrum (CDCl3)

h: 1.7-2.8 (4H,m)

2.9 (lH,s)

5.5 (2H,q)

8.6 (3H,h)

Microanalysis:

Found: C 66.3, H 4.8. Calculated for C-^H-^O^ :

C 66.1, H 4.6%.

Example 2

4-oxo-4H'-1-benzopyran-2-carboxylic acid

(a) 4-(2-bromophenyl)-2,4-dioxobutanoic acid

o-bromoacetophenone (5 g) and ethyl potassium oxalate (3.92 g) were added to a suspension of sodium hydride (2.75 g 50% mineral oil dispersion) in dry dimethylformamide (150 ml). After stirring at room temperature under dry nitrogen for 65 hours, the mixture was diluted with water, acidified with hydrochloric acid and extracted with ethyl acetate. The organic extracts were washed with water, dried and evaporated.

The residue crystallized from toluene as light brown needles (1.5 g), m.p. l48-l49°C (decomp.).

Thin layer chromatography:

One stain in 10 solvent systems

Infrared absorption (KBr disk):

Y max.: 3100 (m), 1710 (s), 1610 (s), 1580 (m) cm<-1>. Ultraviolet absorption:

A EtOH max.: 311 nm (max. 11249)

Mass spectrum:

m/e 270, 272

NMR spectrum (DMSOdg)

t: -1.5 (lH,s)

3.5 (4H,m)

3.15 (lH,s)

(b) 4-oxo-4H-1-benzopyran-2-carboxylic acid

The diketo acid product from step (a) (1.4g) was added to sodium hydride (0.545g 50% mineral oil dispersion) in dry dimethylformamide (50ml). After stirring at 150°C in a nitrogen atmosphere for 20 hours, the reaction mixture was cooled, diluted with water and acidified with hydrochloric acid. The crude product was extracted with ethyl acetate, washed with water and dried. Evaporation of the solvent resulted in a solid which crystallized from aqueous ethanol.

Thin layer chromatography:

One stain in 10 solvent systems.

Infrared absorption (KBr disk):

Y max.: 1730 (s), 1620 (s) cm<-1>

Mass spectrum:

m/e 190

NMR spectrum (DMSOdg):

x : 2.4 (4H, m)

3.1 (1H, s)

Example 3

6, 8- diethyl- 5- hydroxy- 4- oxo- 4H- l- benzopyran- 2- carboxylic acid

2-Bromo-3,5-diethyl-6-hydroxyacetophenone (5 g) and ethyl potassium oxalate (3 g) were added to a suspension of sodium hydride (2.5 g 50% mineral oil dispersion) in dry dimethylformamide (150 ml). After stirring at room temperature in a dry nitrogen atmosphere for 80 hours, the mixture was diluted with water, acidified with hydrochloric acid and extracted with ethyl acetate. The organic extracts were washed with water, dried over MgSO 4 and evaporated to give 4-(2-bromo-3,5-diethyl-5-hydroxyphenyl)-2,4-dioxobutanoic acid.

The remaining oil was used without further purification and was added to sodium hydride (2.0 g 50% mineral oil dispersion) in dry dimethylformamide (150 ml). After stirring at 150°C in a nitrogen atmosphere for 20 hours, the reaction mixture was cooled, diluted with water and acidified with hydrochloric acid. The crude product was extracted with ethyl acetate, washed with water and dried over MgSO 4 . Evaporation gave a yellow solid which, after crystallization from acetic acid, gave the desired compound indicated above, m.p. 220-221°C.

Example 4

6, 8- di- t- butyl- 4- oxo- 4H- l- benzopyran- 2- carboxylic acid

2-Bromo-3,5-di-t-butylacetophenone (5g) and ethyl potassium oxalate (2.85g) were added to a suspension of sodium hydride (2.6g 50% mineral oil suspension) in dry dimethylformamide (150ml). After stirring at room temperature in a dry nitrogen atmosphere for 80 hours, the mixture was diluted with water, acidified with hydrochloric acid and extracted with ethyl acetate. The organic extracts were washed with water, dried over MgSO 4 and evaporated to give 4-(2-bromo-3,5-di-t-butylphenyl)-2,4-dioxobutanoic acid.

The remaining oil was used and without further purification added to sodium hydride (2.2 g 50% mineral oil dispersion) in dry dimethylformamide (150 ml). After stirring at 150°C under a nitrogen atmosphere for 18 hours, the reaction mixture was cooled, diluted with water and acidified with hydrochloric acid. The crude product was extracted with ethyl acetate, washed with water and dried over MgSO 4 . Evaporation gave a solid which after crystallization from acetone gave the desired compound, m.p. 231-233°C.

Claims (6)

1. Method for preparing a compound of the formula: where R;-, Rg, R^ and Rg, which may be the same or different, (each is hydrogen, hydroxy or alkyl, as well as pharmaceutically acceptable derivatives thereof, characterized by ring-closing a compound with the formula: wherein R^ , Rg , R^ and Rg are as defined above, R is a -COOH group or a group hydrolyzable to such a group, and Hal is a halogen atom, and, if desired or necessary, the resulting compound to a compound of formula I and/or the compound of formula I is converted into a pharmaceutically acceptable derivative thereof. 2. Method according to claim 1, characterized in that the group R is the group -CORx where Rx is a C 1-6 alkoxy group. 3- Method according to claim 1 or 2, characterized in that the reaction is carried out in a high-boiling polar solvent. 4. Method according to any one of the preceding claims, characterized in that the solvent is pyridine, dimethylformamide or hexamethylphosphoramide. 5. Method according to any one of the preceding claims, characterized in that the reaction is carried out using a lithium, sodium or potassium hydride hydroxide, alkoxide, aryloxide, aryl or alkyl. 6. Method according to any of the preceding claims, characterized in that the reaction is carried out at a temperature of from 80-200°C. 7 • Method according to any of the preceding claims, characterized in that the reaction is carried out in the absence of free oxygen.