DE1080114B - Process for the preparation of substituted coumarones - Google Patents

Description

GERMAN

The invention relates to a process for the preparation of substituted coumarones of the general formula ■ Process for the production of substituted coumarones

OH

in which R is a methyl, ethyl or phenyl group, X is a CO or CH (O H) group and Y is one or more Means halogen atoms.

The substituted coumarones identified by the above general formula were found to be pronounced Spasmolytics are and are partly also suitable as coronary vasodilators.

Thus, the new compounds prepared according to the invention are most effective against one of the most effective known spasmolytic remedies, namely the 5,8-dimethoxy-2-methylfurano- (4 ', 5': 6,7) -chromon, the the following effects:

Applicant: Societe des Laboratoires LABAZ, Brussels

Representative: Dr. W. Schalk, Dipl.-Ing. P. Wirth,

Dipl.-Ing. G. E. M. Dannenberg and Dr. V. Schmied-Kowarzik, patent attorneys, Frankfurt / M., Große Eschenheimer Str. 39

Claimed priority: <

Belgium 21 December 1956

Buu Hoi, Paris, and Camille Beaudet, Brussels, have been named as inventors

Spasmolytic effect at by. Histamine Induced Cramps Compared To 5,8-dimethoxy-2-methyl: £ urano- (4 ^ 5 ': 6,7) -chromone

the isolated intestine of the
Guinea pig

on the isolated heart of rabbit

5,8-dimethoxy-2-methylfurano- (4 ', 5': 6,7) -chromon .'-.

2-ethyl-3- (4'-oxy-3 ', 5'-dibromobenzoyl) coumarone

2-ethyl-3- (4'-oxy-3 ', 5'-diiodobenzoyl) coumarone.

2-ethyl-3- (4'-oxy-3 ', 5'-diiodophenylcarbinyl) coumarone.

15 times
27.5 times
llfold

■ 1

40-fold 100-fold

30x

As can be seen from the above values, the new substituted coumarones are many times more effective as spasmolytics than 5,8-dimethoxy-2-methylfurano- (4 ', 5: 6.7) -chromone, so that these compounds are a valuable asset of remedies mean. Their usefulness is further improved by the fact that their toxicity is very low and the LD ₅₀ , determined by intraperitoneal administration in mice, is only between IOP and 200 mg / kg.

The process according to the invention for the preparation of those characterized by the above general formula Coumarones consists in the fact that the corresponding halogen-free coumarones are carried out in a manner known per se Implementation halogenated with halogens.

The compounds used as starting materials are obtained as follows: Compounds in which the The radical X stands for the CO group, according to the procedure of patent application S 56 349 IVb / 12q (German Auslegeschrift 1 076 702) produced. Compounds in which the radical X represents the CH (OH) group, can from the corresponding CO compounds according to the Meerwein-Pondorf process by reaction with isopropyl alcohol and aluminum isopropoxide can be produced.

The following examples illustrate the process.

example 1
Production of

2-ethyl-3- (4'-oxy-3 ', 5'-dijodbenzoyl) -cumaron 133 g 2-ethyl-3-p-oxybenzoylcumaron (F. = 124.3 ⁰ C) are from 50 to 6O ⁰ C dissolved in a sodium hydroxide solution (22 g in 400 ecm of water). The solution is diluted by adding 3.5 liters of water; the _H p value is then 10.5 to 11. A solution of 280 g of iodine and 280 g of potassium iodide in 700 ecm of water is then slowly added over a period of ¹ _{l 2 hours with stirring, with}

909 787/415

the _pH value is maintained above 7 by constantly 10% sodium hydroxide solution is added (ECM total of 350 final PJG-WertS.S). The reaction mixture is then stirred for 3 hours and then carefully centrifuged.

The yellow precipitate obtained is suspended in water with stirring, and this suspension is added 400 ecm of 20% sodium bisulfite solution and then 70 ecm of concentrated hydrochloric acid were added. The mixture is stirred for 90 minutes, after which it is left to stand at room temperature for about 10 hours.

The mixture is then centrifuged and the residue washed with 3 to 41 water, whereupon the moist Precipitation suspended in 500 ecm of methanol and the suspension is stirred until a uniform Paste has been obtained, which is then centrifuged and dried at room temperature.

There are 245 g of crude 2-ethyl-3- (4'-oxy-3 ', 5'-driodobenzoyl) coumarone obtained, which corresponds to a yield of 95%. The raw product can be washed by washing be cleaned with diethyl ether or ethyl acetate. M.p. = 167 ° C.

Example 2

Production of
2-ethyl-3- (4'-oxy-3 ', 5'-dibromobenzoyl) coumarone

A solution of 10 g of 2-ethyl-3-p-oxybenzoylcumaron (mp = 124.3 C ⁰⁾ in acetic acid is treated with 12 g of bromine and heated at reflux, will be more given to no gaseous hydrogen bromide. After the solution has been concentrated, the residue is washed several times with water, neutralized with soda and the precipitate is centrifuged. 10 to 12 g of a dibrominated derivative are obtained which can be recrystallized from cyclohexane. M.p. = 151 ° C.

Example 3

Production of
2-ethyl-3- (4'-oxy-3'-bromobenzoyl) -coumarone

2.66 g 2-ethyl-3-p-oxybenzoylcoumarone (m.p. 124.3 ° C) are dissolved in 130 ecm acetic acid and 1.6 g of bromine dissolved in 15 ecm acetic acid are added to this solution. the The solution obtained is stirred and left to stand overnight, whereupon it is treated with 100 ecm of water and the precipitate is separated off and recrystallized from ethyl alcohol. The melting point of the obtained 2-Ethyl-3- (4'-oxy-3'-bromobenzoyl) -coumarone is 60 ° C. Yield: 60%.

Example 4

Production of
2-Ethyl-3- (4'-oxy-3 '-bromo-5 ' -] odbenzoyl) -coumarone

A solution of 2.75 g of iodine in aqueous potassium iodide is added to a solution of 3.45 g of 2-ethyl-3- (4'-oxy-3'-bromobenzoyl) -cumaro * n in 222 ecm of 0.05 η sodium hydroxide solution (2.8 g of potassium iodide in 20 ecm of water) were added. The resulting solution is stirred for 2 hours, acidified, centrifuged and the residue washed with water, whereupon it is dried in vacuo over phosphoric anhydride. The melting point of the obtained 2-ethyl-3- (4'-oxy-3'-bromo-5'-iodobenzoyl) -cumarons is 15O ⁰ C. Yield: 66%.

Example 5

Production of
2-ethyl-3- (4'-oxy-3 ', 5'-diiodophenylcarbinyl) coumarone

0.1 mole (26.8 g) of 2-ethyl-3-p-oxyphenylcarbinylcumaron (mp = 74 C ⁰⁾ is dissolved in a slight excess of a 3% sodium hydroxide solution. A slight excess of iodine dissolved in a 25% strength aqueous solution of potassium iodide is slowly added to the resulting solution. The solution is left to stand for 2 hours at normal temperature, acidified with a 20% strength solution of sodium bisulfite, centrifuged, the residue is washed with water and dried in vacuo. After recrystallization from acetic acid, 41,6 g of 2-ethyl-3- (4'-oxy-3 ', 5'-diiodophenylcarbinyl) -coumarone are obtained. F. = 100 ⁰ C.

40

Claims (1)

Claim: Process for the production of
Coumarones of the general formula substituted OH where R is a methyl, ethyl or phenyl group, X is a CO or CH (OH) group and Y is one or more halogen atoms, characterized in that the corresponding halogen-free coumarones are halogenated in a manner known per se by reaction with halogens . © 909 787/415 + .60