DE954155C - Process for the preparation of 4-aminochromans - Google Patents

Description

Process for the preparation of 4-aminochromans The subject of the main patent 936 541 is a process for the preparation of 4-aminochromans of the general formula in which R1 and R2 represent hydrogen atoms, saturated or unsaturated alkyl radicals or, together with the nitrogen atom, the radical of a heterocyclic ring system and R3 represents a phenyl or aralkyl radical, which is characterized in that the corresponding 4-chromanones are either a) reduced to 4-chromanols, converts these into 4-halochromans and allows ammonia or primary or secondary amines to act on the latter, or b) converts them into primary 4-aminochromes by hydrogenation via their oximes or c) reductive amination, preferably by catalytic hydrogenation in the presence of Ammonia or primary or secondary amines, whereupon the primary or secondary 4-aminochromans obtainable according to a), b) or c) are subjected to further alkylation of their amino group, optionally by customary methods. These 4-aminochromes have therapeutically valuable properties, e.g. B. long-lasting local anesthetic effect.

It has now been found that these properties are also attributable to those 4-aminochromanes which are obtained in a further development of the process according to the main patent by using 8-alkyl-4-chromanones of the general formula in which R3 is a preferably lower alkyl radical and R4 and RS are hydrogen atoms or preferably lower alkyl radicals, are used as starting materials.

So much for the 8-alkyl-4-chromanones used as starting materials a particularly advantageous production method, for the purposes of the present Invention no protection is to be sought, by hydrogenation crude appropriate 4 chromones are obtained, they need them when using variant a of the method not even to be isolated, but instead can be in a dissolved state are immediately further hydrogenated to the corresponding 4-chromanols, which are then further processed according to the procedure mentioned. Example i 4.5 g raw 2, 6, 8-trimethyl-chromanone- (4), prepared from 4.4 g of 2, 6, 8-trimethylchromone- (4) (F. 129 to 130 °) by hydrogenation with Raney nickel and stopping the reaction Uptake of one mole of hydrogen are again with Raney nickel in methanol Hydrogenated under normal conditions, the 2, 6, 8-trimethyl-chromanol- (4) (F. 115 to 116 °) arises. Yield 3.8 g of recrystallized product. The hydrogenation of the Chromons can also be converted into chromanol in one go under the same reaction conditions be performed.

3.8 g of 2, 6, 8-trimethyl-chromanol- (4) are at room temperature treated with 2.7 g of thionyl chloride in chloroform and then set to 50 ° for a few hours warmed up. The reaction liquid is evaporated in vacuo and the residue in Ether added. Now one washes one after the other with water, sodium bicarbonate solution and water. The ether solution is dried over sodium sulfate, evaporated in vacuo and the residue was dried over phosphorus pentoxide in a desiccator. That won Crude chloride is added directly to the reaction with dimethylamine (5 g) in a pressure bottle brought. The batch is left at room temperature overnight. stand and take then the reaction mixture in water and ether. The ethereal solution is made with water washed neutral and dried over calcined potassium carbonate. One concentrates the solution by evaporation and the hydrochloride of 2,6,8-trimethyl-4-dimethylaminochroman falls with essential hydrochloric acid. Melting point of the crude chloride F. 222 to 224 °. The substance can be recrystallized from methanol-ether (mp 225 °).

The previously not described 2, 6, 8-trimethylchromone- (4) can e.g. B. from 1, 3, 4-xylenol via the 2-oxy-3, 5-dimethylacetophenone (F. 57 to 58 °) by further conversion with ethyl acetate and ring closure per se known methods can be obtained.

Example 2 3.5 g of crude, oily 8-ethylchromanone- (4) are dissolved in methanol hydrogenated with Raney nickel in a roller autoclave at Zoo atü and 100 ° to form 8-ethylchromanol- (4). This is obtained after the catalyst has been filtered off with suction and the solvent has been evaporated off in vacuo the 8-ethylchromanQ1- (4) as an oily residue. Yield 3.3g. The exam complete hydrogenation took place with 2,4-dinitrophenylhydrazine. The reagent resulted in no more keto reaction with the oily hydrogenation product.

3.3 g of crude 8-ethylchromanol- (4) are at room temperature with i, 8 g phosphorus tribromide and 10 ccm alcohol-free and anhydrous chloroform are added and then heated to 50 ° for 1/2 hour. The reaction liquid becomes after cooling mixed with ice water, separated the chloroform layer in a separating funnel and washed successively with water, bicarbonate solution and water. You dry now the chloroform solution over calcium chloride and then evaporated it in vacuo. Of the 15 cc of diethylamine are added to the residue and the mixture is kept at room temperature for 48 hours left to stand under exclusion of moisture. The failed diet hylaxnine hydrobromide is sucked off and. the excess diethylamine is distilled off from the filtrate. The The residue is taken up in water and ether. The ether solution becomes neutral with water washed and dried over calcined potassium carbonate. By adding more essential Hydrochloric acid to the dried ether solution falls the hydrochloride of 8-ethyl-4-diethylaminochroman straight away (m. 157 to 16o °).

That as the starting material. required 8-ethylchromanone- (4) can from o-Ethylphenol by reaction with ß-chloropropionic acid and ring closure according to known Methods are obtained.

For the production of the starting materials, in the context of the present Invention Protection not sought. Example 3 7.1 g of 2,6,8-trimethylchromanol- (4) become dissolved in dry, alcohol-free chloroform and treated with 10.4 g of phosphorus tribromide. The mixture is heated to 50 ° for 11/2 hours with exclusion of moisture and then distilled pouring off the precipitated phosphorous acid in vacuo and chloroform excess phosphorus tribromide. The residue is kept in a vacuum desiccator for a day on phosphorus pentoxide and potassium hydroxide. The 2,6,8-trimethyl obtained in this way 4-bromochroman is now with cooling with excess piperidine, which also acts as a solvent acts, added and left to stand overnight at room temperature. Then heated the reaction mixture is kept at 5o to 6o ° for 1 1/2 hours and then it is taken in ether and water. The ether solution is washed neutral with water and washed over dried calcined potassium carbonate. By adding essential hydrochloric acid to the dried ether solution, the hydrochloride of 2,6,8-trimethyl-4-piperidinochroman is precipitated the end. The melting point of the hydrochloride is 237 to 238 °. The yield is 75% of theory, based on the 2,6,8-trimethylchromanol- (4) used.

Claims (1)

PATENT CLAIM: Further development of the process for the preparation of 4-aminochromanes according to Patent 936 571, characterized in that 8-alkyl-4-chromanones of the general formula are used as starting materials in which R3 is a preferably lower alkyl radical and R4 and R6 are hydrogen atoms or preferably lower alkyl radicals.