DE2019570C2 - Water-soluble khellin derivative: 1H, 3H-2-aza-4-methylene-5,8-dimethoxy-furo (2 ", 3", 6,7) xanthone-2-spiro-1'-piperidinium chloride and process for its preparation - Google Patents

Description

Cl ^e

H ₃ CO O

HCl

- ¹ O

by reacting khellin with piperidine and excess Parafonrialdehyde in the presence of a Solvent, characterized in that the reaction is carried out in a mixture 50 parts by volume of benzene and 37 parts by volume of nitrobenzene with boiling on the water separator initially using an equimolecular amount of paraformaldehyde and others equimolecular amounts of paraformaldehyde at intervals of 2, 4 and 6 hours after the start of the reaction clogs.

attributed to.

In no case were, as was found by repeated reworking, yields above 25% of theory. Th. Achieved
It has now been recognized through detailed investigation that this spasmolytic and antihypertensive compound is in fact 1-H3H-2-aza-4-methylene-5,8-dimethoxyfuro (2 ", 3", 6 /; - xanthone- 2-spiro-r-piperidinium chloride and has the following structural formula:

20th

H ₃ CO

H ₃ CO

Cl ^e

Khellin, the dimethyl ether
thy! 4 ', 5': 6,7-furanochromons (I)

H ₃ CO

CH ₃

des 5,8-dioxy-2-me-

OCH ₃

takes one of the asthma drugs because of its coronary-dilating and spasmolytic properties preferred position. The parenteral use of this substance stands in the way of its poor solubility.

There has been no lack of attempts to use solubilizers - e.g. B. theophylline derivatives - Bringing khellin into solution and thus making it usable for injection purposes. Attempts are still being made have been to come to water-soluble substances by converting the khellin, which with the same pharmacological effectiveness enable parenteral administration.

It is known that khellin in solvents of a Mannich aminomethylation by reacting with piperidine and formaldehyde or paraformaldehyde. According to German Patent 11 97 454, the reaction in the presence of glacial acetic acid or dioxane is as Solvent and according to German Patent 12 Ol 840 in the presence of large amounts of water as well Nitrobenzene and benzene carried out. The following formula was assigned to the water-soluble derivative isolated in this way it has now been found that these water-soluble khellin derivatives can be obtained in an improved yield reaches that the reaction is carried out in a mixture of 50 parts by volume of benzene and 37 parts by volume Nitrobenzene boiling on a water separator initially using an equimolecular amount Paraformaldehyde carries out and further equimolecular amounts of paraformaldehyde at intervals of 2, 4 and added 6 hours after the start of the reaction.

example

26.0 g of khellin, 12.16 g of piperidine hydrochloride and 3.0 g of paraformaldehyde are added to a solvent mixture suspended from 50 ml of benzene and 37 ml of nitrobenzene and heated to the boil on a water separator. After 2, 4 and 6 hours, a further 3.0 g of paraformaldehyde are added in each case. After 8 hours it will the resulting yellow, crystalline precipitate is suctioned hot, washed with a little benzene and over

so night dried-st. The crude product is hot with little Boiled benzene, vacuumed off, washed with a little hot • benzene and dried. That from The reaction product freed from residues of khellin is recrystallized from absolute ethanol.

Yellow crystals, m.p. 265 ° C
Yield: 45% of theory Th.

Claims (1)

Claim: Process for the preparation of IH, 3H-2-aza-4-methylene-5,8-dimethoxyfuro- (2 "3", 6,7) xanthone-2-spiro-r-piperidinium chloride the following structural formula H ₃ CO O