CS252345B1 - Process for the preparation of 5- [2- (N-methylamino) ethoxy] -7-oxo-7H-benzo [c] fluorene - Google Patents

Abstract

The solution concerns a method of producing 5- -/2-(N-methylamino)-ethoxy/-7-oxo-7H- -benzo/c/fluorene of formula I O /CH3 och2ch2n^ H CD metabolite of the cytostatic 5-/2-(N,N-dimethyl- -amino)ethoxy/-7-oxo-7H-benzo/c/fluorene. The method of production consists in demethylation of 5- -/2-(N,N-dimethylamino)ethoxy/-7-oxo- -7H-benzo/c/fluorene by reaction with cyanogen bromide in chloroform to 5-/2-(N-cyano- -N-methylamino)ethoxy/-7-oxo-7H-benzo/c/-fluorene and subsequent hydrolysis with potassium hydroxide in ethylene glycol to the substance of formula I.

Description

The invention relates to a process for the preparation of 5- [2- (N-methylamino-ethoxy) -7-oxo-7H-benzo] c] fluoro of formula (I).

OCHjCHjN '(I)

Benzo (c) fluorene derivatives are known to carry various pharmacological activities, among which the best known are antitumor / Křepelka et al., Collection Czechoslovak Chem · Commun. 47. '258 (1982), Křepelka et al., Collection Czechoslovek Chem. Commun · il, '857 (1982), Vancurova et al., Collection Czechoslovek Chem. Commun. AZ,

867 (1982)], and interferonogenic activity (Shraejkal et al., Acta virol. £ 2, 11 (1984)]. A significant antitumor effect is described in 5- (2- (N, N-dimethylamino) ethoxy) -7-oxo-7H-benzo (o) fluorene, a compound of formula II,

CHj

OCH ₃ CH ₃ (II) which, in the form of the hydrochloride, under the designation benfluron, is being developed as a cytostatic for the treatment of human cancer / Paluska et al., Neoplasma 31, 399 (1984), Hrubá et al. , Shallow et al., Chemotherapia oncologica 11, 9 (1984), Francova et al. Neoplasma J2, 529 (1985)]. The compound of formula I is one of the potential metabolites of a compound of formula II, which was first described in an in vitro metabolic transformation study of a compound of formula II / Kvasničková et al., J. Chromatogr. 295. 201 (1984)].

The compound of formula I in evaluating the anti-tumor efficacy in animals with experimental tumors showed lower anti-tumor activity compared to the compound of formula II. At subtoxic doses, it induced a reduction in tumor size and total ascitocrit in animals with tumors STE, HK, Kr2. In vitro experiments reduced DNA biosynthesis less and proteosynthesis in the same manner compared to the compound of Formula II. However, the compound of formula (I) is a valuable intermediate for the preparation of other benzo (c) fluorene derivatives.

According to the invention, the compound of formula I is prepared from 5- [2- (N, N-dimethylamino) ethoxy] -7-oxo-7H-benzo [c] fluorene of formula II by reacting the compound of formula II in a first step with 1 to 3 mol equivalents, preferably 2.5 mol equivalents, of cyanogen bromide in an environment of aliphatic chlorinated hydrocarbons, preferably chloroform, under nitrogen, in the temperature range from 0 ° C to the boiling point of the reaction mixture, to give 5- / 2- (N-cyano) -N-methylamino) ethoxy] -7-oxo-7H-benzo [c] fluorene of formula III,

(III)

OCH ₂ CH ₂ N _x

CN which is hydrolyzed in a second step with 5 to 10 mol equivalents of an alkali hydroxide, preferably potassium hydroxide in a boiling alcohol, preferably ethylene glycol, at a temperature of from 100 ° C to the boiling point of the reaction mixture to give the compound of formula I.

The reaction of the compound of formula II with cyanogen bromide can be carried out in an environment of aliphatic chlorinated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichlorethylene, tetrachloroethane or other mixtures. For economic reasons, the use of chloroform is most preferred.

The preparation of the compound of formula II is described in our art. 212 669 and 235 429 and Publications / Quail et al., Collection Czechoslovak Chem. Commun. 47, 1 258 (1982) and Křepelka et al., '657 (1982)]. _#

The decyanination of the compound of formula III to the compound of formula I can be carried out in an environment of alcohols boiling above 110 ° C, most preferably in a diol environment such as ethylene glycol or propylene glycol by treatment with alkali hydroxides such as potassium hydroxide or sodium hydroxide.

The reaction mixtures after the reactions are worked up according to conventional procedures; for example, after evaporation of the volatile solvents and obtaining the crude product 3e, it is purified by column chromatography or crystallization (compound of formula III), or the reaction mixture is diluted with water (compound of formula I) and taken up in a water-immiscible organic solvent. chromatography or crystallizer.

More detailed information on the preparation of the compound of formula I will be apparent from the following non-limiting example.

Example

5- [2- (N-methylamino) ethoxy] -7-oxo-7H-benzo [c] fluorene

To a solution of 5- (2- (N, N-dimethylamino) ethoxy) -7-oxo-7H-benzo [c] fluorene (12.9 g, 0.04 mol) in chloroform (200 mL) was added under nitrogen for 30 min. solution of 10.5 g (0.1 mol) of broinkyan in 6 ml of chloroform and the reaction mixture was refluxed for 3 h. After filtration of the solid, the filtrate was evaporated to dryness, the residue was dissolved in chloroform and purified by silica gel column chromatography using chloroform. as eluent. Combined fractions gave 11.0 g (0.03 mol) of 5- [2- (N-cyano-N-methylamino) ethoxy] -7-oxo-7H-benzo [c] fluorene, m.p. 178 DEG-180 DEG. C (ethanol) was added to a solution of 17.0 g (0.3 mol) of potassium hydroxide in 180 ml of ethylene glycol and the reaction mixture was stirred at 170 ° C for 3 h. After completion of the reaction, the reaction mixture was diluted with 400 mL of water and extracted with chloroform. After drying over sodium sulfate, the chloroform extracts were evaporated to dryness and the crude product was purified by silica gel column chromatography using chloroform as eluent. Combine the individual fractions to give 5- (2- (N-methylamino) ethoxy) -7-oxo-7H-benzo [c] fluorene, m.p. 95-97 ° C.

Claims (1)

SUBJECT OF THE INVENTION Process for the preparation of 5- (2- (N-methylamino) ethoxy) -7-oxo-7H-benzo [c] fluorene of formula I ..CH, och ₂ ch ₂ < (I) characterized in that in the first step, 5- [2- (N, N-dimethylamino) ethoxy] -7-oxo-7H-benzo [c] fluorene of formula (II) and ₂ ch ₂ n are reacted; , ch ₃ ch, (II) β 1 to 3 mol equivalents, preferably 2.5 mol equivalents, of cyanogen bromide in an environment of aliphatic chlorinated hydrocarbons, preferably chloroform, in a nitrogen atmosphere »ranging from 0 ° C to the boiling point of the reaction mixture to give 5 - (2- (N-cyano-N-methylamino) ethoxy) -7-oxo-7H-benzo [c] fluorene of formula III, (III) which is hydrolyzed in a second step with 5 to 10 moles of alkali hydroxide, preferably potassium hydroxide in a boiling alcohol, preferably ethylene glycol, at a temperature of from 100 ° C to the boiling point of the reaction mixture, to the compound of formula I.