CS235429B1 - Method of 5-(2-(n,n,-dimethylamino)ethoxy)-7-oxo-7h-benzo(c)fluorenhydrochloride production - Google Patents

Abstract

The invention relates to a simplified procedure production of Benfluron cytostatic, chemically 5- / 2- (Ν, Ν-dimethylemino) -ethoxy / -7-oxo-7Hbenzo / c / fluorene hydrochloride in the alkylation of 5-hydroxy-7-oxo-7H-benzo [c] fluorene by treatment with 2- (N, N-dimethylamino) ethyl chloride in an acetone-inert mixture solvents such as toluene or low boilers chlorinated aliphatic hydrocarbons, under anhydrous carbonate catalysis potassium. The reaction mixture after processing a removing inorganic fractions without isolating the intermediate base product to the hydrochloride by ethanolic action hydrogen chloride solution.

Description

The present invention relates to a process for the preparation of 5- (2- (N, N-dimethylamino) ethoxy) -7-oxo-7H-benzo [e] fluorene hydrochloride of formula (1)

The compound of formula (I) is the original Czechoslovak cytostatic, working designation Benfluron, characterized by a broad spectrum of antitumor rtftity in experimental tumor systems in vivo, whose mechanism of action resulting from in vitro evaluation is based on inhibition of proteosynthesis and nucleic acid synthesis in tumor cells. Further details on pharmacological activity, toxicity, immunoauppressive activity and mechanism of action can be found in the Czechoslovak author's certificate No. 212669 and foreign patents: Belgian No. 887327, Spanish No. 499696, Austrian No. 368127, Argentine No. no.

227171 and English No. 2068374. Benfluron is currently under evaluation for Phase 1 clinical trials at CSSR sites.

The present process for the preparation of the compound of formula (1) is described in detail in the specification of the certificate No. 212669 and consists in condensation of the alkali phenolate of the tetracyclic aromatic group benzo / c / fluorene formed from the corresponding hydroxy derivative by strong alkali hydroxides or (N, N-dimethylamino) ethyl chloride, either in the anhydrous or biphasic medium formed by a heterogeneous mixture of the aromatic hydrocarbon and water. However, the implementation of condensation has some disadvantages that prevent it from being transferred to the technological grid; * / the two-phase process yields lower yields than the anhydrous process due to the sensitivity of 2- (N, N-dimethylemino) ethyl chloride to reaction conditions, resulting in unidentified substances, the removal of which increases manufacturing effort and reduces the quality of the final product; The process carried out in an anhydrous environment leads to good yields, but the disadvantage is the considerable complexity of preparing the alkaline phenolate, the need to prepare sodium methylate in the chlorobenzene environment, the condensation reaction at high temperatures and hence the energy consumption of the process <130 to 140 ° C), work and chlorobenzene worsen the working environment and problems with the recovery of the high-boiling solvent. Carrying out the reaction is also demanding in terms of a number of auxiliary operations, such as the preparation of sodium methylene in chlorobenzene, the preparation of the phenolate, the removal of methanol from the reaction mixture, the preparation of the base of the second reaction component.

In focusing on simplifying the condensation reaction while maintaining the desired end product quality, given the industry standard, reducing labor and number of intermediate operations, reducing energy consumption and enhancing work safety and achieving process economization, the inventors have now found that the condensation process can be performed under mild reaction conditions. complying with the above requirements while maintaining! the same process yield.

According to the invention, a compound of formula I is prepared by reacting a compound of formula II

(III), with 2- (Ν, Ν-dimethylamino) ethyl chloride of formula 111

CH,

CH ₂ ; n-ch ₂ ch ₂ ci used in an amount of 1.1 to 3 mol equivalents, preferably 2.5 mol equivalents, in an environment consisting of a mixture of acetone with inert solvents, preferably chlorinated aliphatic hydrocarbons or toluene, the ratio of acetone to inert solvent is in the range of 1: 0.2 to 1: 3 in volume units, catalysing anhydrous potassium carbonate, used in an amount of 1 to 3 mol equivalents, at temperatures from 50 ° C to the boiling point of the reaction mixture, After separation from the reaction mixture, without isolation of the intermediate base, the reaction product is converted to the hydrochloride by treatment with ethanolic hydrogen chloride solution.

As inert solvents to form a mixture with acetone, low boiling aromatic solvents such as benzene on toluene may be used, with toluene being preferred for hygiene reasons, low boiling chlorinated solvents such as dichloromethane, chloroform, dichloroethane; Chloroform appears to be particularly advantageous in terms of reaction progress.

The reaction mixtures after the condensation have been worked up by conventional methods for reactions of this type. for example, after filtering off the inorganic fraction, the organic fraction is evaporated and dissolved in chloroform or directly extracted with aqueous alkaline hydroxide solution (2-10%) and water, dried over anhydrous sodium sulfate, evaporated and converted without isolation to the hydrochloride by ethanolic hydrogen chloride solution.

The compound of formula (II) is a substance known and readily prepared according to U.S. Pat. No. 217732, 213011 and 204211.

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

He did

To a solution of 5-hydroxy-7-oxo-7H-benzo [c] fluorene (12.3 g, 50 mmol) in 500 mL of acetone was added anhydrous potassium carbonate (17.2 g, 0.125 mol) and the reaction was stirred for 30 min. minutes.

A solution of 2- (Ν, Ν-dimethylamino) ethyl chloride (13.5 g, 0.125 mol) in toluene (400 ml) was then added in one portion to the reaction mixture and the reaction mixture was heated at 60 ° C for 4 h. the organic layer is extracted with 10% potassium hydroxide solution, water and dried over anhydrous sodium sulfate and evaporated, and after dissolution in ethanol, acidified with ethanolic hydrogen chloride solution and the precipitated crystals are filtered off with suction, washed with ethanol and dried. 14.2 g (80.6%) of melting point 268-269 ° C are obtained.

Example 2 * To a solution of 5-hydroxy-7-oxo-7H-benzo [c] fluorene (12.3 g, 50 mmol) in 250 mL of acetone was added anhydrous potassium carbonate (17.2 g, 0.125 mol) and the reaction is refluxed for 30 minutes. A solution of 3- (Ν, Ν-dimethylamino) ethyl chloride * (13.5 g, 0.125 mol) in 250 ml of chloroform was then added in one portion to the reaction mixture and the reaction mixture was heated for 3.5 hours. After the reaction was completed, the reaction mixture was filtered from inorganic fractions and evaporated to dryness. The residue was dissolved in chloroform and treated as in Example 1. 13.75 g (77.9%) of melting point 268-269 ° C were obtained.

Claims (1)

5- (2- (N, N-Dimethylamino) ethoxy) -7-oxo-7H-benzo [c] fluorene hydrochloride O AT), -HCl characterized in that 2a is reacted with a compound of formula II i (II), and 2- (N, N-dimethylamino) ethyl chloride of formula XXI CH, CH, n-ch ₂ ch ₂ ci (III), used in an amount of 1.1 to 3 mol equivalents, preferably in an amount of 2.5 mol equivalents, in a mixture of acetone with inert solvents, preferably and chlorinated allphatic hydrocarbons or toluene, wherein in the mixture used the ratio of acetone to inert solvent is in the range of 1: 0.2 to 1: 3 in volume units, catalysing anhydrous potassium carbonate, the amount used is 1 to 3 mol equivalents, at temperatures from 50 ° C to boiling point The reaction product is then directly converted to the hydrochloride by treatment with ethanolic HCl solution after separation from the reaction mixture.