CS242292B1 - Process for the preparation of 5- (2- (N, N-Dimethylamino) ethoxy-7-oxo-7H-benzo (c) fluorene hydrochloride - Google Patents

Abstract

Method for the production of 5-[2-[N,N-dimethylamino)-(ethoxy]-7-oxo-7H-benzo (c)fluorene hydrochloride, the cytostatic Benfluron, consisting in the alkylation of a suspension of 5-hydroxy-7-oxo-7H- -benzojjjfluorene in a toluene medium by the action of 2-(N,N-dimethylamino)ethyl chloride under the catalysis of anhydrous potassium carbonate.

Description

-benzo (c) fluorene hydrochloride

Production method 5- [2- [N, N-dimethylamino). ₍ ethoxy) -7-oxo-7H-benzo (c) fluorene hydrochloride, a cytostatic drug Benfluron, consisting of alkylating a suspension of 5-hydroxy-7-oxo-7H-benzoyl fluoride in toluene with 2- (N, N-dimethylamino) ethyl chloride under catalysis with anhydrous potassium carbonate.

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

HCl (0

The compound of formula I is the original Czechoslovak cytostatic which: after successful preclinical development has reached the phase of clinical trials and is currently being tested clinically, under the designation BENFLURON, on selected; oncological workplaces in CSSR in the framework of phase I of the clinical trial. Further details on pharmacological activity, toxicity, immunosuppressive activity and mechanism of action can be found in the Czechoslovak author's certificate No. 212 669 and foreign patents: (Belgian Pat. No. 368,127, Argentine Pat. No. 227,171 and British Pat. No. 2). 068 374) and scientific papers (Collection Czech. Chem. Ccmniun. 47, 1856 (1982), Czechoslovak. Farm. 33, 103 (1984), Neoplasma 31, 399 (1984), p. 407).

The present process for the preparation of the compound of formula I is described in detail in the Czech Republic. AO No. 212 669 and further in MS. AO No. 235 429. The production methods disclosed in the above-mentioned publications have shown some disadvantageous properties for converting productions to larger scales, although the process disclosed in U.S. Pat. AO No. 235 429 eliminated a number of disadvantages and above all the difficulty and laboriousness of operations of the procedure according to MS. AO No 212 669.

The present method of production, according to the art. AO No. 235 429 consisted of the reaction of 5-hydroxy-7-oxo-7H-benzo (c) fluorene of formula II

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

CH3 \

N — CH2CH2Cl /

CH3 (ΙΠ), in a mixture of acetone with inert solvents, aromatic or chlorinated hydrocarbons, catalysed with anhydrous potassium carbonate, and after working up the reaction mixture by direct conversion of the resulting base to the hydrochloride, by treatment with ethanolic hydrogen chloride solution. Although the actual alkylation reaction proceeds under mild reaction conditions and with a relatively good yield of about 80%, it is nevertheless accompanied by some problems associated with the separation and recovery of the unreacted starting material of formula II from the reaction mixture. Also the use of a mixture of organic solvents increases the labor and energy consumption of the process for their regeneration.

In order to maximize the simplification of the alkylation reaction conditions while maintaining or even improving the quality of the end product, reducing labor and energy consumption during regeneration, increasing work safety and achieving process economization by increasing the alkylation reaction yield, the inventors have now found that the alkylation reaction process can be performed in organic solvent alone and by reacting the components in the initial phase in suspension instead of in solution. Suspending the initial phase of the reaction also allowed a significant reduction in the volume of the reaction mixture to about 1/4 of the previously used volumes. By using the aromatic hydrocarbon alone as the reaction medium, the yield of the compound of formula (I) can be improved by reducing the consumption of 2- (N, N-dimethylamino) ethyl chloride, and the new process of the invention allows easy solvent recovery and reuse without further purification.

According to the invention, a compound of formula I is prepared by adding 2.5 mol equivalents of anhydrous potassium carbonate to a suspension of the compound of formula II in an aromatic hydrocarbon medium, preferably toluene, and first heating the reaction mixture at a temperature of from 50 ° C to boiling point of the reaction mixture, preferably at 80 ° C, and allowed to react with 2 mol equivalents of the compound of formula III sequentially added as a solution in an aromatic hydrocarbon, preferably toluene, over 1 hour, after which the condensation reaction is completed by heating the reaction mixture to boiling , and the reaction product, after separation from the reaction mixture, without isolation of the intermediate base, is converted to the hydrochloride by treatment with ethanolic hydrogen chloride solution.

Conventional lower-boiling aromatic hydrocarbons such as benzene or toluene may be used as the reaction medium, with toluene being preferred for economic and hygienic reasons.

The condensation reaction mixture is worked up according to conventional procedures for this type of reaction; for example, after filtering off the inorganic fraction, the solution of the compound of formula I in the aromatic hydrocarbon is extracted with an aqueous solution of alkali metal hydroxide (2-10%) (removal of traces of unreacted compound of formula IIj), the aromatic hydrocarbon is evaporated and the crude product base of the compound of formula I by treatment with an ethanolic solution of hydrogen chloride.

The compound of formula (II) is known and readily prepared according to U.S. Pat. AO Nos. 213 011, 204 211 and 217 732.

The following example illustrates the process for the preparation of the compound of formula I according to the invention:

To a suspension of 5-hydroxy-7-oxo-7H-benzo (trifluorene (12.2 g 50 mmol) in 150 mL toluene was added anhydrous potassium carbonate (17.2 g, 0.125 mol) and the reaction mixture was heated to 80 ° C. At this temperature, a solution of 2- (Ν, Ν-dimethylamino) ethyl chloride in 150 ml of toluene (10.8 g, 0.100 mol) was added dropwise over 1 h and the reaction mixture was heated to boiling for 4 h.

After cooling, the inorganic fraction was filtered off, the organic layer was extracted with 10% potassium hydroxide solution, dried over anhydrous sodium sulfate and evaporated. After dissolution in ethanol, it is acidified with ethanolic hydrogen chloride solution and the precipitated crystals are filtered off with suction, washed with ethanol and dried. 16.11 g of the compound of formula I (91.3%), m.p. 268-269 ° C, are obtained.

Claims (1)

the subject of the invention Process for the preparation of 5- [2- (Ν, Ν-dimethylamino) -ethoxy] -7-oxo-7H-benzo (fluoro-hydrochloride of formula I) HCt (D by reaction of 5-hydroxy-7-cxo-7H-benzo (cfluorene of formula II) with 2- (Ν, Ν-dimethylaminoethyl ethyl chloride) CH3 \ N - CH2CH2Cl CH3 using inert organic solvents catalysed with anhydrous potassium carbonate and after separation from the reaction mixture by direct conversion of the intermediate base to the hydrochloride, characterized in that 2.5 mol equivalents of anhydrous potassium carbonate are added to the suspension of the compound of formula II in the aromatic hydrocarbon The mixture is first heated to 50 ° C to the boiling point of the reaction mixture and treated with 2 mol equivalents of the compound of formula III gradually added as a solution in the aromatic hydrocarbon, over a period of 1 h, after which the condensation reaction is completed by heating. of the reaction mixture to boiling.