JPS59181245A - Purification of ethophenamate - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to etofenamate (Eto
The present invention relates to a novel purification method for f e namat e).

Etofenamate is used in rheumatoid arthritis (cutaneous).
It is a valuable substance for the treatment of rheumatism. According to DE-PS (German Patent) 1939112, etofename) is prepared by converting 2-(2-chloroethoxy)-ethanol into N-(3-
It is obtained by reaction with the potassium salt of 1-trifluoromethylphenyl-anthranilic acid. In German patent 1939112, etofenamate is described as a bright yellow oil that does not crystallize and is not distillable. According to the disclosure of that patent, purification is carried out by column chromatography using silica gel and cyclohexane/glacial acetic acid as mobile solvent. Such chromatographic purification is impractical in industrial synthesis for technical and economic reasons.

The equipment and materials necessary for the chromatographic removal of undesirable by-products formed in the white S, Z during the synthesis, the maximum possible production per degree hour, the selectivity, and the resulting purity associated with the produced black. Therefore, only a small amount of production is possible.

The need for homogeneous purity h1, which is standardized for a variety of pharmaceutical applications, cannot be produced with reasonable effort and cost by the process described in the L patent.

Surprisingly, according to German Pat.
- The crude product obtained from the potassium salt of ranilic acid and 2-(2-chloroethoxy)-ethanol is subjected to short-path distillation, also referred to as molecular distillation, after distillative removal of the solvent dimethylformamide.
It has now been found that it can be purified in a technically simple manner by carrying out a stilling), extracting the product in toluene, washing the mixture with dilute sodium hydroxide solution and water, and distilling off the toluene. thin layer short path distillation % (thin 1ayer 5hort -
Under path distillation, n) conditions, etofenamate can surprisingly be distilled without decomposition, contrary to the teaching of German Patent No. 1939112 of L., and thus can be used for pharmaceutical purposes without further distillation. It is obtained in a very pure form that can be used for This was unexpected in view of the properties of the compound and the amount, number and physical properties of the by-products.

The thin layer short path distillation of zenamate, hereinafter referred to as short path distillation, according to the invention can be carried out in commercial, general laboratory and pylon plant equipment;
And it can be easily applied to corresponding manufacturing plants.

Thin layer short path distillation of crude etofenamate is carried out at a pressure of less than 10@-2 milliparts and a heating jacket temperature of up to about 180 DEG C. Preferably a pressure of to-' mbar - 10-2 mbar and 30° 0-180°C
A heating jacket temperature of is used. Before distillation, the Japanese product is preferably heated to 5.5 kg to remove low-boiling impurities
Degassing at a heating jacket temperature of up to about 120 DEG C. at a pressure of more than 1 O@-2 mbar. The purified product contains at least 99.0% etofenamate and has a refractive index of 1.5650 to 1.5660.

The following examples are intended to explain in more detail the method described in item 1-1 according to the present invention.

Dissolve 160.0 g (0.5 mol) of the potassium salt of N-(3-1-lifluoromenalphenyl) Niandrani J citric acid in 60 ml of dimethylformamide,
heated to 0 °C and 62.0 g (o, o5 moles) of 2
-(2-Chloroethoxy)~ethanol was added slowly and the reaction mixture was then heated to its boiling point for 2 hours. The precipitated potassium chloride was filtered off and the solvent was evaporated in vacuo. The residual liquid was extracted in toluene at 10100 O, the mixture was washed with 0.5 g of sodium hydroxide solution and then with water until a neutral reaction point was reached.

The toluene was distilled off and the remaining oil was degassed in a short-path nine-fold oven, first at 5.10-2 mbar and a heating jacket temperature of about 120°C, and then at 120°C.
- Distilled at a 10-2 milliliter and a heated Jaquent temperature of approximately 140°C.

140: Og of 2-(2-hydrokine ethoxy)-ethyl-N-(3-trifluoromethylphenyl)-anthranilate with a star content of 1- or more than 99.0% in the form of a bright yellow oil ('J It was done.

Claims (1)

[Claims] 1. It is characterized in that the etofenamate crude product is subjected to short path distillation. Preparation of 2-(2-hydroxyethoxy)-ethyl-N-(3-1,lifluoromethylphenyl)-anthranilate 1 Method. 2. A process according to claim 1, characterized in that the short path distillation is carried out at a pressure below 10@-2 mbar and a heating jacket temperature of up to about 180 DEG C. 3. characterized in that the crude product in Bo 1 of the short path distillation is descaled at a pressure of more than 5Φ10-2 mbar and a heating jacket temperature of up to about 120'C;4. ν Fraud The method according to claim 1 or 2.