JPH0159266B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a new and improved method for producing the known compound 2-(2-hydroxyethoxy)ethyl-N-(α,α,α-trifluoro-m-tolyl)anthranilate (hereinafter referred to as . According to German Patent No. 1939112, N-
The potassium salt of (α,α,α-trifluoro-m-tolyl)anthranilic acid (denoted below) was mixed with 2-(2-chloroethoxy)ethanol at an elevated temperature of 110°C in dimethylformamide as solvent. It is already known how to prepare the compound by reaction, to separate it from the potassium chloride formed, to evaporate the solvent, and to isolate and purify it by chromatography on silica gel. This synthetic method is unsuitable to be carried out on an industrial scale. The disadvantages in this case are as follows: The potassium salt must first be prepared and carefully dried. 2-(2-chloroethoxy)
Ethanol is difficult to obtain in sufficient purity and must be subjected to expensive purification. It can be synthesized from the corresponding 2-(2-hydroxyethoxy)ethanol (denoted below). However, this produces large amounts of by-products (especially monochlorotriethylene glycol), all of which are very difficult to separate, so only 30
It can only be obtained with a yield of ~40% (this has been confirmed experimentally). Furthermore, the use of dimethylformamide as a solvent is physiologically unacceptable (see data on "Working Substances Hazardous to Health" published by the German Committee for Testing and Research of Working Substances Hazardous to Health). can only be purified by chromatography, which is technically very expensive, and purification by short-path distillation cannot be carried out without significant losses because of the by-products present. As a result of repeating the above method, the desired product contained some by-products. The following by-products could be separated: R—O—CH ₂ CH ₂ OH approximately 0.8%, R—O—
CH ₂ CH ₂ -O-CH ₂ CH ₂ -O-R approx. 3%, and
RO―CH ₂ CH ₂ ―O―CH ₂ CH ₂ ―O―CH ₂ CH ₂ ―
O-R approximately 0.9%. Here

[Formula]. This time, (a) N-(α, α, α-trifluoro-m
-Tolyl)anthranilic acid () is first converted to N-(α, α, α-trifluoro-
It has been found that (b) can be obtained in improved yield and purity by converting it to m-tolyl)anthraniloyl halide and then (b) reacting it with 2-(2-hydroxyethoxy)ethanol (). Ta. The process of the invention is conveniently carried out in the presence of a diluent. As diluents, all inert organic solvents which dissolve the reaction components and do not themselves take part in the reaction are used. Preferably halogenated hydrocarbons such as methylene chloride, ethylene chloride and chloroform, benzine, benzene,
These include hydrocarbons such as toluene and xylene, and cyclic or acyclic ethers such as di-n-butyl ether or dioxane. Examples of the halogenating agent include phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, and thionyl chloride, and phosphorus pentachloride is particularly preferably used. The acid halide production reaction (a) is preferably carried out at room temperature or below, and the esterification reaction (b) can be carried out at a temperature of 0 to 50°C, preferably 30 to 40°C. The operation is generally carried out under normal pressure. It has been found advantageous to carry out both reactions in the absence of oxygen. That is, it is carried out under an inert gas atmosphere, for example under a nitrogen atmosphere. When carrying out the esterification, about 7.5 to 15 mol are applied per mol of acid halide. Work-up is preferably carried out by bringing the reaction solution to pH 4-5 with a dilute solution of sodium hydroxide, evaporating the solvent and excess under reduced pressure, taking up the residue in isopropyl ether to remove inorganic substances, and evaporating the isopropyl ether. and short path distillation. The method of the present invention is expressed, for example, by the following reaction formula: The method according to the invention has several significant advantages over the method described in DE 1939112 mentioned above. The potassium salt described in the German patent and 2
-The reaction with (2-chloroethoxy)ethanol is
Requires temperatures exceeding 100℃. Side reactions that occur at such temperatures produce the various by-products mentioned above, which can only be completely removed by chromatographic purification. According to the process of the invention, the first acid halide is produced almost quantitatively and already in very high purity. Excess halogenating agent is easily separated from the acid halide by water. This acid halide can be used as a raw material for the next step without special purification. This acid halide is highly active and can react directly. That is, the reaction takes place at a temperature that does not significantly exceed room temperature and in a significantly short reaction time. Surprisingly then only one of the two hydroxyl groups reacts, giving the crude product already in good quality form. It is also surprising that the products obtained in high purity can be distilled with very little loss and that simple distillation can give final products that meet high pharmaceutical requirements. Another advantage is that it can be obtained in sufficiently good quality and in the desired quantities, so that additional purification can be omitted. Example 2-(2-hydroxyethoxy)ethyl-N-
(α, α, α-trifluoro-m-tolyl) anthranilate 350 g of N-(α, α, α-trifluoro-m-tolyl) anthranilic acid in 600 ml of toluene (1.244
275 g (1.32 mol) of PCl ₅ are added in portions at about 7-10° C. under stirring and nitrogen bubbling. Reaction time was 15-30 minutes. about
The reaction solution was cooled to 10-12°C and was stirred vigorously while nitrogen was introduced while maintaining the temperature at 10-12°C.
Extract by adding 100 ml of water four times over 20 minutes, then separate the aqueous layer. Then 16 of sodium chloride
A further extraction is carried out with 100 ml of % aqueous solution for 20 minutes and the aqueous salt phase is separated. The resulting toluene phase was dried over sodium sulfate and mixed with 300 ml of pure dioxane.
Medium 2-(2-hydroxyethoxy)ethanol
Add dropwise to a homogeneous solution of 1.4 (14.94 mol) over 30-45 minutes at 30-40° C. with stirring and nitrogen flow. This reaction was run for 15 minutes. The reaction solution is then adjusted to pH 4-5 with an aqueous solution of about 50 g (1.244 mol) of NaOH under cooling. Then 600ml with 20mmHg vacuum
The organic phase (dioxane and toluene) is distilled off. Add 300 ml of toluene to the distillation residue and wash twice with 700 ml each of 3% sodium chloride aqueous solution.
80 g of activated carbon are added to the separated toluene phase, stirred, filtered and the liquid is evaporated at 20 mmHg. Assemble yield: 431.4g (based on theoretical 93.8g)
%) The oily residue was subjected to molecular distillation (twice). 1st: Boiling point (2.10 ^-1 torr): 98℃, Yield:
411.4g (89.5% of theory based on) 2nd: Boiling point (2.10 ^-3 Torr): 123℃, Yield:
393.8g (85.7% of theory based on)

Claims (1)

[Claims] 1 (a) N-(α,α,α-trifluoro-m-tolyl)anthranilic acid is reacted with a halogenating agent at a temperature of 0 to 30°C in the presence of an inert organic solvent. (b) converting this into the anthranilic acid halide at a temperature of 0 to 50°C.
7.5 to 15 moles per mole of 2-(2-hydroxyethoxy)ethanol, during which step (a)
and (b) in an inert gas atmosphere. . 2. The method according to claim 1, wherein step (b) is carried out at a temperature of 30 to 50°C. 3. The method according to claim 1, characterized in that phosphorus pentachloride is used as the halogenating agent. 4. Claim 1, characterized in that the reaction is carried out using toluene or xylene as a solvent.
The method described in section.