JPS6126897B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to the use of known N-(α,α,α-trifluoro-m-tolyl)anthranilic acid-2-(2-
Hydroxyethoxy)ethyl ester() The present invention relates to an improved method for manufacturing.

The compound is known under the name INN (rec.) Etofenamat as an anti-inflammatory and anti-rheumatic agent which can be used topically and was previously described in West German Patent Specification 1939112 (Example 1) Therefore, N-(α, α, α-trifluoro-m-
Tolyl) Potassium salt of anthranilic acid () and 2-
It is produced from (2-chloroethoxy)ethanol () by a reaction that can be expressed by the following reaction formula: At this time, an equimolar amount of and was dissolved in dimethylformamide, boiled for 2 hours, precipitated potassium chloride was separated, concentrated, and a mixture of cyclohexane and glacial acetic acid (1:1) was used as the eluent. and purified by silica gel column. A non-crystallized yellow oil is obtained.

Such manufacturing methods have significant drawbacks. For example, it was confirmed through additional tests that the product purified using silica gel contained the following by-products: These by-products, identified by analysis and synthesis, can be purified by repeated molecular distillations, a process that is certainly feasible on a technical scale but economically very expensive. It can only be separated from the main product () with difficulty.

Another drawback is the relatively low yield, which is caused by the conversion on the one hand and by the work-up on the other hand.

To reach a conversion of approximately 80%, the starting compound
() and () must be heated to 140-155°C. However, at such temperatures, another side reaction is the formation of 14-dioxane.
Intramolecular ring closure of () occurs.

Known anti-inflammatory agent N-(α,α,α-trifluoro-m-trifluor)anthranilic acid-2-(2-
Hydroxyethoxy)ethyl ester is N-
Alkali salts of (α,α,α-trifluoro-m-tolyl)anthranilic acid, especially potassium salts (),
general formula In the formula, R is hydrogen or a group Cl—CH ₂ —CH ₂ —O—
can be obtained in better yields and in higher purity when reacting with a compound representing CH ₂ —CH ₂ —O— and then decomposing the benzyl group by hydrogenolysis according to known methods. It was discovered that

The reaction according to the invention can be represented, for example, by the following reaction sequence: The compounds () used as starting compounds are known in the literature, but the starting materials of the general formula () have not yet been described in this publication. These can be easily prepared by the following method: a. The known 2-(2-benzoyloxyethoxy)ethanol is converted into thionyl chloride under heat in the presence of a basic acid binder, preferably pyridine. By reacting with 2-(2-
Benzyloxyethoxy)ethyl chloride (,
R=H); b benzaldehyde is mixed with 2-(2-hydroxyethoxy)ethyl chloride in the presence of a diluent and a catalyst, preferably p-toluenesulfonic acid, in a continuous stream of water at the boiling temperature. heating under separation, thereby bis[2-
(chloroethoxy)ethoxy]toluene (,
R=O—CH ₂ —CH ₂ —O—CH ₂ —CH ₂ —Cl).

The reaction between the potassium salt () and the compound of general formula () is preferably carried out in the presence of a diluent. All inert organic solvents can be considered as diluents. Preferred are hydrocarbons such as benzene, toluene, xylene,
Mention may be made of higher ethers such as glycol dimethyl ether, dioxane, and in particular aprotic solvents such as dimethylformamide, dimethylsulfoxide and hexamethylphosphoric triamide.

The reaction temperature can be varied within a wide range. Usually about 50℃ to about 200℃, preferably 90℃ to 150℃
Perform at ℃.

The reaction can be carried out at normal pressure or under increased pressure. It is usually carried out at normal pressure.

In carrying out the method of the invention, a compound (R=
If H) is used, at least 1 mol is used per mol of potassium salt. However, it is advantageous to use a slight excess (R=H).

Compound (R=O-CH ₂ -CH ₂ -O-CH ₂ -
In carrying out the process of the invention using CH ₂ -Cl), at least 1/2 mole of () is used for each mole of (), again with a slight excess of (). It is preferable to use it.

Post-treatment of the reaction solution involves evaporating the solvent, taking the residue in a suitable solvent that does not dissolve alkali chloride, and
After separating the alkali chloride and evaporating the solvent,
This is carried out by vacuum distillation or purification with a suitable adsorbent.

General formula produced in this way In the above formula, m represents the number 1 or 2, and
means one hydrogen atom when m=2,
Alternatively, X represents two hydrogen atoms when m=1. The intermediate product of is then subjected to a cleavage reaction by hydrogenolysis.

This reaction is preferably carried out in a diluent. As diluent any solvent can be used that dissolves the reactants and does not itself undergo hydrogenation. Examples include alcohols such as methanol, ethanol, and isopropanol, and low-molecular organic esters such as methyl acetate, ethyl acetate, isopropyl acetate, preferably ethyl acetate.

Hydrocracking is carried out by introducing hydrogen in the presence of a catalyst. Catalysts include metals from group 8 of the periodic table. , preferably palladium.

The temperature can be varied within certain limits.
It is generally carried out at a temperature of about 15-40°C, preferably 20-30°C.

Hydrogenolysis can be carried out at normal pressure or also under pressure. Generally, it is carried out at normal pressure.

The synthesis according to the invention has a number of advantages over the methods known in the literature: By blocking the free OH groups during the esterification by etherification, the esterification can be carried out without side reactions and better. Proceed with yield. Thus, no by-products are produced which must be separated by multiple economically and equipment-intensive molecular distillations.

The hydrogenolysis of the intermediate product proceeds almost quantitatively to give a pure final product, which no longer requires expensive purification measures such as, for example, molecular distillation.

Example; N-(α,α,α-trifluoro-m-tolyl)anthranilic acid-2-(2-hydroxyethoxy)ethyl ester 1 a 2-(2-benzyloxyethoxy)ethyl chloride 294 g (1.5 mol) After cooling 2-(2-benzyloxyethoxy)ethanol and 119 g (1.5 mol) of pyridine to -20°C, 178 g (1.5 mol) of thionyl chloride is added dropwise with stirring to react. After stirring for an additional 1/2 hour at low temperature, the reaction solution is warmed to 80° C. for a further 2 hours and then placed in a mixture of ice and 2N hydrochloric acid. The aqueous phase is then extracted with dichloromethane, the extracts are washed several times with water, dried over sodium sulfate and evaporated. By fractional distillation, 270g (=83.8%) of 2-(2-
Obtain benzyloxyethoxy)ethyl chloride.

Boiling point 84-86°C/0.05mmHg; ^n20D _1.5100 .

b 2-(2-benzyloxyethoxy)ethyl-
N-(α,α,α-trifluoro-m-tolyl)anthranilate dissolved in 1.4 dimethylformamide
319 g (1 mol) of the potassium salt of N-(α,α,α-trifluoro-m-tolyl)anthranilic acid
247 g (1.15 mol) of 2-(2-benzyloxyethoxy)ethyl chloride was added dropwise into the solution and boiled for 10 hours. After evaporation of the solvent, the residue was taken up in 3 toluene, the precipitated potassium chloride was separated off, and the organic phase was washed several times with 800 ml of 2N sodium carbonate solution, then with water and dried over sodium sulfate. Later, it is concentrated. After vacuum distillation, 331 g (=72%) of 2-(2-benzyloxyethoxy)ethyl-N- with a boiling point of 190-200°C/0.0001
(α, α, α-trifluoro-m-tolyl) anthranilate is obtained.

C ₂₅ H ₂₄ F ₃ NO ₄ (459.48) Calculated values: C65.35%, H5.27%, F12.41%, N3.05
%; Analysis value: C65.64%, H5.33%, F12.30%, N3.14
%.

c 230g (0.5 mol) of the compound b above, 15
5 g of palladium on carbon catalyst (10%) dissolved in a 1:1 mixture of methanol/ethyl acetate
After adding , hydrogenate at 20℃ and 750 torr. After hydrogen absorption is completed, the catalyst is separated and the liquid is heated to 50℃ with 50g of activated carbon.
After filtration and concentration, it is degassed in a No″lkesmeyer thin layer apparatus.
174.5g (=94.5%) of N-(α,α,α-trifluoro-m-tolyl)anthranilic acid-2-
(2-hydroxyethoxy)ethyl ester is obtained.

2 a Bis[2-(2-chloroethoxy)ethoxy]toluene 106 g (1 mol) dissolved in 1 toluene
of benzaldehyde and 298 g (4 moles) of 2-
(2-Hydroxyethoxy)ethanol is boiled for 14 hours in the presence of 1 g of p-toluenesulfonic acid, with continuous removal of the water formed.
After cooling, the reaction solution is neutralized with sodium methylate, the solution is concentrated and the residue is distilled under high vacuum. 208g (61.7%) with boiling point 125-135℃/0.0001
Bis[2-(2-chloroethoxy)ethoxy]
Obtain toluene.

C ₁₅ H ₂₂ Cl ₂ O ₄ (337.27) Calculated values: C53.42%, H6.58%, Cl21.03%; Analytical values: C53.65%, H6.86%, Cl20.73%.

b α,α-bis-{2-[2-(N-(α,
α,α-Trifluorol-m-tolyl)anthraniloyloxy)ethoxy]ethoxy}toluene 185g (0.55 mol) of the compound prepared in a above was dissolved in hexamethylphosphoric triamide at 50°C, and 319g (1 mol) N-(α,
After adding α,α-trifluoro-m-tolyl) potassium anthranilate, 95°C for 20 hours with stirring.
Warm it with After distilling off the solvent, the residue is dissolved in 1 part of acetone, filtered over 300 g of aluminum oxide, concentrated and then degassed in a Nelkesjayer thin layer apparatus. α,α― of 341g (=82.5%)
Bis-{2-[2-(N-(α,α,α-trifluoro-m-tolyl)anthraniloyloxy)ethoxy]ethoxy}toluene is obtained.

C ₄₃ H ₄₀ F ₆ N ₂ O ₈ (826.81) Calculated values: C62.46%, H4.88%, N3.39% Analyzed values: C62.75%, H5.48%, N3.26%.

c 165 g (0.2 mol) of the compound from b above were dissolved in 500 ml of methanol as purified crude product and after addition of 15 g of 10% palladium on carbon catalyst at 25°C, hydrogen absorption at 756 torr was carried out. Hydrogenate until completion. The catalyst is then separated off, the solvent is distilled off and the residue is degassed in a thin-layer apparatus. 136g (=92%) of N-
(α,α,α-trifluoro-m-tolyl)anthranilic acid-2-(2-hydroxyethoxy)ethyl ester is obtained.

Claims (1)

[Scope of Claims] 1 An alkali salt of N-(α,α,α-trifluoro-m-tolyl)anthranilic acid has the general formula In the formula, R is hydrogen or a group -O-CH ₂ -CH ₂ -O-
CH ₂ —CH ₂ —Cl is reacted with a compound of the general formula In the formula, m represents the numbers 1 and 2, and X is m=
In the case of 2, it represents one hydrogen atom, or in the case of m=1, it represents two hydrogen atoms. -(α,α,α-trifluoro-m-tolyl)anthranilic acid-2-(2-
Method for producing hydroxyethoxy)ethyl ester. 2. The method according to claim 1, which is carried out at a temperature of 90 to 150°C.