CH682747A5 - Di:chloro:anilino-phenyl:acetoxy acetic acid prepn. - by acid hydrolysis of corresp. tetra:hydro-pyranyl ester, giving high yield of analgesic and antiinflammatory prod. - Google Patents

Abstract

Prepn. of 2-(2,6-dichlorophenylamino)-phenylacetoxyacetic acid (I) and its salts with bases comprises acid hydrolysis of a (I) 2-tetrahydropyranyl or 4-methoxy-4-tetrahydropyranyl ester of formula (II), opt. followed by converting the prod. into a salt by reaction with base: A is 2-tetrahydropyranyl or 4-methoxy-4-tetrahydropyranyl. Cpds. (II) A = 2-tetrahydropyranyl are stated to be new. They are prepd. by esterifying 2-(2,6-dichlorophenylamino)-acetic acid (III) (or its salt or deriv.) with the corresp. tetrahydropyranyl haloacetate, e.g. as follows:. USE/ADVANTAGE - (I) is an analgesic and antiinflammatory agent described in EP-119932. Gps. are cleaved without loss of yield due Co side reactions (e.g. cleavage of the Cl atoms) and without using expensive catalysts. Prepn. of (I) via (II), rather than via the corresp. benzyl ester which is cleaved by hydrogenolysis as in EP-119932, gives a greatly increased (more than double) yield.

Description

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description

The invention consists in a process for the preparation of a phenylacetic acid derivative, namely 2- (2,6-dichlorophenylamino) -phenylacetoxyacetic acid and its salts with pharmaceutically acceptable inorganic and organic bases. This acid and its salts have apparently been described for the first time in EP 119 932 AI and have valuable anti-inflammatory and analgesic properties. According to the process for their preparation described there, an alkali metal salt of 2- (2,6-dich! Orphenylamino) phenylacetic acid is condensed with a benzyl haloacetate, preferably benzyl bromoacetate, and the 2- (2 , 6-dichlorophenyl-amino) -phenylacetoxy-benzyl ester hycrogenolytically debenzylated.

Although the cleavage of a benzyl radical by catalytic hydrogenation per se is one of the routine methods of preparative chemistry, it is associated with inconvenience and costs because of the necessity of working under pressure and the use of catalysts and, moreover, with the risk that under the conditions to be observed also other, less stable bonds in the molecule, in this case the aromatically bound chlorine atoms are partially cleaved. In addition, the publication mentioned mentions relatively low yields, 70% of theory for the first step of the condensation reaction and 50% of theory for the debenzylation step, that is to say only 35% overall, which does not appear to be very satisfactory for production on an industrial scale.

There was therefore a search for possible improvements, although attempts to use a tetrahydropyranyl group instead of the benzyl radical used in the known process mentioned and to hydrolytically split it off in the final stage proved to be surprisingly successful.

The usability of a tetrahydropyranyl radical, in particular the tetrahydropyran-2-yl radical (which will hereinafter be referred to as “THP radical”) as a protective group is known per se, cf. T.W. Green, Protective groups in organic synthesis, 1981 John Wiley, New York, pages 160 and 168). With appropriate mentions in the literature, however, its suitability for the protection of an alcoholic OH group was always in the foreground, and as far as examples for the use for the protection of a car-boxyl group were mentioned, it was always about the intermediate formation of a “simple” ester R-COO -THP, during the hydrolytic cleavage of which the formation of a free carboxy group was foreseeable. In the present case, where the formation of a “double ester” R-COO-CHa-COO-TEP is concerned, the question remained open whether, after subsequent acid hydrolysis, one or the other or even both ester bonds would be split predominantly or exclusively . Accordingly, it was not foreseeable that free carboxyl would appear exclusively at the desired location, even if the hydrolytic cleavage was not caused under the mild conditions suggested in the literature, but with hydrochloric acid at temperatures above 60 ° C . At least as surprising is the yield increase that can be achieved in this way to more than double the value specified in EP 119 932 A1.

As the tetrahydropyranyl protective group, the 4-methoxy-tetrahydropyran-4-yl radical can also be used, like the tetrahydropyran-2-yl radical, cf. Tetrahedron £ 2, 1023 (1970).

The process of the invention is accordingly characterized in that a tetrahydropyranyl ester of the formula

- tO

C3L0;>

means, subjecting it to acidic hydrolysis and, if desired, converting the hydrolysis product into a salt by reaction with a base.

The hydrolysis can expediently be carried out using hydrochloric acid at temperatures in the range up to about 70.degree. It is obvious that other mineral acids or organic acids such as acetic acid can also be used for this. The choice of the acid and its optimal concentration is not associated with problems for the person skilled in the art.

The 2- (2,6-dichlorophenylamino) phenylacetoxyacetic acid tetrahydropyranyl ester used as starting materials in the process according to the invention, which has not previously been described, can be classified according to subject 2

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conventional methods are obtained by esterification of 2- (2,6-dichhlorphenylamino) acetic acid or one of its functional derivatives or salts suitable therefor with a corresponding haloacetic acid, preferably chloroacetic acid tetrahydropyranyl ester. The latter are also accessible according to a procedure which is known per se, which is described in detail as the first stage in the following example which serves to explain it.

For a quick understanding of the invention, the example is preceded by a formula scheme.

example

Formula scheme

1st stage

Û Toluoi

H2S04 "C1CH2C0 °" S> -J

2nd stage

Cl

+ C1CH2C00 -O

Cl CH2C00Na

-BÎ3E + NaCI

NaHC03

3rd stage ci ch2cooch2cooh

3rd

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Description of the experimental procedure:

1st stage:

Chloroacetic acid tetrahvdropvranvlester:

To a mixture of 185 g (2.2 mol) of 3,4-dihydro-2H-pyran, 200 ml of toluene and 0.2 ml of conc. A solution of 142 g (1.5 mol) of chloroacetic acid in 500 ml of toluene is added dropwise at 15 ° C. over 15 minutes while cooling with ice. The reaction mixture is then stirred for 2 hours at room temperature, 15 g of anhydrous potassium carbonate are added for stabilization and the mixture is evaporated on a rotary evaporator at 45 ° C./water jet vacuum in order to remove the volatile constituents. 283 g of residue are obtained (mixture of tetrahydropyranyl ester with potassium carbonate). Yield quantitative, based on chloroacetic acid. Before using the chloroacetic acid tetrahydropyranyl ester in the next step, the stabilizer can be separated by filtration.

2nd stage:

2- (2.6-dichlorophenvl-amino) -dhenvlacetoxv-tetrahvdropvranvlester:

318 g (1 mol) of the sodium salt of 2- (2,6-dlchlorophenylamino) phenylacetic acid, 292 g of sodium bicarbonate and 949 g of dimethylformamide are placed in a four-necked flask under nitrogen. The white suspension is stirred for a quarter of an hour at room temperature. Then 220 g of crude chloroacetic acid tetrahydropyranyl ester are added in one pour with gentle water cooling and the mixture is stirred at an internal temperature of 20 to 25 ° C. After 6 to 7 hours, about 70% of the starting substance has reacted, whereupon another 70 g of crude chloroacetic acid tetrahydropyranyl ester are added and stirring is continued for about 15 hours at the same temperature. The reaction mixture is then filtered, the filter residue is washed with dimethylformamide and the combined filtrate is evaporated to dryness in a rotary evaporator.

3rd stage:

2-f2.6-dichlorophenvl-amino-phenvlacetoxv-acetic acid

568 g of the crude tetrahydropyranyl ester obtained in the second stage are taken up in 860 g of toluene and 600 ml of aqueous hydrochloric acid (6.2%) are added. The mixture is stirred at an internal temperature of 60-65 ° G for 30 minutes. The organic phase is separated off, washed with water at 60.degree. C., inoculated during the cooling, left to stand at room temperature overnight, then stirred for 2 hours at an internal temperature from -10 to -12.degree. C. and filtered. The filter residue, washed with cold toluene, provides 231 g of crude product after drying. By expertly working up the filtrate (concentration and liquid-liquid extraction), a further 67.7 g of crude product can be obtained. Raw yield thus a total of 84.4% of theory. Purification with dissolving in toluene / acetone (9: 1), filtration and crystallization leads to 249.3 g of pure dry product or, taking into account the mother liquor product obtainable by working up the filtrate, to 260.4 g of pure product (81.7% of theory .) from the melting point range 149-151 ° C

Claims (1)

Claim Process for the preparation of 2- (2,6-dichlorophenylamino) phenylacetoxyacetic acid and its salts with pharmaceutically acceptable inorganic or organic bases, characterized in that a tetrahydropyranyl ester of the formula Cl CH2COOC32COO - A in which A one of the residues 4th 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 CH 682 747 A5 -Ç> mi 7O0 CE_0 means subjected to acidic hydrolysis and the hydrolysis product is converted into a salt as desired by reaction with a base. 5