AU670139B2 - Phenylacetic acid derivatives, process for the preparation thereof and corresponding use - Google Patents

Description

H

K

I

r r, i; i i II r iliiii i Lil;i.l~i~:~Lil_ i;

AUSTRALIA

Patents Act 1990 r r

I

r r ro r COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): PRODESFARMA, S.A.

Invention Title: PHENYLACETIC ACID DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF AND CORRESPONDING USE The following statement is a full description of this invention, including the best method of performing it known to me/us: r rr s r

I

rr r r h i ,d m j> PHENYLACETIC ACID DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF AND CORRESPONDING USE.

DESCRIPTION

This invention relates to phenylacetic acid derivatives, particularly [2-(2,6-dichloroanilino)phenyl]acetic acid, commonly known as diclofenac, a product known for its analgesic and antiinflammatory properties. The invention also relates to a process for the preparation of said derivatives and to a process for the use thereof in the preparation of dichloroanilino)phenyl]acetoxyacetic acid, also known for its analgesic and antiinflammatory properties.

STATE OF THE ART Diclofenac (formula I) is a product having analgesic and antiinflammatory properties, known since the 60's and which has been extensively used in sodium salt form orally, rectally and parenterally. In view of some of its adverse side S effects (gastrointestinal problems, mainly) numerous attempts 20 have been made to prepare diclofenac derivatives which, while maintaining or improving its analgesic and antiinfiammatory properties, have weaker adverse side effects, or allow other forms of administration topical). One of the diclofenac derivatives used in therapeutics is [2-(2,6-dichloroanilino)phenyl]acetoxyacetic acid (formula II), described for the first time in 1984 (EP-P-0 119 932). Nevertheless, the design S and preparation of agents having good analgesic and antiinflammatory properties, with little or no side effects and good ways of administration, is still a problem of interest 30 in modern therapeutics.

cool r ooo oa 00 9

D

0000 0 p *ee..

CH 2 -COONa

(I)

CH

2

COO-CH

2

-COOH

aNH Cl Cl I I (II) -2- The preparation of [2-(2,6-dichloroanilino)phenyllacetoxyacetic acid of formula II suffers from the chemical drawback of obtaining a free carboxylic group in the presence of a carboxylic acid ester which has not to be modified. Two solutions have been proposed to solve this problem: carry out hydrogenolysis of the formula II benzyl ester (EP-P-0 119 932), and treat certain esters of the formula II ester with iodine trimethylsilane, prepared in situ from chloromethylsilane and anhydrous sodium iodide, in an inert atmosphere, using acetonitrile as solvent (ES-P-2 020 146).

Such esters are prepared, in turn, from diclofenac by reaction in a heterogenous medium and phase transfer conditions (ES-P-2 020 145).

With regard to process as mentioned in ES-P-2 020 146, the main drawback of the hydrogenolysis process lies in the need to have special equipment to handle the pressurized I gases and the concomitant risk of the industrial use of hydrogen and catalysts. Furthermore, the viability of the method is restricted to the use of the formula II esters .020 susceptible of hydrogenolysis and, more precisely, the benzyl Sester.

Process apparently represents a solution to the problems inherent in process although chlorotrimethyl- .o silane and sodium iodide, both relatively expensive, are used as reactants and acetonitrile, highly toxic, as solvent.

Also, by-products or mixtures of solvents (acetonitrile/water) are generated, with disposal problems.

I 9a It will be gathered from the foregoing that the prepara- S. tion on an industrial scale of [2-(2,6-dichloroanilino)phen- **30 yl]acetoxyacetic acid is still a serious technical problem.

DESCRIPTION OF THE INVENTION 1. The object of the present invention are the tertiary alkyl esters of formula III and their pharmaceutically acceptable solvates, where R 1

R

2 and R 3 are the same or different and are either methyl, ethyl or propyl radicals; or R 2 and

R

3 which are attached as shown by -(R 2

R

3 jointly form a -(CH2)n- radical where n 4 or 5. Excepted is the case where R 1

R

2

R

3 CH3. Particularly preferred are the product wherein R 1 is methyl and R 2 and R 3 are both ethyl and ~-i Af 3 3 the product wherein R 1 is methyl and R 2 and R 3 are jointly a radical. Also an object of this patent are the above products for use in therapy, particularly for use as analgesic or antiinflammatory agents.

H2_COO-CH2_C00-C-R2- "-braN H C~ I .1 o rr r rr o r r i r i Also an object of the present invention are the pharmaceutical compositions comprising a therapeutically effective amount of one of the above products and adequate amounts of pharmaceutically acceptable excipients, as well as the use of said products for the manufacture of analgesic or anti inflammatory drugs.

It is also an object of the present invention to provide a process for the preparation of a tertiary alkyl ester of formula III or a pharmaceutically acceptable solvate thereof, where R 1

R

2 and R 3 are the same or different and are either methyl, ethyl or propyl radicals; or R 2 and R 3 which are attached as shown by -(R 2

R

3 jointly form a -(CH2)nradical where n 4 or 5; comprising the reaction of a diclofenac sodium or potassium salt with the corresponding alkyl S haloacetate of formula X-CH2-COO-CR 1

R

2

R

3 where X is chlorine or bromine; the process being characterized in that the reaction is carried out in an homogenous medium, in the presence of a aprotic solvent in which the starting compounds are soluble.

In a preferred embodiment of the above process, the sodium salt of diclofenac of formula I is reacted with a slight excess of the corresponding tertiary alkyl haloacetate chloroacetates of tert.-Lbutyl, 1-ethyl-l-methylpropyl or 1-methylcyclohexyl), in the presence of a high polarity aprotic solvent dimethylformamide). The reaction is carried out preferably at a temperature of 50 to 70'C. At the end of the reaction, it is allowed to cool to room temperar~i

I

i:: 4ture and an excess of water is added, whereby the major portion of the desired product precipitates out and is thereafter separated by filtration. After purification by recrystalli ation in aliphatic hydrocarbon type solvents (e.g.

petroleum ethers), very pure products with a defined melting point are obtained.

Further to their intrinsic therapeutic utility, the formula III tertiary alkyl esters are also useful as synthesis intermediates for the preparation of [2-(2,6-dichloroanilino)phenyl]acetoxyacetic acid of formula II, commercially used as analgesic and antiinflammatory agent. Thus, also an object of this invention is a process fc,- the use of the formula III derivatives for the preparation of the formula II acid from a formula III tertiary alkyl ester or a solvate thereof, where R 1

R

2 and R 3 are methyl, ethyl or propyl radicals; or R 2 and R 3 which are attached as shown by-

(R

2

R

3 jointly form a -(CH2)n- radical where n 4 or this process of use being characterized in that the formula III tertiary 'alkyl ester is treated with an acid or mixture of acids in a solvent. In preferred embodiments of this process, the reaction is carried out in an anhydrous medium, the acids used are trifluoroacetic, formic, acetic, sulphuric, hydrochloric, methane sulphonic, p-toluene sulphonic or sulphonic acids bonded to perfluorinated resins and the solvent is the acid or mixture of acids itself or-is of the hydrocarbon type toluene), halogenated hydrocarbon chloroform or methylene chloride), ketone methylethylketone, or methylisobutylketone) or ether (methyltert.butylether or dioxane). Particularly preferred is the case in which the starting product is R 1

R

2

R

3 CH3.

Under the preferred reaction conditions, the formula III tertiary alkyl ester is reacted at a temperature ranging from to the reflux temperature of the solvent; small amounts up to large excesses of acid using the acid or mixture of acids itself as solvent) are used. A preferred process for the isolation of the product consists of adding an excess of water at room temperature to dilute the acid used, after having concentrated the solvent used, when necessary, to separate the end product by filtration and washing with water or m-..m*i an appropriate solvent. If the reaction is carried out with an acid bonded to a resin, in the first place said resin is removed by filtration under solubility conditions of the reaction product. The last stage of the process consists of purifying the product by recrystallization in an appropriate solvent a hydrocarbon or an ester).

Unlike the process for the preparation of [2-(2,6-dichloroanilino)phenyl]acetoxyacetic acid described in ES-P-2 020 146, which uses alkyl (straight or branched chain) or arylalkyl esters as starting products, the process of the invention is specific for tertiary alkyl esters. Thus, unlike the methyl (-COOCH3), primary alkyl (-COOCH2R), secondary alkyl (-COOCHR 2 monoarylalkyl -COOCH2Ar) and other possible esters, the formula III tertiary alkyl esters involved in the process of the invention undergo, in a highly specific way, an elimination reaction by treatment with acid, preferably in an anhydrous medium. In the particular case of the process for the preparation of [2-(2,6-dichloroanilino)phenyl]acetoxyacetic acid this high specificity is i 2 '0 extremely useful, in view of the presence in the molecule of (II) of a primary alkyl ester group which does not have to be modified. Thus, the process of the present invention allows the formula II acid to be prepared with very high i yields (over 90% in some cases), with an extraordinary purity. Furthermore, the reactants used are common, low-cost acids and the by-products of the elimination are alkenes, non S toxic and easily removable (volatile). Other notable advantages afforded by this process are its easy conversion to industrial scale production and the gentleness and safety of 30 its reaction conditions, which are neither dangerous nor involve complex technology.

EXAMPLES

Example 1: Preparation of tert. butyl [2-(2,6-dichloroanilino)phenyllacetoxy acetate (Formula III where R 1

R

2

R

3 CHa grams of sodium diclofenac were dissolved in 70 ml of dimethylformamide (DMF) under a nitrogen atmosphere and the temperature was raised to between 50 to 70'C. Then 5.6 g of tert. butyl chloroacetate were added and the reaction was 6 continued at the same temperature for 2 hours. The mixture was allowed to cool down to room temperature and an excess of water was added. The product obtained was filtered and dried, to give tert. butyl [2-(2,6-dichloroanilino)phenyl]acetoxy acetate, with an 89% yield. Melting point: 89.5-91.5'C (recrystallized from petroleum ether).

Example 2: Preparation of 1-ethyl-1-methylpropyl dichloroanilino)phenyllacetoxy acetate (Formula III where R' CH3 and R 2

R

3 CH2CH3 Operating in a similar way to Example 1, but replacing the tert. butyl chloroacetate with 1-ethyl-1-methylpropyl chloroacetate (previously prepared according to the synthesis method described in Org. Synth. Coll. Vol. III, p. 142-4), the title product was obtained with m.p. 78.5-80'C.

Example 3: Preparation of 1-methylcyclohexyl [2-(2,6-di- *oo S chloroanilino)phenyllacetoxy acetate (Formula III where R 1 CH3 and -(R 2

,R

3 S Operating in a similar way to Example 1, but replacing the tert. butyl chloroacetate with 1-methylcyclohexyl chloroacetate (previously prepared according to the synthesis method described in Org. Synth. Coll. Vol. III, p. 142-4), the title product was obtained with m.p. 60-62'C.

S" Example 4: Preparation of [2-(2.6-dichloroanilino)phenyl]acetoxyacetic acid (II) fi 10 g of tert.. butyl [2-(2,6-dichloroanilino)phenyl]acetoxy acetate were stirred under nitrogen in 37 g of trifluoro- S.acetic acid at room temperature. After one hour's stirring, the mixture was concentrated by evaporation at reduced pressure and the residue was dispersed in water. After filtration, washing and drying at 40°C, the title product was obtained with a 78% yield. Melting point 149.5-151'C (recrystallized from toluene).

In a similar test, treating 10 of tert. butyl [2-(2,6-dichlo-

I

-7roanilino)phenyl]acetoxy acetate with 34 g of anhydrous formic acid at 50C for 2 hours, the title product was obtained with a 91% yield.

SO

0 00 000 0 0* 00 00 0 0000 00 00 0 *0 0 00 000000

S

00 0000 00 0 0 0000 j (if

Claims (12)

1. A phenylacetic acid derivative of formula III CH,-COO-CH -COO-C-R 2 I __I H (III) or a pharmaceutically acceptable solvate thereof, where R 1 R 2 and R 3 are the same or different and are either methyl, ethyl or propyl radicals; or R 2 and R 3 jointly form a -(CH 2 n radical where n 4 or 5, except where R 1 R 2 R 3 -CH 3

2. A derivative as claimed in claim 1 where R 1 is methyl and R 2 and R 3 are both ethyl.

3. A derivative as claimed in claim 1 where R 1 is methyl and R 2 and R 3 are jointly a -(CH 2 5 radical.

4. A method of treating a patient in need of analgesic therapy comprising administering to the patient a phenylacetic acid derivative of formula III ii 0.0 0 0 go 0S 0 01 0 .00. :o 0 a

9. S *5# Sq 0 5 9 Sr CH 2 _COO-CH 2 COO-C-Ra- H C, Cl S3 S (III) or a pharmaceutically acceptable solvate thereof or a pharmaceutical composition thereof where R 1 R 2 and R 3 are the same or different and are either methyl, ethyl or propyl radicals; or R 2 and R 3 jointly form a -(CH 2 )n- radical where n 4 or 5, except where R 1 2 R 3 CH 3 A method of treating a patient in need of anti- staffidakeep/spec/52177.93 16.5.96 L~L-lli~LL;L~~ -9- inflammatory therapy comprising administering to the patient a phenylacetic acid derivative of formula III CH 2 -C 0 0 -CH 2 -C 0 0 -C-Re- I __f (III) or a pharmaceutically acceptable solvate thereof or a pharmaceutical composition thereof where R 1 R 2 and R 3 are the same or different and are either methyl, ethyl or propyl radicals; or R 2 and R 3 jointly form a radical where n 4 or 5, except where R 1 R R 3 -CH 3 6. A pharmaceutical composition comprising a therapeutically effective amount of a phenylacetic acid derivative of formula III or a pharmaceutically acceptable S" solvate thereof according to any one of claims 1-3, and (b) a pharmaceutically acceptable excipient. 7. A process for the preparation of a phenylacetic acid derivative of formula III R, cH 2 -COO-CH 2 -COO-CR- R or a pharmaceutically acceptable solvate thereof, where R R2 and R are the same or different and are either methyl, sodium or potassium salt of a o [-(CH2,6n- radichloroanilino)phenyl a 4 or 5, comprising reacting a (2,6-dichloroanilino) phenyl]facetic acid with ae 1 S atstaff/ida/keep/spec/52177.93 16.5.96 TN O* corresponding alkyl haloacetate of formula X-CH 2 -COO-CR R R where X is chlorine or bromine in an homogenous medium, in the presence of an aprotic solvent in which the salt of acetic acid and corresponding alkyl haloacetate are soluble. 8. A process as claimed in claim 7, wherein said reaction is carried out with a slight excess of said alkyl haloacetate. 9. A process as claimed in claim 7 or claim 8, wherein said aprotic solvent is highly polar. A method of using a phenylacetic acid derivative of formula III CH2-COO-CH-COO-C-R 2 Cl Cl 1 C'I (III) where R R 2 and R 3 are the same or different and are either methyl, ethyl or propyl radicals; or R 2 and R 3 jointly form a -(CH 2 n radical where n 4 or for the preparation of [2-(2,6-dichloroanilino)phenyl]acetoxyacetic acid, comprising treating said formula III derivative with an acid or mixture of acids.

11. A method as claimed in claim 10, wherein said treatment is carried out in an anhydrous medium.

12. A method as claimed in claim 10 or 11, wherein said acid is triflucroacetic, formic, acetic, sulphuric, hydrochloric, methane sulphonic, p-toluene sulphonic and/or sulphonic acid bonded to perfluorinated resins.

13. A method as defined in any one of claims 10 to 12 wherein R 1 2 R 3 CH 3

14. A method as claimed in claims 10, 11, 12 or 13 wherein the acid or mixture of acids is in a solvent. SRA staflidakeepispec52177.93 16.5.96 It i 11 A method as claimed in claim 14 wherein the solvent is a hydrocarbon, halogenated hydrocarbon, ketone or ether type.

16. A phenylacetic acid derivative as hereinbefore described with reference to any one of the aforegoing examples.

17. A pharmaceutical composition as hereinbefore described with reference to any one of the aforegoing examples.

18. A process for the preparation of a phenylacetic acid derivative as hereinbefore described with reference to any one of the aforegoing examples. 17. A method of using a phenylacetic acid derivative as hereinbefore described with reference to any one of the aforegoing examples. DATED THIS 16th DAY OF May 1996 0000 0**0 0* *SaOOS PRODESFARMA, S.A. By Its Patent Attorneys GRIFFITH HACK CO. Fellows Institute of Patent Attorneys of Australia I' s: I i ,nU j ABSTRACT The invention relates to phenylacetic acid derivatives, a process for the preparation thereof and corresponding use. These derivatives are identified by their formula III, where R 1 R 2 and R 3 are the same or different and are either meth- yl, ethyl or propyl radicals; or R 2 and R 3 which are at- tached as shown by -(R 2 R jointly form a -(CH2)n- radical where n 4 or 5; the process comprises the reaction of a diclofenac salt with the corresponding alkyl haloacetate of formula X-CH2-COO-CR 1 R 2 R 3 (X C1 or Br) in an homogenous medium. They are used for the preparation of [2-(2,6-dichlo- roanilino)phenyl]acetoxyacetic acid, by treatment with acids in an anhydrous medium. The derivatives have therapeutic activity as analgesics or antiinflammatories. ioo 4000 r a ft 4 oW *6 d! j I J, i- J I-