HU209601B - Process for preparing 2,2-dimethyl-5-(2,5-dimethyl-phenoxi)-pentanoic acid - Google Patents

Abstract

The present invention relates to a 2,2-dimethyl-5 (2,5-dimethylphenoxy) pentanoic acid of the formula (I) for the preparation of 2,2-dimethyl-5-halopentanoic acid of formula (V1) wherein X is halogen; and R 1 is C 1-5 alkyl, its ester is converted to a compound of formula Va, wherein R 1 is as defined above, and the resulting compound of formula (Va), optionally without isolation, is directly in the reaction mixture for its preparation. by hydrolysis of the compound of formula (V1) in an aprotic apolar solvent in the presence of a strong base and optionally an alkali metal iodide as a catalyst without external heating of 2,5-dimethylphenol (VIII); wherein R2 is C1-C5 alkyl, reacts with an ester to give the compound of formula Va. t, without isolation, directly in the reaction mixture for its production, by the addition of a further amount of a base and optionally a small amount of water without the external heating of 2,2-dimethyl-5- (2,5-dimethylphenoxy) of formula (I). hydrolyzed to pentanoic acid. EN 209 601 CH, (VIII) Scope of the description: 10 pages (including 2 sheets)

Description

The present invention relates to a novel process for the preparation of 2,2-dimethyl-5- (2,5-dimethylphenoxy) pentanoic acid (Gemfibrozil, Lopid) of formula (I).

It is known that many aryloxyalkanoic acids, and in particular 2,2-dimethyl-5- (2,5-dimethylphenoxy) pentanoic acid, can be used to lower lipid levels in the blood. Thus, these compounds are valuable pharmaceutical agents, see, for example, U.S. Patent No. 3,674,836 and the so-called Helsinki Study: Μ. H. Frick et al., The New England Journal of Medicine, 317, 1237 (1987). The known synthesis methods described so far for the preparation of the compound of formula I fall into two groups according to the order in which the three major structural elements of the molecule are assembled: the phenol derivative, the 1,3-propylene chain and the unit derived from isobutyric acid.

The two routes of synthesis are illustrated in the accompanying scheme. According to this pathway A, the 2,5-dimethylphenol of formula (II) and the C 3 alkylene chain are first coupled and then the resulting compound of formula (III), wherein

X is a leaving group, for example a halogen atom or a sulfonyloxy group, a substituted ether with isobutyric acid or a corresponding group of formula (IV) wherein W is a carboxyl group or a carboxyl group (see below,

A-pathway), with its derivative. The resulting compound of formula (V), wherein W is as defined above, is converted to the target compound of formula (I) by a method known per se, depending on the group W.

In contrast, in another route, Scheme B, the alkylene chain is first coupled to isobutyric acid, a derivative or analogue thereof, and then to the intermediate of formula (VI) wherein X and W are as defined above. by reaction of the phenol of formula (II) with the compound of formula (V), wherein W is as defined above, to obtain the final product of formula (I). The following is a summary of known processes for the preparation of Gemfibrozil of formula (I) in this grouping.

The pathway

The process of first disclosing the target compound in U.S. Patent No. 1,925,423, and the equivalent U.S. Patent No. 3,674,836, comprises first starting from sodium 2,5-dimethylphenol (II) in an aprotic solvent. with a hydride, it is reacted with a 1,3-dihaloalkane and the resulting haloalkylaryl ether of formula (III) wherein X is a halogen atom in tetrahydrofuran wherein

W is a carboxyl group or an alkoxycarbonyl group reacted with alpha-carbanion formed from isobutyric acid or its ester.

This carbanion is prepared with lithium diisopropylamide, while in the case of isobutyric acid the carboxylate salt is formed with the same base or with sodium hydride or magnesium oxide. The yields of the reactions are not disclosed, but U.S. Pat. No. 4,665,226 estimates, by analogy, the desired compound of formula (I) according to the procedure described in U.S. Patent No. 3,674,836. with a gross yield of about 39-46% based on the phenol formula.

In our own studies, the disadvantage of this method, apart from the low yield, is that the second reaction proceeds with poor conversion (about 40%) and that the recovered unreacted intermediate (III) can be reused only after purification.

Intermediate III uses X as mesyl according to Spanish Patent No. 534,473, and the final step with isobutyric acid is carried out in dimethyl sulfoxide in the presence of sodium hydride at 50 ° C, yield 76%. No yield is given for the production of the mesyloxy compound. Since the dimethylsulfoxide / sodium hydride system can be explosive at 50-60 ° C (see, for example, V. Jager in Houben-Weil, Die Methoden der organizchen Chemie, Vol. 5 / 2a, p. 360), this method is commercially available unsuitable.

When a haloalkyl ether of formula (III) does not alkylate such a compound which has two methyl groups in the alpha position, i.e. an alpha position, an analog having only one methyl group, e.g. a methyl malonic acid diester, this reaction can also be carried out using a more convenient base, such as sodium ethylate in ethanol (Spanish Patent No. 549,469). Of course, not the compound of formula (I), but an analog having less than one methyl group on the alpha carbon, is produced, and in the final step of the synthesis, lithium diisopropylamide must be used in this case as well. The yield of the final product of formula (I) obtained by this method is 70% relative to the haloalkyl ether of formula (III), but this haloalkyl ether is known according to the known method (see, for example, U.S. Patent 3,674,836; J. Med. Chem., 8, 356 (1965) can be prepared in only about 30% yield, so the gross yield of this synthesis is low, only 21% based on the starting phenol of formula II.

In another embodiment of Synthesis route A, a halogen alkyl ether of formula (III) wherein X is bromo is converted to a Grignard reagent and reacted with acetone. The resulting compound of formula (V), wherein W is hydroxy, is prepared from a carbinol with thionyl chloride, where W is halogen, and is then reacted with carbon dioxide to form the desired Grignard reagent to afford the desired target compound of formula I (549). Spanish Patent No. 470). The gross yield is 65% based on the haloalkyl ether of formula (III), but the haloalkyl

601 Because of its yield, the compound has a gross yield of only 20% relative to the starting 2,5-dimethylphenol.

In other analogous synthesis variants, the isobutyric acid or derivative thereof is represented by the formula (IV) wherein W is formyl, the aldehyde or the corresponding Schiff base (W is -CH = N-alkyl) or the compound of formula (IV) where W is cyano, the nitrile is alkylated with the haloalkyl ether of formula (III) and the intermediate (V) thus obtained is converted into the compound of formula (I) by methods known per se (3,759,986 and 3,847,994). U.S. Patents). The yields of these reactions are unknown, but the number of reaction steps required for the preparation of the starting material is expected to be less economical to provide the target compound.

It is also known to prepare Gemfibrozil of formula (I) by oxidizing an aldehyde of formula (V), such as that prepared in the preceding paragraph, wherein W is formyl, in the presence of noble metal catalysts to the desired carboxylic acid. The yield of oxidation is about 70%, but the yield of aldehyde V is unknown (U.S. Patent 4,126,637).

The major disadvantage of all of the above variants of the synthesis shown in Scheme A as industrial route is that the intermediate haloalkyl ether of formula III, wherein X is bromine, can be prepared only in a low yield of about 30-40%, Thus, based on the relatively expensive starting 2,5-dimethylphenol, the gross yield of the compound of formula (I) is very low and therefore these synthesis methods are not economical.

B pathway

In the known processes, starting from a suitable derivative, not free isobutyric acid, the alkylene chain of three carbon atoms and then the phenol are coupled thereto. Thus, the process described in Spanish Patent No. 517,665 involves the cleavage of an aryloxyalkyl ketone of formula IV wherein W is benzoyl in the presence of anisole with potassium tert-butylate to give the desired acid of formula (I). The yield of the synthesis is not given in the description.

The most advantageous method in terms of yield is described in U.S. Patent No. 4,665,226 (Hungarian equivalent: U.S. Patent 195,635). According to this, a lower alkyl ester of isobutyric acid, preferably an isobutyl ester (a compound of formula IV where W is isobutylcarbonyl) is alkylated with 1-bromo-3-chloropropane in tetrahydrofuran in the presence of lithium diisopropylamide: 94%) and then the halogenated ester of formula (VI) wherein X is chlorine and W is isobutoxycarbonyl in toluene / dimethylsulfoxide in the presence of sodium iodide as catalyst in the 2,5-dimethyl (II). with anhydrous sodium salt of phenol and finally hydrolyzing the thus obtained Gemfibrozil ester (V), where W is as defined above, directly in the reaction mixture with an excess of alkali (or acid according to the said Hungarian equivalent). The resulting Gemfibrozil of formula (I) is isolated by distilling off the solvent from the reaction mixture, purifying the crude salt in aqueous solution by extraction with hexane and recovering after acidification. The combined yield of phenol coupling and hydrolysis is reported to be 92%. Thus, the target compound of formula (I) is obtained in an excellent yield of 86% relative to isobutyl ester of isobutyric acid.

According to our own studies, both the alkylation of the isobutyric acid ester and the coupling and hydrolysis with phenol can be carried out in high yields similar to those described above. Thus, from the literary synthesis methods, this method would seem to be the most advantageous, but in our experience it also has severe disabilities. The major disadvantage is that the quality of Gemfibrozil obtained in the manner described does not meet the requirements of the Pharmacopoeia and the recrystallization mentioned herein does not allow the preparation of the compound of formula (I) in such quality. The purification of the active ingredient to provide a final pharmacopoeial product, for which the above patent is not described, has been shown to result in a loss of about 15-18%. Another drawback of the process is that the lower alkyl esters of isobutyric acid used as starting material are not commercially available and can, according to our own studies, only be obtained in a moderate yield of about 75%. For all these reasons, the gross yield of pure Gemfibrozil produced by the above synthesis, based on our initial isobutyric acid, is only about 45%.

One particular variant of the B pathway is the process described in European Patent Application 219 117 for the preparation of a lactone of formula VII. Accordingly, the allyl isobutyric acid ester (compound of formula (IV) wherein W is allyloxycarbonyl) is first converted to 2,2-dimethyl-4-pentenoic acid in the presence of sodium hydride and then converted to the compound of formula (VI) by the addition of hydrobromic acid. of the general formula wherein

X is bromine and

W is carboxyl,

5-Bromo-2,2-dimethylpentanoic acid, which is treated with an aqueous base, gives the lactone (VII) in excellent yield. Although this compound may be used in the preparation of Gemfibrozil of formula (I), however, neither the said publication nor any other literature discloses how this conversion can be carried out.

In all of the above procedures, a

The incorporation of the 2,5-dimethylphenoxy group, i.e. the reaction with the 2,5-dimethylphenol salt, requires vigorous reaction conditions such as temperatures above 100 ° C and a relatively longer reaction time. Under these conditions, both 2,5-dimethylphenol and

The reaction partners are already partially degraded and the degradation products contaminate the resulting end product.

It was an object of the present invention to provide a synthesis method for the preparation of Gemfibrozil, wherein the 2,5-dimethylphenoxy group can be incorporated into the molecule under mild conditions.

Surprisingly, it has been found that this object can be advantageously achieved by introducing a C 2 -C 6 carbon atom on the phenolic oxygen atom instead of an alkali metal salt of 2,5-dimethylphenol (II). alkanecarboxylic acid acylated derivative, in other words a compound of formula VIII, wherein

R ² is C 1 -C 5 alkyl using an ester. In this way, the 2,5-dimethylphenoxy group was introduced into the molecule under very mild conditions without reaction heating and in a much shorter reaction time than in the previous methods.

If such an ester is used with a suitable reagent, e.g. the

An ester of 2,2-dimethyl-5-halo-pentanoic acid, e.g.

X is halogen, and

^R1 is C1-5 alkyl, halo ester reacted (optionally an alkali metal iodide as catalyst), the mentioned mild conditions a very rapid reaction, (Va), wherein ^R1 is (VIa) wherein aryloxy substituted ester. The latter compound can be isolated and purified if desired, but is conveniently carried out without isolation directly into the desired end product, 2,2-dimethyl-5- (2,5-dimethylphenoxy) pentanoic acid, in the reaction mixture for its preparation. hydrolysed.

The above preparation of compounds of formula Va is a relatively less commonly used method for the synthesis of arylalkyl ethers, which is prepared by reaction of an alkyl halide with an aryl ester. Only a few such cases are described in the literature [S.

F. McDonald, J. Chem. Soc. 1948, 376; S. K. Banerjee, J. Chem. Soc., Chem. Commun. 1982, 815; Yamashita and A. Toy, Synth. Commun. 19, 755 (1989)]. However, it is to be emphasized that the process of the present invention can be carried out under substantially less stringent conditions than those known in the prior art, said ether bonding without heating, in the examples herein, occurs within 10 minutes while using several hours of boiling or room temperature however, long stirring (24- ^ 18 hours) is required.

Furthermore, it has surprisingly been found that under the reaction conditions used in the process of the present invention, said compounds of formula (Va) may be reacted with 2,2-dimethyl-5- (2,5) of formula (I) in substantially shorter time than previously used. -dimethylphenoxy) -pentanoic acid.

SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of 2,2-dimethyl-5- (2,5-dimethylphenoxy) pentanoic acid of formula (I) according to one of the general formulas (VIa) wherein X is halogen and R ¹ is C 1 -C 5 alkyl, converting its ester to a compound of formula Va, wherein R ¹ is as defined above, and the resulting compound of formula Va, optionally without isolation, directly by hydrolysis with a base in the reaction mixture to prepare the compound of formula (VIa) in an aprotic apolar solvent in the presence of a strong base and optionally an alkali metal iodide as catalyst, without external heating. dimethylphenol has the general formula (VIII) wherein

R ² is a C 1 -C 5 alkyl ester, and the resulting compound of formula Va is optionally isolated without the addition of an additional amount of a base and optionally a small amount of water directly in the reaction mixture without external heating. Hydrolyze to 2,2-dimethyl-5- (2,5-dimethylphenoxy) pentanoic acid of formula I.

For example, R ^{1 in} the starting compound (Via) is, for example, methyl, ethyl, n-propyl, isopropyl, η-butyl, secondary butyl, isobutyl, tert-butyl or pentyl, preferably ethyl, X and may be chlorine, bromine or preferably iodine. The acyl group of the 2,5-dimethylphenol ester of formula II used as starting material in the process of the present invention may be selected from C2-C6 straight or branched chain alkanoic acids such as acetic acid, propionic acid, n-butyric acid, isobutyric acid, an acyl group derived from valeric acid or isovaleric acid, and preferably acetic acid.

Preferred embodiments of the process of the present invention are described in detail below.

In the first step of the process, an ester of Formula VIa of 2,2-dimethyl-5-halopentanoic acid is reacted with an ester of Formula VIII in a suitable aprotic polar organic solvent in the presence of a strong base and optionally an alkali metal iodide.

Suitable solvents are, for example, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, sulfolane, hexamethylphosphoric triamide, N-methylpyrrolidone and the like. The solvent need not be completely anhydrous and may contain up to 1.0% water by volume. A lower water content does not adversely affect the reaction. Preferably, the solvent is dimethyl sulfoxide.

Said base may be, for example, an alkali metal hydroxide or an alcoholate such as sodium hydroxide, potassium hydroxide, and also sodium methylate, sodium ethylate, potassium tert-butylate, and the like. The base is preferably potassium hydroxide or potassium tert-butylate. In the process of the present invention, the base has a dual role, and for these two purposes, different amounts of the base are used, so that the base, on the one hand,

601 The reaction of the compound with the compound of the formula VIII is preferably carried out in an amount of 1 to 4 moles, preferably 2 to 3 moles, per mole of the compound (VHI). On the other hand, after the reaction of the compound (VIa) with the compound (VIII), an additional amount of the base is required to hydrolyze the resulting compound (Va) to the final product (I). Suitable bases for the hydrolysis are preferably from 1 to 4 mol, preferably from 2 to 3 mol, per mole of the starting compound (VIII).

It should be noted that in order to effect the complete hydrolysis, it is also necessary to add water to the reaction mixture, preferably in an amount of 2 to 5 moles relative to the compound (VIII).

Examples of the alkali metal iodide include sodium iodide or potassium iodide.

The process is conveniently carried out by mixing the reagents at room temperature (exothermic) and stirring without external heating until the ether linkage is complete. That's about

It may take from 5 to 10 minutes (as compared to known methods where the alkali metal salt of 2,5-dimethylphenol is coupled with the corresponding halide at about 110-150 ° C for 6-13 hours), the reaction can be followed by thin layer chromatography.

It should be noted that if X is not the preferred iodine in the starting compound of formula (VIa), for example chlorine or bromine, then it is desirable to add an alkali metal iodide such as sodium iodide or potassium to facilitate the formation of the ether linkage. iodide in an amount of from 0.1 to 1.0 mole per mole of the compound (Via).

The esters of formula Va thus obtained may, if desired, be isolated and purified by conventional methods known in the art (e.g., solvent extraction, column chromatography) and then further hydrolyzed without isolation of the said esters. , directly in the reaction mixture for their preparation by adding water and an additional base. The reaction mixture was then stirred at room temperature until the hydrolysis was complete. Under these conditions, the hydrolysis takes about 1-3 hours (compare with known methods where the hydrolysis is performed at about 1 150 ° C for 4-6 hours). The progress of hydrolysis can also be monitored by thin layer chromatography.

The final product of formula (I) thus obtained can be isolated and purified by conventional methods known per se (aqueous precipitation, solvent extraction at various pHs, clarification, recrystallization, and the like).

It is noted that the reaction is carried out under the preferred conditions described above, but using the alkali metal salt of 2,5-dimethylphenol instead of the esters of formula (VIII), to give (I) a lower yield of about 20%. ).

The process according to the present invention in the two steps (ether formation and hydrolysis) yields, in preferred embodiments, the final product of formula (I) having a purity of US XXII based on the starting compound (Via). . Identity and purity requirements as outlined in the pharmacopoeia.

The technological advantages of the process of the invention will be apparent to those skilled in the art.

The compounds of formula (Via) used as starting materials are known in part (see, for example, U.S. Patent No. 4,665,226) and may be prepared starting from such known compounds by a known halogen exchange reaction (see Example 1). .

Esters of formula VIII are partially known [R. J. Highet and P. F. Highet, J. Org. Chem. 30, 902 (1965); O. Jacobsen, Bér. 11, 27 (1878)], partly by known methods (see, e.g., F. D. Chattaway, J. Chem. Soc. 1931, 2495); Baumgarten, E., et al., J. Am. Chem. Soc., 66, 303, 1944 (1944)].

In summary, the process of the present invention is more advantageous than the methods described above, since it allows the 2,5-dimethylphenoxy group to be incorporated into the molecule under substantially milder conditions, at lower temperatures, without external heating, and in a much shorter reaction time. and, under the same mild conditions and in a short reaction time, the intermediate esters can be hydrolyzed to 2,2-dimethyl-5- (2,5-dimethylphenoxy) pentanoic acid (I). The present process provides a better yield of the pharmacologically pure final product of Formula (I) than the literature procedures.

The invention is further illustrated by the following non-limiting examples. These examples describe preferred embodiments of the process of the invention, but it is to be understood that these variants can be converted and / or combined with one another by conventional techniques known to those skilled in the art without departing from the spirit of the invention. Such modifications and combinations are also within the scope of the present invention.

/. example

2,2-Dimethyl-5- (2,5-dimethyl-phenoxy) -pentanoic acid

The crude 2,2-dimethyl-5-iodo-pentanoic acid ethyl ester (7.1 g, 0.02 mol) was dissolved in 40 ml of dimethylsulfoxide (80 ml) and 3.28 g of crude ethyl acetate were added. 0.02 mol) of acetic acid (2,5-dimethylphenyl) ester (e.g. RJ Highet and PF Highet, J. Org. Chem. 30, 902 (1965)] and 6.72 g (0.06 mol) of potassium tert-butylate. After stirring for 10 minutes, potassium tert-butylate (6.72 g, 0.06 mol) and water (0.8 ml) were added. After stirring for sixty minutes, the reaction mixture5

The solution was diluted with 200 mL of water and washed three times with 40 mL of hexane. The aqueous layer was then acidified to pH 1 with 20% hydrochloric acid and extracted with hexane (3 x 40 mL). The latter solutions were combined in hexane, washed with water (3 x 40 ml), dried over sodium sulfate, purified on silica gel (0.4 g) and the solvent was distilled off under reduced pressure. This gave 4.12 g (82.4%) of the crude title compound as an almost colorless solid, m.p. 49-54 ° C. This crude product was recrystallized from 8 mL of acetonitrile to give 3.53 g (70.6%) of the title compound as a colorless crystalline solid, m.p. Identity and purity requirements as outlined in the pharmacopoeia.

The starting 2,2-dimethyl-5-iodo-pentanoic acid ethyl ester can be prepared as follows:

5-bromo-2,2-dimethylpentanoic acid prepared according to European Patent Application A219 117 by M. Brenner and W. Huber, Helv. 36, 1109 (1953)] to give 5-bromo-2,2-dimethylpentanoic acid ethyl ester. 7.69 g (0.027 mol) of crude gas, 85% pure by gas chromatography

5-bromo-2,2-dimethylpentanoic acid ethyl ester (TLC on Kieselgel 60 adsorbent, benzene: ethyl acetate = 8: 1, 0.5) and 8.1 g ( A mixture of sodium iodide (0.054 mol) in acetone (75 mL) was heated to reflux for 8 hours. After cooling, the precipitate was filtered off and the filtrate was evaporated under reduced pressure. The resulting residue was dissolved in diethyl ether (60 mL), washed with water (3 x 25 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. This way

9.5 g (99% yield) of crude 2,2-dimethyl-5-iodo-pentanoic acid ethyl ester are obtained, which is purified by TLC on Kieselgel 60 as 80% pure by TLC. using 8: 1 benzene: ethyl acetate as the eluent: 0.8. This product can be used in the next step without further purification.

Example 2

2,2-Dimethyl-5- (2,5-dimethylphenoxy) -pentanoic acid

2.3 g (0.01 mol) of purified 5-chloro-2,2-dimethylpentanoic acid isobutyl ester (94% purity, e.g., U.S. Pat. No. 4,665,226) were purified by gas chromatography. Prepared in the same manner as in Example 1a), dissolved in 20 ml of dimethyl sulfoxide, 1.64 g (0.01 mol) of acetic acid (2,5-dimethylphenyl) ester (e.g. R. J. Highet and P. E Highet, J. Org. Chem. 30, 902 (1965)], 1.5 g (0.01 mol) of sodium iodide and 3.36 g (0.03 mol) of potassium tert-butylate. After stirring for ten minutes, potassium tert-butylate (3.36 g, 0.03 mol) and water (0.3 ml) were added and stirring was continued for another three hours.

Following the procedure of Example 1, the title compound of the same quality was obtained in 32.5% yield.

Example 3

2.2-Dimethyl-5- (2,5-dimethyl-phenoxy) -pentanoic acid

The procedure described in Example 1 was followed except that isobutyric acid (2,5-dimethylphenyl) ester was used as starting material instead of acetic acid (2,5-dimethylphenyl) ester. This gave the title compound of Example 1 in 64.2% yield.

The starting isobutyric acid (2,5-dimethylphenyl) ester is prepared, for example, by the method of E. Baumgarten et al. Chem. Soc., 66, 303 (1944)]. This gave the ester with a purity of 98.5% in 91% yield, m.p. 81-82 C / 80 Pa.

Example 4

2.2-Dimethyl-5- (2,5-dimethyl-phenoxy) -pentanoic acid

The procedure described in Example 1 was followed except that potassium hydroxide was used instead of potassium tert-butylate. This gave the title compound of Example 1 in 59.0% yield.

Example 5

2.2-Dimethyl-5- (2,5-dimethyl-phenoxy) -pentanoic acid

The procedure described in Example 1 was followed except that 2,2-dimethyl-5-iodo-pentanoic acid methyl ester was used in place of ethyl 2,2-dimethyl-5-iodo-pentanoic acid. This gave the title compound of Example 1 in 54.3% yield.

The starting 2,2-dimethyl-5-iodo-pentanoic acid methyl ester was prepared as described in Example 1. TLC Rf on Kieselgel 60 using benzene / ethyl acetate 8: 1 as eluent: 0.85.

The 5-bromo-2,2-dimethylpentanoic acid methyl ester used for this purpose, starting from the corresponding acid, is described in M. Brenner and W. Huber, Helv. 36, 1109 (1953)] with TLC on Kieselgel 60 using an 8: 1 mixture of benzene and ethyl acetate as eluent: 0.60.

PATENT CLAIMS

Claims (6)

PATENT CLAIMS A process for the preparation of 2,2-dimethyl-5- (2,5-dimethylphenoxy) pentanoic acid of formula (I): A 2,2-dimethyl-5-halopentanoic acid of formula (VIa) wherein X is halogen , and R ¹ is C 1 -C 5 alkyl, the conversion of its ester to a compound of formula (Va) wherein R ¹ is as defined above, and the resulting compound of formula (Va), optionally without isolation, directly in the reaction mixture for its preparation by hydrolysis of a compound of formula (VIa) in an aprotic apolar solvent in the presence of a strong base and optionally an alkali metal iodide as catalyst, without external heating to a compound of formula (VIII). of the formula wherein HU 209 601 A R ² is a C 1 -C 5 alkyl ester and the resulting compound of formula Va, optionally without isolation, is added directly to the reaction mixture in a known manner by addition of an additional base and 5 optionally small amounts of water. without heating, hydrolyze to 2,2-dimethyl-5- (2,5-dimethylphenoxy) pentanoic acid of formula (I). 2. A process according to claim 1, wherein the compound of formula (Via) is 2,2-dimethyl-10 Ethyl 5-iodo-pentanoic acid was used. Process according to claim 1 or 2, characterized in that the compound (VIII) is acetic acid (2,5-dimethylphenyl) ester. Process according to claim 1 or 2, characterized in that the compound (VIII) is isobutyric acid (2,5-dimethylphenyl) ester. 5. A process according to any one of claims 1 to 4, wherein the solvent is dimethyl sulfoxide. 6. A process according to any one of claims 1 to 3, wherein the base is potassium hydroxide or potassium tert-butylate.