HU209281B - Process for producing 2,2-dimethyl-5-(2,5-dimethylphenoxy)-pentanoic acid - Google Patents

Abstract

Novel 2,2-dimethyl-5-(2,5-dimethyl -phenoxy)-pentanoic acid of general formula (1) is prepd. from a cpd. of general formula (X). Z is 1-8C linear or branched alkylene gp. opt. substd. by one or two 2,2-dimethyl-5-halogen-pentanoyl-oxy-gps. Opt. one or two heteroatoms i.e. an oxygen atom or a substd. nitrogen atom are inserted in the chain and X is alpha halogen atom. - Ester (X) reacts with an ester of 2,5-dimethyl-phenol of general formula (XII) in an aprotic polar solvent and in the presence of a strong base. R in formula (XII) is 1-5C alkyl gp. prod. (XI) is hydrolised.

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. 3,647,836 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. In this illustrated 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 reaction of a substituted ether, for example a halogen atom or a sulfonyloxy group, with isobutyric acid or a corresponding derivative of the general formula (IV) wherein W is a carboxyl group or a carboxyl group (see below for the pathway A). 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 German Patent No. 1,925,423 and its equivalent U.S. Patent No. 36,748,336 consist of first forming a salt of sodium 2,5-dimethylphenol with an aprotic solvent in an aprotic solvent. is reacted with a 1,3-dihaloalkane to give a 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 an 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. Patent 4,665,226 estimates, by analogy, the desired compound of formula (I) according to the procedure described in U.S. Patent No. 36,748,336, based on the starting phenol (II). - can only be produced with a gross yield of about 39-46%.

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: Houbenwell, Die Methoden dereorganchen Chemie, Vol. 5 / 2a, p. 360), this method is not commercially available. suitable.

When a haloalkyl ether of formula (III) is not alkylated with such a compound having an isobutyric acid or a derivative thereof having two methyl groups at the alpha position, but an analog having only one methyl group at the alpha position, e.g. a methyl malonic acid diester, this reaction can also be carried out with a more convenient base, such as sodium ethylate in ethanol (Spanish Patent No. 549,469), so naturally not one compound of formula (I) but one less methyl group on the alpha carbon atom. lithium diisopropylamide is used in the final step of the synthesis. The yield of the final product of formula (I) obtained by this method is 70% relative to the haloalkyl ether of formula (III), but the haloalkyl ether is known according to the known method (see, for example, U.S. Patent No. 36,748,336 and J. Augstein et al. J. Med. Chem., 8, 356 (1965)] can only be obtained in a yield of about 30%, 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 haloalkyl 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). Gross yield by (III) 2

However, due to the poor yield of haloalkyl foods mentioned in the previous paragraph, the gross yield of the compound of formula (I) is only 20% of 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). wherein W is cyano, the nitrile is alkylated with the haloalkyl ether of formula (ΙΠ), and the intermediate of formula (V) thus obtained is converted into the compound of formula (I) according to methods known per se (U.S. Patent Nos. 3759986). The yields of these reactions are unknown, but the number of reaction steps required for the preparation of the starting material is expected to provide the target compound less economically.

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 the aldehyde V is unknown (U.S. Patent 4,126,637).

A major drawback of all of the above synthetic variants of the Synthesis route A in the industrial realization is that the haloalkyl ether intermediate of formula (III) wherein X is bromine can only be obtained in a low yield of about 30-40%. Compared to 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. 517665 consists of cleaving the aryloxyalkyl ketone of formula (V) wherein W is benzoyl in the presence of anisole with potassium tert-butylate to 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 4,665,226 (Hungarian equivalent: 195,635). Accordingly, a lower alkyl ester of isobutyric acid, preferably an isobutyl ester (compound of formula (IV) wherein W is isobutoxycarbonyl) is alkylated with 1-bromo-3-chloropropane in tetrahydrofuran in the presence of lithium diisopropylamide. ) 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, 2,5-dimethylphenol anhydrous and the resulting Gemfibrozil ester (V), where W is as defined above, is directly hydrolyzed directly in the reaction mixture with an excess of alkali (or acid according to the Hungarian equivalent) without isolation. 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 (I) is obtained in an excellent yield of 86% based on the isobutyl ester of isobutyric acid.

In our own studies, both the alkylation of the isobutyric acid ester and the coupling and hydrolysis with phenol can be carried out at 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 reported to result in a loss of about 15-18%. Another disadvantage of the process is that the purification and dehydration of the lower alkyl esters of isobutyric acid used as starting material is very laborious. It is known that many lower alkyl esters of isobutyric acid, such as isobutyl ester, are azeotropic with quite a few solvents and therefore cannot be separated from these solvents by simple distillation (see, e.g., Beilstein, Handbuch dérorganchen Chemie, 2). Volume III, Supplementary Volume III, pp. 643-647). Whatever method is used to prepare this ester (for example, by the esterification of isobutyric acid, the oxidation of isobutanol or the Tischenko reaction of isobutyraldehyde (see Beilstein 2, H 291, I 128, II260, III647, IV 847), for this reason, on a column, which entails considerable losses and costs, said ester must be virtually anhydrous, after the base used for the next reaction, the C-alkylation, is decomposed by water, lithium diisopropylamide, or azeotropic distillation. drying with calcium chloride does not sufficiently dehydrate this ester, only distillation from phosphorus pentoxide is sufficient for this purpose, which is already difficult on an industrial scale and also entails considerable losses.calculated - according to our own studies, only about 45%.

One particular variant of the B pathway is the process disclosed in European Patent Application 219117, which produces the lactone of formula VII.

EN 209 281 Β for the purpose of this manual. According to this, the allyl isobutyric acid ester (compound of formula (IV), where W is allyloxycarbonyl) is first converted to 2,2-dimethyl-4-pentenoic acid in the presence of sodium hydride, and thereafter is prepared by the addition of hydrobromic acid. VI) 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.

XI. Hungarian Patent Application Publication No. T 57 176, issued March 28, describes a process for the esterification of isobutyric acid with a polyhydric alcohol of formula VIII, the resulting polyhydric ester of formula IX being alkylated with a 1,3-dihaloalkane, the halogenated polyhydric ester (X) thus prepared is coupled with the alkali metal salt of 2,5-dimethylphenol and finally hydrolyzed to give the Gemfibrozil (I) by hydrolysis of the resulting polyhydric ester (XI).

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 undergo other partial decomposition and the decomposition 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). an ester of an alkanecarboxylic acid acylated ester of formula XII wherein R is a C 1 -C 5 alkyl group. In this way, the 2,5-dimethylphenoxy group was introduced into the molecule under very mild conditions, without heating the reaction mixture, and in a much shorter reaction time compared to the previous methods.

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

With an ester of 2,2-dimethyl-5-halo-pentanoic acid or a polyhydric alcohol, e.g. reacting a halogenated polyhydric ester of the general formula (X) as described in the above-mentioned Hungarian Patent Application T-57,176, wherein Z is an optionally substituted and / or heteroatom containing a heteroatom. a very rapid reaction yields a polyhydric ester of formula (XI) wherein Z is represented by the formula (X) substituted with aryloxy groups. The latter compound can be isolated and purified if desired, but is conveniently carried out without isolation directly into the desired final product, 2,2-dimethyl-5- (2,5-dimethylphenoxy) of the formula (I). hydrolyzed to pentanoic acid.

The above preparation of compounds of formula XI 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; A. Yamashita and A. Toy, Synth. Commun. 19,755 (1989)]. However, it should be emphasized that the process of the present invention can be carried out under substantially less stringent conditions than those known in the known cases, said ether bond being formed without heating, while the above publications employ several hours of reflux or work at room temperature. 24-28 hours).

Furthermore, it has surprisingly been found that under the reaction conditions used in the process of the present invention, the said compounds of formula XI may be used in a substantially shorter period of time than in the previous methods.

Hydrolyze to 2.2-dimethyl-5- (2,5-dimethylphenoxy) pentanoic acid.

Thus, the present invention relates to a novel process of formula (I)

For the preparation of 2,2-dimethyl-5- (2,5-dimethylphenoxy) pentanoic acid, wherein the 2,2-dimethyl-5-halopentanoic acid is formed with a polyhydric alcohol of formula (X), wherein

Z is a linear or branched alkylene group containing from 1 to 8 carbon atoms, optionally substituted with one or two 2,2-dimethyl-5-halopentanoyloxy groups, one or two methylene groups of which is optionally substituted by a heteroatom, e.g. substituted nitrogen, wherein the substituent may be a phenyl group or an optionally substituted C 1-4 alkyl group optionally substituted with a 2,2-dimethyl-5-halopentanoyloxy group, and

X is a halogen atom, its ester in an aprotic polar solvent, in the presence of a strong base and optionally an alkali metal iodide as a catalyst, 2,5-dimethylphenol has the formula:

R is a C 1 -C 5 alkyl group, is reacted with its ester and the resulting compound of formula XI

Z is as defined for formula (X), provided that when the group Z in formula (X) contains 2,2-dimethyl-5-halo-pentanoyloxy group (s), the compound of formula (XI) in 2,2-dimethyl-5-halo-penta4

The 9 noyloxy group (s) is replaced by the 2,2-dimethyl-5- (2,5-dimethylphenoxy) pentanoyloxy group, the compound being optionally directly isolated in the reaction mixture for its preparation, (I). hydrolyzed to 2,2-dimethyl-5- (2,5-dimethylphenoxy) pentanoic acid.

Z in the parent compound of formula X is, for example, ethylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, 1,6-hexylene, 2-methyl-1,3 propylene,

2,2-dimethyl-1,3-propylene, 2-methyl-2- (n-propyl) -1,3-propylene, 2- (2,2-dimethyl-5-halopentanoyloxy) -1, 3- propylene, 2,2-bis (2,2-dimethyl-5-halopentanoyloxy) 1,3-propylene, 3-oxa-1,5-pentylene, 3,6-dioxa-1,8-octylene, 3- (N-methyl-aza) -1,5-pentylene or 3- (N-phenylaza) -1,5-pentylene, and preferably, for example, 1,3-propylene, and X is chlorine, bromine or - preferably - I may have 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 the group consisting of C2-C6 straight-chain and branched alkanoic acids, e.g. an acyl group derived from acetic acid, propionic acid, n-butyric acid, isobutyric acid, valeric acid or isovaleric acid.

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

In the first step of the process, the ester of formula (X) with 2,2-dimethyl-5-halopentanoic acid is reacted with the ester (XII) in a suitable aprotic polar organic solvent in a suitable aprotic polar organic solvent. Suitable solvents are, for example, dimethylsulfoxide, 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 hydroxide or an alcoholate of an alkali metal such as sodium hydroxide, potassium hydroxide, as well as 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 different amounts of the base are used for these two purposes. Thus, on the one hand, the base promotes the reaction of the compound of the formula X with the compound of the formula XII, preferably from 1 to 4 moles, preferably from 2 to 3 moles, of the base per mole of the compound of the formula XII. . On the other hand, after the reaction of the compound of formula (X) with the compound of formula (XII), an additional amount of base is required to hydrolyze the resulting compound of formula (XI) to the final product of formula (I). Suitable bases for the hydrolysis are preferably from 1 to 4 moles, preferably from 2 to 3 moles, per mole of the starting compound (XII).

It should be noted that in order to effect complete hydrolysis, water must be added to the reaction mixture, preferably in an amount of from 2 to 5 moles per compound of formula (XII).

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. This takes about 5 to 10 minutes (compare to the 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), by chromatography.

It should be noted here that if X is not the preferred iodine in the starting compound of formula X but is, for example, chlorine or bromine, then it is desirable to add an alkali metal iodide, such as sodium iodide or potassium, to facilitate the ether bond formation. iodide in an amount of 0.1 to 2.0 moles per mole of compound (X).

The esters of formula XI thus prepared 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, hydrolysis takes about 1 hour (compare to known methods where hydrolysis is performed at about 110-150 ° 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 (XII) gives about 20% lower yield of the compound (I). .

The process of the present invention provides in two steps (ether formation and hydrolysis) the final product of formula (I) having a purity of 65-70% based on the starting compound (X). Identity and purity requirements as outlined in the pharmacopoeia.

As stated above, the present invention provides

The technological advantages of this process are obvious to one skilled in the art.

The preparation of the compounds of formula (X) used as starting materials is partly described in U.S. Pat. and partly starting from the compounds described therein, they can be prepared by a known halogen exchange reaction (see Example 1).

Esters of formula XII are known in part [R. J. Highet and P. F. Highet, J. Org. Chem. 30, 902 (1965); O. Jacobsen, Bér. 77, 27 (1878)], in part 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)].

In summary, the process of the present invention is more advantageous than the methods described above, since it can be used under substantially milder conditions, at lower temperatures, without external heating, and with a much shorter reaction time.

The 2,5-dimethylphenoxy group may be incorporated into the molecule and the esters obtained as an intermediate may be hydrolyzed to 2,2-dimethyl-5- (2,5-dimethylphenoxy) pentanoic acid (I) under the same mild conditions and in a short reaction time. . The present process provides a yield that is comparable to the best yield method known in the art and provides the final product of formula (I) in pharma- ceutical purity.

The invention is further illustrated by the following non-limiting examples. These examples illustrate a preferred embodiment of the process of the invention, but it is to be understood that these variants can be converted and / or combined with one another using standard 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 1

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

13.3 g (0.018 mol) of crude 1,3-bis (2,2-dimethyl-5-iodo-pentanoyloxy) -propane, 76% pure by gas chromatography, are dissolved in 100 ml of dimethylsulfoxide, 6.0 g (0.037 mol) are added. acetic acid (2,5-dimethylphenyl) ester (e.g. RJ Highet and PF Highet, J. Org.). Chem. 30, 902 (1965)] and 12.3 g (0.11 mol) of potassium tert-butylate. After stirring for 10 minutes, potassium tert-butylate (12.3 g, 0.11 mol) and water (1.5 mL) were added. After stirring for another 60 minutes, the reaction mixture was diluted with water (400 mL) and washed with hexane (3 x 80 mL). The aqueous layer was then acidified to pH 1 with 20% hydrochloric acid and extracted with hexane (3 x 80 mL). The latter solutions were combined, washed with water (3 x 80 mL), dried (Na 2 SO 4), purified on silica gel (0.8 g) and the solvent was distilled off under reduced pressure. This gave 7.61 g (84.1%) of the crude title compound as an almost colorless solid, m.p. 48-54 ° C. This crude product was recrystallized from 15 mL of acetonitrile to give 6.32 g (70.2%) of the title compound as a colorless crystalline solid, m.p. 5758 ° C. Identity and purity requirements as outlined in the pharmacopoeia.

For example, the starting 1,3-bis (2,2-dimethyl-5-iodo-pentanoyloxy) -propane can be prepared as follows:

1,3.0-bis (2,2-dimethyl-5-chloro-pentanoyloxy) -propane (10.0 g, 0.021 mol) in crude gas chromatography (77% pure, for example, as described in U.S. Pat. No. 2997/90). can be prepared as described in Example 3 (b) of U.S. Patent Application Serial No. 3, and boiled with 12.5 g (0.084 mol) of sodium iodide in 100 ml of acetone for eight hours. After cooling, the precipitate was filtered off and the filtrate was evaporated under reduced pressure. The resulting residue was dissolved in diethyl ether (100 mL), washed with water (3 x 40 mL), dried over sodium sulfate and the solvent was distilled off under reduced pressure. 14.9 g (99% yield) of crude 1,3bis (2,2-dimethyl-5-iodo-pentanoyloxy) -propane are obtained, which is shown by TLC to be 76% pure by TLC. Kieselgel 60 on adsorbent using a mixture of benzene and ethyl acetate 8: 1 as the eluent: 0.80. This product can be used in the next step without further purification.

Example 2

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

2.4 g (0.005 mol) of crude 1,3-bis (2,2-dimethyl-5-chloropentanoyloxy) propane (77% pure, for example, according to 2997/90) were obtained by gas chromatography. (3), 1.64 g (0.01 mol) of acetic acid (2,5-dimethylphenyl) ester [e.g. Highet and PF 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 a further sixty minutes. Following the procedure of Example 1, the title compound of the same quality was obtained in 41.8% 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. Thus, the title compound of Example 1 was obtained in a yield of 63.2%.

The starting isobutyric acid (2,5-dimethylphenyl) ester

See, e.g., E. Baumgarten et al., J. Med. Chem. Soc., 66, 303 (1944)]. This gave the ester (91.5% purity: 81-82 ° C / 80 Pa) in 91% yield by gas chromatography.

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 69.0% yield.

5-9. example

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

In the same manner as in Example 1, the final product of formula (I) is represented by the following formula (X), wherein X is starting from iodine compounds, having the groups given in the table below.

The starting iodine compounds are disclosed in U.S. Pat. Starting from the analogous chlorine compounds prepared as described in U.S. Patent Application Serial No. 4,666,960, the starting material of Example 1 is shown in the following table.

Example number Z Yield (I),% The Rf value of the parent iodine compound * 5 1,6-hexylene 65.8 0.70 6 3-oxa-l, 5-pentylene 64.3 0.65 7 3- (N-phenyl-aza) -1,5-pentylene 51.2 0.75 8 3- (N-methyl-aza) -1,5-pentylene 54.2 0.70 9 2- (2,2-dimethyl-5-iodo-pentanoyl) -1,3-propylene 42.1 0.70

* Adsorbent: Kieselgel 60; Running solvent: benzene: ethyl acetate = 8: 1

Claims (7)

A novel process for the preparation of 2,2-dimethyl-5- (2,5-dimethylphenoxy) pentanoic acid of formula (I) wherein the 2,2-dimethyl-5-halopentanoic acid is mixed with a polyhydric alcohol. skilled in the general formula (X) wherein Z is a linear or branched alkylene group containing from 1 to 8 carbon atoms, optionally substituted with one or two 2,2-dimethyl-5-halopentanoyloxy groups, one or two methylene groups of which is optionally substituted by a heteroatom, e.g. substituted nitrogen, wherein the substituent may be a phenyl group or an optionally substituted C 1-4 alkyl group optionally substituted with a 2,2-dimethyl-5-halopentanoyloxy group, and X is a halogen atom, its ester in an aprotic polar solvent, in the presence of a strong base and optionally an alkali metal iodide as a catalyst, 2,5-dimethylphenol has the formula: R is a C 1 -C 5 alkyl group, is reacted with its ester and the resulting compound of formula XI Z is as defined for formula (X), provided that when group Z in formula (X) contains 2,2-dimethyl-5-halo-pentanoyloxy (s), then formula (XI) in the compound of the present invention 2,2-dimethyl-5-halo-pentanoyloxy group (s) is replaced by 2,2-dimethyl-5- (2,5-dimethylphenoxy) pentanoyloxy group, optionally directly without preparation - hydrolyzing the compound of formula I to 2,2-dimethyl-5- (2,5-dimethylphenoxy) pentanoic acid. 2. The process of claim 1 wherein the compound of formula X is 1,3bis (2,2-dimethyl-5-chloropentanoyloxy) propane. 3. The process of claim 1 wherein the compound of formula X is 1,3bis (2,2-dimethyl-5-iodo-pentanoyloxy) -propane. 4. Process according to any one of claims 1 to 3, characterized in that the compound of formula (XII) is acetic acid (2,5-dimethylphenyl) ester. 5. Process according to any one of claims 1 to 3, characterized in that the compound (XII) is isobutyric acid (2,5-dimethylphenyl) ester. 6. A process according to any one of claims 1 to 4, wherein the solvent is dimethyl sulfoxide. 7. A process according to any one of claims 1 to 3, wherein the base is potassium hydroxide or potassium tert-butylate.