FR2677981A1 - PROCESS FOR THE PREPARATION OF PURE ISOMERIC FORMS OF -3,3,5-TRIMETHYLCYCLOHEXANOL AMINO ACID ESTERS AND -3,3,5-TRIMETHYLCYCLOHEXANONE - Google Patents

Abstract

Process for the preparation of pure isomeric forms of 3,3,5-trimethyl cyclohexanol amino acid esters and process for the preparation of different pure isomeric forms of 3,3,5-trimethyl cyclohexanone, an intermediate product for the preparation of said esters. The process for the preparation of pure isomeric forms of 3,3,5-trimethyl cyclohexanol amino acid esters is characterized in that: (1) a 3,3,5-trimethyl cyclohexanol alcohol having a previously selected asymmetric carbon configuration (C1 and C5), is prepared by reduction from a pure isomeric trimethyl cyclohexanone, and (2) a suitable isomeric form of an amino acid is reacted with 3,3,5-trimethyl cyclohexanol alcohol of preselected configuration, obtained in (1), in a new stoichiometric ratio by weight and at a temperature sufficient to eliminate the water formed, without causing the ester obtained to be racemized. For use in the correction of dislipidemias.

Description

The present invention relates to a process for the preparation of pure isomeric forms of amino acid esters of -3,3,5-trimethylcyclohexanol and in particular of the -3,3,5-trimethylcyclohexyl ester of pyroglutamic acid as well as to the process for the preparation of the different pure isomeric forms of 3,3,5-trimethylcyclohexanone, an intermediate product for the preparation of said esters. Pyroglutamic acid -3,3,5-trimethylcyclohexyl ester, for example, is one of the products described in the European patent EP 261 017 in the name of PANMEDICA. Examples I to
VII of the aforementioned patent describe in particular the amino acid esters of -3,3,5-trimethylcyclohexanol. More particularly, in Examples II, III, IV, the amino acid chosen is pyroglutamic acid.

 The process described in this patent EP 261 017, for example, involves a protected derivative of pyroglutamic acid, a solvent, a condensing agent and trimethylcyclohexanol, to then separate by-products and optionally to unblock the protective group of the 5-oxo proline; these successive steps reduce the yield and are especially detrimental, especially when one of the stereoisomeric forms involved in the esterification is expensive.

 The pharmacological studies of the derivatives according to the patent EP 261 017 have shown interesting properties for all of these derivatives and more particularly for the ester of the CIS form of trimethylcyclohexanol. Indeed, if all the esters described in the aforementioned European patent have interesting activities on the lipid parameters, it is the -3,3,5-trimethylcyclohexyl ester (in its CIS form) of pyroglutamic acid (in its form -L-) which qualitatively and quantitatively presents the strongest activity. The importance of the stereochemistry and the need to have all the possible isomers are therefore conceived to select the best structure in terms of the hypocholesterolemic activity, to study the pharmacological and toxicological properties of each of the isomers separately, the pharmacological and toxicological results may sometimes be different, depending on the chirality of an asymmetric center or establish correlations between spatial conformation and pharmacological and toxicological properties.

 Recent results show that there may be stereoselectivity of therapeutic activities between two enantiomeric forms.

 Thus, it is known that the so-called natural forms (L) of amino acids are easily transformed by the body, whereas the so-called (D) forms are not. Methotrexate -L- is selectively absorbed relative to its -D- isomer (Hendel J., Brodthagen H., Eur.

J. Pharmacol., 1984, 26, 103-107). Warfarin has different affinities for proteins depending on its configuration (Yacobi A., Levy G., J. Pharmacokinet, Biopharmacol., 1977, 5, 123-131). This stereoselectivity of drugs can be exerted on substrates, on biliary excretion, on renal clearance and on many other parameters.

 The properties of the various isomers are also of particular interest to the regulatory authorities, as evidenced by, for example, the number 1 vol 2 of The Regulatory Affairs Journal in its first twenty pages.

 It is therefore crucial to be able to obtain the different pure isomers of a substance, with a good yield.

 The present invention has accordingly given. to provide a new method for obtaining the amino acid esters of -3,3,5-trimethylcyclohexanol, capable of being applied to the preparation of any of the eight possible isomers of -3,3,5-trimethylcyclohexyl ester selected amino acid, and especially pyroglutamic acid, which better meets the needs of the practice than the methods of the prior art that do not allow a conventional analysis or separation, chiral or not, said stereoisomers.

 3,3,5-Trimethylcyclohexanol is a cycloaliphatic alcohol having two centers of asymmetry, namely, the carbons in position 1 and 5. These carbons may have the absolute configurations R or S (see rule RSCAHN, CK INGOLD, V. PRELOG, Angew.

Chem. 1966, 78, 413) and the isomers of -3,3,5-trimethylcyclohexanol can have the following absolute configurations:
- 1R, 5S
- 1S, 5R
- 1S, 5S
- 1R, 5R
The 50/50 mixture of the first two forms constitutes the TRANS (i) form of -3,3,5-trimethylcyclohexanol. The 50/50 mixture of the last two forms constitutes the CIS (i) form of -3,3,5-trimethylcyclohexanol. . Both forms TRANS and CIS are available in their racemic (+) form.

 Esterification of each of the 4 forms of 3,3,5-trimethylcyclohexanol by each of the two forms of an amino acid and especially pyroglutamic acid determines a possible set of 8 isomers.

The synthesis of CIS (-) and CIS (+) - 3,3,5-trimethylcyclohexanol has been described by ALLINGER and RIEW (J. Org Chem, Vol 40, 9, 1975, 1316/21).
or by resolution of dl-CIS-3,3,5-trimethylcyclohexyl phthalate acid by selective crystallization of cinchonine salts,
or by non-racemic synthesis, -3,3,5 (R) -trimethylcyclohexanone, from the natural pulegone of known structure, and then reducing the ketone to alcohol.

 The first way of obtaining the two isomers (+) and (-) of CIS-3,3,5-trimethylcyclohexanol by selective crystallization of the cinchonine salts has the drawback of being very laborious (the author recommends seven crystallizations successive), and to provide a product of very poor quality (the enrichment does not exceed 75%, according to ALLINGER, in the sole stage of trimethylcyclohexanone).

 The second method, by obtaining -3,3,5 (R) -trimethylcyclohexanone, provides a ketone of good enantiomeric quality, but has the drawback of using a very expensive natural raw material, pulegone, and to require 14 steps with a published overall return of 0.3%.

 In addition, preliminary attempts to separate racemic mixtures have not given encouraging results, the Applicant has developed an original process for obtaining any of these 8 isomers.

dans laquelle R représente le reste d'un aminoacide approprié, Y représente un atome d'hydrogène, un radical acétyle, propionyle, benzoyle, ou bien représente avec R un cycle pyrrolidinone 2 déterminant dans la formule générale un ester pyroglutamique, lequel procédé est caractérisé en ce que
(1) l'on prépare un alcool -3,3,5-triméthylcyclohexanol de configuration présélectionnée au niveau de ses carbones asymétriques (C1 et C5), par réduction à partir d'une triméthylcyclohexanone isomère pure, et
(2) l'on fait réagir une forme isomère appropriée d'un acide aminé avec l'alcool -3,3,5-triméthylcyclohexanol de configuration présélectionnée, obtenu en (1), dans un rapport pondéral proche de la stoechiométrie et à une température suffisante pour éliminer l'eau formée, tout en n'entraînant pas une racémisation de l'ester obtenu.The subject of the present invention is a process for the preparation of a pure isomer of formula I

in which R represents the residue of a suitable amino acid, Y represents a hydrogen atom, an acetyl, propionyl or benzoyl radical, or represents with R a pyrrolidinone 2 ring determining in the general formula a pyroglutamic ester, which process is characterized in that
(1) an alcohol -3,3,5-trimethylcyclohexanol of preselected configuration at its asymmetric carbons (C1 and C5) is prepared by reduction from a pure isomeric trimethylcyclohexanone, and
(2) a suitable isomeric form of an amino acid is reacted with the preselected configuration -3,3,5-trimethylcyclohexanol alcohol obtained in (1) in a weight ratio close to stoichiometry and at a sufficient temperature to remove the water formed, while not causing racemization of the ester obtained.

 Such a method has the advantage of being able to be implemented in the absence of solvent and catalyst.

According to an advantageous embodiment of said process, the pure isomer -3,3,5-trimethylcyclohexanone used during step (1) is obtained beforehand
at. by reaction of an excess of racemic trimethylcyclohexanone with a dialkyl tartrate of appropriate form, in a suitable solvent, that is to say allowing azeotropic removal of water under conditions which favor the obtaining of a dioxolane of selected configuration (5S or 5R conformations), and
b. hydrolysis of the pure dioxolane of tartaric acid obtained in a. under conditions that favor one of the carbon configurations of the cyclohexyl ring.

 According to an advantageous arrangement of this embodiment, said dioxolane is obtained by reacting an excess of racemic trimethylcyclohexanone on a dialkyl-L-tartrate, in a suitable solvent, allowing azeotropic removal of water to promote the S 5 conformation. on dioxolane.

 According to another advantageous provision of this embodiment, said dioxolane is obtained by making an excess of racemic trimethylcyclohexanone on a dialkyl-D-tartrate in a suitable solvent, that is to say allowing azeotropic removal of water to promote the 5 R conformation on dioxolane.

 According to these two provisions, the excess of racemic trimethylcyclohexanone is from 1.1 to 10, preferably from 2 to 5.

 For the purposes of the present invention, the term "alkyl" includes C1 to C5 groups and in particular includes methyl, ethyl and isopropyl groups.

 A mixture of diastereoisomeric dioxolanes is thus obtained, one of which is in a much greater quantity.

Indeed, the preparation of dioxolanes of the prior art, as well at SANZ BURATA (Afinidad
Nov 1970, 705/714), which reacts (i) -3,3,5-trimethylcyclohexanone with diethyl-L-tartrate to give a mixture of the two diastereoisomeric dioxolanes, as in Conan JY et al., Which also synthesize of these dioxolanes (see Bull Soc Chim.Fr 7-8 (2) 1405-10) and use the diastereoisomeric dioxolane hydrolysis rate difference to obtain ketones enriched in an optical isomer, has major drawbacks (difficulty realization, little enrichment)
- SANZ BURATA separates the two diastereoisomers by preparative gas chromatography; these give by hydrolysis the -3,3,5-tri methylcyclohexanones (+) and (-). Preparative gas chromatography has the disadvantage of requiring relatively expensive equipment and having a very low productivity. (SANZ BURATA injects and separates 100 mg per half-hour either a production of a dioxeolane diastereoisomeric pure 100 mg per hour or 40 mg of pure ketone per hour).

 - The technique of CONAN et al. allows only partially enriched enantiomers to be obtained.

The Applicant has found, surprisingly, that the general conditions for the synthesis of dioxolane can be modified so as to promote the synthesis of one diastereoisomer relative to the other. Indeed, there is a stereoselectivity of the condensation of dialkyl-tartrate, and more particularly of diethyl
L-tartrate with one of the enantiomeric forms of -3,3,5-trimethylcyclohexanone making it possible to obtain 75 to 80% of a dioxeolane diastereoisomer and only 20 to 25% of the other (reaction stereoselectivity).

 In the same way, the Applicant has found that the other available variety, (-) diethyl-D-tartrate has the same stereoselectivity, for the other enantiomeric form of -3,3,5-trimethylcyclohexanone, and that it is possible to obtain from 75 to 80% of the dioxolane diethyl-D-tartrate and the other enantiomer of -3,3,5-trimethylcyclohexanone.

 The process according to the invention therefore makes it possible, in an unexpected manner, to enrich, in a simple and inexpensive manner, one and / or the other of the two (+) or (-) varieties of the -3.3 5-trimethylcyclohexanone as a simple derivative.

 According to another advantageous arrangement of this embodiment, the diastereoisomeric dioxeolanes obtained are purified by continuous stripping under high vacuum.

 The Applicant has found that, unexpectedly, under the steric enrichment conditions specified above, it is possible to obtain a total separation of diastereoisomeric dioxolanes by fractional distillation.

 The preparation method according to the invention of each form of -3,3,5-trimethylcyclohexanone thus being made possible by an inexpensive process, access to the corresponding pure isomeric alcohols is -3,3,5-trimethylcyclohexanol is easy by reducing the carbonyl to alcohol with, in each case, the easy separation into the CIS and TRANS forms.

The subsequent esterification of the four isomeric alcohols with each of the forms of the amino acid, and more particularly pyroglutamic acid, as described in US Pat.
European application 261 017, makes it possible to obtain each of the eight isomers sought in its optically pure form and under very advantageous economic conditions by simple heating of the stoichiometric quantities of acid and alcohol, without solvent and without catalyst, as specified above. above.

 According to another advantageous embodiment of said process, the reaction of step (2) between the appropriate isomeric form of the amino acid and the 3,3,5-trimethylcyclohexanol alcohol of preselected configuration is carried out between 120 and 175 ° C, preferably between 145 and 165 ° C.

 According to an advantageous arrangement of this embodiment, the duration of the heating is between 6 and 24 hours, more particularly between 12 and 18 hours.

 According to another advantageous arrangement of this embodiment, the hydrolysis is carried out in a dilute acid medium, followed by steam distillation.

According to the invention
or each pure isomer of 3,3,5-trimethylcyclohexanol is esterified with the chosen form of the amino acid
either a racemic mixture of two enantiomers of -3,3,5-trimethylcyclohexanol is esterified by the chosen form of the amino acid
one of the TRANS or CIS forms of 3,3,5-trimethylcyclohexanol is esterified by the chosen form of the amino acid
each trimethylcyclohexanone of S or R configuration is not specifically reduced to a mixture of each corresponding CIS or TRANS alcohol.

 By amino acids, we understand the alpha amino acids constituting proteins, they therefore include a chiral site in determining L- and -D- isomers.

 The terms amino acids also include the simplest derivatives such as the lower alkyl mono esters of the di-carboxylic amino acids or the N acetyl, N propionyl and N benzoyl derivatives on the nitrogen carried by the carbon in position a.

 Among the most common amino acids are: glycine, alanine, valine, leucine, proline, threonine, serine, phenylalanine, cysteine, cystine, tyrosine, aspartic acid , asparagine, glutamic acid, glutamine, pyroglutamic acid, tryptophan, 5-hydroxytryptophan, arginine, lysine, ornithine, hydroxy-prolines, hydroxy-lysine delta, amino adipic acid, NO-methyl arginines, ss hydroxy phenyl alanine, ss hydroxy tyrosine, ss hydroxy glutamic acid.

 According to another advantageous embodiment of said process, the amino acid is a derivative of pyroglutamic acid.

 According to an advantageous arrangement of this embodiment, the chosen form of the pyroglutamic acid derivative is preferably 5-oxo-proline.

 The process for obtaining the 4 pure enantiomers of -3,3,5-trimethylcyclohexanol, according to the invention, by means of the precursor 5S or 5R ketone and intended to be esterified by an amino acid and in particular the acid Pyroglutamic in one of its commercial forms, L or D, has the advantage of being economical and simple to implement, having none of the disadvantages of the previous method and directly industrializable.

 The process, which is the subject of the present Application, is particularly advantageous since it requires neither a reaction solvent nor a coupling reagent and that the purification process is thereby simplified since the reaction medium contains no by-product such as, for example, dicyclohexylurea resulting from the action of dicyclohexylcarbodiimide in the previous process.

 The present method further comprises an original technique for obtaining a preselected configuration at each asymmetric carbon.

Thanks to the stereospecificity of the synthesis of each dioxolane purified by distillation, the easy and quantitative hydrolysis in a single configuration ketone followed by the reduction and separation of Cis-Trans isomers, the method described makes it possible to obtain any of the eight pure isomers, any one of a racemic mixture of two of them or any one of a mixture of two diastereoisomers selected from among them, by simple, economical esterification and resulting in no racemization. The quality of the optical enrichments is remarkable, as can be seen from the rotational power measurements of each of the synthesized isomers.

 The various isomers obtained, according to the process described above, are particularly useful in the correction of dislipidemias in humans or animals, with particular attention to HMG CoA reductase activity, the main factor in the synthesis of cholesterol and may be administered alone or as a mixture, such as or in the form of pharmaceutically acceptable salts, in the various known forms of administration for the drugs.

 Thus, such compounds can be administered enterally, parenterally, or transcutaneously, alone or in combination with adjuvants or solvents used in the pharmaceutical industry, such as water, polyalkylene glycols, natural oils, starch or gelatin.

 The pharmaceutically solid forms may be, for example, tablets, capsules, capsules or suppositories. Liquid forms can be solutions, suspensions or emulsions. The unit dose of the pharmaceutical preparation is between 10 and 1000 mg.

The present invention also relates to a process for the preparation of pure isomers of -3,3,5-trimethylcyclohexanone, characterized in that each isomer is obtained
at. by reaction of an excess of racemic trimethylcyclohexanone with a dialkyl tartrate of appropriate form, in a suitable solvent, that is to say allowing azeotropic removal of water to favor obtaining a dioxolane of selected configuration ( conformations 5S or 5R), and
b. hydrolysis of the pure dioxolane of tartaric acid obtained in a. under conditions that favor one of the carbon configurations of the cyclohexyl ring.

 According to an advantageous embodiment of said process, said dioxolane is obtained by reacting an excess of racemic trimethylcyclohexanone on a dialkyl-L-tartrate, in a suitable solvent, allowing azeotropic removal of water to promote the S 5 conformation on dioxolane.

 According to another advantageous embodiment of said process, said dioxolane is obtained by reacting an excess of racemic trimethylcyclohexanone on a dialkyl-D-tartrate in a suitable solvent, that is to say allowing azeotropic removal of water to favor the 5 R conformation on dioxolane.

 According to these two modes of implementation, the excess of racemic trimethylcyclohexanone is from 1.1 to 10, preferably from 2 to 5.

 For the purposes of the present invention, the term alkyl comprises groups C1 to C5 and especially methyl, ethyl, isopropyl.

 A mixture of diastereoisomeric dioxolanes is thus obtained, one of which is in a much greater quantity.

 In accordance with the process for preparing the pure isomeric forms of trimethylcyclohexanone, said dioxolanes are purified by continuous rectification under high vacuum.

 According to another advantageous embodiment of the process for preparing the pure isomeric forms of trimethylcyclohexanone, the hydrolysis of step b. is carried out in a dilute acid medium, followed by steam distillation.

 In addition to the foregoing, the invention also comprises other provisions, which will emerge from the description which follows, which refers to examples of implementation of the method which is the subject of the present invention.

 It should be understood, however, that these examples are given solely by way of illustration of the object of the invention, of which they in no way constitute a limitation.

More specifically, the preparation process according to the invention consists, for the preparation of a dioxolane, in reacting diethyl L-tartrate with (+) -3,3,5-trimethylcyclohexanone in solution in the toluene in the presence of an acidic catalyst, for example paratoluene sulphonic acid, at the boiling point, in an apparatus equipped with a
Dean-Stark for azeotropic separation of water. Four molecular equivalents of ketone are reacted for one mole of diethyl L-tartrate and 0.01 to 0.05 molecular equivalents of para-toluenesulfonic acid. After 15 to 17 hours of reflux, the theoretical amount of water is collected and the operation is stopped. The organic solution is washed with water and after evaporation, the crude dioxolane is collected in a yield of 85 to 90%.

Its relative composition determined by GPC, (semi-capillary column, type DBFFAP, 15 or 30 meters, FID detection, is substantially the following
25 to 30% of the first isomer, (first GPC outgoing isomer), dioxolane of diethyl-L-tartrate, (R, R configuration) and -3,3,5-trimethylcyclohexanone, (5R configuration) , and
from 70 to 75% of the second isomer, dioxolane of diethyl-L-tartrate (R, R configuration), and -3,3,5-trimethylcyclohexanone, (5S configuration).

 The carbon configurations of -3,3,5-trimethylcyclohexanone are those published by ALLINGER, (5. Org Chem 40, 9, 1975, pages 1316-1321).

By operating in exactly the same manner with diethyl-D - (-) tartrate (S, S configuration), a crude dioxolane containing the same yield is obtained with the same yield.
25 to 30% of the first isomer (1st isomer leaving in GPC), dioxolane of D (-) diethyl tartrate (S, S configuration) and of 3,3,5-trimethylcyclohexanone (5S configuration),
70 to 75% of the second isomer, dioxolane of D (-) diethyl tartrate (S, S configuration) and -3,3,5-trimethylcyclohexanone (R configuration).

 Enrichment to an isomer is continued by fractional distillation under vacuum. One operates, for example, in a 1 liter distilling apparatus with a column packed with metal knit Multiknit6 type (registered trademark) with a height of 900 mm and fully thermostatically circulating oil. The pressure is maintained between 5.10-3 and 1.10-3 mBar. By slow fractional distillation, the minority most volatile isomer is progressively removed, partially mixed with the heaviest isomer, and about 20% by weight of the least volatile isomer is obtained as the last fraction. purity> 98%, (always measured in GPC).

By combining the operations, it is thus possible, at each rectification, to isolate about 20% of the less volatile majority isomer, namely
or dioxolane diethyl-L-tartrate and -3,3,5-trimethylcyclohexanol (5S), if one operated with -L-tartrate,
or dioxolane diethyl-D-tartrate and -3,3,5-trimethylcyclohexanol (5R), if one operated with -D-tartrate.

 The two pure diastereoisomers are combined and hydrolysed with aqueous hydrochloric acid in each of the two enantiomeric S and R forms of the ketone.

Since the reduction of the carbonyl is not stereospecific, each enantiomeric ketone is suitably reduced by LiAlH 4 in a suitable solvent such as diethyl ether or tetrahydrofuran. Thus, -3,3,5-trimethylcyclohexanone (5S) will yield, by reduction, a substantially 50/50 mixture of (1S, 5S) and (1R, 5S) -3,3,5-trimethylcyclohexanol. These two isomers
CIS / TRANS separate conventionally, for example on a silica column. The same operation carried out with the second enantiomer of -3,3,5-trimethylcyclohexanone (5R) results similarly to the two corresponding alcohols - CIS and TRANS -, namely (1S, 5R) and (1R, 5R).

 From these four isomeric alcohols (two pairs of diastereoisomers) and a suitable amino acid such as 5-oxo-L-proline or 5-oxo-D-proline, the esterification can be conducted by heating quantities stoichiometrically equivalent amounts of alcohol and acid at a temperature suitable for distilling the reaction water without racemizing the pyroglutamic acid. This temperature is chosen between 120 and 170.degree. C., preferably 155.degree.

 The duration of the heating depends in part on the mass of the reagents and the nature of the apparatus used, but is generally between 10 and 24 hours, more particularly between 15 and 20 hours.

The removal of water may possibly be facilitated by establishing a reduced pressure in the apparatus or by a slight flow of inert gas. The residual mass is taken up by a solvent for separating the unreacted pyroglutamic acid, all of the immiscible solvents is suitable, it may be preferably used chloroform or ethyl acetate. After filtration of a portion of the unreacted and reusable pyroglutamic acid, the solvent is evaporated, the excess -3,3,5-tri methylcyclohexanol is distilled under reduced pressure and recovered. The pure ester is obtained by chromatography on a silica column with chloroform for small amounts or by continuous distillation under reduced pressure for larger amounts.

EXAMPLE I 5-oxo-L-Droline, -3.3.5- fiS. 5S) trimethylcyclohexyl ester.

 a) Dioxolane of diethyl-L-Tartrate and 3,3,5-trimethylcyclohexanone or diethyl ester of (2R, 3R, 8RS) -6,6,8-trimethyl-1,4-dioxaspiro [4] , 4] decane -2,3-dicarboxylic acid.

 In a Pyrex flask equipped with stirring and a Dean Stark separator, the following mixture is refluxed: (+) - 3,3,5-trimethylcyclohexanone 896 g, (6.4 moles) , - (+) diethyl-L-tartrate 329 g, (1.6 moles), - para-toluenesulphonic acid 12 g, - toluene 2.5 1.

 The dehydration water gradually separates and the reflux is stopped when the theoretical volume of water is collected, ie after about 15 hours. The solvent is washed with water, then with sodium bicarbonate solution and again with water.

 After drying and evaporation of the solvent, the mixture is subjected to distillation under reduced pressure (approximately 15 mbar) and approximately 500 to 550 g of -3,3,5-trimethylcyclohexanone are collected at approximately 80.degree. The vacuum is then increased to about 10-3 mBar and the mixture of pure diastereoisomers is collected at 115 ° C., with a yield of 85 to 90%.

The relative composition of diastereoisomers is determined in GPC with a semi-capillary column
DB5 or DBFFAP of 15 or 30 m, FID detection, isothermal 180'C, It is substantially the following - 30 9s of dioxolane of configuration (5R) on the cycle
trimethylcyclohexyl, (retention time 7mn), - 70% dioxolane of (5S) configuration on the ring
trimethylcyclohexyl, (retention time 8mn).

 (b) Dioxolane of (-) diethyl-L-tartrate and -3,3,5-trimethylcyclohexanone, of (5S) configuration, or diethyl ester of (2R, 3R, 8S) -6,6,8 trimethyl-1,4-dioxaspiro [4,4] decane-2,3-dicarboxylic acid.

 A 1-liter distillation apparatus is used, equipped with a MultiknitO-type metal packing column (Prolabo trademark), with a useful height of 900 mm and a diameter of 22 mm, thermostated by circulating fluid in the jacket. equipped with an analyzer at the top of the column and a pumping system capable of maintaining a residual pressure of 10-3 mBar.

The conditions of careful correction are as follows
Pressure: 1 to 5.10-3 mBar,
Boiler temperature: about 190-C,
Temperature of the column: 173 C,
Boiling point: 118 C,
Tapping rate: about 20 g / hour.

 Each fraction collected is subjected to analysis by GPC under the conditions already described. The last fractions are collected when the residual level of the minority isomer falls to less than 2%. 15% diethyl ester of (2R, 3R, 8S) -6,6,8-trimethyl-1,4-dioxaspiro [4,4] decane-2,3-dicarboxylic acid of isomeric purity> 98 is thus collected. %.

The different distillation cuts are collected in the successive distillations and thus allow, step by step, to isolate a new fraction of diethyl ester of (2R, 3R, 8S) -6,6,8-trimethyl-1 acid Pure 4-dioxaspiro [4,4] decane-2,3-dicarboxylic acid from an initial mixture of approximate composition 30 / 70.The diethyl ester of the acid (2R, 3R, 8S) - 6,6 8-trimethyl-1,4-dioxaspiro [4,4] decane-2,3-dicarboxylic acid, dissolved in 2% ethanol, has a [a] D = -20.7
Successive rectifications of the head fractions make it possible to obtain a few "%" of the first isomer in the pure state, namely diethyl ester of (2R, 3R, 8R) -6,6,8-trimethyl-1 acid, 4-dioxaspiro [4,4] decane-2,3-dicarboxylic acid.

 His [a] D = -29.6 (C = 2, ethanol).

 c) -3,3,5 (S) -trimethylcyclohexanone.

The dioxolane described in the previous paragraph is treated with 2.5 N hydrochloric acid to boiling, at a rate of 1.3 1 of acid solution for one molecule of dioxolane. 3,3,5 (S) -trimethylcyclohexanone is entrained with water vapor with a yield greater than or equal to 90%. Measured at various wavelengths, the rotatory power, in 1% solution in chloroform, has the following values:

<tb> LENGTH <SEP> OF WAVE <SEP> (nm) <SEP> | <SEP> 365 <SEP> | <SEP> 436 <SEP> 546 <SEP> 578 <SEP> 589
<tb> (+) - 3,3,5 (S) <SEP>
<tb> trimethylcyclohexanone <SEP> +67.3 '<SEP> +43.8 <SEP> +25.1 <SEP> +21.9 <SEP> +21.1
<Tb>
d) -3,3,5 (5S) -trimethylcyclohexanol cis / trans.

 0.33 mole of lithium aluminum hydride is added to 500 ml of ether and a solution of 69 g (0.49 mole) of -3,3,5 (S) -trimethylcyclohexanone is slowly poured into the mixture. ether, maintaining the reaction temperature close to 25 C. At the end of the casting, stirring is allowed for a few hours, and then it is conventionally treated with dilute sulfuric acid. The organic layer, after washing with water and drying, is evaporated to dryness. More than 95% of -3,3,5- (5S) -trimethylcyclohexanol is obtained.

The GPC ana-lysis on DBWAX FID isothermal detection column 120 * C gives the following relative composition
Trans -3,3,5-trimethylcyclohexanol, about 50%,
* -3,3,5-trimethylcyclohexanol cis, about 50%,
There is therefore a substantially equimolecular mixture of
* (1S, 5S) -3,3,5-trimethylcyclohexanol,
* (1R, 5S) -3,3,5-trimethylcyclohexanol.

 e) (1S, 5S) -3,3,5-trimethylcyclohexanol.

The mixture resulting from the previous test is chromatographed on 2 kg of Kieselgel Merck A 60 (0.0630.2 mm) with chloroform. We get, in order
25 g of trans, ie (1R, 5S) -3,3,5-trimethylcyclohexanol, then 19.2 g of incompletely separated mixture to be reprocessed and finally 18.8 g of (1S, 5S) -3, 3,5-trimethylcyclohexanol.The rotatory power of the latter isomer is measured in 1% solution in chloroform at various wavelengths, the results are shown below

<tb> LENGTH <SEP> OF WAVES <SEP> (nm) <SEP> 365 <SEP> 436 <SE> 546 <SE> 578 <SEP> 589
<tb> Rotational <SEP> Potency <SEP>(')<SEP> +25.6 <SEP> +16.5 <SEP> + <SEP> 9.8 <SEP> + <SEP> 8.5 <SEP > + <SEP> 8.2
<Tb>
f) 5-oxo-L-proline, (1S, 5S) -3,3,5-trimethylcyclohexyl ester, by direct esterification.

In a glass apparatus, equipped with a condenser, 15.8 g of (1S, 5S) -3,3,5-trimethylcyclohexanol (0.11 mol) and 14.2 g of 5-oxo-L- proline (0.11 mol). It is heated to 160 ° C. for 16 hours and the distilled water is collected. After cooling, it is taken up in 200 ml of chloroform and the unreacted acid is filtered off. The product is purified from unreacted alcohol by chromatography on Kieselgel A 60 with chloroform. 60% of 5-oxo-Lproline (1S, 5S) -3,3,5-trimethylcyclohexyl ester with a stereochemical purity greater than 98%, determined by
GPC on chiral phase.

 The measurements of the rotation power are collated in EXAMPLE IX, hereinafter.

EXAMPLE II 5-Oxo-L-Droline, (1R, 5S) -3,3,5-trimethylcycloexyl ester.

 From the (5S) trans or (1R, 5S) -3,3,5-trimethylcyclohexanol obtained in EXAMPLE I, e), the first column chromatography collection is carried out.

The rotatory power of this (1R, 5S) -3,3,5-trimethylcyclohexanol in a 1% solution in chloroform can be measured. The read values are as follows

<tb> LENGTH <SEP> OF WAVES <SEP> (nm) <SEP> 365 <SEP> 436 <SE> 546 <SE> 578 <SEP> 589
<tb> (1R, 5S) -3,3,5- <SEP>
<tb> trimethylcyclohexanol <SEP> +49.8 <SEP> +31.5 <SEP> +18.7 <SEP> +16.4 <SEP> +15.6
<Tb>
This optically pure alcohol is reacted with 5-oxo-L-proline under the conditions of
EXAMPLE I, f)

 After purification under the same conditions, the 5-oxo-L-proline derivative (1R, 5S) -3,3,5-trimethylcyclohexyl ester is obtained in the form of a thick oil and whose rotational power values are gathered in EXAMPLE IX.

EXAMPLE III 5-Oxo-D-proline, (1S, 5S) -3,3,5-trimethylcyclohexyl ester.

We operate under the conditions of the EXAMPLE
I, f), replacing 5-oxo-L-proline by the equivalent amounts of 5-oxo-D-proline. The desired derivative is obtained in the form of an oil; its polarimetric performances are gathered in EXAMPLE IX.

 EXAMPLE IV 5-oxo-D-oroline, (1R, 5S) -3,3,5-trimethylcyclohexyl ester.

The procedure is carried out under the conditions of EXAMPLE II, substituting (1R, 5S) -3,3,5-trimethylcyclohexanol for (1S, 5S) -3,3,5-trimethylcyclohexanol. The desired ester is then obtained in the form of a thick oil; its polarimetric performances are gathered in the EXAMPLE
IX.

EXAMPLE V 5-oxo-L-rolinol. (IR 5R) -3.3. 5-trimethylcyclohexyl ester.

 a) Dioxolane of (-) diethyl-D-tartrate and -3,3,5-trimethylcyclohexanone or diethyl ester of (2S, 3S, 8RS) -6,6,8-trimethyl-1,4- dioxaspiro [4,4] decane-2,3-dicarboxylic acid.

In a 4 liter Pyrex flask equipped as described in EXAMPLE I, a), the following mixture is refluxed.
* -3,3,5-trimethylcyclohexanone, 1386 g,
(9.9 moles),
* (-) diethyl-D-tartrate, 510 g, (2.5 moles),
* para-toluenesulfonic acid 18 g,
* toluene 2.5 1.

The rest of the operation is carried out in a manner identical to that described in EXAMPLE I, a). 950 g of unreacted ketone and 680 g of dioxolanes, a mixture of the two diastereoisomers, ie a yield of 83%, are recovered under 15 mbar. The relative composition of the two diastereoisomers, determined by GPC under the conditions described in EXAMPLE I, a), is substantially the following: - 30% diethyl ester of (2S, 3S, 8S) -6.6 acid, 8
1,4-trimethyl dioxaspiro [4.4] decane -2,3-dicarboxy
70% diethyl ester of (2S, 3S, 8R) -6.6,8 acid
1,4-trimethyl dioxaspiro [4,4] decane -2,3-dicarboxy
lic.

The rotary power of such a mixture measured in 1% solution in ethanol is [a] D = + 20.7
b) Dioxolane of (+) diethyl-D-tartrate and -3,3,5-trimethylcyclohexanone of 5R configuration or diethyl ester of (2S, 3S, 8R) -6,6,8-trimethyl-1-acid , 4 dioxaspiro [4,4] decane -2,3-dicarboxylic acid.

 The mixture synthesized above is ground in the equipment and under the conditions described in EXAMPLE I, b). After the gradual elimination of the minor isomer, approximately 15% of the majority isomer is the diethyl ester of (2S, 3S, 8R) -6,6,8-trimethyl-1,4 dioxaspiro [4 4] -2,3-dicarboxylic decane, 99% pure, (determination by GPC). This isomer has a [a] D = + 20.3 measured in 2% methanol. The distillation heads, after several successive distillations, make it possible to obtain some of the non-isomers in the pure state, either (2S, 3S, 8S) -6,6,8-trimethyl-1,4-dioxaspiro [4,4] decane 2,3-dicarboxylic acid diethyl ester.If [a] D, measured at 2% in ethanol is +30.3 '.

 c) -3,3,5 (R) -trimethylcyclohexanone.

The diethyl ester isomer of pure (2S, 3S, 8R) 6,6,8-trimethyl-1,4-dioxaspiro [4,4] decane-2,3-dicarboxylic acid, resulting from the preceding distillation is treated with boiling with 2.5N hydrochloric acid under the conditions of EXAMPLE I, c). The -3,3,5 (5R) -trimethylcyclohexanone is perfectly isolated by steam stripping with a practically quantitative yield. Measurements of the rotational powers of a 1% solution in chloroform are summarized in the following Table

<tb> LENGTH <SEP> OF WAVES <SEP> (nm) <SEP> 365 <SEP> 436 <SE> 546 <SE> 578 <SEP> 589
<tb> -3,3,5- (5R)
<tb> trimethylcyclohexanone <SEP> -65.9 <SEP> -42.9 <SEP> -24, <SEP> -21.4 <SEP> -20.5
<Tb>
d) -3,3,5- (5R) trimethylcyclohexanol cis / trans.

 From the previous ketone, the procedure is as in EXAMPLE I, d). A mixture of the two alcohols of cis and trans form is thus obtained. The precise percent composition is given by the GPC: 58% trans isomer and 42% cis isomers.

 e) (1R, 5R) -3,3,5-trimethylcyclohexanol.

 The mixture of the two cis and trans alcohols resulting from the preceding test is chromatographed on a column under the conditions of EXAMPLE I (c).

From the charged mixture, 60% trans or (1S, 5R) -3,3,5-trimethylcyclohexanol alcohol and 40% cis or (1R, 5R) -3,3,5-trimethylcyclohexanol alcohol are obtained. will be used for the rest of the synthesis. The rotatory power of the latter isomer is measured in 1% solution in chloroform, at various wavelengths, the results are illustrated below.

<tb> LENGTH <SEP> OF WAVES <SEP> (nm) <SEP> 365 <SEP> 436 <SE> 546 <SE> 578 <SEP> 589
<tb> 1R, 5R-3,3,5- <SEP>
<tb> trimethylcyclohexanol <SEP> -27.7 '<SEP> -17.8 <SEP> -10.4 <SEP> -9.2 <SEP> -8.8
<Tb>
f) 5-oxo-L-proline, (1R, 5R) -3,3,5-trimethylcyclohexyl ester.

 The operation is carried out according to EXAMPLE I (f), using identical amounts of (1R, 5R) -3,3,5-trimethylcyclohexanol in place of (1S, 5S) -3,3,5-trimethylcyclohexanol. and 5-oxo-L-proline. About 60% of 5-oxo-L-proline (1R, 5R) -3,3,5-trimethylcyclohexyl ester is obtained with a purity greater than 99%, determined by GPC on chiral phase.

Measurements of the rotational power at different wavelengths are collated in the table of
EXAMPLE IX

 EXAMPLE VI 5-Oxo-1, -Droline, (1S, 5R) -3,3-trimethylhexylhexyl ester.

The procedure is as above, but using trans alcohol of 5R configuration, isolated in the EXAMPLE
V, c), in the pure state.

The rotational powers of this isomer are also verified in 1% solution in chlorine form

<tb> LENGTH <SEP> OF WAVES <SEP> (nm) <SEP> 365 <SEP> 436 <SE> 546 <SE> 578 <SEP> 589
<tb> 1S, 5R-3,3,5- <SEP>
<tb> trimethylcyclohexanol <SEP> -49.7 '<SEP> -31.4 <SEP> -18.5 <SEP> -16.3 <SEP> -15.5
<Tb>
This pure enantiomer is reacted with 5-oxo-L-proline after treatment and purification under the conditions of EXAMPLE I, f). The title derivative is obtained in the form of a thick oil whose rotatory power is measured at various wavelengths (cf.
EXAMPLE IX)

EXAMPLE VII 5-oxo-D-nroline (1R, 5R) -3,3,5-trimethylcyclohexyl ester.

The procedure is carried out under the conditions of EXAMPLE I, f), using stoichiometric amounts of 5-oxo
D-proline and (1R, 5R) -3,3,5-trimethylcyclohexanol, as prepared in EXAMPLE V, e). The title derivative whose rotational power measurements are collected is obtained. EXAMPLE IX

EXAMPLE VIII 5-oxo-D-oroline, (1S, 5R) -3,3,5-trimethylcyclohexyl ester.

 For the esterification, 5-oxo-Dproline and (1S, 5R) -3,3,5-trimethylcyclohexanol prepared in EXAMPLE V (e) are used. The title derivative is obtained in the form of a thick oil, the measurements of its rotatory power are collected, EXAMPLE IX.

EXAMPLE IX
The various isomeric esters exhibit large variations in rotatory power depending on the chosen solvent and on the basis of the dilution. The following measurements were carried out in chloroform (containing 0.75% ethanol) at a concentration of 1.5 g of 9 ml ester of solvent with a Perkin-Elmer polarimeter.

<Tb>

LENGTH <SEP> OF WAVES
<tb><SEP> (nm) <SEP> 365 <SEP> 436 <SE> 546 <SE> 578 <SEP> 589
<tb> Product <SEP> of
<tb> EXAMPLE <SEP> I <SEP> +59.6 '<SEP>+28.2'<SEP> +13.4 '<SEP>+11.2'<SEP> +10.6 '
<tb> Product <SEP> of
<tb> EXAMPLE <SEP> II <SEP> -57.0 <SEP> -27.0 <SEP> -12.6 <SEP> - <SEP> 9.8 '<SEP> - <SEP> 9 , 6 '<SEP>
<tb> Product <SEP> of
<tb> EXAMPLE <SEP> III <SEP> + <SEP> 4.1 '<SEP> - <SEP> 7.5 <SEP> - <SEP> 8.5 <SEP> - <SEP> 8, 0 '<SEP> - <SEP>8,0'
<tb> Product <SEP> of
<tb> EXAMPLE <SEP> IV <SEP> - <SEP> 3,7 <SEP> + <SEP> 8,3 '<SEP> + <SEP>8,9'<SEP> + <SEP> 8 , 5 '<SEP> + <SEP>8.3'
<tb> Product <SEP> of
<tb> EXAMPLE <SEP> V <SEP> - <SEP> 1.6 <SEP> - <SEP> 9.4 <SEP> - <SEP> 8.9 <SEP> - <SEP> 8.4 '<SEP> - <SEP> 8.2 <SEP>
<tb> Product <SEP> of
<tb> EXAMPLE <SEP> VI <SEP> + <SEP> 0.9 <SEP> + <SEP> 9.0 '<SEP> + <SEP>8.5'<SEP> + <SEP> 7 , 7 <SEP> + <SEP> 7.7 <SEP>
<tb> Product <SEP> of
<tb> EXAMPLE <SEP> VII <SEP> + <SEP> 4.4 <SEP> - <SEP> 5.2 <SEP> - <SEP> 6.3 <SEP> - <SEP> 6.0 '<SEP> - <SEP> 5.9 <SEP>
<tb> Product <SEP> of
<tb> EXAMPLE <SEP> VIII <SEP> - <SEP> 4.8 '<SEP> + <SEP> 5.4 <SEP> + <SEP>6.5'<SEP> + <SEP> 6 , 1 '<SEP> + <SEP>6,1'
<tb> EXEMPLEX 5-oxo-proline. (1S, 5S) -3,3,5-trimethylcyclohexyl ester.

 The following esterification is carried out with dicyclohexylcarbodiimide to verify the absence of racemization of the new process.

 The procedure is carried out under the conditions of French Pat. No. 8612915, by mixing 50 mmol of 5-oxo-L-proline and 50-mmol of (1S, 5S) -3,3,5-trimethylcyclohexanol in 50 ml of dimethylformamide containing 0.2 ml of dimethylaminopyridine then slowly poured 50 millimoles of dicyclohexylcarbodiimide dissolved in 15 ml of dimethylformamide. Stirred for 24 hours, evaporated, taken up with dilute hydrochloric acid to remove the tertiary amine, extracted with chloroform several times to get rid of dicyclohexylurea. After purification, chromatography on silica A60 with chloroform, the title derivative is isolated in a yield of 42%.

 The rotatory power of this product is measured and verified to be in all respects identical to that obtained in EXAMPLE I (f).

 EXAMPLE XI 5-oxo-L-nroline (cis) (-) - 3,3 '- 5-trimethylpylhexyl ester.

* method A
Exactly the same weight of (1S, 5S) -3,3,5-trimethylcyclohexanol, as prepared in EXAMPLE
I, c), and (1R, 5R) -3,3,5-trimethylcyclohexanol, as prepared in EXAMPLE V, e), and they are intimately mixed by fusion, and then reacted with the stoichiometric amount. calculated from 5-oxo-L-proline under the conditions described in EXAMPLE I, f). The title derivative, 5-oxo-L-proline, (cis) (+) - 3,3,5-trimethylcyclohexyl ester, is obtained, ie the mixture of the two diastereoisomers in equal proportions
5-oxo-L-proline, (1S, 5S) -3,3,5-trimethylcyclohexyl ester,
5-oxo-L-proline, (1R, 5R) -3,3,5-trimethylcyclohexyl ester.

This product has the same properties as the derivative synthesized from 5-oxo-L-proline and pure commercial cis (+) -3,3,5-trimethylcyclohexanol, described below.
* method B
928 g (7.19 mol) of 5-oxo-L-proline and 1021 g (7.19 mol) of pure commercial 3,3,5-trimethylcyclohexanol CIS (+) are used for the esterification. racemic mixture of the two forms (1S, 5S) and (1R, 5R).

The mixture is heated for 16 hours in a glass flask of distillation tubing. After cooling, 2.5 liters of ethyl acetate are added and the mixture is left standing for 24 hours to filter out the unreacted excess of the pyroglutamic acid (about 0.7 mole) which can be reused.

The solvent is then evaporated off, followed by unreacted trimethylcyclohexanol under reduced pressure; finally the pure product is obtained by distillation to 150/160 ° C under a pressure of 10-2 / 10-3 mbar, in the form of a thick oil, the yield is 64% and does not take into account recyclable recoveries.

 The rotational powers of products made according to method A or method B are identical. The equimolar mixture of the two diastereoisomers 5-oxo-L-proline, (1S, 5S) -3,3,5-trimethylcyclohexyl ester and 5-oxo-L-proline, (1R, 5R) was obtained in A or B. ) -3,3,5-trimethylcyclohexyl ester representing 5-oxo-L-proline, (cis) (+) - 3,3,5-trimethylcyclohexyl ester. Rotatory powers were measured in chloroform solution at 25 ° C at various concentrations; the results are summarized below.

At a concentration of 1.5%, the values are as follows

<tb> LENGTH <SEP> WAVE <SEP> (nm) <SEP> 365 <SEP> | <SEP> 436 <SEP> 546 <SEP> | <SEP> 578 <SEP> | <SEP> 589
<tb> 5-oxo-L-proline
<tb> cis <SEP> (+) <SEP> -3.3.5 <SEP> - <SEP> +36.1 '<SEP> +11.7 <SEP> + <SEP> 2.3 <SEP > + <SEP> 1,3 <SEP> + <SEP> 1,1
<tb> trimethylcyclohexanol
<Tb>
At a concentration of 2.5%, the values are as follows

<tb> LENGTH <SEP> OF WAVES <SEP> (nm) <SEP> 365 <SEP> 436 <SE> 546 <SE> 578 <SEP> 589
<tb> 5-oxo-L-proline,
<tb> cis <SEP> (+) <SEP> -3.3.5 <SEP> - <SEP> +31.2 '<SEP> + <SEP> 9.3 <SEP> + <SEP> 1, 3 <SEP> + <SEP> 0.5 <SEP> + <SEP> 0.3
<tb> trimethyl <SEP> cyclohexanol <SEP>
<Tb>
At a concentration of 5 96, the values are as follows

<tb> LENGTH <SEP> OF WAVES <SEP> (nm) <SEP> 365 <SEP> 436 <SE> 546 <SE> 578 <SEP> 589
<tb> 5-oxo-L-proline <SEP>
<tb> cis <SEP> (+) <SEP> -3.3.5 <SEP> - <SEP> +25.2 '<SEP> + <SEP> 6.1 <SEP> - <SEP> 0, 4 <SEP> - <SEP> 0.7 <SEP> - <SEP> 0.7
<tb> trimethylcyclohexanol
<Tb>
At a concentration of 10%, the values are as follows:

<tb> LENGTH <SEP> OF WAVES <SEP> (nm) <SEP> 365 <SEP> 436 <SE> 546 <SE> 578 <SEP> 589
<tb> 5-oxo-L-proline,
<tb> cis <SEP> (f) <SEP> -3.3.5 <SEP> - <SEP> +17.3 '<SEP> + <SEP> 1.3 <SEP> - <SEP> 3, 0 <SEP> - <SEP> 3,4 <SEP> - <SEP> 3,5
<tb> trimethylcyclohexanol
<Tb>
As is apparent from the above, the invention is not limited to those of its modes of implementation, implementation and application which have just been described more explicitly; it encompasses all the variants that may come to the mind of the technician in the field, without departing from the scope or scope of the present invention.

Claims (23)

(2) an appropriate isomeric form of an amino acid is reacted with the pre-selected 3,3,5-trimethylcyclohexanol alcohol obtained in (1) in a weight ratio close to stoichiometry and at a temperature sufficient to remove the formed water, while not causing racemization of the obtained ester.  (1) an alcohol -3,3,5-trimethylcyclohexanol of preselected configuration at its asymmetric carbons (C1 and C5) is prepared by reduction from a pure isomeric trimethylcyclohexanone, and  in which R represents the residue of a suitable amino acid, Y represents a hydrogen atom, an acetyl, propionyl or benzoyl radical, or represents with R a pyrrolidinone 2 ring determining in the general formula a pyroglutamic ester, which process is characterized in that

 1 ') Process for preparing a pure isomer of formula I  b. hydrolysis of the pure dioxolane of tartaric acid obtained in a. under conditions that favor one of the carbon configurations of the cyclohexyl ring.  at. by reacting an excess of racemic trimethylcyclohexanone with a dialkyl tartrate of appropriate form, in a suitable solvent, that is to say allowing azeotropic removal of water under conditions which favor the production of a dioxolane of selected configuration (5S or 5R conformations), and  2 ') Process according to claim 1, characterized in that the pure isomer -3,3,5-trimethylcyclohexanone used during step (1) is obtained beforehand  3 ') Process according to claim 2, characterized in that said dioxolane is obtained by reacting an excess of racemic trimethylcyclohexanone on a dialkyl-L-tartrate, in a suitable solvent, allowing azeotropic removal of water to promote the conformation S on dioxolane. D-tartrate in a suitable solvent, i.e., allowing azeotropic removal of water to promote R-conformation on dioxolane.  4 ') Process according to claim 2, characterized in that said dioxolane is obtained by making an excess of racemic trimethylcyclohexanone on a dialkyl  5 ') Process according to any one of claims 2 to 4, characterized in that the excess of racemic trimethylcyclohexanone is from 1.1 to 10, preferably from 2 to 5.  6 ') Process according to any one of claims 2 to 5, characterized in that one purifies diastereoisomeric dioxolanes obtained, by continuous rectification under high vacuum.  7 ') Process according to any one of claims 1 to 6, characterized in that the reaction of step (2) between the appropriate isomeric form of the amino acid and alcohol -3,3,5-trimethylcyclohexanol preselected configuration is carried out between 120 and 175 'C, preferably between 145 and 165' C.  8 ') Process according to any one of claims 2 to 7, characterized in that the hydrolysis is carried out in a dilute acid medium, followed by a steam distillation.  9 ') Process according to any one of claims 1 to 8, characterized in that the duration of heating is between 6 and 24 hours, more particularly between 12 and 18 hours.  10 ') Process according to any one of claims 1 to 9, characterized in that the amino acid is a derivative of pyroglutamic acid.  11. The process as claimed in claim 10, characterized in that the chosen form of the pyroglutamic acid derivative is preferably 5-oxo-proline.  b. hydrolysis of the pure dioxolane of tartaric acid obtained in a. under conditions that favor one of the carbon configurations of the cyclohexyl ring.  at. by reaction of an excess of racemic trimethylcyclohexanone with a dialkyl tartrate of appropriate form, in a suitable solvent, that is to say allowing azeotropic removal of water to favor obtaining a dioxolane of selected configuration ( conformations 5S or 5R), and  12 ') Process for the preparation of pure isomers of -3,3,5-trimethylcyclohexanone, characterized in that each isomer is obtained  13 ') Process according to claim 12, characterized in that said dioxolane is obtained by reacting an excess of racemic trimethylcyclohexanone on a dialkyl-L-tartrate, in a suitable solvent, allowing azeotropic removal of water to promote the conformation S on dioxolane.  14 ') Process according to claim 12, characterized in that said dioxolane is obtained by reacting an excess of racemic trimethylcyclohexanone on a dialkyl-D-tartrate in a suitable solvent, that is to say allowing azeotropic removal of water for promote the 5 R conformation on dioxolane.  15 ') Process according to any one of claims 12 to 14, characterized in that the excess of racemic trimethylcyclohexanone is from 1.1 to 10, preferably from 2 to 5.  16 ') Process according to any one of claims 12 to 15, characterized in that said dioxolanes are purified by continuous rectification under high vacuum.  17 ') Process according to any one of claims 12 to 16, characterized in that the hydrolysis of step b. is carried out in a dilute acid medium, followed by steam distillation.  18 ') Pure isomeric form of trimethylcyclohexanone, characterized in that it is obtained by the process according to any one of claims 12 to 17.  19 ') Application of the pure isomeric form of trimethylcyclohexanone according to claim 18 to the preparation of an amino acid ester of -3,3,5-trimethylcyclohexanol.  20 ') -3,3,5-trimethylcyclohexanol (1S, 5R) trans (-), intermediate product for carrying out the method according to any one of claims 1 to 11.  21 ') -3,3,5-trimethylcyclohexanol (1R, 5S) trans (+), an intermediate product for carrying out the process according to any one of claims 1 to 11.  22 ') Pure isomer of formula I, characterized by the process of any one of claims 1 to 11.  23 ') Use of at least one pure isomer according to claim 22 for obtaining a medicament for combating disorders of lipidemia in humans or animals.