EP0594645A1 - Verfahren zur herstellung von aminosaüreestern des 3,3,5-trimethylcyclohexanols und des 3,3,5-cyclohexanons in isomerenreiner form - Google Patents

Verfahren zur herstellung von aminosaüreestern des 3,3,5-trimethylcyclohexanols und des 3,3,5-cyclohexanons in isomerenreiner form

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Publication number
EP0594645A1
EP0594645A1 EP92912768A EP92912768A EP0594645A1 EP 0594645 A1 EP0594645 A1 EP 0594645A1 EP 92912768 A EP92912768 A EP 92912768A EP 92912768 A EP92912768 A EP 92912768A EP 0594645 A1 EP0594645 A1 EP 0594645A1
Authority
EP
European Patent Office
Prior art keywords
trimethyl
dioxolane
trimethylcyclohexanone
pure
cyclohexanol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP92912768A
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English (en)
French (fr)
Inventor
Claude Laruelle
Marcel Lepant
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Panmedica SA
Original Assignee
Panmedica SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Panmedica SA filed Critical Panmedica SA
Publication of EP0594645A1 publication Critical patent/EP0594645A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/32—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic
    • C07C35/08—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic containing a six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
    • C07C45/59—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/385—Saturated compounds containing a keto group being part of a ring
    • C07C49/403—Saturated compounds containing a keto group being part of a ring of a six-membered ring

Definitions

  • the present invention relates to a process for the preparation of the pure isomeric forms of 3,3,5 trimethyl cyclohexanol amino acid esters, sometimes called -3,3,5-trimethylcyclohexanol and in particular of the 3-trimethyl ester, 3,5 cyclohexylic acid pyroglutamic as well as the process for the preparation of the various pure isomeric forms of trimethyl-3,3,5 cyclohexanone, sometimes called -3,3,5-trimethylcyclohexanone, intermediate product for the preparation of said esters .
  • the 3,3,5 trimethyl cyclohexylic ester of pyroglutamic acid for example, is one of the products described in 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 trimethyl cyclohexanol. More particularly, in Examples II, III, IV, the amino acid chosen is pyroglutamic acid.
  • 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 object of the present invention is therefore to provide a new method for obtaining the amino acid esters of 3,3,5 trimethyl cyclohexanol, capable of being applied to the preparation of any one of the eight isomers.
  • trimethyl3,3,5 cyclohexyl ester of the amino acid chosen, and in particular pyroglutamic acid which better meets the needs of the practice than the methods of the prior art, which do not allow analysis or separation conventional, chiral or not, of said stereoisomers.
  • Trimethyl-3,3,5 cyclohexanol is a cycloaliphatic alcohol having two centers of asymmetry, namely, the carbons in position 1 and 5. These carbons can have the absolute configurations R or S (see rule RSCAHN, CK INGOLD, V. PRELOG, Angew. Chem. 1966, 78, 413) and the isomers of trimethyl-3,3,5 cyclohexanol can have the following absolute configurations:
  • the 50/50 mixture of the first two forms constitutes the TRANS ( ⁇ ) form of 3,3,5-trimethyl cyclohexanol.
  • the 50/50 mixture of the last two forms constitutes the CIS ( ⁇ ) form of 3,3,5-trimethyl cyclo hexanol.
  • TRANS and CIS are available in their racemic form ( ⁇ ).
  • the first way of obtaining the two isomers (+) and (-) of CIS trimethyl-3,3,5 cyclohexanol by selective crystallization of cinchonine salts has the disadvantage of being very laborious, (The Author recommends seven crystallizations successive), and to provide a very poor quality product (enrichment does not exceed 75%, according to ALLINGER, at the trimethylcyclohexanone stage only).
  • the second method by obtaining (R) -trimethyl-3,3,5 cyclohexanone, provides a ketone of good enantiomeric quality, but has the disadvantage of using a very expensive raw material of natural origin, pulegone, and require 14 steps with an overall published yield of 0.3%.
  • the subject of the present invention is a process for the preparation of a pure isomer of formula I:
  • R represents the remainder of a suitable amino acid
  • Y represents a hydrogen atom, an acetyl, propionyl or benzoyl radical, or else represents with R a pyrrolidinone 2 ring determining in the general formula a pyroglutamic ester
  • a trimethyl-3,3,5 cyclohexanol alcohol of preselected configuration is prepared at its asymmetric carbons (Cl and C5), by reduction from a pure isomeric trimethylcyclohexanone, and
  • Such a method has the advantage of being able to be carried out in the absence of solvent and catalyst.
  • the pure isomer 3,3,5-trimethyl cyclohexanone used during step (1) is obtained beforehand:
  • said dioxolane is obtained by reacting an excess of racemic trimethylcyclohexanone on a dialkyl-L-tartrate, in a suitable solvent, allowing an azeotropic elimination of water to promote the 5 S conformation. on dioxolane.
  • 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 an azeotropic elimination of water to promote the 5 R conformation on dioxolane.
  • the excess of racemic trimethylcyclohexanone is 1.1 to 10, preferably between 2 and 5.
  • alkyl includes C 1 to C 5 groups and in particular includes methyl, ethyl, isopropyl groups.
  • a mixture of diastereoisomeric dioxolanes is thus obtained, one of which is in a significantly higher amount.
  • SANZ BURATA separates the two diastereoisomers by preparative gas chromatography; the latter give by hydrolysis the 3,3,5-trimethyl cyclohexanones (+) and (-).
  • Preparative gas chromatography has the disadvantage of requiring fairly expensive equipment and of having very low productivity.
  • SANZ BURATA injects and separates 100 mg per half hour, either a production of a pure diastereoisomeric dioxolane of 100 mg per hour or even 40 mg of pure ketone per hour).
  • the Applicant has surprisingly found that the general conditions for the synthesis of dioxolane can be modified so as to favor the synthesis of one diastereoisomer over 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 trimethyl-3,3,5 cyclohexanone making it possible to obtain from 75 to 80% d 'one diastereoisomeric dioxolane and only 20 to 25% of the other (reaction stereoselectivity).
  • the process according to the invention therefore makes it possible, unexpectedly, to enrich, in a simple and inexpensive manner, one and / or the other of the two varieties (+) or (-) of trimethyl-3, 3,5 cyclohexanone in the form of a simple derivative.
  • the diastereoisomeric dioxolanes obtained are purified by continuous rectification under high vacuum.
  • step (2) the reaction of step (2) between the appropriate isomeric form of the amino acid and the 3,3,5-trimethyl alcohol cyclohexanol of preselected configuration tioned is carried out between 120 and 175 oC, preferably between 145 and 165 oC.
  • the duration of the heating is between 6 and 24 hours, more particularly between 12 and 18 hours.
  • the hydrolysis is carried out in a dilute acid medium, then entrainment with steam.
  • either one of the TRANS or CIS forms of 3,3,5 trimethyl cyclohexanol is esterified by the chosen form of the amino acid;
  • each trimethylcyclohexanone of configuration 5 S or 5 R is not specifically reduced to a mixture of each corresponding alcohol CIS or TRANS.
  • amino acids By amino acids, one understands the alpha amino acids constituting proteins, these thus comprise a chiral site in ⁇ determining isomers -L- and -D-.
  • amino acids include: glycine, alanine, valine, leucine, proline, threonine, serine, phenyl-alanine, cysteine, cystine, tyrosine, aspartic acid , asparagine, glutamic acid, glutamine, acid pyroglutamic, tryptophan, 5-hydroxy tryptophan, arginine, lysine, ornithine, hydroxy-prolines, delta hydroxy-lysine, ⁇ amino adipic acid, N- ⁇ -methyl arginines, ⁇ hydroxy phenyl alanine, ⁇ hydroxy tyrosine, ⁇ hydroxy glutamic acid.
  • the amino acid is a derivative of pyroglutamic acid.
  • the chosen form of the pyroglutamic acid derivative is preferably 5-oxo-proline.
  • the present method also comprises an original technique for obtaining a preselected configuration at the level of each asymmetric carbon. Thanks to the stereospecificity of the synthesis of each dioxolane purified by distillation, to the easy and quantitative hydrolysis into a ketone of unique configuration followed by the reduction and separation of Cis-Trans isomers, the process described makes it possible to obtain any one of the eight pure isomers, any one of a racemic mixture of two of them or any one of a mixture of two diastereoisomers chosen from them, by simple, economical esterification which does not lead to racemization. The quality of the optical enrichments is remarkable, as can be seen from the measurements of the rotary powers of each of the isomers synthesized.
  • the various isomers obtained, in accordance with the method described above, are particularly useful in the correction of lipidemia in humans or animals, by acting in particular on the HMG CoA reductase activity, the main factor in the synthesis of cholesterol and can be administered alone or as a mixture, such as or in the form of pharmaceutically acceptable salts, in the various forms of administration known for medicaments.
  • 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, polyalkyleneglycols, natural oils, starch or gelatin.
  • adjuvants or solvents used in the pharmaceutical industry such as water, polyalkyleneglycols, natural oils, starch or gelatin.
  • the pharmaceutically solid forms can be, for example, tablets, capsules, capsules or suppositories.
  • the 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 the pure isomers of trimethyl-3,3,5 cyclohexanone, characterized in that each isomer is obtained:
  • said dioxolane is obtained by reacting an excess of racemic trimethylcyclohexanone on a dialkyl-L-tartrate, in a suitable solvent, allowing azeotropic elimination of water to promote the 5 S conformation on dioxolane.
  • 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 an azeotropic elimination of water to promote the 5 R conformation on dioxolane.
  • the excess of racemic trimethylcyclohexanone is from 1.1 to 10, preferably between 2 and 5.
  • alkyl includes C 1 to C 5 groups and in particular methyl, ethyl and isopropyl groups.
  • a mixture of diastereoisomeric dioxolanes is thus obtained, one of which is in a significantly higher amount.
  • the said dioxolanes are purified by continuous rectification under high vacuum.
  • step b. the hydrolysis of step b. is carried out in a dilute acid medium, followed by training with steam.
  • 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.
  • the preparation process according to the invention consists, for the preparation of a dioxolane, in reacting diethyl -L-tartrate with ( ⁇ ) trimethyl-3,3,5 cyclohexanone in solution in the toluene in the presence of an acid catalyst, for example paratoluene sulfonic acid, at the boiling temperature, in an apparatus equipped with a Dean-Stark for azeotropic separation of water.
  • an acid catalyst for example paratoluene sulfonic acid
  • the enrichment in an isomer is continued by fractional distillation under vacuum.
  • One operates, for example, in a 1 liter distilling apparatus with a column furnished with metallic knitting of the Multiknit® type (registered trademark) with a height of 900 mm and fully thermostatically controlled by oil circulation.
  • the pressure is maintained between 5.10 -3 and 1.10 -3 mBar.
  • distillation slow fractionated the most volatile minority isomer is gradually eliminated, partially mixed with the heaviest isomer and we obtain in the last fraction about 20% relative to the loaded weight of the least volatile isomer, with a purity > 98%, (always measured in GPC).
  • the two pure diastereoisomers are combined and hydrolyzed by aqueous hydrochloric acid into each of the two enantiomeric forms 5 S and 5 R of the ketone.
  • each enantiomeric ketone is usually reduced by LiAlH4 in an appropriate solvent such as diethyl ether or tetrahydrofuran.
  • an appropriate solvent such as diethyl ether or tetrahydrofuran.
  • 3,3,5-trimethyl cyclohexanone (5S) will give, by reduction, a substantially 50/50 mixture of (1S, 5S) and (1R, 5S) 3,3,5-trimethyl cyclohexanol.
  • These two CIS / TRANS isomers separate in a conventional manner, for example on a silica column.
  • the duration of the heating partly depends on the mass of the reagents and on the nature of the device used, but is generally between 10 and 24 hours, more particularly between 15 and 20 hours.
  • the elimination of water can possibly be facilitated by the establishment of a reduced pressure in the device or by a slight flow of inert gas.
  • the residual mass is taken up in a solvent making it possible to separate the unreacted pyroglutamic acid, all of the immiscible solvents are suitable, chloroform or ethyl acetate may preferably be used.
  • the solvent is evaporated, the trimethyl-3,3,5 cyclohexanol in excess is distilled under reduced pressure and recovered.
  • the pure ester is obtained by chromatography on a silica column with chloroform for small quantities or by continuous distillation under reduced pressure for larger quantities.
  • the dehydration water gradually separates and the reflux is stopped when the theoretical volume of water is collected, that is to say after approximately 15 hours.
  • the solvent is washed with water, then with a solution of sodium bicarbonate, then again with water.
  • 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 180oC. It is substantially the following:
  • a one-liter distillation apparatus is used, equipped with a column with metal lining of the Multiknit® type (registered trademark Prolabo), of useful height of 900 mm and diameter of 22 mm, thermostatically controlled by circulation of fluid in the double enclosure fitted with an analyzer at the head of the column and a pumping system capable of maintaining a residual pressure of 10 -3 mBar.
  • the Multiknit® type registered trademark Prolabo
  • Boiler temperature around 190oC
  • Withdrawal rate approximately 20 g / hour.
  • the different distillation cuts are brought together in successive distillations and thus allow, step by step, to isolate a new fraction of diethyl ester from the acid (2R, 3R, 8S) -6,6,8-trimethyl1-1 , 4-dioxaspiro [4,4] decane-2,3-dicarboxylic pure from an initial mixture of approximate composition 30/70.
  • (2R, 3R, 8S) -6,6,8-trimethyl-1,4-dioxaspiro [4,4] decane-2,3-di diethyl ester carboxylic, in solution in 2% ethanol, has a [ ⁇ ] D -20.7o.
  • the dioxolane described in the preceding paragraph is treated with 2.5N hydrochloric acid at boiling point, in an amount of 1.3 l of acid solution for one molecule of dioxolane.
  • the 3, 3, 5 (S) -trimethylcyclohexanone is entrained in steam with a yield greater than or equal to 90%.
  • the rotary power, in 1% solution in chloroform has the following values:
  • distillation heads after several successive distillations, make it possible to obtain a few "%" of the minority isomer in the pure state, namely the diethyl ester of the acid (2S, 3S, 8S) -6.6.8 -1,4-trimethyl dioxaspiro [4,4] decane -2,3-dicarboxylic. Its [ ⁇ ] D , measured at 2% in ethanol is equal to + 30.3o. c) trimethyl1,3,3,5 (R) cyclohexanone.
  • the various isomeric esters have large variations in rotational power as a function of the solvent chosen and as a function of the dilution.
  • the following measurements were carried out in chloroform (containing 0.75% ethanol) at the concentration of 1.5 g of ester% ml of solvent with a Perkin-Elmer polarimeter.
  • esterification is carried out with dicyclohexylcarbodiimide, in order to verify the absence of racemization of the new process.
  • This product has the same properties as the derivative synthesized from 5-oxo-L-proline and cis ( ⁇ ) trimethyl-3,3,5 pure commercial cyclohexanol, described below:
  • the rotary powers of the products produced according to method A or method B are identical.
  • the equimolecular 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.
  • the rotatory powers were measured in solution in chloroform, at 25oC, at various concentrations; the results are summarized below.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP92912768A 1991-06-19 1992-06-17 Verfahren zur herstellung von aminosaüreestern des 3,3,5-trimethylcyclohexanols und des 3,3,5-cyclohexanons in isomerenreiner form Withdrawn EP0594645A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9107518A FR2677981A1 (fr) 1991-06-19 1991-06-19 Procede de preparation des formes isomeres pures d'esters d'aminoacides du -3,3,5-trimethylcyclohexanol et de la -3,3,5-trimethylcyclohexanone.
FR9107518 1991-06-19
PCT/FR1992/000546 WO1992022529A1 (fr) 1991-06-19 1992-06-17 Procede de preparation des formes isomeres pures d'esters d'aminoacides du trimethyl-3,3,5 cyclohexanol et de la trimethyl-3,3,5 cyclohexanone

Publications (1)

Publication Number Publication Date
EP0594645A1 true EP0594645A1 (de) 1994-05-04

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Application Number Title Priority Date Filing Date
EP92912768A Withdrawn EP0594645A1 (de) 1991-06-19 1992-06-17 Verfahren zur herstellung von aminosaüreestern des 3,3,5-trimethylcyclohexanols und des 3,3,5-cyclohexanons in isomerenreiner form

Country Status (5)

Country Link
EP (1) EP0594645A1 (de)
KR (1) KR940701385A (de)
CA (1) CA2111309A1 (de)
FR (1) FR2677981A1 (de)
WO (1) WO1992022529A1 (de)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2603888B1 (fr) * 1986-09-16 1990-12-21 Panmedica Sa Esters d'amino acides du trimethyl cyclohexanol, procede de preparation et utilisation comme medicaments

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9222529A1 *

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Publication number Publication date
CA2111309A1 (fr) 1992-12-23
KR940701385A (ko) 1994-05-28
WO1992022529A1 (fr) 1992-12-23
FR2677981A1 (fr) 1992-12-24

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