WO2018114732A1 - Procédé de préparation de (4s)- ou de (4r)-3,4-dihydroxy-2,6,6-triméthylcyclohex-2-énone - Google Patents

Procédé de préparation de (4s)- ou de (4r)-3,4-dihydroxy-2,6,6-triméthylcyclohex-2-énone Download PDF

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WO2018114732A1
WO2018114732A1 PCT/EP2017/083192 EP2017083192W WO2018114732A1 WO 2018114732 A1 WO2018114732 A1 WO 2018114732A1 EP 2017083192 W EP2017083192 W EP 2017083192W WO 2018114732 A1 WO2018114732 A1 WO 2018114732A1
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formula
compound
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chiral
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PCT/EP2017/083192
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Bernd Schaefer
Wolfgang Siegel
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Basf Se
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    • 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
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/713—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups a keto group being part of a six-membered ring

Definitions

  • the present invention relates to a new process for the preparation of one of the enantiomers of 3,4-dihydroxy-2,6,6-trimethylcyclohex-2-enone and to a process for preparing (3S,3'S)-astaxanthin, which comprises the step of providing the
  • 3 and 3' astaxanthin 3,3'-dihydroxy-3,3'- carotene-4,4'-dione
  • 3S,3'S 3R,3'R
  • 3S,3'S 3R,3'S-diastereomers or a mixture of these stereoisomers.
  • (3R,3'S)-diastereomers are identical and constitute a meso form (see: Carotenoids Handbook, 2004 (eds.: G. Britton, S. Liaaen-Jensen, H. Pfander), main list nos. 404, 405 and 406).
  • the resulting three diastereomeric forms of astaxanthin are found in various natural sources.
  • the chemical total synthesis leads to a 1 :2:1 mixture of (3S,3'S)-, meso- and (3R,3'R)-astaxanthin, when starting from a racemic precursor (see e.g. E. Widmer et al., Helvetica Chimica Acta 1981 , 64, 2436).
  • the (3S,3'S)-diastereomer of astaxanthin (also called herein (3S,3'S)-astaxanthin) is of particular significance. It is biosynthesized in enantio- and diastereomerically enriched form by green algae (Haematococcus pluvialis) which are possibly the richest natural source for this diastereomer (see: M. Grung et al., J. Applied Phycology 1992, 4, 165; B. Renstram et al., Phytochemistry 1981 , 20, 2561 ). (3S,3'S)-Astaxanthin from green algae is used as a food supplement with positive effects on human health (see: G.
  • (3S,3'S)-astaxanthin is present in the algae as a mixture of mono- and di-fatty acid esters and free astaxanthin, which causes a considerable level of complexity for the isolation and purification (see e.g. M. Grung et al., J. Applied Phycology 1992, 4, 165; B. Renstram et al., Phytochemistry 1981 , 20, 2561 ).
  • 3S,3'S)-astaxanthin in larger quantities and high purity, chemical synthesis is therefore the technology of choice.
  • the synthetic preparation of astaxanthin is extensively described in the literature, e.g. in the monograph G. Britton, S. Liaanen-Jensen, H.
  • the procedure includes the steps of introducing in position 1 (which is position 6 in apocarotenoid numbering) an ethinyl moiety carrying a substituted butenyl group via a Grignard reaction, elimination of water, partial reduction of the triple bond to a double bond and introduction of the phosphonium moiety or the phenylsulfonyl group.
  • the compound of formula IV is finally coupled via a Wittig reaction or a Julia olefination with the C10-dialdehyde of the formula V, as depicted in step b) below, to afford the all-trans derivative of astaxanthin, which however is a mixture of the three diastereomeric forms.
  • WO 2006/039685 describes, inter alia, the enantioselective preparation of the
  • the catalysts used for this conversion are preferably ruthenium complexes with optically active amines as ligands.
  • this process is disadvantageous because it requires a methoxy protective group in position 3.
  • the prior introduction as well as the subsequent removal of this protective group entail additional synthetic complexity as the 3-OH derivative of the compound of formula B is the desired precursor for preparing (3S,3'S)-astaxanthin.
  • WO 2008/1 16714 discloses the preparation of the S-enantiomer of the compound of formula I by enantioselective reduction of 3-hydroxy-4-oxo-2,6,6-trimethylcyclohex-2- enone with the reductant 2-propanol, using a chiral ruthenium complex as catalyst. This process suffers from incomplete conversion rates and very long reaction times, which renders it unsuitable for industrial syntheses of astaxanthin.
  • the invention firstly relates to a process for the enantioselective preparation of one of the enantiomers of the compound of the formula I,
  • M + is selected from alkali metal cations, the group (M 1 i 2) + and the group (M 1 X) + , where M 1 is an alkaline earth metal atom and X is a singly charged anion, with a salt of formic acid in the presence of a chiral transition metal catalyst.
  • This process of the invention is hereinafter also referred to as "process A”.
  • the invention further relates to processes for the preparation of (3S,3S')-astaxanthin of formula Vl-S and (3R,3R')-astaxanthin of formula Vl-R, respectively, which comprise the step of providing the 4S- or the 4R-enantiomer of the compound of formula I by the aforementioned process A.
  • inventive process A affords an easy and efficient access to the 4S-enantiomer as well as to the 4R-enantiomer of the compound of formula I in high yields and good enantioselectivity.
  • either the 4S-enantiomer or the 4R-enantiomer of formula I is obtained with high enantiomeric excess (ee), which is generally higher than 90% ee.
  • ee enantiomeric excess
  • Each of said enantiomers of the compound of formula I that are obtainable by inventive process A opens the path to a straightforward and entirely stereoselective synthesis of either (3S,3S')-astaxanthin or (3R,3R')-astaxanthin, which synthesis is highly suitable for the production on an industrial scale.
  • the compound of the formula I regardless of whether it is in the form of one of its enantiomers or in the form of the racemic mixture, may also be represented by the following tautomeric compounds of formulae I and l-T in equilibrium, which is usually shifted to the side of the tautomer I:
  • the term "compound of the formula I” encompasses not only the tautomer I but also the tautomer l-T.
  • the compounds of the formula ⁇ which is the alcohol from which the enolate of the formula II is derived, may also be represented by the following tautomeric compounds of formula ⁇ and ⁇ - ⁇ in equilibrium, which is usually shifted to the side of the tautomer ⁇ :
  • the term "compound of the formula ⁇ ⁇ " ecompasses not only the tautomer ⁇ ⁇ but also the tautomer ⁇ ⁇ - ⁇ .
  • the prefix C x -C y denotes the number of possible carbon atoms in the particular case.
  • halogen denotes in each case fluorine, bromine, chlorine or iodine, especially chlorine or bromine.
  • Ci-C4-alkyl denotes a linear or branched alkyl radical comprising from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 1 -methylethyl (isopropyl), butyl, 1 -methyl- propyl (sec-butyl), 2-methylpropyl (isobutyl) or 1 , 1 -dimethylethyl (tert-butyl).
  • the term "enantiomer” relates to the configuration at the asymmetric carbon atom in position 4 of the formula I, which may be an S- or an R-configuration. Accordingly, the compound of the formula I may be in the S-enantiomer of the formula l-S, the R-enantiomer of the formula l-R or a mixture thereof:
  • the expression "high enantiomeric excess" or "high ee” means an enantiomeric excess of at least 90%, preferably at least 95%, more preferably at least 98%, in particular at least 99% and specifically more than 99%.
  • variable M + in the compound of the formula I I is selected from:
  • alkali metal cations such as Li + , Na + , K + , Rb + or Cs + , in particular Li + , Na + or K + ; a group (M 1 i 2) + or a group (M 1 X) + , wherein M 1 is an alkaline earth metal cation such as Be 2+ , Mg 2+ , Ca 2+ , Sr 2+ or Ba 2+ , in particular Mg 2+ or Ca 2+ , and X is a singly charged anion preferably selected from hydrocarbonate, cyanide, hydroxide, nitrate and halogenides, such as in particular iodide, bromide or chloride.
  • variable M + in the compound of the formula II is selected from Li + , Na + , K + , a group (M 1 i 2 ) + or a group (M 1 X) + with M 1 being Mg 2+ or Ca 2+ and X being bromide or chloride.
  • variable M + in the compound of the formula II is Na + or K + .
  • the reaction of process A according to the invention for preparing the compound of the formula I may be regarded a transfer hydrogenation.
  • the conversion is effected by reacting the compound of the formula II with a salt of formic acid in the presence of a chiral transition metal catalyst.
  • the salt of formic acid acts as a hydrogen donor, where a hydride is transferred from the formate anion to the compound of formula (II) and carbon dioxide is formed.
  • the formed carbon dioxide can easily be released in its gaseous state from the reaction vessel either during the reaction or at the end of the reaction, which significantly facilitates the work-up process after completion of the reaction.
  • the reaction of the compound of formula II with the formate can advantageously be driven towards the side of the product of formula I, simply by expelling carbon dioxide from the reaction mixture.
  • the salt of formula II may be added to the reaction mixture, in particular in the form of the sodium salt, i.e.
  • the salt of formula II may is prepared in-situ by reacting a compound of the formula ⁇ ,
  • Suitable bases for this purpose are preferably selected from alkali metal hydroxides, such as LiOH, NaOH or KOH, alkaline earth metal hydroxides, such as Mg(OH)2 or Ca(OH)2, and alkali metal and alkaline earth metal carbonates, such as U2CO3, Na2C03, K2CO3, MgC03 or CaC03, in particular selected from alkali metal hydroxides and alkaline earth metal hydroxides, and specifically selected from NaOH and KOH. It is apparent that in these cases, preferably at least 1 molar equivalent of base is used to transfer the compound of formula ⁇ into the compound of formula II.
  • the process A is carried out in the presence of a base, regardless of whether the salt of the formula II is directly added to the reaction mixture or generated in situ from the compound of formula ⁇ .
  • Suitable bases here are those mentioned herein above.
  • the reaction of the process A is carried out in the presence of NaOH or KOH.
  • the base is preferably introduced to the reaction mixture in the form of an aqueous or alcoholic solution and preferably in the form of an aqueous solution. If an aqueous solution of a base, such as in particular NaOH or KOH, is used in process A, the concentration of the base in the aqueous solution is preferably in the range of 1 to 20% by weight and in particular of 5 to 15% by weight.
  • the base is typically used in in such an amount that the starting material to be hydrogenated is essentially present as the salt of formula II.
  • the base is used in at least equimolar amounts, if a compound of formula ⁇ is used.
  • a slight excess of base is used, preferably in an amount of 1 .005 to 2 molar equivalents, in particular 1 .01 to 1 .6 molar equivalents and specifically 1 .01 to 1 .4 molar equivalents per 1 mol of the compound of the formula ⁇ .
  • a compound of formula II is used as a starting material, it is preferred that additional base is used in amounts of at least 0.005 molar equivalents, in particular at least 0.01 molar equivalents, e.g. 0.005 to 1 molar equivalents, in particular 0.01 to 0.6 molar equivalents and specifically 0.01 to 0.4 molar equivalents per 1 mol of the compound of the formula II.
  • the salt of formic acid acts as a hydrogen donor.
  • salts of formic acid or the synonymous term “formates” are understood herein as compounds consisting of a formate anion and an organic or an anorganic cation as counterion.
  • Formates that are suitable for the inventive process A are selected from alkali metal formates, alkaline earth metal formates and mono-, di-, tri-, and tetra-Ci-C 4 - alkylammonium formates, such as sodium formate, potassium formate, magnesium formate, calcium formate, methylammonium formate, ethylammonium formate, n-propylammonium formate, isopropylammonium formate, sec-butylammonium formate, tert-butylammonium formate, dimethylammonium formate, diethylammonium formate, di-n-propylammonium formate, di-n-butylammonium formate,
  • alkali metal formates such as sodium formate, potassium formate, magnesium formate, calcium formate, methylammonium formate, ethylammonium formate, n-propylammonium formate, isopropylammonium formate
  • trimethylammonium formate triethylammonium formate, tri-n-propylammonium formate, tri-n-butylammonium formate, ethyldiisopropylammonium formate, tetramethylammonium formate, tetraethylammonium formate, tetra-n-butylammonium formate, ethyltriisopropylammonium formate, and mixtures of these salts.
  • Formates that are preferably used in the inventive process A are typically selected from alkali metal formates and alkaline earth metal formates, such as sodium formate, potassium formate, magnesium formate, calcium formate and mixtures thereof, and especially selected from alkali metal formates, such as sodium formate, potassium formate and mixtures thereof.
  • the process A is carried out by using an alkali metal formate, such as sodium formate or potassium formate, as the salt of formic acid.
  • the formates can be prepared in situ by using formic acid and a suitable amount of base for neutralizing the formic acid to the formate. However, it is preferred to use a preformed formate.
  • the salt of formic acid is used in an amount of typically 1 to 20 mol, preferably 2 to 15 mol, in particular 3 to 12 mol, and specifically 4 to 10.5 mol, based in each case on 1 mol of the compound of the formula II' or its salt of the formula II.
  • the compound of the formula II is reacted with the formate in the presence of a chiral transition metal catalyst, which is characterized in that it comprises a transition metal atom and at least one chiral ligand, in particular exactly one chiral ligand per transition metal atom.
  • the transition metal atom of the chiral transition metal catalyst is selected from Ti, Zr, Hf, V, Nb, Ta, Cr, Mo, W, Mn, Re, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag and Au, preferably selected from Zr, Nb, Mo, W, Ru, Co, Rh, Ir, Ni and Pd, more preferably selected from Mo, Ru, Co, Rh, Ir, Ni and Pd, in particularly selected from Ru, Ir, Ni and Pd.
  • reaction of the process A is carried out in the presence of chiral transition metal catalyst which comprises as transition metal a ruthenium atom.
  • each chiral transition metal catalytic complex comprises just one ruthenium atom.
  • Preferred chiral transition metal catalysts such as in particular chiral ruthenium catalysts, can be obtained e.g. by reacting a suitable transition metal precursor compound, such as in particular a ruthenium compound, for example a ruthenium compound of the formula Ru-I
  • Ru-I [RuY 2 (n 6 -Ar)] 2 (Ru-I), with a suitable chiral Iigand, where in formula Ru-I, the variable Y is halogen selected from fluorine, chlorine, bromine and iodine, and in particular is chlorine, and Ar is benzene or a substituted benzene derivative, especially a benzene derivative substituted by one or more Ci-C4-alkyl groups, such as in particular p-cymene.
  • a particularly preferred ruthenium compound is of the formula Ru-I with Y being chlorine and Ar being p-cymene, i.e. 1 -methyl-4-(propan-2-yl)benzene.
  • the chiral transition metal catalyst used in process A comprises one chiral Iigand which is derived from optically active amines or optically active amino acids, and in particular derived from optically active amines.
  • the optically active amine Iigand preferably has an enantiomeric excess of at least 90% ee.
  • the optically active amines or the optically active amino acids are converted into the chiral ligands during the reaction with the suitable transition metal compound, such as e.g. [RuY 2 (n 6 -Ar)] 2 , by deprotonating an amino group of the optically active amine or amino acid.
  • Preferred optically active amines here are the optically active diastereomers of an amine having two chiral centers. It is apparent that a particular optically active diastereomer of such an amine will selectively produce one enantiomer of the compound of formula I, while its optical antipode will produce the other enantiomer of the compound of formula I. A skilled person can readily find out by routine, which antipode is required to selectively form the desired enantiomer of the compound of formula I.
  • the amine having two chiral centers is preferably selected from 1 ,2-diphenyl- 2-amino-ethanol (H 2 N-CHPh-CHPh-OH), 1 -phenyl-2-methyl-2-amino-ethanol (H 2 N- CHMe-CHPh-OH), N-methyl-1 -phenyl-2-methyl-2-amino-ethanol (MeHN-CHMe-CHPh- OH) and N-p-toluenesulfonyl-1 ,2-diphenyl-ethylenediamine (H 2 N-CHPh-CHPh-NHTs), and in particular is H 2 N-CHPh-CHPh-NHTs.
  • 1 ,2-diphenyl- 2-amino-ethanol H 2 N-CHPh-CHPh-OH
  • 1 -phenyl-2-methyl-2-amino-ethanol H 2 N- CHMe-CHPh-OH
  • MeHN-CHMe-CHPh-OH N
  • the chiral Iigand of the chiral transition metal catalyst used in process A is preferably the monoanion of an amine which is selected from H 2 N-CHPh-CHPh-OH, H 2 N-CHMe-CHPh-OH, MeHN-CHMe-CHPh-OH and H 2 N-CHPh-CHPh-NHTs, and in particular is H 2 N-CHPh-CHPh-NHTs.
  • these preferred chiral ligands are formed when an optically active diastereomer, selected from the diamines of the group H 2 N-CHPh-CHPh-OH, H 2 N-CHMe-CHPh-OH, MeHN-CHMe-CHPh-OH or H 2 N-CHPh-CHPh-NHTs, in particular a diastereomer of H 2 N-CHPh-CHPh-NHTs, is reacted with a suitable transition metal compound, in particular a suitable ruthenium compound, such as especially the compound of the formula Ru-I.
  • a suitable transition metal compound in particular a suitable ruthenium compound, such as especially the compound of the formula Ru-I.
  • optically active diastereomers in this context are selected from (1 S,2S)-N-p-toluenesulfonyl-1 ,2-diphenyl-ethylenediamine
  • the chiral transition metal catalyst is obtainable by reacting a suitable ruthenium compound, such as especially [RuY 2 (n. 6 -Ar)] 2 , with one of the diastereomers of H 2 N-CHPh-CHPh-OH, H 2 N-CHMe-CHPh-OH, MeHN-CHMe-CHPh-OH or H 2 N-CHPh-CHPh-NHTs, and in particular with (1 S,2S)-H 2 N-CHPh-CHPh-NHTs or (1 R,2R)-H 2 N-CHPh-CHPh-NHTs.
  • a suitable ruthenium compound such as especially [RuY 2 (n. 6 -Ar)] 2
  • one preferred embodiment of the present invention relates to the process A of the invention, wherein the the formula l-S,
  • Another preferred embodiment of the present invention relates to the process A of the invention, whe the formula l-R,
  • the chiral transition metal catalyst is used in an amount of typically 0.1 to 20 mmol, preferably 0.5 to 10 mmol, in particular 1 to 5 mmol, and specifically 1 .5 to 2 mmol, based in each case on 1 mol of the compound of the formula II' or its salt of the formula II.
  • the reaction of the inventive process A is typically carried out in a solvent comprising a polar aprotic organic solvent and optionally up to 90% by volume of water.
  • the reaction of process A is carried out in a solvent, wherein the polar aprotic organic solvent accounts for at least 80%, preferably at least 90%, in particular at least 95% and especially at least 98%by volume of the total volume of the solvent.
  • the reaction of process A is carried out in a solvent comprising a mixture of a polar aprotic organic solvent and water, wherein the ratio by volume of the polar aprotic organic solvent to water is in the range of 60:40 to 10:90, preferably 50:50 to 15:85 and in particular 40:60 to 20:80.
  • the combined volumes of polar aprotic organic solvent and of water account for at least 80%, preferably at least 90%, in particular at least 95% and specifically at least 98% of the total volume of the solvent.
  • Useful polar aprotic organic solvents here include halogenated Ci-C4-alkanes, such as dichloromethane, i.e. methylene chloride, and trichloromethane, Ci-C4-alkyl nitriles, such as acetonitrile, ethers, for example aliphatic C2-Cio-ethers having 1 , 2, 3, or 4 oxygen atoms, such as Ci-C4-alkoxy-Ci-C4-alkanes, e.g.
  • substituents selected from Ci-C4-alkyl and chlorine such as chlorobenzene, toluene, the xylenes and mesitylene, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), or mixtures of these solvents with one another.
  • the polar aprotic organic solvent for use in the reaction solvent of process A is preferably selected from ethers, such as in particular diethyl ether, dipropyl ether, methyl isobutyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, glyme, diglyme, triglyme, THF, 1 ,4-dioxane and mixtures thereof, and in particular selected from glyme, diglyme, triglyme, THF, 1 ,4-dioxane and mixtures thereof.
  • ethers such as in particular diethyl ether, dipropyl ether, methyl isobutyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, glyme, diglyme, triglyme, THF, 1 ,4-dioxane and mixtures thereof, and in particular selected from
  • the total amount of the solvent used in the reaction A of the inventive process is typically in the range from 200 to 8000 g, preferably in the range from 400 to 4000 g and in particular in the range from 500 to 2000 g, based on 1 mol of the compound of the formula II' or its salt of the formula II.
  • the reactants of the process A can in principle be contacted with one another in any desired sequence.
  • the compound of formula II' or its salt of formula II, the formate and typically the base can be initially charged and mixed with each other. The obtained mixture can then be admixed with the chiral transition metal catalyst or a solution or dispersion thereof.
  • the compound of formula II' or its salt of formula II and the base if appropriate in dissolved or dispersed form, can be initially charged and firstly admixed with the chiral transition metal catalyst or a solution or dispersion thereof and then with the formate.
  • all reactants can be added simultaneously to the reaction vessel.
  • the reactants can also be added separately to the reaction vessel, with the compound of formula II', if used at all, being contacted with the catalyst preferably only after the addition of the base.
  • the reaction vessel has been found to be beneficial to initially charge the reaction vessel with a solution or dispersion including the compound of formula II' or its salt of formula II and the base, and then to add a solution or dispersion of the chiral transition metal catalyst in a polar aprotic organic solvent.
  • the formate may be included in the initially charged solution or dispersion, or be added after the addition of the catalyst.
  • the initial solution or dispersion including the compound II' or its salt II and the base is typically obtained by mixing the compound II' or its salt II with a solution or dispersion of the base in water, in a polar aprotic organic solvent or in a mixture thereof, and preferably with an aqueous solution of the base.
  • the chiral transition metal catalyst is typically prepared prior to the reaction of the process A by reacting an optically active amine with a transition metal compound, such as in particular the aforementioned ruthenium compound of the formula Ru-I, with the variables Y and Ar having the meanings defined above, in particular those mentioned as preferred.
  • the reaction between the optically active amine and the transition metal compound is preferably carried out at an elevated temperature of about 40 to 120°C, in particular 60 to 100°C, in one of the aforementioned polar aprotic organic solvents, particularly in one mentioned as preferred.
  • the partial or total amount of the polar aprotic organic solvent that is intended for the reaction of process A is used.
  • the obtained solution of the finished chiral transition metal catalyst is then directly introduced to the reaction of process A.
  • the reaction of the inventive process A is performed under temperature control.
  • the reaction is typically effected in a closed or preferably in an open reaction vessel with stirring apparatus.
  • the reaction temperature of the inventive process depends on different factors, in particular on the catalyst used, and can be determined by the person skilled in the art in the individual case, for example by simple preliminary tests.
  • the conversion of the inventive process is performed at a temperature in the range from 0 to 120°C, preferably in the range from 10 to 80°C, and in particular in the range from 20 to 60°C.
  • the reactions of the invention as described hereinafter are performed in reaction vessels customary for such reactions, the reaction being carried out in a continuous, semicontinuous or batchwise manner.
  • the particular reactions will be carried out under atmospheric pressure.
  • the reactions may, however, also be carried out under reduced or elevated pressure, e.g. at pressures in the range from 0.1 to 20 bar. It may be beneficial to carry out the reaction under an inert atmosphere, in particular under argon or nitrogen. Inert atmosphere means that oxygen is essentially absent.
  • M + has the meaning defined above, in particular the meaning mentioned as preferred.
  • the salt of the formula ⁇ is converted into the compound of the formula I by a acidification step that is integrated in the work-up process, as described in the following.
  • the work-up of the reaction mixture obtained in the reaction A of the inventive process and the isolation of one of the enantiomers of the compound of formula I are effected in a customary manner, for example by diluting with water or an aqueous base and washing the aqueous phase with a suitable organic solvent. Afterwards the separated aqueous phase is adjusted to a pH value of from 1 to 3 and in particular to a pH value of 1 using preferably a mineral acid, such as an aqueous solution of hydrochloric acid or of sulfuric acid.
  • the aqueous phase is then repeatedly extracted with a suitable organic solvent and after removal of the solvent from the combined organic phases the product of formula l-S or formula l-R is isolated and can optionally be crystallized from a suitable solvent. Frequently, the product is obtained in sufficient purity by applying such measures. Thus, additional purification steps, in particular elaborated ones such as chromatography are often not necessary. If desired, however, further purification can be effected by methods commonly used in the art.
  • the reaction mixture of the process A is initially cooled to ambient temperature and then diluted with water or an aqueous base such as an aqueous solution of KOH or NaOH.
  • a suitable solvent such as in particular methylene chloride
  • it is adjusted to pH 1 with an acid, such as in particular concentrated aqueous HCI.
  • the aqueous phase is subsequently extracted several times with a suitable organic solvent, such as in particular methylene chloride, and the organic phases are combined.
  • a suitable organic solvent such as in particular methylene chloride
  • the organic phase containing the enantiomer of the compound of formula (I) that is obtained with the work-up procedure described above may afterwards be introduced into a further reaction step, either directly or after partial or complete removal of the solvent, if applicable, and optional further purification steps, such as column chromatography.
  • the organic phase may be subjected to crystallisation conditions and after completion of the crystallisation the formed crystals are isolated, washed and dried.
  • the process A according to the present invention affords one of the enantiomers of the compound of formula I in good yields, which are typically > 70%, often > 75% and in particular > 80%, and with enantiomeric excess that is usually > 98% ee and in particular > 99% ee.
  • a further aspect of the present invention relates to processes for the preparation of (3S,3S')-astaxanthin and (3R,3R')-astaxanthin, respectively, which comprise the step of providing one of the enantiomers of the compound of formula I in high enantiomeric purity by the process A of the invention.
  • Starting from either the 4S- or the 4R-enantiomer of the compound of formula I (3S,3S')-astaxanthin or (3R,3R')- astaxanthin can be prepared following the established non-stereoselective synthesis routes that are described herein above and are summarized in Scheme 1 . These routes are known from the aforementioned literature, such as the monograph
  • the compound of the formula II used as a starting material in the reaction of the inventive process A can be prepared e.g. by the process described by Widmer et al., Helvetica Chimica Acta 1981 , 64, 2436, which starts from commercially available 4-oxo-isophorone.
  • Epoxidation with hydrogen peroxide in the presence of catalytic amounts of an aqueous NaOH solution affords 2,3-epoxy-4-oxo-2,6,6-trimethylcyclo- hexanone, which on increasing the amount of NaOH to more than 1 molar equivalent is readily converted to the desired compound of formula II with M + being a sodium cation.
  • the combined organic phases were concentrated by evaporation to afford 47.88 g of the desired product with a chemical purity of 84.0 wt-% determined by quantitative HPLC.
  • the product had >99 ee as determined by HPLC using a Chiralpak AS-RH column, 150 mm x 4.6 mm, from Daicel. Based on the chemical purity the yield was 80.5%.
  • the combined organic phases were concentrated by evaporation to afford 3.6 g of the desired product with a chemical purity of 76.3 wt-% determined by quantitative HPLC.
  • the product had >98 ee as determined by HPLC using a Chiralpak AS-RH column, 150 mm x 4.6 mm, from Daicel. Based on the chemical purity the yield was 76.2%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne un nouveau procédé de préparation d'un des énantiomères de 3,4-dihydroxy-2,6,6-triméthylcyclohex-2-énone et un procédé de préparation de (3S,3'S)-astaxanthine, qui comprend l'étape consistant à fournir l'énantiomère (4S)- de 3,4-dihydroxy-2,6,6-triméthylcyclohex-2-énone.
PCT/EP2017/083192 2016-12-19 2017-12-18 Procédé de préparation de (4s)- ou de (4r)-3,4-dihydroxy-2,6,6-triméthylcyclohex-2-énone WO2018114732A1 (fr)

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US11261145B2 (en) 2017-03-20 2022-03-01 Basf Se Process for preparing bromotrichloromethane

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11261145B2 (en) 2017-03-20 2022-03-01 Basf Se Process for preparing bromotrichloromethane

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