EP2142494A1 - Procede de production enantioselective de derives optiquement actifs de 4-hydroxy-2,6,6-trimethylcyclohex-2-enone - Google Patents

Procede de production enantioselective de derives optiquement actifs de 4-hydroxy-2,6,6-trimethylcyclohex-2-enone

Info

Publication number
EP2142494A1
EP2142494A1 EP08717062A EP08717062A EP2142494A1 EP 2142494 A1 EP2142494 A1 EP 2142494A1 EP 08717062 A EP08717062 A EP 08717062A EP 08717062 A EP08717062 A EP 08717062A EP 2142494 A1 EP2142494 A1 EP 2142494A1
Authority
EP
European Patent Office
Prior art keywords
optically active
formula
chph
compound
transition metal
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Withdrawn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
EP08717062A
Other languages
German (de)
English (en)
Inventor
Rainer STÜRMER
Hansgeorg Ernst
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.)
BASF SE
Original Assignee
BASF SE
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 BASF SE filed Critical BASF SE
Priority to EP08717062A priority Critical patent/EP2142494A1/fr
Publication of EP2142494A1 publication Critical patent/EP2142494A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/24—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by six-membered non-aromatic rings, e.g. beta-carotene
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • 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
    • C07C45/64—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 by introduction of functional groups containing oxygen only in singly bound form

Definitions

  • the present invention relates to a process for the enantioselective preparation of optically active 4-hydroxy-2,6,6-trimethyl-cyclohex-2-en-1-one derivatives of the formulas (I) or (Ia) and to a process for the preparation of (3S, 3'S) -Astaxanthin of the formula comprising the process for the preparation of the compound of formula (I).
  • Astaxanthin (3,3'-dihydroxy-ß, ß'-carotene-4,4'-dione) can be present in the form of the following configurational isomers because of its two chiral centers in 3 and 3 ' position: (3S, 3 ' S), ( 3R, 3 ' R), (3S, 3 ' R) and (3R, 3 ' S).
  • the latter two configuration isomers are identical and represent a meso-form (Carotenoids Handbook, 2004, Main List No. 405).
  • (S, S) astaxanthin from green algae is used as a food supplement with positive effects on human health (J. Nat. Prod., 2006, 69, 443). In addition, it is useful to completely block the adverse pro-oxidative effects of rofecoxib (Vioxx) (J. Cardiovasc Pharmacol., 2006, 47 Suppl 1, p. However, given the low concentration of (S, S) -astaxanthin in green algae (J. Agric. Food Chem., 1998, 46, 3371), the availability of this agent is very limited. In addition, the active substance is present in the algae in a mixture of mono- and di-fatty acid esters and free astaxanthin, which causes a considerable effort for isolation and purification (see also Phytochemistry, 20, 11, 2561 (1981);
  • Another synthetic strategy is to arrive at enantiomerically pure synthesis building blocks via microbial or enzymatic processes (Helvetica Chimica Acta, 1978, 61, 2609, Helvetica Chimica Acta, 1981, 64, 2405). Since these building blocks have a too low oxidation state, they had to be in multistage syntheses to (S, S) -Astaxanthin precursors are converted.
  • WO 2006/039685 describes on the one hand in Scheme II a two-stage enantioselective hydrogenation of ketoisophorone to an enantiomerically pure C9-diol, from which after re-oxidation of a hydroxy group based on the in HeIv. Chim. Acta, 1978 61, 2609 described in a multi-step synthesis to (S, S) -Astaxanthin- precursors passes. Furthermore, WO 2006/039685 describes an enantioselective catalytic transfer hydrogenation of a C9 enol ether of the formula (II-a) to the corresponding enantiomerically pure alcohol of the formula (I-b).
  • Suitable hydrogenation catalysts are metals with chiral ligands, preferably ruthenium catalysts with optically active amines as ligands. Disadvantageous this process is that an oxygen-protected derivative of a technical intermediate of the formula (M-OH) is used,
  • R 1 is an alkali metal M 1 or an alkaline earth metal fragment M 2 1/2 or (M 2 ) + X-, where M 1 is Li, Na, K, Rb or Cs and M 2 is Mg, Ca, Sr or Ba and X "represents a singly charged anion, in the presence of a reducing agent RM and a chiral transition metal catalyst to give a compound of formula (I) or (Ia), wherein the carbonyl distr in position 1 of the compound of formula (II) in the presence of the chiral transition metal catalyst, preferably either to the secondary (4S ) Alcohol of the formula (I) or preferably to the secondary (4R) -alcohol of the formula (Ia) is hydrogenated, and optionally the oxidized reducing agent RM is at least partially removed from the reaction equilibrium,
  • R 1 is an alkali metal M 1 or an alkaline earth metal fragment M 2 I / 2 or (M 2 ) + X-
  • M 1 is Li, Na, K, Rb or Cs, preferably Na or K, in particular Na and M 2 for Mg, Ca, Sr or Ba, in particular Mg and X "is a singly charged anion, such as halide , Acetate or dihydrogen phosphate.
  • R 1 is preferably Na or K, in particular Na.
  • the compound of the formula (II) is converted in the presence of a chiral transition metal catalyst to give a compound of the formula (I) or (Ia).
  • the chiral transition metal catalyst which is suitable for the reduction of the carboxyl group on the carbon atom 4 to the secondary alcohol preferably contains a transition metal atom and at least one optically active, chiral ligand.
  • a transition metal atom in principle, all transition metals, such as Ti, Zr, Hf, V, Nb, Ta, Cr, Mo, W, Mn, Re, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt, Cu , Ag or Au in question, which can form a suitable chiral transition metal catalyst.
  • a chiral transition metal catalyst which contains a transition metal atom and at least one optically active, chiral ligand, wherein the transition metal atom is ruthenium.
  • Preferred chiral ruthenium catalysts can be prepared, for example, by reacting a suitable ruthenium compound such as [RuX2 ( ⁇ 6 -Ar)] 2 with a suitable chiral ligand, where X is a halogen atom such as fluoro, chloro, bromo or iodo, and Ar is benzene or substituted benzene derivative, in particular a Ci-C4-alkyl radicals substituted benzene derivative.
  • the chiral ruthenium catalyst is preferably characterized in that the optically active chiral ligand is an optically active amine or an optically active amino acid.
  • optically active amines which are reacted with a suitable ruthenium compound, in particular [RuX2 ( ⁇ 6 -Ar)] 2, to the catalytically active complex may, for example, H 2 N-CHPh-CHPh-OH, H 2 N-CHMe-CHPh-OH, MeHN-CHMe-CHPh-OH or TsNH-CHPh-CHPh-NH 2 , in particular (1S, 2S) -Np-toluenesulfonyl -1,2-diphenylethylenediamine or (1R, 2R) -Np-toluenesulfonyl-1,2-diphenylethylenediamine.
  • a chiral ruthenium catalyst in which the optically active chiral ligand is prepared by simple deprotonation of H 2 N-CHPh-CHPh-OH, H 2 N-CHMe-CHPh-OH, MeHN-CHMe-CHPh-OH or TsNH-CHPh-CHPh -NH 2 , in particular by simple deprotonation of (1 S, 2S) -Np-toluenesulfonyl-1, 2-diphenylethylenediamine or (1 R, 2R) - Np-toluenesulfonyl-1, 2-diphenylethylenediamine is available.
  • the reducing agent RM used is preferably an organic compound which contains at least one primary or secondary alcohol function CH (OH), for example isopropanol, 2-butanol, 2-pentanol, 2-hexanol or 3-hexanol, in particular isopropanol.
  • CH primary or secondary alcohol function
  • the oxidized reducing agent RM formed in the process according to the invention for example acetone when using isopropanol as the reducing agent RM, can be at least partially removed from the reaction medium or from the reaction equilibrium.
  • the reducing agent RM is a secondary alcohol, it is also often referred to as sacrificial alcohol and the correspondingly formed oxidation product as sacrificial ketone.
  • the process according to the invention is usually carried out in the liquid phase, that is to say in at least one solvent or solvent mixture.
  • the liquid phase contains at least one organic solvent, wherein the liquid phase usually consists of more than 50% by volume of organic solvents.
  • the liquid phase may in particular contain water.
  • the liquid phase can represent a 1-phase, 2-phase or even multi-phase system.
  • the process according to the invention is preferably carried out in a 1-phase system, in which case mixtures of a secondary alcohol, in particular isopropanol, and water are used as the solvent.
  • the oxidation product formed can be at least partially removed from the reaction medium or from the reaction equilibrium.
  • secondary alcohols such as isopropanol as a reducing agent (RM)
  • the removal of the so-called sacrificial ketones formed, acetone in the case of isopropanol as a sacrificial alcohol can be carried out in various ways, for example by selective membranes or by extraction or distillation processes.
  • the inventive method is advantageously carried out at a temperature between 0 0 C and 150 0 C, preferably between 10 0 C and 85 ° C, more preferably between 15 ° C and 75 ° C.
  • Optically active compounds in the process according to the invention are enantiomers which show an enantiomeric enrichment.
  • the compounds of the formulas (I) or (Ia) prepared in the process according to the invention can be prepared by acidification into the corresponding diol, for example (4S) -3,4-dihydroxy-2,6,6-trimethylcyclohex-2-one. Enone, which can be obtained by known methods, such as extraction or precipitation.
  • the product solution can in principle be carried out as described in Helv. Chim. Acta 64, 2436, 1981.
  • the product solution can first be adjusted to a pH of 1 to 3, preferably pH 1.
  • the acidification is preferably carried out with mineral acids such as hydrochloric or sulfuric acid, more preferably with sulfuric acid.
  • the product precipitates frequently and can be separated or the acid product solution is extracted several times with an organic, not water-miscible solvent.
  • Suitable solvents here are chlorinated hydrocarbons, in particular methylene chloride, ethers such as MTBE or disopropyl ether and ethyl acetate. This extraction can be carried out batchwise or continuously. Extraction of the product may be assisted by concentration of the aqueous phase prior to acidification or by "salting out", but these operations are not essential for separation of the product from the reaction solution.
  • the diol can be obtained in an enantiomeric purity of greater than 98% ee. It may, if desired, by crystallization according to HeIv. Chim. Acta 64, 2436, 1981, but is preferably without further purification operation in the further synthesis of S, S-astaxanthin according to HeIv. Chim. Acta 64, 2447, 1981 used.
  • the process according to the invention can be operated batchwise, semi-batchwise or continuously.
  • Another object of the present invention is a process for the preparation of (3S, 3'S) -Astaxanthin of formula (III),
  • the advantage of the process according to the invention lies in the simplified recovery of compounds of the formulas (I) or (Ia) with high enantiomeric purity coupled with good yields of these compounds.
  • the educt and product concentration can be determined by HPLC. Depending on the choice of stationary and mobile phase, ee value can be determined in addition to the concentration.
  • Authentic material is used to create a set of standards that can be used to determine the concentration of unknown samples and to allow assignment of the enantiomers.
  • a chiral catalyst was prepared by reacting 26.8 mg of (1R, 2R) - (-) - Np-toluenesulfonyl-1-2-diphenylethylenediamine with 11.8 mg of dichloro (p-cymene) ruthenium ( ll) dimer and used according to Example 2 for the reduction of the compound (N-Na) to the compound (Ia-OH), wherein a quantitative conversion was achieved and the product had an enantioselectivity greater than 99% ee.
  • Example 2 Analogously to Example 2, the reduction of compound (N-Na) was carried out with one tenth of the amount of catalyst (S / C 1000: 1) from Example 2. The reaction control by HPLC analysis gave after 72 h 72% conversion and after 48 h full conversion at identical enantiomeric excesses.

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

Abstract

La présente invention concerne un procédé de production énantiosélective de dérivés optiquement actifs de 4-hydroxy-2,6,6-triméthylcyclohex-2-én-1-one de formules (I) ou (Ia) ainsi qu'un procédé de production de (3S, 3'S)-astaxanthine de formule (III) et le procédé de production du composé de formule (I).
EP08717062A 2007-03-28 2008-02-22 Procede de production enantioselective de derives optiquement actifs de 4-hydroxy-2,6,6-trimethylcyclohex-2-enone Withdrawn EP2142494A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP08717062A EP2142494A1 (fr) 2007-03-28 2008-02-22 Procede de production enantioselective de derives optiquement actifs de 4-hydroxy-2,6,6-trimethylcyclohex-2-enone

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP07105089 2007-03-28
PCT/EP2008/052202 WO2008116714A1 (fr) 2007-03-28 2008-02-22 Procédé de production énantiosélective de dérivés optiquement actifs de 4-hydroxy-2,6,6-triméthylcyclohex-2-énone
EP08717062A EP2142494A1 (fr) 2007-03-28 2008-02-22 Procede de production enantioselective de derives optiquement actifs de 4-hydroxy-2,6,6-trimethylcyclohex-2-enone

Publications (1)

Publication Number Publication Date
EP2142494A1 true EP2142494A1 (fr) 2010-01-13

Family

ID=39587937

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08717062A Withdrawn EP2142494A1 (fr) 2007-03-28 2008-02-22 Procede de production enantioselective de derives optiquement actifs de 4-hydroxy-2,6,6-trimethylcyclohex-2-enone

Country Status (5)

Country Link
US (1) US20100041922A1 (fr)
EP (1) EP2142494A1 (fr)
CN (1) CN101646642A (fr)
TW (1) TW200909406A (fr)
WO (1) WO2008116714A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE502007003046D1 (de) * 2006-11-10 2010-04-15 Basf Se Verfahren zur herstellung von (4s)-3,4-dihydroxy-2,6,6-trimethyl-cyclohex-2-enon und derivaten davon unter verwendung der azoarcus phenylethanol dehydrogenase
CN103980270A (zh) * 2014-05-19 2014-08-13 埃斯特维华义制药有限公司 一种（r）-3-奎宁醇的制备方法
ES2736128T3 (es) * 2014-08-12 2019-12-26 Basf Se Procedimiento para la preparación de astaxantina a partir de astacina
WO2018114733A1 (fr) 2016-12-19 2018-06-28 Basf Se Procédé de préparation d'acétals c9 purs stéréoisomères
WO2018114732A1 (fr) 2016-12-19 2018-06-28 Basf Se Procédé de préparation de (4s)- ou de (4r)-3,4-dihydroxy-2,6,6-triméthylcyclohex-2-énone

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004022686A1 (de) * 2004-05-05 2005-11-24 Basf Ag Verfahren zur Herstellung optisch aktiver Alkohole
US20060088904A1 (en) * 2004-10-01 2006-04-27 Lockwood Samuel F Methods for the synthesis of astaxanthin
DE502007003046D1 (de) * 2006-11-10 2010-04-15 Basf Se Verfahren zur herstellung von (4s)-3,4-dihydroxy-2,6,6-trimethyl-cyclohex-2-enon und derivaten davon unter verwendung der azoarcus phenylethanol dehydrogenase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008116714A1 *

Also Published As

Publication number Publication date
TW200909406A (en) 2009-03-01
CN101646642A (zh) 2010-02-10
US20100041922A1 (en) 2010-02-18
WO2008116714A1 (fr) 2008-10-02

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