CN110088094A - The method for preparing the pure C9- acetal of alloisomerism - Google Patents
The method for preparing the pure C9- acetal of alloisomerism Download PDFInfo
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- CN110088094A CN110088094A CN201780078360.5A CN201780078360A CN110088094A CN 110088094 A CN110088094 A CN 110088094A CN 201780078360 A CN201780078360 A CN 201780078360A CN 110088094 A CN110088094 A CN 110088094A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
- C07D317/64—Oxygen atoms
Abstract
The present invention relates to stereoselectivity preparations at least 90% enantiomer and general formula S, S-I or the R of diastereomer purity, the method for the compound of R-I, wherein R1For C1‑C4Alkyl, C2‑C4Alkenyl, C2‑C4Alkynyl, phenyl or benzyl, wherein phenyl and benzyl are unsubstituted or are selected from halogen, C with one or two1‑C3Alkyl and C1‑C3The group R of alkoxy1a, and the invention further relates to the methods of preparation (3S, 3'S)-astaxanthin or (3R, 3'R)-astaxanthin, wherein using general formula S, S-I or R, the compound of R-I.
Description
The present invention relates to stereoselectivity preparations at least 90% enantiomer and the general formula S, S-I of diastereomer purity
Or the method for R, R-I compound,
With the method for preparation (3S, 3'S)-astaxanthin or (3R, 3'R)-astaxanthin, wherein use general formula S, S-I or R, R-I
Compound.
Background technique
Due to be located at the position 3 and 3' two chiral centres, astaxanthin (3,3'- carrotene -4 dihydroxy-β, β ' -,
4'- diketone) it can be with (3S, 3'S)-, (3R, 3'R)-, (3S, 3'R)-, (3R, 3'S)-diastereomer or these stereoisomers
Mixture form exist.(3S, 3'R)-and (3R, 3'S)-diastereomer are identical and constitute meso-form (ginseng
See: Carotenoids Handbook, 2004 (editors: G.Britton, S.Liaaen-Jensen, H.Pfander) are main clear
Single number 404,405 and 406).
The astaxanthin of three kinds of obtained diastereoisomeric forms is present in various natural origins.However, working as from racemic
When precursor starts, chemistry is fully synthetic to be caused (3S, 3'S)-, the 1:2:1 mixture of meso-and (3R, 3'R)-astaxanthin (referring to
Such as E.Widmer et al., Helvetica Chimica Acta1981,64,2436).
(3S, 3'S)-diastereomer (referred to herein as (3S, 3'S)-astaxanthin) of astaxanthin has especially important
Meaning.It is enriched with by green alga (haematococcus pluvialis (Haematococcus pluvialis)) with enantiomer and diastereomer
Form carry out biosynthesis, green alga may be this diastereomer the most abundant natural origin (referring to M.Grung et al.,
J.Applied Phycology 1992,4,165；B.Deng Phytochemistry 1981,20,2561).
(3S, 3'S)-astaxanthin from green alga be used as to human health have positive effect food supplement (referring to:
G.Hussein et al., J.Nat.Prod.2006,69,443).It is reported that it is also adaptable as blocking rofecoxib (Vioxx)
Unfavorable pro-oxidant activity effective antioxidant (referring to R.P.Mason, J.Cardiovasc.Pharmacol.2006,
47Suppl.1,7)。
However, it is contemplated that (3S, 3'S)-astaxanthin of low concentration is (referring to J.-P.Yuan, J.Agric.Food in green alga
Chem.1998,46,3371), the availability of this active constituent is very limited.In addition, (3S, 3'S)-astaxanthin as mono- and
Two-aliphatic esters and the mixture of free astaxanthin are present in algae, this to separate and purify have sizable complexity
Property is (see, for example, M.Grung et al., J.Applied Phycology 1992,4,165；B.Et al.,
Phytochemistry 1981,20,2561).Therefore, green in order to provide (3S, 3'S)-shrimp of a greater amount of and high-purity
Element, chemical synthesis are selected technologies.
Being synthetically prepared for astaxanthin is described extensively in document, for example, in monograph G.Britton, S.Liaanen-
Jensen, H.Pfander (editor), Carotenoids, Vol.2,Verlag, Basel are 1996, special
It is not page 11, page 267 and then each page and page 281 and then each page and the document quoted there, is described in each
Kind is taught in book, such as B.Natural Products in the Chemical Industry,Springer,
Heidelberg, page 2014,626 and then each page and the document quoted there, is described in H.Ernst, Pure and
Applied Chemistry in 2002,74,2213, and is described in patent document, for example, EP1197483 or EP
1285912。
The known route of synthesis for astaxanthin is usually from 3,4 dihydroxy -2,6,6- front three basic ring of the racemic of Formula II
Hex- 2- ketenes starts, as shown in following scheme 1.In general, the Formulas I precursor initially by be converted into ketal or the acetal of formula A come
Protection.In multistage method, usually it converts formula A compound to the C15- phosphonium salt or its benzenesulfonyl analog of formula B.The party
Method by grignard reaction position 1 (being 6 in carotenoid number) the following steps are included: introduced with substituted butylene
The acetylene moieties of base eliminate water, three key sections are reduced to double bond and the Ru Phosphonium part Yin or benzenesulfonyl.Finally by
The C10- dialdehyde of formula B compound and formula C are coupled by Wittig reaction or Julia alkylene, as shown in below step b), obtain shrimp blueness
The alltrans derivative of element, however it is the mixture of three kinds of diastereomer forms.
Scheme 1:
It from the discussion above, it is apparent that can be in the form of its (4S)-or (4R)-enantiomer of formula S-II or R-II
Existing C9 glycol 3,4- dihydroxy -2,6,6- trimethyl-cyclohex-2-en -1- ketone II is namely for industrial production class Hu trailing plants
The valuable intermediate of Bu Suru astaxanthin.
In these preparation methods, compound II is usually made in the form of the racemic mixture of (4S)-and (4R)-enantiomer
With and being used with protection form, for example, their acetone solvate form (compound A, wherein R1And R2For methyl).These methods
There is good description in the art.
For example, E.Widmer et al., Helvetica Chimica Acta 1981,64,2436, disclose by using
Racemic 3,4- dihydroxy -2,6,6- trimethyl-cyclohex-2-en -1- ketone (S/R-II) synthesis of its acetone solvate form is outer to disappear
Revolve the method for astaxanthin.
0633258 B1 of EP discloses a kind of method for preparing racemic astaxanthin, including racemic 3, dihydroxy -2 4-,
6,6- trimethyl-cyclohex-2-en -1- ketone (S/R-II) and acetone, the reaction of 2,2-dimethoxypropane or ethyl vinyl ether.
Then such shielded C9 glycol is further converted to racemic astaxanthin.
As described above, the synthesizing astaxanthin obtained by these methods is usually by (3S, 3'S)-, meso-and (3R, 3'R)-
The 1:2:1 mixture of astaxanthin forms.Due to only needing individual isomers for certain applications, have made efforts to prepare enantiomer
C9 the glycol S-II and R-II of pure form allow enantioselectivity to produce (3S, 3'S)-and (3R, 3'R) astaxanthin.
R.Zell et al., Helvetica Chimica Acta 1981,64,2447, for example, describe it is several by using
From chiral 4- hydroxyl -2,6, the multistep synthesis that 6- trimethyl-cyclohex-2-en -1- ketone starts, or the diastereomer for passing through R/S-II
The optical resolution of the crystallization of salt, or the method for preparing by using microbe conversion enantiomer-pure S-II and R-II.However, these
Method is usually aborative and low yield.
Another method be related to the microorganism optical resolution-of racemic 3- acetoxyl group -4- oxo-beta-ionone referring to
E.Becher etc., Helvetica Chimica Acta 1981,64,2419.
Up to the present, only seldom S- enantiomer for attempting to come preparation of compounds of formula I is used as (3S, 3'S)-astaxanthin
Chiral synthesis precursor, allow from the beginning stereoselectivity prepare (3S, 3'S)-astaxanthin.
WO2008/116714A1 discloses the method that enantioselectivity prepares C9 glycol S-II and R-II, is included in chirality
Hydride donor enantioselective reduction 3,5,5- trimethyl-cyclohex-2-en -1,4- two is used in the presence of transition-metal catalyst
The derivative of ketone.Enantiomer S-II and R-II is with the acquisition of high antimer purity.Further disclose it is a kind of prepare optical voidness (3S,
3'S)-astaxanthin method, wherein using such available enantiomer-pure glycol S-II.
In order to obtain with (3S, 3'S)-needed for enough high-optical-purities or (3R, 3'R)-astaxanthin, it is highly desirable to mention
For with the excessive compound II of high antimer or its suitable derivative.However, preparation mapping as described in the prior art
The method of the pure C9 glycol S-II and R-II of body is usually aborative.
Summary of the invention
The object of the present invention is to provide the effective ways that a kind of enantioselectivity prepares C9 glycol S-II or R-II derivative,
The derivative can be used for compound stereoscopic isomer-pure (3S, 3'S)-or (3R, 3'R)-astaxanthin.Particularly, this method should permit
Perhaps C9 the glycol S-II or R-II being enriched with using enantiomer, only have medium optical purity.
It is surprisingly found that general formula S, S-I or R, the C9 acetal of R-I can be by including the method for following reaction with height
Stereocpecificity obtains: in acid and in the presence of anhydrous aprotic solvent, have at least S-II of the enantiomeric excess of 80%ee or
R-II is reacted with the prochirality enol ether of the prochirality acetal of formula III or formula IV respectively
Respectively in formula S, S-I and R, R-I, equally in formula III, group R1Selected from C1-C4Alkyl, C2-C4Alkenyl,
C2-C4Alkynyl, phenyl and benzyl, wherein phenyl and benzyl are unsubstituted or are selected from halogen, C with one or two1-C3Alkane
Base and C1-C3The group R of alkoxy1a。
Respectively in formula S, S-I and R, R-I, asterisk indicates chiral centre.
In formula III and IV, group R2It is C1-C4Alkyl.
In formula IV, group R3It is independently from each other hydrogen, C1-C3Alkyl, C2-C3Alkenyl, C2-C3Alkynyl and phenyl,
Wherein phenyl is unsubstituted or is selected from halogen, C with one or two1-C3Alkyl and C1-C3The group R of alkoxy1a, item
Part is in a group R3In the case where being phenyl, another group R3It is hydrogen, and if group R in formula IV3Independently of one another
Ground is selected from hydrogen, C1-C3Alkyl, C2-C3Alkenyl and C2-C3Alkynyl, two group R3Maximum C atomicity be 3.
Therefore, the first aspect of the present invention, which is related to preparation, has at least 90%, especially at least 95% enantiomer and non-
General formula S, S-I or the R of enantiomeric purity, the method for R-I compound are included in the presence of acid and anhydrous aprotic solvent, have
At least compound of the formula S-II or R-II of the enantiomeric excess of the 80%ee enol with the acetal of general formula III or general formula IV respectively
Ether reaction.
Method of the invention provides formula S, S-I and R respectively with high yield and high antimer and diastereomer purity, R-I's
C9 acetal, about formula S, the S of S-I, the R of S- diastereomer and formula R, R-I, R- diastereomer is respectively at least 90%, especially
At least 95%., it is surprising that can be held by approach described in scheme 2 despite the presence of acid reaction condition and compound
It changes places the fact that carry out isomerization, but the racemization of the Stereocenter of C-4 in compound S-II and R-I1 is not observed.
Scheme 2:
But the Stereocenter at the position 4 of formula S-II and R-II compound is respectively for positioned at R1Carbon atom
On formula S, S-I and R, the second Stereocenter in R-I provides strong chiral induction.Furthermore, it is possible to by conventional purification method, it is special
It is not the formation that any possible unwanted stereoisomer occurred is removed by preferential crystallization.
Formula S, S-I and R, the compound of R-I can especially be used separately as preparation (3S, 3'S)-astaxanthin and (3R, 3'R)-shrimp
The raw material of green element.Therefore, another aspect of the present invention relates to preparation (3S, 3'S)-astaxanthin methods comprising by above
General formula S, the compound of S-I are provided with method defined below, or is related to the method for preparing (3R, 3'R)-astaxanthin comprising
General formula R, the compound of R-I are provided by the method defined above and below.
It is described in detail
As used herein, term " enantiomeric purity " or " optical purity " refer to the enantiomeric excess of chiral material (usually
Be abbreviated as ee) measurement.It is more that term " enantiomeric excess " or " ee " refer to that a kind of enantiomer exists compared with another enantiomer
Few measurement.For the mixture of R and S enantiomer, enantiomeric excess percentage is defined as | R-S | * 100, and wherein R and S is mixed
Corresponding mole or weight fraction for closing enantiomer in object, so that R+S=1.According to the knowledge of chiral material optical activity, enantiomer mistake
Amount percentage is defined as ([α] obs/ [α] max) * 100, wherein [α] obs is the optical activity of mixture of enantiomers, [α]maxIt is pure
The optical activity of enantiomer.The term as used herein " diastereomer purity ", " diastereomeric excess " or " de " by be similar to pair
Body purity, enantiomeric excess or ee are reflected to define.Enantiomer or diastereomeric excess can be measured by using various analytical technologies,
Including such as NMR spectroscopy, the chromatography or optical polarization measuring method of chiral stationary phase are used.
The term as used herein " mapping is pure ", " enantiomer-pure ", " diastereomer is pure ", " alloisomerism is pure " or " optical voidness "
It is intended to indicate that substantially by a kind of Stereoisomeric compounds that stereoisomer forms.Term is " substantially by a kind of alloisomerism
Body composition " refers to that these Stereoisomeric compounds have at least 95%, especially at least 98% ee and/or de.
For purposes of the present invention, term " C1-C4Alkyl " refers to methyl, ethyl, n-propyl, isopropyl, and normal-butyl is different
Butyl, sec-butyl or tert-butyl.Preferably, C1-C4Alkyl is selected from methyl, ethyl, n-propyl and isopropyl, particularly C1-C4Alkane
Base is methyl or ethyl.
Term " C1-C3Alkyl " refers to methyl, ethyl, n-propyl or isopropyl.Preferably, C1-C3Alkyl is selected from methyl
And ethyl, especially methyl.
Term " C2-C4Alkenyl " refers to the unbranched group of 2 to 4 carbon atoms containing 1 or 2 double bond or containing 1
The branched group of 3 to 4 carbon atoms of double bond.C2-C4The example of alkenyl is vinyl, 1- acrylic, 2- acrylic, 1- butylene
Base, 2- cyclobutenyl, 3- cyclobutenyl, 2- methyl-1-propylene base, 2- methyl -2- acrylic etc..Preferably, C2-C4Alkenyl is selected from second
Alkenyl, 2- acrylic, 1- cyclobutenyl, 2- cyclobutenyl, 3- cyclobutenyl and 2- methyl-1-propylene base, especially vinyl and 2- third
Alkenyl.
Term " C2-C3Alkenyl " refers to vinyl, 1- acrylic and 2- acrylic.Preferably, C2-C3Alkenyl is selected from second
Alkenyl and 2- acrylic, especially vinyl.
Term " C2-C4Alkynyl " refers to, for example, acetenyl, 1- propinyl, 2-propynyl, 1- butynyl, 2- butynyl and
1- methyl -2-propynyl.Preferably, C2-C4Alkynyl is selected from acetenyl, 1- propinyl, 1- butynyl and 2- butynyl, especially
Acetenyl and 1- propinyl.
Term " C2-C3Alkynyl " refers to acetenyl, 1- propinyl and 2-propynyl.Preferably, C2-C3Alkynyl is selected from second
Alkynyl and 1- propinyl, especially acetenyl.
Term " halogen " refers to fluorine, chlorine, bromine and iodine.Preferably, halogen is fluorine or chlorine, especially chlorine.
Term " C1-C4Alkoxy " refers to, for example, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy,
Tert-butoxy.Preferably, C1-C4Alkoxy is selected from methoxyl group, ethyoxyl and isopropoxy, more preferable methoxyl group and ethyoxyl,
Especially methoxyl group.
Term " C1-C3Alkoxy " refers to methoxyl group, ethyoxyl, positive propoxy and isopropoxy.Preferably, C1-C3Alkane
Oxygroup is selected from methoxyl group and ethyoxyl, especially methoxyl group.
Preferably, the group R in formula S, S-I, R, R-I and III1Selected from C1-C4Alkyl, phenyl and benzyl, wherein phenyl and
Benzyl is unsubstituted or is selected from halogen, C with one or two1-C3Alkyl and C1-C3The group R of alkoxy1a。
It is highly preferred that the group R in formula S, S-I, R, R-I and III1Selected from C1-C4Alkyl, phenyl and benzyl, wherein phenyl
It is unsubstituted or with one or two selected from chlorine, the group R of methyl and methoxyl group with benzyl1a。
Particularly, the group R in formula S, S-I, R, R-I and III1Selected from C1-C4Alkyl and phenyl.
Preferably, the group R in formula III and IV2Selected from methyl, ethyl, n-propyl and isopropyl, especially methyl and second
Base.
Obviously, the R in formula IV3R3The part C=corresponds to group R1Subtract a hydrogen atom.Therefore, two group R3In
The total number of carbon atoms corresponds to group R1Carbon atom number subtract a carbon atom.Preferably, the group R in formula IV3Independently of one another
Selected from hydrogen, C1-C3Alkyl and phenyl, wherein phenyl is unsubstituted or is selected from halogen, C with one or two1-C3Alkyl and
C1-C3The group R of alkoxy1a, condition is a group R if in formula IV3It is phenyl, then another group R3It is hydrogen, and
And if group R in formula IV3It is independently from each other hydrogen and C1-C3Alkyl, then two group R3Maximum C atomicity be 3.
It is highly preferred that the group R in formula IV3It is independently from each other hydrogen, C1-C3Alkyl and phenyl, wherein phenyl is not
Replace or with one or two be selected from chlorine, the group R of methyl and methoxyl group1a, condition is a group if in formula IV
R3It is phenyl, then another group R3It is hydrogen, and if group R in formula IV3It is independently from each other hydrogen and C1-C3Alkyl,
Then two group R3Maximum C atomicity be 3.
Particularly, the group R in formula IV3It is independently from each other hydrogen and C1-C3Alkyl, especially hydrogen, methyl and ethyl,
Condition is two group R3Maximum C atomicity be 3.
Above-mentioned group R1, R2And R3Preferred embodiment can any combination each other.
Therefore, the present invention is more particularly directed to methods as defined above, wherein
R in formula S, S-I, R, R-I and III1Selected from C1-C4Alkyl, phenyl or benzyl, wherein phenyl and benzyl are not take
Generation or with one or two be selected from chlorine, the group R of methyl and methoxyl group1a,
R in formula III and IV2It is methyl or ethyl, and
R in formula IV3It is independently from each other hydrogen, C1-C3Alkyl and phenyl, wherein phenyl is unsubstituted or with one
It is a or two be selected from chlorine, the group R of methyl and methoxyl group1a, condition is if a group R in formula IV3Phenyl, then another
Group R3It is hydrogen, and if group R in formula IV3It is independently from each other hydrogen and C1-C3Alkyl, two group R3Maximum C
Atomicity is 3.
Particularly, the present invention relates to methods as defined above, wherein
R in formula S, S-I, R, R-I and III1Selected from C1-C4Alkyl and phenyl,
R in formula III and IV2Selected from methyl and ethyl, and
R in formula IV3It is independently from each other hydrogen, methyl and ethyl, condition is two group R in formula IV3Maximum C
Atomicity is 3.
The acetal applied in the methods of the invention is preferably selected from compounds of formula III, wherein R1It is C1-C4Alkyl, phenyl
Or benzyl, wherein phenyl and benzyl are unsubstituted or are selected from chlorine, the group R of methyl and methoxyl group with one or two1a, R2
Selected from methyl or ethyl.
It is highly preferred that the acetal applied in the method for the invention is selected from compounds of formula III, wherein R1It is C1-C4Alkane
Base or phenyl, R2Selected from methyl or ethyl.
Particularly preferred compound of formula III is 1,1- dimethoxy-ethane, 1,1- dimethoxy propane, 1,1- dimethoxy
Base butane, 1,1- dimethoxy -2- methylpropane, 1,1- diethoxyethane, 1,1- di ethyl propyl ether, 1,1- diethoxy
Butane, 1,1- diethoxy -2- methylpropane, dimethoxy-methyl benzene and diethoxymethyl benzene.
Enol ether for the method for the present invention is preferably selected from compounds of formula IV, wherein R2For methyl or ethyl, R3Each other
Independently selected from hydrogen, C1-C3Alkyl and phenyl, wherein phenyl is unsubstituted or is selected from chlorine, methyl and first with one or two
The group R of oxygroup1a, condition is a group R if in formula IV3It is phenyl, then another group R3It is hydrogen, and if formula
Group R in IV3It is independently from each other hydrogen and C1-C3Alkyl, then two group R3Maximum C atomicity be 3.
It is highly preferred that the enol ether compound applied in the method for the invention is selected from compounds of formula IV, wherein R2
It is methyl or ethyl, and group R3First is that hydrogen, another group R3Selected from hydrogen, C1-C3Alkyl and phenyl.
Particularly preferred compound of Formula IV is ethyleneoxy methane, ethyleneoxy ethane, 1- methoxy propyl -1- alkene, 1-
Ethoxy-c -1- alkene, 1- methoxyl group but-1-ene and 1- ethyoxyl but-1-ene.
The compound of general formula III and IV can be bought or they can be by synthesis well known to those skilled in the art
Method preparation.
According to the present invention, glycol S-II or R-II is reacted with the enol ether of the acetal of general formula III or general formula IV respectively
It is carried out in the presence of acid.
The acid for being commonly used for the method for the present invention is selected from
Inorganic acid, such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid or nitric acid,
Alkyl sulfonic acid, such as methanesulfonic acid, ethanesulfonic acid or camphorsulfonic acid,
Halogenated alkylsulfonic acids, such as trifluoromethanesulfonic acid,
Aryl sulfonic acid, such as benzene sulfonic acid or p-methyl benzenesulfonic acid, and
-C1-C7Carboxylic acid, such as formic acid and acetic acid,
Halogenated carboxylic acid, such as trichloroacetic acid or trifluoroacetic acid.
Preferably, alkyl sulfonic acid, halogenated alkylsulfonic acids, aryl sulfonic acid and halogenated carboxylic are selected from for the acid of the method for the present invention
Acid.
It is highly preferred that the acid for the method for the present invention is selected from methanesulfonic acid and p-methyl benzenesulfonic acid.
It particularly, is p-methyl benzenesulfonic acid for the acid of the method for the present invention.
In general, use in the method for the invention acid amount in the range of 0.1 to 5 mole of %, preferably 0.2 to 3
In the range of mole %, especially in the range of 0.5 to 1 mole of %, it is based on 1 mole compound S-II or R-II.
Glycol S-II or R-II respectively on the reaction principle of acetal III or enol ether IV can in the solution, with suspend
The form of liquid carries out in the form of an emulsion.Preferably, glycol S-II or R-II is reacted with acetal III or enol ether IV respectively
It carries out in the solution.
According to the present invention, glycol S-II or R-II is molten in anhydrous aprotic with reacting for acetal III or enol ether IV respectively
It is carried out in the presence of agent.Herein, term " anhydrous " refers to containing at most 0.1 weight %, preferably up to 0.05 weight %, especially
It is the solvent of the at most water of 0.01 weight %.As used herein, term " non-proton ", which refers to, cannot provide or receive the molten of proton
Agent.
Aprotic solvent for the method for the present invention is preferably selected from
-C5-C8Alkane, such as pentane, hexane, heptane, petroleum ether or volatile oil,
-C5-C8Cycloalkane, such as pentamethylene, hexamethylene or cycloheptane,
Chlorination C1-C2Alkane, such as methylene chloride, chloroform or 1,2- dichloroethanes,
C is selected from optionally with 1-41-C4Alkyl, C1-C4The benzene of the substituent group of alkoxy and chlorine, such as benzene, toluene, second
Benzene, dimethylbenzene, methoxybenzene or chlorobenzene,
-C1-C4Dialkyl ether, such as ether, diisopropyl ether, methyl tertiary butyl ether(MTBE),
Cyclic ethers, such as tetrahydrofuran or Isosorbide-5-Nitrae-dioxanes,
And its mixture.
It is highly preferred that the aprotic solvent for the method for the present invention is selected from hexane, heptane, hexamethylene, methylene chloride, first
Benzene, diisopropyl ether, methyl tertiary butyl ether(MTBE) and its mixture.
The aprotic solvent of azeotropic mixture can be particularly preferably formed with methanol or ethyl alcohol.Therefore, it is used for this hair
The aprotic solvent of bright method is particularly preferably selected from methylene chloride, toluene and hexamethylene, especially methylene chloride.
Reaction according to the present invention can carry out in -10 DEG C to specific aprotic solvent used of boiling point temperature range.
In general, reaction according to the present invention carries out within the temperature range of 0 DEG C to 110 DEG C, preferably in 0 DEG C to 80 DEG C of temperature
It spends in range, especially in the range of 0 DEG C to 50 DEG C.
Reaction according to the present invention can usually carry out under ambient pressure or under reduction or raised pressure.It is preferred that
Ground, reaction according to the present invention carry out under 0.1 to 10 bar of pressure.
Reaction according to the present invention can be being not present or there are carry out in the case where inert gas.It is logical to state inert gas
Refer to gas, under main reaction condition not with react in raw material, reagent or solvent or occur to appoint with products therefrom
What is reacted.Reaction according to the present invention preferably carries out in the presence of an inert gas.
In general, glycol S-II or R-II pass through with reacting for acetal III or enol ether IV first by anhydrous aprotic respectively
The acid of the glycol S-II or R-II with catalytic amount of solution form are added in suitable reaction vessel together to carry out in solvent.So
Afterwards, the enol ether of the acetal of general formula III or general formula IV is added in the solution of glycol S-II or R-II and acid respectively.Acetal
III or enol ether IV can be added respectively when reacting beginning with a part, or a point several parts are added, for example, 2 to 20 parts, or
It is continuous in reaction process, for example, being added in the solution of glycol S-II or R-II and acid within 5 minutes to a few houres time.
Preferably, acetal III or enol ether IV is added in the solution of glycol S-II or R-II and acid with 5 to 20 parts respectively, or
It was continuously added within 10 minutes to 3 hours time.
It is excessively used in general, the acetal of general formula III or the enol of general formula IV are respectively relative to glycol S-II or R-II.At this
Glycol S-II or R-II used in the method for invention respectively with the molar ratio of acetal III or enol ether IV usually 1:1.2 extremely
In the range of 1:5, preferably in the range of 1:1.5 to 1:3, in the range of especially 1:1.8 to 1:2.6.
According to the method for the present invention, glycol S-II or R-II or with the aldolisation of general formula III or with general formula IV's
Enol ether reaction.Two kinds of variants of the conversion substantially carry out under identical reaction conditions, therefore it is logical to be equally applicable to preparation
Formula S, S-I or R, the compound of R I.However, enol ether compound IV is usually more stronger than acetal III reactivity.
Therefore, the preferred embodiments of the invention are related to general formula S, S-I or R as defined above, the system of the compound of R-I
It is standby, wherein the glycol S-II or R-II at least enantiomeric excess of 80%ee is reacted with the enol ether of general formula IV.
Reaction according to the present invention can be designed as continuous, semi-batch or be conducted batch-wise.Batch reactions can used usually
It is carried out in the reaction unit of this purpose, for example, stirred reactor.Successive reaction can be for example in tubular reactor or extremely
It is carried out in the cascade of few three reversed mixing reactors.Reactor almost isothermal or almost can be operated adiabatically.Continuously grasping
In the case where the reactor of work, it regard glycol S-II or R-II, acetal III or enol ether IV, solvent and acid as liquid respectively
Stream is added in reactor.Preferably, the temperature of charging, pressure and composition are selected, so that the mixed feeding at reactor inlet
Stream is liquid (do not have gas phase) and homogeneously (not being separated into two liquid phases).
It after completion of the reaction, will include required C9 acetal S, S-I or R, the reaction mixture of R-I carries out conventional post-processing journey
Sequence, preferably extraction post-processing.In general, first by the way that inorganic base is added come neutralization reaction mixture, for example, KHCO3, NaHCO3Or
NaOH, preferably aqueous solution form.Then the water phase and organic phase of the separating obtained biphase mixture of conventional method can be used.From
After removing volatile matter in isolated organic phase, acetal S, S-I or R, R-I are usually obtained with high-purity.
Method of the invention provides C9 acetal S, S-I or R, R-I with high yield and high-optical-purity.In general, passing through this hair
C9 acetal S, S-I or the R that bright method obtains, enantiomer and diastereomer purity of the R-I at least 90%.
Acetal S, S-I and the R obtained by means of the present invention, the enantiomer and diastereomer purity of R-I are usually distinguished
Enantiomeric purity depending on applied glycol S-II or R-II.But, if it is desired, it can be by using conventional purifying
Method, such as chromatographic process or method for crystallising further increase acetal S, S-I and R, the optical purity of R-I.In particular, acetal
The optical purity of S, S-I and R, R-I can further be improved by crystallizing.
Therefore, it is pure at least 90% enantiomer and diastereomer to be related to preparation for a preferred embodiment of the invention
General formula S, S-I or the R of degree, the method for the compound of R-I, as defined above, wherein by compound S-II or R-II and acetal III
Or the crude product obtained after enol ether IV reaction passes through crystallization purifying.
The crystallization of thick C9 acetal S, S-I and R, R-I can be carried out by using conventional crystallization technique, for example, by making
With temperature gradient, back-diffusion or evaporation, optionally be put into together with crystal seed.Preferably, thick C9 acetal is carried out by using crystal seed
S, S-I and R, the crystallization of R-I.In general, by preparing acetal S, S-I or R to be purified first, the supersaturated solution of R-I come into
Row crystallization.Then, it will be added in the solution by the crystal seed of required acetal S, S-I or the R of optical voidness form, R-I composition, to promote
The selective crystallization of corresponding stereoisomer.
Thus obtained C9 acetal S, S-I and R, enantiomer and diastereomer purity of the R-I at least 95%, usually extremely
Few 96%, more often at least 97%.In general, for analyzing acetal S, S-I and R, the chromatographic process of the purity and composition of R-I
In detection limit, other stereoisomers are undetectable.The detection limit of chromatographic analysis system used is estimated as about 0.1 weight
Measure %.
As described above, the C9 glycol that can be used for the formula S-II and R-II of the method for the present invention is not necessarily required to the mapping for having high
Body purity, for example, being greater than the enantiomeric purity of 95%ee.On the contrary, the formula S-II and R- that the use of enantiomeric purity are 80-95%ee
The C9 glycol of II may be sufficient.The C9 glycol of the general formula S-II and R-II that apply in the methods of the invention preferably have at least
The enantiomeric purity of 85%ee, especially at least 90%ee.
Methods known in the art system can be used in the C9 glycol of general formula S-II and R-II with above-mentioned enantiomeric purity
It is standby.Preferably, enantiomer-pure glycol S-II and R-II are similar to the preparation of method described in WO 2008/116714A1.In this side
Face, with reference to the complete disclosure of WO2008/116714A1.
Therefore, a preferred embodiment of the invention is related to method as defined above, wherein at least 80%ee
The compound of the general formula S-II or R-II of enantiomeric excess are prepared by following reaction: being matched comprising transition metal and a chirality
Compounds of formula V is reacted with hydrogen donor in the presence of the chiral transition metal of body
Wherein,
M+Selected from alkali metal cation, group (M1 1/2)+With group (M1X)+, wherein M1It is alkaline earth metal cation, X is single
Charge anions.
Preferably, the variable M in Formula II compound+It is selected from:
Alkali metal cation, such as Li+, Na+, K+, Rb+Or Cs+, preferably Na+Or Ka+, especially Na+；
Group (M1 1/2)+Or group (M1X)+, wherein M1It is alkaline earth metal cation, such as Mg2+, Ca2+, Sr2+Or Ba2+,
Especially Mg2+, X is single charge anions, such as halogen, acetate or dihydrogen phosphate.
The transition metal of chiral transition metal is preferably ruthenium.Particularly, chiral transition metal only includes
One ruthenium atom.
Preferred chiral transition metal, such as especially chiral ruthenium catalyst, can be for example suitable by making
Transition metal precursors compound, such as especially ruthenium compound, for example, formula Ru-I ruthenium compound and suitable chiral ligand it is anti-
It should obtain
[RuY2(η6-Ar)]2, (Ru-I)
Wherein in formula Ru-I, variable Y is selected from fluorine, and chlorine, the halogen of bromine and iodine, especially chlorine, Ar is benzene or substitution
Benzene derivative, especially by one or more C1-C4Alkyl-substituted benzene derivative, such as especially p -Methylisopropylbenzene.It is special
Not preferred ruthenium compound has formula Ru-I, and wherein Y is chlorine, and Ar is p -Methylisopropylbenzene, i.e. 1- methyl -4- (propyl- 2- yl)
Benzene.
In a preferred embodiment, it is used to prepare the chiral transition metal catalysis of general formula S-II or R-II compound
Agent includes a chiral ligand, is derived from optically active amines or optically active amino acids, is especially derived from optical activity ammonia
Base acid.Optical activity amine ligand preferably has at least enantiomeric excess of 90%ee.In general, optically active amines or optical activity ammonia
Base acid by with suitable transistion metal compound such as [RuY2(η6-AR)]2Make optically active amines or amino in reaction process
Acid amino deprotonation and be converted to chiral ligand.
Here preferred optically active amines are that there are two the optical activity diastereomers of the amine of chiral centre for tool.Obviously, this
The particular optical activity diastereomer of kind of amine will selectively generate a kind of enantiomer of formula II compound, and its optical antipode
Another enantiomer of formula II compound will be generated.Technical staff can easily find out by conventional method, which kind of is needed right
It reflects body and is formed selectively required enantiomer S-II or R-II.There are two the amine of chiral centre to be preferably selected from 1,2- hexichol for tool
Base -2- ethylaminoethanol (H2N-CHPh-CHPh-OH), 1- phenyl -2- methyl-2-amino ethyl alcohol (H2N-CHMe-CHPh-OH), N-
Methyl-1-phenyl-2- methyl-2-amino ethyl alcohol (MeHN-CHMe-CHPh-OH) and N- p-toluenesulfonyl-1,2- diphenyl second
Diamines (H2N-CHPh-CHPh-NHTs), especially H2N-CHPh-CHPh-NHTs。
Therefore, the chiral ligand of chiral transition metal is preferably the single anion of amine, is selected from H2N-CHPh-
CHPh-OH, H2N-CHMe-CHPh-OH, MeHN-CHMe-CHPh-OH and H2N-CHPh-CHPh-NHTs, especially H2N-CHPh-
CHPh-NHTs.Therefore, when selected from H2N-CHPh-CHPh-OH, H2N-CHMe-CHPh-OH, MeHN-CHMe-CHPh-OH and H2N-
The optical activity diastereomer of the diamines of CHPh-CHPh-NHT, especially H2The diastereomer of N-CHPh-CHPh-NHTs and conjunction
Suitable transistion metal compound, especially suitable ruthenium compound form this for example, especially when the compound reaction of formula Ru-I
A little preferred chiral ligands.
Particularly preferred optical activity diastereomer herein is selected from (1S, 2S)-N- p-toluenesulfonyl -1,2- hexichol
Base-ethylenediamine ((1S, 2S)-H2) and (1R, 2R)-N- p-toluenesulfonyl -1,2- diphenyl-second two N-CHPh-CHPh-NHTs
Amine ((1R, 2R)-H2N-CHPh-CHPh-NHTs)。
Therefore, in a preferred embodiment of the invention, chiral transition metal can be by making suitable ruthenium
Compound, such as it is especially [RuY2(η6-Ar)]2With H2N-CHPh-CHPh-OH, H2N-CHMe-CHPh-OH, MeHN-CHMe-
CHPh-OH or H2One of diastereomer of N-CHPh-CHPh-NHTs, especially with (1S, 2S)-H2N-CHPh-CHPh-NHTs or
(1R, 2R)-H2N-CHPh-CHPh-NHTs reaction obtains.
As (1S, 2S)-H with deprotonation2N-CHPh-CHPh-NHTs or (1R, 2R)-H of deprotonation2N-CHPh-
CHPh-NHTs as chiral transition metal, especially chiral ruthenium catalyst chiral ligand carry out compound S-II or
When the preparation of R-II, the S- enantiomer and R- enantiomer of formula (I) compound can be obtained excessively with high antimer respectively.
Preferably, it is selected from organic compound for the hydrogen donor of enantioselective reduction Formula V compound, it includes at least one
A secondary alcohol groups, such as isopropanol, 2- butanol, 2- amylalcohol, 2- hexanol or 3- hexanol.In particular, being used in enantioselective reduction
Hydrogen donor be isopropanol.
Based on 1 mole of Formula V compound, the amount of the chiral transition metal for enantioselective reduction is preferably
0.5 to 10 mM, especially 1 to 5 mM.
Enantioselective reduction preferably 10 DEG C to 85 DEG C at a temperature of carry out, especially 15 DEG C to 75 DEG C at a temperature of
It carries out.
Enantioselective reduction preferably carries out in the presence of solvent.Preferably, solvent is selected from secondary alcohol, especially isopropanol,
With the mixture of water.
Particularly preferably chiral transition metal, wherein chiral ligand passes through optical activity H2N-CHPh-CHPh-
OH, H2N-CHMe-CHPh-OH, MeHN-CHMe-CHPh-OH or H2The single deprotonation of N-CHPh-CHPh-NHTs obtains, special
It is not by (1S, 2S)-N- tosyl -1,2- diphenyl-ethylenediamine or (1R, 2R)-N- p-toluenesulfonyl -1,2- bis-
The single deprotonation of phenyl-ethylenediamine obtains.
Preferably, the aqueous solution of inorganic basis such as KOH, NaOH are used for the single deprotonation of optical activity ligand.
After completing enantioselective reduction, the compound of formula S-II' or R-II' is obtained, they are required product S- respectively
The salt of II or R-II,
Wherein M+With one of meaning as defined above.
In general, the salt of formula S-II' or R-II' are separately converted to the compound of formula S-II or R-II by acidification step,
Such as Helvetica Chimica Acta 1981, described in 64,2436.
If using (1S, 2S)-H of deprotonation2N-CHPh-CHPh-NHTs or (1R, 2R)-H of deprotonation2N-
CHPh-CHPh-NHTs carries out general formula Vization as the chiral ligand of chiral transition metal, especially chiral ruthenium catalyst
The enantioselective reduction of object is closed, acid post-processing then is carried out to gained reaction mixture, respectively obtains high antimer excess
S- enantiomer S-II and R- enantiomer R-II.
Therefore, the formula S-II compound at least enantiomeric excess of 80%ee particularly preferably passes through side as defined above
Method preparation, wherein (1S, 2S)-N- tosyl -1,2- diphenyl-ethylenediamine of deprotonation is used as chiral ligand.
Equally, the formula R-II compound at least enantiomeric excess of 80%ee particularly preferably passes through side as defined above
Method preparation, wherein (1R, 2R)-N- p-toluenesulfonyl -1,2- diphenyl-ethylenediamine of deprotonation is used as chiral ligand.
C9 acetal S, S-I and the R that can be obtained by means of the present invention, R-I is to can be used for preparing having for carotenoid
The intermediate of value, such as in G.Britton, S.Liaanen-Jensen, H.Pfander, Vol.2,Verlag, Basel, 1996, page 283 and then describe in each page.Particularly, C9 acetal S, S-I and
R, R-I are advantageously used for preparation (3S, 3'S)-or (3R, 3'R)-astaxanthin.
Therefore, another aspect of the present invention relates to preparation (3S, 3'S)-astaxanthin methods comprising by as defined above
Method provide general formula S, the compound of S-I, and preparation (3R, 3'R)-astaxanthin method comprising by as defined above
Method provide general formula R, the compound of R-I.
From S, S-I or R, R-I starts, and (3S, 3S')-astaxanthin or (3R, 3R')-astaxanthin can be according to established non-
The preparation of stereoselective syntheses approach, such as describe in G.Britton, S.Liaanen-Jensen, H.Pfander,
Carotenoids,Vol.2,In Verlag, Basel, 1996, or description is in Helvetica
In Chimica Acta 1981,64,2447, or description is in the patent literature, such as in EP 1197483 or EP 1285912
In.
Following embodiment is intended to provide to further explanation of the invention.
Embodiment
I) high performance liquid chromatography (HPLC) is analyzed:
HPLC system: Agilent series 1100
HPLC- column: it comes fromZorbax Eclipse XDB-C18,1.8 μm, 50 × 4.6mm
Eluent: eluent A: contain 0.1 volume %H3PO4Water
Eluent B: there is 0.1 volume %H3PO4Acetonitrile
Detektor:UV-Detektor λ=262nm, BW=6nm
II) NMR is analyzed
1H-1H-ZQF-NOESY experiment is carried out at 360MHz
III embodiment) is prepared:
Embodiment III.1
(2S, 7aS) -2,4,6,6- tetramethyl -7,7a- dihydro -1,3- benzodioxoles (benzodioxol) -
The preparation of 5- ketone.
To 108.7g 40.6% (4S) -3,4- dihydroxy -2,6,6- trimethyl-cyclohex-2-en -1- ketone at 25 DEG C
279mg (1.47mmol) p-methyl benzenesulfonic acid monohydrate is added in methylene chloride (259mmol) solution.In 1 hour thereto
42.4g (588mmol) ethyl vinyl ether is added dropwise.Then gained mixture is stirred 80 minutes at 40 DEG C.After the reaction was completed,
5% sodium hydrate aqueous solution of 30ml is added, obtained two-phase mixture is stirred 15 minutes at 20 DEG C.Organic phase is separated, is used
30ml water washing, is removed under reduced pressure volatile matter.Residue is dissolved in 30ml methanol at 45 DEG C.Then, 20ml water is added, it will be molten
Liquid slowly cools to 0 DEG C.At 34 DEG C, crystal seed is added.Obtained suspension is stirred 1 hour at 0 DEG C, filters and uses 40ml
Methanol: cold mixt and 50ml the cold water washing of water (1:1).Then by the solid of acquisition in a vacuum drying oven at 30 millibars and
It is dry at 40 DEG C.It obtains 39.7g (2S, 7aS) -2,4,6,6- tetramethyl -7,7a- dihydro -1,3- benzodioxole -5-
Ketone (purity 95.4%, yield 74.4%) is colorless crystalline solid, uniform product is proved to be in HPLC and NMR spectra.Make
With1H-1H-ZQF-NOESY-NMR is tested and in the case where being understood the absolute configuration of starting material, will be not right at position 2
Absolute configuration at title center is determined as (S).
Embodiment III.2
(2S, 7aS) -2- ethyl -4,6, the system of 6- trimethyl -7,7a- dihydro -1,3- benzodioxole -5- ketone
It is standby.
By (4S) -3,4- dihydroxy -2,6,6- trimethyl-cyclohex-2-en -1- ketone of 10g 25% in dichloro at 25 DEG C
Solution and 36.5mg p-methyl benzenesulfonic acid monohydrate in methane (15mmol) are placed in suitable reaction vessels.It is added dropwise thereto
2.86g (33mmol, 2.2 equivalents) ethyl -1- propenyl ether.Then gained mixture is stirred 1 hour under reflux.Then,
Reaction mixture is cooled to 20 DEG C and with 5% sodium bicarbonate aqueous solution of 10ml and 10ml water washing.Organic phase Na2SO4It is dry
It is dry, volatile matter is removed under reduced pressure.Obtain 2.83g (2S, 7aS) -2- ethyl -4,6,6- trimethyl -7,7a- dihydro -1,3- benzo two
Oxole -5- ketone proves that it is uniform product in achirality and chirality HPLC.
Embodiment III.3
(2S, 7aS) -2- n-propyl -4,6,6- trimethyl -7,7a- dihydro -1,3- benzodioxole -5- ketone
Preparation.
By (4S) -3,4- dihydroxy -2,6,6- trimethyl-cyclohex-2-en -1- ketone of 10g 25% in dichloro at 25 DEG C
Solution and 36.5mg p-methyl benzenesulfonic acid monohydrate in methane (15mmol) are placed in suitable reaction vessels.It is added dropwise thereto
3.31g (33mmol, 2.2 equivalents) ethyl -1- n-butene base ether.Then gained mixture is stirred 1 hour under reflux.So
Afterwards, reaction mixture is cooled to 20 DEG C and with 5% sodium bicarbonate aqueous solution of 10ml and 10ml water washing.Organic phase Na2SO4
It is dry, volatile matter is removed under reduced pressure.Obtain 2.48g (2S, 7aS) -2- n-propyl -4,6,6- trimethyl -7,7a- dihydro -1,3- benzene
And dioxole -5- ketone, prove that it is uniform product in achirality and chirality HPLC.
Embodiment III.4
(2S, 7aS) -2- isopropyl -4,6,6- trimethyl -7,7a- dihydro -1,3- benzodioxole -5- ketone
Preparation.
By (4S) -3,4- dihydroxy -2,6,6- trimethyl-cyclohex-2-en -1- ketone of 10g 25% in dichloro at 25 DEG C
Solution and 36.5mg p-methyl benzenesulfonic acid monohydrate in methane (15mmol) are placed in suitable reaction vessels.It is added dropwise thereto
5.1g (33mmol, 2.2 equivalents) isobutylaldehyde diethyl acetal.Then gained mixture is stirred 1 hour under reflux.Then,
Reaction mixture is cooled to 20 DEG C and with 5% sodium bicarbonate aqueous solution of 10ml and 10ml water washing.Organic phase Na2SO4It is dry
It is dry, volatile matter is removed under reduced pressure.Obtain 2.61g (2S, 7aS) -2- isopropyl -4,6,6- trimethyl -7,7a- dihydro -1,3- benzo
Dioxole -5- ketone proves that it is uniform product in achirality and chirality HPLC.
Embodiment III.5
(2S, 7aS) -2- phenyl -4,6, the system of 6- trimethyl -7,7a- dihydro -1,3- benzodioxole -5- ketone
It is standby.
It is similar with embodiment III.2 to III.4, make (4S) -3,4- dihydroxy -2,6,6- trimethyl-cyclohex-2-en -1-
Ketone is reacted with benzaldehyde dimethyl acetal.Thus obtained (2S, 7aS) -2- phenyl -4,6,6- trimethyl -7,7a- dihydro -1,
3- benzodioxole -5- ketone is proved to be uniform product in achirality and chirality HPLC.
Claims (13)
1. a kind of prepare at least 90% enantiomer and general formula S, S-I or the R of diastereomer purity, the compound of R-I
Method,
Wherein R1For C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, phenyl or benzyl, wherein phenyl and benzyl are unsubstituted
Or halogen, C are selected from one or two1-C3Alkyl and C1-C3The group R of alkoxy1a, wherein asterisk indicates in chirality
The heart,
The method includes having the formula S-II of at least enantiomeric excess of 80%ee in the presence of acid and anhydrous aprotic solvent
Or the compound of R-II
It is reacted respectively with the acetal or enol ether of general formula III or IV,
Wherein
R in formula III1As defined above,
R in formula III and IV2For C1-C4Alkyl, and
R in formula IV3It is independently from each other hydrogen, C1-C3Alkyl, C2-C3Alkenyl, C2-C3Alkynyl and phenyl, wherein phenyl be
It is unsubstituted or with one or two be selected from halogen, C1-C3Alkyl and C1-C3The group R of alkoxy1a, condition is in formula IV
In a group R3For phenyl, another group R3For hydrogen, and if group R3It is independently from each other hydrogen, C1-C3Alkane
Base, C2-C3Alkenyl and C2-C3Alkynyl, two group R3Maximum C atomicity be 3.
2. according to the method described in claim 1, wherein it is described acid be selected from alkyl sulfonic acid, halogenated alkylsulfonic acids, aryl sulfonic acid and
Trifluoroacetic acid.
3. method according to claim 1 or 2, wherein the acid is selected from methanesulfonic acid and p-methyl benzenesulfonic acid.
4. method according to any of the preceding claims, wherein being based on 1 mole compound S-II or R-II, sour use
Amount is 0.1-5 moles of %.
5. method according to any of the preceding claims, wherein anhydrous aprotic solvent is selected from C5-C8Alkane, C5-
C8Cycloalkane, chlorination C1-C2Alkane is selected from C optionally with 1-41-C4Alkyl, C1-C4The substituent group of alkoxy and chlorine
Benzene, C1-C4Dialkyl ether, cyclic ethers and its mixture.
6. method according to any of the preceding claims, wherein anhydrous aprotic solvent is selected from methylene chloride, toluene
And hexamethylene.
7. method according to any of the preceding claims, wherein compound S-II or R-II and acetal III or enol
The reaction of ether IV 0 to 50 DEG C at a temperature of carry out.
8. method according to any of the preceding claims, wherein having the formula S- of at least enantiomeric excess of 80%ee
The compound of II or R-II is reacted with the enol ether of general formula IV.
9. method according to any of the preceding claims, wherein
R in formula S, S-I, R, R-I and III1Selected from C1-C4Alkyl and phenyl,
R in formula III and IV2Selected from methyl and ethyl, and
R in formula IV3It is independently from each other hydrogen, methyl and ethyl, condition is two group R3Maximum C atomicity be 3.
10. method according to any of the preceding claims, wherein with the logical of at least enantiomeric excess of 80%ee
The compound of formula S-II or R-II in the chiral transition metal comprising transition metal and a chiral ligand by existing
Lower compounds of formula V reacts preparation with hydrogen donor,
Wherein,
M+Selected from alkali metal cation, group (M1 1/2)+With group (M1X)+, wherein M1For alkaline earth metal cation, X is single charge
Anion.
11. according to the method described in claim 10, wherein compound S-II by using deprotonation-N- pairs of (1S, 2S)
Tosyl -1,2- diphenyl ethylene diamine is prepared as chiral ligand or compound R-II is by using deprotonation
(1R, 2R)-N- p-toluenesulfonyl -1,2- diphenyl ethylene diamine is prepared as chiral ligand.
12. method according to any of the preceding claims, wherein in compound S-II or R-II and acetal III or alkene
The crude product obtained after alcohol ether IV reaction passes through crystallization purifying.
13. the method that one kind is used to prepare (3S, 3'S)-astaxanthin comprising by according to claim 1 to any one of 12
Method provide general formula S, the method that the compound or one kind of S-I is used to prepare (3R, 3'R)-astaxanthin comprising pass through root
General formula R, the compound of R-I are provided according to the method for any one of claims 1 to 12.
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2017
- 2017-12-18 WO PCT/EP2017/083193 patent/WO2018114733A1/en active Application Filing
- 2017-12-18 CN CN201780078360.5A patent/CN110088094A/en active Pending
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| CN1098101A (en) * | 1993-07-05 | 1995-02-01 | Basf公司 | The preparation of astaxanthin, prepare it new intermediate with and preparation |
| CN1245166A (en) * | 1998-08-05 | 2000-02-23 | 霍夫曼-拉罗奇有限公司 | Process for preparing 4,4'-diketo carotenoid |
| US20060088905A1 (en) * | 2004-10-01 | 2006-04-27 | Lockwood Samuel F | Methods for the synthesis of zeazanthin |
| CN101646642A (en) * | 2007-03-28 | 2010-02-10 | 巴斯夫欧洲公司 | Enantioselectivity prepares optical activity 4-hydroxyl-2,6, the method for 6-3-methyl cyclohexanol-2-ketenes derivative |
| CN102002033A (en) * | 2010-12-23 | 2011-04-06 | 厦门金达威集团股份有限公司 | Protection method for astaxanthin intermediate |
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