CN109715638A - The method for preparing the structural unit phosphonium salt ester as carotenoid - Google Patents

The method for preparing the structural unit phosphonium salt ester as carotenoid Download PDF

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CN109715638A
CN109715638A CN201780056631.7A CN201780056631A CN109715638A CN 109715638 A CN109715638 A CN 109715638A CN 201780056631 A CN201780056631 A CN 201780056631A CN 109715638 A CN109715638 A CN 109715638A
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alkyl
base
hydrogen
carbon
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B·舍费尔
W·西格尔
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BASF SE
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BASF SE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5442—Aromatic phosphonium compounds (P-C aromatic linkage)

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Abstract

The present invention relates to a kind of method of phosphonium salt ester for preparing formula (I), wherein R1It is such as hydrogen, C1‑C20Alkyl, C2‑C20Alkenyl, C4‑C20Dialkylene, C6‑C20Trialkenyl or C8‑C20Apos, R2It is such as hydrogen or-NRaRb, wherein RaIt is such as hydrogen, C1‑C4Alkyl ,-C (O)-C1‑C3Alkyl ,-Boc or-Cbz, RbIt is such as hydrogen or C1‑C4Alkyl, R3It is such as hydrogen, X is CH2Or C=O, R4It is phenyl, tert-butyl or tolyl, Y‑It is suitable counter anion, the method is characterized in that making the alcohol of formula (IV) and the carboxylic acid of formula (V) or reacts with one of its derivative, wherein variable R1、R2And R3As defined above, and in n=1, variable Z is halogen ,-OH or-O-C (O)-C1‑C4Alkyl, and in n=2, variable Z is O or S, wherein the reaction also carries out in the presence of an activator in progress in the presence of tertiary amine and using the compound of the formula (IV) of Z=-OH.The invention further relates to specific formula (I) phosphonium salt esters.

Description

The method for preparing the structural unit phosphonium salt ester as carotenoid
The present invention relates to a kind of new methods of phosphonium salt ester for preparing formula (I)
Wherein R1、R2、R3、R4, X and Y-As defined herein.
Background of invention
In DE 26 53 838, DE 44 30 289, F.Kienzle et al. 1978, Helv.Chim.Acta 61,2609 With had been disclosed in J.Liu et al. 1997, Tetrahedron Lett.38,8495 as synthesizing astaxanthin and its symmetrical The intermediate formula A phosphonium salt ester of diester
Wherein variable R is acetyl group, chloracetyl, dichloro-acetyl, Ethoxyacetyl base, nitrophenoxyacetyl, propionyl Base, bytyry, valeryl, caproyl, palmityl, stearyl or oleoyl, variable V are aryl such as phenyl, and variable T- It is suitable anion such as bromide ion.Similarly, such as such as Y.Yamano et al. 1995, J.Chem.Soc.Perkin Trans.1,1895；Y.Yamano et al. 1994, Chem.Pharm.Bull.42,410 and K.Bernhard et al. 1980, It is recorded in Helv.Chim.Acta 63,1473, using (the slight difference of A) phosphonium salt ester is that they have modified ring with formula Outside chain phosphonium salt ester is as the precursor for synthesizing carotenoid and related polyenoid class.In these synthesis, acyl group R only fills When intermediate protecting group.
So far, formula A phosphonium salt ester and its close variant by introducing ester group and only hereafter just subsequent anti-at first Xing Cheng phosphonium salt part is answered in step to prepare.But this method confirmation is tediously long and expensive.
Summary of the invention
It is an object of the present invention to provide a kind of method of preparation formula A phosphonium salt ester and its variant, the method is not related to And problem of the prior art.This method should especially implement good yield that is simple and should obtaining Suo Xu phosphonium salt ester.
It has been found that can be acylated true by non-Zhiization phosphonium salt of formula (IV) by carboxylic acid in the presence of tertiary amine or activating carboxy acid It is positive to realize this purpose
Wherein R4, X and Y-As defined herein.This discovery is astonishing, because of phosphonium salt it is known that unstable and logical It is usually used in decomposing under acylated condition (such as the acid for especially using alkali, strong acid or milder with high temperature bond).Therefore ability Field technique personnel will not expect that (IV) phosphonium salt is possible to efficiently be esterified formula.This especially because formula (IV) phosphonium salt is due to it Polyene structure replaced and even also unstable to mild alkali by electron acceptor.
Therefore, present invention firstly relates to a kind of methods of phosphonium salt ester for preparing formula (I) comprising make the phosphonium salt of formula (IV) with The carboxylic acid of formula (V) is reacted with one of its derivative, wherein the reaction carries out in the presence of tertiary amine, and is using Z=-OH Formula (V) compound in the case where also carry out in the presence of an activator.
In formula (I), variable R1、R2、R3、R4, X and Y-With following meanings:
R1Selected from hydrogen, C1-C20Alkyl, C2-C20Alkenyl, C4-C20Dialkylene, C6-C20Trialkenyl, C8-C20Tetraene Base, C10-C20- five alkenyls, C1-C4Alkoxy, wherein alkyl, alkenyl, dialkylene, trialkenyl, the apos of above-mentioned seven kinds of groups It is unsubstituted or with 1,2 or 3 selected from halogen ,-OH and C with pentaene based moiety1-C4The substituent group of alkoxy,
C6-C10Aryl, benzyl, phenoxy group, benzoyloxy, wherein the aryl moieties of above-mentioned four kinds of groups are not Replace or with 1,2 or 3 be selected from halogen ,-OH, C1-C4Alkyl and C1-C4The substituent group of alkoxy,
A-COOH、A-CONH2、A-COO-(C1-C4Alkyl), and
A-NRaRb,
R2And R3It is respectively selected from hydrogen, C independently of each other1-C20Alkyl, C2-C20Alkenyl, C4-C20Dialkylene, C6-C20- three Alkenyl, C8-C20Apos, C10-C20- five alkenyls, C1-C4Alkoxy, wherein alkyl, alkenyl, the diene of above-mentioned seven kinds of groups Base, trialkenyl, apos and pentaene based moiety are unsubstituted or with 1,2 or 3 selected from halogen and C1-C4Alkoxy Substituent group,
R2Also selected from
-COOH、-COO-(C1-C4Alkyl), and
-NRaRb, or
R1And R2It is formed together the group of formula (II),
Wherein
It * is the tie point with the rest part of molecule,
RcSelected from hydrogen, C1-C19Alkyl, C2-C19Alkenyl, C4-C19Dialkylene, C6-C19Trialkenyl, C8-C19Tetraene Base, C1-C4Alkane diyl-COOH, C2-C4Alkene diyl-COOH, C2-C4Alkynes diyl-COOH, and
RdIt is hydrogen or C1-C4Alkyl, or
R1、R2And R3It is formed together the group of formula (III),
Wherein * and RcWith meaning defined above, or
If R2It is-NRaRb, R1With RaC can be formed together3-C4Alkane diyl,
R4Selected from phenyl, tert-butyl and tolyl,
X is CH2Or C=O,
Y-Selected from halide ion, sulfate radical, bisulfate ion, methanesulfonate, tosylate, benzene sulfonic acid root, nitrate anion and C1-C3Alkyl formate root,
RaSelected from hydrogen, C1-C4Alkyl ,-C (O) H ,-C (O)-C1-C3Alkyl, C4-C7Naphthenic base and N-protected base, such as uncle Butoxy carbonyl (- Boc) and carboxybenzyl (- Cbz),
RbSelected from hydrogen, C1-C4Alkyl ,-C (O)-C1-C3Alkyl and N-protected base, such as-Boc and-Cbz, and
A is selected from C1-C5Alkane diyl, C2-C5Alkene diyl and C2-C5Alkynes diyl.
In formula (IV), variable X, Y-And R4With the meaning defined to formula (I).
In formula (V), variable R1、R2And R3With the meaning defined to formula (I), and
In n=1, variable Z is selected from halogen ,-OH ,-O-C (O)-C1-C4Alkyl, and
In n=2, variable Z is O or S.
The invention further relates to formula as defined herein, (I) phosphonium salt ester, condition are group-C (O) CR1R2R3It is not second Acyl group, Ethoxyacetyl base, nitrophenoxyacetyl, propiono, bytyry, valeryl, caproyl, palmityl, stearyl Or oleoyl.
Method of the invention has the advantages that several.It is provided by non-Zhiization phosphonium salt of corresponding formula (IV) first with good Good yield and good specificity obtain formula (the simple approach of I) phosphonium salt ester.Correspondingly, method of the invention can be led to by itself It is often easy to obtain with sufficient quantity and also (IV) phosphonium salt starts simply to prepare a series of with difference the single formula of shelf-stable Formula (the I) phosphonium salt ester of acyl group.
Detailed description of the invention
In the present invention, general term is such as given a definition:
Prefix Cx-CyRefer to the possibility carbon atom number in concrete condition.
Term " halogen " refers to fluorine, bromine, chlorine or iodine, preferably fluorine, chlorine or bromine in each case, the especially chlorine for Z, With regard to Y-For especially bromine.
As herein and term " the C used in the Alliyl moieties of alkoxy etc.1-C20Alkyl " refers to 1 to 3 ("C1-C3Alkyl "), 1 to 4 (" C1-C4Alkyl ") or 1 to 20 (" C1-C20Alkyl ") saturated straight chain of a carbon atom or branching Alkyl.C1-C3Alkyl is methyl, ethyl, propyl or isopropyl.C1-C4In addition alkyl is butyl, 1- methyl-propyl (Zhong Ding Base), 2- methyl-propyl (isobutyl group) or 1,1- dimethyl ethyl (tert-butyl).C1-C20Alkyl in addition still such as amyl, 1- Methyl butyl, 3- methyl butyl, 2,2- dimethyl propyl, 1- ethyl propyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, Hexyl, 1- methyl amyl, 4- methyl amyl, 1,1- dimethylbutyl, 1,3- dimethylbutyl, 2,2- dimethylbutyl, 3,3- Dimethylbutyl, 1- ethyl-butyl, 2- ethyl-butyl, 1,1,2- thmethylpropyl, 1- ethyl -1- methyl-propyl, 1- ethyl -2- Methyl-propyl, heptyl, octyl, 2- ethylhexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, myristyl, Pentadecyl, cetyl, heptadecyl, octadecyl, nonadecyl, eicosyl and its position isomer.
The term as used herein " C2-C20Alkenyl " refers to the list with 2 to 20 carbon atoms and double bond in any position Unsaturated straight chain or branched hydrocarbyl radical, such as vinyl, 1- acrylic, 2- acrylic, 1- methyl ethylene, 1- cyclobutenyl, 2- Cyclobutenyl, 3- cyclobutenyl, 1- methyl-1-propylene base, 2- methyl-1-propylene base, 1- methyl -2- acrylic, 2- methyl -2- propylene Base, 1- pentenyl, 3- pentenyl, 4- pentenyl, 1- methyl-1-cyclobutenyl, 3-methyl-1-butene base, 1- methyl-2-butene Base, 2- methyl-2-butene base, 2- methyl -3- cyclobutenyl, 3- methyl -3- cyclobutenyl, 1,1- dimethyl -2- acrylic, 1,2- bis- Methyl-1-propylene base, 1,2- dimethyl -2- acrylic, 1- ethyl -1- acrylic, 1- ethyl -2- acrylic, 1- hexenyl, 3- Hexenyl, 5- hexenyl, 1- methyl-1-pentene alkenyl, 3- methyl-1-pentene alkenyl, 2- methyl -2- pentenyl, 4- methyl -2- amylene Base, 1- methyl-3-pentenyl, 4- methyl-3-pentenyl, 2- methyl -4- pentenyl, 4- methyl -4- pentenyl, 1,1- diformazan Base -2- cyclobutenyl, 1,1- dimethyl -3- cyclobutenyl, 1,2- dimethyl -1- cyclobutenyl, 1,2- dimethyl -2- cyclobutenyl, 1,2- Dimethyl -3- cyclobutenyl, 1,3- dimethyl -1- cyclobutenyl, 1,3- dimethyl -2- cyclobutenyl, 1,3- dimethyl -3- cyclobutenyl, 2,2- dimethyl -3- cyclobutenyl, 2,3- dimethyl -1- cyclobutenyl, 2,3- dimethyl -2- cyclobutenyl, 2,3- dimethyl -3- butylene Base, 3,3- dimethyl -1- cyclobutenyl, 3,3- dimethyl -2- cyclobutenyl, 1- ethyl -1- cyclobutenyl, 1- ethyl -2- cyclobutenyl, 1- Ethyl -3- cyclobutenyl, 2- ethyl -1- cyclobutenyl, 2- ethyl -2- cyclobutenyl, 2- ethyl -3- cyclobutenyl, 1,1,2- trimethyl -2- Acrylic, 1- ethyl -1- methyl -2- acrylic, 1- Ethyl-2-Methyl -1- acrylic, 1- Ethyl-2-Methyl -2- acrylic, 1- hexenyl, 2- hexenyl, 3- hexenyl, 1- heptenyl, 2- heptenyl, 3- heptenyl, 1- octenyl, 2- octenyl, 3- are pungent Alkenyl, 4- octenyl and in terms of the position of double bond and configuration and possible branched type may different nonenyl line Type and branched isomer such as (8Z)-nonenyl and its mixture, in terms of the position of double bond and configuration and possible branched type May different decene base line style and branched isomer and its mixture, in the position of double bond and configuration and possible branching class The line style and branched isomer and its mixture of hendecene base that may be different in terms of type, in the position of double bond and configuration and may Branched type in terms of may different laurylene base line style and branched isomer such as (7Z)-laurylene base and its mixture, In terms of the position of double bond and configuration and possible branched type may different tridecylene base line style and branched isomer and Its mixture, in terms of the position of double bond and configuration and possible branched type may different tetradecene base line style and branching Isomers such as (7Z)-tetradecene base and (4Z)-tetradecene base and its mixture, in the position of double bond and configuration and possible branching The line style and branched isomer and its mixture of 15 alkenyls that may be different in terms of type, in the position of double bond and configuration and can The line style and branched isomer such as (7Z)-hexadecylene base, (7E)-ten six of hexadecylene base that may be different in terms of the branched type of energy Alkenyl may be different with (9E)-hexadecylene base and its mixture, in terms of the position of double bond and configuration and possible branched type 17 alkenyls line style and branched isomer and its mixture, in terms of the position of double bond and configuration and possible branched type The line style and branched isomer of octadecylene base that may be different such as (7Z)-octadecylene base and (9Z)-octadecylene base and its mixture, In terms of the position of double bond and configuration and possible branched type may different 19 alkenyls line style and branched isomer and Its mixture, and in terms of the position of double bond and configuration and possible branched type may different icosa alkene base line style and branch Change isomers such as (9Z)-icosa alkene base and (11Z)-icosa alkene base and its mixture.
The term as used herein " C4-C20Dialkylene " refers to two pairs with 4 to 20 carbon atoms and in any position The unsaturated straight chain of the two of key or branched hydrocarbyl radical, condition are the two double bonds conjugation or isolated, such as 1,3-butadiene base, 1,3- Pentadienyl, 2,4- pentadienyl, 1,4- pentadienyl, 1,3- hexadienyl, 1,4- hexadienyl, 1,5- hexadienyl, 2, 4- hexadienyl, 2,5- hexadienyl, 1,3- heptadiene base, 1,4- heptadiene base, 1,5- heptadiene base, 1,6- heptadiene base, 2,4- heptadiene base, 2,5- heptadiene base, 2,6- heptadiene base, 3,5- heptadiene base, 3,6- heptadiene base, 1,3- octadiene Base, 1,5- octadienyl, 1,7- octadienyl, 2,4- octadienyl, 2,6- octadienyl, 3,5- octadienyl, 3,7- pungent two Alkenyl, 4,6- octadienyl, 5,7- octadienyl, 1,3- nonadiene base, 1,4- nonadiene base, 1,6- nonadiene base, 1,8- nonyl Dialkylene, 2,4- nonadiene base, 2,7- nonadiene base, 3,5- nonadiene base, 4,6- nonadiene base, 5,7- nonadiene base, 6,8- Nonadiene base, 1,3- decadinene base, 1,6- decadinene base, 2,4- decadinene base, 2,8- decadinene base, 3,5- decadinene base, 4, 6- decadinene base, 5,7- decadinene base, 6,8- decadinene base, 7,9- decadinene base, 11 carbon dialkylene of 1,3-, 11 carbon of 1,8- Dialkylene, 11 carbon dialkylene of 2,4-, 11 carbon dialkylene of 2,9-, 11 carbon dialkylene of 3,5-, 11 carbon dialkylene of 4,6-, 5, 11 carbon dialkylene of 7-, 11 carbon dialkylene of 5,10-, 11 carbon dialkylene of 6,8-, 11 carbon dialkylene of 7,9-, 8,10- 11 Carbon dialkylene, 12 carbon dialkylene of 1,3-, 12 carbon dialkylene of 1,8-, 12 carbon dialkylene of 2,4-, 12 carbon dialkylene of 2,7-, 12 carbon dialkylene of 3,5-, 12 carbon dialkylene of 4,6-, 12 carbon dialkylene of 5,7-, 12 carbon dialkylene of 5,11-, 6,8- 12 Carbon dialkylene, 12 carbon dialkylene of 7,9-, 12 carbon dialkylene of 8,10-, 12 carbon dialkylene of 9,11-, 1,3- oleatridecadiene Base, 1,8- oleatridecadiene base, 2,4- oleatridecadiene base, 3,5- oleatridecadiene base, 4,6- oleatridecadiene base, 5,7- ten Three carbon dialkylenes, 5,11- oleatridecadiene base, 6,8- oleatridecadiene base, 7,9- oleatridecadiene base, 13 carbon two of 8,10- Alkenyl, 9,11- oleatridecadiene base, 10,12- oleatridecadiene base, 14 carbon dialkylene of 1,3-, 14 carbon dialkylene of 1,9-, 14 carbon dialkylene of 2,4-, 14 carbon dialkylene of 3,5-, 14 carbon dialkylene of 4,6-, 14 carbon dialkylene of 5,7-, 5,11- 14 Carbon dialkylene, 14 carbon dialkylene of 6,8-, 14 carbon dialkylene of 7,9-, 14 carbon dialkylene of 8,10-, 14 carbon diene of 9,11- Base, 14 carbon dialkylene of 10,12-, 14 carbon dialkylene of 11,13-, 1,3- pentadecane dialkylene, 1,9- pentadecane dialkylene, 2, 4- pentadecane dialkylene, 3,5- pentadecane dialkylene, 4,6- pentadecane dialkylene, 5,7- pentadecane dialkylene, 5,12- pentadecane Dialkylene, 6,8- pentadecane dialkylene, 7,9- pentadecane dialkylene, 8,10- pentadecane dialkylene, 9,11- pentadecane dialkylene, 10,12- pentadecane dialkylene, 11,13- pentadecane dialkylene, 12,14- pentadecane dialkylene and position and structure in double bond The line style and branched isomer such as (7Z, 10Z)-ten six of 16 carbon dialkylenes that may be different in terms of type and possible branched type Carbon dialkylene and (7E, 10E)-ten six carbon dialkylenes and its mixture, in the position of double bond and configuration and possible branched type Aspect may different 17 carbon dialkylenes line style and branched isomer and its mixture, in the position of double bond and configuration and can The line style and branched isomer and its mixture, the position in double bond of 18 carbon dialkylenes that may be different in terms of the branched type of energy The line style and branched isomer of 19 carbon dialkylenes that may be different in terms of setting with configuration and possible branched type and its mixing Object, and in terms of the position of double bond and configuration and possible branched type may different 20 carbon dialkylenes line style and branching Isomers and its mixture.
The term as used herein " C6-C20Trialkenyl " refers to three pairs with 6 to 20 carbon atoms and in any position The triunsaturated straight chain or branched hydrocarbyl radical of key, it is conjugation or isolated that condition, which is each pair of in these three double bonds, such as 1,3, 5- hexatriene base, 1,3,5- heptantriene base, 1,4,6- heptantriene base, 1,3,6- heptantriene base, 2,4,6- heptantriene base, 1,3,5- Sarohornene base, 1,3,6- sarohornene base, 1,3,7- sarohornene base, 1,4,6- sarohornene base, 1,4,7- sarohornene base, 1,5,7- are pungent Trialkenyl, 2,4,6- sarohornene base, 2,4,7- sarohornene base, 2,5,7- sarohornene base, 3,5,7- sarohornene base, 1,3,5- nonyl three Alkenyl, 1,3,8- nonyl trialkenyl, 2,4,6- nonyl trialkenyl, 2,4,7- nonyl trialkenyl, 3,5,7- nonyl trialkenyl, 4,6,8- nonyl triolefin Base, 1,4,7- nonyl trialkenyl, 1,3,5- last of the ten Heavenly stems trialkenyl, 1,3,8- last of the ten Heavenly stems trialkenyl, 2,4,6- last of the ten Heavenly stems trialkenyl, 2,4,9- last of the ten Heavenly stems triolefin Base, 3,5,7- last of the ten Heavenly stems trialkenyl, 4,6,8- last of the ten Heavenly stems trialkenyl, 5,7,9- last of the ten Heavenly stems trialkenyl, 2,5,7- last of the ten Heavenly stems trialkenyl, 1,6,8- last of the ten Heavenly stems triolefin Base, 2,7,9- last of the ten Heavenly stems trialkenyl, 1,4,7- last of the ten Heavenly stems trialkenyl, 2,5,9- last of the ten Heavenly stems trialkenyl, 11 carbon trialkenyl of 1,3,5-, 1,3,8- 11 Carbon trialkenyl, 11 carbon trialkenyl of 1,6,8-, 11 carbon trialkenyl of 2,4,6-, 11 carbon trialkenyl of 2,4,10-, 2,6,9- 11 Carbon trialkenyl, 11 carbon trialkenyl of 2,7,9-, 11 carbon trialkenyl of 3,5,7-, 11 carbon trialkenyl of 4,6,8-, 4,7,10- 11 Carbon trialkenyl, 11 carbon trialkenyl of 5,7,9-, 11 carbon trialkenyl of 6,8,10-, 12 carbon trialkenyl of 1,3,5-, 1,3,8- 12 Carbon trialkenyl, 12 carbon trialkenyl of 1,6,8-, 12 carbon trialkenyl of 2,4,6-, 12 carbon trialkenyl of 2,4,10-, 2,6,9- 12 Carbon trialkenyl, 12 carbon trialkenyl of 3,5,7-, 12 carbon trialkenyl of 4,6,8-, 12 carbon trialkenyl of 4,7,11-, 5,7,9- 12 Carbon trialkenyl, 12 carbon trialkenyl of 6,8,10-, 12 carbon trialkenyl of 7,9,11-, 1,3,5- tridecatriene base, 1,3,7- ten Three carbon trialkenyls, 1,8,10- tridecatriene base, 2,4,6- tridecatriene base, 2,4,10- tridecatriene base, 2,7,10- Tridecatriene base, 3,5,7- tridecatriene base, 4,6,8- tridecatriene base, 4,7,11- tridecatriene base, 5,7,9- Tridecatriene base, 6,8,10- tridecatriene base, 7,9,11- tridecatriene base, 8,10,12- tridecatriene base, 1, 14 carbon trialkenyl of 3,5-, 14 carbon trialkenyl of 1,3,9-, 14 carbon trialkenyl of 2,4,6-, 14 carbon trialkenyl of 2,4,10-, 2, 14 carbon trialkenyl of 7,10-, 14 carbon trialkenyl of 3,5,7-, 14 carbon trialkenyl of 4,6,8-, 14 carbon trialkenyl of 4,7,11-, 14 carbon trialkenyl of 5,7,9-, 14 carbon trialkenyl of 6,8,10-, 14 carbon trialkenyl of 7,9,11-, 14 carbon triolefin of 7,10,12- Base, 14 carbon trialkenyl of 8,10,12-, 14 carbon trialkenyl of 9,11,13-, 1,3,5- pentadecane trialkenyl, 1,3,11- pentadecane Trialkenyl, 2,4,6- pentadecane trialkenyl, 2,4,9- pentadecane trialkenyl, 2,9,12- pentadecane trialkenyl, 3,5,7- pentadecane Trialkenyl, 4,6,8- pentadecane trialkenyl, 4,7,10- pentadecane trialkenyl, 5,7,9- pentadecane trialkenyl, 6,8,10- 15 Carbon trialkenyl, 7,9,11- pentadecane trialkenyl, 7,10,12- pentadecane trialkenyl, 8,10,12- pentadecane trialkenyl, 9,11, 13- pentadecane trialkenyl, 10,12,14- pentadecane trialkenyl and in the position of double bond and configuration and possible branched type The line style and branched isomer such as (7Z, 10Z, 13Z)-ten six carbon trialkenyl of the possible 16 different carbon trialkenyls of aspect, (4Z, 7Z, 10Z)-ten six carbon trialkenyls, (6E, 8E, 10Z)-ten six carbon trialkenyl, (7Z, 9E, 11Z)-ten six carbon trialkenyl, (7Z, 9E, 11E)-ten six carbon trialkenyls and (7E, 9E, 11E)-ten six carbon trialkenyl and its mixture, in the position of double bond and configuration and The line style and branched isomer and its mixture of 17 carbon trialkenyls that may be different in terms of possible branched type, in double bond The line style and branched isomer of 18 carbon trialkenyls that may be different in terms of position and configuration and possible branched type and its mixed Close object, in terms of the position of double bond and configuration and possible branched type may different 19 carbon trialkenyls line style and branching Isomers and its mixture, and 20 carbon triolefins that may be different in terms of the position of double bond and configuration and possible branched type The line style and branched isomer and its mixture of base.
The term as used herein " C8-C20Apos " refer to four pairs with 8 to 20 carbon atoms and in any position The unsaturated straight chain of the four of key or branched hydrocarbyl radical, it is conjugation or isolated that condition, which is each pair of in this four double bonds, such as 1,3, 5,7- octatetraene base, 1,3,5,7- nonyl apos, 1,3,5,8- nonyl apos, 2,4,6,8- nonyl apos, 1,4,6,8- nonyl four Alkenyl, 1,3,6,8- nonyl apos, 1,3,5,7- decatetraene base, 1,3,5,9- decatetraene base, 2,4,6,8- decatetraene base, 2,4, 7,9- decatetraene base, 3,5,7,9- decatetraene base, 11 carbon apos of 1,3,5,7-, 11 carbon apos of 1,3,8,10-, 2,4, 11 carbon apos of 6,8-, 11 carbon apos of 2,4,7,10-, 11 carbon apos of 3,5,7,9-, 11 carbon four of 4,6,8,10- Alkenyl, 12 carbon apos of 1,3,5,7-, 12 carbon apos of 1,3,6,8-, 12 carbon apos of 2,4,6,8-, 2,5,8,10- 12 carbon apos, 12 carbon apos of 3,5,7,9-, 12 carbon apos of 4,6,8,10-, 12 carbon tetraene of 4,6,9,11- Base, 12 carbon apos of 5,7,9,11-, 13 carbon apos of 1,3,5,7-, 13 carbon apos of 1,3,8,10-, 2,4,6,8- 13 carbon apos, 13 carbon apos of 2,5,8,11-, 13 carbon apos of 3,5,7,9-, 13 carbon tetraene of 3,5,8,11- Base, 13 carbon apos of 4,6,8,10-, 13 carbon apos of 5,7,9,11-, 13 carbon apos of 6,8,10,12-, 1,3,5, 14 carbon apos of 7-, 14 carbon apos of 1,3,9,11-, 14 carbon apos of 2,4,6,8-, 14 carbon tetraene of 2,5,8,11- Base, 14 carbon apos of 3,5,7,9-, 14 carbon apos of 3,5,9,12-, 14 carbon apos of 4,6,8,10-, 5,7,9,11- 14 carbon apos, 14 carbon apos of 6,8,10,12-, 14 carbon apos of 7,9,11,13-, 1,3,5,7- pentadecane tetraene Base, 1,4,10,13- pentadecane apos, 2,4,6,8- pentadecane apos, 2,4,9,11- pentadecane apos, 3,5,7,9- Pentadecane apos, 3,5,8,11- pentadecane apos, 4,6,8,10- pentadecane apos, 5,7,9,11- pentadecane tetraene Base, 6,8,10,12- pentadecane apos, 7,9,11,13- pentadecane apos, 8,10,12,14- pentadecane apos, 1,3, 16 carbon apos of 5,7-, 16 carbon apos of 2,4,6,8-, 16 carbon apos of 2,6,9,12-, 16 carbon four of 3,5,7,9- Alkenyl, 16 carbon apos of 4,6,8,10-, 16 carbon apos of 5,7,9,11-, 16 carbon apos of 6,8,10,12-, 6,8, 16 carbon apos of 11,14-, 16 carbon apos of 7,9,11,13-, 16 carbon apos of 8,10,12,14-, 8,10,13,15- 16 carbon apos, 16 carbon apos of 9,11,13,15-, 1,3,5,7- aplotaxene base, 2,4,6,8- aplotaxene Base, 3,5,7,9- aplotaxene base, 4,6,8,10- aplotaxene base, 4,7,10,13- aplotaxene base, 5,7,9, 11- aplotaxene base, 6,8,10,12- aplotaxene base, 6,8,11,14- aplotaxene base, 7,9,11,13- 17 Carbon apos, 7,9,12,14- aplotaxene base, 8,10,12,14- aplotaxene base, 9,11,13,15- aplotaxene Base, 10,12,14,16- aplotaxene base and may not in terms of the position of double bond and configuration and possible branched type With stearidonic base line style and branched isomer such as (3Z, 6Z, 9Z, 12Z)-stearidonic base and its mixture, The line style and branched isomer of 19 carbon apos that may be different in terms of the position of double bond and configuration and possible branched type And its mixture, and in terms of the position of double bond and configuration and possible branched type may different Eicosatetraenoic base line Type and branched isomer and its mixture.
The term as used herein " C10-C20- five alkenyls " refer to five with 10 to 20 carbon atoms and in any position The unsaturated straight chain of the five of double bond or branched hydrocarbyl radical, it is conjugation or isolated that condition, which is each pair of in this five double bonds, such as 1, Five alkenyl of the 3,5,7,9- last of the ten Heavenly stems, 11 light dydrocarbon alkenyl of 1,3,5,7,9-, 11 light dydrocarbon alkenyl of 1,3,6,8,10-, 1,4,6,8,10- ten One light dydrocarbon alkenyl, 11 light dydrocarbon alkenyl of 2,4,6,8,10-, 1,3,5,7,9- dodecapentaene base, 12 light dydrocarbon of 1,3,6,8,10- Alkenyl, 1,4,6,9,11- dodecapentaene base, 2,4,6,8,10- dodecapentaene base, 3,5,7,9,11- dodecapentaene base, 13 light dydrocarbon alkenyl of 1,3,5,7,9-, 13 light dydrocarbon alkenyl of 1,4,7,10,12-, 13 light dydrocarbon alkenyl of 2,4,6,8,10-, 2,5, 13 light dydrocarbon alkenyl of 7,9,11-, 13 light dydrocarbon alkenyl of 3,5,7,9,11-, 13 light dydrocarbon alkenyl of 4,6,8,10,12-, 1,3,5,7, 14 light dydrocarbon alkenyl of 9-, 14 light dydrocarbon alkenyl of 1,4,7,10,13-, 14 light dydrocarbon alkenyl of 2,4,6,8,10-, 2,5,8,11,13- 14 light dydrocarbon alkenyls, 14 light dydrocarbon alkenyl of 3,5,7,9,11-, 14 light dydrocarbon alkenyl of 3,5,8,10,12-, 4,6,8,10,12- ten Four light dydrocarbon alkenyls, 14 light dydrocarbon alkenyl of 4,6,8,10,13-, 14 light dydrocarbon alkenyl of 5,7,9,11,13-, 1,3,5,7,9- pentadecane Five alkenyls, five alkenyl of 2,4,6,8,10- pentadecane, five alkenyl of 2,5,8,11,14- pentadecane, 3,5,7,9,11- pentadecane pentaene Base, five alkenyl of 3,5,8,11,14- pentadecane, five alkenyl of 4,6,8,10,12- pentadecane, 4,6,8,11,14- pentadecane pentaene Base, five alkenyl of 5,7,9,11,14- pentadecane, five alkenyl of 5,7,9,12,14- pentadecane, 6,8,10,12,14- pentadecane pentaene Base, 16 light dydrocarbon alkenyl of 1,3,5,7,9-, 16 light dydrocarbon alkenyl of 2,4,6,8,10-, 16 light dydrocarbon alkenyl of 2,5,8,11,14-, 3, 16 light dydrocarbon alkenyl of 5,7,9,11-, 16 light dydrocarbon alkenyl of 3,5,8,10,12-, 16 light dydrocarbon alkenyl of 4,6,8,10,12-, 5,7, 16 light dydrocarbon alkenyl of 9,11,13-, 16 light dydrocarbon alkenyl of 6,8,10,12,14-, 16 light dydrocarbon alkenyl of 7,9,11,13,15-, 1,3, 17 light dydrocarbon alkenyl of 5,7,9-, 17 light dydrocarbon alkenyl of 1,3,6,9,11-, 17 light dydrocarbon alkenyl of 2,4,6,8,10-, 2,4,7,10, 17 light dydrocarbon alkenyl of 14-, 17 light dydrocarbon alkenyl of 3,5,7,9,11-, 17 light dydrocarbon alkenyl of 4,6,8,10,12-, 5,7,9,11,13- 17 light dydrocarbon alkenyls, 17 light dydrocarbon alkenyl of 6,8,10,12,14-, 17 light dydrocarbon alkenyl of 6,8,11,13,15-, 7,9,11,13, 17 light dydrocarbon alkenyl of 15-, 17 light dydrocarbon alkenyl of 8,10,12,14,16- and in the position of double bond and configuration and possible branching The line style and branched isomer such as (3Z, 6Z, 9Z, 12Z, 15Z)-ten eight light dydrocarbon of 18 light dydrocarbon alkenyls that may be different in terms of type Alkenyl and its mixture, the possible 19 different light dydrocarbon alkenyls in terms of the position of double bond and configuration and possible branched type Line style and branched isomer and its mixture, and may be different in terms of the position of double bond and configuration and possible branched type The line style and branched isomer such as (5Z, 8Z, 11Z, 14Z, 17Z)-eicosapentaenoic base and its mixture of eicosapentaenoic base.
Term " C1-C4Alkoxy " refers to the straight chain or branched-alkyl comprising 1 to 4 carbon atom through oxygen atoms bond. C1-C4The example of alkoxy is methoxyl group, ethyoxyl, positive propoxy, 1- methyl ethoxy (isopropoxy), n-butoxy, 1- Methyl propoxyl group (sec-butoxy), 2- methyl propoxyl group (isobutoxy) and 1,1- dimethylethyloxy (tert-butoxy).
Term " C6-C10Aryl " is understood to be unsaturated monocycle or bicyclic hydrocarbons base at least one phenyl ring；Example Including phenyl, indanyl and naphthalene.
Term "-COO- (C1-C4Alkyl) " refer to C as defined above through carbonyl linkage to molecule rest part1-C4- Alkoxy.Example is methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, Zhong Ding oxygen Base carbonyl, isobutoxy carbonyl and tert-butoxycarbonyl.
Term "-C (O)-C1-C3Alkyl " refers to the C as defined above through carbonyl linkage to molecule rest part1-C3Alkane Base.Example is methyl carbonyl, ethylcarbonyl group, propyl carbonyl and Isopropylcarbonyl.
Term " C4-C7Naphthenic base " refers to the cyclic saturated hydrocarbon base comprising 4 to 7 carbon atoms.Example is cyclobutyl, ring penta Base, cyclohexyl, bicyclic [2.1.1] hexyl, suberyl, bicyclic [2.2.1] heptyl, bicyclic [3.1.1] heptyl and bicyclic [2.2.1] Heptyl.
Term " C1-C5Alkane diyl " refers to straight chain or branched hydrocarbyl radical with 1 to 5 carbon atom, such as methylene, second -1, 2- diyl, propyl- 1,3- diyl, 2- methyl propyl- 1,3- diyl, butyl- 1,3- diyl, butyl- 1,4- diyl, 2- methyl butyl- 1,4- bis- Base and amyl- 1,5- diyl.
Term " C2-C5Alkene diyl " refers to straight chain or branching unsaturated alkyl with 2 to 5 carbon atoms, such as ethylene -1, 2- diyl, propyl- 1- alkene -1,3- diyl, but-2-ene -1,4- diyl, but-1-ene -1,3- diyl and amyl- 2- alkene -1,5- diyl.
Term " C2-C5Alkynes diyl " refers to the straight chain or branched hydrocarbyl radical with 2 to 5 carbon atoms and including three keys, such as second Alkynes -1,2- diyl, propyl- 1- alkynes -1,3- diyl, butyl- 2- alkynes -1,4- diyl and amyl- 2- alkynes -1,5- diyl.
Term " N-protected base " refers to the protecting group for being suitable for protecting or close amino.About N-protected base, reference P.G.M.Wuts,"Greene's Protective Groups in Organic Synthesis",5th ed.John Wiley And Sons, the 2014, the 7th chapter, page 895-1194 and references cited therein.N-protected base is especially and nitrogen-atoms one The protecting group for forming carbamate types group is acted, the carbamate types group is, for example, 9- fluorene methyl carbamate (Fmoc), replace 9- fluorene methyl carbamate such as Bts-Fmoc, Dtb-Fmoc, Mio-Fmoc, Dio-Fmoc and 9- (2,7- bis- Bromine) fluorene methyl carbamate, the chloro- 3- indenyl methyl carbamate (Climoc) of 3- indenyl methyl carbamate such as 2- and Benzo [f] indenes -3- ylmethyl (Bimoc), takes 1,1- dioxo benzo [b] thiophene -2- vlmethyl formic acid esters (Bsmoc) For ethyl carbamate such as 2,2,2- trichloroethyl carbamate (Troc), 2- trimethylsilyethyl carbamic acid Ester (Teoc), (2- phenyl -2- trimethyl silyl) ethyl carbamate (Psoc), 2- chloroethyl amino formic acid esters, 2- Phenyl ethyl carbamate (hZ), 1,1- dimethyl -2,2- dibromoethyl carbamate (DB-t-Boc), 1,1- diformazan Base -2,2,2- trichloroethyl carbamate (TCBOC), 2- pyridyl-ethyl group carbamate (Pyoc), tert-butylamino first Acid esters (BOC), fluorine-containing (fluorous) BOC (FBOC), 1- and 2- adamantylamino formic acid esters (Adoc and 2-Adoc), 1- (1- adamantyl) -1- methyl ethyl carbamate (Adpoc), 1- (3,5- di-tert-butyl-phenyl) -1- methylethylamine Formic acid esters (t-Bumeoc), N- (2- valeryl amino) -1,1- dimethylethyl carbamic ester, allyl carbamate (Alloc), Benzylcarbamate (Cbz or Z) and substituted benzyl carbamate, such as 4- methoxYbenzylamino formic acid esters (Moz), 4- nitrobenzylamino formic acid esters (PNZ), 4- methyl sulfinyl Benzylcarbamate (Msz), 4- trifluoromethyl Benzylcarbamate (CTFB) and 2- menaphthyl carbamate (CNAP).Preferably Cbz and BOC.
Below with reference to formula involved in method of the invention, reaction condition and this method (I), (Ia), (II), (III), (IV), the preferred embodiment of the compound of (IVa) and (V), especially with respect to their substituent R1、R2、R3、R4、X、Z、A、 Ra、Rb、Rc、RdAnd Y-The explanation made is not only suitable for themselves, and particularly, is suitable for mutual every kind possible combination In.
Variable Y in formula (I) and (IV)-Counter ion counterionsl gegenions are acted as to balance the anion equivalents of positively charged Phosphonium group And it can freely be selected from the ratio of univalent anion and multivalent anions corresponding with single negative electrical charge in principle.Suitable yin The example of ion shows those on being especially.
Two C-C double bonds in the ring exterior chain of the compound of formula (I) and (IV) can have E or Z configuration independently of each other.Root According to the preferred embodiments of the invention group, the compound of formula (I) and (IV) mainly have E configuration, the i.e. chemical combination of formula (I) and (IV) Object contains a high proportion of formula (Ia) and (IVa) respectively:
In the method for the invention, the compound of the formula (IV) for reacting with the compound of formula (V) contains a high proportion of E, E isomer (IVa), i.e. E, the amount of E isomer IVa are usually at least 80 moles of % of the total amount of compound of formula (IV), especially It is at least 90 moles of %, more particularly at least 95 moles of %, especially at least 98 moles of %.In the method for the invention, two The configuration of the outer C-C double bond of ring generally remains during method of the invention to be basically unchanged, i.e., they are in the product of formula (I) Configuration with it is essentially identical in the educt of formula (IV) (educt).Therefore, C-C double bond outside the ring of the educt of formula (IV) Configuration is at least 80% degree, corresponding to the outer C-C double bond of ring of the product of formula (I) especially at least 90% degree Configuration.Particularly, by it is basic there are two the educt for the formula (IV) that C-C double bond outside ring is E configuration (i.e. at least 90 moles of %, The educt of preferably at least 95 moles of %, especially at least 98 moles % have the E as shown in formula (IVa), E configuration) conversion There are two the product for the formula (I) that C-C double bond outside ring is E configuration, (i.e. at least 80 moles of %, preferably at least 90 rub at basic You are %, and the product of the formula (I) of especially at least 95 moles % has the E as shown in formula (Ia), E configuration.
Formula (I), 3 of each comfortable 6 member ring of compound of (Ia), (IV), (IVa) there is asymmetric center and therefore can As the mixture of enantiomers of 3R and 3S isomers, such as racemate, or be respectively provided with formula (I-1), (IV-1), (I-2) exist with the form of the pure isomer of (IV-2):
According to a preferred embodiment, wherein X be C=O formula (I) and (IV) compound it is main, i.e., at least 80 Mole %, preferably at least 90 moles of %, in the degree of especially at least 95 moles %, as they S isomers (I-1) or (IV-1) exist.Similarly, according to another preferred embodiment, wherein X is CH2Formula (I) and (IV) compound it is main, i.e., As their R isomers at least 80 moles of %, preferably at least 90 moles of %, the degree of especially at least 95 moles % (I-1) or (IV-1) exists.
Preferably, the variable R in the compound of formula (I), (Ia) and (V)1、R2、R3With following meanings:
R1Selected from hydrogen, C1-C20Alkyl, C2-C20Alkenyl, C4-C20Dialkylene, C6-C20Trialkenyl, C8-C20Tetraene Base, C10-C20- five alkenyls, A-COOH, A-CONH2、A-COO-(C1-C4Alkyl), C1-C4Alkoxy and phenoxy group, especially Hydrogen, C1-C20Alkyl, C2-C20Alkenyl, C4-C20Dialkylene, C6-C20Trialkenyl, C8-C20Apos, C10-C20Pentaene Base, A-COOH, A-CONH2With A-COO- (C1-C4Alkyl), especially C1-C20Alkyl, C2-C20Alkenyl, C4-C20Diene Base, C6-C20Trialkenyl, C8-C20Apos, A-COOH, A-CONH2With A-COO- (C1-C4Alkyl),
Wherein A is as defined above at each occurrence, and especially C1-C4Alkane diyl, especially CH2Or CH2CH2,
R2Selected from hydrogen ,-COOH ,-COO- (C1-C4Alkyl) and-NRaRb, wherein RaAnd RbWith meaning defined above, Particularly, R2It is hydrogen or-NRaRb, wherein RaAnd RbWith meaning defined above, especially there are following meanings:
RaSelected from hydrogen, C1-C4Alkyl ,-C (O)-C1-C3Alkyl and N-protected base, especially-Boc or-Cbz, and
RbIt is hydrogen or C1-C4Alkyl, or
R1And R2It can be formed together formula (II) or the group of (III), especially can only form the group of formula (II), especially not Form formula (II) or the group of (III).Herein, RcAnd RdIn variable it is as defined above, especially have following meanings:
RcSelected from hydrogen, C1-C19Alkyl, C2-C19Alkenyl, C4-C19Dialkylene, C6-C19Trialkenyl and C8-C19Tetraene Base, especially hydrogen, C1-C19Alkyl, C2-C19Alkenyl, C4-C19Dialkylene and C6-C19Trialkenyl, especially hydrogen, C1-C17- Alkyl, C2-C17Alkenyl and C4-C17Dialkylene, and
RdIt is hydrogen or C1-C4Alkyl, especially hydrogen,
R3Selected from hydrogen, C1-C20Alkyl and C2-C20Alkenyl, especially hydrogen.
It is highly preferred that the variable R in the compound of formula (I), (Ia) and (V)1、R2、R3With following meanings:
R1Selected from hydrogen, C1-C18Alkyl, C2-C18Alkenyl, C4-C18Dialkylene, C6-C18Trialkenyl, C8-C18Tetraene Base, A-COOH, A-CONH2With A-COO- (C1-C4Alkyl), especially hydrogen, C1-C18Alkyl, C2-C18Alkenyl, C4-C18- two Alkenyl, C6-C18Trialkenyl, A-COOH, A-CONH2With A-COO- (C1-C4Alkyl), wherein A is as above fixed at each occurrence Justice, and especially C1-C4Alkane diyl, especially CH2Or CH2CH2,
R2It is hydrogen or-NRaRb, wherein RaAnd RbWith meaning defined above, especially there are following meanings:
RaSelected from hydrogen, C1-C4Alkyl ,-C (O)-C1-C3Alkyl and N-protected base, such as-Boc and-Cbz, especially hydrogen ,- Boc and-Cbz, and
RbIt is hydrogen or C1-C4Alkyl, especially hydrogen, and
R3It is hydrogen or C1-C20Alkyl, especially hydrogen.
Preferably, the variable R in the compound of formula (I), (Ia), (IV) and (IVa)4And Y-With following meanings:
R4Selected from phenyl, tert-butyl and tolyl, especially phenyl,
Y-Selected from halide ion, such as bromide ion or chloride ion, sulfate radical, bisulfate ion, methanesulfonate and tosylate, Especially bromide ion, chloride ion, sulfate radical and bisulfate ion, especially bromide ion.
Preferably, the variable X in the compound of formula (I), (Ia), (IV) and (IVa) has following meanings:
X is CH2Or C=O, especially C=O.
An embodiment according to the present invention, the variable in formula (I), (Ia), (IV) and (IVa) is CH2。
According to a preferred embodiment of the invention, the variable X in formula (I), (Ia), (IV) and (IVa) is C=O.
Preferably, the variable Z in the compound of formula (V) is chlorine ,-OH or-O-C (O)-CH in the case where n=13, special It is not chlorine or-OH, is O in the case where n=2.
Preferably, in the method for the invention, any group NR in the compound of formula (V)aRbIt is tertiary amino, or at least One group RaOr RbIt is N-protected base, can be broken after the compound of formula (IV) is reacted with the compound of formula (V).
First group of preferred embodiment according to the present invention, group-C (O) CR in formula (I), (Ia) and (V)1R2R3It is derivative From with 2 to 22 carbon atoms, the saturation or unsaturated fatty acid of especially 10 to 20 carbon atoms, i.e. R2And R3It is H and R1Choosing From hydrogen, C1-C20Alkyl, C2-C20Alkenyl, C4-C20Dialkylene, C6-C20Trialkenyl, C8-C20Apos, C10-C20Pentaene Base, in particular selected from C1-C18Alkyl, C2-C18Alkenyl, C4-C18Dialkylene, C6-C18Trialkenyl and C8-C18Apos, especially Selected from hydrogen, C6-C18Alkyl, C6-C18Alkenyl, C6-C18Dialkylene and C6-C18Trialkenyl.Such group-C (O) CR1R2R3's Example includes but is not limited to acetyl group, caproyl, lauroyl, myristoyl, palmityl, stearyl, mace oil Acyl group (myristoleoyl), palmitoleoyl (palmitoleoyl), oleoyl, sub-oleoyl, α-linolenyl, γ-Asia Numb acyl group and arachidonic acyl group, especially acetyl group, lauroyl, myristoyl, palmityl, oleoyl, sub- oleoyl Base, α-linolenyl, γ-linolenyl, arachidonic acyl group, especially acetyl group, lauroyl, myristoyl, palm Acyl group, oleoyl, sub-oleoyl, α-linolenyl, γ-linolenyl.In the embodiment of this specific group, formula (I) and (Ia) the variable X especially C=O in.
Second group of embodiment according to the present invention, group-C (O) CR in formula (I), (Ia) and (V)1R2R3Derived from alpha- The a-amino acid of amino acid or N-protected, i.e. R2It is group NRaRb, wherein RaAnd RbAs defined above and wherein particularly, RaWith RbOne or both of be N-protected base respectively, such as BOC or Cbz, and another group RaAnd RbIt is hydrogen, C1-C4Alkyl ,-C (O) H ,-C (O)-C1-C3Alkyl or C4-C7Naphthenic base, especially hydrogen or C1-C4Alkyl or RaWith R1C can be formed together3-C4Alkane two Base.In this group of embodiment, R3Especially hydrogen.R1It is as defined above and in particular selected from hydrogen, unsubstituted or with OH group C1-C4Alkyl, A-CO2H、A-CONH2, wherein A is as defined above, especially CH2Or CH2CH2And benzyl unsubstituted or with OH Base.Such group-C (O) CR1R2R3Example include but is not limited to N-Boc- glycyl, N-Cbz- glycyl, flesh aminoacyl Base, N-Boc- flesh aminoacyl, N-Cbz- flesh aminoacyl, prolyl, N-Boc- prolyl, N-Cbz- prolyl, N- Boc- alanyl, N-Cbz- alanyl, N-Boc- valyl base, N-Cbz- valyl base, N-Boc- leucyl-, N- Cbz- leucyl-, N-Boc- isoleucyl-, N-Cbz- isoleucyl-, N-Boc- phenylalanyl, N-Cbz- phenyl Alanyl, N-Boc- tyrosyl-, N-Cbz- tyrosyl-, N-Boc- seryl-, N-Cbz- seryl-, N-Boc- Soviet Union Aminoacyl, N-Cbz- Threonyl, N-Boc- asparaginyl-, N-Cbz- asparaginyl-, N-Boc- glutaminyl Base, N-Cbz- glutaminyl, especially N-Boc- glycyl, N-Cbz- glycyl, N-Boc- alanyl, N- Cbz- alanyl, N-Boc- valyl base, N-Cbz- valyl base, N-Boc- leucyl-, N-Cbz- leucyl-, N- Boc- isoleucyl-, N-Cbz- isoleucyl-, N-Boc- flesh aminoacyl, N-Cbz- flesh aminoacyl, N-Boc- prolyl, N-Cbz- prolyl, especially N-Boc- glycyl and N-Boc- flesh aminoacyl and it is deprotected group accordingly.At this Variable X especially C=O in the embodiment of one specific group, in formula (I) and (Ia).
Third group preferred embodiment according to the present invention, group-C (O) CR in formula (I), (Ia) and (V)1R2R3It is derivative Self-saturation or unsaturated dicarboxylic or its half ester.In this group of embodiment, R2And R3It is H and R1It is group A-COOH or A- COO-C1-C4Alkyl, wherein A is as defined above and especially CH2Or CH2CH2.Such group-C (O) CR1R2R3Example include but It is not limited to succinyl group, i.e.-C (=O)-CH2CH2COOH and corresponding C1-C4Arrcostab-C (=O)-CH2CH2COO-C1-C4- Alkyl.Variable X especially C=O in the embodiment of this specific group, in formula (I) and (Ia).
Correspondingly, one of carboxylic acid of formula (V) or derivatives thereof is preferably selected from:
There are 3 to 20 C atoms, especially with the saturation and unsaturated fatty acid of 8 to 20 C atoms, and by its derivative Acyl halide, special such as acid chloride,
Chloroacetic chloride, acetic anhydride,
Succinic acid, succinic anhydride, and
The a-amino acid of the a-amino acid of N-protected, especially N-Boc or N-Cbz protection, the a-amino acid preferably select From glycine, alanine, valine, leucine, isoleucine, sarcosine and proline.
Reaction of the invention as described below carries out in the reaction vessel conventionally used for such reaction, and the reaction is with even Continuous, semicontinuous or batch mode carries out.In general, the specific reaction carries out under atmospheric pressure.But the reaction can also be It is carried out under reduction or raised pressure.
Being used to prepare formula, (reaction according to the method for the present invention of I) phosphonium salt ester can be considered as esterification or acylation reaction. By in the presence of tertiary amine, and also in the presence of an activator in the case where using compound of the free carboxy acid as formula (V) Make the phosphonium salt of formula (IV) and the carboxylic acid of formula (V) or react with one of its derivative to implement the conversion.
Suitable tertiary amine is the amine of formula (A)
NReRfRg (A)
Wherein Re、RfAnd RgIt is each independently selected from C1-C6Alkyl, C5-C8Naphthenic base, phenyl and by 1,2 or 3 C1- C4Alkyl-substituted phenyl or ReAnd RfBeing formed together in addition to tertiary N atom with nitrogen-atoms can also have selected from O, S and N-Rx(its Middle RxIt is C1-C6Alkyl) saturation N- heterocycle or R as ring members of additional hetero atom or heteroatom groupe、RfAnd RgWith nitrogen Atom is formed together that 8 to 12 yuan of N- are miscellaneous bicyclic, and especially 8 to 12 yuan of N- are miscellaneous bicyclic, and wherein tertiary hetero atom is amidine group in ring A part.Further suitable tertiary amine is N- heteroaromatics, and wherein N atom is the annular atom of Aromatic moieties.N- is miscellaneous Aromatic compounds is optionally selected from C by 1,2 or 31-C4Alkyl, halogen, 1- pyrrolidinyl and two (C1-C3Alkyl) amino base Group replaces.Suitable N- heteroaromatics is pyridine, N- (C1-C4)-alkyl imidazole and quinoline, wherein carbon atom is unsubstituted Or with 1,2 or 3 be selected from C1-C4Alkyl, halogen, 1- pyrrolidinyl and two (C1-C3Alkyl) amino group.
The example of tertiary amine includes but is not limited to three-C1-C6Alkylamine (or (C1-C6Alkyl)3N), such as Trimethylamine, methyl Diethylamide, methyl diisopropylamine and ethyl diisopropyl amine, cyclohexyldimethyl amine, cyclohexyl diethylamide, N- methyl Piperidines, N-methylmorpholine, N, N- lupetazin, 1,4- diazabicyclo [2.2.2] octane (DABCO), 1,5- diaza are double Ring [4.3.0] nonyl- 5- alkene (DBN), 11 carbon -7- alkene (DBU) of 1,8- diazabicyclo [5.4.0], N- methylimidazole, optional band There are pyridine, 4- (dimethylamino) pyridine and 4- (1- pyrrolidinyl) pyrrole of 1,2 or 3 substituent group selected from methyl and ethyl Pyridine.
The preferred tertiary amine of conversion for method of the invention is (C1-C6Alkyl)3N, DBU, DABCO, N- methylimidazole, Optionally with pyridine, 4- (dimethylamino) pyridine and 4- (the 1- pyrrolidines of 1,2 or 3 substituent group selected from methyl and ethyl Base) pyridine, especially Trimethylamine, N- methylimidazole, the pyridine optionally with 1,2 or 3 methyl, 4- (dimethylamino) pyrrole Pyridine and 4- (1- pyrrolidinyl) pyridine, especially N- methylimidazole and pyridine.
The suitable activators of conversion for method of the invention be essentially it is all can be by carboxylic acid (the i.e. formula (V) of formula (V) In variable Z be-OH) be converted to the compound of corresponding Acibenzolar or mixed anhydride, the Acibenzolar or mixed anhydride can be in tertiary amines In the presence of the alcohol of formula (IV) is converted to required formula (I) phosphonium salt ester.Preferred active agent is N, N'- dicyclohexylcarbodiimide (DCC), 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide (EDC), N, N'- diisopropylcarbodiimide (DIC), 1, 1'- carbonyl dimidazoles (CDI), pivalyl chloride, chloro-carbonic acid C1-C3Arrcostab, phosgene, thionyl chloride and phosphoryl chloride phosphorus oxychloride, especially It is DCC, EDC and DIC.
In the reaction of method of the invention, (one of IV) phosphonium salt and the carboxylic acid of formula (V) or derivatives thereof are logical for formula Normal 1:1 to 1:5, preferably 1:1 to 1:4, the molar ratio reaction in the range of more preferable 1:1 to 1:3, especially 1:1.1 to 1:2. Particularly, using the carboxylic acid of formula (V), i.e. Z in formula (V) is-OH, and the molar ratio of compound (IV) and (V) exist In the range of usual 1:1 to 1:2, preferably 1:1 to 1:1.5, and using the carboxylic acid derivates of formula (V), i.e. formula (V) In Z be not-OH, the molar ratio of compound (IV) and (V) are in the range of usual 1:1.2 to 1:5, preferably 1:1.5 to 1:4.
In the reaction of method of the invention, tertiary amine is with usual 1.0 to 3.0mol, preferably 1.0 to 2.0mol, especially The amount of 1.0 to 1.5mol, especially 1.0 to 1.3mol use, in each case the carboxylic acid based on 1 mole of formula (V) or its spread out One of biology.
In the reaction of method of the invention, if the Z that is, in formula (V) is-OH using the carboxylic acid of formula (V), activator with The amount of usual 1.0 to 2.0mol, especially 1.0 to 1.5mol, especially 1.1 to 1.3mol uses, and is based on 1 in each case The carboxylic acid of mole formula (V).
The reaction of method of the invention preferably carries out in organic solvent.
It usually has been found that advantageously, the reaction to method of the invention uses aprotic organic solvent, especially pole Property aprotic organic solvent.Aprotic organic solvent useful herein includes halogenated C1-C4Alkane, such as methylene chloride and three chloromethanes Alkane, C1-C4Alkyl nitrile, such as acetonitrile, ether, such as the aliphatic C with 1,2,3 or 4 oxygen atom2-C10Ether, such as C1-C4Alcoxyl Base-C1-C4Alkane, such as Anaesthetie Ether, dipropyl ether, methyl-isobutyl ether, methyl tertiary butyl ether(MTBE) or ethyl tert-butyl ether (ETBE), second Glycol dimethylether (glyme), diethylene glycol dimethyl ether (diglyme) and triethylene glycol dimethyl ether (triglyme), rouge Ring race C4-C6Ether, such as tetrahydrofuran (THF), oxinane, 2- methyltetrahydrofuran, 3- methyltetrahydrofuran and Isosorbide-5-Nitrae-dioxy Azacyclohexane, aliphatic (acid) ester, such as C1-C4Alkanoic acid C1-C4Arrcostab, such as ethyl acetate or isopropyl acetate, aromatic hydrocarbons are such as appointed Choosing is selected from C with 1 to 41-C4The benzene of the substituent group of alkyl and chlorine, such as chlorine benzene,toluene,xylene and mesitylene, dimethyl Formamide (DMF), n-methyl-2-pyrrolidone (NMP) or these solvents and mutual mixture.
The solvent of reaction for method of the invention is preferably selected from halogenated C1-C4Alkane, C1-C4Alkyl nitrile, C1-C4- Alkoxy -C1-C4Alkane, THF, 1,4- dioxane, C1-C4Alkanoic acid C1-C4Arrcostab, optionally with 1 to 4 Selected from C1-C4Benzene, DMF and the NMP of the substituent group of alkyl and chlorine, in particular selected from methylene chloride, acetonitrile, methyl tertiary butyl ether(MTBE), THF, 1,4- dioxane, ethyl acetate, isopropyl acetate and toluene.
Based on 1 mole of formula (IV) phosphonium salt, the solvent total amount of the reaction for method of the invention usually 1000 to Within the scope of 10000 grams, within the scope of preferably 2000 to 8500 grams.
It is preferable to use substantially anhydrous solvents, that is, have and be less than 1000ppm, be especially not more than the water content of 200ppm.
Reactant can be contacted with each other in principle with any required sequence.For example, phosphonium salt and the uncle of formula (IV) can be loaded at first Amine (if appropriate, with dissolution or discrete form) simultaneously mutually mixes.Then can by gained mixture and the carboxylic acid of formula (V) or its spread out Biology mixing.On the contrary, carboxylic acid of formula (V) or derivatives thereof (if appropriate, with dissolution or discrete form) can be loaded at first simultaneously (mixture of IV) phosphonium salt and tertiary amine mixes with formula.Alternatively, all reactants can also be added in reaction vessel simultaneously.It replaces The phosphonium salt and tertiary amine of generation joint addition formula (IV), they can also be added separately in reaction vessel.It both can be independently of each other Before or after the carboxylic acid or derivatives thereof of formula (V) is added, in a solvent or in the body it is added.In the carboxylic using formula (V) In the case where sour (Z=-OH), activator can be added before or after carboxylic acid is added.
Have been found that it is advantageous that in the reaction vessel at first load formula (IV) phosphonium salt or itself and tertiary amine mixture, Such as in a dispersed form or preferably with dissolved form, tertiary amine (if applicable) then is added, then gradually or is added at one time formula (V) carboxylic acid or derivatives thereof.The carboxylic acid or derivatives thereof of formula (V) uses same as before or with dissolved form.Using activator In the case where, preferably (before IV) phosphonium salt, later or together it is loaded into reaction vessel, and only just phase hereafter in formula After the carboxylic acid (wherein Z=-OH) that tertiary amine and formula (V) is added.
In general, the reaction of method of the invention carries out under temperature control.The reaction is usually having agitating device Closing or preferred open reaction vessel in carry out.The reaction temperature of method of the invention depends on different factors, especially depends on The reactivity for the active ester that carboxylic acid derivates in formula used (V) or the carboxylic acid by formula (V) are formed, and can be by those skilled in the art Member is for example determined by simple preliminary experiment in single situation.In general, the conversion of method of the invention -78 to It is carried out at a temperature of 100 DEG C, preferably -20 to 80 DEG C, more preferably -10 to 60 DEG C, especially -5 to 50 DEG C.
An embodiment according to the present invention, the reaction of method of the invention at a lower temperature, such as -10 to 40 DEG C, start at a temperature of preferably -5 to 20 DEG C, then gradually or continuously improves temperature to ceiling temperature, such as to 0 to 80 DEG C, it is excellent Select 10 to 50 DEG C of temperature.
Whether there is exhaust outlet depending on solvent for use, reaction temperature and reaction vessel, establish usual 1 during the reaction To 5 bars, preferably 1 to 3 bar of pressure.
The post-processing of the reaction mixture obtained in the reaction of method of the invention and formula (separation of I) phosphonium salt ester with Usual manner carries out, such as by quenching step, then aqueous extraction post-processes or for example remove under reduced pressure solvent.Instead of removing Solvent is removed, can also be substituted waiting to hold in the way of distillation by another solvent, (I) phosphonium salt ester therefrom crystallizes formula.In general, passing through application These measures or combinations thereof obtain formula (I) phosphonium salt ester with enough purity.Therefore, further purification step, especially complicated step Suddenly, as chromatography or distillation are not usually necessary.But, if it is desired, it can be real by method usually used in this field Apply further purification.
Preferably as the initial step of post-processing, by the way that nucleophilic is added in the reaction mixture that obtains into the reaction Compound, such as alcohol, such as methanol, water or diluted acid, such as the aqueous solution of acetic acid or hydrochloric acid and the reaction for quenching method of the invention.Such as Fruit is applicable in, and then removes water phase, organic phase water or diluted acid, such as acetic acid or the aqueous solution extraction of hydrochloric acid, usually followed by with The step of water washing.Then can containing formula, (organic phase of I) phosphonium salt ester is direct or is partially or completely removing solvent and is appointing Single step reaction step is introduced into after selecting further purification step.Alternatively, imposing crystallization condition to organic phase and after the completion of crystallization, Separate crystal, washing and the drying formed.It is frequently advantageous that, is tied in the solvent other than the solvent for the reaction It is brilliant.In this case, original solvents are substituted with the solvent for being more suitable for crystallization, such as by simply removing original solvents, example As removed under reduced pressure, and gained residue is re-dissolved in novel solvent, or by using equal appearance way of distillation.
(IV) phosphonium salt can be for example similar to the existing of introductory song description for formula as the raw material in method of the invention The preparation of method disclosed in technology.Wherein X is CH2Formula (IV) compound can for example by J.A.Haugan 1994, The method of Acta Chem.Scand.48,657 description passes through 3- hydroxy-beta-irisone or 3- oxo -4- hydroxy-beta-purple sieve Blue ketone obtains corresponding tertiary C with the Grignard reaction of vinyl magnesium bromide15-ol makes itself and suitable phosphonate reagent, such as hydrobromic acid Triphen phosphine reaction is prepared with providing the phosphonium salt of required formula (IV).Wherein X is that the compound of the formula (IV) of C=O can be such as Pass through E.Becher et al. Helv.Chim.Acta 64 (1981), the method preparation of 2419 descriptions.
It is as previously mentioned, the invention further relates to formula (I) phosphonium salt esters, wherein mentioned above about the preferred of them itself Feature, such as in 3 enantiomer configurations of 6 member rings, the configuration and variable R of ring exterior chain1、R2、R3、R4, X and Y-Meaning explanation It is also fully applicable for this, sole exception is group-C (O) R in formula (I)1R2R3It is not acetyl group, Ethoxyacetyl base, benzene Oxygroup acetyl group, propiono, bytyry, valeryl, caproyl, palmityl, stearyl or oleoyl.
Preferred formula (I) phosphonium salt ester be include be selected from lauroyl, myristoyl, sub-oleoyl, α-linolenyl, γ-linolenyl, arachidonic acyl group, N-Boc- glycyl, N-Cbz- glycyl, glycyl, succinyl group, N- Boc- flesh aminoacyl, flesh aminoacyl and N-Cbz- flesh aminoacyl, especially lauroyl, γ-linolenyl and N-Boc- flesh ammonia Group-C (O) CR of acyl group1R2R3Those of.
The phosphonium salt ester of formula (I) may act as the asymmetric diester that raw material are used to prepare the tetraterpenes of carotenoid type, And the monoesters of the tetraterpenes of symmetrical carotenoids type, such as astaxanthin or the monoesters of luteole.Monoesters and asymmetry Diester can by formula (I) phosphonium salt ester by respectively with corresponding 12 '-apocarotenal, such as 12 '-apo- luteole aldehyde With the Wittig reaction or the preparation of Julia alkylene of 12 '-apo- astaxanthin aldehyde.
The following example is further intended to illustrate the present invention.
Embodiment
Underneath with following abbreviations:
Aq.=is aqueous
Wt-%=weight %
DCM=methylene chloride
MeOH=methanol
EDC=1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride
NMI=1- methylimidazole
Embodiment 1:(S) -3- methyl -5- (4- palm acyloxy -2,6,6- trimethyl -3- oxo -1- cyclohexene -1- Base)-three phenyl-bromide Phosphonium of -2,4- pentadienyl
By (S) -3- methyl -5- (4- hydroxyl -2,6,6- trimethyl -3- oxo -1- cyclohexene -1- base) -2,4- pentadiene - three phenyl-bromide Phosphonium of base (575.5 grams, 1 mole) and (2000 milliliters) of DCM 4 liters of reactors of loading and the temperature for being cooled to 0 DEG C. Be added pyridine (119.6 grams, 1512 mMs), then through 1 hour dropwise metered palmitoyl chloride (358.7 grams, 1375 mmoles You).After stirring other 18 hours at 0 DEG C, water (1000 milliliters) are added and the mixture is heated to 20 DEG C.By organic phase with Aqueous phase separation is simultaneously washed with water (1000 milliliters).The solvent of organic phase is substituted for thereafter through the distillation of the appearances such as under ambient pressure Isopropyl acetate.After 2000 milliliters of isopropyl acetates have been added, 20 DEG C at a temperature of crystal seed is added.After the completion of precipitating, The solid of formation is separated, washed with isopropyl acetate (400 milliliters of 2x) and is dried whole night at 20 DEG C in nitrogen stream. Title compound is obtained with 707 grams of amount, the purity with 98.4 weight % is equivalent to 854.7 mMs and 85% yield.
Embodiment 2:(R) -3- methyl -5- (4- palm acyloxy -2,6,6- trimethyl -3- oxo -1- cyclohexene -1- Base)-three phenyl-bromide Phosphonium of -2,4- pentadienyl
Similar to embodiment 1, make (R) -3- methyl -5- (4- hydroxyl -2,6,6- trimethyl -3- oxo -1- cyclohexene -1- Base) -2,4- pentadienyl-three phenyl-bromide Phosphonium (115.1 grams, 200 mMs) and palmitoyl chloride (71.7 grams, 275 mMs) To provide 137.7 grams of title compounds, the purity with 92.8 weight % is equivalent to 153.6 mMs and 77% yield for reaction.
Embodiment 3:(S) -3- methyl -5- (4- laurel acyloxy -2,6,6- trimethyl -3- oxo -1- cyclohexene -1- Base)-three phenyl-bromide Phosphonium of -2,4- pentadienyl
By (S) -3- methyl -5- (4- hydroxyl -2,6,6- trimethyl -3- oxo -1- cyclohexene -1- base) -2,4- pentadiene - three phenyl-bromide Phosphonium of base (20 grams, 34.75 mMs), DCM (276.7 grams) and (4.81 grams, 60.8 mMs) of pyridine loadings 750 milliliters of reactors, then 20 DEG C at a temperature of lauroyl chloride (11.4 grams, 52.1 mMs) is added dropwise to the mixing In object.The reaction mixture then heats 23.5 hours under reflux.After MeOH (0.5 milliliter) is added, the reaction mixture First with acetic acid aqueous solution (10 weight %, 110 milliliters), then extracted with water (110 milliliters of 2x).Organic phase is dense by evaporating It contracts and DCM/MeOH 10:1 (v/v) is used to carry out column chromatography to gained residue as eluant, eluent on silica gel.Major fraction contains There are 4.54 grams of title compounds.
Embodiment 4:(S) -3- methyl -5- (4- (N-Boc- flesh aminoacyl oxygroup) -2,6,6- trimethyl -3- oxo -1- hexamethylene Alkene -1- base)-three phenyl-bromide Phosphonium of -2,4- pentadienyl
By (S) -3- methyl -5- (4- hydroxyl -2,6,6- trimethyl -3- oxo -1- cyclohexene -1- base) -2,4- pentadiene - three phenyl-bromide Phosphonium of base (57.6 grams, 100 mMs), DCM (400 milliliters) and EDC (28.75 grams, 150 mMs) are at 20 DEG C At a temperature of be packed into 1 liter of three-neck flask.After the mixture is cooled to 0 DEG C of temperature, be sequentially added NMI (12.3 grams, 150 MM) and N-Boc- sarcosine (22.7 grams, 120 mMs) and continue at 0 DEG C stirring 24 hours.Hydrochloric acid water is then added Solution (10 weight %, 100 milliliters), organic phase is separated from the water and first with aqueous hydrochloric acid solution (10 weight %, 100 millis Rise), then washed with water (100 milliliters of 2x).Organic phase be finally dried over sodium sulfate and be reduced to it is dry, with provide 73.6 grams mark Inscribe compound.
Embodiment 5:(S) -3- methyl -5- (4- (γ-flax acyloxy) -2,6,6- trimethyl -3- oxo -1- cyclohexene - 1- yl)-three phenyl-bromide Phosphonium of -2,4- pentadienyl
By (S) -3- methyl -5- (4- hydroxyl -2,6,6- trimethyl -3- oxo -1- cyclohexene -1- base) -2,4- pentadiene - three phenyl-bromide Phosphonium of base (51.5 grams, 84.4 mMs), DCM (666.5 grams) and (20 grams, 253.2 mMs) of pyridine loadings 2.5 liters of reactors, then 20 DEG C at a temperature of γ-flax acyl chlorides (62.6 grams, 211 mMs) is added dropwise to the mixing In object.The reaction mixture then heats 15 hours under reflux.After being cooled to 20 DEG C, MeOH (15.6 millis are added dropwise Rise), then by the mixture 30 DEG C at a temperature of keep 1.5 hours.Hereafter the reaction mixture uses acetic acid aqueous solution first (10 weight %, 200 milliliters) are then extracted with water (200 milliliters of 2x).Organic phase is dried over sodium sulfate and in rotary evaporator In be concentrated to dryness at 40 DEG C of temperature and 50 millibars of pressure to provide 110.6 grams of sticky brown oils, be dissolved in ring DCM/MeOH 20:1 (v/v) is used in the mixture of hexane/ethyl acetate 2:1 (v/v) and on silica gel to carry out as eluant, eluent Column chromatography.Obtain 50.7 grams of title compounds.

Claims (15)

1. a kind of method for the phosphonium salt ester for preparing formula (I),
Wherein
R1Selected from hydrogen, C1-C20Alkyl, C2-C20Alkenyl, C4-C20Dialkylene, C6-C20Trialkenyl, C8-C20Apos, C10- C20- five alkenyls, C1-C4Alkoxy, wherein alkyl, alkenyl, dialkylene, trialkenyl, apos and the pentaene of above-mentioned seven kinds of groups Based moiety is unsubstituted or with 1,2 or 3 selected from halogen ,-OH and C1-C4The substituent group of alkoxy,
C6-C10Aryl, benzyl, phenoxy group, benzoyloxy, wherein the aryl moieties of above-mentioned four kinds of groups are unsubstituted Or with 1,2 or 3 be selected from halogen ,-OH, C1-C4Alkyl and C1-C4The substituent group of alkoxy,
A-COOH、A-CONH2、A-COO-(C1-C4Alkyl), and
A-NRaRb,
R2And R3It is respectively selected from hydrogen, C independently of each other1-C20Alkyl, C2-C20Alkenyl, C4-C20Dialkylene, C6-C20Triolefin Base, C8-C20Apos, C10-C20- five alkenyls, C1-C4Alkoxy, wherein the alkyl of above-mentioned seven kinds of groups, alkenyl, dialkylene, Trialkenyl, apos and pentaene based moiety are unsubstituted or with 1,2 or 3 selected from halogen and C1-C4Alkoxy Substituent group,
R2Also selected from
-COOH、-COO-(C1-C4Alkyl), and
-NRaRb, or
R1And R2It is formed together the group of formula (II),
Wherein
It * is the tie point with the rest part of molecule,
RcSelected from hydrogen, C1-C19Alkyl, C2-C19Alkenyl, C4-C19Dialkylene, C6-C19Trialkenyl, C8-C19Apos, C1- C4Alkane diyl-COOH, C2-C4Alkene diyl-COOH, C2-C4Alkynes diyl-COOH, and
RdIt is hydrogen or C1-C4Alkyl, or
R1、R2And R3It is formed together the group of formula (III),
Wherein * and RcWith meaning as defined above, or
If R2It is-NRaRb, R1With RaC can be formed together3-C4Alkane diyl,
R4Selected from phenyl, tert-butyl and tolyl,
X is CH2Or C=O,
Y-Selected from halide ion, sulfate radical, bisulfate ion, methanesulfonate, tosylate, benzene sulfonic acid root, nitrate anion and C1-C3- Alkyl formate root,
RaSelected from hydrogen, C1-C4Alkyl ,-C (O) H ,-C (O)-C1-C3Alkyl, C4-C7Naphthenic base and N-protected base, such as tertiary fourth oxygen Base carbonyl (- Boc) and carboxybenzyl (- Cbz),
RbSelected from hydrogen, C1-C4Alkyl ,-C (O)-C1-C3Alkyl and N-protected base, such as-Boc and-Cbz, and
A is selected from C1-C5Alkane diyl, C2-C5Alkene diyl and C2-C5Alkynes diyl；
The method is characterized in that making the phosphonium salt of formula (IV),
Wherein variable X, R4And Y-With meaning as defined above,
It is reacted with the carboxylic acid of formula (V) or with one of its derivative,
Wherein
Variable R1、R2And R3With meaning as defined above, and
In n=1, variable Z is selected from halogen ,-OH ,-O-C (O)-C1-C4Alkyl, and
In n=2, variable Z is O or S,
Wherein the reaction carries out in the presence of tertiary amine, and also in work using the compound of the formula (V) of Z=OH It is carried out in the presence of agent.
2. the method according to claim 1, wherein the phosphonium salt of formula (IV) includes at least 80 moles of %, especially at least 90 moles of % Formula (IVa) full E isomer,
3. method according to claim 1 or 2, wherein in formula (I) and (V):
R1Selected from hydrogen, C1-C20Alkyl, C2-C20Alkenyl, C4-C20Dialkylene, C6-C20Trialkenyl, C8-C20Apos, C10- C20- five alkenyls, A-COOH, A-CONH2With A-COO- (C1-C4Alkyl), wherein A has meaning defined in claim 1,
R2It is hydrogen or-NRaRb, wherein RaAnd RbWith meaning defined in claim 1, or
R1And R2It is formed together the group of formula (II), wherein
RcSelected from hydrogen, C1-C19Alkyl, C2-C19Alkenyl, C4-C19Dialkylene, C6-C19Trialkenyl and C8-C19Apos, and
RdIt is hydrogen, and
R3It is hydrogen.
4. according to the method for any one of preceding claims, wherein in formula (I) and (V):
R1Selected from hydrogen, C1-C20Alkyl, C2-C20Alkenyl, C4-C20Dialkylene, C6-C20Trialkenyl, C8-C20Apos, A- COOH、A-CONH2With A-COO- (C1-C4Alkyl), wherein A is CH2Or CH2CH2；
R2It is hydrogen or-NRaRb, wherein
RaSelected from hydrogen, C1-C4Alkyl ,-C (O)-C1-C3Alkyl ,-Boc and-Cbz,
RbSelected from hydrogen and C1-C4Alkyl, and
R3It is hydrogen.
5. according to the method for any one of preceding claims, wherein variable X is C=O in formula (I) and (IV).
6. wherein one of carboxylic acid of formula (V) or derivatives thereof is selected from acetic anhydride, amber according to the method for any one of preceding claims Amber acid anhydrides, saturation and unsaturated fatty acid, saturation and unsaturated lipid with 8 to 20 C atoms with 8 to 20 C atoms Chloride and N-Boc or the N-Cbz protection of fat acid are selected from glycine, sarcosine, proline, alanine, valine, leucine With the a-amino acid of isoleucine.
7. according to the method for any one of preceding claims, wherein the tertiary amine is selected from (C1-C6Alkyl)3N, 1,8- diaza is double 11 carbon -7- alkene (DBU) of ring, 1,4- diazabicyclo [2.2.2] octane (DABCO), N- methylimidazole, optionally with 1,2 or 3 Pyridine, 4- (dimethylamino) pyridine and 4- (1- pyrrolidinyl) pyridine of a substituent group selected from methyl and ethyl.
8. according to the method for any one of preceding claims, wherein the activator is selected from N, N'- dicyclohexylcarbodiimide (DCC), 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide (EDC), N, N'- diisopropylcarbodiimide (DIC), 1, 1'- carbonyl dimidazoles (CDI), pivalyl chloride, chloro-carbonic acid C1-C3Arrcostab, phosgene, thionyl chloride and phosphoryl chloride phosphorus oxychloride.
9. the reaction wherein between formula (IV) and the compound of (V) is non-in polarity according to the method for any one of preceding claims It carries out, is preferably selected from optionally with 1 to 4 selected from C in proton-organic solvent1-C4Benzene, the C of the substituent group of alkyl and chlorine1- C4Alkoxy -C1-C4Alkane, halogenated C1-C4Alkane, C1-C4Alkyl nitrile, dimethylformamide (DMF), N- methyl -2- pyrrole Pyrrolidone (NMP), tetrahydrofuran (THF), 1,4- dioxane and C1-C4Alkanoic acid C1-C4Arrcostab.
10. wherein the reaction between formula (IV) and the compound of (V) is at -78 DEG C according to the method for any one of preceding claims It is carried out at a temperature of to 100 DEG C, preferably -20 DEG C to 80 DEG C.
11. according to the method for any one of preceding claims, wherein the compound of formula (IV) and (V) are in 1:1 to 1:3, preferably Molar ratio reaction in the range of 1:1.1 to 1:2.
12. formula (I) phosphonium salt ester,
Wherein X, R1、R2、R3And R4As defined in one of claim 1,3,4 or 5, wherein-C (O) CR1R2R3It is acetyl group, ethoxy Base acetyl group, nitrophenoxyacetyl, propiono, bytyry, valeryl, caproyl, palmityl, stearyl or oleoyl Except the compound of formula (I).
It is the full E isomer of formula (Ia) or comprising at least 80 moles of %, especially 13. 2 phosphonium salt ester according to claim 1 The full E isomer of the formula (Ia) of at least 90 moles %
14. any one of 2 or 13 phosphonium salt ester according to claim 1, wherein group-C (O) CR in formula (I) or (Ia)1R2R3Choosing From lauroyl, myristoyl, sub-oleoyl, α-linolenyl, γ-linolenyl, arachidonic acyl group and succinyl group.
15. any one of 2 or 13 phosphonium salt ester according to claim 1, wherein group-C (O) CR in formula (I) or (Ia)1R2R3Choosing From N-Boc- glycyl, N-Cbz- glycyl, N-Boc- flesh aminoacyl, N-Cbz- flesh aminoacyl, glycyl and flesh ammonia Acyl group.
CN201780056631.7A 2016-09-16 2017-09-15 The method for preparing the structural unit phosphonium salt ester as carotenoid Pending CN109715638A (en)

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