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WO2018050792A1 - Procédé de préparation d'esters de 12'-apocarotènes en tant que blocs de construction pour des caroténoïdes - Google Patents

Procédé de préparation d'esters de 12'-apocarotènes en tant que blocs de construction pour des caroténoïdes Download PDF

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WO2018050792A1
WO2018050792A1 PCT/EP2017/073218 EP2017073218W WO2018050792A1 WO 2018050792 A1 WO2018050792 A1 WO 2018050792A1 EP 2017073218 W EP2017073218 W EP 2017073218W WO 2018050792 A1 WO2018050792 A1 WO 2018050792A1
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alkyl
group
formula
hydrogen
boc
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Bernd Schaefer
Wolfgang Siegel
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BASF SE
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BASF SE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds

Definitions

  • the present invention relates to a new process for preparing an 12'-apocarotenal ester of the formula (I),
  • Apocarotenals are naturally occurring degradation products of the corresponding carotenoid-type tetraterpenes, e.g. ⁇ -carotene, astaxanthin, zeaxanthin or lutein, and, thus, are present in many carotenoid-containing foods (see e.g. H. Etoh et al. 2012, J. Oleo Sci. 61 ,17; N. Akimoto et al. 2000, J. Mass Spectrom. Soc. 48, 32). Since zeaxanthin and astaxanthin stemming from natural sources are usually mono- or diesterified, the respective esterified apocarotenals have also to be expected in food products (see Y.
  • apocarotenals are known to be valuable building blocks for the synthesis of asymmetric carotenoids. 12'-Apocarotenals are particularly useful for this purpose, because they can be converted to asymmetric tetraterpenes, such as lutein, via a Wittig reaction or a Julia olefination with the corresponding Ci5-phosphonium salts and Ci5-sulfones, respectively, which are well established starting compounds for carotenoid syntheses.
  • 12'-Apozeaxanthinal as well as 12'-apoastaxanthinal of the formula (IV) are typically prepared by the Wittig reaction of the appropriate Ci5-phosphonium salt with the respective Cio-dial, as described e.g. by J. A. Haugan et al. 1994, Acta Chem. Scand. 48, 899; and K. Bernhard et al. 1981 , Helv. Chim. Acta 64, 2469.
  • esters are derived from a variety of different acids, including in particular fatty acids and optionally N-protected amino acids.
  • the process should, in addition, be simple to perform and should enable good yields of the desired esters.
  • R 1 is selected from the group consisting of hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C4-C2o-alkdienyl, C6-C2o-alktrienyl, C8-C2o-alktetraenyl, Cio-C2o-alkpentaenyl, Ci-C4-alkoxy, where the alkyl, alkenyl, alkdienyl, alktrienyl, alktetraenyl and alkpentaenyl moieties of the seven aforementioned residues are unsubstituted or carry 1 , 2 or 3 substituents selected from the group consisting of halogen, -OH and Ci-C4-alkoxy,
  • R 2 and R 3 are each independently from one another selected from the group consisting of hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C4-C2o-alkdienyl, C6-C2o-alktrienyl, Cs-C2o-alktetraenyl and Cio-C2o-alkpentaenyl, where the alkyl, alkenyl, alkdienyl, alktrienyl, alktetraenyl and alkpentaenyl moieties of the six aforementioned residues are unsubstituted or carry 1 , 2 or 3 substituents selected from the group consisting of halogen and Ci-C4-alkoxy,
  • R 2 may also be selected from the group consisting of
  • R c is selected from the group consisting of hydrogen, Ci-Cig-alkyl,
  • R 1 , R 2 and R 3 together form a group of the formula
  • R 1 together with R a may form a C3-C4-alkandiyl group
  • R a is selected from the group consisting of hydrogen, Ci-C4-alkyl, -C(0)H,
  • R b is selected from the group consisting of hydrogen, Ci-C4-alkyl,
  • A is selected from the group consisting of d-Cs-alkandiyl, C2-Cs-alkendiyl and C2-C5-alkyndiyl.
  • variable Z is selected from the group consisting of halogen, -OH,
  • the invention further relates to 12'-apocarotenal esters of the formula (I) as defined herein, provided that the group -C(0)CR 1 R 2 R 3 is not acetyl, i.e. R 1 , R 2 and R 3 are not simultaneously hydrogen.
  • the inventive process affords an easy and efficient access to the 12'-apocarotenal ester of the formula (I) in sufficient yield and good specificity by starting from the corresponding alcohol of the formula (IV), which itself is generally readily obtainable in good quality and high yield.
  • the 12'-apocarotenal esters of the formula (I) may serve as a starting material for monoesters of symmetric tetraterpenes, such as astaxanthin or zeaxanthin via Wittig reaction or a Julia olefination with the corresponding Ci5-phosphonium salts and
  • the prefix C x -C y denotes the number of possible carbon atoms in the particular case.
  • halogen in each case denotes fluorine, bromine, chlorine or iodine, preferably fluorine, chlorine or bromine, and specifically chlorine.
  • Ci-C2o-alkyl as used herein and in the alkyl moieties of alkoxy and the like refers to saturated straight-chain or branched hydrocarbon radicals having 1 to 3
  • Ci-C 3 -alkyl 1, 1 to 4 (“Ci-C 4 -alkyl”) or 1 to 20 (“Ci-C 20 -alkyl”) carbon atoms.
  • Ci-C3-Alkyl is methyl, ethyl, propyl or isopropyl.
  • Ci-C 4 -Alkyl is additionally butyl,
  • Ci-C2o-Alkyl is additionally also, for example, pentyl, 1 -methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1 -ethylpropyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, hexyl, 1 -methylpentyl, 4-methylpentyl, 1 ,1 -dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1 ,1 ,2-trimethylpropyl,
  • C2-C2o-alkenyl refers to monounsaturated straight-chain or branched hydrocarbon radicals having 2 to 20 carbon atoms and a double bond in any position, for example ethenyl 1 -propenyl, 2-propenyl, 1 -methylethenyl, 1 -butenyl,
  • C4-C2o-alkdienyl refers to diunsaturated straight-chain or branched hydrocarbon radicals having 4 to 20 carbon atoms and two double bonds in any positions, provided that the two double bounds are either conjugated or isolated, for example 1 ,3-butadienyl, 1 ,3-pentadienyl, 2,4-pentadienyl, 1 ,4-pentadienyl,
  • C6-C2o-alktrienyl refers to triunsaturated straight-chain or branched hydrocarbon radicals having 6 to 20 carbon atoms and three double bonds in any positions, provided that the each pair out of the three double bounds is either conjugated or isolated, for example 1 ,3,5-hexatrienyl, 1 ,3,5-heptatrienyl,
  • C8-C2o-alktetraenyl refers to tetraunsaturated straight-chain or branched hydrocarbon radicals having 8 to 20 carbon atoms and four double bonds in any positions, provided that the each pair out of the four double bounds is either conjugated or isolated, for example 1 ,3,5,7-octatetraenyl, 1 ,3,5,7-nonatetraenyl, 1 ,3,5,8-nonatetraenyl, 2,4,6,8-nonatetraenyl, 1 ,4,6,8-nonatetraenyl, 1 ,3,6,8-nonatetraenyl, 1 ,3,5,7-decatetraenyl, 1 ,3,5,9-decatetraenyl,
  • octadecatetraenyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, such as
  • Cio-C2o-alkpentaenyl refers to pentaunsaturated straight- chain or branched hydrocarbon radicals having 10 to 20 carbon atoms and five double bonds in any positions, provided that the each pair out of the five double bounds is either conjugated or isolated, for example 1 ,3,5,7,9-decapentaenyl,
  • Ci-C4-alkoxy denotes straight-chain or branched saturated alkyl groups comprising 1 to 4 carbon atoms which are bonded via an oxygen atom.
  • Examples of Ci-C4-alkoxy are methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n-butoxy,
  • C6-Cio-aryl is understood as an unsaturated mono- or dicyclic hydrocarbon group having at least one benzene ring; examples include phenyl, indanyl and naphthyl.
  • -COO-(Ci-C4-alkyl) refers to a Ci-C4-alkoxy group, as defined above, which is bound to the remainder of the molecule via a carbonyl group. Examples are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
  • -C(0)-Ci-C3-alkyl refers to a Ci-C3-alkyl group, as defined above, which is bound to the remainder of the molecule via a carbonyl group. Examples are
  • C4-C7-cycloalkyl denotes a cyclic, saturated hydrocarbyl radical comprising 4 to 7 carbon atoms. Examples are cyclobutyl, cyclopentyl, cyclohexyl,
  • d-Cs-alkandiyl denotes a straight-chain or branched hydrocarbon diradical having 1 to 5 carbon atoms, such as methylene, ethan-1 ,2-diyl, propan-1 ,3-diyl,
  • C2-C5-alkendiyl denotes a straight-chain or branched unsaturated hydrocarbon diradical having 2 to 5 carbon atoms, such as ethen-1 ,2-diyl, prop-1 -en- 1 ,3-diyl, but-2-en-1 ,4-diyl but-1 -en-1 ,3-diyl and pent-2-en-1 ,5-diyl.
  • C2-C5-alkyndiyl denotes a straight-chain or branched hydrocarbon diradical which has 2 to 5 carbon atoms and includes a triple bond, such as ethyn-1 ,2-diyl, prop- 1 -yn-1 ,3-diyl, but-2-yn-1 ,4-diyl and pent-2-yn-1 ,5-diyl.
  • N-protecting group denotes a protective group suitable for protecting or blocking amino groups.
  • N-protecting groups are in particular protecting groups, which together with the nitrogen atom form carbamate type group, such as 9-fluorenylmethyl carbamate (Fmoc), substituted 9-fluorenylmethyl carbamates such as Bts-Fmoc, Dtb-Fmoc, Mio-Fmoc, Dio-Fmoc, and 9-(2,7-dibromo)fluorenylmethyl carbamate, 3-idenylmethyl carbamates such as
  • PNZ 4-nitrobenzyl carbamate
  • Msz 4-methylsulfinylbenzyl carbamate
  • CFB 4-trifluoromethylbenzyl carbamate
  • CNAP 2-naphtylmethyl carbamate
  • the six C-C double bonds in the exocyclic chain of the compounds of formulae (I) and (IV) may independently from each other have E or Z configuration.
  • the compounds of formulae (I) and (IV) predominately have E configuration, i.e. the compounds of formulae (I) and (IV) contain a high proportion of formulae (la) and (IVa), respectively:
  • the compound of formula (IV) used for the reaction with the compound of formula (V) contains a high proportion of the all-E isomer (IVa), i.e. the amount of the all-E isomer IVa is frequently at least 80 mol-%, in particular at least 90 mol-% more particularly at least 95 mol-% and specifically at least 98 mol-% of the total amount of the compound of formula (IV).
  • the configurations of all six exocyclic C-C double bonds usually remain essentially unchanged during the process of the invention, i.e. their configurations in the product of the formula (I) is essentially the same as in the educt of the formula (IV).
  • the configurations of the exocyclic C-C double bonds of the educt of formula (IV) correspond to the configurations of the exocyclic C-C double bonds of the product of formula (I) to a degree of at least 80%, in particular to a degree of at least 90%.
  • an educt of formula (IV) with essentially all six exocyclic C-C double bonds being E configurated i.e. at least 90 mol-%, preferably at least 95 mol-% and in particular at least 98 mol-% of the educt have an all-E configuration as depicted in formula (IVa)
  • a product of formula (I) with essentially all six exocyclic C-C double bonds being E configurated i.e. at least 80 mol-%, preferably at least 90 mol-% and in particular at least 95 mol-% of the product of formula (I) have an all-E configuration as depicted in formula (la).
  • the compounds of the formulae (I), (la), (IV), (IVa) each have an asymmetric center in position 3 of the 6-membered cycle and can therefore exist as an enantiomeric mixture of the 3R and 3S isomers, e.g. as a racemate, or in the form of the pure isomers having the formulae (1-1 ), (IV-1 ), (I-2) and (IV-2), respectively:
  • the compounds of formulae (I) and (IV) with X being Chb are predominately, i.e. to an extent of at least 80 mol-%, preferably at least 90 mol-% and in particular at least 95 mol-%, present as their R isomers (1-1 ) or (IV-1 ).
  • variables R 1 , R 2 , R 3 in the compounds of formulae (I), (la) and (V) have the following meanings:
  • R 1 is selected from the group consisting of hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C4-C2o-alkdienyl, C6-C2o-alktrienyl, C8-C2o-alktetraenyl, Cio-C2o-alkpentaenyl,
  • A-COOH, A-CON H2, A-COO-(Ci-C 4 -alkyl) and Ci-C 4 -alkoxy in particular hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C 4 -C2o-alkdienyl, C6-C2o-alktrienyl, C8-C20- alktetraenyl, Cio-C 20 -alkpentaenyl, A-COOH , A-CON H2 and A-COO-(Ci-C 4 -alkyl), and specifically Ci-C2o-alkyl, C2-C2o-alkenyl, C 4 -C2o-alkdienyl, C6-C2o-alktrienyl, C 8 -C 20 -alktetraenyl, A-COOH , A-CON H2 and A-COO-(Ci-C 4 -alkyl),
  • A at each occurrence, is as defined above and in particular C1-C4- alkandiyl and especially CH2 or CH2CH2,
  • R 2 is selected from the group consisting of hydrogen, -COOH , -COO-(Ci-C 4 -alkyl), and -NR a R b , where R a and R b have the meanings defined above, in particular R 2 is hydrogen or -NR a R b , where R a and R b have the meanings defined above and specifically have the following meanings:
  • R a is selected from the group consisting of hydrogen, Ci-C4-alkyl,
  • R 1 and R 2 together may form a group of formulae (I I) or (I II), in particular may form a group of formula (II) only, and specifically do not form a group of formulae (I I) or (I I I).
  • the variables in R c and R d are as defined above and in particular have the following meanings:
  • R c is selected from the group consisting of hydrogen, Ci-Cig-alkyl, C2-C19- alkenyl, C4-Cig-alkdienyl, C6-Ci9-alktrienyl and Cs-dg-alktetraenyl, in particular hydrogen, Ci-Cig-alkyl, C2-Cig-alkenyl, C4-Cig-alkdienyl and C6-Ci9-alktrienyl and specifically hydrogen, Ci-Ci7-alkyl, C2-Ci7-alkenyl and C4-Ci7-alkdienyl, and
  • R d is hydrogen or Ci-C4-alkyl and in particular hydrogen
  • R 3 is selected from the group consisting of hydrogen, Ci-C2o-alkyl and C2-C20- alkenyl, and in particular is hydrogen.
  • variables R 1 , R 2 , R 3 in the compounds of formulae (I), (la) and (V) have the following meanings:
  • R 1 is selected from the group consisting of hydrogen, Ci-Cis-alkyl, C2-Ci8-alkenyl, C 4 -Ci8-alkdienyl, C 6 -Ci 8 -alktrienyl, C 8 -Ci 8 -alktetraenyl, A-COOH, A-CONH2 and A-COO-(Ci-C4-alkyl), and in particular hydrogen, Ci-Cis-alkyl, C2-Ci8-alkenyl, C 4 -Ci8-alkdienyl, C 6 -Ci 8 -alktrienyl, A-COOH, A-CONH2 and A-COO-(Ci-C 4 -alkyl), where A, at each occurrence, is as defined above and in particular C1-C4- alkandiyl and especially CH2 or CH2CH2,
  • R 2 is hydrogen or -NR a R b , where R a and R b have the meanings defined above and in particular have the following meanings:
  • R a is selected from the group consisting of hydrogen, Ci-C4-alkyl,
  • N-protecting groups such as -Boc and -Cbz, specifically hydrogen, -Boc and -Cbz, and
  • R b is hydrogen or Ci-C4-alkyl, specifically hydrogen
  • R 3 is hydrogen or Ci-C2o-alkyl, in particular hydrogen.
  • variable X in the compounds of formulae (I), (la), (IV) and (IVa) has the following meaning:
  • variable X in in formulae (I), (la), (IV) and (IVa) is CH 2 .
  • any group NR a R b in the compound of formula (V) is a tertiary amino group or at least one radical R a or R b is an N-protecting group, which can be cleaved after the reaction of the compound of formula (IV) with the compound of formula (V).
  • R 2 R 3 in formulae (I), (la) and (V) is derived from a saturated or unsaturated fatty acid, having 2 to 22 carbon atoms, in particular 10 to 20 carbon atoms i.e. R 2 and R 3 are H and R 1 is selected from hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C4-C20- alkdienyl, C6-C2o-alktrienyl, C8-C2o-alktetraenyl, Cio-C2o-alkpentaenyl, in particular from Ci-Ci8-alkyl, C2-Ci8-alkenyl, C4-Ci8-alkdienyl, C6-Ci8-alktrienyl and Cs-ds-alktetraenyl and especially from hydrogen, C6-Ci8-alkyl, C6-Ci8-alkenyl, C6-Cis-alkdie
  • Examples of such groups -C(0)CR 1 R 2 R 3 include but are not limited to acetyl, caproyl, lauroyl, myristoyl, palmitoyl, stearoyl, myristoleoyl, palmitoleoyl, oleoyl, linoleoyl, a-linolenoyl, ⁇ -linolenoyl, and arachidonoyl, in particular acetyl, lauroyl, myristoyl, palmitoyl, oleoyl, linoleoyl, a-linolenoyl, ⁇ -linolenoyl, arachidonoyl, and specifically acetyl, lauroyl, myristoyl, palmitoyl, oleoyl, linoleoyl, a-linolenoyl, ⁇ -linolenoyl.
  • the group -C(0)CR 1 R 2 R 3 in formulae (I), (la) and (V) is derived from an a-amino acid or an N-protected a-amino acid, i.e. R 2 is a radical NR a R b , where R a and R b are as defined above and where in particular one or both of R a and R b are an N-protecting groups such as BOC or Cbz, respectively, while the other group R a and R b is hydrogen, Ci-C4-alkyl,
  • R 3 is in particular hydrogen.
  • R 1 is as defined above and in particular selected from hydrogen, Ci-C4-alkyl, which is unsubstituted or carries one OH group, A-CO2H , A-CON H2, where A is as defined above and in particular CH2 or CH2CH2, and benzyl, which is unsubstituted or carries OH.
  • Examples of such groups -C(0)CR 1 R 2 R 3 include but are not limited to N-Boc-glycyl, N-Cbz-glycyl, sarconsinyl, N-Boc-sarcosinyl, N-Cbz-sarcosinyl, prolinyl, N-Boc-prolinyl, N-Cbz-prolinyl, N-Boc-alaninyl,
  • N-Cbz-alaninyl N-Boc-valinyl, N-Cbz-valinyl, N-Boc-leucinyl, N-Cbz-leucinyl,
  • N-Cbz-glutaminyl in particular N-Boc-glycyl, N-Cbz-glycyl, N-Boc-alaninyl,
  • N-Cbz-alaninyl N-Boc-valinyl, N-Cbz-valinyl, N-Boc-leucinyl, N-Cbz-leucinyl,
  • N-Boc-isoleucinyl N-Cbz-isoleucinyl, N-Boc-sarcosinyl, N-Cbz-sarcosinyl,
  • -C(0)CR 1 R 2 R 3 in formulae (I), (la) and (V) is derived from a saturated or unsaturated dicarboxylic acid or a semi-ester thereof.
  • R 2 and R 3 are H and R 1 is a group A-COOH or A-COO-Ci-C4-alkyl, where A is as defined above and in particular Chb or CH2CH2.
  • the carboxylic acid or one of its derivatives of the formula (V) is preferably selected from the group consisting of:
  • N-N-protected a-amino acids in particular N-Boc or N-Cbz protected a-amino acids preferably selected from glycine, alanine, valine, leucine, isoleucine, sarcosine and proline.
  • the reactions of the invention as described hereinafter are performed in reaction vessels customary for such reactions, the reaction being carried out in a continuous, semicontinuous or batchwise manner. In general, the particular reactions will be carried out under atmospheric pressure. The reactions may, however, also be carried out under reduced or elevated pressure.
  • the reaction of the process according to the invention for preparing an ester of the formula (I) may be regarded as an esterification or acylation reaction.
  • the conversion is effected by reacting an alcohol of the formula (IV) with a carboxylic acid or one of its derivatives of the formula (V) in the presence of a tertiary amine and, in case a free carboxylic acid is used as the compound of formula (V), also in the presence of an activator.
  • Suitable tertiary amines are amines of the formula (A)
  • R e , R f and Rs each independently are selected from the group consisting of Ci-C6-alkyl, Cs-Cs-cycloalkyl, phenyl and phenyl which is substituted by 1 , 2, or 3 Ci-C4-alkyl radicals, or R e and R f together with the N-atom form a saturated N- heterocycle, which in addition to the tertiary nitrogen atom may have a further heteroatom or heteroatom group selected from O, S and N-R x , where R x is Ci-C6-alkyl, as a ring member, or R e , R f and Rs together with the nitrogen atom form a 8 to 12 membered N-heterobicycle, in particular a 8 to 12 membered N-heterobicycle where the tertiary heteroatom is part of an endocyclic amidine group.
  • N-heteroaromatic compounds where the N-atom is a ring-atom of the aromatic moiety.
  • the N-heteroaromatic compounds are optionally substituted by 1 , 2, or 3 radicals selected from Ci-C4-alkyl, halogen, 1-pyrrolidinyl and di(Ci-C3-alkyl)- amino.
  • Suitable N-heteroaromatic compounds are pyridine, N-(Ci-C4)-alkylimidazoles and quinolines, wherein the carbon atoms are unsubstituted or carry 1 , 2, or 3 radicals selected from Ci-C4-alkyl, halogen, 1-pyrrolidinyl and di(Ci-C3-alkyl)amino.
  • tertiary amines include, but are not limited to tri-Ci-C6-alkyl amines (or (Ci-C6-alkyl)sN), such as trimethylamine, methyldiethylamine, methyldiisopropylamine and ethyldiisopropylamine, cyclohexyldimethylamine, cyclohexyldiethylamine,
  • DBU 1 ,4-diazabicyclo[2.2.2]octane
  • DBN 1 ,5-diazabicyclo[4.3.0]non-5-ene
  • DBU 1 ,8-diazabicyol[5.4.0]undec-7-ene
  • N-methylimidazole pyridine optionally carrying 1 , 2 or 3 substituents selected from methyl and ethyl
  • Preferred tertiary amines for the transformation of the inventive process are
  • the tertiary amine is selected from trimethylamine, N-methylimidazole, 4-(dimethylamino)pyridine and 4-(1 -pyrrolidinyl)pyridine, and in particular is N-methylimidazole.
  • the tertiary amine is pyridine optionally carrying 1 , 2 or 3 methyl groups, and in particular is pyridine.
  • Suitable activators for the transformation of the inventive process are in principle all compounds capable of converting a carboxylic acid of the formula (V), i.e. the variable Z in formula (V) is -OH, into an corresponding activated ester or a mixed anhydride, which is able to convert an alcohol of formula (IV) in the presence of a tertiary amine into the desired ester of formula (I).
  • Preferred activators are
  • DCC ⁇ , ⁇ '-dicyclohexylcarbodiimide
  • EDC 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • DIC ⁇ , ⁇ '-diisopropylcarbodiimide
  • CDI 1 ,1 '-carbonyldiimidazole
  • pivaloyl chloride Ci-C3-alkyl ester of chloroformic acid, phosgene, thionyl chloride and phosphoryl chloride, in particular DCC, EDC and DIC.
  • the alcohol of formula (IV) and the carboxylic acid or one of its derivatives of formula (V) are reacted in a molar ratio within the range of typically 1 :1 to 1 :5, preferably 1 : 1 to 1 :4, more preferably 1 : 1 to 1 :3 and specifically 1 :1 .1 to 1 :2.
  • a carboxylic acid of formula (V) is used, i.e.
  • Z in formula (V) is -OH
  • the molar ratio of the compounds (IV) and (V) is within the range of typically 1 :1 to 1 :2 and preferably 1 : 1 to 1 :1 .5, while in case a carboxylic acid derivative of formula (V) is used, i.e. Z in formula (V) is not -OH, the molar ratio of the
  • compounds (IV) and (V) is within the range of typically 1 : 1 to 1 :5 and preferably 1 : 1 to 1 :4.
  • the tertiary amine is used in an amount of typically 1 .0 to 4.0 mol, preferably 1 .0 to 3.0 mol, in particular 1 .0 to 1 .5 mol, and specifically 1 .0 to 1 .3 mol, based in each case on 1 mol of the carboxylic acid or one of its derivatives of formula (V).
  • pyridine is employed as tertiary amine, it is used in an amount of typically 1 .0 to 1 .5 mol, preferably 1 .0 to 1 .3 mol and in particular 1 .0 to 1 .1 mol, based in each case on 1 mol of the carboxylic acid or one of its derivatives of formula (V).
  • the activator is used in an amount of typically 1.0 to 2.0 mol, in particular 1.0 to 1 .5 mol, and specifically 1 .1 to 1.3 mol, based in each case on 1 mol of the carboxylic acid of formula (V).
  • the tertiary amine used in the process is selected from trimethylamine, N-methylimidazole,
  • the reaction of the inventive process is preferably carried out in an organic solvent.
  • aprotic organic solvent in particular a polar aprotic organic solvent
  • useful aprotic organic solvents include halogenated Ci-C4-alkanes, such as dichloromethane and trichloromethane, Ci-C4-alkyl nitrile, such as acetonitrile, ethers, for example, aliphatic C2-Cio-ethers having 1 , 2, 3, or 4 oxygen atoms, such as C1-C4- alkoxy-Ci-C4-alkanes, e.g.
  • diethyl ether dipropyl ether, methyl isobutyl ether, methyl tert-butyl ether or ethyl tert-butyl ether, ethylene glycol dimethyl ether (glyme), diethylene glycol dimethyl ether (diglyme) and triethylene glycol dimethyl ether
  • alicyclic C4-C6-ethers such as tetrahydrofuran (THF), tetrahydropyran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran and 1 ,4-dioxane, aliphatic esters, such as C1-C4-alkyl-C1-C4-alkanoat.es, e.g.
  • aromatic hydrocarbons such as benzene optionally carrying 1 to 4 substituents selected from Ci-C4-alkyl and chlorine, such as chlorobenzene, toluene, the xylenes and mesitylene, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), or mixtures of these solvents with one another.
  • aromatic hydrocarbons such as benzene optionally carrying 1 to 4 substituents selected from Ci-C4-alkyl and chlorine, such as chlorobenzene, toluene, the xylenes and mesitylene, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), or mixtures of these solvents with one another.
  • DMF dimethylformamide
  • NMP N-methyl-2-pyrrolidone
  • the solvent for the reaction of the inventive process is preferably selected from halogenated Ci-C4-alkane, Ci-C4-alkyl nitrile, Ci-C4-alkoxy-Ci-C4-alkane, THF, 1 ,4-dioxane, Ci-C4-alkyl-Ci-C4-alkanoate, benzene optionally carrying 1 to 4 substituents selected from Ci-C4-alkyl and chlorine, DMF and NMP, and in particular from dichloromethane, acetonitrile, methyl tert-butyl ether, THF, 1 ,4-dioxane, ethyl acetate, isopropyl acetate and toluene.
  • the total amount of the solvent used in the reaction of the process according to the invention is typically in the range from 500 to 15000 g, preferably in the range from 1000 to 12000 g and in particular in the range from 1000 to 4000 g, based on 1 mol of the alcohol of formula (IV). Preference is given to using solvents which are essentially anhydrous, i.e. have a water content of less than 1000 ppm and especially not more than 200 ppm.
  • the reactants can in principle be contacted with one another in any desired sequence.
  • the alcohol of formula (IV) and the tertiary amine if appropriate in dissolved or dispersed form, can be initially charged and mixed with each other.
  • the obtained mixture can then be admixed with the carboxylic acid or its derivative of the formula (V).
  • the carboxylic acid or its derivative of formula (V) if appropriate in dissolved or dispersed form, can be initially charged and admixed with a mixture of the alcohol of formula (IV) and the tertiary amine.
  • all reactants can also be added simultaneously to the reaction vessel.
  • the alcohol of formula (IV) and the tertiary amine can also be added separately to the reaction vessel. Both of them can independently of one another be added, either in a solvent or in bulk, before or after the addition of the carboxylic acid or its derivative of formula (V).
  • the activator may be added before or after the addition of the carboxylic acid.
  • the reaction of the inventive process is performed under temperature control.
  • the reaction is typically effected in a closed or preferably in an open reaction vessel with stirring apparatus.
  • the reaction temperature of the inventive process depends on different factors, in particular on the reactivity of either the carboxylic acid derivative of formula (V) used or of the active ester formed from the carboxylic acid of formula (V), and can be determined by the person skilled in the art in the individual case, for example by simple preliminary tests.
  • the conversion of the inventive process is performed at a temperature in the range from -78 to 100°C, preferably in the range from -20 to 50°C, more preferably in the range from -10 to 35°C and specifically in the range from -5 to 25°C.
  • the reaction of the inventive process is initiated at a lower temperature, for instance at a temperature in the range of -10 to 40°C and preferably -5 to 20°C, and the temperature is then increased stepwise or continuously to an upper temperature, for instance to an temperature in the range of 0 to 80°C and preferably 10 to 50°C.
  • a pressure of generally 1 to 5 bar and preferably of 1 to 3 bar is established during the reaction.
  • the work-up of the reaction mixtures obtained in the reaction of the inventive process and the isolation of the ester of formula (I) are effected in a customary manner, for example by a quenching step followed by an aqueous extractive work-up or removal of the solvent, for example under reduced pressure.
  • a quenching step followed by an aqueous extractive work-up or removal of the solvent, for example under reduced pressure.
  • it may alternatively be replaced in an isochoric distillation process with another solvent from which the ester of formula (I) crystallizes.
  • the esters of formula (I) are obtained in sufficient purity by applying such measures or a combination thereof.
  • additional purification steps in particular elaborated ones such as chromatography or distillation are often not necessary. If desired, however, further purification can be effected by methods commonly used in the art.
  • the reaction of the inventive process is quenched by adding to the reaction mixture obtained in the reaction a nucleophilic compound, such as an alcohol, e.g. methanol, water or a diluted acid such as an aqueous solution of acetic acid or hydrochloric acid.
  • a nucleophilic compound such as an alcohol, e.g. methanol, water or a diluted acid such as an aqueous solution of acetic acid or hydrochloric acid.
  • the aqueous phase is then removed, if applicable, and the organic phase is extracted with water or a diluted acid, such as an aqueous solution of acetic acid or of hydrochloric acid, usually followed by washing steps with a diluted base, such as an aqueous solution of sodium hydrogen carbonate, and/or water.
  • the organic phase containing the ester of formula (I) can afterwards be introduced into a further reaction step, either directly or after partial or complete removal of the solvent and optional further purification steps.
  • the organic phase is subjected to crystallisation conditions and after completion of the crystallisation the formed crystals are isolated, washed and dried. It is often
  • the original solvent is replaced with one that is more appropriate for crystallization, for example by simply removing the original solvent, e.g. under reduced pressure, and re-dissolving the obtained residue in the new solvent, or, alternatively, by using an isochoric distillation process.
  • the alcohols of the formula (IV) used as starting materials in the inventive process can be prepared e.g. analogous to the process disclosed in J. A. Haugan et al. 1994, Acta Chem. Scand. 48, 899, or in K. Bernhard et al. 1981 , Helv. Chim. Acta 64, 2469, by a Wittig reaction of (S)-3-methyl-5-(4-hydroxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen-1 -yl)- 2,4-pentadienyl-triphenylphosphonium bromide or its 3-deoxo derivative
  • Ci5-phosphonium salts in turn, can be prepared e.g. by analogy to the process disclosed in J. A. Haugan 1994, Acta Chem. Scand. 48, 657, via a Grignard reaction of 3-hydroxy-p-ionone or 3-oxo-4-hydroxy-p-ionone with vinylmagnesium bromide to obtain the corresponding tertiary Cis-alcohol, which is then reacted with suitable phosphine reagent, such as triphenylphosphine hydrobromide.
  • suitable phosphine reagent such as triphenylphosphine hydrobromide.
  • the present invention also relates to the esters of formula (I) as such, wherein the aforementioned statements regarding their preferred characteristics, such as the enantiomeric configuration in position 3 of the 6-membered cycle, the configuration of the exocyclic chain and the meanings of the variables R 1 , R 2 , R 3 and X, fully apply here, too, with the only exception that the group -C(0)CR 1 R 2 R 3 in formula (I) is not acetyl.
  • Preferred esters of the formula (I) are those which include the group -C(0)CR 1 R 2 R 3 selected from the group consisting of lauroyl, myristoyl, oleoyl, linoleoyl, a-linolenoyl, ⁇ -linolenoyl, arachidonoyl, succinoyl, glycyl, sarcosinyl, N-Boc-glycyl, N-Cbz-glycyl, N-Boc-sarcosinyl and N-Cbz-sarcosinyl, and in particular lauroyl, linoleoyl, oleoyl and N-Boc-sarcosinyl.
  • the 12'-apocarotenal esters of the formula (I) may serve as a starting material for the preparation of asymmetric diesters of carotenoid-type tetraterpenes but also of monoesters of symmetric carotenoid-type tetraterpenes, such as monoesters of astaxanthin or zeaxanthin.
  • the monoesters as well as the asymmetric diesters can be prepared from 12'-apocarotenal esters of the formula (I) via Wittig reaction or a Julia olefination with the corresponding Cis-phosphonium salts and Cis-sulfones,
  • DIPE diisopropyl ether
  • EDC 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • NMI 1 -methylimidazole
  • Example 1 (S)-2,7,1 1 -Trimethyl-13-(4-acetyloxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen- 1 -yl)-2,4, 6,8,10,12-tridecahexaen-1 -al (Acetyl-12'-apo-(S)-astaxanthinal)
  • Example 2 (S)-2,7,1 1 -Trimethyl-13-(4-(N-Boc-sarcosinyloxy)-2,6,6-trimethyl-3-oxo- 1 -cyclohexen-1 -yl)-2,4,6,8, 10,12-tridecahexaen-1 -al (N-Boc-sarcosinyl-12'-apo-(S)- astaxanthinal) (S)-2,7,1 1 -Trimethyl-13-(4-hydroxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen-1 -yl)- 2,4,6,8,10,12-tridecahexaen-1 -al (25.0 g, 60.5 mmol), EDC (17.4-(N-Boc-sarcosinyloxy)-2,6,6-trimethyl-3-oxo- 1 -cyclohexen-1 -yl)-2,4,6,8,10,12-tridecahexaen-1

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Abstract

La présente invention concerne un procédé de préparation d'un ester 12'-apocaroténique de formule (I), R 1 est par exemple, de l'hydrogène, C 1 -C 20 -alkyle, C2-C2o-alcényle, C 4 -C 20 -alcadiényle, C 6 -C 20 -alcatriényle ou C 8 -C 20 -alcatétraényle, R 2 est par exemple l'hydrogène ou -NRaRb, où R a est, par exemple, de l'hydrogène, C 1 -C 4 -alkyle, -C (0)-C 1 -C 3 -alkyle, -Boc ou -Cbz, R b est par exemple l'hydrogène ou C 1 -C 4 -alkyle, R 3 est, par exemple, de l'hydrogène, et X est CH 2 ou C = 0, le procédé étant caractérisé en ce qu'un alcool de formule (IV) est mis en réaction avec un acide carboxylique ou un de ses dérivés de formule (V), les variables R 1 , R 2 et R 3 étant telles que définies ci-dessus, et pour n = 1, la variable Z est halogène, -OH ou -0-C (0)-C 1 -C 4 -alkyle, et pour n = 2, la variable Z est O ou S, la réaction étant réalisée en présence d'une amine tertiaire et dans le cas où un composé de formule (IV) avec Z = -OH est également utilisé en présence d'un activateur. L'invention concerne en outre certains esters de 12'-apocarotènes de la formule (I).
PCT/EP2017/073218 2016-09-16 2017-09-15 Procédé de préparation d'esters de 12'-apocarotènes en tant que blocs de construction pour des caroténoïdes Ceased WO2018050792A1 (fr)

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