WO2018050793A1 - Procédé de préparation d'esters de sel de phosphonium en tant que blocs de construction pour carotinoïdes - Google Patents
Procédé de préparation d'esters de sel de phosphonium en tant que blocs de construction pour carotinoïdes Download PDFInfo
- Publication number
- WO2018050793A1 WO2018050793A1 PCT/EP2017/073219 EP2017073219W WO2018050793A1 WO 2018050793 A1 WO2018050793 A1 WO 2018050793A1 EP 2017073219 W EP2017073219 W EP 2017073219W WO 2018050793 A1 WO2018050793 A1 WO 2018050793A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- group
- formula
- hydrogen
- phosphonium salt
- Prior art date
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- -1 phosphonium salt esters Chemical class 0.000 title claims abstract description 453
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- 235000021466 carotenoid Nutrition 0.000 title description 3
- 125000001895 carotenoid group Chemical group 0.000 title description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 55
- 239000001257 hydrogen Substances 0.000 claims abstract description 55
- 238000000034 method Methods 0.000 claims abstract description 45
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 33
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 25
- 150000003512 tertiary amines Chemical class 0.000 claims abstract description 18
- 229910003827 NRaRb Inorganic materials 0.000 claims abstract description 14
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000002367 halogens Chemical class 0.000 claims abstract description 12
- 239000012190 activator Substances 0.000 claims abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 4
- 125000003944 tolyl group Chemical group 0.000 claims abstract description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
- 150000004714 phosphonium salts Chemical class 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
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- 125000001424 substituent group Chemical group 0.000 claims description 13
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
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- 125000003118 aryl group Chemical group 0.000 claims description 4
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- NQGIJDNPUZEBRU-UHFFFAOYSA-N dodecanoyl chloride Chemical compound CCCCCCCCCCCC(Cl)=O NQGIJDNPUZEBRU-UHFFFAOYSA-N 0.000 description 1
- 125000005066 dodecenyl group Chemical class C(=CCCCCCCCCCC)* 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000000265 myristoleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- CIXSDMKDSYXUMJ-UHFFFAOYSA-N n,n-diethylcyclohexanamine Chemical compound CCN(CC)C1CCCCC1 CIXSDMKDSYXUMJ-UHFFFAOYSA-N 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- GNVRJGIVDSQCOP-UHFFFAOYSA-N n-ethyl-n-methylethanamine Chemical compound CCN(C)CC GNVRJGIVDSQCOP-UHFFFAOYSA-N 0.000 description 1
- ISRXMEYARGEVIU-UHFFFAOYSA-N n-methyl-n-propan-2-ylpropan-2-amine Chemical compound CC(C)N(C)C(C)C ISRXMEYARGEVIU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001196 nonadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005187 nonenyl group Chemical class C(=CCCCCCCC)* 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 125000005064 octadecenyl group Chemical class C(=CCCCCCCCCCCCCCCCC)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001236 palmitoleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000005496 phosphonium group Chemical group 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- OCAAZRFBJBEVPS-UHFFFAOYSA-N prop-2-enyl carbamate Chemical compound NC(=O)OCC=C OCAAZRFBJBEVPS-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004673 propylcarbonyl group Chemical group 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 125000005930 sec-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical compound O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 125000005063 tetradecenyl group Chemical class C(=CCCCCCCCCCCCC)* 0.000 description 1
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 description 1
- 125000005040 tridecenyl group Chemical class C(=CCCCCCCCCCCC)* 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 125000005065 undecenyl group Chemical class C(=CCCCCCCCCC)* 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
- 235000010930 zeaxanthin Nutrition 0.000 description 1
- 239000001775 zeaxanthin Substances 0.000 description 1
- 229940043269 zeaxanthin Drugs 0.000 description 1
Classifications
-
- 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)
Definitions
- the present invention relates to a new process for preparing a phosphonium salt ester of the formula (I),
- variable R is acetyl, chloroacetyl, dichloroacetyl, ethoxyacetyl,
- variable V is an aryl group such as phenyl
- variable T- is a suitable anion such as bromide
- phosphonium salt esters that slightly differ from those of formula (A) in that they have a modified exocyclic side chain were used as precursors for the syntheses of carotenoids and related polyenes, as documented e.g. in 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, Helv. Chim. Acta 63,1473. In these syntheses the acyl group R functioned merely as an intermediate protection group.
- the process should in particular be simple to perform and should enable good yields of the desired phosphonium salt esters.
- R 4 , X, and Y are as defined herein, with a carboxylic acid or an activated carboxylic acid in the presence of a tertiary amine.
- phosphonium salts are generally known to be labile and to decompose under conditions typically used for acylations, such as in particular the use of bases, of strong acids or of milder acids in combination with higher temperatures. Therefore a person skilled in the art would not have expected that an efficient esterification of phosphonium salts of the formula (IV) would be possible. This is especially true since the
- phosphonium salts of the formula (IV) are even labile towards mild bases, due to their polyene structure substituted with an electron acceptor.
- the invention firstly relates to a process for the preparation of a
- 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, C o -C20-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 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 together with R a may form a C3-C4-alkandiyl group
- R 4 is selected from the group consisting of phenyl, tert-butyl and tolyl,
- Y " is selected from the group consisting of halide, sulfate, hydrogensulfate, mesylate, tosylate, benzenesulfonate, nitrate and Ci-C3-alkyl-carboxylate
- 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-
- variable Z is selected from the group consisting of halogen, -OH,
- the invention further relates to phosphonium salt esters of the formula (I) as defined herein, provided that the group -C(0)CR 1 R 2 R 3 is not acetyl, ethoxyacetyl,
- the inventive process has several advantages. First of all it affords an easy access to the phosphonium salt esters of the formula (I) in good yields and good specificity by starting from the corresponding unesterified phosphonium salt of the formula (IV).
- the inventive process allows for the straightforward preparation of a series of phosphonium salt esters of the formula (I) with different acyl groups starting from a single phosphonium salt of the formula (IV), which itself is generally readily accessible in sufficient quantities and also storable.
- 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 in the context of Z and bromine in the context of Y "
- 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 to 4 (“Ci-C 4 -alkyl”) or 1 to 20 (“Ci-C 20 -alkyl”) carbon atoms.
- C1-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,
- 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
- variable Y- in formulae (I) and (IV) is an anion equivalent serving as counterion to balance the positively charged phosphonium group and can in principle be selected freely from among monovalent anions and the proportions of polyvalent anions corresponding to a single negative charge. Examples of suitable anions are in particular those indicated above.
- the two 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 E,E isomer (IVa), i.e. the amount of the E,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 the two 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 two 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 E,E configuration as depicted in formula (IVa)
- 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 ).
- the 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-CONH2, A-COO-(Ci-C 4 -alkyl), Ci-C 4 -alkoxy and phenoxy, in particular hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C 4 -C2o-alkdienyl, C6-C20- alktrienyl, C 8 -C 2 o-alktetraenyl, Cio-C 2 o-alkpentaenyl, A-COOH, A-CONH2 and A-COO-(Ci-C 4 -alkyl) and specifically Ci-C 2 o
- 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-C 4 -alkyl,
- R 1 and R 2 together may form a group of formulae (II) or (III), in particular may form a group of formula (II) only, and specifically do not form a group of formulae (II) or (III).
- 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-Ci9-alkdienyl, C6-Ci9-alktrienyl and Cs-dg-alktetraenyl, in particular hydrogen, Ci-Cig-alkyl, C2-Cig-alkenyl, C4-Cig-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.
- variables R 4 and Y- in the compounds of formulae (I), (la), (IV) and (IVa) have the following meanings:
- R 4 is selected from the group consisting of phenyl, tert-butyl and tolyl, and in
- Y " is selected from the group consisting of halide, such as bromide or chloride, sulfate, hydrogensulfate, mesylate and tosylate, in particular bromide, chloride, sulfate and hydrogensulfate, and specifically is bromide,
- variable X in the compounds of formulae (I), (la), (IV) and (IVa) has the following meaning:
- 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 a phosphonium salt ester of the formula (I) may be regarded as an esterification or an acylation reaction.
- the conversion is effected by reacting a phosphonium salt 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 nitrogen 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-C 4 )- alkylimidazoles and quinolines, wherein the carbon atoms are unsubstituted or carry 1 , 2, or 3 radicals selected from Ci-C 4 -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,
- DABCO 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 C1-C6- alkyl)3N , DBU, DABCO, N-methylimidazole, pyridine optionally carrying 1 , 2 or 3 substituents selected from methyl and ethyl, 4-(dimethylamino)pyridine and 4-(1 - pyrrolidinyl)pyridine, in particular trimethylamine, N-methylimidazole, pyridine optionally carrying 1 , 2 or 3 methyl groups, 4-(dimethylamino)pyridine and 4-(1 - pyrrolidinyl)pyridine, and specifically N-methylimidazole and 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 phosphonium salt 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 phosphonium salt 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
- the molar ratio of the compounds (IV) and (V) is within the range of typically 1 :1 .2 to 1 :5 and preferably 1 :1 .5 to 1 :4.
- the tertiary amine is used in an amount of typically 1.0 to 3.0 mol, preferably 1 .0 to 2.0 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).
- 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 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 1000 to 10000 g and preferably in the range from 2000 to 8500 g, based on 1 mol of the phosphonium salt of formula (IV).
- 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 phosphonium salt 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 phosphonium salt of formula (IV) and the tertiary amine.
- all reactants can also be added simultaneously to the reaction vessel.
- 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 80°C, more preferably in the range from -10 to 60°C and specifically in the range from -5 to 50°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 phosphonium salt 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 phosphonium salt ester of formula (I) crystallizes.
- the phosphonium salt 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 water.
- the organic phase containing the phosphonium salt 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 advantageous to perform the crystallization in a solvent other than that used for the reaction. In that case 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 phosphonium salts of the formula (IV) used as starting materials in the inventive process can be prepared e.g. by analogy to the process disclosed in the prior art discussed at the outset.
- Compounds of the formula (IV), where X is Chb can e.g. be prepared by the process described by J. A. Haugan 1994, Acta Chem. Scand.
- the present invention also relates to the phosphonium salt 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 , R 4 , X and Y-, fully apply here, too, with the only exception that the group -C(0)R 1 R 2 R 3 in formula (I) is not acetyl, ethoxyacetyl, phenoxyacetyl, propionyl, butyryl, pentanoyl, hexanoyl, palmitoyl, stearoyl or oleoyl.
- Preferred phosphonium salt 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, linoleoyl, a-linolenoyl, ⁇ -linolenoyl, arachidonoyl, N-Boc-glycyl, N-Cbz-glycyl, glycyl, succinoyl, N-Boc-sarcosinyl, sarcosinyl and N-Cbz-sarcosinyl, and in particular lauroyl, ⁇ -linolenoyl and N-Boc-sarcosinyl.
- the phosphonium salt 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 the phosphonium salt esters of the formula (I) via Wittig reaction or a Julia olefination with the corresponding 12'-apocarotenals such as, 12'- apozeaxanthinal and 12'-apoastaxanthinal, respectively.
- the following examples are intended to serve as further illustration of the invention.
- EDC 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
- NMI 1 -methylimidazole
- Example 1 (S)-3-Methyl-5-(4-palmitoyloxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen-1 -yl)- 2,4-pentadienyl-triphenylphosphonium bromide (S)-3-Methyl-5-(4-hydroxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen-1 -yl)-2,4-pentadienyl- triphenylphosphonium bromide (575.5 g, 1 mol) and DCM (2000 mL) were charged to a 4L reactor and cooled to a temperature of 0°C.
- Example 4 (S)-3-Methyl-5-(4-(N-Boc-sarcosinyloxy)-2,6,6-trimethyl-3-oxo- 1 -cyclohexen-1 -yl)-2,4-pentadienyl-triphenylphosphonium bromide (S)-3-Methyl-5-(4-hydroxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen-1 -yl)-2,4-pentadienyl- triphenylphosphonium bromide (57.6 g, 100 mmol), DCM (400 mL) and EDC (28.75 g, 150 mmol) were charged at a temperature of 20°C to a 1 L three-necked flask.
- Example 5 (S)-3-Methyl-5-(4-(y-linolenoyloxy)-2,6,6-trimethyl-3-oxo-1 -cyclohexen- 1 -yl)-2,4-pentadienyl-triphenylphosphonium bromide (S)-3-Methyl-5-(4-hydroxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen-1 -yl)-2,4-pentadienyl- triphenylphosphonium bromide (51.5 g, 84.4 mmol), DCM (666.5 g) and pyridine (20 g, 253.2 mmol) were charged to a 2.5 L reactor followed by the dropwise addition of ⁇ -linolenoyl chloride (62.6 g, 21 1 mmol) to the mixture at a temperature of 20°C.
- reaction mixture was then heated under reflux for 15 hours. After cooling down to 20°C MeOH (15.6 mL) was added dropwise and the mixture was then kept at a temperature of 30°C for 1.5 hours. The reaction mixture was afterwards extracted initially with an aq. solution of acetic acid (10 wt-%, 200 mL) and then with water (2 x 200 mL).
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Abstract
La présente invention concerne un procédé de préparation d'ester de sel de phosphonium de formule (I), dans laquelle R1 est par exemple l'hydrogène, C1-C20-alkyle, C2-C20-alcényle, C4-C20-alkdienyl, C6-C20-alktrienyl ou C8-C20-alktétraenyl, R2 est par exemple l'hydrogène ou -NRaRb, où Ra est par exemple l'hydrogène, C1-C4-alkyle, -C(O)-C1-C3-alkyle, -Boc ou -Cbz, Rb est par exemple l'hydrogène ou C1-C4-alkyle, R3 est par exemple l'hydrogène, X est CH2 ou C=O, R4 est un phényle, tert-butyle ou tolyle, Y- est un contre-anion approprié, le procédé étant caractérisé en ce qu'un alcool de formule (IV), est mise en réaction avec un acide carboxylique ou un de ses dérivés de la formule (V), les variables R1, R2 et R3 sont tel que défini dans la description, et pour n = 1 la variable Z est halogène, -OH ou -O-C(O)-C1-C4-alkyle, et pour n = 2 la variable Z est O ou S, la réaction étant effectuée en présence d'une amine tertiaire et dans le cas d'un composé de formule (IV) avec Z = -OH est également utilisé en présence d'un activateur. L'invention concerne en outre certains esters de sel de phosphonium de formule (I).
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| US11261145B2 (en) | 2017-03-20 | 2022-03-01 | Basf Se | Process for preparing bromotrichloromethane |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2653838A1 (de) | 1975-11-30 | 1977-06-02 | Hoffmann La Roche | Polyenverbindungen |
| EP0005749A2 (fr) * | 1978-06-02 | 1979-12-12 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Dérivés de la cyclohexéne, procédé de leur préparation, ainsi que leur utilisation |
| EP0005748A2 (fr) * | 1978-06-02 | 1979-12-12 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Procédé de préparation de dérivés cyclohexéniques, ainsi que composés intermédiaires de synthèse |
| EP0100839A1 (fr) * | 1982-07-16 | 1984-02-22 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Hydrogénation catalytique de sels de phosphonium acétyléniques |
| DE4430289A1 (de) | 1993-09-04 | 1995-03-09 | Basf Ag | Verbessertes Verfahren zur Herstellung von Astaxanthin |
| EP0908449A1 (fr) * | 1997-10-03 | 1999-04-14 | F. Hoffmann-La Roche Ag | Préparation de caroténoides |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| IL164089A0 (en) * | 2002-04-30 | 2005-12-18 | Suntory Ltd | Astaxanthin medium-chain fatty acidester, production method of the same, and composition comprising the same |
| WO2006081659A1 (fr) * | 2005-02-01 | 2006-08-10 | The University Of British Columbia | Inhibiteurs meroterpenoides de la phosphoinositide 3 kinase (pi3k) |
-
2017
- 2017-09-15 WO PCT/EP2017/073219 patent/WO2018050793A1/fr active Application Filing
- 2017-09-15 CN CN201780056631.7A patent/CN109715638A/zh active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2653838A1 (de) | 1975-11-30 | 1977-06-02 | Hoffmann La Roche | Polyenverbindungen |
| EP0005749A2 (fr) * | 1978-06-02 | 1979-12-12 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Dérivés de la cyclohexéne, procédé de leur préparation, ainsi que leur utilisation |
| EP0005748A2 (fr) * | 1978-06-02 | 1979-12-12 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Procédé de préparation de dérivés cyclohexéniques, ainsi que composés intermédiaires de synthèse |
| EP0100839A1 (fr) * | 1982-07-16 | 1984-02-22 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Hydrogénation catalytique de sels de phosphonium acétyléniques |
| DE4430289A1 (de) | 1993-09-04 | 1995-03-09 | Basf Ag | Verbessertes Verfahren zur Herstellung von Astaxanthin |
| EP0908449A1 (fr) * | 1997-10-03 | 1999-04-14 | F. Hoffmann-La Roche Ag | Préparation de caroténoides |
Non-Patent Citations (8)
| Title |
|---|
| E. BECHER ET AL., HELV. CHIM. ACTA, vol. 64, 1981, pages 2419 |
| F. KIENZLE ET AL., HELV. CHIM. ACTA, vol. 61, 1978, pages 2609 |
| J. A. HAUGAN, ACTA CHEM. SCAND., vol. 48, 1994, pages 657 |
| J. LIU ET AL., TETRAHEDRON LETT., vol. 38, 1997, pages 8495 |
| K. BERNHARD ET AL., HELV. CHIM. ACTA, vol. 63, 1980, pages 1473 |
| P.G.M. WUTS: "Greene's Protective Groups in Organic Synthesis", 2014, JOHN WILEY AND SONS, pages: 895 - 1194 |
| Y. YAMANO ET AL., CHEM. PHARM. BULL., vol. 42, 1994, pages 410 |
| Y. YAMANO ET AL., J. CHEM. SOC. PERKIN TRANS., vol. 1, 1995, pages 1895 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11261145B2 (en) | 2017-03-20 | 2022-03-01 | Basf Se | Process for preparing bromotrichloromethane |
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