DE3221464A1 - Process for the preparation of tocopherols and in particular of d- alpha -tocopherol, intermediates in the process and their use - Google Patents
Process for the preparation of tocopherols and in particular of d- alpha -tocopherol, intermediates in the process and their useInfo
- Publication number
- DE3221464A1 DE3221464A1 DE19823221464 DE3221464A DE3221464A1 DE 3221464 A1 DE3221464 A1 DE 3221464A1 DE 19823221464 DE19823221464 DE 19823221464 DE 3221464 A DE3221464 A DE 3221464A DE 3221464 A1 DE3221464 A1 DE 3221464A1
- Authority
- DE
- Germany
- Prior art keywords
- metal
- carbonyl
- tocopherol
- tocopherols
- metal complex
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 26
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 239000011732 tocopherol Substances 0.000 title claims abstract description 21
- 229930003799 tocopherol Natural products 0.000 title claims abstract description 17
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 title claims abstract description 15
- 229960000984 tocofersolan Drugs 0.000 title claims abstract description 10
- 235000019149 tocopherols Nutrition 0.000 title claims abstract description 10
- 239000002076 α-tocopherol Substances 0.000 title claims abstract description 10
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 235000004835 α-tocopherol Nutrition 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 239000000543 intermediate Substances 0.000 title abstract description 4
- 150000004696 coordination complex Chemical class 0.000 claims abstract description 13
- 229910052751 metal Inorganic materials 0.000 claims abstract description 12
- 239000002184 metal Substances 0.000 claims abstract description 12
- 239000000047 product Substances 0.000 claims abstract description 11
- 229960001295 tocopherol Drugs 0.000 claims abstract description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 8
- 235000010384 tocopherol Nutrition 0.000 claims abstract description 7
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 6
- 230000002378 acidificating effect Effects 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- 125000001033 ether group Chemical group 0.000 claims abstract description 5
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims abstract description 4
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 3
- 125000002877 alkyl aryl group Chemical group 0.000 claims abstract description 3
- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- 125000001424 substituent group Chemical group 0.000 claims abstract description 3
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 16
- -1 1 Chemical class 0.000 claims description 14
- 239000011651 chromium Substances 0.000 claims description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 7
- 229910052804 chromium Inorganic materials 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 235000019165 vitamin E Nutrition 0.000 claims description 6
- 239000011709 vitamin E Substances 0.000 claims description 6
- 229930003427 Vitamin E Natural products 0.000 claims description 5
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 5
- 230000001681 protective effect Effects 0.000 claims description 5
- 229940046009 vitamin E Drugs 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 239000013067 intermediate product Substances 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 150000001844 chromium Chemical class 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 230000000707 stereoselective effect Effects 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-WFGJKAKNSA-N deuterated acetone Substances [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 6
- AUFZRCJENRSRLY-UHFFFAOYSA-N 2,3,5-trimethylhydroquinone Chemical compound CC1=CC(O)=C(C)C(C)=C1O AUFZRCJENRSRLY-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical class O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 description 3
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 235000005074 zinc chloride Nutrition 0.000 description 3
- 239000011592 zinc chloride Substances 0.000 description 3
- 239000001707 (E,7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-ol Substances 0.000 description 2
- 150000005208 1,4-dihydroxybenzenes Chemical class 0.000 description 2
- TUAMRELNJMMDMT-UHFFFAOYSA-N 3,5-xylenol Chemical compound CC1=CC(C)=CC(O)=C1 TUAMRELNJMMDMT-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- 125000006519 CCH3 Chemical group 0.000 description 2
- KEVYVLWNCKMXJX-ZCNNSNEGSA-N Isophytol Natural products CC(C)CCC[C@H](C)CCC[C@@H](C)CCC[C@@](C)(O)C=C KEVYVLWNCKMXJX-ZCNNSNEGSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- BLUHKGOSFDHHGX-UHFFFAOYSA-N Phytol Natural products CC(C)CCCC(C)CCCC(C)CCCC(C)C=CO BLUHKGOSFDHHGX-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HNZBNQYXWOLKBA-UHFFFAOYSA-N Tetrahydrofarnesol Natural products CC(C)CCCC(C)CCCC(C)=CCO HNZBNQYXWOLKBA-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- BOTWFXYSPFMFNR-OALUTQOASA-N all-rac-phytol Natural products CC(C)CCC[C@H](C)CCC[C@H](C)CCCC(C)=CCO BOTWFXYSPFMFNR-OALUTQOASA-N 0.000 description 2
- 229940087168 alpha tocopherol Drugs 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- BOTWFXYSPFMFNR-PYDDKJGSSA-N phytol Chemical compound CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC\C(C)=C\CO BOTWFXYSPFMFNR-PYDDKJGSSA-N 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- VLLHEPHWWIDUSS-ONEGZZNKSA-N (e)-4-methoxybut-3-en-2-one Chemical compound CO\C=C\C(C)=O VLLHEPHWWIDUSS-ONEGZZNKSA-N 0.000 description 1
- GWHJZXXIDMPWGX-UHFFFAOYSA-N 1,2,4-trimethylbenzene Chemical compound CC1=CC=C(C)C(C)=C1 GWHJZXXIDMPWGX-UHFFFAOYSA-N 0.000 description 1
- ADMGWHTWSYEIOQ-UHFFFAOYSA-N 1-(2,5-dihydroxy-3,4,6-trimethylphenyl)ethanone Chemical compound CC(=O)C1=C(C)C(O)=C(C)C(C)=C1O ADMGWHTWSYEIOQ-UHFFFAOYSA-N 0.000 description 1
- LOYZVRIHVZEDMW-UHFFFAOYSA-N 1-bromo-3-methylbut-2-ene Chemical compound CC(C)=CCBr LOYZVRIHVZEDMW-UHFFFAOYSA-N 0.000 description 1
- VTWTUVLDYHBQTC-UHFFFAOYSA-N 1-methoxybut-1-en-3-yne Chemical compound COC=CC#C VTWTUVLDYHBQTC-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- QIXDHVDGPXBRRD-UHFFFAOYSA-N 2,3,5-trimethylcyclohexa-2,5-diene-1,4-dione Chemical compound CC1=CC(=O)C(C)=C(C)C1=O QIXDHVDGPXBRRD-UHFFFAOYSA-N 0.000 description 1
- PUMRUSBKNSBTAL-UHFFFAOYSA-N 3,4-dihydro-2h-chromene-2-carbaldehyde Chemical compound C1=CC=C2OC(C=O)CCC2=C1 PUMRUSBKNSBTAL-UHFFFAOYSA-N 0.000 description 1
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical group CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000003855 acyl compounds Chemical class 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012084 conversion product Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- LTUMRKDLVGQMJU-UHFFFAOYSA-N famesylacetone Natural products CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=O LTUMRKDLVGQMJU-UHFFFAOYSA-N 0.000 description 1
- LTUMRKDLVGQMJU-IUBLYSDUSA-N farnesyl acetone Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CCC(C)=O LTUMRKDLVGQMJU-IUBLYSDUSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- LOFJKBAHPJENQS-UHFFFAOYSA-N tris(oxomethylidene)chromium Chemical compound O=C=[Cr](=C=O)=C=O LOFJKBAHPJENQS-UHFFFAOYSA-N 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/04—Compounds containing oxirane rings containing only hydrogen and carbon atoms in addition to the ring oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
- C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
-
- 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
- C07F11/00—Compounds containing elements of Groups 6 or 16 of the Periodic Table
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Verfahren zur Herstellung von Tocopherolen und insbe-Process for the production of tocopherols and in particular
sondere von d-α-Tocopherol, Zwischenprodukte des Verfahrens und deren Verwendung Die Erfindung betrifft ein Verfahren zur Herstellung von Tocopherolen und insbesondere von d-α-Tocopherol, sowie Zwischenprodukte des Verfahrens und deren Verwendung.special of d-α-tocopherol, intermediate products of the process and their use. The invention relates to a process for the production of tocopherols and in particular of d-α-tocopherol, as well as intermediates of the process and their use.
Die technische Totalsynthese von Tocopherolen, insbesondere von d,1-α-Tocopherol (Vitamin E), geht auf die in den Jahren 1938-1940 veröffentlichten Arbeiten von P. Karrer (z.B. P. Karrer, H. Fritzsche, B.H. Ringier, H. Salomon, Helv. Chim. Acta 21, 520 (1938) zurück und beruht auf der Kondensation von Trimethylhydrochinon mit Phytol oder Isophytol. Hierfür sind saure Kondensationsmittel wie Ameisensäure, Zinkchlorid oder Bortrifluoridetherat erforderlich (DRP 713 749, 1939; 731 972, 1938) Statt Trimethylhydrochinon kann auch Trimethylbenzochinon in Gegenwart von Kupfer/Zink-Pulver und Ameisensäure verwendet werden (M. Kajiwara, D.Sakamoto, S. Ohta, Heterocycles 14, 1995 (1980)).The technical total synthesis of tocopherols, in particular of d, 1-α-tocopherol (Vitamin E), based on work published by 1938-1940 P. Karrer (e.g. P. Karrer, H. Fritzsche, B.H. Ringier, H. Salomon, Helv. Chim. Acta 21, 520 (1938) and is based on the condensation of trimethylhydroquinone with Phytol or isophytol. Acid condensing agents such as formic acid, Zinc chloride or boron trifluoride etherate required (DRP 713 749, 1939; 731 972, 1938) Trimethylbenzoquinone can also be used instead of trimethylhydroquinone be used in the presence of copper / zinc powder and formic acid (M. Kajiwara, D. Sakamoto, S. Ohta, Heterocycles 14, 1995 (1980)).
Basische Kondensationsmittel, wie Pyrrolidin werden bei der Reaktion von 2-Acetyl-3,5,6-trimethylhydrochinon mit Farnesylaceton verwendet, die in nachfolgenden Reduktions- und Hydrierungsschritten ebenfalls zum d,l-Tocopherol führt (H.J. Kabbe, H Heitzer, Synthesis 1978, 888).Basic condensing agents such as pyrrolidine are used in the reaction of 2-acetyl-3,5,6-trimethylhydroquinone with farnesylacetone used in subsequent Reduction and hydrogenation steps also lead to d, l-tocopherol (H.J. Kabbe, H Heitzer, Synthesis 1978, 888).
Statt Phytol oder Isophytol kann auch 3,7,11,15-Tetramethyl-1,3-hexadecandiol in Gegenwart von sauren Katalysatoren #ZnCl2, BF3-OEt2) an Trimethylhydrochinon kondensiert werden (L. Bláha, J. HodrovE, J. Weichet, Collection Czechosloc. Chem. Commun. 24, 2023 (1959); M. Matsui, S. Kitamura, Agr. Biol. Chem. (Tohio) 29, 978 (1965)).Instead of phytol or isophytol, 3,7,11,15-tetramethyl-1,3-hexadecanediol can also be used in the presence of acidic catalysts # ZnCl2, BF3-OEt2) on trimethylhydroquinone be condensed (L. Bláha, J. HodrovE, J. Weichet, Collection Czechosloc. Chem. Commun. 24: 2023 (1959); M. Matsui, S. Kitamura, Agr. Biol. Chem. (Tohio) 29,978 (1965)).
Die Darstellung des nahezu ausschliesslich als Ausgangsprodukt verwendeten Trimethylhydrochinons. erfordert eine Reihe von Reaktionsschritten (ausgehend von 3,5-Dimethylphenol oder 1,2,4-Trimethylbenzol (Pseudocumol)) Die aus der Literatur bekannten Gesamtausbeuten liegen unter 30 %.The representation of the used almost exclusively as a starting product Trimethylhydroquinones. requires a series of reaction steps (starting from 3,5-dimethylphenol or 1,2,4-trimethylbenzene (pseudocumene)) those from the literature known overall yields are below 30%.
Eine vierstufige neuere Synthese von Trimethylhydrochinon mit einer Gesamtausbeute von 60 % erfordert als Ausganysprodukt neben Sulfanilsäure 4-Methoxy-3-buten-2-on, das in 60 bis 70 % aus 4-Methoxy-3-buten-1-in erhalten wird.A four step recent synthesis of trimethylhydroquinone with a Overall yield of 60% requires 4-methoxy-3-buten-2-one as an Ausganysprodukt in addition to sulfanilic acid, which is obtained in 60 to 70% from 4-methoxy-3-buten-1-yne.
Die herkömmlichen Verfahren können nicht zur Darstellung des natürlichen Vitamins E modifiziert werden. Die Synthese des natürlich vorkoinmenden d-α-Tocopherols ist bisher nur über schwer zugängliche 2R-konfigurierte Chroman-Vorstufen (z.B. 2-Formylchroman) möglich, an die die Isopren-Seitenkette angeknüpft wird (H. Mayer, P.The conventional methods cannot be used to represent the natural Vitamins E can be modified. The synthesis of naturally occurring d-α-tocopherol has so far only been possible via difficult-to-access 2R-configured Chroman precursors (e.g. 2-formylchroman), to which the isoprene side chain is attached (H. Mayer, P.
Schudel, R. Rüegg, O. Isler, Helv. Chim. Acta 46, 650, 963 (1963); N. Cohen, R.J. Lopresti, G. Saucy, J. Amer.Schudel, R. Rüegg, O. Isler, Helv. Chim. Acta 46,650,963 (1963); N. Cohen, R.J. Lopresti, G. Saucy, J. Amer.
Chem. Soc., 101, 6710 (1979); R. Barner, M. Schmid, Helv.Chem. Soc., 101, 6710 (1979); R. Barner, M. Schmid, Helv.
Chim. Acta 62, 2384 (1979)).Chim. Acta 62, 2384 (1979)).
Der Erfindung liegt die Aufgabe zugrunde, ein Verfahren zur.Herstellung von Tocopherolen und insbesondere des natürlichen Vitamins E zu schaffen, das unter Vermeidung der Verwendung von Trialkylhydrochinonen in flexibler Weise abläuft. Insbesondere soll das Verfahren die Synthese von natürlichem d-α-Tocopherol zulassen, da das natürliche Tocopherol in seiner biologischen Aktivität das racemische d,l-Produkt um bis zu 35 % übertrifft (vgl. "Methods in Vitamin Assay", 3rd Ed., Interscience 1966). Weitere Aspekte dieser Aufgabe ergeben sich aus der nachfolgenden Beschreibung.The invention is based on the object of a method for manufacturing of tocopherols and in particular of the natural vitamin E, the under Avoidance of the use of trialkylhydroquinones runs in a flexible manner. In particular, the method is intended to synthesize natural d-α-tocopherol allow, since the natural tocopherol in its biological activity the racemic Exceeds d, l product by up to 35% (cf. "Methods in Vitamin Assay", 3rd Ed., Interscience 1966). Further aspects of this task emerge from the following Description.
Diese Aufgabe wird durch die Schaffung eines Verfahrens der eingangs genannten Art gelöst, das dadurch gekennzeichnet ist, dass man einen Carbonyl-Alkenylcarben-Metallkomplex mit Sub stituenten R1 und R2 an der Alkenylgruppe und einem Ethersubtituenten R3, worin R1=CH3, OCH3; R2=H, CH3, OCH3 und R3=CH3, C2H5, COR oder SiR3 dars-Eellen, wobei R ein Alkyl, Aryl bzw.This task is accomplished by creating a method of the initially mentioned type, which is characterized in that one has a carbonyl-alkenylcarbene metal complex with substituents R1 and R2 on the alkenyl group and an ether substituent R3, wherein R1 = CH3, OCH3; R2 = H, CH3, OCH3 and R3 = CH3, C2H5, COR or SiR3 dars-Eellen, where R is an alkyl, aryl or
Alkylaryl ist, mit einem Alkinol der Formel (9) bedeuten, wobei X=H, OH, COOR6 und R6= Niedrigalkyl ist, umsetzt, sodann aus dem entstandenen Reaktion produkt (10) den Metallcarbonylanteil abspaltet, das metallfreie Produkt (11) entethert und in Gegenwart saurer Katalysatoren zu dem gewünschten Tocopherol zyklisiert.Is alkylaryl, with an alkynol of formula (9) mean, where X = H, OH, COOR6 and R6 = lower alkyl, then split off the metal carbonyl component from the resulting reaction product (10), deether the metal-free product (11) and cyclized to the desired tocopherol in the presence of acidic catalysts.
Das in dem erfindungsgemäss verwendeten Carbonyl-Alkenylcarben-Metallkomplex (1) enthaltene Metallatom stellt im allgemeinen eines der sechsc Nebengruppe dar, wobei hierunter wiederum Chrom besonders bevorzugt ist. Besonders günstige Ergebnisse der Synthese haben sich bei Einsatz einer Verbindung der Formel (i) ergeben. In der Verbindung kennen eine oder mehrere Carbonylfunktionen durch andere Liganden. ersetzt sein, beispielsstceise Phosphin-, Aminliyanden, etc wobei deren Wasserstoffatom wiederum im Regelfall alkyliert oder aryliert ist, oder #-gebundene Aromaten wie z.B. Benzol, Cyclopentadienyl. Solche und andere Liganden sind aus der Carben-Chemie bekannt.The metal atom contained in the carbonyl-alkenylcarbene metal complex (1) used according to the invention generally represents one of the six subgroups, with chromium being particularly preferred among these. Particularly favorable results of the synthesis have been found when using a compound of the formula (i) result. In the compound know one or more carbonyl functions through other ligands. be replaced, for example phosphine, amine ligands, etc. where their hydrogen atom is again usually alkylated or arylated, or # -bound aromatics such as benzene, cyclopentadienyl. Such and other ligands are known from carbene chemistry.
Die Reaktion des Carbonyl-Alkenylcarben-Metallkomplexes mit dem Alkinol wird im Regelfall unter Schutzgas durchgeführt. Als Schutzgas können beispielsweise Stickstoff, Argon, etc., genannt werden. Als Lösungsmittel kommen mit Vorteil Donorlösungsmittel in Betracht, z.B. Dialkylether, THF, etc.. Die Reaktion läuft mit guter Reaktionsgeschwindigkeit im Temperaturbereich von 20 bis 800C ab.The reaction of the carbonyl-alkenylcarbene metal complex with the alkynol is usually carried out under protective gas. As a protective gas, for example Nitrogen, argon, etc. can be mentioned. Donor solvents are advantageously used as solvents into consideration, e.g. dialkyl ether, THF, etc .. The reaction proceeds at a good rate in the temperature range from 20 to 800C.
Der Ausgangscarbenkomplex (1) kann auf an sich bekannte Weise hergestellt werden, was anhand des Chrompentacarbonylkomplexes näher erläutert werden soll. The starting carcinoma complex (1) can be produced in a manner known per se which will be explained in more detail with reference to the chromium pentacarbonyl complex.
Im letzteren Fall geht man von handelsüblichem Hexacarbonylchrom und 1-Lithioalkenen sowie einem elektrophilen Alkylierungsmittel (z.B. Oxoniumsalz, Dialkylsulfat, Trialkylhalogensilan, Acylverbindungen) aus wobei die Ausgangsverbindungen (1) in Ausbeuten von etwa 70 bis 90 % aniallen. Die Synthese verläuft bezüglich der C=C-Doppelbindung stereospezifisch. 1-Lithioalkene stellt man aus 1-Halogenalkenen und Lithium oder Lithium-Alkylverbindungen her (F.G. Bordwell, Ph. S. Landis, J.Amer.Chem.Soc. 79, 1593 (1957); D.Seebach H. Neumann, Chem. Ber. 107, 847 (1974)). In the latter case, commercial hexacarbonylchromium is used and 1-lithioalkenes as well as an electrophilic alkylating agent (e.g. oxonium salt, Dialkyl sulfate, trialkylhalosilane, acyl compounds) from where the starting compounds (1) aniallen in yields of about 70 to 90%. The synthesis proceeds with respect to the C = C double bond stereospecifically. 1-lithioalkenes are made from 1-haloalkenes and lithium or lithium-alkyl compounds (F.G. Bordwell, Ph. S. Landis, J.Amer.Chem.Soc. 79: 1593 (1957); D. Seebach H. Neumann, Chem. Ber. 107, 847 (1974)).
Die Carbenkomplexe des Chroms stellen im allgemeinen rote Kristalle mit Schmelzpunkten von zum Teil unter 0°C dar und sind unter Schutzgas (Stickstoff, Argon, etc.) in der Kalte gut lagerbar.The carbene complexes of chromium are generally red crystals with melting points of sometimes below 0 ° C and are under protective gas (nitrogen, Argon, etc.) can be stored well in the cold.
Die Darstellung der Alkinole erfolgt ausgehend von Alkin-enen, , wobei letztere Synthese ausgehend von Prenylbromid und Alkinyl-Grignard-Reagenz in der europäischen Patentschrift 0 015 436 (Hof fmann-La Roche) (Veröffentlichungsnummer 00 100 822.8) beschrieben ist.The alkynols are prepared starting from alkyne-enes,, where the latter synthesis starting from prenyl bromide and alkynyl Grignard reagent in the European Patent specification 0 015 436 (Hofmann-La Roche) (publication number 00 100 822.8) is described.
Diese Alkin-ene werden mit Persäure, beispielsweise m-Chlor-perbenzoesäure, zu Epoxy-alkinen oxidiert, die sich zu den gewünschten Alkinolen leicht reduzieren lassen, beispielsweise mit LiAlH4, etc..These alkynes are mixed with peracid, for example m-chloroperbenzoic acid, oxidized to epoxy alkynes, which are easily reduced to the desired alkynols let, for example with LiAlH4, etc ..
Die Umsetzung des Carbonyl-Alkenylcarben-Metallkomplexes mit dem Alkinol erfolgt in praktisch quantitativer Ausbeute, wobei das Umsetzungsprodukt noch einen Metallcarbonylanteil enthält. Das Umsetzungsprodukt kann in Abhängigkeit von der Art des Ausgangsalkinols ein reines Enantiomeres oder ein racemisches Gemisch darstellen.The implementation of the carbonyl-alkenylcarbene metal complex with the alkynol takes place in practically quantitative yield, with the reaction product still one Contains metal carbonyl content. The reaction product can depending on the Type of starting alkynol represent a pure enantiomer or a racemic mixture.
Wird das Alkinol in der Form des reinen Enantiomeren eingesetzt, fällt das Produkt (10) ebenfalls in Form des reinen Enantiomeren an. Das Umsetzungsprodukt (10) kann von dem Metallcarbonylanteil leicht unter Ausbildung des Produktes (11) befreit werden. Im Regelfall wird man hier mit Kohlenmonoxid unter Druck arbeiten, wobei das entstehende Metallcarbonyl zur Bildung des Ausgangscarbonyl-Alkenylcarben-Metallkomplexes (1) zurückgeführt werden kann. Durch diese Variante ist ein besonders günstiger und rationeller Ablauf des Verfahrens möglich. Auch die Bildung des metallfreien Hydrochinonmonoether-Produktes (11) erfolgt in praktisch quantitativer Ausbeute. Dieses metallfreie Produkt (11) kann auf verschiedene We:ise entethert werden Dies kann durch Hydrolyse, Hydrogenolyse oder unter Verwendung von Lewis-Säure erfolgen, was beispielsweise von der Art des Etherrestes R3 abhängig sein kan£ Ist der Ethersubstituent ein Acylrest wird man diesel häufig über Hydrolyse entfernen. Stellt R3 z.B. SiR3 (R3 = Niedrigalkyl) dar, lässt sich dieser Rest leicht durch Hydrogenolyse oder, wenn R3=Niedrigalkyl ist, auch mit Bortribromid entfernen.Auch die Entetherung erfolgt in hohen Ausbeuten, beispielsweise im Bereich von 80 bis 96 %. Das Hydrochinonderivat (12) wird dann zu dem gewünschten Tocopherol,vorteilhaS mit saurem Katalysator, z.B. Bortrifluorid-Etherat, p-Toluolsulfonsäure, Ameisensäure, etc., zyklisiert.If the alkynol is used in the form of the pure enantiomer, falls the product (10) also in the form of the pure enantiomer. The conversion product (10) can easily be derived from the metal carbonyl content with the formation of the product (11) to be freed. As a rule, you will work here with carbon monoxide under pressure, wherein the resulting metal carbonyl to form the starting carbonyl-alkenylcarbene metal complex (1) can be traced back. This variant is a particularly favorable one and rational process flow is possible. Also the formation of the metal-free Hydroquinone monoether product (11) takes place in practically quantitative yield. This metal-free product (11) can be de-etherified in various ways can be done by hydrolysis, hydrogenolysis or using Lewis acid, what can be dependent, for example, on the type of the ether residue R3 is the ether substituent an acyl residue becomes diesel often remove via hydrolysis. Provides For example, R3 represents SiR3 (R3 = lower alkyl), this radical can be easily removed by hydrogenolysis or, if R3 = lower alkyl, also remove with boron tribromide. Also the de-etherification takes place in high yields, for example in the range from 80 to 96%. The hydroquinone derivative (12) is then converted to the desired tocopherol, advantageously with an acidic catalyst, e.g. boron trifluoride etherate, p-toluenesulfonic acid, formic acid, etc., cyclized.
Der Ablauf des erfindungsgemässen Verfahrens ist in dem nachstehenden Reaktionsschema 1 dargestellt, wobei als Metallcarbenkomplex hier Pentacarbonylchrom-Carbenkomplex verwendet ist. Der Einsatz dieses speziellen Carbens dient jedoch lediglich zur Veranschaulichung des Ablaufs, weshalb hierdurch keine Beschränkung des erfindungsgemässen Verfahrens bezweckt sein soll. The sequence of the process according to the invention is shown in reaction scheme 1 below, the metal carbene complex used here being pentacarbonylchromium-carbene complex. The use of this special carbene only serves to illustrate the process, which is why this is not intended to restrict the method according to the invention.
Die erfindungsgemässe Synthese ist insbesondere deshalb von besonderer Bedeutung, da die Umsetzung in stereoselektiver Weise erfolgt und dadurch die Synthese von natürlichem d-α-Tocopherol ohne weiteres möglich ist. Dies wird aus dem nachstehenden Reaktion schema 2 deutlich.The synthesis according to the invention is therefore particularly special Importance, since the conversion takes place in a stereoselective manner and thereby the synthesis of natural d-α-tocopherol is readily possible. This becomes from the below reaction scheme 2 clearly.
Schema 2 Bemerkenswert ist, dass im obigen Reaktionsschema 2 das Inol unter Invers Ion beim Kondensationsschritt (Ringschluss zum Chroman) umgesetzt wird. Ausgehend von einem 6S-Inol wird daher unter Invers ion beim Kondensationsschritt ein neuer Weg zum natürliclen 2R-Tocopherol (Vitamin E) möglich.Scheme 2 It is noteworthy that in the above reaction scheme 2 the inol is converted with inverse ion in the condensation step (ring closure to give the chroman). Starting from a 6S-inol, a new route to the natural 2R-tocopherol (vitamin E) is possible with inversion during the condensation step.
Die Darstellung der enantiomeren 6S- (oder GR-)InoI-e kann über die enantioselektive Alkylierung von Ketonen, beispielsweise mit axial dissymmetrischen Metall-Alkylverbindungen, erfolgen (vgl. D. Seebach, Organometallic Compounds in Organic Synthesis, Symposium Wageningen/Niederlande, 18./19.3.1982).The representation of the enantiomeric 6S- (or GR-) InoI-e can be via the enantioselective alkylation of ketones, for example with axially dissymmetric Metal-alkyl compounds take place (cf. D. Seebach, Organometallic Compounds in Organic Synthesis, Symposium Wageningen / Netherlands, March 18/19, 1982).
In alternativer Weise erhält man auch die enantiomeren 6S- bzw. 6R-Inole, wenn man die entsprechenden En-ine (2) enantioseiektiv zu (8) oxidiert.Alternatively, one also obtains the enantiomeric 6S- or 6R-ynoles, if the corresponding enyne (2) is oxidized enantioseectively to (8).
In die Erfindung sind auch die Zwischenprodukte der Formeln (10) und (11) eingeschlossen, wobei (10) noch den Metalltricarbonylanteil enthält. Insbesondere-umfasst die Erfindung daher Verbindungen der Formel (10) In gleichel Weise sind die-IIydrocllLnonmonoethez: der Formel (11) erfindungsgemäss umfasst. The invention also includes the intermediates of the formulas (10) and (11), (10) still containing the metal tricarbonyl portion. In particular, the invention therefore includes compounds of the formula (10) In the same way, the-IIydrocllLnonmonoethez: the formula (11) are encompassed according to the invention.
Schliesslich wird erfindungsgemäss auch die Verwendung der Hydrochinonmonoether (11) sowie deren metalltricarbonylsubstituierte Derivate (10) zur Herstellung von Tocopherolen, insbesondere Vitamin E, beansprucht.Finally, according to the invention, there is also the use of the hydroquinone monoethers (11) and their metal tricarbonyl-substituted derivatives (10) for the preparation of Tocopherols, especially vitamin E, claimed.
Die Erfindung wird nachstehend in den Arbeitsvorschriften weiter veranschaulicht, die jedoch nicht als Einschrsinkung auszulegen sind.The invention is further illustrated below in the working instructions, which, however, are not to be interpreted as a restriction.
ARBEITSVORSCHRiF1EN Herstellung von Metall-carben-Komplex (1), z.B.WORKING RULES Preparation of metal-carbene complex (1), e.g.
Pentacarbony(E-2-alkenylcarben)chrom-Komplex (1) Zu 6,6 g (30 mmol) Hexacarbonylchrom in 300 ml Tetrahydrofuran (oder Diethylether) wird unter Schutzgas bei -40°C eine auf -30°C gekühlte etherische Lösung einer äquimolaren Menge von Z-2-Lithio-2-alken getropft. Die Farbe verändert sich dabei nach gelborange. Nach 1 Stunde bei -40°C zieht man das Lösungsmittel ab. Der Rück~ stand w:ird in 50 ml Wasser aufgeschlämmt, mit 200 ml Pentan überschichtet und mit 4,5 g Trimethyloxoniumtetrafluoroborat versetzt, wobei die Farbe sofort nach tiefrot umschlägt. Die Pentanphase wird über Natriumsulfat getrocknet und eingeengt. Beim Abkühlen erhält man rote Kris Lc ile Das Acylmetallat kann auch als Tetraalkylammoniumsalz isoliert und in homogener Phase in Methylenchlorid mit Triethyloxoniumtetrafluoroborat, Acylhalogeniden (Acetylchlorid, Benzoylchlorid) oder Trimethylsilylchlorid alkyliert werden. Pentacarbony (E-2-alkenylcarbene) chromium complex (1) To 6.6 g (30 mmol) of hexacarbonylchromium in 300 ml of tetrahydrofuran (or diethyl ether) is an ethereal solution cooled to -30 ° C under protective gas at -40 ° C equimolar amount of Z-2-lithio-2-alkene added dropwise. The color changes to yellow-orange. After 1 hour at -40 ° C., the solvent is drawn off. The residue is suspended in 50 ml of water, covered with a layer of 200 ml of pentane and mixed with 4.5 g of trimethyloxonium tetrafluoroborate, the color immediately turning deep red. The pentane phase is dried over sodium sulfate and concentrated. Red crystals are obtained on cooling. The acyl metalate can also be isolated as the tetraalkylammonium salt and alkylated in a homogeneous phase in methylene chloride with triethyloxonium tetrafluoroborate, acyl halides (acetyl chloride, benzoyl chloride) or trimethylsilyl chloride.
C14H19CrNO6 Molmasse 349,3 Analysenwerte: Berechnet: C 48,14 H 5,48 Cr 14,89 N 4,01 Gefunden : 48,00 5,56 14,76 3,97 IR (CH2Cl2): 2033 m, 1903 vs H-NMR (Aceton-D6) : 4,37 (qq, 1), 3,48 (s, 12), 1,65 (d, J ), 1,52 (s, 3) C14H19CrNO6 Molmasse 349,3 Analysenwerte: Berechnt: C 48,14 H 5,48 Cr 14,89 N 4,01 Gefuriden : 47,96 5,31 14,82 4,10 IR (CH2Cl2): 2030 m, 1937 sh, 1908 sh, 1896 vs 1H-NMR (Aceton-D6): 5,92 (qq, 1), 3,48, (s, 12), 1,69 (d, 3), 1,50 (s,3) C11H10CrO6 Molmasse 290,2 Ms: m/e 290, 262, 234, 206, 178, 150 (100 %) IR (Hexan): 2064 m, 1960 s, 1949 vs H-NMR (Aceton-D6): 5,73 (qq, 1), 4,67 (s, 3), 1,86 (dq, 3), 1,83 (br, 3) C11H10CrO6 Molmasse 290,2 MS: m/e 290, 262, 234, 206, 178, 150 (100 %) IR (Hexan) : 2065 m, 1963 s, 1949 vs 1H-NMR (Aceton-D6); 5,17 (qq, 1), 4,52 (s, 3), 1,93 (dq, 3), 1,55 (dq, 3) C13H16CrO6Si Molmasse 348,3 MS: m/e 348, 320, 292, 264, 236, 208 (100 %) 1H-NMR (Aceton-D6): 7,13 (qq, 1), 1,90 (dq, 3), 1,57 (dq, 3), 0,07 (s, 9) C13H16CrO6Si Molmasse 348,3 MS: m/e 348, 320, 292, 264, 236, 208 (100 %) H-NMR (Aceton-D6) : 4,83 (qq, 1), 2,03 (dq, 3), 1,93 (dq, 3), 0,46 (s, 9) C10H8CrO6 Molmasse 276,2 MS: m/e 276, 248, 220 192, 164, 136 (100 %) IR (Hexan): 2068 m, 1967 s, 1951 vs Epoxidierung der Enine Beispiel: Darstellung von 5,6-Epoxy-6,10,14,18-tetramethyl-2-nonadecin (8) Zu 3,44 g 3-Chlorperbenzoesäure (77 %-ig) in 50 ml Methylenchlorid tropft man bei 0°C eine Lösung von 4,50 g 6,10,14,18-Tetramethyl-5-nonadecen-2-in in 20 ml Methylenchlorid. Nach 2-stündigem Rühren wird filtriert, das Filtrat mit 10 %-iger Natriumsulfit- und 5 %-iger Natriumbikarbonatlösung gewaschen und ausgeethert. Die eingeengte organische Phase wird an Kieselgel chromatograf iert. Mit Methylenchlorid als Laufmittel erhält man 4t25 g eines farblosen Ols (Ausbeute 91 %).C14H19CrNO6 Molar mass 349.3 Analysis values: Calculated: C 48.14 H 5.48 Cr 14.89 N 4.01 Found: 48.00 5.56 14.76 3.97 IR (CH2Cl2): 2033 m, 1903 vs H. -NMR (acetone-D6): 4.37 (qq, 1), 3.48 (s, 12), 1.65 (d, J), 1.52 (s, 3) C14H19CrNO6 Molar mass 349.3 Analysis values: Calculated: C 48.14 H 5.48 Cr 14.89 N 4.01 Gefurids: 47.96 5.31 14.82 4.10 IR (CH2Cl2): 2030 m, 1937 sh, 1908 sh, 1896 vs 1H-NMR (acetone-D6): 5.92 (qq, 1), 3.48, (s, 12), 1.69 (d, 3), 1.50 (s, 3) C11H10CrO6 molar mass 290.2 Ms: m / e 290, 262, 234, 206, 178, 150 (100%) IR (hexane): 2064 m, 1960 s, 1949 vs H-NMR (acetone-D6): 5.73 (qq, 1), 4.67 (s, 3), 1.86 (dq, 3), 1.83 (br, 3) C11H10CrO6 molar mass 290.2 MS: m / e 290, 262, 234, 206, 178, 150 (100%) IR (hexane): 2065 m, 1963 s, 1949 vs 1H-NMR (acetone-D6); 5.17 (qq, 1), 4.52 (s, 3), 1.93 (dq, 3), 1.55 (dq, 3) C13H16CrO6Si molecular weight 348.3 MS: m / e 348, 320, 292, 264, 236, 208 (100%) 1 H-NMR (acetone-D6): 7.13 (qq, 1), 1.90 (dq, 3 ), 1.57 (dq, 3), 0.07 (s, 9) C13H16CrO6Si molecular weight 348.3 MS: m / e 348, 320, 292, 264, 236, 208 (100%) H-NMR (acetone-D6): 4.83 (qq, 1), 2.03 (dq, 3 ), 1.93 (dq, 3), 0.46 (s, 9) C10H8CrO6 Molar mass 276.2 MS: m / e 276, 248, 220 192, 164, 136 (100%) IR (hexane): 2068 m, 1967 s, 1951 vs epoxidation of enynes Example: Preparation of 5,6-epoxy 6,10,14,18-tetramethyl-2-nonadecyne (8) A solution of 4.50 g 6.10 is added dropwise to 3.44 g of 3-chloroperbenzoic acid (77%) in 50 ml of methylene chloride at 0.degree , 14,18-tetramethyl-5-nonadecen-2-yne in 20 ml of methylene chloride. After stirring for 2 hours, it is filtered, the filtrate is washed with 10% sodium sulfite and 5% sodium bicarbonate solution and extracted with ether. The concentrated organic phase is chromatographed on silica gel. With methylene chloride as the mobile phase, 4t25 g of a colorless oil are obtained (yield 91%).
C23H42O Molmasse 334,6 MS: m/e 334, 319, 305, 281, 151, 137, 124 1H-NMR (CDCl3): 2,87 (5-H), 2,34 (CH2), 1,75 (=C-CH3), 1,40 (CH2), 1,23, 1,18 (CH2, CH), 0,83 (CH3) 13C-NMR (Benzol-D6): 77,4, 75,0 (#C-); 61,1, 60, Reduktion der Epoxide Beispiel: Darstellung von 6,10,14,18-Tetramethyl-2-nonadecin-6-ol (9) Eine Suspension von 0,45 g Lithiumaluminiumhydrid in 30 ml Ether wird tropfenweise mit einer Lösung von 2,04 g 5,6-Epoxy-6,10,14,18-tetramethyl-2-nonadecin in 10 ml Ether versetzt. Man erwärmt 4 Stunden unter Rückiluss, zersetzt anschliessend überschüssiges Lithiumaluminiumhydrid unter Eiskühlung mit Wasser, säuert mit 0,1 m Schwefelsäure an und ethert aus. Der eingeengte Etherextrakt wird mit Pentan/Methylenchlorid/ Ether an Kieselgel gereinigt Das Ethereluat liefert 1,78 g eines farblosen Öls (Ausbeute 87 t).C23H42O Molar mass 334.6 MS: m / e 334, 319, 305, 281, 151, 137, 124 1H-NMR (CDCl3): 2.87 (5-H), 2.34 (CH2), 1.75 ( = C-CH3), 1.40 (CH2), 1.23, 1.18 (CH2, CH), 0.83 (CH3) 13C-NMR (benzene-D6): 77.4, 75.0 (# C-); 61.1, 60, Reduction of the epoxides Example: Preparation of 6,10,14,18-tetramethyl-2-nonadecin-6-ol (9) A suspension of 0.45 g of lithium aluminum hydride in 30 ml of ether is added dropwise with a solution of 2.04 g of 5 , 6-epoxy-6,10,14,18-tetramethyl-2-nonadecine in 10 ml of ether was added. The mixture is heated under reflux for 4 hours, then excess lithium aluminum hydride is decomposed with water while cooling with ice, acidified with 0.1 M sulfuric acid and etherified. The concentrated ether extract is purified on silica gel with pentane / methylene chloride / ether. The ether eluate gives 1.78 g of a colorless oil (yield 87 t).
C23H44O Molmasse 336,6 MS: m/e 336, 321, 307 IR: 3390 (OH) 1H-NMR (CDCl3): 3,53 (OH), 2,28 (CH2), 1,79 (#C-CH3), 1,68 (CH2), 1,23 (CH2, CH), 0,88 (CH3) Tricarbonyl(hydrochinonmonoether)chrom-Komplex (10) Beispiel: Darstellung von Tricarbonyl(4-methoxy-3(2), 5,6-trimethyl-2(3)-(3'-hydroxy-3',7',11',15' tetramethyl-hexadecyl)-phenol)-chrom Eine Lösung von 1,65 g Pentacarbonyl (E-2-butenylmethoxy-carben)-chrom und 2,10 g 6,10,14,18-Tetramethyl-2-nonadecin-6-ol in 20 ml t-Butylmethylether wird 2 Stunden auf 500C erwärmt. Nach dem Abziehen des Lösungsmittels wird an Kieselgel chromatografiert. Mit Methylenchlorid eluiert man eine gelbe Zone, die den Tricarbonylchrom-Komplex enthält (Ausbeute 2,95 gr 87 %). C23H44O molecular weight 336.6 MS: m / e 336, 321, 307 IR: 3390 (OH) 1 H-NMR (CDCl3): 3.53 (OH), 2.28 (CH2), 1.79 (# C-CH3), 1.68 (CH2), 1.23 (CH2, CH), 0.88 (CH3) tricarbonyl (hydroquinone monoether) chromium complex (10) Example: Representation of tricarbonyl (4-methoxy-3 (2), 5,6-trimethyl-2 (3) - (3'-hydroxy-3 ', 7', 11 ', 15' tetramethyl-hexadecyl) -phenol) -chrome A solution of 1.65 g of pentacarbonyl (E-2-butenylmethoxy-carbene) chromium and 2.10 g of 6,10,14,18-tetramethyl-2-nonadecin-6-ol in 20 ml of t-butyl methyl ether is 2 hours heated to 500C. After the solvent has been stripped off, it is chromatographed on silica gel. With Methylene chloride elutes a yellow zone containing the tricarbonylchromium complex contains (yield 2.95 g 87%).
C33H54CrO6 Molmasse 598,7 MS: m/e 598, 514, 462 IR (Hexan): 3400 (OH), 1954 s, 1881 s, 1872 s (CO) 1H-NMR (Benzol-D6): 2-(3'-Hydroxy-3',7',11',15'-tetramethyl-hexadecyl)-phenol-Komplex 3,35 (OCH3), 2,50 (CH2), 2,11, 2,07 (CH3), 1,53 (Ch2), 1,27 (CH2, CH), 0,90 (CH3) Abspaltung des Hydrochinonmonoether-Liganden Beispiel: Abspaltung in Gegenwart von Kohlenmonoxid Eine Lösung von 1 mmol Hydrochinonmonoether-Komplex in 50 ml Ether wird unter 100 bar Kohlenmonoxid 80 Stunden auf 70°C erwärmt. Nach dem Entspannen wird die Lösung auf -40°C abgekühlt und vom ausgefallenen Hexacarbonylchrom abgetrennt. Nach dem Einengen des Filtrats bleibt ein gelbes Öl.C33H54CrO6 molar mass 598.7 MS: m / e 598, 514, 462 IR (hexane): 3400 (OH), 1954s, 1881s, 1872s (CO) 1H-NMR (benzene-D6): 2- (3'-hydroxy-3 ', 7', 11 ', 15'-tetramethylhexadecyl) phenol complex 3.35 (OCH3), 2.50 (CH2), 2.11, 2.07 (CH3), 1.53 (Ch2), 1.27 (CH2, CH), 0.90 (CH3) Cleavage of the hydroquinone monoether ligand Example: cleavage in the presence of Carbon monoxide A solution of 1 mmol hydroquinone monoether complex in 50 ml ether is heated to 70 ° C under 100 bar carbon monoxide for 80 hours. After relaxing the solution is cooled to -40 ° C and separated from the precipitated hexacarbonylchromium. A yellow oil remains after the filtrate has been concentrated.
Beispiel: 4-Methoxy-3(2),5,6-trimethyl-2(3)-(3'-hydroxy 3',7',11',15'-tetramethyl-hexadecyl)phenol (Ausbeute 95 %) C30H5403 Molmasse 462,6 MS: m/e 462, 447 IR: 3390 (OH) 1H-NMR (Benzol-D6): 3,29 (OCH3), 2,48 (CH2), 2,16, 2,12 (CH3), 1,60 (CH2), 1,27 (CH2, CH), 0,88 (CH3) Etherabspaltung und Rinqschluss zum Chroman ((6) über Stufe (12)) Beispiel: Darstellung von d,l-&t-Tocopherol (6) Eine Lösung von 1 mmol Hydrochinonmonomethyletherverbindung (1la, b) in 10 ml Chloroform wird bei -78°C mit 0,5 ml Bortribromid in 3 ml Chloroform versetzt.Example: 4-methoxy-3 (2), 5,6-trimethyl-2 (3) - (3'-hydroxy 3 ', 7', 11 ', 15'-tetramethyl-hexadecyl) phenol (Yield 95%) C30H5403 molecular weight 462.6 MS: m / e 462, 447 IR: 3390 (OH) 1H-NMR (Benzene-D6): 3.29 (OCH3), 2.48 (CH2), 2.16, 2.12 (CH3), 1.60 (CH2), 1.27 (CH2, CH), 0.88 (CH3) elimination of ether and connection to the chroman ((6) via Stage (12)) Example: Representation of d, l- & t-tocopherol (6) A solution of 1 mmol of hydroquinone monomethyl ether compound (1la, b) in 10 ml of chloroform is added to -78 ° C with 0.5 ml of boron tribromide in 3 ml of chloroform.
Man lässt langsam auf Raumtemperatur ansteigen, giesst in Wasser und ethert aus. Der Etherextrakt wird eingeengt und unter Zugabe von 20 ml Heptan und einem über schuss von wasserfreiem Zinkchlorid 3 Stunden auf 700C erwärmt. Die Reinigung an Kieselgel mit Pentan/Ether liefert d,1-α-Tocopherol (Ausbeute 87 %).It is allowed to rise slowly to room temperature, poured into water and ethert out. The ether extract is concentrated and with the addition of 20 ml of heptane and an excess of anhydrous zinc chloride heated to 700C for 3 hours. The cleaning on silica gel with pentane / ether gives d, 1-α-tocopherol (yield 87%).
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DE19823221464 DE3221464A1 (en) | 1982-06-07 | 1982-06-07 | Process for the preparation of tocopherols and in particular of d- alpha -tocopherol, intermediates in the process and their use |
JP10156983A JPS591476A (en) | 1982-06-07 | 1983-06-07 | Tocopherol and preparation of particularly d-alpha- tocopherol, intermediate product of said method and application thereof |
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FR2566778A1 (en) * | 1984-01-24 | 1986-01-03 | Centre Nat Rech Scient | CARBENIC COMPLEXES OF TRANSITION METALS, PROCESS FOR OBTAINING AND APPLICATION AS CATALYSTS FOR POLYMERIZATION AND COPOLYMERISATION |
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FR2566778A1 (en) * | 1984-01-24 | 1986-01-03 | Centre Nat Rech Scient | CARBENIC COMPLEXES OF TRANSITION METALS, PROCESS FOR OBTAINING AND APPLICATION AS CATALYSTS FOR POLYMERIZATION AND COPOLYMERISATION |
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