USRE30260E - 1-(2,6,6-Trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-methyl-penta-1,4-diene[or 1-yn-4-en]-3-ols - Google Patents
1-(2,6,6-Trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-methyl-penta-1,4-diene[or 1-yn-4-en]-3-ols Download PDFInfo
- Publication number
- USRE30260E USRE30260E US06/016,868 US1686879A USRE30260E US RE30260 E USRE30260 E US RE30260E US 1686879 A US1686879 A US 1686879A US RE30260 E USRE30260 E US RE30260E
- Authority
- US
- United States
- Prior art keywords
- formula
- compound
- trimethyl
- reaction
- methyl
- 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.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 claims description 57
- PPEXHEZQKRHDII-UHFFFAOYSA-N 3-(3-hydroxy-3-methylpenta-1,4-dienyl)-2,4,4-trimethylcyclohex-2-en-1-ol Chemical compound CC1=C(C=CC(C)(O)C=C)C(C)(C)CCC1O PPEXHEZQKRHDII-UHFFFAOYSA-N 0.000 claims description 5
- FDSDTBUPSURDBL-LOFNIBRQSA-N canthaxanthin Chemical compound CC=1C(=O)CCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)C(=O)CCC1(C)C FDSDTBUPSURDBL-LOFNIBRQSA-N 0.000 abstract description 12
- UZFLPKAIBPNNCA-BQYQJAHWSA-N alpha-ionone Chemical compound CC(=O)\C=C\C1C(C)=CCCC1(C)C UZFLPKAIBPNNCA-BQYQJAHWSA-N 0.000 abstract description 8
- OOUTWVMJGMVRQF-DOYZGLONSA-N Phoenicoxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)C(=O)C(O)CC1(C)C)C=CC=C(/C)C=CC2=C(C)C(=O)CCC2(C)C OOUTWVMJGMVRQF-DOYZGLONSA-N 0.000 abstract description 6
- 235000012682 canthaxanthin Nutrition 0.000 abstract description 6
- 239000001659 canthaxanthin Substances 0.000 abstract description 6
- 229940008033 canthaxanthin Drugs 0.000 abstract description 6
- DTATXKHAJFDHQB-XYOKQWHBSA-N (4e)-4-(2,2,6-trimethylcyclohexylidene)butan-2-one Chemical compound CC1CCCC(C)(C)\C1=C\CC(C)=O DTATXKHAJFDHQB-XYOKQWHBSA-N 0.000 abstract description 4
- 239000000576 food coloring agent Substances 0.000 abstract 1
- 235000002864 food coloring agent Nutrition 0.000 abstract 1
- 238000006257 total synthesis reaction Methods 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 52
- 238000006243 chemical reaction Methods 0.000 description 41
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000203 mixture Substances 0.000 description 23
- 239000000243 solution Substances 0.000 description 20
- 239000002904 solvent Substances 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000003960 organic solvent Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 8
- UZFLPKAIBPNNCA-UHFFFAOYSA-N alpha-ionone Natural products CC(=O)C=CC1C(C)=CCCC1(C)C UZFLPKAIBPNNCA-UHFFFAOYSA-N 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- ODMUHAHUBCUABS-UHFFFAOYSA-N 4-(4,4,6-trimethyl-7-oxabicyclo[4.1.0]heptan-5-yl)but-3-en-2-one Chemical compound C1CC(C)(C)C(C=CC(=O)C)C2(C)OC21 ODMUHAHUBCUABS-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 229940093499 ethyl acetate Drugs 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- VOPQCTRWKRAMBB-UHFFFAOYSA-N 3-(3-hydroxy-3-methylpenta-1,4-dienyl)-2,4,4-trimethylcyclohex-2-en-1-one Chemical compound CC1=C(C=CC(C)(O)C=C)C(C)(C)CCC1=O VOPQCTRWKRAMBB-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 150000002009 diols Chemical class 0.000 description 4
- 150000002118 epoxides Chemical class 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 150000004714 phosphonium salts Chemical class 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- LICNQDPDQQOXCU-UHFFFAOYSA-N (2,6,6-Trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-oxo-trans-1-butene Natural products CC(=O)C=CC1=C(C)C(O)CCC1(C)C LICNQDPDQQOXCU-UHFFFAOYSA-N 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 150000004703 alkoxides Chemical class 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- IJMWREDHKRHWQI-UHFFFAOYSA-M magnesium;ethene;chloride Chemical compound [Mg+2].[Cl-].[CH-]=C IJMWREDHKRHWQI-UHFFFAOYSA-M 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 3
- LICNQDPDQQOXCU-AATRIKPKSA-N (e)-4-(3-hydroxy-2,6,6-trimethylcyclohexen-1-yl)but-3-en-2-one Chemical compound CC(=O)\C=C\C1=C(C)C(O)CCC1(C)C LICNQDPDQQOXCU-AATRIKPKSA-N 0.000 description 2
- RRJBYVJCXFAEJN-UHFFFAOYSA-N 3-(5-bromo-3-methylpenta-1,3-dienyl)-2,4,4-trimethylcyclohex-2-en-1-one Chemical compound BrCC=C(C)C=CC1=C(C)C(=O)CCC1(C)C RRJBYVJCXFAEJN-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- QKBVMLAOBPMNDR-UHFFFAOYSA-N carbonic acid;3-(3-hydroxy-3-methylpenta-1,4-dienyl)-2,4,4-trimethylcyclohex-2-en-1-one Chemical compound OC(O)=O.CC1=C(C=CC(C)(O)C=C)C(C)(C)CCC1=O QKBVMLAOBPMNDR-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- -1 methoxy, ethoxy, isopropoxy Chemical group 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 description 2
- 229940043349 potassium metabisulfite Drugs 0.000 description 2
- 235000010263 potassium metabisulphite Nutrition 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- RIRFIIYTPSKYBB-UHFFFAOYSA-N 1-(1,3,3-trimethyl-7-oxabicyclo[4.1.0]heptan-2-ylidene)but-3-en-2-one Chemical compound C1CC(C)(C)C(=CC(=O)C=C)C2(C)C1O2 RIRFIIYTPSKYBB-UHFFFAOYSA-N 0.000 description 1
- HHDFCSOJTZJNEN-UHFFFAOYSA-N 3-(4-hydroxyhexa-2,5-dien-2-yl)-2,4,4-trimethylcyclohex-2-en-1-ol Chemical compound C=CC(O)C=C(C)C1=C(C)C(O)CCC1(C)C HHDFCSOJTZJNEN-UHFFFAOYSA-N 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- QBXSXOYVLNNJRY-UHFFFAOYSA-N OOO.CC1=C(C=CC(C)(O)C=C)C(C)(C)CCC1=O Chemical compound OOO.CC1=C(C=CC(C)(O)C=C)C(C)(C)CCC1=O QBXSXOYVLNNJRY-UHFFFAOYSA-N 0.000 description 1
- 229910020667 PBr3 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 101150108015 STR6 gene Proteins 0.000 description 1
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- XQJPQIGNUIXGQD-UHFFFAOYSA-N carbonic acid;3-(3-hydroxy-3-methylpenta-1,4-dienyl)-2,4,4-trimethylcyclohex-2-en-1-ol Chemical compound OC(O)=O.CC1=C(C=CC(C)(O)C=C)C(C)(C)CCC1O XQJPQIGNUIXGQD-UHFFFAOYSA-N 0.000 description 1
- 235000021466 carotenoid Nutrition 0.000 description 1
- 150000001747 carotenoids Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- ZCDOYSPFYFSLEW-UHFFFAOYSA-N chromate(2-) Chemical compound [O-][Cr]([O-])(=O)=O ZCDOYSPFYFSLEW-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000002035 hexane extract Substances 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011981 lindlar catalyst Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000401 methanolic extract Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 101150035983 str1 gene Proteins 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 150000004794 vinyl magnesium halides Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/24—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by six-membered non-aromatic rings, e.g. beta-carotene
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/02—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains containing only carbon and hydrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
- C07C403/08—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by hydroxy groups
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- C—CHEMISTRY; METALLURGY
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- 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
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/32—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by aldehydo- or ketonic radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5407—Acyclic saturated phosphonium compounds
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- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Definitions
- halogen as used throughout this specification includes all four halogens, i.e. chlorine, fluorine, bromine and iodine.
- lower alkyl as used herein designates a saturated aliphatic straight or branched chain hydrocarbon containing from 1 to 7 carbon atoms such as ethyl, methyl, isopropyl, etc.
- lower alkoxy as used throughout the specification denotes lower alkoxy groups containing from 1 to 7 carbon atoms such as methoxy, ethoxy, isopropoxy, etc.
- aryl designates mononuclear aromatic hydrocarbon groups such as phenyl, tolyl, which can be unsubstituted or substituted in one or more positions with a halogen, nitro, lower alkyl or lower alkoxy substituent and polynuclear aryl groups such as naphthyl, anthryl, phenanthryl, which can be unsubstituted or substituted with one or more of the aforementioned groups.
- the preferred aryl groups are the substituted and unsubstituted mononuclear groups, particularly phenyl.
- alkali metal includes all alkali metals such as sodium, potassium and lithium.
- lower alkanol designates aliphatic unsaturated alcohols containing from 1 to 7 carbon atoms such as methanol, ethanol, isopropanol, n-butanol etc.
- the compound of formula II is converted to the compound of formula V by reaction with a per-organic acid.
- a per-organic acid any method of converting an unsaturated double bond to an epoxy bridge can be utilized.
- per-organic acids are included per-acetic acid, per-benzoic acid, m-chloroper-benzoic acid etc. Any conventional per-organic acid can be utilized for this purpose. Any of the conventional reaction conditions utilized in forming epoxides can be used in this reaction.
- the compound of formula V is converted to the compound of formula IV by treatment with alklai metal lower alkoxide.
- Any conventional alklai metal lower alkoxide can be utilized such as sodium or potassium methoxide.
- This reaction is carried out in a lower alkanol solvent.
- the preferred solvents are methanol and ethanol.
- any conventional lower alkanol can be utilized.
- an inert organic solvent such as benzene, toluene, etc. can be used with the lower alkanol solvent.
- any conventional inert organic solvent can, if desired, be incorporated in the lower alkanol solvent medium.
- temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. On the other hand, any temperature of from 10° C. to 100° C. can be utilized in carrying out this reaction.
- the compound of formula IV can be prepared from retroionone, i.e. a compound of formula II-a via the following intermediate: ##STR6##
- the compound of formula II-a is converted to the compound of formula VI by epoxidation via a per-organic acid in the manner described in connection with the reaction of a compound of formula II to a compound of formula V.
- the compound of formula VI is converted to the compound of the formula IV by treating the compound of formula VI with an alklai metal lower alkoxide in a lower alkanol solvent in the same manner as described in connection with the conversion of a compound of the formula V to a compound of formula IV.
- the compound of formula IV is treated with a vinylmetalic halide such as vinyl magnesium chloride under conditions conventional for reacting a ketone with an organo metallic halide.
- a vinylmetalic halide such as vinyl magnesium chloride
- the vinylmetalic halide can be utilized in amounts of 10 moles or more per mole of the compound of formula IV.
- no beneficial results are achieved by utilizing such large an amount of the vinyl magnesium halide.
- amounts of the vinyl metallic halide of greater than 10 moles per mole of the compound of formula IV are seldom utilized.
- the compound of formula X can be prepared from the compound of formula IV by reacting the compound of formula IV with an alkali metal acetalide such as sodium acetalide. Any of the conditions conventional in reacting a ketone with an acetalide to form an addition product can be utilized in accordance with this invention.
- the compound of formula X can be converted to the compound of formula IX via hydrogenation utilizing a Lindlar catalyst. Any conventional method of selectively reducing a triple bond to a double bond can be utilized in carrying out this reaction.
- the compound of formula IX is converted to the compound of formula XI by treatment with a oxidizing agent.
- a oxidizing agent Any conventional oxidizing agent can be utilized to affect this conversion.
- maganese dioxide and the chromate oxidizing agents such as Jones reagent. Any of the conditions conventional in carrying out oxidation utilizing these reagents can be utilized in the conversion of a compound of formula X to a compound of formula XI.
- the aluminum isopropoxide can be present in catalytic quantities, i.e. at least 0.1 mole percent based upon the moles of the compound of formula IX. If desired, the aluminum isopropoxide can be present in an amount of 100 mole percent based upon the compound of formula IX. In fact, any excess of the aluminum isopropoxide will not deleteriously affect this reaction. However, for economics it is generally preferred to utilize the aluminum isopropoxide in an amount of from 0.1 mole percent to 100 mole percent based upon the weight of the compound of formula IX.
- the oxidation with aluminum isopropoxide and acetone can be carried out in the presence of an inert organic solvent such as methylene chloride, benzene and toluene.
- an inert organic solvent such as methylene chloride, benzene and toluene.
- any inert organic solvent can, if desired, be utilized in a mixture with acetone.
- this reaction is carried out at the reflux temperature of the reaction medium.
- the compound of formula XI is converted to the compound of formula XII by treating the compound of formula XI with a phosphorous trihalide.
- this reaction is carried out in an inert organic solvent. Any conventional inert organic solvent can be utilized to carry out this reaction.
- the preferred solvents are the ether solvents such as diethyl ether, tetrahydrofuran, etc.
- temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. Generally it is preferred to carry out this reaction at a temperature of from 10° C. to 100° C.
- the compound of formula XII is converted to the compound of formula X by reacting the compound of formula XII with a phosphine of the formula ##STR9## wherein R 1 , R 2 and R 3 are as above.
- This reaction is generally carried out in an inert organic solvent. Any conventional inert organic solvent can be utilized to carry out this reaction. Among the preferred solvents are the ether solvents and the hydrocarbon solvents such as benzene, toluene, etc. In carrying out this reaction, temperature and pressure are not critical and generally this reaction can be carried out at room temperature and atmospheric pressure. Generally, it is preferred to carry out this reaction by heating the reaction medium to the reflux temperature.
- the compound of formula X can be directly prepared from the compound of formula XI by treating the compound of formula XI with the hydrohalic acid salt of the phosphine of formula XIII.
- hydrohalic acid salts triphenylphosphine hydrobromide is preferred.
- This reaction is generally carried out in a inert organic solvent. Any conventional inert organic solvent can be utilized for this purpose.
- the halogenated hydrocarbon solvents such as dichloromethane, methylene, chloride, etc.
- temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. If desired, higher or lower temperatures can be utilized.
- the compound of formula I is formed from the compound of formula X by reacting the compound of formula X with a compound of the formula: ##STR10## via a Wittig reaction.
- This reaction is carried out utilizing conditions that are conventional in Wittig type reactions. In this reaction, two moles of the compound of formula X are reacted per mole of the compound of formula XX.
- hydroxyketone 1-(2,6,6-Trimethyl-3-oxo-1-cyclohexen-1-yl)-3-methyl-penta-1,4-dien-3-ol (4 g) dissolved in diethyl ether (40 ml) was cooled to -20° and treated with a solution of phosphorous tribromide in diethyl ether (1 mole. equiv PBr 3 ; 80 ml) and then warmed to RT.
- Example 6 The bromide of Example 6 was added to triphenylphosphine (4.4 g) in benzene (30 ml) and heated at reflux for 1 hour. The mixture was then cooled to RT treated with diethyl ether (50 ml) and filtered to yield the 5-(2,6,6-trimethyl-3-oxo-cyclohexen-1-yl)-3-methyl-2,3-pentadiene-1-triphenylphosphonium bromide as a white powder (6.6 g).
- Retro-ionone (1.9 g) was added to a solution of m-chloroperbenzoic acid (2.2 g) dissolved in dichloromethane. This resulted in an exothermic reaction ( ⁇ 40°). After cooling, the mixture was washed with an aqueous sodium carbonate solution dried over MgSO 4 and taken to dryness to yield the epoxide, the 1-(2,6,6-Trimethyl-2,3-epoxy-1-cyclohexylidene)-buten-2-one. This epoxide ( ⁇ 2 g) was dissolved in a solution of methanolic sodium methoxide (1.4 Molar; 20 ml) and left at RT for 1/2 hour (instant color change and probably complete reaction). Dilution with ether followed by a brine washing yielded 1-(2,6,6,-trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-oxo-1-butene, upon chromatography over silica gel.
- This crude diol (216.9 g) in a mixture of acetone and dichloromethane (1:1; 2000 ml) containing aluminum isopropoxide (400 g) was heated at reflux for 5 hours (tlc; 1:1 benzene/ethyl acetate), cooled, treated with more dichloromethane (1000 ml) and then acidified with aqueous sulfuric acid (2 N; 2000 ml) with ice cooling.
- the hydroxyketone 1-(2,6,6-Trimethyl-3-oxo-1-cyclohexene-1-yl)-3-methyl-penta-1,4-diene-3-ol (136.6 g) was dissolved in diethyl ether (1000 ml) cooled to -20° and exposed to a solution of phosphorous tribromide (50 ml) in ether (250 ml) and then stirred for 1 hour at RT. After this period, the mixture was cooled to 5°, treated with water (500 ml; care) and the ether layer was then washed well with water, saturated aqueous sodium bicarbonate solution, brine and then dried over anhydrous magnesium sulfate. (All the aqueous extracts were back-washed with more diethyl ether.)
- hydroxyketone 1-(2,6,6-Trimethyl-3-hydroxy-1-cyclohexene-1-yl)-3-methyl-penta-1,4-diene-3-ol (10.7 g) dissolved in dichloromethane (25 ml) was treated with triphenylphosphine hydrobromide (14.4 g; 0.9 mol equiv) in more dichloromethane (50 ml) and left overnight at RT (the reaction is exothermic and complete in ca 1 hours). Most of the solvents were then evaporated off and thick syrupy residue was digested with diethyl ether and filtered.
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Abstract
A total synthesis of canthaxanthin, a known food coloring agent from alpha or retro ionone.
Description
This application is related to Ser. No. 585,224, filed Jul. 9, 1975, Rosenberger et al. now U.S. Pat. No. 4,006,186.
In accordance with this invention, a method is provided for synthesizing canthaxanthin which has the formula; ##STR1## from either α-ionone which has the formula ##STR2## or retroionone ##STR3##
The term halogen as used throughout this specification includes all four halogens, i.e. chlorine, fluorine, bromine and iodine. The term "lower alkyl" as used herein designates a saturated aliphatic straight or branched chain hydrocarbon containing from 1 to 7 carbon atoms such as ethyl, methyl, isopropyl, etc. The term "lower alkoxy" as used throughout the specification denotes lower alkoxy groups containing from 1 to 7 carbon atoms such as methoxy, ethoxy, isopropoxy, etc.
As used herein, the term "aryl" designates mononuclear aromatic hydrocarbon groups such as phenyl, tolyl, which can be unsubstituted or substituted in one or more positions with a halogen, nitro, lower alkyl or lower alkoxy substituent and polynuclear aryl groups such as naphthyl, anthryl, phenanthryl, which can be unsubstituted or substituted with one or more of the aforementioned groups. The preferred aryl groups are the substituted and unsubstituted mononuclear groups, particularly phenyl. The term "alkali metal" includes all alkali metals such as sodium, potassium and lithium. The term "lower alkanol" designates aliphatic unsaturated alcohols containing from 1 to 7 carbon atoms such as methanol, ethanol, isopropanol, n-butanol etc.
In the first steps in the production of the compound of formula I in accordance with this invention, the compound of formula II is converted to a compound of formula ##STR4## via the following intermediate: ##STR5##
The compound of formula II is converted to the compound of formula V by reaction with a per-organic acid. In this procedure, any method of converting an unsaturated double bond to an epoxy bridge can be utilized. Among the preferred per-organic acids are included per-acetic acid, per-benzoic acid, m-chloroper-benzoic acid etc. Any conventional per-organic acid can be utilized for this purpose. Any of the conventional reaction conditions utilized in forming epoxides can be used in this reaction.
The compound of formula V is converted to the compound of formula IV by treatment with alklai metal lower alkoxide. Any conventional alklai metal lower alkoxide can be utilized such as sodium or potassium methoxide. This reaction is carried out in a lower alkanol solvent. Among the preferred solvents are methanol and ethanol. However, any conventional lower alkanol can be utilized. If desired, an inert organic solvent such as benzene, toluene, etc. can be used with the lower alkanol solvent. In this regard, any conventional inert organic solvent can, if desired, be incorporated in the lower alkanol solvent medium. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. On the other hand, any temperature of from 10° C. to 100° C. can be utilized in carrying out this reaction.
On the other hand, the compound of formula IV can be prepared from retroionone, i.e. a compound of formula II-a via the following intermediate: ##STR6##
The compound of formula II-a is converted to the compound of formula VI by epoxidation via a per-organic acid in the manner described in connection with the reaction of a compound of formula II to a compound of formula V. The compound of formula VI is converted to the compound of the formula IV by treating the compound of formula VI with an alklai metal lower alkoxide in a lower alkanol solvent in the same manner as described in connection with the conversion of a compound of the formula V to a compound of formula IV.
The compound of formula IV is converted in the next series of steps to a phosphonium salt of the formula: ##STR7## wherein R1, R2 and R3 are aryl or lower alkyl; and X is halogen.
In this conversion, the following intermediates are formed ##STR8## where X is as above.
In the conversion of a compound of formula IV to a compound of formula IX, the compound of formula IV is treated with a vinylmetalic halide such as vinyl magnesium chloride under conditions conventional for reacting a ketone with an organo metallic halide. In carrying out this reaction, it is generally preferred to utilize at least 2 moles of the vinyl metallic halide per mole of the compound of formula IV. If desired, the vinylmetalic halide can be utilized in amounts of 10 moles or more per mole of the compound of formula IV. However, no beneficial results are achieved by utilizing such large an amount of the vinyl magnesium halide. Furthermore, due to the cost of utilizing such large amounts, amounts of the vinyl metallic halide of greater than 10 moles per mole of the compound of formula IV are seldom utilized.
The compound of formula X can be prepared from the compound of formula IV by reacting the compound of formula IV with an alkali metal acetalide such as sodium acetalide. Any of the conditions conventional in reacting a ketone with an acetalide to form an addition product can be utilized in accordance with this invention. The compound of formula X can be converted to the compound of formula IX via hydrogenation utilizing a Lindlar catalyst. Any conventional method of selectively reducing a triple bond to a double bond can be utilized in carrying out this reaction.
The compound of formula IX is converted to the compound of formula XI by treatment with a oxidizing agent. Any conventional oxidizing agent can be utilized to affect this conversion. Among the preferred oxidizing agents are included maganese dioxide and the chromate oxidizing agents such as Jones reagent. Any of the conditions conventional in carrying out oxidation utilizing these reagents can be utilized in the conversion of a compound of formula X to a compound of formula XI.
Among the preferred methods for carrying out the conversion of a compound of formula X to a compound of formula XI is by oxidation with aluminum isopropoxide in the presence of acetone. It is through this method that the compound of formula XI is produced in high yields from the compound of formula X. In carrying out this reaction, the aluminum isopropoxide can be present in catalytic quantities, i.e. at least 0.1 mole percent based upon the moles of the compound of formula IX. If desired, the aluminum isopropoxide can be present in an amount of 100 mole percent based upon the compound of formula IX. In fact, any excess of the aluminum isopropoxide will not deleteriously affect this reaction. However, for economics it is generally preferred to utilize the aluminum isopropoxide in an amount of from 0.1 mole percent to 100 mole percent based upon the weight of the compound of formula IX.
Generally, the oxidation with aluminum isopropoxide and acetone can be carried out in the presence of an inert organic solvent such as methylene chloride, benzene and toluene. In fact, any inert organic solvent can, if desired, be utilized in a mixture with acetone. Generally, this reaction is carried out at the reflux temperature of the reaction medium.
The compound of formula XI is converted to the compound of formula XII by treating the compound of formula XI with a phosphorous trihalide. Generally, this reaction is carried out in an inert organic solvent. Any conventional inert organic solvent can be utilized to carry out this reaction. Among the preferred solvents are the ether solvents such as diethyl ether, tetrahydrofuran, etc. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. Generally it is preferred to carry out this reaction at a temperature of from 10° C. to 100° C.
The compound of formula XII is converted to the compound of formula X by reacting the compound of formula XII with a phosphine of the formula ##STR9## wherein R1, R2 and R3 are as above.
This reaction is generally carried out in an inert organic solvent. Any conventional inert organic solvent can be utilized to carry out this reaction. Among the preferred solvents are the ether solvents and the hydrocarbon solvents such as benzene, toluene, etc. In carrying out this reaction, temperature and pressure are not critical and generally this reaction can be carried out at room temperature and atmospheric pressure. Generally, it is preferred to carry out this reaction by heating the reaction medium to the reflux temperature.
In accordance with another embodiment of this invention, the compound of formula X can be directly prepared from the compound of formula XI by treating the compound of formula XI with the hydrohalic acid salt of the phosphine of formula XIII. Among the hydrohalic acid salts, triphenylphosphine hydrobromide is preferred. This reaction is generally carried out in a inert organic solvent. Any conventional inert organic solvent can be utilized for this purpose. Among the preferred solvents are included the halogenated hydrocarbon solvents such as dichloromethane, methylene, chloride, etc. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. If desired, higher or lower temperatures can be utilized.
The compound of formula I is formed from the compound of formula X by reacting the compound of formula X with a compound of the formula: ##STR10## via a Wittig reaction.
This reaction is carried out utilizing conditions that are conventional in Wittig type reactions. In this reaction, two moles of the compound of formula X are reacted per mole of the compound of formula XX.
The invention will be more fully understood from the specific examples which follow. These examples are intended to illustrate the invention and are not to be construed as limitative thereof. In the Examples, the temperatures utilized are in degrees centigrade. When a mixture of organic liquids are utilized, the ratios set forth in the Examples is a volume ratio unless indicated otherwise.
A solution of m-chloro perbenzoic acid (23 g; 133 mol) in dichloromethane (200 ml) was cooled to 10° and treated with α-ionone (20.8 g; 92% purity) with cooling. After the complete addition, the mixture was stirred a further 20 min at room temperature (RT) and then cooled to 10° (t.l.c. analysis showed no α-ionone; 3:1 benzene/ethylacetate system).
To the cooled solution was added an aqueous solution of sodium hydroxide (100 ml; 2 N) and the phases were then separated and the organic layer was washed with more base (100 ml; 2 N), brine and dried over magnesium sulfate (MgSO4).
Removal of the solids and distillation of the filtrate yielded pure 4-(2,6,6-Trimethyl-2,3-epoxy-cyclohex-1-yl)-3-buten-2-one (19.51 g); bp 113°-120° (0.5 mm) (4 inch vacuum jacketed vigreaux column).
A mixture of peracetic acid (40%; 54 g), anhydrous sodium acetate (10 g) and dichloromethane (200 ml) was treated at RT with α-ionone (30 g; 94% purity) and the temperature was kept at RT with ice cooling. After the exotherm had subsided, the reaction mixture was stirred for a further 2 hours, treated with benzene (300 ml) and washed with a aqueous sodium bicarbonate solution (saturated), aqueous potassium metabisulfite and dried over Mgg SO4.
Removal of the solids and concentrations to dryness yielded a 100% material balance of excellent quality 4-(2,6,6-Trimethyl-2,3-epoxy-cyclohex-1-yl)-3-buten-2-one (by pmr analysis).
The α-ionone epoxide 4-(2,6,6-Trimethyl-2,3-epoxycyclohex-1-yl)-3-buten-2-one (10 g) was dissolved in methanol, treated with a solution of sodium methoxide in methanol (1.41 Molar; 5 ml) and heated at reflux for 2 hours (tlc, 3:1 benzene/ethylacetate, showed virtually complete conversion to product). After cooling to RT, diethyl ether (300 ml) was added and the mixture was washed with water and concentrated to dryness to yield the crude product (9 g). This material was distilled through a short vigreaux column (3 cm) to yield pure (2,6,6-Trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-oxo-trans-1-butene (5.95 g) bp 130°-140° (0.2-0.5 mm).
A solution of vinylmagnesium chloride in tetrahydrofuran (THF; 190 ml; 2.3 Molar) was cooled to 0° and treated with a solution of the hydroxyketone, 4-(2,6,6-trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-oxo-trans-1-butene (17 g; distilled material) dissolved in THF (150 ml). After complete addition the reaction mixture was stirred an additional 1 hour at RT and then quenched with an aqueous solution of ammonium chloride (10% by weight; 200 ml).
Extraction with diethyl ether and concentration yielded the crude diol, 1-(2,6,6-trimethyl-3-hydroxy-1-cyclohexene-1-yl)-3-methyl-penta-1,4-diene-3-ol (30 g) as a thick oil.
A sample of this material (1 g) was chromatographed on silica gel (100 g) and yielded analytically pure 1-(2,6,6-trimethyl-3-hydroxy-1-cyclohexene-1-yl)-methyl-penta-1,4-diene-3-ol on elution with an ethylacetatebenzene mixture (1:1).
The crude diol 1-(2,6,6-Trimethyl-3-hydroxy-1-cyclohexene-1-yl)-3-methyl-penta-1,4-diene-3-ol (25 g) was dissolved in a mixture of dichloromethane (250 ml) and acetone (250 ml) and then heated at reflux for 16 hours with aluminum isopropoxide (50 g).
After cooling to RT the mixture was washed with dilute aqueous sulfuric acid (1 N) and dried over MgSO4.
Removal of the solids and solvents yielded the 1-(2,6,6-Trimethyl-3-oxo-1-cyclohexen-1-yl)-3-methyl-penta-1,4-dien-3-ol as a crude product (30 g).
Chromatography on silica gel (27 g product on 400 g) yielded the ketoalcohol 1-(2,6,6-Trimethyl-3-oxo-1-cyclohexen-1-yl)-3-methyl-penta-1,4-dien-3-ol (9.8 g) on elution with an ether/hexane mixture (80%).
The hydroxyketone 1-(2,6,6-Trimethyl-3-oxo-1-cyclohexen-1-yl)-3-methyl-penta-1,4-dien-3-ol (4 g) dissolved in diethyl ether (40 ml) was cooled to -20° and treated with a solution of phosphorous tribromide in diethyl ether (1 mole. equiv PBr3 ; 80 ml) and then warmed to RT. After stirring a further 1 hour at RT (while tlc indicated the rapid disappearance of starting material the yields of bromide were low if the reaction is worked up too soon) the mixture was cooled to 5° and carefully quenched with water (100 ml) and extracted with more ether.
The combined ether extracts were washed with saturated aqueous sodium bicarbonate solution, brine and dried over MgSO4. Removal of the solids and concentration in vacuo yielded the 1-(2,6,6-Trimethyl-3-oxo-1-cyclohexen-1-yl)-3-methyl-5-bromo-penta-1,3-diene (4.15 g).
The bromide of Example 6 was added to triphenylphosphine (4.4 g) in benzene (30 ml) and heated at reflux for 1 hour. The mixture was then cooled to RT treated with diethyl ether (50 ml) and filtered to yield the 5-(2,6,6-trimethyl-3-oxo-cyclohexen-1-yl)-3-methyl-2,3-pentadiene-1-triphenylphosphonium bromide as a white powder (6.6 g).
Retro-ionone (1.9 g) was added to a solution of m-chloroperbenzoic acid (2.2 g) dissolved in dichloromethane. This resulted in an exothermic reaction (˜40°). After cooling, the mixture was washed with an aqueous sodium carbonate solution dried over MgSO4 and taken to dryness to yield the epoxide, the 1-(2,6,6-Trimethyl-2,3-epoxy-1-cyclohexylidene)-buten-2-one. This epoxide (˜2 g) was dissolved in a solution of methanolic sodium methoxide (1.4 Molar; 20 ml) and left at RT for 1/2 hour (instant color change and probably complete reaction). Dilution with ether followed by a brine washing yielded 1-(2,6,6,-trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-oxo-1-butene, upon chromatography over silica gel.
A solution of α-ionone (202.5 g; 94% by glc) in dichloromethane (1100 ml) containing anhydrous sodium acetate (50 g) was cooled to 15° and treated over 30 min with peracetic acid (250 ml; 40% in acetic acid; from FMC).
After stirring for 21/2 hours the reaction was no longer exothermic and the reaction mixture was stirred a further 3 hours at RT and then washed with water (2×500 ml), aqueous potassium metabisulfite solution (10%; 2×250 ml), sodium hydroxide solution (2 M; 400 ml) and water (400 ml). Removal of the solvents gave the 4-(2,6,6-trimethyl-2,3-epoxy-cyclohex-1-yl)-3-buten-2-one having a nmr spectrum virtually identical with a distilled sample.
This material was dissolved in methanol (800 ml), treated with a methanolic solution of sodium methoxide (100 ml; 1.4 M) and heated at reflux for 3 hours (tlc; 1:1 benzene/ethylacetate). After cooling to RT acetic acid (9 ml) was added, followed by water (180 ml) and the mixture was then extracted with hexane saturated with an 80% methanol/water mixture (500 & 2×250 ml). The hexane extracts were back extracted with an 80% methanol/water mixture (saturated with hexane) and the combined methanolic extracts were concentrated and re-extracted into ether. Removal of the ether gave the desired hydroxyketone 4-(2,2,6-Trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-oxo-trans-1-butene; (204.1 g) as an oil.
This crude product was dissolved in tetrahydrofuran THF; 1000 ml) cooled to -30° and then treated with a freshly prepared solution of vinylmagnesium chloride (680 ml; 3.3 M) in THF. The first portion (350 ml) was added between -30° and -10° followed by the remainder at -10°→0°. At this stage the mixture is difficult to stir and after a further 30 min at 10° diethyl ether (1000 ml) was added (to help the stirring) followed by a saturated solution of ammonium chloride (250 ml). The solids were filtered off, washed well with more ether and the combined filtrates were concentrated to yield the diol, 1-(2,6,6-Trimethyl-3-hydroxy-1-cyclohexene-1-yl)-3-methyl-penta-1,4-diene-3-ol (231.8 g).
This crude diol (216.9 g) in a mixture of acetone and dichloromethane (1:1; 2000 ml) containing aluminum isopropoxide (400 g) was heated at reflux for 5 hours (tlc; 1:1 benzene/ethyl acetate), cooled, treated with more dichloromethane (1000 ml) and then acidified with aqueous sulfuric acid (2 N; 2000 ml) with ice cooling. The aqueous layer was back-washed with more dichloromethane (4×500 ml) and the combined extracts were then concentrated to ca 600 ml, dried over magnesium sulfate and then taken to dryness to yield a crude hydroxyketone, 1-(2,6,6-trimethyl-3-oxo-1-cyclohexen-1-yl)-3-methyl-penta-1,4-dien-3-ol (219.5 g).
The hydroxyketone 1-(2,6,6-Trimethyl-3-oxo-1-cyclohexene-1-yl)-3-methyl-penta-1,4-diene-3-ol (136.6 g) was dissolved in diethyl ether (1000 ml) cooled to -20° and exposed to a solution of phosphorous tribromide (50 ml) in ether (250 ml) and then stirred for 1 hour at RT. After this period, the mixture was cooled to 5°, treated with water (500 ml; care) and the ether layer was then washed well with water, saturated aqueous sodium bicarbonate solution, brine and then dried over anhydrous magnesium sulfate. (All the aqueous extracts were back-washed with more diethyl ether.)
Removal of the solvents yielded the crude bromide (147 g) 1-(2,6,6-Trimethyl-3-oxo-1-cyclohexene-1-yl)-3-methyl-5-bromo-penta-1,3-diene, which was dissolved in benzene (1000 ml) containing triphenylphosphine (144 g) and heated at reflux for 11/2 hours. The mixture, was then cooled to RT, treated with diethyl ether (1000 ml) and stirred for ca 1 hour (the thick syrup slowly yields a granular product).
The solids were filtered off and washed with more diethyl ether and dried to yield the crude salt (296.7 g) which was a mixture of at least two salts (tlc; n-butyl acetate/formic acid/water; 80:18:2). This material (269.3 g) was dissolved in dichloromethane (2500 ml) and treated with diethyl ether (125 ml) and filtered. The filtrate was concentrated to dryness to yield 5-(2,6,6-Trimethyl-3-oxo-cyclohexen-1-yl)-2-methyl-2,3-pentadiene-1-triphenylphonium bromide (38.5 g) mp 261°-63°.
The hydroxyketone 1-(2,6,6-Trimethyl-3-hydroxy-1-cyclohexene-1-yl)-3-methyl-penta-1,4-diene-3-ol (10.7 g) dissolved in dichloromethane (25 ml) was treated with triphenylphosphine hydrobromide (14.4 g; 0.9 mol equiv) in more dichloromethane (50 ml) and left overnight at RT (the reaction is exothermic and complete in ca 1 hours). Most of the solvents were then evaporated off and thick syrupy residue was digested with diethyl ether and filtered. The residue was then dried to give 5-(2,6,6-Trimethyl-3-oxo-cyclohexen-1-yl)-3-methyl-2,4-pentadiene-1-triphenylphosphonium bromide as solid (23.5 g) which assayed for ca 84% pure by nmr analysis.
A solution of the pure trans dialdehyde-2,7-dimethyl-2,4,6-octatriene-1,8-dial (1.64 g) and the phosphonium salt, 5-(2,6,6-Trimethyl-3-oxo-cyclohexen-1-yl)-3-methyl-2,4-pentadiene-1-triphenylphosphonium bromide (14.6 g) in dichloromethane (50 ml) was cooled to -10° and treated over 15 min with a methanolic solution of sodium methoxide (3.6 Molar; 6.7 ml) and then stirred a further 30 min at -10°→-5°.
After this time the mixture was washed with water and the solvents were removed to give the crude product and triphenylphosphine oxide (14.5 g). This material was chromatographed on silica gel (200 g) to yield the carotenoid fraction (6.47 g) on elution with benzene/ethyl acetate mixtures (tlc; 10% ether/dichloromethane). Crystallization from dichloromethane/methanol gave canthaxanthin (2.76 g). The mother liquors were concentrated to dryness, dissolved in hot isopropanol and cooled to RT. Filtering of the solvents gave a further amount of canthaxanthin (0.91 g). The filtrate from this crystallization was concentrated and the residue was then heated at reflux in water (100 ml) for 18 hours. Crystallization of the residue from a dichloromethane/methanol mixture gave a further quantity of canthaxanthin (1.02 g).
Claims (3)
1. A compound of the formula: ##STR11## where the dotted bond is hydrogenated..]. .[.
2. The compound of claim 1 wherein said compound is 1-(2,6,6-trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-methyl-penta-1,4-diene-3-ol..]. .Iadd.
3. A compound of the formula: ##STR12## .Iaddend.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/016,868 USRE30260E (en) | 1977-01-17 | 1979-03-02 | 1-(2,6,6-Trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-methyl-penta-1,4-diene[or 1-yn-4-en]-3-ols |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US05/759,703 US4098827A (en) | 1977-01-17 | 1977-01-17 | 1-(2,6,6-Trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-methyl-penta-1,4-diene[or 1-yn-4-EN]-3-ols |
US06/016,868 USRE30260E (en) | 1977-01-17 | 1979-03-02 | 1-(2,6,6-Trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-methyl-penta-1,4-diene[or 1-yn-4-en]-3-ols |
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Application Number | Title | Priority Date | Filing Date |
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US05/759,703 Reissue US4098827A (en) | 1977-01-17 | 1977-01-17 | 1-(2,6,6-Trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-methyl-penta-1,4-diene[or 1-yn-4-EN]-3-ols |
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USRE30260E true USRE30260E (en) | 1980-04-22 |
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2726269A (en) * | 1955-12-06 | Method of making acetylenic carbinols | ||
US2819298A (en) * | 1955-07-22 | 1958-01-07 | Hoffmann La Roche | Process for the manufacture of carotenoids |
DE2037935A1 (en) | 1969-08-01 | 1971-02-11 | F Hoffmann La Roche & Co AG, Basel (Schweiz) | Process for the production of polyene compounds |
US3932485A (en) * | 1974-08-28 | 1976-01-13 | Hoffmann-La Roche Inc. | Improved preparation of Wittig salt of vinyl β-ionol |
US3947498A (en) * | 1973-04-23 | 1976-03-30 | Scm Corporation | Vitamin A intermediates |
US4000198A (en) * | 1975-06-09 | 1976-12-28 | Hoffmann-La Roche Inc. | Hydroxy-acetylene-substituted cyclohexenone |
-
1979
- 1979-03-02 US US06/016,868 patent/USRE30260E/en not_active Expired - Lifetime
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2726269A (en) * | 1955-12-06 | Method of making acetylenic carbinols | ||
US2819298A (en) * | 1955-07-22 | 1958-01-07 | Hoffmann La Roche | Process for the manufacture of carotenoids |
DE2037935A1 (en) | 1969-08-01 | 1971-02-11 | F Hoffmann La Roche & Co AG, Basel (Schweiz) | Process for the production of polyene compounds |
US3947498A (en) * | 1973-04-23 | 1976-03-30 | Scm Corporation | Vitamin A intermediates |
US3932485A (en) * | 1974-08-28 | 1976-01-13 | Hoffmann-La Roche Inc. | Improved preparation of Wittig salt of vinyl β-ionol |
US4000198A (en) * | 1975-06-09 | 1976-12-28 | Hoffmann-La Roche Inc. | Hydroxy-acetylene-substituted cyclohexenone |
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