US2411967A - Dl-tocopherols and process for the manufacture of same - Google Patents
Dl-tocopherols and process for the manufacture of same Download PDFInfo
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- US2411967A US2411967A US231846A US23184638A US2411967A US 2411967 A US2411967 A US 2411967A US 231846 A US231846 A US 231846A US 23184638 A US23184638 A US 23184638A US 2411967 A US2411967 A US 2411967A
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- tocopherol
- weight
- ether
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- 238000004519 manufacturing process Methods 0.000 title description 17
- 238000000034 method Methods 0.000 title description 16
- 235000001815 DL-alpha-tocopherol Nutrition 0.000 title description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 72
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 49
- 239000011732 tocopherol Substances 0.000 description 41
- 239000000047 product Substances 0.000 description 39
- 229930003799 tocopherol Natural products 0.000 description 39
- 229960001295 tocopherol Drugs 0.000 description 38
- 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 description 37
- 235000010384 tocopherol Nutrition 0.000 description 36
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 30
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 28
- 150000001875 compounds Chemical class 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 15
- AUFZRCJENRSRLY-UHFFFAOYSA-N 2,3,5-trimethylhydroquinone Chemical compound CC1=CC(O)=C(C)C(C)=C1O AUFZRCJENRSRLY-UHFFFAOYSA-N 0.000 description 14
- 229910052739 hydrogen Chemical group 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- 239000011592 zinc chloride Substances 0.000 description 14
- 235000005074 zinc chloride Nutrition 0.000 description 14
- 239000003921 oil Substances 0.000 description 13
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- -1 phytyl bromide Chemical compound 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 10
- 229960005363 aluminium oxide Drugs 0.000 description 10
- 239000001257 hydrogen Chemical group 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- AVWRKZWQTYIKIY-UHFFFAOYSA-N urea-1-carboxylic acid Chemical compound NC(=O)NC(O)=O AVWRKZWQTYIKIY-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- SGWZVZZVXOJRAQ-UHFFFAOYSA-N 2,6-Dimethyl-1,4-benzenediol Chemical compound CC1=CC(O)=CC(C)=C1O SGWZVZZVXOJRAQ-UHFFFAOYSA-N 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 238000009835 boiling Methods 0.000 description 7
- 229940072033 potash Drugs 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- 235000015320 potassium carbonate Nutrition 0.000 description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- 229930003427 Vitamin E Natural products 0.000 description 6
- 230000001476 alcoholic effect Effects 0.000 description 6
- 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 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 229910001961 silver nitrate Inorganic materials 0.000 description 6
- 239000011709 vitamin E Substances 0.000 description 6
- 235000019165 vitamin E Nutrition 0.000 description 6
- 229940046009 vitamin E Drugs 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 239000007859 condensation product Substances 0.000 description 4
- 235000005911 diet Nutrition 0.000 description 4
- 230000037213 diet Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005979 thermal decomposition reaction Methods 0.000 description 4
- 229940088594 vitamin Drugs 0.000 description 4
- 229930003231 vitamin Natural products 0.000 description 4
- 235000013343 vitamin Nutrition 0.000 description 4
- 239000011782 vitamin Substances 0.000 description 4
- 150000003722 vitamin derivatives Chemical class 0.000 description 4
- 239000001707 (E,7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-ol Substances 0.000 description 3
- GPASWZHHWPVSRG-UHFFFAOYSA-N 2,5-dimethylbenzene-1,4-diol Chemical compound CC1=CC(O)=C(C)C=C1O GPASWZHHWPVSRG-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- BLUHKGOSFDHHGX-UHFFFAOYSA-N Phytol Natural products CC(C)CCCC(C)CCCC(C)CCCC(C)C=CO BLUHKGOSFDHHGX-UHFFFAOYSA-N 0.000 description 3
- HNZBNQYXWOLKBA-UHFFFAOYSA-N Tetrahydrofarnesol Natural products CC(C)CCCC(C)CCCC(C)=CCO HNZBNQYXWOLKBA-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 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 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 3
- 238000000199 molecular distillation Methods 0.000 description 3
- 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 3
- 238000010992 reflux Methods 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 235000019149 tocopherols Nutrition 0.000 description 3
- 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 description 3
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N 1,4-Benzenediol Natural products OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- 150000005208 1,4-dihydroxybenzenes Chemical class 0.000 description 2
- BXJGUBZTZWCMEX-UHFFFAOYSA-N 2,3-dimethylbenzene-1,4-diol Chemical compound CC1=C(C)C(O)=CC=C1O BXJGUBZTZWCMEX-UHFFFAOYSA-N 0.000 description 2
- 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 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PXXNTAGJWPJAGM-VCOUNFBDSA-N Decaline Chemical compound C=1([C@@H]2C3)C=C(OC)C(OC)=CC=1OC(C=C1)=CC=C1CCC(=O)O[C@H]3C[C@H]1N2CCCC1 PXXNTAGJWPJAGM-VCOUNFBDSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 description 2
- SUNVJLYYDZCIIK-UHFFFAOYSA-N durohydroquinone Chemical compound CC1=C(C)C(O)=C(C)C(C)=C1O SUNVJLYYDZCIIK-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 2
- 239000010497 wheat germ oil Substances 0.000 description 2
- HVTQDSGGHBWVTR-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-phenylmethoxypyrazol-1-yl]-1-morpholin-4-ylethanone Chemical group C(C1=CC=CC=C1)OC1=NN(C=C1C=1C=NC(=NC=1)NC1CC2=CC=CC=C2C1)CC(=O)N1CCOCC1 HVTQDSGGHBWVTR-UHFFFAOYSA-N 0.000 description 1
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical group C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000003512 Claisen condensation reaction Methods 0.000 description 1
- 239000011627 DL-alpha-tocopherol Substances 0.000 description 1
- 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 1
- 241001465754 Metazoa Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- NYTOUQBROMCLBJ-UHFFFAOYSA-N Tetranitromethane Chemical compound [O-][N+](=O)C([N+]([O-])=O)([N+]([O-])=O)[N+]([O-])=O NYTOUQBROMCLBJ-UHFFFAOYSA-N 0.000 description 1
- 239000003181 biological factor Substances 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 1
- 238000012505 colouration Methods 0.000 description 1
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 1
- SBPHMRSYBPXBIP-UHFFFAOYSA-N ethyl n-(4-nitrophenyl)carbamate Chemical compound CCOC(=O)NC1=CC=C([N+]([O-])=O)C=C1 SBPHMRSYBPXBIP-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 230000021595 spermatogenesis Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
Classifications
-
- 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
Definitions
- cz-TOCODhGlOl was characterized by the empirical formula CznHsoOa, by an allophanate melting at 158 C., by a p-nitr'ophenylurethane melting at 131 (3., and by a sublimate of durohydroquinone on thermal decomposition.
- B-Tocopherol possessesthe empirical formula C2aH4aO2, yields an allophanate melting at 143-144 C. and a sublimate of trimethylhydroquinone on thermal decomposition. An allophanate melting at 135 C.
- the new compounds are the racemates with respect to carbon atom 2 of the chromane ring of tocopherols obtained from natural raw materials. They are light yellow, slightly viscous oils which, in the cold, gradually reduce alcoholic silver nitrate solution. ceeds quickly. These oils dissolve in concentrated sulphuric acid with a yellow colour and the solutions fluoresce intensively after a few hours exposure to ultra ,violet light. The solution of the compounds in chloroform yields a deep dark brown colouration on the addition of tetranitromethane, which gradually clears up. On thermal decomposition the compounds form sublimates of durohydroquinone or trixnethylhydroquinone. When rats so far kept on a vitamin E-free diet were given these synthetic compounds it could be established that they enabled a litter of healthy young rats to be born exactly as did tocopherols isolated from natural products.
- the new compounds are to be used as pharmaceutical preparations or as starting materials for the manufacture of pharmaceutical preparations,
- the new compound from trimethylhydroquinone and phytyl bromide contains 80.9 percent of carbon and 11.8 percent of hydrogen.
- the dete mination according to ,Zerewitinoff indicates the presence of one active hydrogen atom, i. e., a
- the compound possesses a characteristic absorption spectrum with a maximum absorption at 294/4]!- and a minimum absorption at 256/.L/L. It forms various crystalline derivatives, such as a p-nitrophenyl-urethane melting at 131 C., an allophanate melting at 172 C., and a 3,5-dinitro benzoic ester melting at 63 C.
- a dose of 5 mg to a rat kepton a vitamin E-free diet the full action of the pure vitamin was' observed.
- Example 2 4 parts by weight of trimethylhydroquinone are prepared by the addition of hydrogen bromide to phytyl bromide, are added and the reaction product heated in a current of nitrogen for 4 hours at a bath temperature of 140 C. The reaction product becomes brown with a vigorous evolution of hydrogen bromide.
- the chr'omatogram shows an upper zone which is grey, and a lower zone which is light yellow.
- the product is eluted with a mixture of methyl alcohol and ether, the extract boiled in an atmosphere of nitrogen with 4 percent methylalcoholic potash in order to remove adhering bromine.
- another chromatrogram is prepared from the product obtained by the extraction of the alkaline-aqueous methyl-alcoholic solution with ether.
- Example 4 4 parts by weight of phytol, 2.2 parts by weight of trimethylhydroquinone and 1 part by weight of anhydrous zinc chloride are suspended in 10 parts by weight of decaline and then heated to 150160 C. for one hour while stirring and passing carbon dioxide. dissolves completely, whereby the liquid becomes 'yellowish brown. The product is cooled, water and ether added with stirring, the ether solution washed successively with water, a solution of caustic soda, hydrochloric acid, andwater, dried with sodium sulphate and the ether evaporated.
- the residue is adsorbed on an aluminium-oxide column. After development of the chromatogram with a good deal of petroleum ether, the column is uniformly grey. At the foot thereof there is a violet zone. The'grey main zone is eluted with a mixture of methyl alcohol and ether (3:1), the solvent evaporated and the extract.
- Example 5 11 parts by weight of phytol, 5 parts by weight of trimethylhydroquinone and parts by weight of anhydrous formic acid are boiled together for 4-5 hours under reflux. The product is then diluted with water, extracted with ether, the ether evaporated and the residue saponified with an alcoholic solution of sodium ethylate or alcoholic potash. When the alcoholhas been distilled ofi, the crude dl-a-tocopherol is extracted The ether solution is washed and dried The solvent is then evaporated and the residue fractionated in high vacuum at a pressure of 10- -10 mm. A small preliminary fraction evaporating at -90 C. is separated; the principal quantity of the compound evaporates at -120 C. It is identical with the compound obtained in accordance with Examples 1-4.
- the product is cooled, water and ether added while stirring, the ether solution washed with water, potash, hydrochloric acid and water, dried with sodium sulphate and the ether evaporated.
- the residue is adsorbed on an aluminium oxide column. Alter developing the chromatogram with much petroleum ether, the column appears. almost uniformly yellowish-grey. At the bottom there is a small yellow zone. The yellowish-grey principal layer is eluted, the solvent evaporated and the residue purified by the preparation of a second chromatogram.
- the product is then dis-- tilled in a'molecular distillation apparatus andthe compound described tained.
- Example 11 2.5 parts by weight or 3,5-dimethylhydroquinone, 4 parts by weight of 3-bromo-dihydrophytylbromide and 1.5 parts by weight of anhydrous zinc chloride are disolved in 20 parts by weight of petroleum ether (boiling point 80-105" C.) and then heated to 100 C. for two hours while stirring. The solution evolves a considerable quantity of hydrogen bromide and becomes brown. Finally, water and ether are added, the ether solution is then washed with potash and water, dried, and the solvent evaporated. The residue is dissolved in petroleum ether and adsorbed on an aluminium oxide column. After development of the chromatogram with petroleum ether it shows a nearly colourless principal zone and a yellow ring at the bottom. The principal zone is eluted with a mixture of methyl alcohol and ether,
- c CII It is a viscous oil which has a strong reducing action. Its analysis corresponds with the formula Casi-14802. The compound possesses an active hydrogen atom (calculated 0.24 per cent, found 0.24 per cent active hydrogen). When tested on rats-which had been kept on a vitamin E-free diet, the compound proved fully active in a dose of 20 mg.
- a synthetic tocopherol which is racemic at the C atom in position 2 or the chromane ring. of the formula wherein two of the R radicals represent a methyl group and the third R radical represents a radicalselected from the group consisting of hydrogen and methyl radicals.
- Example 7 1.5 parts by weight of 2,5-dimethylhydroquinone, 5.5 parts by weight of phytyl bromide,
- This compound possesses vitamin E activity and is the same compound as is obtained in Example. 6.
- the oil obtained from the lowest part of the tube also reduces a solution of silver nitrate and an allophanate can be prepared therefrom which, when analysed, gave figures which agree with the formula C5oHaaO4N2.
- Example 10 4 parts by weight of phytol, 2.5 parts by weight of 3,5-dimethylhydroquinone and 1 part by weight of zinc chloride are suspended in 10 parts by weight of decaline and then heated to C.
- R radicals represent a methyl group and the third R radical represents, a radical selected from the group consisting of hydrogen and methyl radicals.
- a synthetic, optically inactive tocopherol of the formula CH3 CH1 H CH:
- a synthetic, optically inactive tocopherol of the formula I 8.
- a process for the manufacture of a to-- copherol product the steps of producing a to copherol of the formula wherein two of the R radicals represent a methyl group and the third R radical a radical selected from the group consisting of hydrogen and meth- -yl radicals, by condensing a methyl substituted hydroquinone of the formula CHalCHzCHzHal OH -(
- JCH CH2 under acid conditions, and recovering a tocopherol product from the reaction mixture thus ohtained.
- R radicals represent a methyl group and the third R radical represents a radical selected from the group consisting of hydrogen and methyl radicals, with an aliphatic di-terpene derivative of the formula H: H: H: wherein R represents one of the following radii, cals:
- tocopherol of the formula v 0 H: which comprises condensing 3,5-dimethylhydroquinone with analiphatic di-te rpene derivative of the formula CHPCHF-(CHQ):-CH (CHi)i-CH(CH:)a-'R' Ha HI Ha wherein R represents one ofthe following radicals:
Description
Patented Dec. 3, 1946 DL-TOCOPHERQLS AND PROCESS FOR THE MANUFACTURE OF SADIE Paul Karrer, Zurich, and Otto Isler, Basel, Switzen-land, assi'gnors to Hoffman-La Roche Inc., Nutley, N. J., a corporation of New Jersey no Drawing. Application September 26, 1938, Serial No. 231,846. In Switzerland March 31,
23 Claims. (Cl. 260-333) Evans and collaborators (Mem. Univ. California, vol. 8, year 1927) discovered that a nutritive factor" which is indispenable for spermatogenesis in male rats and the successful completion of an existing pregnancy in female rats is contained in wheat germ oil and various foodstuffs. They named the new biological factor vitamin E and described a biological method of determination using female rats. Evans, Emerson and Emerson (J. Biol. Chem, vol. 113, year 1936, page 319, and vol. 122, year 1937, page 99) succeeded in isolating three distinct chemical substances from wheat germ oil and various other.vegetab1e oils which are responsible for the vitamin E action or the starting materials. These closely related compounds were named a-, B- and 'y-lIOCODhGIOlS. Investigations by Fernholz (J. -Amer. Chem. Soc., vol. 59, year 1937, page 1154; vol. 60, year 1938, page 700), Karrer and collaborators (Helvetica Chimica Acta, vol. 20, year 1937, page 1422; vol. 21, year 1938, page 309), Bergel, Todd and coliaborators (Biochem. J., vol. 31, year 1937, page 2257; J. Chem. 800., year 1938, page 253), as well as John and collaborators (Zeitschrift fiir physioiogische Chemie, vol 250, year 1937, page 11; vol. 252, year 1938, pages 201, 208) confirm and supplement the knowledge of the first named investigators regarding tocopherols. I
cz-TOCODhGlOl was characterized by the empirical formula CznHsoOa, by an allophanate melting at 158 C., by a p-nitr'ophenylurethane melting at 131 (3., and by a sublimate of durohydroquinone on thermal decomposition. B-Tocopherol possessesthe empirical formula C2aH4aO2, yields an allophanate melting at 143-144 C. and a sublimate of trimethylhydroquinone on thermal decomposition. An allophanate melting at 135 C.
was produced from 'y-tocopherol which has the The new compounds are the racemates with respect to carbon atom 2 of the chromane ring of tocopherols obtained from natural raw materials. They are light yellow, slightly viscous oils which, in the cold, gradually reduce alcoholic silver nitrate solution. ceeds quickly. These oils dissolve in concentrated sulphuric acid with a yellow colour and the solutions fluoresce intensively after a few hours exposure to ultra ,violet light. The solution of the compounds in chloroform yields a deep dark brown colouration on the addition of tetranitromethane, which gradually clears up. On thermal decomposition the compounds form sublimates of durohydroquinone or trixnethylhydroquinone. When rats so far kept on a vitamin E-free diet were given these synthetic compounds it could be established that they enabled a litter of healthy young rats to be born exactly as did tocopherols isolated from natural products.
The new compounds are to be used as pharmaceutical preparations or as starting materials for the manufacture of pharmaceutical preparations,
Erample 1 1.7 parts by weight of trimethylhydroquinone are covered with 10 parts by weight of dry benzine (boiling point -100 C). 1.0 part by weight of anhydrous zinc chloride and 4.8 parts by weight of phytyl bromide of the formula this, a chromatogram prepared on aluminium oxide. The chromatogram consists of two layers: an upper layer which is grey, and a lower layer which is light yellowish. The upper main layer is eluted by a mixture of methanol and ether and purified by the preparation of a sec- R HO CE:
-CHnCHnCHgCHCHsCHnCHgCHCKaCHgCHaCHCH;
R 0 En H9 H5 H8 wherein R is methyl or hydrogen.
On heating the reduction prond chromatogram. Th following condensation product is thereby obtained in a pure-state:
CH; OH /C Iia on, o H,
The new compound from trimethylhydroquinone and phytyl bromide contains 80.9 percent of carbon and 11.8 percent of hydrogen. The dete mination according to ,Zerewitinoff indicates the presence of one active hydrogen atom, i. e., a
.phenolic hydroxyl group. The compound possesses a characteristic absorption spectrum with a maximum absorption at 294/4]!- and a minimum absorption at 256/.L/L. It forms various crystalline derivatives, such as a p-nitrophenyl-urethane melting at 131 C., an allophanate melting at 172 C., and a 3,5-dinitro benzoic ester melting at 63 C. On administering a dose of 5 mg to a rat kepton a vitamin E-free diet the full action of the pure vitamin was' observed.
Example 2 4 parts by weight of trimethylhydroquinone are prepared by the addition of hydrogen bromide to phytyl bromide, are added and the reaction product heated in a current of nitrogen for 4 hours at a bath temperature of 140 C. The reaction product becomes brown with a vigorous evolution of hydrogen bromide. Finally, the
product is treated with water, much petroleum ether added, the benzine layer thoroughly washed with Claisens solution (a solution of 350 grams of potassium hydroxide in 250 grams of water and sufiicient methyl alcohol to prepare one liter, see "Annalen der Chemie vol. 418 1919], page 96) and water, dried, adsorbed on aluminium oxide and-developed with petroleum ether.
The chr'omatogram shows an upper zone which is grey, and a lower zone which is light yellow.
' The product is eluted with a mixture of methyl alcohol and ether, the extract boiled in an atmosphere of nitrogen with 4 percent methylalcoholic potash in order to remove adhering bromine. For the preparation of the pure compound, another chromatrogram is prepared from the product obtained by the extraction of the alkaline-aqueous methyl-alcoholic solution with ether.
, from the alkaline mixture with ether.
brown solution whereby a little hydrogen chloride escapes and a small quantity oftrimethylhydro- I quinone sublimes. The product is now cooled, precipitated with water, a lot of ether added, the ether solution washed with water, a solution of caustic soda, and water, dried and the solvent evaporated. The extract is dissolved in petroleum ether and adsorbed on an aluminium-oxide column. The chromatogram is developed with much petroleum ether. grey zone contains the condensation product which has-the same properties as the productobtained in accordance with Examples 1 and 2.
Example 4 4 parts by weight of phytol, 2.2 parts by weight of trimethylhydroquinone and 1 part by weight of anhydrous zinc chloride are suspended in 10 parts by weight of decaline and then heated to 150160 C. for one hour while stirring and passing carbon dioxide. dissolves completely, whereby the liquid becomes 'yellowish brown. The product is cooled, water and ether added with stirring, the ether solution washed successively with water, a solution of caustic soda, hydrochloric acid, andwater, dried with sodium sulphate and the ether evaporated.
The residue is adsorbed on an aluminium-oxide column. After development of the chromatogram with a good deal of petroleum ether, the column is uniformly grey. At the foot thereof there is a violet zone. The'grey main zone is eluted with a mixture of methyl alcohol and ether (3:1), the solvent evaporated and the extract.
further purified by the preparation of a second chromatogram. The product is then-distilled in a molecular distillation apparatus and the compound described in the. previous examples obtained. This compound was given in doses of 3 and 10 mg. each to four rats which had been kept on a diet free from vitamin E. All the animals became pregnant and brought forth healthy young.
Example 5 11 parts by weight of phytol, 5 parts by weight of trimethylhydroquinone and parts by weight of anhydrous formic acid are boiled together for 4-5 hours under reflux. The product is then diluted with water, extracted with ether, the ether evaporated and the residue saponified with an alcoholic solution of sodium ethylate or alcoholic potash. When the alcoholhas been distilled ofi, the crude dl-a-tocopherol is extracted The ether solution is washed and dried The solvent is then evaporated and the residue fractionated in high vacuum at a pressure of 10- -10 mm. A small preliminary fraction evaporating at -90 C. is separated; the principal quantity of the compound evaporates at -120 C. It is identical with the compound obtained in accordance with Examples 1-4.
of trimethylhydroquinone and 1 part by weight of anhydrous zinc chloride are heated to C. in a current of .nitrogen for half whom. The suspended matter gradually gives a homogeneous Example 6 1 part by weight of 2,5-dimethylhydroquinone is heated on a boiling water-bath for three hours with 3 parts by weight of phytyl bromide, 1 part by weight of anhydrous zinc chloride and 10 parts by weight of benzine boiling at 80-100 C. The reaction mixture is then decomposed by the addition of water, the benzine layer removed,
'washed, first with potash solution, then with water, and the solvent evaporated. The remaining residue is dissolved in a little low-boiling petroleum ether, filtered from a small quantity The upper uniformly The trimethylhydroquinone for one hour-'whileheating and introducing carbon dioxide. The m-xy'lohydroquinone dissolves completely. The fluid'becomes yellowish-brown.
The product is cooled, water and ether added while stirring, the ether solution washed with water, potash, hydrochloric acid and water, dried with sodium sulphate and the ether evaporated. The residue is adsorbed on an aluminium oxide column. Alter developing the chromatogram with much petroleum ether, the column appears. almost uniformly yellowish-grey. At the bottom there is a small yellow zone. The yellowish-grey principal layer is eluted, the solvent evaporated and the residue purified by the preparation of a second chromatogram. The product is then dis-- tilled in a'molecular distillation apparatus andthe compound described tained.
Example 11 2.5 parts by weight or 3,5-dimethylhydroquinone, 4 parts by weight of 3-bromo-dihydrophytylbromide and 1.5 parts by weight of anhydrous zinc chloride are disolved in 20 parts by weight of petroleum ether (boiling point 80-105" C.) and then heated to 100 C. for two hours while stirring. The solution evolves a considerable quantity of hydrogen bromide and becomes brown. Finally, water and ether are added, the ether solution is then washed with potash and water, dried, and the solvent evaporated. The residue is dissolved in petroleum ether and adsorbed on an aluminium oxide column. After development of the chromatogram with petroleum ether it shows a nearly colourless principal zone and a yellow ring at the bottom. The principal zone is eluted with a mixture of methyl alcohol and ether,
the extract boiled in an atmosphere of nitrogen with methyl alcoholic potash for the removal of adhering bromine. The alkaline aqueous methylalcoholic solution is extracted with ether and another chromatogram prepared from the extraction-residue in order to obtain the pure compound which is of the same structure as the first product described in Example 8 Example 12 2 parts by weight of 2,3-dimethylhydroquinone,
' 6.5 parts by weight of phythyl bromide, 1.5 parts by weight. of zinc chloride and 20 parts by weight of benzene are boiled for 4 hours under reflux. The working up of the reaction product is carried out as described in Example '7.
The preparation of a chromatogram of the product gives a narrow brownish layer in the upper part of the absorption column, then a yellow ring, and, at the foot thereof, a nearly colourless zone. The 'eluate of the brownish layer contains the expected condensation product of the following formula:
OH CH:
c CII IS It is a viscous oil which has a strong reducing action. Its analysis corresponds with the formula Casi-14802. The compound possesses an active hydrogen atom (calculated 0.24 per cent, found 0.24 per cent active hydrogen). When tested on rats-which had been kept on a vitamin E-free diet, the compound proved fully active in a dose of 20 mg.
in Example 9 is obm l 1 1 1.5 parts by weight or trimethylhydroquinone mula omomonmon onmomomnown .on=om H; B1 1 1; HI
- are heated with 10 parts by weight oi anhydrous formic acid ior 6. hours. The mixture is diluted with water, extracted with'ether, the ether layer washed with sodium hydroxide, then with water and the solvent evaporated. The condensation product remains as a viscous oil which readily reduces methyl-alcoholic silver nitrate solution. Its absorption spectrum hasa maximum at 294m; The compound forms a crystalline allophanate of melting point172-173 C. It is identical with dl-a-tOCOPhBIOl. 1
We claim: r
1. A synthetic tocopherol, which is racemic at the C atom in position 2 or the chromane ring. of the formula wherein two of the R radicals represent a methyl group and the third R radical represents a radicalselected from the group consisting of hydrogen and methyl radicals.
2. A synthetic tocopherol, which is racemic at the O atom in position 2 of the chromane ring,v or the formula CHI e 40 H0 cm 33' (CH:):CH(CH|):CH(CH:);CHCH2 0 (EH; H: H] H3 H: i Y
3. A synthetic tocopherol, which is racemic at the C atom in position 2 of the chromane rin 01.
the formula CHI CH; H0 CH1 H (CHI):CH(CH:):CH(CH:)ICHCH;
O Ha Ha Ha HI HI 4. A synthetic tocopherol, the allophanate of which melts at about 172 C. and which is racemic at the C atom in position 2 of the chromane ring,-
of the formula and 3.0 parts by weight of .isophytol of the ior- Yo Eih From the second and third layers viscous oils are obtained after evaporation of the solvent which do not possess vitamin E activity.
Example 7 1.5 parts by weight of 2,5-dimethylhydroquinone, 5.5 parts by weight of phytyl bromide,
1.2 parts by weight of zinc chloride'and 35 parts by volume of ligroin are boiled for 2 hours under a reflux condenser. The reaction mixture is then decomposed with water, the ligroin layer removed, washed with potash solution, then with water, and the solvent evaporated. The residue is dissolved in a small quantity of lowboiling petroluem ether and a chromatogram prepared on an aluminium oxide column. By eluting the yellowish-brown top zone with a mixture of ether and methanol,'an oil is obtainedwhich reduces a neutral methyl alcoholic solution of silver nitrate on boiling, and contains 0.2 per' cent of active hydrogen according to the Zerewitinofl determination. These properties indicate that the oil isolated from the yellowish-brown upper zone is a compound of the following formula:
This compound possesses vitamin E activity and is the same compound as is obtained in Example. 6.
From the lower part of the aluminium oxide column an oil can be eluted by means of a mixture of ether and methanol the analysis of which reveals that it has the formula C4sHaoO2. The compound contains no active hydrogen (Zerewitinofi determination), and it does not reduce a methyl alcoholic solution of silver nitrate even on boiling. An allophanate cannot be prepared therefrom. This indicates that the compound does not contain a free hydroxyl group and that it probably has the following constitution:
CH3 on, 0 l
CH; O CH:
Its absorption spectrum shows a maximum at 296 pa and a minimum at 260 1141..
6 Example, 8
1.5 g. of 3,5-dimethylhydroquinone, 5 g. of phytyl bromide, 1.2 g. -of zinc chloride and 30 cc. of ligroin are boiled for 2 hours under refiux. The treatment of the reaction product is effected as described in Example '7. The preparation of a chromatogramon aluminium oxide gave at the top of the column a narrow, dark brown zone which is neglected, while the remainder of the column was of a light brownish colour. From the upper half of this part of the column an oil could be eluted which reducesa neutral solution of silver nitrate already on standing at room temperature; the reduction proceeds more quickly on heating. The analysis gave figures which show that the compound is of the following composition:-
CH: OH I CH: CH u u This compound possesses vitamin E activity.
The oil obtained from the lowest part of the tube also reduces a solution of silver nitrate and an allophanate can be prepared therefrom which, when analysed, gave figures which agree with the formula C5oHaaO4N2.
Consequently, the oil probably has the following constitution:
Yo om Example 9 whole of the lower part of the column is whitishgrey. The top layer of aluminium oxide, which is hardly coloured, is removed and the whitishgrey principal zone eluted with a mixture of methyl alcohol and ether (3:1). The solvent is evaporated in vacuo and the residue distilled in a molecular distillation apparatus. The compound is a yellow, slightly viscous oil, nD =-1.501, and is identical with the first product described in Example 8. A sublimate of trimethylhydroquinone results on thermal decomposition. An
allophanate melting at 143 C. is obtained with cyanic acid in benzene solution. A 10 mg. dose of this compound was biologically fully active.
Example 10 4 parts by weight of phytol, 2.5 parts by weight of 3,5-dimethylhydroquinone and 1 part by weight of zinc chloride are suspended in 10 parts by weight of decaline and then heated to C.
- 9 wherein two of the R radicals represent a methyl group and the third R radical represents, a radical selected from the group consisting of hydrogen and methyl radicals.
6. A synthetic, optically inactive tocopherol, of the formula CH3 CH1 H CH:
-(CH:)3CH(CH:)3CH(CHghCHCHt CH 0 Ha Ha a 7. A synthetic, optically inactive tocopherol, of the formula I 8. A synthetic tocopherol, which is racemic at the C atom in position 2 of the chromane ring, of the formula O JIH: H3 Ha Ha 9. In a process for the manufacture of a to-- copherol product, the steps of producing a to copherol of the formula wherein two of the R radicals represent a methyl group and the third R radical a radical selected from the group consisting of hydrogen and meth- -yl radicals, by condensing a methyl substituted hydroquinone of the formula CHalCHzCHzHal OH -(|JCH=CH2 under acid conditions, and recovering a tocopherol product from the reaction mixture thus ohtained.
10. In a process for the manufacture of a tocopherol product, the steps of producing a tocopherol of the formula wherein two of the R radicals represent a methyl group and the third R radical a radical selected from the group consisting of hydrogen and meth-= yl radicals, by condensing a methyl substituted hydroquinone of the formula HO H R OE
wherein two of the R radicals represent a methyl group and the third R radical represents a radical selected from the group consisting of hydrogen and methyl radicals, with an aliphatic di-terpene derivative of the formula H: H: H: wherein R represents one of the following radii, cals:
C=CH-CHIOH CHalCHa-CH2Hal o=cn-crnna1 on H! .'l-CH=CE5 in the presence of zinc chloride, and recovering a tocopherol product from the reaction mixture thus obtained.
11. In a process for the manufacture of a tocopherol product, the steps of producing an a-tOCOPhElOl of the formula C5: B0 I CH9 CH '-(CH1);CH(CHMCIHCHahCHCHn 0 Ha H3 H3 H; I
which comprises condensing. trimethylhydroqui= none with analiphatlc di-terpene derivative of the formula wherein R represents one of the following radicals:
under acid conditions, and recovering a tocopherol product from the reaction mixture thus obtained.
12. In a process for the manufacture of a to 1 l copherol product, the steps of producing an a-tO- copherol of the formula CHi ' H l CH! C JJ-(CHz) CH(CH|)|CH(CHa)aCHCH 0 Ha Ha H: H:
which comprises condensing trimethylhydroquinone with an aliphatic di-terpene derivative of the formula v oHi-c'H- cm)rcn-(cnnr-cnoncr-n' Ha Ha H: wherein R represents one of the following radicals:
in the presence of zinc chloride, and recovering a tocopherol product from the reaction mixture thus obtained.
13. In a process for the manufacture of a tocopherol product, the steps of producing an a-tO- copheroi of the formula:
H0 CH2 CH I-(CH MCHUJHQMCH(CHghCHCH:
0 I Ha Ha a t H:
which comprises condensing trimethylhydroquinone with phytyi halide of the formula wherein Hal represents a halogen radical, under acid conditions, and recovering a tocopherol product from thereaction mixture thus obtained.
14. In a process for the manufacture of a tocopherol product, the steps of producing an a-tocopherol of the formula CH; Cg:
, H0 CH,
CH cumen(cm omonmcncm o H, H. H. .n- HI I which comprises condensing trimethylhydroqui none with phytyi bromide of the formula.-
CHz-CH-(CHz)x-CH(CHz)r-CH-(CH:)xC=CH CH:Br
- H; H, H: H:
under acid conditions, and recovering a tocopheroi product from the reaction mixture thus obtained.
15 In a process for the manufacture of a tocopherol product, the steps of producingan a-tO- copheroi of the formula which-comprises condensing trimethylhydroquinone with phytyi bromide of the formula CHz-OH-(CHfla-CH-(OHz):-CH-(CH:):C=CH-CHzBr H: H: Ha H:
in the presence of zinc chloride, and recovering a tocopherol product from the reaction mixture thus obtained. 7
16. In a process for the manufacture of a tocopheroi product, the'steps of. producing tocopherol of the formula v 0 H: which comprises condensing 3,5-dimethylhydroquinone with analiphatic di-te rpene derivative of the formula CHPCHF-(CHQ):-CH (CHi)i-CH(CH:)a-'R' Ha HI Ha wherein R represents one ofthe following radicals:
which comprises condensing 3,5-dimethylhydroquinone with a phytyi halide under acid conditions, and recovering a tocopherol product from the reaction mixture thus obtained.
18. In a. process for the manufacture of a tocopherol product,- the steps of producing a tocopherol of the formula CH: no u CH, CH (CH2)xCH(CH:)aC H(CH1)aCHCHi 04:11, H; Ha H: which comprises condensing 3,5- dimethyl hydroquinone with phytyl bromide of the formula under acid conditions, and recovering a tocopherol product from the reaction mixture thus obtained.
19; In a process for the manufacture of a tocopherol product, the steps of producing a tocopherol of the formula HO \CH:
CH c-(cnmon ormrcmonmcncna ,0, H. Hz
H; CHE
which comprises condensing 3,5-dimethylhydroquinone with phytyl bromide of the formula in the presence of zinc chloride, and recovering a tocopherolproduct from the reaction mixture thus obtained.
20. In a process for th manufacture of a tocopherol product, the steps of producing a tocopherol of the formula HO CH:
H c-(onznomcm)somcmhcnm O CH: H3 H; CH3
which comprises condensing 2,5-dimethylhydro- Ha Ha C=CHCHzHal OH Hz --C H==CH2 under acid conditions, and recovering a tocopheroi product from the reaction mixture thus obtained.
21. In a process for the manufacture of a tocopherol product, the steps of producing a tocopherol of the formula which comprises condensing 2,5-dimethy1 h drovquinone with a phytyl halide under acid conditions, and recovering a tocopherol product from the reaction mixture thus obtained.
22. In a process for the manufacture of a tocopherol product, the steps of producing a tocopherol of the formula CH: W011, Ho \CH:
H c-rcnoicmcm)lcmcnmoncm 0 H3 Ha Ha, Ha
which comprises condensing 2,5-dimethylhydroquinone with phytyl bromide of the formula under acid conditions, and recovering a, tocopherol product from the reaction mixture thus oftained.
23. In a process for the manufacture of a. tocopherol product, the steps of producinget0- copherol of the formula CH; H0 7 on, v H (CH2)|CH(CH2)aQH(CH2)aCHCH 0 Ha Ha Ha H8 which comprises condensing 2,5-dirnethylhydroquinone with phytyl bromide of the formula in the presence of zinc chloride, and recoveringa tocopherol product from the reaction mixture' thus obtained.
PAUL KARRER. OTTO ISLER.
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CH2411967X | 1938-03-31 |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2723278A (en) * | 1954-01-25 | 1955-11-08 | Hoffmann La Roche | Preparation of alpha-tocopherol |
US3444213A (en) * | 1967-07-12 | 1969-05-13 | Eastman Kodak Co | Continuous process for producing dl alpha tocopherol |
US4016178A (en) * | 1975-06-17 | 1977-04-05 | Hoffmann-La Roche Inc. | Synthesis of vitamin E |
US20050277777A1 (en) * | 2004-06-11 | 2005-12-15 | Werner Bonrath | Process for the manufacture of chroman derivatives, especially alpha-tocopherol and alkanoates thereof |
-
1938
- 1938-09-26 US US231846A patent/US2411967A/en not_active Expired - Lifetime
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2723278A (en) * | 1954-01-25 | 1955-11-08 | Hoffmann La Roche | Preparation of alpha-tocopherol |
US3444213A (en) * | 1967-07-12 | 1969-05-13 | Eastman Kodak Co | Continuous process for producing dl alpha tocopherol |
US4016178A (en) * | 1975-06-17 | 1977-04-05 | Hoffmann-La Roche Inc. | Synthesis of vitamin E |
US20050277777A1 (en) * | 2004-06-11 | 2005-12-15 | Werner Bonrath | Process for the manufacture of chroman derivatives, especially alpha-tocopherol and alkanoates thereof |
US20090176998A1 (en) * | 2004-06-11 | 2009-07-09 | Werner Bonrath | Process for the manufacture of chroman derivatives, especially alpha-tocopherol and alka-noates thereof |
US8431727B2 (en) | 2004-06-11 | 2013-04-30 | Dsm Assets B.V. | Process for the manufacture of chroman derivatives, especially α-tocopherol and alka-noates thereof |
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