US20020017451A1 - Process for the preparation of tocol acylates and tocopherol acylates - Google Patents
Process for the preparation of tocol acylates and tocopherol acylates Download PDFInfo
- Publication number
- US20020017451A1 US20020017451A1 US09/900,587 US90058701A US2002017451A1 US 20020017451 A1 US20020017451 A1 US 20020017451A1 US 90058701 A US90058701 A US 90058701A US 2002017451 A1 US2002017451 A1 US 2002017451A1
- Authority
- US
- United States
- Prior art keywords
- tocopherol
- acylate
- tocol
- reaction mixture
- process according
- Prior art date
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- Granted
Links
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 title claims abstract description 78
- 239000011732 tocopherol Substances 0.000 title claims abstract description 69
- 229930003799 tocopherol Natural products 0.000 title claims abstract description 67
- 229960001295 tocopherol Drugs 0.000 title claims abstract description 61
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 title claims abstract description 61
- 235000010384 tocopherol Nutrition 0.000 title claims abstract description 60
- DFUSDJMZWQVQSF-XLGIIRLISA-N (2r)-2-methyl-2-[(4r,8r)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-ol Chemical compound OC1=CC=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 DFUSDJMZWQVQSF-XLGIIRLISA-N 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims description 33
- 238000002360 preparation method Methods 0.000 title description 4
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims abstract description 45
- 239000011541 reaction mixture Substances 0.000 claims abstract description 35
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 230000001678 irradiating effect Effects 0.000 claims abstract description 6
- 239000003054 catalyst Substances 0.000 claims description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 11
- 235000019149 tocopherols Nutrition 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 4
- PZZKGQBMBVYPGR-UHFFFAOYSA-N η-tocopherol Chemical compound OC1=C(C)C=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 PZZKGQBMBVYPGR-UHFFFAOYSA-N 0.000 claims description 4
- GJJVAFUKOBZPCB-ZGRPYONQSA-N (r)-3,4-dihydro-2-methyl-2-(4,8,12-trimethyl-3,7,11-tridecatrienyl)-2h-1-benzopyran-6-ol Chemical class OC1=CC=C2OC(CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1 GJJVAFUKOBZPCB-ZGRPYONQSA-N 0.000 claims description 2
- 229940087168 alpha tocopherol Drugs 0.000 claims description 2
- 229960000984 tocofersolan Drugs 0.000 claims description 2
- 229930003802 tocotrienol Natural products 0.000 claims description 2
- 239000011731 tocotrienol Substances 0.000 claims description 2
- 229940068778 tocotrienols Drugs 0.000 claims description 2
- 235000019148 tocotrienols Nutrition 0.000 claims description 2
- RZFHLOLGZPDCHJ-XZXLULOTSA-N α-Tocotrienol Chemical compound OC1=C(C)C(C)=C2O[C@@](CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1C RZFHLOLGZPDCHJ-XZXLULOTSA-N 0.000 claims description 2
- 239000002076 α-tocopherol Substances 0.000 claims description 2
- FGYKUFVNYVMTAM-WAZJVIJMSA-N β-tocotrienol Chemical compound OC1=CC(C)=C2O[C@@](CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1C FGYKUFVNYVMTAM-WAZJVIJMSA-N 0.000 claims description 2
- 239000012345 acetylating agent Substances 0.000 claims 3
- WGVKWNUPNGFDFJ-DQCZWYHMSA-N β-tocopherol Chemical compound OC1=CC(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C WGVKWNUPNGFDFJ-DQCZWYHMSA-N 0.000 claims 2
- GZIFEOYASATJEH-VHFRWLAGSA-N δ-tocopherol Chemical compound OC1=CC(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-VHFRWLAGSA-N 0.000 claims 2
- FGYKUFVNYVMTAM-UHFFFAOYSA-N (R)-2,5,8-trimethyl-2-(4,8,12-trimethyl-trideca-3t,7t,11-trienyl)-chroman-6-ol Natural products OC1=CC(C)=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1C FGYKUFVNYVMTAM-UHFFFAOYSA-N 0.000 claims 1
- GZIFEOYASATJEH-UHFFFAOYSA-N D-delta tocopherol Natural products OC1=CC(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-UHFFFAOYSA-N 0.000 claims 1
- 229940066595 beta tocopherol Drugs 0.000 claims 1
- 235000010389 delta-tocopherol Nutrition 0.000 claims 1
- FGYKUFVNYVMTAM-MUUNZHRXSA-N epsilon-Tocopherol Natural products OC1=CC(C)=C2O[C@@](CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1C FGYKUFVNYVMTAM-MUUNZHRXSA-N 0.000 claims 1
- 235000010382 gamma-tocopherol Nutrition 0.000 claims 1
- 235000004835 α-tocopherol Nutrition 0.000 claims 1
- 235000007680 β-tocopherol Nutrition 0.000 claims 1
- 239000011590 β-tocopherol Substances 0.000 claims 1
- 239000002478 γ-tocopherol Substances 0.000 claims 1
- 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 claims 1
- QUEDXNHFTDJVIY-DQCZWYHMSA-N γ-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-DQCZWYHMSA-N 0.000 claims 1
- 239000002446 δ-tocopherol Substances 0.000 claims 1
- 229940042585 tocopherol acetate Drugs 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 13
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 11
- 230000010933 acylation Effects 0.000 description 6
- 238000005917 acylation reaction Methods 0.000 description 6
- -1 tocopherol acetates Chemical class 0.000 description 6
- 125000002640 tocopherol group Chemical class 0.000 description 6
- 239000002253 acid Substances 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 229930003427 Vitamin E Natural products 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 229940046009 vitamin E Drugs 0.000 description 3
- 239000011709 vitamin E Substances 0.000 description 3
- 235000019165 vitamin E Nutrition 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- DFUSDJMZWQVQSF-UHFFFAOYSA-N 2-methyl-2-(4,8,12-trimethyltridecyl)-3,4-dihydrochromen-6-ol Chemical compound OC1=CC=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 DFUSDJMZWQVQSF-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000005350 fused silica glass Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- ZYURHZPYMFLWSH-UHFFFAOYSA-N n-octacosane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCC ZYURHZPYMFLWSH-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010626 work up procedure Methods 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
- the present invention relates to a process for the preparation of tocol acylates and tocopherol acylates.
- the present invention relates to a process for the preparation of tocol and tocopherol acylates, more particularly tocopherol acetates.
- the main commercial form of vitamin E being (all-rac)- ⁇ -tocopherol acetate
- the invention in a preferred embodiment, provides a process for the preparation of (all-rac)- ⁇ -tocopherol acetate.
- other tocopherols can be readily acylated by the process of the present invention.
- the process of the instant invention the tocopherols can be acylated in the form of their racemates or individual enantiomers.
- One embodiment of the present invention is a process for preparing tocol acylate or tocopherol acylate having the following steps:
- Another embodiment of the present invention is a process for preparing tocopherol acylate having the following steps:
- a further embodiment of the present invention is a process for preparing tocol acylate or tocopherol acylate having the following steps:
- reaction mixture consisting essentially of tocol or tocopherol and an acylating agent
- the acylation of tocol and tocopherols can advantageously be effected under irradiation with microwaves.
- the process of the present invention requires shorter reaction time, gives better yield, and has a simpler work-up of the reaction mixture.
- the process of this invention does not require external heating of the reaction mixture, thus providing uniform reaction conditions throughout the entire reaction mixture.
- the present invention is process for preparing tocol acylate or tocopherol acylate having the following steps:
- the present invention also provides a process for preparing tocopherol acylate having the following steps:
- Tocol is the compound 2-methyl-2(4,8,12-trimethyl-tridecyl)-chroman-6-ol.
- the term “tocopherol” as used herein means all the compounds derived from the basic structure of tocol and having vitamin E character, such as, for example, the tocopherols having a saturated (tocol) side chain, such as ⁇ -, ⁇ -, ⁇ -, ⁇ 2 - and ⁇ -tocopherol, and the tocotrienols having three double bonds in the side chain such as ⁇ - and ⁇ 1 -tocopherol.
- (all-rac)- ⁇ -tocopherol (generally referred to as vitamin E) is preferred.
- microwave refers to the region of the electromagnetic spectrum having frequencies of 30 GHz to 300, MHz thus corresponding to wavelengths of 1 cm to 1 m.
- household or industrial microwave heaters are required to operate at either 12.2 cm (2.45 GHz) or 33.3 cm (918 MHz).
- the term microwaves refers particularly to such wavelengths.
- conventional microwave equipment can be used.
- Microwave equipment suitable in the process of this invention is readily available, e.g., MLS, Leutkirch, Germany (Lavis Multiquant 1000); or MILESTONE Inc., Monroe, Conn. 06468, USA (Ethos reactors).
- the irradiation in the process of this invention is carried out by applying a power of irradiation of from about 600 to about 1200 W, more preferably from about 800 to about 1000 W.
- the acylation can be carried out using any acylating agent conventionally used for the acylation of a phenolic hydroxy group as is present in tocol and tocopherols, e.g., acyl anhydrides or halogenides.
- the acyl groups in such acylating agent may be derived from aliphatic carboxylic acids, e.g., from alkanoic acids, in particular C1-7-alkanoic acids such as acetic acid, propionic acid, butyric acid, or pivalic acid, or higher alkanoic acids, such as palmitic acid; or from aromatic carboxylic acids, e.g., benzoic acid; or araliphatic acids, e.g. phenylacetic acid.
- the acylation can be carried out in the presence or in the absence of a catalyst such as an organic base, e.g. pyridine or dimethylamino pyridine, or an organic or inorganic acid, e.g., sulfuric acid or p-toluenesulfonic acid.
- a catalyst such as an organic base, e.g. pyridine or dimethylamino pyridine, or an organic or inorganic acid, e.g., sulfuric acid or p-toluenesulfonic acid.
- a catalyst e.g. pyridine or dimethylamino pyridine
- an organic or inorganic acid e.g., sulfuric acid or p-toluenesulfonic acid.
- a catalyst e.g., a volatile catalyst is selected.
- the acylation is carried out in the absence of a catalyst.
- the acylating agent is suitably used in excess, i.e. in an excess of about 100%
- the desired tocol acylate or tocopherol acylate can be isolated from the reaction product by conventional means, e.g., by heating the reaction mixture under reduced pressure to remove excess acylating agent and catalyst, if any, and other unwanted products. While the process of the present invention is preferably concerned with the acylation of (all-rac)-tocopherols, particularly (all-rac)- ⁇ -tocopherol, the process can also be used to acylate optically pure enantiomers, such as (d-)- ⁇ -tocopherol.
- Table 1 Conversion of Tocopherol to Tocopherol Acetate; Catalyst Present; Irradiation at 800 W Time (in minutes) 5 10 20 30 tocopherol acetate [%] 43 94 99 99 tocopherol [%] 48 0 0 0
- Table 2 Conversion of Tocopherol to Tocopherol Acetate; Catalyst Present; Irradiation at 1000 W Time (in minutes) 5 10 20 30 tocopherol acetate [%] 98 98 100 100 tocopherol [%] 1 0 0 0 0
- Table 3 Conversion of Tocopherol to Tocopherol Acetate; no Catalyst; Irradiation at 800 W Time (in minutes) 5 10 20 30 tocopherol acetate [%] 62 76 97 99 tocopherol [%] 37 24 3 1
- Table 4 Conversion of Tocopherol to Tocopherol Acetate; no Catalyst; Irradiation at 1000 W Time (in minutes) 5 10 20 30 tocopherol acetate [%] 73 86 98 99 tocopherol [%] 27 14 2 2
- Table 5 Conventional Conversion of Tocopherol to Tocopherol Acetate (no Catalyst) Time (in minutes) 30 60 90 120 tocopherol acetate [%] 69 93 94 95 tocopherol [%] 30 9 6 5
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrane Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to a process for preparing tocol acylate or tocopherol acylate having the following steps:
a) combining tocol or tocopherol with an acylating agent to form a reaction mixture;
b) irradiating the reaction mixture with microwave energy to from tocol acylate or tocopherol acylate; and
c) isolating the tocol acylate or tocopherol acylate from the reaction mixture.
Description
- The present invention relates to a process for the preparation of tocol acylates and tocopherol acylates.
- The synthesis of (all-rac)-α-tocopherol acetate starting from acetic anhydride and (all-rac)-α-tocopherol, without a catalyst, in an excess of acetic anhydride has been reported by Surmatis et al., U.S. Pat. No. 2,723,278. The mixture was refluxed for three hours to form the product. The yield was not reported. This reaction can also be carried out in the presence of pyridine (as a catalyst) at room temperature to yield, after a reaction time of three days, 96% (all-rac)-α-tocopherol acetate. See Cohen et al., Helv. Chim. Acta 1981, 64, 1158.
- The present invention relates to a process for the preparation of tocol and tocopherol acylates, more particularly tocopherol acetates. The main commercial form of vitamin E being (all-rac)-α-tocopherol acetate, the invention, in a preferred embodiment, provides a process for the preparation of (all-rac)-α-tocopherol acetate. However, other tocopherols can be readily acylated by the process of the present invention. Further, by the process of the instant invention, the tocopherols can be acylated in the form of their racemates or individual enantiomers.
- One embodiment of the present invention is a process for preparing tocol acylate or tocopherol acylate having the following steps:
- a) combining tocol or tocopherol with an acylating agent to form a reaction mixture;
- b) irradiating the reaction mixture with microwave energy to form tocol acylate or tocopherol acylate; and
- c) isolating the tocol acylate or tocopherol acylate from the reaction mixture.
- Another embodiment of the present invention is a process for preparing tocopherol acylate having the following steps:
- a) combining tocopherol and an acylating agent to form a reaction mixture;
- b) exposing the reaction mixture to microwave energy at about 600 to about 1200 watts; and
- c) recovering the tocopherol acylate from the reaction mixture.
- A further embodiment of the present invention is a process for preparing tocol acylate or tocopherol acylate having the following steps:
- a) providing a reaction mixture consisting essentially of tocol or tocopherol and an acylating agent;
- b) irradiating the reaction mixture with microwave energy to form tocol acylate or tocopherol acylate; and
- c) isolating the tocol acylate or tocopherol acylate from the reaction mixture.
- In accordance with the present invention it has been found that the acylation of tocol and tocopherols can advantageously be effected under irradiation with microwaves. As compared to prior art processes, the process of the present invention requires shorter reaction time, gives better yield, and has a simpler work-up of the reaction mixture. In particular, the process of this invention does not require external heating of the reaction mixture, thus providing uniform reaction conditions throughout the entire reaction mixture.
- The present invention is process for preparing tocol acylate or tocopherol acylate having the following steps:
- a) combining tocol or tocopherol with an acylating agent to form a reaction mixture;
- b) irradiating the reaction mixture with microwave energy to from tocol acylate or tocopherol acylate; and
- d) isolating the tocol acylate or tocopherol acylate from the reaction mixture.
- The present invention also provides a process for preparing tocopherol acylate having the following steps:
- a) combining tocopherol and an acylating agent to form a reaction mixture;
- b) exposing the reaction mixture to microwave energy at about 600 to about 1200 watts; and
- c) recovering the tocopherol acylate from the reaction mixture.
- Tocol is the compound 2-methyl-2(4,8,12-trimethyl-tridecyl)-chroman-6-ol. The term “tocopherol” as used herein means all the compounds derived from the basic structure of tocol and having vitamin E character, such as, for example, the tocopherols having a saturated (tocol) side chain, such as α-, β-, γ-, δ-, ζ 2- and η-tocopherol, and the tocotrienols having three double bonds in the side chain such as ε- and ζ1-tocopherol. Of the various tocopherols, (all-rac)-α-tocopherol (generally referred to as vitamin E) is preferred.
- The term “microwave” as used herein refers to the region of the electromagnetic spectrum having frequencies of 30 GHz to 300, MHz thus corresponding to wavelengths of 1 cm to 1 m. In order not to interfere with wavelengths for Radar (1 cm-25 cm), household or industrial microwave heaters are required to operate at either 12.2 cm (2.45 GHz) or 33.3 cm (918 MHz). Thus, in a preferred embodiment of the invention, the term microwaves refers particularly to such wavelengths. In the process of this invention, conventional microwave equipment can be used. Microwave equipment suitable in the process of this invention is readily available, e.g., MLS, Leutkirch, Germany (Lavis Multiquant 1000); or MILESTONE Inc., Monroe, Conn. 06468, USA (Ethos reactors). Conveniently, the irradiation in the process of this invention is carried out by applying a power of irradiation of from about 600 to about 1200 W, more preferably from about 800 to about 1000 W.
- The acylation can be carried out using any acylating agent conventionally used for the acylation of a phenolic hydroxy group as is present in tocol and tocopherols, e.g., acyl anhydrides or halogenides. The acyl groups in such acylating agent may be derived from aliphatic carboxylic acids, e.g., from alkanoic acids, in particular C1-7-alkanoic acids such as acetic acid, propionic acid, butyric acid, or pivalic acid, or higher alkanoic acids, such as palmitic acid; or from aromatic carboxylic acids, e.g., benzoic acid; or araliphatic acids, e.g. phenylacetic acid.
- The acylation can be carried out in the presence or in the absence of a catalyst such as an organic base, e.g. pyridine or dimethylamino pyridine, or an organic or inorganic acid, e.g., sulfuric acid or p-toluenesulfonic acid. Advantageously, if a catalyst is used, a volatile catalyst is selected. In a preferred embodiment of this invention, the acylation is carried out in the absence of a catalyst. The acylating agent is suitably used in excess, i.e. in an excess of about 100% over the stoichiometrically required amount. Suitably, the reaction is carried out in an inert atmosphere. The desired tocol acylate or tocopherol acylate can be isolated from the reaction product by conventional means, e.g., by heating the reaction mixture under reduced pressure to remove excess acylating agent and catalyst, if any, and other unwanted products. While the process of the present invention is preferably concerned with the acylation of (all-rac)-tocopherols, particularly (all-rac)-α-tocopherol, the process can also be used to acylate optically pure enantiomers, such as (d-)-α-tocopherol.
- The following examples are provided to further illustrate the process of the present invention. These examples are illustrative only and are not intended to limit the scope of the invention in any way.
- (All-rac)-α-Tocopherol (52.63 g, 95% pure, corresponding to 116 mmol) and acetic anhydride (22.69 ml; 242 mmol) were placed in a flask. Pyridine catalyst (0.31 ml, 3.9 mmol) was immediately added to the reaction mixture. The reaction mixture was stirred and irradiated with 800 W or 1000 W microwaves using a LAVIS Multiquant reactor under an inert gas atmosphere (Argon). The reaction product obtained was purified by heating to 70° C. under 25 mbar. The residue was analyzed by gas chromatography (GC) (XTI-5, 30 m×0.32 mm, Film 0.25 mm, fused silica; 150° C. (0 min) 5° C./min 335° C. (8 min), He 2.0 ml/min) against an internal standard (1.0 g octacosan in 100 ml n-heptane). The conversion of the tocopherol to its acetate after 5, 10, 20 and 30 minutes is shown in Tables 1 and 2 below. (Deviations in the sum of the percentages from 100 are due to analytical errors.)
- Table 1: Conversion of Tocopherol to Tocopherol Acetate; Catalyst Present; Irradiation at 800 W
Time (in minutes) 5 10 20 30 tocopherol acetate [%] 43 94 99 99 tocopherol [%] 48 0 0 0 - Table 2: Conversion of Tocopherol to Tocopherol Acetate; Catalyst Present; Irradiation at 1000 W
Time (in minutes) 5 10 20 30 tocopherol acetate [%] 98 98 100 100 tocopherol [%] 1 0 0 0 - When carrying out the above reaction under conventional conditions (no irradiation, heating to 100° C.) 91% of tocopherol acetate and 0% of tocopherol were found in the reaction product after 30 minutes of reaction time.
- The acetylation of tocopherol was carried out using the procedure in Example 1, but in the absence of the catalyst (pyridine). The conversion of tocopherol to its acetate after 5, 10, 20 and 30 minutes is shown in Tables 3 and 4 below. (Deviations in the sum of the percentages from 100 are due to analytical errors.)
- Table 3: Conversion of Tocopherol to Tocopherol Acetate; no Catalyst; Irradiation at 800 W
Time (in minutes) 5 10 20 30 tocopherol acetate [%] 62 76 97 99 tocopherol [%] 37 24 3 1 - Table 4: Conversion of Tocopherol to Tocopherol Acetate; no Catalyst; Irradiation at 1000 W
Time (in minutes) 5 10 20 30 tocopherol acetate [%] 73 86 98 99 tocopherol [%] 27 14 2 2 - When carrying out the above reaction under conventional conditions (no irradiation, no catalyst, reflux temperature, reaction time 3.5 hours) the conversion of tocopherol to its acetate proceeded as shown in Table 5 below (Deviations in the sum of the percentages from 100 are due to analytical errors.)
- Table 5: Conventional Conversion of Tocopherol to Tocopherol Acetate (no Catalyst)
Time (in minutes) 30 60 90 120 tocopherol acetate [%] 69 93 94 95 tocopherol [%] 30 9 6 5 - The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.
Claims (20)
1. A process for preparing tocol acylate or tocopherol acylate comprising:
a)combining tocol or tocopherol with an acylating agent to form a reaction mixture;
b)irradiating the reaction mixture with microwave energy to form tocol acylate or tocopherol acylate; and
c)isolating the tocol acylate or tocopherol acylate from the reaction mixture.
2. A process according to claim 1 further comprising adding a catalyst to the reaction mixture prior to step b).
3. A process according to claim 2 wherein the catalyst is pyridine.
4. A process according to claim 1 wherein step a) is carried out with tocopherol.
5. A process according to claim 4 wherein the tocopherol is selected from the group consisting of the tocopherols having a saturated tocol side chain and the tocotrienols having three double bonds in the side chain.
6. A process according to claim 4 wherein the tocopherol is selected from the group consisting of (all-rac)-α-tocopherol, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, ζ2-tocopherol, η-tocopherol, ε-tocopherol and ζ1-tocopherol.
7. A process accordingly to claim 4 wherein the tocopherol is (all-rac)-α-tocopherol.
8. A process according to claim 1 wherein the acylating agent is an acetylating agent.
9. A process according to claim 8 wherein the acetylating agent is acetic anhydride.
10. A process according to claim 1 wherein the tocopherol is (all-rac)-α-tocopherol, and the acylating agent is acetic anhydride.
11. A process according to claim 1 wherein the microwave energy is in the range of about 600 to about 1200 watts.
12. A process according to claim 11 wherein the microwave energy is in the range of about 800 to about 1000 watts.
13. A process according to claim 10 wherein the microwave energy is at about 800 or about 1000 watts.
14. A process for preparing tocopherol acylate comprising:
a)combining tocopherol and an acylating agent to form a reaction mixture;
b)exposing the reaction mixture to microwave energy at about 600 to about 1200 watts; and
c)recovering the tocopherol acylate from the reaction mixture.
15. A process according to claim 14 further comprising adding a catalyst to the reaction mixture prior to step b).
16. A process according to claim 15 wherein the catalyst is pyridine.
17. A process accordingly to claim 14 wherein the tocopherol is (all-rac)-α-tocopherol.
18. A process according to claim 14 wherein the acetylating agent is acetic anhydride.
19. A process according to claim 14 wherein the microwave energy is in the range of about 800 to about 1000 watts.
20. A process for preparing tocol acylate or tocopherol acylate comprising:
a) providing a reaction mixture consisting essentially of tocol or tocopherol and an acylating agent;
b) irradiating the reaction mixture with microwave energy to form tocol acylate or tocopherol acylate; and
c) isolating the tocol acylate or tocopherol acylate from the reaction mixture.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP00114768 | 2000-07-10 | ||
| EP00114768 | 2000-07-10 | ||
| EP00114768.5 | 2000-07-10 |
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| US20020017451A1 true US20020017451A1 (en) | 2002-02-14 |
| US6444098B2 US6444098B2 (en) | 2002-09-03 |
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| US09/900,587 Expired - Fee Related US6444098B2 (en) | 2000-07-10 | 2001-07-09 | Process for the preparation of tocol acylates and tocopherol acylates |
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| US (1) | US6444098B2 (en) |
| JP (1) | JP2002047284A (en) |
| KR (1) | KR100798506B1 (en) |
| CN (1) | CN1200937C (en) |
| AT (1) | ATE296299T1 (en) |
| BR (1) | BR0102769A (en) |
| CA (1) | CA2352447A1 (en) |
| DE (1) | DE60110975T2 (en) |
| ES (1) | ES2241718T3 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060293491A1 (en) * | 2005-06-23 | 2006-12-28 | Sumitomo Chemical Company, Limited | Method for producing polyester |
| WO2014023848A1 (en) * | 2012-08-10 | 2014-02-13 | Dsm Ip Assets B.V. | Protected tocopherol with reduced content of free tocopherol |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE411307T1 (en) * | 2003-12-05 | 2008-10-15 | Dsm Ip Assets Bv | METHOD FOR PRODUCING ALKENYLATED HYDROXYLATED AROMATIC COMPOUNDS, CHROME COMPOUNDS AND THEIR ACYLATED DERIVATIVES |
| JP5077908B2 (en) * | 2006-02-07 | 2012-11-21 | 独立行政法人産業技術総合研究所 | Method for producing acylated tocopherol |
| CN104016856A (en) * | 2014-02-21 | 2014-09-03 | 华东理工大学 | Method for carrying out acetylation on hydroxyl of aromatic compound |
| CN105801551B (en) * | 2014-12-29 | 2018-11-30 | 浙江新和成药业有限公司 | A kind of clean preparation method of Vitwas E |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2723278A (en) | 1954-01-25 | 1955-11-08 | Hoffmann La Roche | Preparation of alpha-tocopherol |
| FR2666581B1 (en) | 1990-09-06 | 1993-05-28 | Rhone Poulenc Nutrition Animal | PROCESS FOR THE PREPARATION OF TOCOPHEROL ACETATE. |
| JPH06145200A (en) * | 1992-09-11 | 1994-05-24 | Maruha Corp | Production of acylated gelatin |
| WO1997028151A1 (en) | 1996-01-29 | 1997-08-07 | Basf Aktiengesellschaft | METHOD OF PRODUCING DL-α-TOCOPHEROL OR DL-α-TOCOPHERYL ACETATE |
| FR2760744B1 (en) | 1997-03-12 | 1999-04-23 | Rhodia Chimie Sa | PROCESS FOR ACYLATION OF AN AROMATIC COMPOUND |
| KR100408991B1 (en) * | 2000-03-23 | 2003-12-11 | 에스케이 주식회사 | The improved method for the preparation of DL-α-tocopherol acetate |
-
2001
- 2001-07-02 AT AT01116014T patent/ATE296299T1/en not_active IP Right Cessation
- 2001-07-02 DE DE60110975T patent/DE60110975T2/en not_active Expired - Lifetime
- 2001-07-02 ES ES01116014T patent/ES2241718T3/en not_active Expired - Lifetime
- 2001-07-05 CA CA002352447A patent/CA2352447A1/en not_active Abandoned
- 2001-07-06 BR BR0102769-7A patent/BR0102769A/en not_active Application Discontinuation
- 2001-07-09 US US09/900,587 patent/US6444098B2/en not_active Expired - Fee Related
- 2001-07-09 JP JP2001207414A patent/JP2002047284A/en not_active Withdrawn
- 2001-07-10 KR KR1020010041096A patent/KR100798506B1/en not_active IP Right Cessation
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060293491A1 (en) * | 2005-06-23 | 2006-12-28 | Sumitomo Chemical Company, Limited | Method for producing polyester |
| US7635726B2 (en) | 2005-06-23 | 2009-12-22 | Sumitomo Chemical Company, Limited | Method for producing polyester |
| WO2014023848A1 (en) * | 2012-08-10 | 2014-02-13 | Dsm Ip Assets B.V. | Protected tocopherol with reduced content of free tocopherol |
Also Published As
| Publication number | Publication date |
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| JP2002047284A (en) | 2002-02-12 |
| KR20020005510A (en) | 2002-01-17 |
| KR100798506B1 (en) | 2008-01-28 |
| US6444098B2 (en) | 2002-09-03 |
| CA2352447A1 (en) | 2002-01-10 |
| CN1332164A (en) | 2002-01-23 |
| DE60110975D1 (en) | 2005-06-30 |
| DE60110975T2 (en) | 2005-10-27 |
| ATE296299T1 (en) | 2005-06-15 |
| BR0102769A (en) | 2002-02-26 |
| CN1200937C (en) | 2005-05-11 |
| ES2241718T3 (en) | 2005-11-01 |
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