Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-06
2001-07-17
McKane, Joseph K. (Department: 1613)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S412000
Reexamination Certificate
active
06262279
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally processes for producing vitamin E and related compounds. In particular, the invention relates to processes for producing tocopherols and certain tocopherol derivatives, including gamma
1=d-tocopherols
1a=d-alpha tocopherol R
1
═R
2
═R
3
═CH
3
1b=d-beta tocopherol R
1
═R
3
═CH
3
, R
2
═H
1c=d-gamma tocopherol R
1
═H, R
2
═R
3
═CH
3
1d=d-delta tocopherol R
1
═R
2
═H, R
3
═CH
3
tocopherol.
BACKGROUND OF THE INVENTION
The naturally occurring vitamin E family of compounds includes a number of homologous tocopherols 1, and tocotrienols 2.
These compounds differ in the number and position of aromatic ring methyl groups, and in the degree of side chain unsaturation.
Naturally occurring vitamin E (d-alpha-tocopherol, 1a) is an important nutritional supplement in humans and animals, and is obtained commercially by isolation from a variety of plant oils, or semi-synthetically by ring methylation of less-substituted tocopherol compounds, such as the related naturally occurring d-gamma-tocopherol 1b. An important source of tocopherols is chemical synthesis, which provides d,l-alpha-tocopherol, 3. Commercially available samples of 3 are typically composed of mixtures of optical isomers at the 2, 4′, and 8′ positions,
D,L-gamma tocopherol, 4, differs from 3 only by the presence or absence of a 5-methyl substituent on the aromatic ring.
3 and 4 provide much of the biological activity of 1a, and are widely used due to lower cost and greater availability. The other tocopherols have also been shown to possess important antioxidant or vitamin E activity in mammals and humans, and are included in many modern commercial nutritional supplements. For a general discussion of vitamin E chemistry, see L. Machlin, ed., “Vitamin E: A Comprehensive Treatise”, Marcel Dekker, NY, 1980.
It is known that d,l-alpha-tocopherol 3 is obtained by reacting trimethylhydroquinone with either phytol or isophytol in the presence of an acid. Other known technologies for preparation of tocopherols and tocotrienols were reviewed by S. Kasparek in chapter 2 of Machlin's Treatise, pp. 8-65. References 140-166 of Kasparek's chapter provide the primary references to other methods of preparing compound 3.
Kabbe and Heitzer reported a multi-step synthesis of d,l-alpha-tocopherol, 3, (Synthesis 888, 1978). Two known compounds, (2-acetyl-3,5,6-trimethylhydroquinone and farnesylacetone 5) were condensed to give a 4-chromanone tocotrienol compound 6, whose structure is shown in Scheme 1 below.
The 4-keto group of compound 6 was (a) reduced with sodium borohydride to give the corresponding alcohol, (b) the alcohol was dehydrated to give the tetra-olefin, and (c) the four carbon-carbon double bonds of the tetra-olefin were hydrogenated to give d,l-alpha-tocopherol 3. Kabbe et.al.'s multi-step process to produce alpha tocopherol from a 4-chromanone trienol is industrially undesirable however, because stoichiometric quantities of expensive borohydride reagents are consumed and undesirable borate wastes are formed, multiple reaction steps and solvents are employed, and equipment and operational costs are high. Kabbe et.al. made no suggestion that a simpler process could be employed.
The multi-step sequence is apparently necessary, at least in the case of preparation of alpha-tocopherol. The current inventors have found that the tri-methyl-4-chromanone compound 6, is not detectably converted to alpha-tocopherol by direct catalytic hydrogenation. Attempts to carry out direct hydrogenation of compound 6, (as illustrated in Scheme 2 and described in Comparative Example 1) have led instead to formation of a saturated ketone, 7. No further hydrogenation of 7 occurs, and no detectible quantity of 3 is produced.
In the “gamma” series of compounds (i.e. 7,8-dimethyl tocopherols and tocotrienols), gamma tocopherol, 4, was first chemically synthesized by Jacob, Steiger, Todd and Wilcox (
J. Chem. Soc.
1939, 542) by reacting the monobenzoate ester of 2,3-dimethylhydroquinone with phytyl bromide in the presence of zinc chloride, followed by removal of the benzoate to give a low yield (22%) of gamma-tocopherol. More recently, U.S. Pat. No. 5,591,772 to Lane, Qureshi, and Salser reported isolation of the 7,8-dimethyl-4-chromanone trienol compound 8 (whose structure is shown in Scheme 3) from natural sources.
Pearce et al. (
J. Med. Chem.
37, 526-541, 1994) adapted the method of Kabbe and Heitzer to synthesize compound 8 in racemic form and partially reduce it. See Scheme 3. 2-Acetyl-5,6-dimethyl-hydroquinone, 9, and farnesylacetone, 5, were condensed to give compound 8, then the 4-keto group of 8 was chemically reduced and removed with stoichiometric quantities of aluminum hydride reagents, to give the gamma-tocotrienol derivative 10. Lane et. al. and Pearce et.al. did not suggest a process for converting the 4-chromanone compound 8 to gamma tocopherol 4. Conversion of compound 8 to compound 10 with aluminum hydrides, then to gamma-tocopherol, compound 4, would require additional reduction steps and have many of the disadvantages of Kabbe's process for the production of alpha-tocopherol.
Thus, despite the various known methods for preparing or isolating compounds related to the vitamin E family of compounds, there remains a need for simpler and more efficient methods of production of tocopherol derivatives.
SUMMARY OF THE INVENTION
In accordance with the purpose(s) of this invention, as embodied and broadly described herein, this invention, in one aspect, relates to a process for preparing a tocopherol compound, comprising reducing a 4-chromanone trienol material
in the presence of at least one hydrogen donor and a catalyst, under conditions and for a time sufficient to form at least some of a tocopherol compound
wherein R
2
and R
3
are methyl or hydrogen, and PG is hydrogen or a removable protecting group.
The invention further provides a process for preparing gamma-tocopherol by hydrogenation, comprising reacting
and H
2
at a pressure from about 400 to about 750 psig; in a reactor containing a solvent and a Raney nickel catalyst, at a temperature from about 135° C. to about 200° C., for a time from about 1 to about 10 hours.
In view of Kabbe et.al.'s failure to suggest direct hydrogenation of the 4-chromanone compound 6 to produce alpha-tocopherol, and the failure of attempts by the current inventors to produce alpha-tocopherol by direct hydrogenation of 6, it is particularly unexpected and surprising that gamma tocopherol, which differs from alpha-tocopherol only by the absence of a methyl group at the 5-position of the aromatic ring, can be produced in very high yield by the instant methods.
Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention may be understood more readily by reference to the following detailed description of preferred embodiments of the invention and the examples included therein.
Definitions and Use of Terms
Before the present compounds, compositions and methods are disclosed and described, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an aromatic compound” in
Eastman Chemical Co.
Graves, Jr. Bernard J.
McKane Joseph K.
Smith Matthew W.
Solola Taofiq A
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