Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2002-09-30
2004-11-16
Shippen, Michael L. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C435S067000
Reexamination Certificate
active
06818798
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention is in the field of organic chemistry. The invention relates in part to a process for conversion of (3R,3′R,6′R)-lutein to (3R,3′S,6′R)-lutein (3′-Epilutein), a carotenoid precursor for industrial production of naturally occurring (3R,3′R)-zeaxanthin.
2. Related Art
As a result of a high intake of fruits and vegetables, 34 carotenoids and their metabolites are found in human serum and tissues at varying concentrations. Among these, only two dietary carotenoids, (3R,3′R,6′R)-lutein and (3R,3′R)-zeaxanthin, accumulate in the human retina. Epidemiological and experimental data suggest that the function of these carotenoids is to protect the photo-sensing cells in the human retina, and particularly macula, from exposure to short-wavelength blue light, and thus prevent age-related macular degeneration (AMD) (Bone, R. A., et al.,
Invest. Ophthalmol. Vis. Sci.
34:2033-2040 (1993); Seddon, J. M., et al.,
J. Am. Med. Assoc.
272:1413-1420 (1994)).
While several patented processes for the industrial production of (3R,3′R,6′R)-lutein have been reported, (3R,3′R)-zeaxanthin is not commercially available. Currently the most promising route to this carotenoid is by chemical synthesis (Widmer et al.,
Helv. Chim. Acta
73:861-867 (1990)). However, the production of (3R,3′R)-zeaxanthin by total synthesis can be quite costly. Furthermore, the absence of possible residual contaminants in (3R,3′R) zeaxanthin prepared by synthesis must be established before this carotenoid can be safely used as a nutritional supplement or food coloring additive.
U.S. Pat. No. 5,523,494, European Patent Appl. 834536 and WO99/03830 describe the conversion of commercially available (3R,3′R,6′R) lutein or crude marigold meal to (3R,3S,meso)-zeaxanthin by base-catalyzed isomerization. (3R,3S,meso)-Zeaxanthin is absent from foods and its stereochemistry is different from that of dietary (3R,3′R)-zeaxanthin.
WO97/31894 describes a process wherein (3R,3′R,6′R)-lutein is first converted to (3R,3S,meso)-zeaxanthin and then is oxidized to &bgr;,&bgr;-carotene-3,3′-dione. In the final step of this process &bgr;,&bgr;-carotene-3,3′-dione is reduced with sodium or potassium borohydride to give a racemic mixture of (3R,3′R)-zeaxanthin, (3R,3′S,meso)-zeaxanthin, and (3S,3′S)-zeaxanthin (Scheme 1).
Therefore with the exception of total synthesis, the other reported procedures either prepare (3R,3′S,meso)-zeaxanthin, which is not the natural dietary form of this carotenoid, or use chemical reagents and additional steps to prepare a racemic mixture of (3R,3′R)-zeaxanthin, (3R,3′S,meso)-zeaxanthin, and (3S,3′S)-zeaxanthin.
The present invention seeks to produce a precursor to (3R,3′R)-zeaxanthin in high diastereomeric excess (de). The precursor may then be transformed to (3R,3′R)-zeaxanthin by methods that are well known in the an.
SUMMARY OF THE INVENTION
According to the present invention, (3R,3′R,6′R)-lutein can be epimerized at C-3′ in one convenient step using dilute acids to give a 1:1 diastereomeric mixture of 3′-epilutein and (3R,3′R,6′R)-lutein as shown in Scheme 2.
In the course of the work-up of the epimerization reaction, most of the (3R,3′R,6′R)-lutein is removed from this 1:1 mixture by filtration to produce a diastereomeric mixture in which the ratio of 3′-epilutein to (3R,3′R,6′R)-lutein is in the range of 3.4 to 3.5. A de of 54-90% can be accomplished by a) solvent extraction, b) preferential crystallization, c) Soxhlet extraction, d) enzymatic acylation, and e) supercritical extraction with carbon dioxide of either an about 1:1 mixture of (3R,3′R,6′R)-lutein and 3′-epilutein or the partially separated mixture (with ratio of 3.4 to 3.5).
Only enzymatic acylation of the 1:1 diastereomeric mixture of 3′-epilutein and (3R,3′R,6′R)-lutein, affords 3′-epilutein in 90% de whereas the other methods require additional purification to increase de of this carotenoid. The partially separated mixture can be subjected to low temperature crystallization to crystallize most of the (3R,3′R,6′R)-lutein and increase the de of 3′-epilutein in the mother liquor of this crystallization. Under these conditions, most of the (3R,3′R,6′R)-lutein is crystallized and can be recovered. At any stage of these processes, the recovered solid which is predominantly enriched in (3R,3′R,6′R)-lutein, can be recycled into the epimerization reaction.
The isolated 3′-epilutein may then be directly converted to naturally occurring (3R,3′R)-zeaxanthin by base-catalyzed isomerization (vide supra). All of the above separation procedures can be readily implemented on industrial scale with the advantage that the recovered (3R,3′R,6′R)-lutein can be recycled and epimerized to 3′-epilutein. The present invention does not employ any reagents other than commonly used organic solvents and acids which can be safety handled under mild conditions.
In particular the invention relates to a method of epimerizing (3R,3′R,6′R)-lutein to give a mixture of (3R,3′R,6′R)-lutein and 3′-epilutein, comprising reacting (3R,3′R,6′R)-lutein in the presence of aqueous acid in a water miscible organic solvent to give a mixture of (3R,3′R,6′R)-lutein and 3′-epilutein.
The invention further relates to a method of purifying 3′-epilutein from a mixture of (3R,3′R,6′R)-lutein and 3′-epilutein comprising extracting the mixture of (3R,3′R,6′R)-lutein and 3′-epilutein with an organic solvent and recovering the 3′-epilutein from the organic solvent.
The invention further relates to a method of purifying 3′-epilutein from a mixture of (3R,3′R,6′R)-lutein and 3′-epilutein comprising low temperature crystallization of the mixture in a C
1-4
alcohol and recovering the 3′-epilutein from the alcohol.
The invention further relates to a method of purifying 3′-epilutein from a mixture of (3R,3′R,6′R)-lutein and 3′-epilutein comprising:
(a) reacting a mixture of (3R,3′R,6′R)-lutein and 3′-epilutein with an acyl donor in the presence of lipase PS from
Pseudomonas cepacia
or lipase AK from
Pseudomonas fluorescens
in an first organic solvent;
(b) adding a second organic solvent to dissolve the mixture and removing the enzyme by filtration to give a filtrate;
(c) concentrating the filtrate to give a residue;
(d) adding a C
5-7
hydrocarbon or ether to the residue to give a solution in which 3′-epilutein and 3′-epilutein-3′-acetate are preferentially solubilized;
(e) filtering the solution to give a filtrate;
(f) hydrolyzing the 3′-epilutein-3′-acetate contained in the filtrate to give 3′-epilutein; and
(g) recovering the 3′-epilutein;
thereby obtaining purified 3′-epilutein.
The invention further relates to a method of purifying 3′-epilutein from a mixture of (3R,3′R,6′R)-lutein and 3′-epilutein comprising extracting the mixture with supercritical carbon dioxide and evaporating the carbon dioxide to give purified 3′-epilutein.
The invention further relates to a method for producing 3′-epilutein comprising:
(a) epimerizing (3R,3′R,6′R)-lutein to 3′-epilutein in the presence of an aqueous acid in a water miscible organic solvent thereby giving a mixture of (3R,3′R,6′R)-lutein and 3′-epilutein; and
(b) separating 3′-epilutein from (3R,3′R,6′R)-lutein.
The invention further relates to a method for converting (3R,3′R,6′R)-lutein to a mixture of 3′-epilutein and (3R,3′R,6′R)-lutein comprising:
(a) reacting (3R,3′R,6′R)-lutein with
Shippen Michael L.
Sterne Kessler Goldstein & Fox P.L.L.C.
University of Maryland College Park
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