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Process for the preparation of alpha- and beta-cryptoxanthinRelated Patent Categories: Food Or Edible Material: Processes, Compositions, And Products, Addition Of Dye Or Pigment, Including Optical BrightenerProcess for the preparation of alpha- and beta-cryptoxanthin description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060088631, Process for the preparation of alpha- and beta-cryptoxanthin. Brief Patent Description - Full Patent Description - Patent Application Claims
BACKGROUND OF THE INVENTION [0001] 1. Field of Invention [0002] The invention is in the field of organic chemistry. The invention relates to a process that converts a mixture of dehydration products of (3R,3'R,6'R)-lutein, hereto after referred to as anhydroluteins, to a mixture of (3R)-.beta.-cryptoxanthin and (3R,6'R)-.alpha.-cryptoxanthin by catalytic hydrogenation with a variety of heterogeneous and homogeneous catalysts under mild conditions at atmospheric pressure. Two alternative processes have also been developed that can convert unesterified lutein to anhydroluteins. The invention also relates to a process that converts other lutein sources to anhydroluteins. [0003] 2. Background of the Art [0004] .beta.-Cryptoxanthin, as measured through blood plasma samples, is associated with blood pressure reduction as seen in an Oxford University large intervention trial (John J H, Ziebland S, Yudkin P, Roe L S, Neil H A. Effects of fruit and vegetable consumption on plasma antioxidant concentrations and blood pressure: a randomised controlled trial. Lancet 2002; 359(9322):1969-74). Healthy and diseased subjects have been studied in a variety of prospective trials to correlate .beta.-cryptoxanthin levels with cardiovascular parameters (John et al.; Appel L, Moore T, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med 1997; 336(16):1117-24). There seems to be a relationship with cardiovascular markers such as LDL oxidation (Roberts W G, Gordon M H, Walker A F. Effects of enhanced consumption of fruit and vegetables on plasma antioxidant status and oxidative resistance of LDL in smokers supplemented with fish oil. Eur J Clin Nutr 2003; 57:1303-10), DNA synthesis (aortic cells) (Carpenter K L, Hardwick S J, Albarani V, Mitchinson M J. Carotenoids inhibit DNA synthesis in human aortic smooth muscle cells. FEBS Lett 1999; 447(1):17-20), malondialdehyde, and myocardial infarction onset. Subjects with either coronary artery disease (CAD), congestive heart failure (CHF), coronary heart disease (CHD), angina pectoris, or myocardial infarction onset have all shown to have lower .beta.-crytpoxanthin levels with respect to healthy age-matched subjects (Meraji S, Abuja P M, Hayn M, et al. Relationship between classic risk factors, plasma antioxidants and indicators of oxidant stress in angina pectoris (AP) in Tehran. Atherosclerosis 2000; 150(2):403-12; Morris D, Kritchevsky S, Davis C. Serum carotenoids and coronary heart disease: the Lipid Research Clinics Coronary Primary Prevention Trial and Follow-up Study. JAMA 1994; 272:1439-41; Ruiz Rejon F, Martin-Pena G, Granado F, Ruiz-Galiana J, Blanco I, Olmedilla B. Plasma status of retinol, alpha- and gamma-tocopherols, and main carotenoids to first myocardial infarction: case control and follow-up study. Nutrition 2002; 18(1):26-31; Dwyer J H, Paul-Labrador M J, Fan J, Shircore A M, Bairey Merz C N, Dwyer K M. Progression of Carotid Intima-Media Thickness and Plasma Antioxidants: The Los Angeles Atherosclerosis Study. Arterioscler Thromb Vasc Biol 2004; 24:313-19; Vogel S, Contois J H, Tucker K L, Wilson P W, Schaefer E J, Lammi-Keefe C J. Plasma retinol and plasma and lipoprotein tocopherol and carotenoid concentrations in healthy elderly participants of the Framingham Heart Study. Am J Clin Nutr 1997; 66(4):950-8). Inflammatory markers such as C-reactive protein and fibrinogen have also been linked to low .beta.-cryptoxanthin levels (Kritchevsky S B, Bush A J, Pahor M, Gross M D. Serum carotenoids and markers of inflammation in nonsmokers. Am J Epidemiol 2000; 152(11):1065-71). Inflammation and the relationship to heart disease is a relatively new area of study. Currently, there are no products available for the dietary supplement market which have appreciable levels of .beta.-cryptoxanthin in them or contain .beta.-cryptoxanthin as the major ingredient. [0005] There have also been some preliminary studies looking at the effect of beta cryptoxanthin on bone growth and the inhibition of bone reabsorption. In vitro studies have shown a positive effect of .beta.-cryptoxanthin increasing bone calcium and enhancing bone alkaline phosphatase (Yamaguchi, M, Uchiyama, S. Effect of carotenoid on calcium content and alkaline phosphatase activity in rat femoral tissues in vitro: the unique anabolic effect of beta-cryptoxanthin Biol. Pharm. Bull 2003; 26(8): 1188-91) (Uchiyama, A, Yamaguchi, M. Inhibitory effect of beta cryptoxanthin on osteoclast-like cell formation in mouse marrow cultures. Biochem. Pharmacol. 2004; 67: 1297-13-5). Oral studies in rats have shown similar results. (Uchiyama, S, Sumida, T, Yamaguchi, M. Oral administration of beta-cryptoxanthin induces effects on bone components in the femoral tissues of rats in vivo. Biol. Pharm. Bull. 2004; 27(2): 232-5. A PCT was filed on these findings (Yamaguchi, M. Osteogenesis promoter containing .beta.-cryptoxanthin as the active ingredient PCT WO 2004/037236 A1). [0006] This invention is an improvement to the process described in PCT US03/23422 (which is incorporated herein by this reference) that converts commercially available (3R,3'R,6'R)-lutein containing 5% (3R,3'R)-zeaxanthin in two steps to a mixture of (3R)-.beta.-cryptoxanthin and (3R,6'R)-.alpha.-cryptoxanthin. In the first step according to PCT US03/23422, (3R,3'R,6'R)-lutein is allowed to react with an alcohol, used as solvent, in the presence of catalytic amount of an acid between 45-50.degree. C. to give the corresponding 3'-alkyl ethers of lutein. Water and additional acid is then added to the mixture and the temperature is raised to 78-88.degree. C. to convert the resulting lutein 3'-alkyl ethers to a mixture of anhydroluteins I, II, and III, quantitatively (Scheme 1 of FIG. 1). At the beginning of this transformation, anhydrolutein I is the major product and anhydrolutein II and III are the minor products. As heating continues at 78-88.degree. C., anhydroluteins I and II are partially isomerized to anhydrolutein III within 7-20 h depending on the nature of the alcohol. In the second step of the PCT US03/23422, the resulting product, rich in anhydrolutein III is allowed to react with about 1.3 equivalent of a hydride donor and about 3.5-4 equivalent of a strong organic acid in a chlorinated solvent at ambient temperature for about 1-5 hours to give a mixture of E/Z-(3R)-.beta.-cryptoxanthin, E/Z-(3R,6'R)-.alpha.-cryptoxanthin, and minor quantities of unreacted anhydroluteins I and II, as well as recovered E/Z-(3R,3'R)-zeaxanthin. [0007] The present invention provides an alternative route to the second step of PCT US03/23422 for making (3R)-.beta.-cryptoxanthin and (3R,6'R)-.alpha.-cryptoxanthin from anhydroluteins and eliminates the use of chlorinated solvents and reagents such as trifluoroacetic acid, and borane-amine complex. This is accomplished by heterogeneous or homogeneous catalytic hydrogenation of anhydroluteins according to the scheme illustrated in FIG. 1. [0008] In addition, the present invention improves the first step of transformation of (3R,3'R,6'R)-lutein to anhydroluteins to reduce the amounts of solvents used as well as increasing the purity and stability of the products. [0009] While in all of the above processes, unesterified lutein has been employed as the starting material, the present invention has further developed two alternative processes that can employ a mixture of esterified luteins as the starting material to prepare anhydroluteins that can then be transformed to (3R)-.beta.-cryptoxanthin and (3R,6'R)-.alpha.-cryptoxanthin by catalytic hydrogenation. SUMMARY OF THE INVENTION [0010] In an attempt to eliminate the use of chlorinated solvents and reagents that may be toxic to humans, an alternative process for the second step of the partial synthesis of (3R)-.beta.-cryptoxanthin and (3R,6'R)-.alpha.-cryptoxanthin from anhydroluteins has been developed. This has been accomplished by heterogeneous or homogeneous catalytic hydrogenation of anhydroluteins. Catalytic hydrogenation has been extensively used in pharmaceutical and food industries and offers an economical route to products that can be safely used by humans. There are numerous literature examples that deal with heterogeneous and homogeneous hydrogenation of cycloalkenes and cyclodienes (H. Takaya, R. Noyori in Comprehensive Organic Synthesis, Eds. B. M. Trost and I. Fleming, Pergamon, Oxford, 1991, Vol 8, pp 417-470). However, to date, there are no literature reports on regioselective catalytic hydrogenation of carotenoids. This is primarily due to the presence of a highly conjugated polyene chain in carotenoids that makes these compounds readily susceptible to hydrogenation and as a result the regioselectivity of this process is difficult to control. Nonetheless, the present invention will demonstrate that under carefully controlled conditions, hetereogeous and homogeneous catalytic hydrogenation of anhydroluteins with a wide range of catalysts in various solvents can yield a mixture of (3R)-.beta.-cryptoxanthin and (3R,6'R)-x-cryptoxanthin in moderate to excellent selectivity and yields. [0011] Therefore, in an alternative embodiment, the present invention converts anhydroluteins rich in anhydrolutein III to a mixture of (3R)-.beta.-cryptoxanthin and (3R,6'R)-.alpha.-cryptoxanthin by heterogeneous catalytic hydrogenation employing transition elements group VIII such as platinum, palladium, or rhodium supported on carbon or alumina at temperatures ranging from -15.degree. C. to 40.degree. C. in a variety of organic solvents. Among these catalysts, platinum supported on alumina provides the best yield of (3R)-.beta.-cryptoxanthin and (3R,6'R)-.alpha.-cryptoxanthin. [0012] Similarly, the present invention demonstrates that several homogeneous catalysts can also promote the regioselective catalytic hydrogenation of anhydroluteins to yield a mixture of (3R)-.beta.-cryptoxanthin and (3R,6'R)-.alpha.-cryptoxanthin in moderate yields. However, depending on the nature of the catalyst and the reaction conditions, approximately 30-82% of the anhydroluteins remain unreacted. The homogeneous catalysts may be transition metal complexes such as palladium acetylacetonate, tris(triphenylphosphine)rhodium (I) chloride [Rh(Ph.sub.3P).sub.3Cl] (Wilkinson's catalyst), (tricyclohexylphosphine)(1,5-cyclooctadiene)pyridine Iridium (I) hexafluorophosphate [(C.sub.6H.sub.11).sub.3P[C.sub.8H.sub.12][C.sub.5H.sub.5N]Ir.sup.+PF6.su- p.- (Crabtree catalyst), and (1,5-cyclooctadiene)bis(methyldiphenylphosphine) Iridium (I) hexafluorophosphate [C.sub.8H.sub.12][(MePh.sub.2P).sub.2]Ir.sup.+PF6.sup.-. Among these, hydrogenation of anhydroluteins with calculated amounts of Wilkinson's catalyst yields (3R)-.beta.-cryptoxanthin and (3R,6'R)-.alpha.-cryptoxanthin in almost quantitative yield. Various formulations of commercially available lutein that are employed as the starting material in this invention, also contain approximately 5-9% (3R,3'R)-zeaxanthin. This carotenoid remains unreacted throughout the reaction sequences described above and is recovered as a minor constituent in the final products. [0013] The above processes employ unesterified lutein from saponified extracts of marigold oleoresin as the starting material. However, the present invention also provides two alternative routes to anhydroluteins from unsaponified extracts of marigold oleoresin that contains lutein fatty acid esters (e.g. lutein bispalmitate, lutein bismyristate, lutein 3-myristate 3'-palmitate, lutein 3-palmitate 3'-myristate), as shown in the scheme of FIG. 2. Lutein esters in marigold oleoresin are also accompanied by approx. 5-9% of zeaxanthin fatty acid esters (e.g. zeaxanthin bismyristate, zeaxanthin 3-myristate 3'-palmitate, zeaxanthin bispalmitate). The preparation of anhydroluteins from unsaponified extracts of marigold oleoresin is accomplished by acid-catalyzed transesterification of lutein esters with an alcohol at an elevated temperature, preferably between about 45 to 50.degree. C. Under these controlled conditions, the acylester at the 3'-position in lutein esters preferentially undergoes transesterification while the acylester group at the 3-position remains unchanged. In the presence of an alcohol and catalytic amount of an acid, the transesterification is also accompanied by etherification at the 3'-position (see the scheme of FIG. 2). The resulting lutein 3-acylester 3'-alkyl ether can then be converted to anhydroluteins at elevated temperature, preferably ranging from about 78 to 88.degree. C. Alternatively, lutein 3-acyl ester 3'-alkyl ether can be subjected to saponification to hydrolyze the acyl ester at the 3-position and yield lutein 3'-alkyl ether; the latter can then be converted to anhydroluteins according to the PCT US03/23422. Catalytic hydrogenation of the resulting anhydroluteins according to the processes of the present invention can yield a mixture of (3R)-.beta.-cryptoxanthin and (3R,6'R)-.alpha.-cryptoxanthin. (3R,3'R)-Zeaxanthin esters that are present as minor constituents in the starting material are converted to unesterified (3R,3'R)-zeaxanthin but otherwise remain unchanged throughout the entire process. [0014] The present invention also improves the process that converts lutein to anhydroluteins by reducing the volume of solvents and increasing the purity and stability of the products. In addition to the use of dry lutein powder as the starting material, the present invention further demonstrates that lutein-containing products with considerable amounts of water content, hereinafter referred to as wet lutein, can be employed to convert this carotenoid to anhydroluteins in excellent yields. Wet lutein, as used in this disclosure includes any lutein-containing product that includes more water than dry lutein-powder. Specifically included in the term wet lutein is the product produced as described in U.S. Pat. No. 5,648,564 at the point where water has been added to the saponified oleoresin and some of the liquid removed by centrifugation. Kemin Industries (Des Moines, Iowa) sells OroGLO.RTM. Liquid products that are also included in the term wet lutein. [0015] (3R)-.beta.-Cryptoxanthin and (3R,6'R)-.alpha.-cryptoxanthin can be used as dietary supplements, nutritional ingredients, or as a food coloring additives. The commercial availability of these carotenoids allows scientists to investigate the potential chemopreventive efficacy of these compounds as neuroprotectors and in the promotion of bone health as well as in the prevention of cancer, cardiovascular disease, and macular degeneration. BRIEF DESCRIPTION OF THE FIGURES [0016] FIG. 1 is a scheme which depicts the conversion of (3R,3'R,6'R)-lutein to .beta.-cryptoxanthin and .alpha.-cryptoxanthin; (3R,3'R)-zeaxanthin which is present in the starting material remains unreacted throughout the entire process and is recovered in the final product. [0017] FIG. 2 is a scheme which depicts the conversion of lutein esters to .beta.-cryptoxanthin and .alpha.-cryptoxanthin via anhydroluteins I-III prepared by acid-catalyzed transesterification; (3R,3'R)-zeaxanthin esters that are present as minor constituents in the starting material are converted to unesterified (3R,3'R)-zeaxanthin but otherwise remain unchanged throughout the entire process. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS [0018] According to earlier application PCT US03/23422, commercially available (3R,3'R,6'R)-lutein containing approximately 5% (3R,3'R)-zeaxanthin can be dehydrated with a strong mineral acid at 50-60.degree. C. to yield anhydrolutein I as the major product and anhydroluteins II and III as the minor products. However as the temperature is elevated to 78-88.degree. C., anhydrolutein I slowly isomerizes to anhydrolutein III; the latter is the preferred starting material for the second step of the fore-mentioned process (PCT US03/23422). Therefore the resulting product of this isomerization is a mixture of anhydroluteins in which anhydrolutein III is the major product and the rest is anhydrolutein I and anhydrolutein II as well as minor quantities of unreacted zeaxanthin (FIG. 1). In the second step of PCT US03/23422, this mixture is subjected to ionic hydrogenation with a strong acid and a hydride ion donor at ambient temperature to yield (3R)-.beta.-cryptoxanthin and (3R,6'R)-.alpha.-cryptoxanthin in excellent yields. [0019] The present invention relates to a catalytic hydrogenation process that converts a mixture of anhyroluteins which consists of approximate ratios of anhydrolutein I: anhydrolutein II: anhydrolutein III (1.4:1.0:10) to a mixture of .beta.-cryptoxanthin and .alpha.-cryptoxanthin by heterogeneous and homogeneous catalytic hydrogenation in a variety of solvents under mild conditions at atmospheric or elevated pressure (FIG. 1). The heterogeneous catalyst may be selected from the transition elements of group VIII such as platinum (Pt) supported on alumina (5%), Pt supported on activated carbon (5% or 10%), palladium (Pd) supported on activated carbon (Pd/C, 5% or 10%), Pd supported on alumina (5% or 10%), Pd supported on calcium carbonate (Pd/CaCO.sub.3, 5%), Pd 3% on polyethyleneimine/SiO.sub.2 (Royer Pd catalyst), or rhodium (Rh) supported on alumina (5%). Among these, the best results are obtained with Pt supported on alumina that transforms a mixture of anhydroluteins to .beta.-cryptoxanthin and .alpha.-cryptoxanthin in yields ranging from 77-99% of total carotenoids. [0020] The homogeneous catalyst may be transition metal complexes such as palladium acetylacetonate, tris(triphenylphosphine)rhodium (I) chloride [Rh(Ph.sub.3P).sub.3Cl] (Wilkinson's catalyst), (tricyclohexylphosphine)(1,5-cyclooctadiene)pyridine Iridium (I) hexafluorophosphate [(C.sub.6H.sub.1).sub.3P[C.sub.8H.sub.12] [C.sub.5H.sub.5N]Ir.sup.+PF6.sup.- (Crabtree catalyst), and (1,5-cyclooctadiene)bis(methyldiphenylphosphine) Iridium (I) hexafluorophosphate [C.sub.8H.sub.12] [(MePh.sub.2P).sub.2]Ir.sup.+PF6.sup.-. Continue reading about Process for the preparation of alpha- and beta-cryptoxanthin... Full patent description for Process for the preparation of alpha- and beta-cryptoxanthin Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Process for the preparation of alpha- and beta-cryptoxanthin patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. 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