US6818798B1 — Process for making a (3R,3′R)-zeaxanthin precursor

Claim 1

Independent Claim 36 words

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.

Claim 2

Independent Claim 36 words

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.

Claim 3

Dependent Claim 14 words

The method of claim 1 , wherein the water miscible organic solvent is THF.

Claim 4

Dependent Claim 17 words

The method of claim 1 , wherein the aqueous acid is aqueous hydrochloric, sulfuric or phosphoric acid.

Claim 5

Independent Claim 32 words

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.

Claim 6

Independent Claim 32 words

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.

Claim 7

Dependent Claim 22 words

The method of claim 4 , wherein the mixture of (3R,3′R,6′R)-lutein and 3′-epilutein is an about 1:1 mixture of (3R,3′R,6′R)-lutein and 3′-epilutein.

Claim 8

Dependent Claim 20 words

The method of claim 4 , wherein the organic solvent is a mixture of a non-polar hydrocarbon and a ether.

Claim 9

Dependent Claim 27 words

The method of claim 6 , wherein the non-polar hydrocarbon is pentane, hexane, heptane or petroleum ether and the ether is diethyl ether, diisopropyl ether or TMBE.

Claim 10

Dependent Claim 13 words

The method of claim 4 , wherein said extracting is by Soxhlet extraction.

Claim 11

Independent Claim 31 words

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.

Claim 12

Independent Claim 31 words

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.

Claim 13

Dependent Claim 15 words

The method of claim 9 , wherein the alcohol is methanol, ethanol, propanol or 2-propanol.

Claim 14

Dependent Claim 22 words

The method of claim 9 , wherein the mixture of (3R,3′R,6′R)-lutein and 3′-epilutein is an about 1:1, mixture of (3R,3′R,6′R)-lutein and 3′-epilutein.

Claim 15

Independent Claim 124 words

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.

Claim 16

Independent Claim 124 words

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.

Claim 17

Dependent Claim 18 words

The method of claim 12 , wherein said hydrolyzing is carried out by treating 3′-epilutein-3′-acetate with alcoholic alkali.

Claim 18

Dependent Claim 27 words

The method of claim 12 , wherein the 3′-epilutein is recovered by partitioning with water and TBME, separating the TBME from the water and evaporating the TBME.

Claim 19

Dependent Claim 22 words

The method of claim 1 wherein the mixture of (3R,3′R,6′R)-lutein and 3′-epilutein is an about 1:1 a mixture of (3R,3′R,6′R)-lutein and 3′-epilutein.

Claim 20

Dependent Claim 18 words

The method of claim 12 , wherein the first organic solvent is pentane, hexane, TMBE or petroleum ether.

Claim 21

Independent Claim 17 words

The method of claim wherein the second organic solvent is THF, diethyl ether, TBME or diisopropyl ether.

Claim 22

Dependent Claim 25 words

The method of claim 12 , wherein the hydrocarbon is pentane, hexane or heptane and the ether is THF, diethyl ether, TBME or diisopropyl ether.

Claim 23

Dependent Claim 16 words

The method of claim 12 , wherein the acyl donor is vinyl acetate or isopropenyl acetate.

Claim 24

Independent Claim 29 words

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.

Claim 25

Independent Claim 29 words

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.

Claim 26

Dependent Claim 22 words

The method of claim 20 , wherein the mixture of (3R,3′R,6′R)-lutein and 3′-epilutein is an about 1:1 mixture of (3R,3′R,6′R)-lutein and 3′-epilutein.

Claim 27

Independent Claim 38 words

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.

Claim 28

Independent Claim 38 words

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.

Claim 29

Dependent Claim 15 words

The method of claim 22 , wherein said 3′-epilutein has a de greater than 50%.

Claim 30

Dependent Claim 17 words

The method of claim 22 , wherein the aqueous acid is aqueous hydrochloric, sulfuric or phosphoric acid.

Claim 31

Dependent Claim 14 words

The method of claim 22 , wherein the water miscible organic solvent is THF.

Claim 32

Dependent Claim 16 words

The method of claim 22 , wherein 3′-epilutein is separated from (3R,3′R,6′R)-lutein by low temperature crystallization.

Claim 33

Dependent Claim 17 words

The method of claim 22 , wherein the (3R,3′R,6′R)-lutein is a crude saponified extract from marigold flowers.

Claim 34

Dependent Claim 12 words

The method of claim 22 , wherein the (3R,3′R,6′R)-lutein is 70% (3R,3′R,6′R)-lutein.

Claim 35

Dependent Claim 20 words

The method of claim 22 , wherein the (3R,3′R,6′R)-lutein is 97% pure and is obtained by crystallization of 70% (3R,3′R,6′R)-lutein.

Claim 36

Dependent Claim 19 words

The method of claim 27 , wherein the crude saponified extract from marigold flowers further comprises several minor carotenoids.

Claim 37

Dependent Claim 15 words

The method of claim 22 , wherein 3′-epilutein is separated from (3R,3′R,6′R)-lutein by preferential crystallization.

Claim 38

Dependent Claim 15 words

The method of claim 22 , wherein 3′-epilutein is separated from (3R,3′R,6′R)-lutein by solvent extraction.

Claim 39

Dependent Claim 15 words

The method of claim 22 , wherein 3′-epilutein is separated from (3R,3′R,6′R)-lutein by Soxhlet extraction.

Claim 40

Dependent Claim 27 words

The method of claim 22 , wherein 3′-epilutein is separated from (3R,3′R,6′R)-lutein by enzymatic acylation, separation of 3′-epilutein-3′-acetate from (3R,3′R,6′R)-lutein, and alcoholic alkali hydrolysis to give 3′-epilutein.

Claim 41

Dependent Claim 28 words

The method of claim 22 , wherein 3′-epilutein is separated from (3R,3′R,6′R)-lutein by extraction with supercritical carbon dioxide and evaporation of the carbon dioxide to give the 3′-epilutein.

Claim 42

Dependent Claim 25 words

The method of any one of claim 32 , 33 , 34 or 35 , wherein the 3′-epilutein is further purified by low temperature crystallization.

Claim 43

Dependent Claim 52 words

The method of claim 31 , wherein the preferential crystallization comprises: (a) treating a mixture of 3′-epilutein and (3R,3′R,6′R)-lutein with a solvent or mixture of solvents giving a 3′-epilutein enriched solution and a (3R,3′R,6′R)-lutein enriched precipitate; (b) filtering the solution to give a filtrate; and (c) concentrating the filtrate to give 3′-epilutein.

Claim 44

Dependent Claim 19 words

The method of claim 37 , wherein the mixture of solvents consists of an ether and a non-polar hydrocarbon.

Claim 45

Dependent Claim 27 words

The method of claim 38 , wherein the ether is diisopropyl ether, TBME or diethyl ether and the non-polar hydrocarbon is pentane, hexane, heptane or petroleum ether.

Claim 46

Dependent Claim 17 words

The method of claim 37 , wherein the mixture of 3′-epilutein and (3R,3′R,6′R)-lutein is treated with alcohol.

Claim 47

Dependent Claim 15 words

The method of claim 40 , wherein the alcohol is ethanol, propanol, 2-propanol or methanol.

Claim 48

Independent Claim 52 words

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 an aqueous acid in a solvent at ambient temperature to obtain a crude product; (b) neutralizing the crude product; and (c) removing the water; thus obtaining a crude diastereomeric crystalline mixture of 3′-epilutein and (3R,3′R,6′R)-lutein.

Claim 49

Independent Claim 52 words

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 an aqueous acid in a solvent at ambient temperature to obtain a crude product; (b) neutralizing the crude product; and (c) removing the water; thus obtaining a crude diastereomeric crystalline mixture of 3′-epilutein and (3R,3′R,6′R)-lutein.

Claim 50

Dependent Claim 47 words

The method of claim 42 , wherein the crude product is neutralized by adding aqueous base, and the water is removed by partitioning into an organic solvent, the water is separated and the solvent is evaporated to obtain the crude diastereomeric crystalline mixture of 3′-epilutein and (3R,3′R,6′R)-lutein.

Claim 51

Dependent Claim 12 words

The method of claim 43 , wherein the base is sodium bicarbonate.

Claim 52

Dependent Claim 17 words

The method of claim 43 , wherein the organic solvent is TBME, diethyl ether or ethyl acetate.

Claim 53

Dependent Claim 40 words

The method of claim 42 , further comprising: (d) extracting the crude diastereomeric crystalline mixture of 3′-epilutein and (3R,3S,6′R)-lutein at ambient temperature thereby precipitating and removing most of the (3R,3′R,6′R)-lutein by filtration, thus obtaining a filtrate comprising 3′-epilutein and (3R,3′R,6′R)-lutein.

Claim 54

Dependent Claim 70 words

A method for partial separation of 3′-epilutein from a diastereomeric mixture of 3′-epilutein and (3R,3′R,6′R)-lutein according to the method of claim 42 by extracting the crude crystalline mixture with pentane or petroleum ether (b.p.=35-60° C.) in a Soxhlet apparatus to obtain a pentane or petroleum ether soluble fraction comprising of a diastereomeric mixture of 3′-epilutein (80%) and (3R,3′R,6′R)-lutein (20%), evaporating the solvents to obtain a crystalline mixture enriched in 3′-epilutein.

Claim 55

Independent Claim 97 words

A method for the separation of 3′-epilutein from a mixture of 3′-epilutein and (3R,3′R,6′R)-lutein by enzymatic acylation, comprising reacting 3′-epilutein with vinyl acetate as an acyl donor in the presence of a lipase in pentane, hexane or TBME at 36° C. to convert 95% of 3′-epilutein to 3′-epilutein-3′-acetate while (3R,3′R,6′R)-lutein remains unreacted; subjecting the crude product to hydrolysis with alcoholic potassium or sodium hydroxide at ambient temperature; removing the base by extracting the product with water and an organic solvent; and evaporating the solvent to obtain diastereomeric luteins comprising 95% 3′-epilutein and 5% (3R,3′R,6′R)-lutein as red crystals.

Claim 56

Independent Claim 97 words

A method for the separation of 3′-epilutein from a mixture of 3′-epilutein and (3R,3′R,6′R)-lutein by enzymatic acylation, comprising reacting 3′-epilutein with vinyl acetate as an acyl donor in the presence of a lipase in pentane, hexane or TBME at 36° C. to convert 95% of 3′-epilutein to 3′-epilutein-3′-acetate while (3R,3′R,6′R)-lutein remains unreacted; subjecting the crude product to hydrolysis with alcoholic potassium or sodium hydroxide at ambient temperature; removing the base by extracting the product with water and an organic solvent; and evaporating the solvent to obtain diastereomeric luteins comprising 95% 3′-epilutein and 5% (3R,3′R,6′R)-lutein as red crystals.

Claim 57

Dependent Claim 28 words

The method of claim 48 , wherein the (3R,3′R,6′R)-lutein that remains unreacted is separated from 3′-epilutein and 3′-epilutein-3′-acetate by filtration prior to subjecting the crude product to hydrolysis.

Claim 58

Independent Claim 49 words

A method for separating 3′-epilutein from a diastereomeric mixture of 3′-epilutein and (3R,3′R,6′R)-lutein comprising extracting the diastereomeric mixture of luteins with carbon dioxide thereby extracting most of 3′-epilutein with carbon dioxide and leaving behind most of the (3R,3′R,6′R)-lutein thus yielding a product consisting of 86% 3′-epilutein and 14% (3R,3′R,6′R)-lutein.

Claim 59

Independent Claim 49 words

A method for separating 3′-epilutein from a diastereomeric mixture of 3′-epilutein and (3R,3′R,6′R)-lutein comprising extracting the diastereomeric mixture of luteins with carbon dioxide thereby extracting most of 3′-epilutein with carbon dioxide and leaving behind most of the (3R,3′R,6′R)-lutein thus yielding a product consisting of 86% 3′-epilutein and 14% (3R,3′R,6′R)-lutein.

Claim 60

Independent Claim 57 words

A method for separating 3′-epilutein from a diastereomeric mixture of 3′-epilutein and (3R,3′R,6′R)-lutein comprising low temperature crystallization with an alcohol at −70° C. to crystallize most of the (3R,3′R,6′R)-lutein and increasing the purity of 3′-epilutein in the mother liquor of this crystallization; and evaporation of the alcohol; thus obtaining red crystals containing 94% 3′-epilutein and 6% (3R,3′R,6′R)-lutein.

Claim 61

Independent Claim 57 words

A method for separating 3′-epilutein from a diastereomeric mixture of 3′-epilutein and (3R,3′R,6′R)-lutein comprising low temperature crystallization with an alcohol at −70° C. to crystallize most of the (3R,3′R,6′R)-lutein and increasing the purity of 3′-epilutein in the mother liquor of this crystallization; and evaporation of the alcohol; thus obtaining red crystals containing 94% 3′-epilutein and 6% (3R,3′R,6′R)-lutein.

Claim 62

Independent Claim 32 words

A method of preparing 3′-epilutein-3′-acetate comprising 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.

Claim 63

Independent Claim 32 words

A method of preparing 3′-epilutein-3′-acetate comprising 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.

Claim 64

Dependent Claim 16 words

The method of claim 52 , wherein the acyl donor is vinyl acetate or isopropenyl acetate.

Claim 65

Dependent Claim 26 words

A process for obtaining 3′-epilutein, comprising reacting a lutein-containing extract with aqueous sulfuric or phosphoric acid in the presence of tetrahydrofuran, to obtain a 3′-epilutein solution.

Claim 66

Dependent Claim 26 words

A process for obtaining 3′-epilutein, comprising reacting a lutein-containing extract with aqueous sulfuric or phosphoric acid in the presence of tetrahydrofuran, to obtain a 3′-epilutein solution.

Claim 67

Dependent Claim 23 words

The process according to claim 54 , further comprising reacting said lutein-containing extract with said aqueous sulfuric or phosphoric acid at ambient temperature.

Claim 68

Dependent Claim 12 words

The process according to claim 54 , further comprising neutralizing the solution.

Claim 69

Dependent Claim 21 words

The process according to claim 56 , further comprising neutralizing the solution with an aqueous solution of about 5% sodium bicarbonate.

Claim 70

Dependent Claim 18 words

The process according to claim 54 , further comprising partitioning the 3′-epilutein solution with a second organic solvent.

Claim 71

Dependent Claim 15 words

The process according to claim 58 , wherein said second organic solvent is methylene dichloride.

Claim 72

Dependent Claim 13 words

The process according to claim 54 , further comprising washing the 3′-epilutein solution.

Claim 73

Dependent Claim 15 words

The process according to claim 54 , further comprising washing the 3′-epilutein solution with water.

Claim 74

Dependent Claim 16 words

The process according to claim 54 , further comprising drying the 3′-epilutein solution with sodium sulfate.

Claim 75

Dependent Claim 19 words

The process according to claim 54 , further comprising crystallizing the 3′-epilutein by solvent evaporation to obtain 3′-epilutein crystals.

Claim 76

Dependent Claim 16 words

The process according to claim 63 , further comprising purifying the 3′-epilutein crystals by preparative HPLC.

Claim 77

Dependent Claim 20 words

The process according to claim 54 , further comprising reacting an extract containing lutein with about 1 N sulfuric acid.

Claim 78

Dependent Claim 75 words

A process for obtaining 3′-epilutein, comprising: (a) reacting a lutein-containing extract with an aqueous solution of sulfuric acid, in the presence of tetrahydrofuran, to obtain a solution of 3′-epilutein; (b) neutralizing the solution; (c) partitioning the 3′-epilutein solution with dichloromethane; (d) washing the 3′-epilutein solution with water; (e) drying the 3′-epilutein solution with anhydrous sodium sulfate; (f) crystallizing the 3′-epilutein by evaporation, to obtain 3′-epilutein crystals; and (g) purifying the 3′-epilutein crystals by preparative HPLC.

Claim 79

Dependent Claim 75 words

A process for obtaining 3′-epilutein, comprising: (a) reacting a lutein-containing extract with an aqueous solution of sulfuric acid, in the presence of tetrahydrofuran, to obtain a solution of 3′-epilutein; (b) neutralizing the solution; (c) partitioning the 3′-epilutein solution with dichloromethane; (d) washing the 3′-epilutein solution with water; (e) drying the 3′-epilutein solution with anhydrous sodium sulfate; (f) crystallizing the 3′-epilutein by evaporation, to obtain 3′-epilutein crystals; and (g) purifying the 3′-epilutein crystals by preparative HPLC.

Claim 80

Dependent Claim 24 words

The process according to claim 66 , wherein the lutein containing extract is reacted with an aqueous solution of sulfuric acid at ambient temperature.

Claim 81

Dependent Claim 20 words

The process according to claim 66 , further comprising reacting the lutein containing extract with about 1 N sulfuric acid.

Claim 82

Dependent Claim 49 words

A process for obtaining optically active (3R,3′R)-zeaxanthin, comprising: (a) reacting a lutein-containing extract with an aqueous solution of an inorganic or organic acid in the presence of tetrahydrofuran, to obtain a 3′-epilutein solution; (b) neutralizing the solution; and (c) reacting 3′-epilutein crystals, with an aqueous alkali metal hydroxide solution.

Claim 83

Dependent Claim 49 words

A process for obtaining optically active (3R,3′R)-zeaxanthin, comprising: (a) reacting a lutein-containing extract with an aqueous solution of an inorganic or organic acid in the presence of tetrahydrofuran, to obtain a 3′-epilutein solution; (b) neutralizing the solution; and (c) reacting 3′-epilutein crystals, with an aqueous alkali metal hydroxide solution.

Claim 84

Dependent Claim 34 words

A process for obtaining optically active (3R,3′R)-zeaxanthin, according to claim 69 , wherein the inorganic or organic acid is selected from the group consisting of sulfuric acid, phosphoric acid, hydrochloric acid and trifluoroacetic acid.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	2007-11-16	2008-05-17	2008-11-16	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	2011-11-16	2012-05-17	2012-11-16	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	2015-11-16	2016-05-17	2016-11-16	$7700.00	Window Closed / Lapsed

Process for making a (3R,3′R)-zeaxanthin precursor

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