US6911564B2 — Method for production of rare carotenoids from co…

Claim 1

Independent Claim 53 words

A process for converting (3R,3′R,6′R)-lutein to a mixture of anhydroluteins I, II, III, (3R,6′R)-α-cryptoxanthin and (3R)-β-cryptoxanthin, comprising reacting (3R,3′R,6′R)-lutein in the presence of a strong acid and a hydride ion donor in a chlorinated solvent or toluene under an inert atmosphere to give a mixture of anhydroluteins I, II, III, (3R,6′R)-α-cryptoxanthin and (3R)-β-cryptoxanthin.

Claim 2

Dependent Claim 53 words

A process for converting (3R,3′R,6′R)-lutein to a mixture of anhydroluteins I, II, III, (3R,6′R)-α-cryptoxanthin and (3R)-β-cryptoxanthin, comprising reacting (3R,3′R,6′R)-lutein in the presence of a strong acid and a hydride ion donor in a chlorinated solvent or toluene under an inert atmosphere to give a mixture of anhydroluteins I, II, III, (3R,6′R)-α-cryptoxanthin and (3R)-β-cryptoxanthin.

Claim 3

Dependent Claim 13 words

The method of claim 1 , wherein said (3R,3′R,6′R)-lutein comprises 85% total carotenoids.

Claim 4

Dependent Claim 15 words

The method of claim 1 , wherein said (3R,3′R,6′R)-lutein contains greater than 97% total carotenoids.

Claim 5

Dependent Claim 13 words

The method of claim 1 , wherein said (3R,3′R,6′R)-lutein comprises about 5-7% (3R,3′R)-zeaxanthin.

Claim 6

Dependent Claim 14 words

The method of claim 1 , wherein the strong acid is trifluoroacetic acid (TFA).

Claim 7

Dependent Claim 16 words

The method of claim 1 , wherein the hydride ion donor is triethylsilane (Et 3 SiH).

Claim 8

Dependent Claim 14 words

The method of claim 1 , wherein the chlorinated solvent is dichloromethane or 1,2-dichloroethane.

Claim 9

Dependent Claim 47 words

The method of claim 1 , wherein one mole equivalent of (3R,3′R,6′R)-lutein, containing about 5-7% (3R,3′R)-zeaxanthin in a chlorinated solvent is stirred with about 2-3 equivalent of Et 3 SiH and about 3.0-3.5 equivalent of TEA at ambient temperature for about 5-10 hours under an inert atmosphere.

Claim 10

Dependent Claim 46 words

The method of claim 8 , wherein the mixture of anhydroluteins I, II, III, (3R,6′R)-α-cryptoxanthin, and (3R)-β-cryptoxanthin is isolated by neutralizing the strong acid with a base and displacing the chlorinated solvent with a higher boiling alcohol by distillation until carotenoids crystallize from the aqueous alcohol.

Claim 11

Dependent Claim 26 words

The method of claim 9 , farther comprising collecting the crystalline carotenoids, washing with acetone or alcohol, and drying under high vacuum at about 40-60° C.

Claim 12

Dependent Claim 47 words

The method of claim 10 , wherein the crystalline carotenoids are washed at ambient temperature or 0° C. to −20° C. with a C 5 -C 7 -hydrocarbon solvent or petroleum ether to remove the Z(cis)-carotenoids and give a crystalline mixture of all-E(trans)-carotenoids enriched in recovered (3R,3′R)-zeaxanthin.

Claim 13

Dependent Claim 58 words

The method of claim 10 , wherein the crystalline carotenoids are subjected to column chromatography employing a hydrocarbon solvent in combination with acetone or methyl ethyl ketone, ethyl acetate, a C 4 -C 6 -ether or mixtures thereof to obtain a pure mixture of (3R,6′R)-α-cryptoxanthin and (3R)-β-cryptoxanthin, a separate mixture of anhydroluteins I, II, III, and pure (3R,3′R)-zeaxanthin.

Claim 14

Dependent Claim 34 words

The method of claim 12 , wherein the hydrocarbon solvent is pentane, hexane, heptane, or petroleum ether and C 4 -C 6 -ethers are diethyl ether, diisopropyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, or THF.

Claim 15

Dependent Claim 78 words

The method of claim 1 , wherein (a) (3R,3′R,6′R)-lutein (85% total carotenoids) or (b) purified lutein (greater than 97% total carotenoids) containing about 5-7% (3R,3′R)-zeaxanthin or mixtures of (a) and (b) is first converted to a mixture of anhydroluteins and this product is then allowed to react with a strong acid and a hydride ion donor in a chlorinated solvent or toluene under an inert atmosphere to give a mixture of unreacted anhydroluteins, (3R,6′R)-α-cryptoxanthin, (3R)-β-cryptoxanthin and recovered (3R,3′R)-zeaxanthin.

Claim 16

Dependent Claim 72 words

A process for converting (a) (3R,3′R,6′R)-lutein (85% total carotenoids) or (b) purified lutein (greater than 97% total carotenoids) containing 5-7% (3R,3′R)-zeaxanthin or mixtures of (a) and (b) to a mixture of anhydroluteins I, I, III, comprising reacting (3R,3′R,6′R)-lutein with an acid selected from the group consisting of TFA and boron trifluoride, or an aqueous mineral acid in a solvent at ambient temperature to give a mixture of anhydroluteins and the recovered (3R,3′R)-zeaxanthin.

Claim 17

Dependent Claim 72 words

A process for converting (a) (3R,3′R,6′R)-lutein (85% total carotenoids) or (b) purified lutein (greater than 97% total carotenoids) containing 5-7% (3R,3′R)-zeaxanthin or mixtures of (a) and (b) to a mixture of anhydroluteins I, I, III, comprising reacting (3R,3′R,6′R)-lutein with an acid selected from the group consisting of TFA and boron trifluoride, or an aqueous mineral acid in a solvent at ambient temperature to give a mixture of anhydroluteins and the recovered (3R,3′R)-zeaxanthin.

Claim 18

Dependent Claim 39 words

The process of claim 15 , wherein said aqueous mineral acid is aqueous sulfuric acid, aqueous hydrochloric acid or aqueous phosphoric acid; said solvent is dichloromethane, 1,2-dichloroethane, tetrahydrofuran, tert-butyl methyl ether, toluene, or a C 1 -C 4 alcohol.

Claim 19

Dependent Claim 12 words

The method of claim 14 , wherein the strong acid is TFA.

Claim 20

Dependent Claim 15 words

The method of claim 14 , wherein the hydride ion donor is Et 3 SiH.

Claim 21

Dependent Claim 14 words

The method of claim 14 , wherein the solvent is dichloromethane, 1,2-dichloroethane or toluene.

Claim 22

Dependent Claim 64 words

The method of claim 14 , wherein one mole equivalent of anhydroluteins I, II, and III, containing 6-10% (3R,3′R)-zeaxanthin in a chlorinated solvent or toluene is stirred with about 2.8-3 equivalent of Et 3 SiH and about 3.8-12 equivalent of TFA at ambient temperature for about 2.5-6 hours under an inert atmosphere to give a mixture of unreacted anhydroluteins, (3R,6′R)-α-cryptoxanthin, (3R)-β-cryptoxanthin and recovered (3R,3′R)-zeaxanthin.

Claim 23

Dependent Claim 48 words

The method of claim 20 , wherein the product mixture is worked up by neutralizing the acid with an aqueous or an organic base and displacing the chlorinated solvent or toluene with a higher boiling alcohol by distillation under reduced pressure until carotenoids crystallize from the aqueous alcohol.

Claim 24

Dependent Claim 26 words

The method of claim 21 , wherein the crystalline carotenoids are collected and washed with acetone or alcohol and dried under high vacuum at 40-60° C.

Claim 25

Dependent Claim 47 words

The method of claim 21 , wherein the crystalline product is washed at ambient temperature or 0° C. to −20° C. with a C 5 -C 7 -hydrocarbon solvent or petroleum ether to remove the Z(cis)-carotenoids and yield a crystalline mixture of all-E(trans)-carotenoids enriched in recovered (3R,3′R)-zeaxanthin.

Claim 26

Dependent Claim 56 words

A process for converting (a) (3R,3′R,6′R)-lutein (85% total carotenoids) or (b) purified lutein (greater than 97% total carotenoids) containing 5-7% (3R,3′R)-zeaxanthin or mixtures thereof to (3R,6′R)-α-cryptoxanthin, comprising reacting (3R,3′R,6′R)-lutein with a zinc halide and sodium cyanoborohydride in a chlorinated solvent or an ether at ambient temperature under an inert atmosphere to give (3R,6′R)-α-cryptoxanthin and recovered (3R,3′R)-zeaxanthin.

Claim 27

Dependent Claim 56 words

A process for converting (a) (3R,3′R,6′R)-lutein (85% total carotenoids) or (b) purified lutein (greater than 97% total carotenoids) containing 5-7% (3R,3′R)-zeaxanthin or mixtures thereof to (3R,6′R)-α-cryptoxanthin, comprising reacting (3R,3′R,6′R)-lutein with a zinc halide and sodium cyanoborohydride in a chlorinated solvent or an ether at ambient temperature under an inert atmosphere to give (3R,6′R)-α-cryptoxanthin and recovered (3R,3′R)-zeaxanthin.

Claim 28

Dependent Claim 22 words

The method of claim 24 , wherein the chlorinated solvent is dichloromethane or 1,2-dichloroethane and the ether is tert-butyl methyl ether (TBME).

Claim 29

Dependent Claim 55 words

The method of claim 24 , wherein one mole equivalent of (3R,3′R,6′R)-lutein containing 5-7% (3R,3′R)-zeaxanthin in a chlorinated solvent or TBME is stirred with 7.5 equivalent of NaCNBH 3 and 4.0 equivalent of zinc iodide or zinc bromide at ambient temperature for about 1-5 hours under an inert atmosphere to give (3R,6′R)-α-cryptoxanthin and recovered (3R,3′R)-zeaxanthin.

Claim 30

Dependent Claim 42 words

The method of claim 26 , wherein the product is worked up by filtering the crude mixture of (3R,6′R)-α-cryptoxanthin and (3R,3′R)-zeaxanthin and evaporating the chlorinated solvent or TBME under reduced pressure by displacement with a higher boiling alcohol until carotenoids crystallize out.

Claim 31

Dependent Claim 23 words

The method of claim 27 , wherein the crystallized carotenoids are collected by centrifugation or filtration and are washed with alcohol or acetone.

Claim 32

Dependent Claim 26 words

The method of claim 28 , further comprising drying the crystals under high vacuum at 60° C. to obtain a mixture of recovered (3R,3′R)-zeaxanthin and (3R,6′R)-α-cryptoxanthin.

Claim 33

Dependent Claim 64 words

A process for converting (a) (3R,3′R,6′R)-lutein (85% total carotenoids) or (b) purified lutein (greater than 97% total carotenoids) containing 5-7% (3R,3′R)-zeaxanthin or mixtures thereof to (3R,6′R)-α-cryptoxanthin, comprising reacting (3R,3′R,6′R)-lutein with borane-trimethylamine or borane-dimethylamine complex in the presence of aluminum chloride in a first solvent at ambient temperature under an inert atmosphere to give (3R,6′R)-α-cryptoxanthin and recovered (3R,3′R)-zeaxanthin, wherein said first solvent is an ether.

Claim 34

Dependent Claim 64 words

A process for converting (a) (3R,3′R,6′R)-lutein (85% total carotenoids) or (b) purified lutein (greater than 97% total carotenoids) containing 5-7% (3R,3′R)-zeaxanthin or mixtures thereof to (3R,6′R)-α-cryptoxanthin, comprising reacting (3R,3′R,6′R)-lutein with borane-trimethylamine or borane-dimethylamine complex in the presence of aluminum chloride in a first solvent at ambient temperature under an inert atmosphere to give (3R,6′R)-α-cryptoxanthin and recovered (3R,3′R)-zeaxanthin, wherein said first solvent is an ether.

Claim 35

Dependent Claim 13 words

The method of claim 30 , wherein said ether is tetrahydrofuran or 1,2-dimethoxyethane.

Claim 36

Dependent Claim 58 words

The method of claim 30 , wherein one mole equivalent of (3R,3′R,6′R)-lutein containing 5-7% (3R,3′R)-zeaxanthin in an ether is stirred with about 6 mole equivalent of borane-trimethylamine or borane-dimethylamine complex in the presence of about 2.3 mole equivalent of aluminum chloride at ambient temperature for about 1-2 hours under an inert atmosphere to give (3R,6′R)-α-cryptoxanthin and recovered (3R,3′R)-zeaxanthin.

Claim 37

Dependent Claim 40 words

The method of claim 32 , wherein the (3R,6′R)-α-cryptoxanthin and recovered (3R,3′R)-zeaxanthin is isolated by partitioning into an aqueous solution of sodium bicarbonate, separating resulting organic layer, and evaporating the solvent until a mixture of (3R,6′R)-α-cryptoxanthin and unreacted (3R,3′R)-zeaxanthin crystallizes.

Claim 38

Dependent Claim 44 words

The method of claim 33 , wherein the first solvent is THF and a second solvent selected from the group consisting of ethytlacetate and a C 4 -C 6 -ether is added together with the aqueous sodium bicarbonate before the organic layer is separated.

Claim 39

Dependent Claim 24 words

The method of claim 33 , wherein the crystallized mixture is collected by centrifugation or filtration and is washed with an alcohol or acetone.

Claim 40

Dependent Claim 28 words

The method of claim 35 , further comprising drying the washed crystallized mixture under high vacuum at 60° C. to obtain a mixture of recovered (3R,3′R)-zeaxanthin and (3R,6′R)-α-cryptoxanthin.

Claim 41

Dependent Claim 72 words

A process for converting (a) (3R,3′R,6′R)-lutein (85% total carotenoids) or (b) purified lutein (greater than 97% total carotenoids) containing 5-7% (3R,3′R)-zeaxanthin or a mixture of (a) and (b) to a mixture of anhydrolutein I and (3R,6′R)-α-cryptoxanthin, comprising reacting (3R,3′R,6′R)-lutein with an ether solution of lithium perchlorate in the presence of a hydride ion donor at ambient temperature under an inert atmosphere to give a mixture of anhydrolutein I, (3R,6′R)-α-cryptoxanthin, and recovered (3R,3′R)-zeaxanthin.

Claim 42

Dependent Claim 72 words

A process for converting (a) (3R,3′R,6′R)-lutein (85% total carotenoids) or (b) purified lutein (greater than 97% total carotenoids) containing 5-7% (3R,3′R)-zeaxanthin or a mixture of (a) and (b) to a mixture of anhydrolutein I and (3R,6′R)-α-cryptoxanthin, comprising reacting (3R,3′R,6′R)-lutein with an ether solution of lithium perchlorate in the presence of a hydride ion donor at ambient temperature under an inert atmosphere to give a mixture of anhydrolutein I, (3R,6′R)-α-cryptoxanthin, and recovered (3R,3′R)-zeaxanthin.

Claim 43

Dependent Claim 15 words

The method of claim 37 , wherein the hydride ion donor is Et 3 SiH.

Claim 44

Dependent Claim 16 words

The method of claim 37 , wherein the ether is ethyl ether, isopropyl ether or TBME.

Claim 45

Independent Claim 29 words

A method for converting (3R,3′R,6′R)-lutein to a mixture of anhydrolutein I and (3R,6′R)-α-cryptoxanthin, comprising reacting said (3R,3′R,6′R)-lutein with lithium perchlorate and a hydride ion donor in an organic solvent.

Claim 46

Independent Claim 29 words

A method for converting (3R,3′R,6′R)-lutein to a mixture of anhydrolutein I and (3R,6′R)-α-cryptoxanthin, comprising reacting said (3R,3′R,6′R)-lutein with lithium perchlorate and a hydride ion donor in an organic solvent.

Claim 47

Independent Claim 63 words

A method for converting (3R,3′R,6′R)-lutein to a mixture of anhydrolutein I and (3R,6′R)-α-cryptoxanthin, comprising reacting one mole equivalent of lutein, containing 5-7% (3R,3′R)-zeaxanthin in diethyl ether with 167 mole equivalent of lithium perchlorate in the presence of 3.5-4.0 mole equivalent of Et 3 SiH at ambient temperature under an inert atmosphere overnight to give a mixture of anhydrolutein I, (3R,6′R)-α-cryptoxanthin, and recovered (3R,3′R)-zeaxanthin.

Claim 48

Independent Claim 63 words

A method for converting (3R,3′R,6′R)-lutein to a mixture of anhydrolutein I and (3R,6′R)-α-cryptoxanthin, comprising reacting one mole equivalent of lutein, containing 5-7% (3R,3′R)-zeaxanthin in diethyl ether with 167 mole equivalent of lithium perchlorate in the presence of 3.5-4.0 mole equivalent of Et 3 SiH at ambient temperature under an inert atmosphere overnight to give a mixture of anhydrolutein I, (3R,6′R)-α-cryptoxanthin, and recovered (3R,3′R)-zeaxanthin.

Claim 49

Dependent Claim 44 words

The method of claim 41 , wherein the product mixture of anhydrolutein I, (3R,6′R)-α-cryptoxanthin and recovered (3R,3′R)-zeaxanthin is isolated by addition of water, separating the organic layer, and displacing the ether with a higher boiling hydrocarbon or alcohol by distillation until carotenoids crystallize out.

Claim 50

Dependent Claim 16 words

The method of claim 42 , wherein the crystals are removed by filtration or by centrifugation.

Claim 51

Dependent Claim 29 words

The method of claim 43 , fierier comprising drying the crystalline carotenoids under high vacuum at 60° C. to give a mixture of anhydrolutein I, (3R,6′R)-α-cryptoxanthin, and recovered (3R,3′R)-zeaxanthin.

Claim 52

Dependent Claim 51 words

A process for converting (a) (3R,3′R,6′R)-lutein (85% total carotenoids) or i(b) purified lutein (greater than 97% total carotenoids) containing 5-7% (3R,3′R)-zeaxanthin or mixtures thereof to (3R,6′R)-α-cryptoxanthin, comprising reacting (3R,3′R,6′R)-lutein with zinc bromide or iodide and sodium (trifluoroacetoxy)borohydride in a chlorinated solvent under an inert atmosphere to give (3R,6′R)-α-cryptoxanthin and recovered (3R,3′R)-zeaxanthin.

Claim 53

Dependent Claim 51 words

A process for converting (a) (3R,3′R,6′R)-lutein (85% total carotenoids) or i(b) purified lutein (greater than 97% total carotenoids) containing 5-7% (3R,3′R)-zeaxanthin or mixtures thereof to (3R,6′R)-α-cryptoxanthin, comprising reacting (3R,3′R,6′R)-lutein with zinc bromide or iodide and sodium (trifluoroacetoxy)borohydride in a chlorinated solvent under an inert atmosphere to give (3R,6′R)-α-cryptoxanthin and recovered (3R,3′R)-zeaxanthin.

Claim 54

Dependent Claim 14 words

The method of claim 45 , wherein the chlorinated solvent is dichloromethane or 1,2-dichloroethane.

Claim 55

Dependent Claim 16 words

The method of claim 45 , wherein the reaction is carried out at about 0-5° C.

Claim 56

Dependent Claim 40 words

The method of claim 45 , wherein about 1.3 mole equivalents of zinc bromide or iodide, and about 4 mole equivalents of sodium (trifluoroacetoxy)-borohydride are reacted at 0° C. for up to about 5 hours to give a crude product.

Claim 57

Dependent Claim 28 words

The method of claim 48 , wherein an aqueous solution of sodium bicarbonate is added to the crude product, the resulting organic layer is separated and then dried.

Claim 58

Dependent Claim 24 words

The method of claim 49 , wherein the dried organic layer is evaporated by gradual displacement with a higher boiling alcohol until (3R,6′R)-α-cryptoxanthin crystallizes.

Claim 59

Dependent Claim 22 words

The method of claim 50 , wherein the crystallized (3R,6′R)-α-cryptoxanthin is collected and the crystals are washed with an alcohol or acetone.

Claim 60

Dependent Claim 14 words

The method of claim 51 , wherein the washed crystals are dried under vacuum.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	2008-06-27	2008-12-27	2009-06-28	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	2012-06-27	2012-12-27	2013-06-28	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	2016-06-27	2016-12-27	2017-06-28	$7700.00	Window Closed / Lapsed

Method for production of rare carotenoids from commercially available lutein

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