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Methods for the synthesis of astaxanthin

Inactive Publication Date: 2006-04-27
CARDAX PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0023] Use of a chiral catalyst to reduce the diketone starting material may lea

Problems solved by technology

As stated above, the Z conformational change may lead to a higher steric interference between the two parts of the carotenoid molecule, rendering it less stable, more reactive, and more susceptible to reactivity at low oxygen tensions.
Problems related to the use of some carotenoids and structural carotenoid analogs or derivatives include: (1) the complex isomeric mixtures, including non-carotenoid contaminants, provided in natural and synthetic sources leading to costly increases in safety and efficacy tests required by such agencies as the FDA; (2) limited bioavailability upon administration to a subject; and (3) the differential induction of cytochrome P450 enzymes (this family of enzymes exhibits species-specific differences which must be taken into account when extrapolating animal work to human studies).

Method used

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  • Methods for the synthesis of astaxanthin
  • Methods for the synthesis of astaxanthin
  • Methods for the synthesis of astaxanthin

Examples

Experimental program
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Effect test

example 1

Preparation of (R)-4-hydroxyisophorone (R)-116

[0154]

[0155] All solvents were free of O2. And the reactions were done under N2. Benzeneruthenium (II) dimer (19.72 g, 39.42 mmol, 0.4 mol %) and (1R, 2S)-(−)-norephedrine (99%) (24.14 g, 159.67 mmol, 1.62 mol %) were dissolved in a 12 L three-necked flask containing 2-propanol (7.5 L). After stirring the red solution for 45 min at 80° C., the heat was removed. It was transferred to a 50 L three-necked flask containing 2-propanol (28 L). 109 (1500 g, 9.86 mol) and 0.1 M potassium hydroxide in 2-propanol (3945 ml, 0.0.395 mol, 4 mol %) were added. After 3 h (TLC showed the reaction was done), the red solution was filtered through a short silica gel pad and the filtrate was evaporated to dryness to obtain solids (about 1600 g). After five times recrystallization from iPr2O (500 ml×5), 912 g of (R)-116 was obtained. The yield: 60%. 1H NMR (CDCl3, 300 MHz): δ 1.02 (s, 3H), 1.07 (s, 3H), 1.97 (s, 1H), 2.04 (t, J=1.2 Hz, 3H), 2.21 (d, J=16.3 H...

example 2

Preparation of (1R, 4S)-2,6,6-trimethyl-2-cyclohexen-1,4-diol (1R,4S)-118

[0156]

[0157] To a solution of L-Selectride (5674 mL, 1 M in THF, 1.25 equiv), a solution of compound (R)-116 (700 g, 4.54 mol, 1 equiv) in THF (3000 mL) was added dropwise at −78° C. After stirring for 1.5 h, the mixture was sequentially treated with H2O (600 mL), 4N NaOH (1450 mL). After extractions with AcOEt (500 ml×5) and the combined organic phase was dried and concentrated. To the residue was charged 3000 mL of hexanes, then the mixture was filtered. The solid was washed with hexanes (200 mL×3). The solid crude product was purified by flash chromatography using Hexanes / AcOEt (3 / 1) as an eluent. 645 g of compound (1R,4S)-118 was obtained (yield: 91%). Recrystallized from 1000 ml of EtOAc to obtain 504 g (70%) of (1R,4S)-118. 1H NMR (CDCl3, 500 MHz): δ 0.86 (s, 3H), 1.02(s, 3H), 1.45 (dd, J=12.8,9.5 Hz, 1H), 1.67 (ddt, J=12.8, 6.3, 1.1 Hz, 1H), 1.84 (t, J=1.7 Hz, 3H), 3.34 (s, 1H), 4.18 (m, 1H), 5.54 (br s,...

example 3

Preparation of (1R, 4S)-4-tert-Butyidimethylsilyloxy-2,6,6-trimethyl-2-cyclohexen-1-ol (1R, 4S)-120a

[0158]

[0159] A mixture of enantiomerically pure (1R, 4S)-118 (1000 g, 6.40 mol), TBDMSCI (1194 g, 7.68 mol, 1.2 eq) and imidazole (566.37 g, 8.32 mol, 1.3 eq) in DMF (9 L) was stirred at room temperature for 1 hr and 20 min. Water (2 L) was added, aqueous phase was extracted with diethyl ether (2000 ml×3). The combined organic layer was dried over Na2SO4. After concentration, the crude product (1R, 4S)-120a was subjects to next step without further purification.

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Abstract

A method used for synthesizing intermediates for use in the synthesis of carotenoids and carotenoid analogs, and / or carotenoid derivatives. In some embodiments, the invention includes methods for synthesizing optically active intermediates useful for the synthesis of optically active carotenoids. Synthesis of optically active carotenoids, in one embodiment, may be accomplished by forming an optically active dihydroxy ketone intermediate from ketoisopherone. The optically active dihydroxy ketone intermediate may be converted into optically active astaxanthin derivatives.

Description

PRIORTY CLAIM [0001] This application claims priority to U.S. Provisional Patent Application No. 60 / 615,032 entitiled “Methods for Synthesis of Carotenoids, Including Analogs, Derivatives, and Synthetic and Biological Intermediates” filed on Oct. 1, 2004; U.S. Provisional Patent Application No. 60 / 675,957 entitiled “Methods for Synthesis of Carotenoids, Including Analogs, Derivatives, and Synthetic and Biological Intermediates” filed on Apr. 29, 2005; U.S. Provisional Patent Application No. 60 / 691,518 entitiled “Methods for Synthesis of Carotenoids, Including Analogs, Derivatives, and Synthetic and Biological Intermediates” filed on Jun. 17, 2005; U.S. Provisional Patent Application No. 60 / 692,682 entitiled “Methods for Synthesis of Carotenoids, Including Analogs, Derivatives, and Synthetic and Biological Intermediates” filed on Jun. 21, 2005; U.S. Provisional Patent Application No. 60 / 699,653 entitiled “Methods for Synthesis of Carotenoids, Including Analogs, Derivatives, and Synth...

Claims

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Application Information

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IPC IPC(8): C12P23/00C07C45/45C07C29/145C07C33/14C07C45/61C07C45/64C07C45/65C07C45/74C07C49/713C07C49/753C07C401/00C07F7/04
CPCC07B2200/07C07B2200/09C07C29/143C07C45/298C07C45/511C07C45/61C07C45/64C07C45/673C07C45/70C07C45/71C07C47/21C07C49/713C07C49/753C07C403/08C07C403/24C07C2101/16C07D319/06C07F7/188C07F7/1892C07F9/113C07F9/5442C12P23/00C07C49/603C07C33/02C07C35/08C07C35/21C07C2601/16
Inventor LOCKWOOD, SAMUEL F.TANG, PENG CHONADOLSKI, GEOFF T.JACKSON, HENRY L.FANG, ZHIQIANGDU, YISHUYANG, MINGEISS, WILLIAM B.WILLIAMS, RICHARDBURDICK, DAVID C.
Owner CARDAX PHARMA
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