Method for synthesis of 9-cis-beta-carotene and formulations thereof

Patent metadata

Field	Value
Publication number	US-11142496-B2
Application number	US-201716303604-A
Country	US
Kind code	B2
Filing date	May 21, 2017
Priority date	May 25, 2016
Publication date	Oct 12, 2021
Grant date	Oct 12, 2021

Abstract

The present invention relates to a method for total chemical synthesis of 9-cis-β-carotene (9CBC), and further provides stable formulations thereof.

First claim

The invention claimed is:

1. A method for the synthesis of 9-cis β-carotene (9CBC) or a derivative thereof, said method comprising:
(i) reducing 4-methyl-6-(2,6,6-trimethylcyclohex-1-en-1-yl)-5,6-dihydro-2H-pyran-2-one, herein identified compound 3, and opening the ring of the lactol obtained with complete retention of the double bond configuration, to thereby obtain (2Z,4E)-3-methyl-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-2,4-dienal, herein identified compound 5;
(ii) subjecting the (2Z,4E)-3-methyl-5-(2,6,6-trimethylcyclohex-1-en-1-yl)penta-2,4-dienal to Horner-Emmons reaction to obtain a 9-cis retinyl ester, herein identified compound 6;
(iii) reducing the 9-cis retinyl ester to obtain 9-cis retinol, herein identified compound 7; and
(iv) converting the 9-cis retinol to its triphenylphosphonium salt, herein identified compound 8, and subjecting said triphenylphosphonium salt to Wittig reaction with a compound of the formula A:

wherein R 2 is H or methyl; X is

 optionally substituted with one or more methyl groups; n is an integer of 0-16; and the asterisk represents the point of attachment to the cyclohexene ring, in the presence of a strong base, to thereby obtain said 9CBC or derivative thereof.

2. The method of claim 1 , wherein:
(i) the reduction in step (i) is carried out with diisobutylaluminum hydride (DIBAL-H); or
(ii) opening the ring of the lactol in step (i) is carried out in the presence of a strong acid; or
(iii) the Horner-Emmons reaction in step (ii) is carried out with triethyl 3-methyl-4-phosphono-2-butenoate to obtain 9-cis retinyl ethyl ester; or
(iv) converting the 9-cis retinol to its triphenylphosphonium salt in step (iv) is carried out with triphenylphosphine; or
(v) said compound of the formula A is all-trans retinal, to obtain 9CBC.

3. The method of claim 1 , wherein said 4-methyl-6-(2,6,6-trimethylcyclohex-1-en-1-yl)-5,6-dihydro-2H-pyran-2-one is synthesized by reacting β-cyclocitral, herein identified compound 1, with a compound of the formula B:

wherein R 1 is (C 1 -C 8 )alkyl or (C 6 -C 10 )aryl, in the presence of metallic Zn, in a Reformatsky reaction.

4. The method of claim 3 , wherein said β-cyclocitral is reacted with a compound of the formula B wherein R 1 is ethyl.

Assignees

• Univ Ramot

Inventors

• Gazit Ehud
• Buzhansky Ludmila
• Ioffe Michael
• Sayer Alon

Classifications

• C07C2601/16

  the ring being unsaturated · CPC title

• C07C403/02

  having side-chains containing only carbon and hydrogen atoms · CPC title

• C07C67/44

  by oxidation-reduction of aldehydes, e.g. Tishchenko reaction · CPC title

• A61K31/015

  carbocyclic · CPC title

• A61K47/14

  Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters · CPC title