US 11,912,654 B2
Process for stereospecific synthesis of vitamin K2 and its novel intermediates
Dilip Mehta, Mumbai (IN); Mayank Shashtri, Lubbock, TX (US); BNS Raju, Hyderabad (IN); Ashwin Shah, Mumbai (IN); Parin Vora, Mumbai (IN); and Umakant Mahale, Thane (IN)
Assigned to SYNERGIA LIFE SCIENCES PVT. LTD., Mumbai (IN)
Filed by SYNERGIA LIFE SCIENCES PVT. LTD., Mumbai (IN)
Filed on Apr. 29, 2022, as Appl. No. 17/733,687.
Claims priority of application No. 202121040002 (IN), filed on Sep. 3, 2021.
Prior Publication US 2023/0093176 A1, Mar. 23, 2023
Int. Cl. C07C 46/06 (2006.01); C07C 317/14 (2006.01)
CPC C07C 46/06 (2013.01) [C07C 317/14 (2013.01)] 3 Claims
 
1. A process for the synthesis of Vitamin K2 of Formula I,

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wherein n is 3 or 4, and the process comprises:
(a) adding menadione/cyclopentadiene adduct to t-butanol:toluene mixture that is in the range of 10:90 to 20:80 v/v, at a temperature ranging from 20° C. to 40° C.;
(b) dissolving potassium t-butoxide in reaction mixture of (a);
(c) adding prenyl chloride to the reaction mixture of (b) and stirring the mixture for an hour;
(d) quenching the reaction mixture of (c) in distilled water;
(e) adjusting the pH of the reaction mixture of (d) to 5-6 and isolating the non-aqueous layer;
(f) washing the non-aqueous layer of (e) with water and brine, and drying the washed non-aqueous layer over sodium sulfate;
(g) recovering the product Vitamin K2-3 from the non-aqueous layer of (f) by reflux and distilling off the solvent under vacuum, wherein Vitamin K2-3 has the chemical structure:

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(h) converting the Vitamin K2-3 obtained in (g) into its dibenzyl ether having the chemical structure:

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wherein Ph is a phenyl group;
(i) converting the dibenzyl ether of Vitamin K2-3 obtained in (h) into its bromohydrin derivative in the presence of N-bromo succinamide and tetrahydrofuran, wherein the bromohydrin derivative of dibenzyl ether of vitamin K2-3 has the chemical structure:

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(j) converting the bromohydrin derivative of dibenzyl ether of vitamin K2-3 obtain in (i) to its epoxide in the presence of potassium carbonate and methanol, wherein the epoxide derivative of dibenzyl ether of vitamin K2-3 has the chemical structure:

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(k) converting the epoxide derivative of dibenzyl ether of vitamin K2-3 obtained in (j) into Vitamin K2-3 alcohol in the presence of aluminium isopropoxide in toluene, wherein the Vitamin K2-3 alcohol has the chemical structure:

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(l) reacting the Vitamin K2-3 alcohol obtained in (k) with thionyl chloride in hexane to form Vitamin K2-3 chloride having the chemical structure:

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(m) reacting the Vitamin K2-3 chloride obtained in (l) with a prenyl phenyl sulphonate to obtain a compound, wherein the prenyl phenyl sulphonate is selected from:

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(n) desulphonating, deprotecting, and oxidizing the compound obtained in (m) to obtain Vitamin K2 of Formula I.