Process for the synthesis of calebin-a and its intermediates

Patent metadata

Field	Value
Publication number	US-12240808-B2
Application number	US-202217825689-A
Country	US
Kind code	B2
Filing date	May 26, 2022
Priority date	May 28, 2021
Publication date	Mar 4, 2025
Grant date	Mar 4, 2025

Abstract

The invention discloses novel intermediates in the synthesis of Calebin A represented by formula 3. The invention also covers processes for the synthesis of Calebin-A and its analogs using compounds of formula 3.

First claim

We claim:

1. A compound of general formula 3 represented below

wherein X is selected from the group consisting of Cl, Br, and I; and
R is selected from the group consisting of OMe, and H.

2. A process for the preparation of Calebin-A, and its analogs represented by general formula 5, from general formula 3,

comprising:
a) reacting a compound of formula 1 with a compound of formula 2 in the presence of a solvent and sodium bicarbonate or in the presence of potassium iodide, potassium carbonate, and 1,2 dibromoethane to obtain a compound of formula 3

b) reacting a compound of formula 3 with triphenyl phosphine (TPP), in the presence of a solvent under reflux, cooling, and then charging with sodium carbonate followed by a compound of formula 4 or reacting a compound of formula 3 with a compound of formula 4, in the presence of an organo catalyst and methanol to obtain a compound represented by formula 5:

wherein, R is selected from the group consisting of OMe and H; and X is selected from the group consisting of Cl, Br, I, and H.

3. The process as in claim 2 , wherein the solvent from step a) is selected from the group consisting of N, N-dimethyl formamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, acetone, acetonitrile, tetrahydrofuran and dioxane.

4. The process as in claim 2 , wherein the solvent from step b) is selected from the group consisting of acetonitrile, tetrahydrofuran, 1,4-dioxane, diisopropyl methyl ether, dimethoxy ethane, cyclopentyl methyl ether, 2-methyl tetrahydrofuran, methyl tert-butyl ether, methanol, and ethanol.

5. The process as in claim 2 , wherein the organo catalyst is selected from the group consisting of L-proline, 4-hydroxy L-proline, L-piperidine-2-carboxylic acid, L-azetidine-2-carboxylic acid, S-(−)-indoline-2-carboxylic acid, and L-4-thiazolidinecarboxylic acid.

6. A process for the preparation of Calebin-A, and its analogs represented by general formula 5,

wherein,
R is selected from group consisting of OMe and H;
comprising the steps of
a) mixing hydroxy acetone represented by formula 6 with pyridine in a reaction flask containing dichloromethane and cooling to 0-5° C.;
b) adding acetyl chloride to the reaction mixture slowly at a temperature of 0-5° C. and then stirring at room temperature for 5 hours;
c) diluting the reaction mass with water and washing with brine;
d) separating the organic layer to obtain a compound of formula 7,
e) charging compound of formula 7 from step d) into a reaction flask containing a 1 : 1 (v/v) ethanol:water mixture, calcium hydroxide, and a compound of formula 4;
f) heating the reaction mixture to 50° C. for 15 h and cooling the reaction mass after completion of reaction to produce a solid, followed by filtering the resultant solid;
g) washing the resultant solid of step f) with an ethanol:water mixture, concentrating the reaction mixture and drying under vacuum to yield Calebin A or its analogs as represented by general formula 5.

Assignees

• Majeed Muhammed
• Nagabhushanam Kalyanam
• Muthukaman Nagarajan
• Naidu Pentakota Paradesi

Inventors

• Majeed Muhammed
• Nagabhushanam Kalyanam
• Muthukaman Nagarajan
• Naidu Pentakota Paradesi

Classifications

• C07C67/11 Primary

  being mineral ester groups · CPC title

• C07C69/734

  Ethers · CPC title

• C07C69/736

  the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07C67/293

  by isomerisation; by change of size of the carbon skeleton · CPC title

• C07C2601/16

  the ring being unsaturated · CPC title