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US 2026/0042741 A1Published application
Methods for preparing (-)-epicatechin
AssigneeMars, Incorporated
InventorGodwin Pais
Life of this patent
Estimating the term…
Abstract
Methods steps for the synthesis of (−)-epicatechin are provided herein. The synthetic methods are provided in two phases: (1) synthesis of epoxide intermediates and (2) synthesis of (−)-epicatechin.
Claims18
A method for preparing (−)-epicatechin, the method comprising:
- a) providing a compound of Formula V:
- wherein X is O or S, R3 is Ph, Bn, or CH(CH3)2, and R4 is Ph or H, and further providing a compound of Formula II:
- wherein R1 is MOM or Bn;
- b) coupling the compounds of Formula II and V to form a first intermediate, wherein the first intermediate comprises a secondary alcohol;
- c) protecting the secondary alcohol in the first intermediate to form a second intermediate;
- d) reducing the second intermediate to form a third intermediate, wherein the third intermediate comprises a primary alcohol;
- e) removing the Bn group of Formula V to form a fourth intermediate;
- f) selectively forming a sulfonate ester from the primary alcohol of the fourth intermediate to form a fifth intermediate;
- g) epoxidizing the fifth intermediate to form a sixth intermediate;
- h) alkylating the sixth intermediate to form a seventh intermediate, wherein the seventh intermediate comprises an alcohol;
- i) protecting the alcohol of the seventh intermediate to form an eighth intermediate;
- j) cyclizing the eighth intermediate to form a ninth intermediate;
- k) deprotecting the ninth intermediate to form a tenth intermediate;
- l) deprotecting the tenth intermediate to form (−)-epicatechin.
11 more elements
A method of preparing (−)-epicatechin, the method comprising:
- a) providing (S)-2-(benzyloxy)-1-(4-phenyl-2-thioxooxazolidin-3-yl)ethan-1-one and 3,4-bis(methoxymethoxy)benzaldehyde;
- b) adding titanium tetrachloride to produce (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-hydroxy-1-((S)-4-phenyl-2-thioxooxazolidin-3-yl)propan-1-one;
- c) protecting (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-hydroxy-1-((S)-4-phenyl-2-thioxooxazolidin-3-yl)propan-1-one with TBSCl to produce (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-1-((S)-4-phenyl-2-thioxooxazolidin-3-yl)propan-1-one;
- d) reducing (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-1-((S)-4-phenyl-2-thioxooxazolidin-3-yl)propan-1-one with LiBH4 to produce (2R,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propan-1-ol;
- e) deprotecting (2R,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propan-1-ol with Pd/C under H2 gas to produce (2R,3R)-3-(3,4-Bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propane-1,2-diol;
- f) tosylating (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propane-1,2-diol with tosylic acid to produce (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl 4-methylbenzenesulfonate;
- g) epoxidizing (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl 4-methylbenzenesulfonate using potassium carbonate in methanol to produce ((R)-(3,4-Bis(methoxymethoxy)phenyl)((R)-oxiran-2-yl)methoxy)(tert-butyl)dimethylsilane;
- h) alkylating ((R)-(3,4-bis(methoxymethoxy)phenyl)((R)-oxiran-2-yl)methoxy)(tert-butyl)dimethylsilane with (((5-fluoro-1,3-phenylene)bis(oxy))bis(methylene))dibenzene using n-butyl lithium to produce (1R,2R)-3-(2,4-Bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol;
- i) protecting (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol with MOMCl to produce (5R,6R)-5-{[2,4-bis(benzyloxy)-6-fluorophenyl]methyl}-6-[3,4-bis(methoxymethoxy)phenyl]-8,8,9,9-tetramethyl-2,4,7-trioxa-8-siladecane;
- k) deprotecting (5R,6R)-5-{[2,4-bis(benzyloxy)-6-fluorophenyl]methyl}-6-[3,4-bis(methoxymethoxy)phenyl]-8,8,9,9-tetramethyl-2,4,7-trioxa-8-siladecane with TBAF to product (1R,2R)-3-(2,4-Bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-2-(methoxymethoxy)propan-1-ol;
- l) cyclizing (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-2-(methoxymethoxy)propan-1-ol using potassium hydride to product (2R,3R)-5,7-Bis(benzyloxy)-2-(3,4-bis(methoxymethoxy)phenyl)-3-(methoxymethoxy)chromane;
- m) deprotecting (2R,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(methoxymethoxy)phenyl)-3-(methoxymethoxy)chromane with HCl to produce 4-((2R,3R)-5,7-Bis(benzyloxy)-3-hydroxychroman-2-yl)benzene-1,2-diol;
- and
- n) deprotecting 4-((2R,3R)-5,7-bis(benzyloxy)-3-hydroxychroman-2-yl)benzene-1,2-diol with Pd/C under H2 to give (−)-epicatechin.
11 more elements
Dependencies are inferred from the claim text.