Process for producing (R)-3-hydroxybutyl (R)-3-hydroxybutyrate
Inventors
Clarke, Kieran • Veech, Richard Lewis • King, M. Todd
Assignees
Oxford University Innovation Ltd • US Department of Health and Human Services
Publication Number
US-11566268-B2
Publication Date
2023-01-31
Expiration Date
2034-03-14
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Abstract
Embodiments of the present invention are directed to processes for the production of (R)-3-hydroxybutyl (R)-3-hydroxybyrate. Poly (R)-3-hydroxybyrate is transesterified with an alcohol, to form a first ester portion and a second ester portion. The first ester portion is reduced to the diol to form a diol portion and the diol portion is reacted with the second ester portion to produce (R)-3-hydroxybutyl (R)-3-hydroxybyrate.
Core Innovation
The invention relates to a process for producing (R)-3-hydroxybutyl (R)-3-hydroxybutyrate from a single starting material feedstock of poly-(R)-3-hydroxybutyrate. The process involves transesterifying poly-(R)-3-hydroxybutyrate with an alcohol under transesterification conditions to produce an ester of (R)-3-hydroxybutyrate and the alcohol. Then, the product is separated into two portions, and the first portion is reduced to (R)-1,3-butanediol. Finally, the (R)-1,3-butanediol is reacted with the second portion of the ester to produce (R)-3-hydroxybutyl (R)-3-hydroxybutyrate.
The problem being solved is improving the industrial-scale production of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, which is useful as a precursor to ketone bodies with clinical benefits. Existing methods for producing this stereoisomer from poly-(R)-3-hydroxybutyrate or other starting materials are complex, involve many steps, have low yields, produce impure products, and are not commercially practical or cost-effective on a large scale.
This invention addresses these problems by using a transesterification process that divides the starting material into two streams. The first stream is reduced to form a diol intermediate, and then reacts with the second stream to produce the desired (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. The process preferably uses poly-(R)-3-hydroxybutyrate derived from fermentation of corn starch or sugar cane, and uses ethanol as the transesterification alcohol when the product is intended for consumption.
Claims Coverage
The patent includes one independent claim focusing on a process with three main steps for producing (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate from poly-(R)-3-hydroxybutyrate.
Transesterification of poly-(R)-3-hydroxybutyrate with an alcohol
The process involves contacting poly-(R)-3-hydroxybutyrate with an alcohol under transesterification conditions for between 1 and 30 hours to produce an ester of (R)-3-hydroxybutyrate and the alcohol.
Enzymatic reduction of the first portion of the ester to (R)-1,3-butanediol
Separating the product of transesterification into two portions, then reducing the first portion in a solvent using a ketoreductase or alcohol dehydrogenase enzyme to form (R)-1,3-butanediol.
Enzyme-catalyzed transesterification of (R)-1,3-butanediol with the second ester portion
Contacting the (R)-1,3-butanediol with the second portion of the ester under enzyme-catalyzed transesterification conditions for 1 to 20 hours to produce (R)-3-hydroxybutyl-(R)-3-hydroxybutanoate.
The claim covers a process using poly-(R)-3-hydroxybutyrate as the sole feedstock, involving transesterification with an alcohol, enzymatic reduction to (R)-1,3-butanediol, and enzymatic transesterification with the second ester portion to yield enantiomerically enriched (R)-3-hydroxybutyl-(R)-3-hydroxybutanoate.
Stated Advantages
The process enables industrial scale production of enantiomerically enriched (R)-3-hydroxybutyl (R)-3-hydroxybutyrate from relatively low cost, commercially available poly-(R)-3-hydroxybutyrate derived from fermentation of corn starch or sugar cane.
The process is suitable for high throughput production and improves the economics of producing (R)-3-hydroxybutyl (R)-3-hydroxybutyrate compared to previous methods involving costly starting materials and complex steps.
Documented Applications
The (R)-3-hydroxybutyl (R)-3-hydroxybutyrate produced is useful as a precursor to ketone bodies which can be administered to enhance physical and cognitive performance and to treat cardiovascular conditions, diabetes, neurodegenerative diseases, and epilepsy.
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