Methods for the synthesis of plasmalogens and plasmalogen derivatives, and therapeutic uses thereof
Inventors
Khan, M. Amin • Wood, Paul L. • Goodenowe, Dayan
Assignees
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Publication Number
US-9169280-B2
Publication Date
2015-10-27
Expiration Date
Abstract
A method for preparing plasmalogens and derivatives thereof represented by Formula B, wherein R1 and R2 are similar or different, derived from fatty acids; R3 is selected from hydrogen and small alkyl groups. The synthetic route involves production of novel cyclic plasmalogen precursors of Formula A and their conversion to plasmalogens and plasmalogen derivatives of Formula B. Also disclosed is the therapeutic use of plasmalogens and derivatives thereof as produced by the synthetic route of the present invention.
Core Innovation
The invention relates to chemical synthesis of plasmalogens and plasmalogen derivatives, where formation of the vinyl-ether-linked alkyl chain is sensitive to acidic and oxidative conditions and is stereoselective toward Z-O-alkenyl formation. The disclosed approach prepares a compound represented by Formula A from defined solketal and fatty-acid derived components, using cyclic plasmalogen precursors and sequential protection and deprotection of ketal, diol, ether, and primary alcohol functionalities.
The process begins by coupling a solketal represented by Formula 1 with an allyl halide to obtain Formula 2, then deprotecting the ketal to obtain Formula 3 and protecting the diol to obtain Formula (iv). Formula (iv) is reacted with a compound as represented by Formula X-R1, ether groups are deprotected to obtain Formula 6, the primary alcohol is protected to yield Formula (vii), and a fatty acid represented by R2-COOH is esterified to obtain Formula (viii).
The ether present in Formula (viii) is deprotected to obtain Formula 9, and POCl3 is reacted with Formula 9, ethanolamine, and triethanolamine (TEA) to yield Formula A. A second process converts the compound represented by Formula A to a compound represented by Formula B in the presence of tetrahydrofuran (THF) and H2O.
Claims Coverage
The document provides two independent claims. Together they cover a multi-step process for preparing Formula A and a separate conversion process from Formula A to Formula B; these claims recite at least two inventive features.
Stepwise preparation of a formula a compound via solketal coupling, protection/deprotection, esterification, and POCl3 conversion
A process of preparing a compound represented by Formula A by coupling a solketal represented by Formula 1 with an allyl halide to obtain Formula 2; deprotecting the ketal in Formula 2 to obtain Formula 3; protecting the diol in Formula 3 to obtain Formula (iv); reacting X-R1 with Formula (iv) to obtain Formula (v) (X is halogen); deprotecting ether groups in Formula (v) to obtain Formula 6; protecting the primary alcohol in Formula 6 to yield Formula (vii); esterifying a fatty acid represented by R2-COOH to Formula (vii) to obtain Formula (viii); deprotecting the ether in Formula (viii) to obtain Formula 9; and reacting POCl3 with Formula 9, ethanolamine, and triethanolamine (TEA) to yield Formula A.
Conversion of a formula a compound to a formula b compound in thf and water
A process of converting a compound represented by Formula A to a compound represented by Formula B, wherein the conversion is carried out in the presence of tetrahydrofuran (THF) and H2O.
Claim coverage centers on a stepwise, function-group managed synthetic route to prepare Formula A and on a separate conversion step that transforms Formula A to Formula B using THF and H2O.
Stated Advantages
Improved purification due to increased polarity/solubility of cyclic intermediates.
Stability under chromatographic/HPLC conditions.
Hydrolysis to plasmalogens in aqueous media.
Potential to obtain high-purity plasmalogen with reduced downstream processing.
Reduced costs.
Documented Applications
Preparation and conversion of plasmalogens and plasmalogen derivatives via cyclic plasmalogen precursors represented by Formula A to Formula B.
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