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Publication Number
US-10266509-B2
Publication Date
2019-04-23
Expiration Date
Abstract
An improved method is described for making single isomers of synthetic benzoprostacyclin analog compounds, in particular the pharmacologically active 314-d isomer of beraprost. In contrast to the prior art, the method is stereoselective and requires fewer steps than the known methods for making these compounds.
Core Innovation
The invention relates to improved stereoselective synthesis of single-isomer benzoprostacyclin derivatives, with particular emphasis on the 314-d active isomer of beraprost. The disclosed concept focuses on preparing substantially isomerically pure stereoisomers rather than mixtures, and on producing the desired single-isomer material with specified isomeric purity thresholds.
The synthesis is described as a stereoselective sequence that forms key intermediates and then converts them to the target benzoprostacyclin derivative. The sequence includes a cycloaddition to a key intermediate, followed by aromatization, then functional group interconversions to an alkyne, and finally coupling of a side-chain aldehyde or side-chain precursor to form the target formula.
The disclosure also describes side-chain coupling strategies used to obtain a trans-alkene single isomer outcome, including a Wadworth-Emmons-type strategy and phosphonate-derived coupling products. The overall design emphasizes defined alkene stereochemistry, high chiral purity, and substantially isomerically pure potassium salt, acid, ester-deprotected, and single-isomer forms of beraprost stereoisomers.
Claims Coverage
The independent claims cover two inventive features: a potassium salt of a beraprost stereoisomer with a specified minimum isomeric purity, and a pulmonary hypertension treatment method that administers such a potassium salt to a subject in need. The common inventive limitation is the isomeric purity threshold, with dependent refinements tightening that threshold to higher values.
Potassium salt of beraprost stereoisomer with specified isomeric purity
A potassium salt of a beraprost stereoisomer having an isomeric purity of at least 90%.
Treating pulmonary hypertension by administering high-purity potassium salt of a beraprost stereoisomer
A method of treating pulmonary hypertension comprising administering to a subject in need thereof a potassium salt of a beraprost stereoisomer having an isomeric purity of at least 90%.
The claim set is directed to potassium salt forms of beraprost stereoisomers defined by isomeric purity and to using those defined high-purity potassium salt compositions as active ingredients in a pulmonary hypertension treatment method. The principal claimed differentiation among dependents is the tightening of the isomeric purity threshold.
Stated Advantages
Substantially isomerically pure stereoisomers rather than mixtures.
Single-isomer trans-alkene outcome.
High chiral purity values.
Defined alkene stereochemistry.
Documented Applications
Treating pulmonary hypertension by administering a potassium salt of a beraprost stereoisomer with at least 90% isomeric purity.
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