Methods for producing Beraprost and its derivatives
Inventors
Batra, Hitesh • TULADHAR, Sudersan M. • Tummala, Sri Harsha • Penmasta, Raju • Walsh, David A.
Assignees
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Publication Number
US-10246430-B2
Publication Date
2019-04-02
Expiration Date
Abstract
The present invention is directed to methods for preparing Beraprost and novel synthetic intermediates for Beraprost.
Core Innovation
The invention relates to a method of preparing a compound represented by structural Formula (I) and salts thereof, including substantially isomerically pure Formula (I) compounds. The method starts from a substituted halophenol and 6-oxabicyclo[3.1.0]hex-2-ene and forms an ether compound represented by structural Formula (III), then continues through acetylation, allylation using allyltributylstannane and AIBN, and intermolecular allylic acetoxylation.
The terminal alkene compound of Formula (V) is subjected to dihydroxylation to form Formula (VII), the dihydroxy compound is oxidized to an aldehyde compound of Formula (VIII), and the aldehyde is reduced while removing the acetyl group to provide the diol compound of Formula (IX). The diol is converted to a protected aldehyde of Formula (VIIIA), which is then reacted with a phosphonate of Formula (X) to obtain the compound represented by Formula (I).
The document also describes prostacyclin derivatives and new intermediates, including Beraprost and Treprostinil derivatives, and provides a separate scheme for preparing the phosphonate side-chain from pseudoephedrine derivatives. Example content includes Beraprost (I) preparation and alternative pathways to a racemic Beraprost ester diol, with definitions relating to pharmaceutically acceptable salts, protecting-group terminology, and selective purity.
Claims Coverage
The independent claim covers a method of preparing a compound represented by structural Formula (I) and salts thereof, including substantially isomerically pure Formula (I) compounds, through a defined multi-step sequence. The claim includes nine transformation stages and explicit substituent definitions for X, R1, R2, R3, and R6.
Preparing a Formula (I) compound by a substituted halophenol-to-phosphonate multi-step sequence
A method of preparing a compound represented by structural Formula (I) and salts thereof comprising: reacting a substituted halophenol with 6-oxabicyclo[3.1.0]hex-2-ene in presence of a palladium catalyst to form an ether compound of Formula (III); acetylating the ether of Formula (III) to form Formula (IV); allylating the compound of Formula (IV) with allyltributylstannane in presence of AIBN to form the allylation product (V); subjecting the terminal alkene compound of Formula (V) to intermolecular allylic acetoxylation to form Formula (VI); subjecting the compound of Formula (VI) to dihydroxylation to form Formula (VII); subjecting the dihydroxy compound (VII) to oxidation to form an aldehyde compound of Formula (VIII); reducing the aldehyde compound of Formula (VIII) and removing the acetyl group to provide the diol compound of Formula (IX); converting the diol of Formula (IX) to a protected aldehyde of Formula (VIIIA); and reacting the protected aldehyde of Formula (VIIIA) with a phosphonate of Formula (X) to obtain a compound of Formula (I).
Phosphonate substituent constraints for Formula (X) and substituent definitions
The method is performed wherein X is F, Cl, Br or I; R1 is an alkyl, cycloalkyl or TBDMS; R2 is independently H or an alcohol protecting group; R3 is a straight or branched alkyl group having 1-4 carbon atoms; and R6 is an alcohol protecting group.
The claim coverage centers on a defined multi-step synthetic method that converts a substituted halophenol and 6-oxabicyclo[3.1.0]hex-2-ene into an ether, allylated/acetoxylated and dihydroxylated intermediate, then to an aldehyde, reduced/deacetylated diol, protected aldehyde, and finally a phosphonate-coupling step to obtain the Formula (I) compound, with explicit substituent constraints for X, R1, R2, R3, and R6.
Stated Advantages
Documented Applications
The document includes Example 2: Beraprost (I) and a scheme showing preparation of Beraprost (I) from 1,3-cyclopentadiene through cyclopentadiene monoepoxide and further intermediates.
The document describes prostacyclin derivatives including Beraprost and Treprostinil derivatives.
The document provides a separate scheme for preparing the phosphonate side-chain from pseudoephedrine derivatives.
The document discusses alternate routes to a racemic Beraprost ester diol and determining chiral purity via racemic analog synthesis.
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