producing cyclic phosphonic acid diesters prodrugs, used to improve the oral bioavailability; by reacting a chiral 1,3-diol and an activated phosphonic acid in the presence of a Lewis acid; Adefovir drug target delivery to liver
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Publication Number
US-7582758-B2
Publication Date
2009-09-01
Expiration Date
Abstract
Methods for the synthesis of cyclic phosphonic acid diesters from 1,3-diols are described, whereby cyclic phosphonic acid diesters are produced by reacting a chiral 1,3-diol and an activated phosphonic acid in the presence of a Lewis acid.
Core Innovation
The patent describes a diastereoselective preparation of compounds of Formula II by combining a 1-(V)-1,3-propane diol with a compound of Formula III in the presence of a Lewis acid. The method controls the stereochemical outcome such that the ratio of cis- to trans-diastereomers of the compounds of Formula II formed is greater than or equal to 3:1.
The disclosed approach further includes cis/trans-selective coupling supported by representative examples that report in situ yield and cis:trans diastereomer ratios for the resulting products. The document describes Lewis-acid mediated formation of phosphorylated/nucleoside-like cis-rich products, with reported cis:trans ratios reaching values such as about 97.8:1.7 and about 99.5:0.5.
The patent also presents diastereoselective preparation of compounds of Formula IV and Formula V using the same stereocontrol concept, by combining (R)-1-(3-chlorophenyl)-1,3-propanediol with a compound of Formula III or Formula VI in the presence of a Lewis acid. In these cases, the cis- to trans-diastereomer ratio of the compounds of the respective formula formed is greater than or equal to 3:1.
Claims Coverage
The document provides three independent claims directed to diastereoselective preparation of compounds of Formula II, Formula IV, and Formula V, each requiring cis-rich cis/trans diastereomer ratios (≥ 3:1) produced using Lewis acids.
Diastereoselective preparation of Formula II via Lewis-acid cis/trans control
A method for the diastereoselective preparation of compounds of Formula II by combining a 1-(V)-1,3-propane diol with a compound of Formula III in the presence of a Lewis acid, wherein the ratio of cis- to trans-diastereomers of the compounds of Formula II formed is greater than or equal to 3:1.
Diastereoselective preparation of Formula IV via Lewis-acid cis/trans control using (R)-1-(3-chlorophenyl)-1,3-propanediol
A method for the diastereoselective preparation of compounds of Formula IV by combining (R)-1-(3-chlorophenyl)-1,3-propanediol with a compound of Formula III in the presence of a Lewis acid, wherein the ratio of cis- to trans-diastereomers of the compounds of Formula IV formed is greater than or equal to 3:1.
Diastereoselective preparation of Formula V via Lewis-acid cis/trans control
A method for the diastereoselective preparation of compounds of Formula V by combining (R)-1-(3-chlorophenyl)-1,3-propanediol with said compound of Formula VI in the presence of a Lewis acid, wherein the ratio of cis- to trans-diastereomers of the compounds of Formula V formed is greater than or equal to 3:1.
Across the independent claims, the inventive coverage centers on Lewis-acid mediated diastereoselective preparation in which combining a defined 1,3-propane diol with a corresponding compound yields cis-rich cis/trans diastereomer ratios of at least 3:1.
Stated Advantages
Improved diastereoselectivity, with cis:trans diastereomer ratios ≥ 3:1.
Improved in situ yield as demonstrated under Lewis acid catalysis.
Achieves cis-rich cis/trans diastereomer ratios of greater than or equal to 3:1 for the compounds of Formula II, Formula IV, and Formula V.
Documented Applications
Examples tied to PMEA (Adefovir) and (R)-PMPA (Tenofovir) derivatives, including isolation/enrichment of desired cis isomers and reported high chemical purity and diastereomeric purity.
Selective crystallization and enrichment leading to isolation of desired cis isomers (e.g., mesylate salt) for PMEA/(R)-PMPA-related derivatives.
Representative chemical examples support Lewis-acid mediated cis/trans-selective coupling to form cis-rich phosphorylated/nucleoside-like products.
Isomeric analysis of cis/trans diastereomers of the coupled products is documented using HPLC and chiral HPLC.
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