Methods for the synthesis of phosphonate esters
First Claim
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1. A method for preparing a phosphonic acid monoester from a phosphonate with a structure:
- ##STR12## wherein R1 is selected from the group consisting of alkyl, aryl, Substituted alkyl, substituted aryl, heteroaryl, alkylaryl, and aminoalkyl, and R2 is selected from the group consisting of methyl, ethyl, benzyl, and substituted benzyl,by treating said phosphonate with a dialkylazodicarboxylate, a triarylphosphine, wherein at least one of the aryl groups of said triarylphosphine bears an electron withdrawing substituent, and a primary or secondary alcohol with a structure R3 OH, wherein R3 is selected from the group consisting of alkyl, aryl, substituted alkyl, substituted aryl, and aminoalkyl, and an exogenous base in an aprotic solvent, to yield a phosphonate diester with a structure;
##STR13## wherein R2 and R3 are not identical, and R2 can be selectively hydrolyzed without hydrolyzing R3, and then treating said phosphonate diester to hydrolyze selectively said phosphonate diester to yield said phosphonic acid monoester with a structure;
##STR14## wherein said phosphonate is present in excess, said excess being greater than a ratio of 1.1 equivalents of phosphonate to one equivalent of alcohol.
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Abstract
Phsophonate esters can be synthesized in high yields by condensations of alcohols with methyl phosphonates followed by selective demethylation. The reaction is general, relativly insensitive to steric constraints of hindered phosphonic acids, and can also be carried out on a solid support to synthesize large collections of compounds to screen for pharmacological activity.
93 Citations
11 Claims
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1. A method for preparing a phosphonic acid monoester from a phosphonate with a structure:
- ##STR12## wherein R1 is selected from the group consisting of alkyl, aryl, Substituted alkyl, substituted aryl, heteroaryl, alkylaryl, and aminoalkyl, and R2 is selected from the group consisting of methyl, ethyl, benzyl, and substituted benzyl,
by treating said phosphonate with a dialkylazodicarboxylate, a triarylphosphine, wherein at least one of the aryl groups of said triarylphosphine bears an electron withdrawing substituent, and a primary or secondary alcohol with a structure R3 OH, wherein R3 is selected from the group consisting of alkyl, aryl, substituted alkyl, substituted aryl, and aminoalkyl, and an exogenous base in an aprotic solvent, to yield a phosphonate diester with a structure;
##STR13## wherein R2 and R3 are not identical, and R2 can be selectively hydrolyzed without hydrolyzing R3, and then treating said phosphonate diester to hydrolyze selectively said phosphonate diester to yield said phosphonic acid monoester with a structure;
##STR14## wherein said phosphonate is present in excess, said excess being greater than a ratio of 1.1 equivalents of phosphonate to one equivalent of alcohol. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11)
- ##STR12## wherein R1 is selected from the group consisting of alkyl, aryl, Substituted alkyl, substituted aryl, heteroaryl, alkylaryl, and aminoalkyl, and R2 is selected from the group consisting of methyl, ethyl, benzyl, and substituted benzyl,
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Current AssigneeAffymax Incorporated
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Original AssigneeAffymax Incorporated
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InventorsCampbell, David A.
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Primary Examiner(s)Lee, Mary C.
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Assistant Examiner(s)AMBROSE, MICHAEL GEORGE
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Application NumberUS08/119,700Time in Patent Office628 DaysField of Search558/110US Class Current558/110CPC Class CodesC07F 9/40 Esters thereofC07K 5/06191 containing heteroatoms diff...
