US5420328A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Methods for the synthesis of phosphonate esters
Assignee: Affymax Technologies NV
•
Filing: 1993-09-09
•
Granted: 1995-05-30
•
Expires: 2013-09-09
Abstract
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.
Inventors
- 👤 David A. Campbell
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-02 16:28
CPC Classifications
C; C07; C07K; C07K5/00; C07K5/04; C07K5/06; C07K5/06191; C07F; C07F9/00; C07F9/02; C07F9/28; C07F9/38; C07F9/40
Claims Analysis
Total Claims: 12
Claim 1
Independent Claim
190 words
A method for preparing a phosphonic acid monoester from a phosphonate with a structure: ##STR12## wherein R 1 is selected from the group consisting of alkyl, aryl, Substituted alkyl, substituted aryl, heteroaryl, alkylaryl, and aminoalkyl, and R 2 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 R 3 OH, wherein R 3 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 R 2 and R 3 are not identical, and R 2 can be selectively hydrolyzed without hydrolyzing R 3 , 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.
Claim 2
Independent Claim
190 words
A method for preparing a phosphonic acid monoester from a phosphonate with a structure: ##STR12## wherein R 1 is selected from the group consisting of alkyl, aryl, Substituted alkyl, substituted aryl, heteroaryl, alkylaryl, and aminoalkyl, and R 2 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 R 3 OH, wherein R 3 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 R 2 and R 3 are not identical, and R 2 can be selectively hydrolyzed without hydrolyzing R 3 , 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.
Claim 3
Dependent Claim
19 words
The method of claim 1 wherein R 2 is methyl, said dialkylazodicarboxylate is diisopropylazodicarboxylate, and said triarylphosphine is tris(4-chlorophenyl)phosphine.
Claim 4
Dependent Claim
12 words
The method of claim 1 wherein said alcohol is a primary alcohol.
Claim 5
Dependent Claim
12 words
The method of claim 1 wherein said alcohol is a secondary alcohol.
Claim 6
Dependent Claim
11 words
The method of claim 1 wherein said phosphonate is an alpha-aminoalkylphosphonate.
Claim 7
Dependent Claim
15 words
The method of claim 5 wherein said alcohol is covalently linked to a solid support.
Claim 8
Dependent Claim
15 words
The method of claim 6, wherein said solid support is a bead or a particle.
Claim 9
Dependent Claim
69 words
The method of claim 6 wherein said solid support is prepared by treating a solid support to which an amino acid or peptide is covalently linked so as to have an amine group of said amino acid or peptide on a surface of said support with a hydroxy acid to couple said hydroxy acid to said amine group and to yield a hydroxy group covalently linked to said support.
Claim 10
Dependent Claim
86 words
The method of claim 8, wherein, after said hydroxy acid is coupled to said amine group, said support is treated with an alpha-aminoalkylphosphonate with the following structure: ##STR15## wherein R 4 is an alpha-aminoalkyl group, and R 2 is selected from the group consisting of methyl, ethyl, benzyl, and substituted benzyl; a dialkylazodicarboxylate; an exogenous base; and a triarylphosphine, wherein at least one of the aryl groups of said triarylphosphine bears an electron withdrawing substituent, to couple said alpha-aminoalkylphosphonate to said hydroxyl groups on said surface.
Claim 11
Dependent Claim
25 words
The method of claim 9, further comprising the step of treating said support with thiophenol and triethylamine whereby the R 2 group is selectively hydrolyzed.
Claim 12
Dependent Claim
21 words
The method of claim 10, further comprising the step of coupling an amino acid to the amino group of said alpha-aminoalkylphosphonate.
References Cited (Backward Citations)
US5143854A
Cited
US5183810A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1998-05-29 | 1998-11-28 | 1999-05-30 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2002-05-29 | 2002-11-28 | 2003-05-30 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2006-05-29 | 2006-11-28 | 2007-05-30 | $7700.00 | Window Closed / Lapsed |