Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2000-08-17
2002-10-15
Richter, Johann (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C556S404000, C556S405000, C562S008000
Reexamination Certificate
active
06465649
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of the Invention
This invention is directed to methods for the dealkylation of phosphonate esters by use of trimethylchlorosilane as the dealkylating agent. In particular, this invention is directed to the discovery that high yields for the dealkylation of phosphonate esters can be achieved within relatively short reaction times by the use of trimethylchlorosilane provided that the dealkylation procedure occurs in a compatible solvent. In a preferred embodiment, the reaction is conducted in a sealed container.
This invention is further directed to novel compositions used in the methods of this invention.
References
The following publications are cited in this application as superscript numbers:
1
Kim, et al.,
Acyclic Purine Phosphonate Analogues as Antiviral Agents. Synthesis and Structure
-
Activity Relationships
, J. Med. Chem., 33:1207-1213 (1990)
2
Schultze, et al.,
Practical Synthesis of the anti
-
HIV Drug, PMPA
, Trahedron Letters, 39:1853-1856 (1998)
3
Tsai, et al.,
Prevention of SIV Infection in Macaques
by (R)-9-(2-Phosphonylmethoxypropyl)adenine, Science, 270:1197-1199
4
Kosolopoff, et al.,
Organophosphorus Compounds
, John Wiley & Sons, New York, N.Y. (1950)
5
McKenna, et al.,
Functional Selectivity in Phosphonate Ester Dealkylation with Bromotrimethylsilane
, J.C.S. Chem. Comm., p. 739 (1979)
6
McKenna, et al.,
The Facile Dealkylation of Phosphonic Acid Dialkyl Esters by Bromotrimethylsilane
, Tetrahedron Letters, 2:155-158 (1977)
7
Rabinowitz,
The Reactions of Phosphonic Acid Esters with Acid Chlorides. A Very Mild Reaction
, J. Org. Chem., 28:2975-2978 (1963)
8
Machida, et al.,
A Useful Methodfor the Dealkylation of Dialkyl Phosphonates
, Synthetic Communications, 9(2):97-102 (1979)
9
Morita, et al.,
A Convenient Dealkylation of Dialkyl Phosphonates by Chlorotrimethylsilane in the Presence of Sodium Iodide
., Tetrahedron Letters, 28:2523-2526 (1978)
10
Klug, et al., J. Org. Chem., 44:4847 (1979)
11
Hampton, et al., J. Am. Chem. Soc., 95:4404-4414
12
Holy, et al., Collect. Czech. Chem. Commun., 52:2801-2809 (1987)
13
Papapoulos, et al., Bone, 13:S41-S49 (1992)
14
Ebetino, et al., Rev. Contemp. Pharmacother., 9:233-243 (1998)
15
Bilezikian, et al., Bone Biol., 1037 (1996)
16
Nakumura, et al., Journal of Antibiotics, 48:1134 (1995)
17
Magnin, et al., J. Med. Chem., 38:2596 (1995)
18
Goto, et al., Chem. Pharm. Bull., 44:547 (1996)
19
Rowosky, et al., Biochem. Pharmacol., 35:3327 (1986)
All of the above publications are herein incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety.
STATE OF THE ART
Numerous antiviral agents described in the literature are phosphonate compounds. Examples of such antiviral compounds include acyclic purine phosphonates as described by Kim et al.
1
and 9-[2-(phosphonomethoxy)ethyl]-adenine and R-9-[2-(phosphonomethoxy)propyl]adenine as described by Schultze, et al.
2,3
.
Phosphonate compounds have also been described for use in treating bone degeneration/osteoporosis
13-15
, in relationship to platlet activating factors, herbicical antibiotics
16
, in relationship to cholesterol drugs
17-18
, and with anti-neoplastic agents.
19
Accordingly, phosphonate compounds have a wide diversity of uses in the medicinal arts.
Such phosphonates can be represented by the general formula:
where X and X′ are independently selected from hydrogen, alkyl and halogen and R is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic. Preferred antiviral phosphonate compounds are represented by the formula:
wherein A and B are, for example, alkylene, substituted alkylene, alkylene-O-alkylene, or alkylene-S-alkylene; X is, for example, hydrogen, hydoxyl or amino; and Y is, for example, hydrogen or amino.
The synthesis of these phosphonates typically proceeds through intermediates employing phoshonate esters which are employed as blocking or protecting groups. Subsequent removal of these groups reestablishes the phosphonate functionality which typically occurs as the terminal step in the synthesis. Conventional methods for dealkylating phosphonate esters include reaction with aqueous solutions of concentrated HCl or HBr. However, many of the functional groups on the phosphonates are acid labile which cannot tolerate these harsh acidic conditions.
4
Milder reagents to effect dealkylation are trialkylsilylhalides which selectively cleave PO alkylesters yielding trialkylsilyl esters which are readily hydrolyzed with water (pH~7). Trimethylbromosilane (TMSBr) is the most commonly used reagent in this class due to its high reactivity and chemoselectivity.
5,6
However, the use of trimethylbromosilane requires special handling procedures due its high corrosivity (relative to trimethyl-chlorosilane) and this compound is approximately three times more expensive than the corresponding trimethylchlorosilane. Such differences provide a compelling basis to employ trimethylchlorosilane as the reagent of choice in the dealkylation of phosphonate esters.
Notwithstanding the above, the use of trimethylchlorosilane as a dealkylation reagent in reactions with phosphonate esters has been hindered by its poor reactivity (relative to trimethylbromosilane). In this regard, the literature is replete with references stating that prolonged reaction times and/or poor yields arise from use of trimethylchlorosilane in such dealkylation reactions.
6-9
In order to address this problem, it has been reported that the addition of either sodium or lithium iodide to the reaction medium results in substantially faster reaction times and provided high yields of the product.
8,9
However, the addition of such salts was also reported to lead to contamination of the resulting phosphonate product with lithium halide salts requiring crystallization of this product as its monoanilinium salt to effect removal of this salt.
8
In view of the above, methods to efficiently effect dealkylation of phosphonate esters in high yield with trimethylchlorosilane would be particularly desirable. Preferably, such methods would not employ alkali iodide salts such that purification of the resulting products would be simplified.
SUMMARY OF THE INVENTION
This invention is based on the novel and unexpected discovery that dealkylation of phosphonate esters using trimethylchlorosilane can be consistently achieved for a wide variety of ester groups in the absence of added alkali iodide salts by use of a solvent. In experiments reported below, the combination of trimethylchlorosilane and solvent provided for almost quantitative recovery of dealkylated product in approximately 10% of the time required by prior art processes employing no solvent. Subsequent hydrolysis of the trialkylsilyl phosphonate provided for desired phosphonate in almost quantitative amounts.
In view of the above, this invention is directed to methods for dealkylation of phosphonate esters using trimethylchlorosilane as the dealkylating agent. Specifically, in a first method aspect, this invention is directed to a method for dealkylation of phosphonate esters which method comprises:
(a) combining a phosphonate ester and trimethylchlorosilane in a solvent in the absence of alkali iodide salts; and
(b) maintaining the resulting reaction mixture under conditions wherein the phosphonate ester is converted to trimethylsilyl phosphonate.
In one preferred embodiment, the reaction is conducted in a sealed reaction vessel.
In another preferred embodiment, the trimethylsilyl phosphonate is subsequently hydrolyzed in an aqueous solution under conditions which provide for the phosphonic acid [i.e., R
1
and R
2
(if present) are hydrogen].
In still another preferred embodiment, the methods of this invention are employed to dealkylate bisphosphonate esters (i.e., compounds of formula I wherein both R
1
and R
2
are other than hyd
Gutierrez Arnold J.
Prisbe Ernest J.
Rohloff John C.
Gilead Sciences, Inc.
Hensley Max D.
Richter Johann
Sackey Ebenezer
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