One pot synthesis of 5′-hydroxy phosphorylated...

Details One pot synthesis of 5′-hydroxy phosphorylated... One pot synthesis of 5′-hydroxy phosphorylated...

2001-09-19

2002-10-15

Wilson, James O. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S022100, C536S018700, C536S055300, C536S124000

Reexamination Certificate

active

06465641

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a one pot synthetic method for the synthesis of 5′-hydroxy phosphorylated nucleoside derivatives.
BACKGROUND OF THE INVENTION
The spread of AIDS and the ongoing efforts to control the responsible virus are well-documented. One way to control HIV is to inhibit its reverse transcriptase activity (RT). Thus, novel, potent, and selective inhibitors of HIV RT are needed as useful therapeutic agents. Known, potent inhibitors of HIV RT include 5′-triphosphates of 2′,3′-dideoxynucleoside (“ddN”) analogues. Various 5′-hydroxy phosphorylated 2′,3′-dideoxynucleoside derivatives such as phenyl phosphate derivatives of 3′-azidothymidine (AZT), 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T) and 3′-deoxythymidine (3dT) have long been tested as anti-HIV agents. Given the significance of ddN derivatives, development of new methodologies for their synthesis, especially syntheses amenable to large scale commercial production and affording a high yields, is important.
Despite intensive research regarding the preparation of ddN derivatives, the synthesis of 5′-hydroxy phosphorylated ddN derivatives has involved synthetic methodology requiring at least three separate synthetic steps each usually involving purification of the resulting intermediate. The most commonly used synthetic procedure affording 5′-hydroxy phosphorylated ddN derivatives is the three-step synthetic sequence shown in Scheme 1.
The current methods for the synthesis of 5′-hydroxy phosphorylated ddN derivatives suffer from a variety of disadvantages. For example, the commonly used synthetic method of Scheme 1 involves multiple solvents and a variety of work up and purification procedures. Specifically, the method of Scheme 1 uses three different solvents for the three separate steps, namely Et
2
O in the first step, CHCl
3
in the second step and THF in the third step. Additionally, the method of Scheme 1 requires purification of the p-bromophenyl phosphorodichloridate intermediate via distillati In at the end of step 1 and removal of HCl amine salts formed at the end of step 2. The use of these additional work up, and purification steps, as well as multiple reagents increases the production costs and decreases the yields of 5′-hydroxy phosphorylated ddN derivatives. Furthermore, existing synthetic methods for production of 5′-hydroxy phosphorylated ddN derivatives are not amenable to large scale commercial production.
SUMMARY OF THE INVENTION
Generally, the present invention relates to a method for preparing a 5′-hydroxy phosphorylated nucleoside compound in a single reaction vessel. The method provides a high yielding synthesis of 5′-hydroxy phosphorylated nucleoside compounds and related derivatives without the need for purification and isolation of intermediates, and is amenable to large scale synthesis.
The invention provides a method for preparing a 5′-hydroxy phosphorylated nucleoside compound in a single reaction vessel. Phosphorous oxychloride is contacted with a halophenol moiety to produce a halophenyl phosphorodichloridate. Without purification, the halophenyl phosphorodichloridate is reacted with a carboxy-protected amino acid to produce a halophenyl carboxy-protected amino acid phosphorochloridate. Without purification, the halophenyl carboxy-protected amino acid phosphorochloridate is reacted with a nucleoside.
One embodiment of the invention provides a method of preparing AZT-5′-(para-bromophenyl methoxyalaninyl phosphate) in a single reaction vessel without purification of the intermnediates formed. Phosphorous oxychloride is reacted with a para-bromophenol moiety to form para-bromophenyl phosphorodichloridate. Without purification, the para-bromophenyl phosphorodichloridate is contacted with alanine methyl ester to produce para-bromophenyl methoxyalaninyl phosphorochloridate. Without purification, the para-bromophenyl methoxyalaninyl phosphorochloridate is reacted with AZT.
Another embodiment of the invention provides a method of preparing d4T-5′-(para-bromophenyl methoxyalaninyl phosphate) in a single reaction vessel without purification of the intermediates formed. Phosphorous oxychloride is reacted with a para-bromophenol moiety to form para-bromophenyl phosphorodichloridate. Without purification, the para-bromophenyl phosphorodichloridate is contacted with alanine methyl ester to produce para-bromophenyl methoxyalaninyl phosphorochloridate. Without purification, the para-bromophenyl methoxyalaninyl phosphorochloridate is reacted with d4T.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The present invention is applicable to the preparation of 5′-hydroxy phosphorylated nucleoside derivatives. In particular, the present invention is directed to a method for the synthesis of 5′-hydroxy phosphorylated nucleoside derivatives in a single reaction vessel without the need for purification or isolation of reaction intermediates. While the present invention is not so limited, an appreciation of various aspects of the invention will be gained through a discussion of the examples provided below.
The method involves the synthesis of 5′-hydroxy phosphorylated nucleoside derivatives in a single reaction vessel by the sequential addition of various reagents. Synthesis of 5′-hydroxy phosphorylated 2′,3′-dideoxynucleoside derivatives is carried out in a single reaction vessel. Phosphorous oxychloride is contacted with a halophenol moiety to produce a halophenylphosphorodichloridate. Without purification, the halophenyl phosphorochloridate is reacted with a carboxy-protected amino acid to produce a halophenyl carboxy-protected amino acid phosphorochloridate. Without purification, the halophenyl carboxy-protected amino acid phosphorochloridate is reacted with a nucleoside.
First, a halophenyl phosphorodichloridate species is formed by contacting phosphorous oxychloride with a halophenol moiety in the presence of an organic solvent and a tertiary amine. Suitable halophenol moieties include a phenyl group substituted with 1 to 5 halogens selected from fluorine, chlorine, bromine, iodine, or a mixture thereof. Preferred halophenol moieties include para-halogenated phenol moieties. A most preferred halophenol moiety is a para-bromo phenol moiety.
The phosphorous oxychloride and halophenol moiety are typically contacted in an organic solvent which is suitable for every chemical transformation involved in synthesizing 5′-hydroxy phosphorylated 2′,3′-dideoxynucleoside derivatives in a single reaction vessel. Examples of suitable organic solvents include ethers, such as diethyl ether (Et
2
O), chlorinated solvents, such as methylene chloride (CH
2
Cl
2
), chloroform, or dichloroethane, and aromatics, such as toluene, or tetrahydrofurane (THF). Preferably, the organic solvent is THF or methylene chloride. The phosphorous oxychloride and halophenol moiety are typically contacted in the presence of a tertiary amine. Examples of tertiary amines include triethylamine (Et
3
N), 1-methylimidazole, trimethylamine, tri-n-propylamine, N,N-dimethylaniline, and triphenylamine. Preferably, the tertiary amine is triethylamine or 1-methylimidazole. Most preferably the tertiary amine is triethylamine.
The present method typically employs a molar ratio of POCl
3
to the halophenol moiety of about 0.5:1 to about 1:3. Preferably, the molar ratio of POCl
3
to the halophenol moiety is equal or a slight molar excess of the halophenol moiety is employed. Preferably, the molar ratio of POCl
3
to the halophenol moiety is from about 1:1 to about 1:2. Most preferably, a POCl
3
to halophenol moiety ratio of about 1:1 to about 1:1.2 is employed. Additionally, the molar ratio of tertiary amine to halophenol moiety is from about 0.5:1 to about 3:1. Preferably, the molar ratio of tertiary amine to halophenol moiety is from about 1:1 to about 2:1. Most preferably, the molar ratio of tertiary amine to halophenol moiety is from abo

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