Process for the production of 2-halo-6-aminopurine derivatives

Details Process for the production of 2-halo-6-aminopurine derivatives Process for the production of 2-halo-6-aminopurine derivatives

2001-03-12

2003-07-22

Wilson, James O. (Department: 1623)

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

Organic compounds

Carbohydrates or derivatives

C536S027110, C536S027130, C536S027140, C536S027200, C536S027600, C536S027800, C544S264000

Reexamination Certificate

active

06596858

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a novel process for preparing 2-halo-6-aminopurine compounds and derivatives thereof, comprising halogenation of 2,6-diaminopurine compounds at the C-2 position to give the corresponding halogenated compounds, including halogenated
nucleosides. These nucleosides, e.g., 2-chloro-6-aminopurine-2′-deoxyribonucleoside, i.e., the compound with the above structure wherein R is 2′-deoxyribose and X is Cl (2-chloro-2′-deoxyadenosine), are useful as antileukemic agents, e.g., in treating leukemias such as hairy cell leukemia.
The invention also relates to methods for the synthesis of acyclic derivatives of 2-halo-6-aminopurines and 2-halo-6-aminopurine morpholino derivatives which are useful in the preparation of synthetic oligonucleotide analogs.
BACKGROUND OF THE INVENTION
Processes for preparing 2-chloro-6-aminopurine-2′-deoxyribonucleoside (2-chloro-2′-deoxyadenosine, hereinafter “2-CdA”) and other 2-chloro-6-aminopurines are known in the art. Such processes are described in, e.g., U.S. Pat. No. 4,760,137; Kazimierzuk et al., J. Am. Chem. Soc., 106:6379, 1984; Wright et al., J. Org. Chem., 52:4617, 1987 and Christensen et al., J. Med. Chem., 15:735, 1972. The preparation of 2-CdA described by these workers requires the glycosylation of a dihalogenated purine to give an intermediate dihalogenated nucleoside which is then transformed into the desired nucleoside. More specifically, these workers described the glycosylation of 2,6-dichloropurine with 1-chloro-2′-deoxy-3′,5′-di-O-p-toluyl-&bgr;-D-erythropentofuranose to give a mixture of N-7 and N-9 isomers of 2,6-dichloro-(2′-deoxy-3′,5′-di-O-p-toluyl-&bgr;-D-erythropentofuranosyl)-purine. This process suffers from several shortcomings, such as the formation of isomeric side products at the 1′-carbon and the utilization of costly starting materials, such as 2,6-dichloropurine.
U.S. Pat. No. 5,208,327 discloses a method for preparation of 2-CdA from guanosine in eight steps via a 2-chloroadenosine intermediate in 2.8% overall yield (from guanosine). This method is inefficient and requires several protection and deprotection steps in order to remove the 2′ hydroxyl to yield a 2′-deoxy product. The synthesis of the 2-chloroadenosine intermediate also disclosed in the same patent uses protecting group chemistry and an alternate halogenation/amination strategy. This process is extremely expensive because of the multiple steps involved and the use of expensive 2-chloroguanosine starting material, and is not suitable for truly large scale production.
Processes for the preparation of compounds of the formula:
wherein R
1
is acyl or tolyl and W
1
and W
2
are independently halogen or amino from the corresponding per-O-protected nucleosides are disclosed, e.g., in Robins & Uznanski, Can. J. Chem. 59, 2601, 1981; Montgomery & Hewson, J. Med. Chem. 12, 498, 1969; and Huang et. al. J. Med. Chem., 27, 800-802, 1984. The transformation of the starting nucleosides to 2-halopurines requires several steps, including diazotization of the 2-amino intermediates in non-polar organic solvents, followed by halogenation. Thus, this method is completely unfeasible when it is necessary to utilize starting materials that are not soluble or only sparingly soluble in non-polar organic solvents, in contrast to the methods of the present invention, detailed below.
Methods for the conversion of unprotected purine ribonucleosides having the formula:
wherein R
1
is hydrogen, W
3
is halogen or hydrogen, and W
1
and W
2
are independently amino or halogen, to 2-halogenated nucleosides are known in the art (Gerster et. al., J. Org. Chem., 33, 1070, 1968; Gerster et. al., J. Org. Chem., 31, 3258, 1966; Gerster et. al., J. Am. Chem. Soc, 87, 3752, 1965). However, these methods provide low yields of products, and require reactions to be performed with sodium nitrite at temperatures below 0° C. in aqueous solution, thus making drying and separation of products difficult. The prior art also discloses that diazotization of 2-amino groups is only possible for ribonucleosides, because the reaction conditions cleave the glycosyl linkage of the corresponding deoxynucleosides (see Montgomery & Hewson, J. Med. Chem. 12, 498, 1969).
Thus, while the prior art discloses processes for the preparation of 2-CdA and other 2-halo-6-amino nucleosides and deoxynucleosides, these methods all have disadvantages, such as including a glycosylation reaction, or the need for a series of nucleoside hydroxyl protection/deprotection reactions, or the need to manipulate 2-halo-ribonucleosides or analogs at sub-zero temperatures using aqueous reaction conditions.
The present inventors have now surprisingly and unexpectedly discovered methods that make it possible to convert unprotected 2′- or 3′-deoxynucleosides, ribonucleosides or analogs to the corresponding 2-halo derivatives. Also discovered by the present inventors are methods for performing such transformations on unprotected nucleosides where the unprotected nucleosides are highly insoluble in non-polar organic solvents.
SUMMARY OF THE INVENTION
The present invention overcomes the difficulties and shortcomings of the prior art with regard to the synthesis 2-halo-6-aminopurine compounds and derivatives thereof and especially of 2-halogenated purine ribonucleosides and 2-halogenated-2′- and 3′-deoxy and 2′ and 3′-substituted purine ribonucleosides. Disclosed herein are methods for producing 2-halo-6-aminopurine compounds and derivatives thereof and especially 2-halogenated-2′-deoxy purine nucleosides, 2-halogenated purine ribonucleosides, and 2′ and 3′-substituted analogs thereof via halogenation at the 2 position in a unique organic solvent system at room temperature.
Thus, in one aspect the invention relates to methods for producing 2-halo-6-amino derivatives, comprising the steps of:
admixing a nonpolar aprotic organic solvent with a polar aprotic organic solvent to produce a solvent mixture;
dissolving in the solvent mixture a compound having the formula
where R is selected from the group consisting of hydrogen, C
1
to C
20
alkyl, including linear and branched chain alkyl, cycloalkyl, alkoxyalkyl, alkylamino, ether, thioether, haloalkyl, a monocyclic aryl group, a multicyclic aryl group, a heterocyclic aryl group having from 1 to 20 carbon atoms and 1 to 10 heteroatoms, sugar moieties selected from the group consisting of &bgr;-D-ribofuranosyl, deoxy-&bgr;-D-furanosyl, xylofuranosyl, arabinofuranosyl, and 2′-, 3′-, and 2′,3′-substituted or derivatized analogs of &bgr;-D-ribofuranosyl, deoxy-&bgr;-D-furanosyl, xylofaranosyl, and arabinofuranosyl sugar moieties; and
reacting the compound in the solvent mixture with an organic nitrite and a metal halide, where the metal halide is a Lewis acid, to produce a reaction product.
In another aspect the invention relates to the methods for producing 2-halonucleosides comprising the steps of:
admixing a nonpolar aprotic organic solvent with a polar aprotic organic solvent to produce a solvent mixture;
dissolving in the solvent mixture a nucleoside having the formula
 where Q is O or S;
where R
1
and R
2
together form a moiety with the formula O—A(Y)—O, where A is C, S, or P—R and where Y is O, S, N—R, or 2R;
or where R
1
and R
2
are independently hydrogen, O—R, R, N—R
2
, N
3
, X, or S—R;
where R is hydrogen, C
1
to C
20
alkyl, including linear and branched chain alkyl, cycloalkyl, alkoxyalkyl, alkylamino, ether, thioether, haloalkyl, a monocyclic aryl group, a multicyclic aryl group, or a heterocyclic aryl group having from 1 to 20 carbon atoms and 1 to 10 heteroatoms and where X is Cl, Br, F, or I; and
reacting the nucleoside in the solvent mixture with an organic nitrite and a metal halide, where the metal halide is a Lewis acid, to produce a reaction product.
In yet another aspect the invention relates to the methods for producing 2-halo-6-aminoalkyloxy derivatives comprisin

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