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Process for the synthesis of pyrazolopyrimidines

a technology of pyrazolopyrimidine and pyrazolopyrimidine, which is applied in the field of pyrazolopyrimidine production, can solve the problems of increasing the production cost of ppg phosphoramidite, chromatography purification of a compound is not suitable for a large volume, and the chromatography process is generally time-consuming and laborious

Inactive Publication Date: 2006-01-19
EPOCH BIOSCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010] Another aspect of the present invention provides a process for producing a nucleoside or nucleotide comprising a pyrazolopyrimidine base. In particular, the processes of the present invention comprise using a halogenated pyrazolopyrimidine base and removing the halogen after the base is coupled to a sugar moiety. The presence of a halogen on the base allows the nucleoside to be purified by a non-chromatography method, preferably by recrystallization or precipitation. Thus, processes of the present invention allow economical production of a large quantity of nucleosides, including PPG phosphoramidite. Definitions

Problems solved by technology

Unfortunately, conventional processes for producing PPG phosphoramidite require a numerous chromatography separations including that of the nucleoside produced from coupling an activated sugar moiety to a pyrazolopyrimidine base.
Typically, chromatography purification of a compound is not suitable for a large scale (e.g., tens or hundreds of grams or more) production because a chromatography process is generally time consuming and labor intensive.
Moreover, a large scale chromatography purification process requires a correspondingly large amount of chromatography material, e.g., silica gel and chromatography solvent(s), which increases the production cost of PPG phosphoramidite.
Because the pyrazolopyrimidine base containing nucleoside is produced relatively early in the conventional synthesis of PPG phosphoramidite, purification of this nucleoside by chromatography is one of the major hindrances in a cost effective large scale PPG phosphoramidite synthesis.

Method used

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  • Process for the synthesis of pyrazolopyrimidines
  • Process for the synthesis of pyrazolopyrimidines
  • Process for the synthesis of pyrazolopyrimidines

Examples

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example 1

[0077]

[0078] This example illustrate a method for producing 2-amino-4,6-dichloropyrimidine-5-carboxaldehyde (2).

[0079] Absolute DMF (210 ml, 1.38 mol) was added drop wise to an ice-cold solution of POCl3 (900 ml) over a 20 min period. The ice-bath was removed and 150 g (1.17 mol) of powdered 2-amino-6-hydroxypyrimidine-4(3H)-one (1) was added over a 20 min period. The mixture was then heated to 100° C. and stirred for 3-4 h. The solution was cooled to room temperature and poured into 10 L of ice water (4 L of crushed ice diluted to 10 L with water). This aqueous solution was then heated to 50° C. and stirred for 2 h. The mixture was refrigerated overnight and the precipitate was filtered and dried to provide 160 g (71% yield) of 2-amino-4,6-dichloropyrimidine-5-carboxaldehyde (2).

example 2

[0080]

[0081] This example illustrate a method for producing 4-chloro-6-aminopyrazolo[3,4-d]pyrimidine (3).

[0082] To a mixture of 2-amino-4,6-dichloropyrimidine-5-carboxaldehyde (2) (150 g, 0.785 mol), THF (2.7 L) and triethylamine (125 ml) was added anhydrous hydrazine (25.5 ml in 600 ml of water) drop wise over 25 min. Alternatively, hydrazine monohydrate can be used instead of anhydrous hydrazine. The mixture was stirred for 1 h. The solids were filtered off and the filtrate was evaporated to remove about 80% of the THF. Water was added and the resulting precipitate was filtered and dried under vacuum. The solid was then dissolved in a minimum volume of hot DMF and precipitate by addition of water to provide 112 g (85% yield) of 4-chloro-6-aminopyrazolo[3,4-d]pyrimidine (3).

example 3

[0083]

[0084] This example illustrates a method for producing 4-methoxy-6-aminopyrazolo[3,4-d]pyrimidine (4).

[0085] Compound 3 (70.4 g, 0.416 mol) was refluxed in methanolic sodium methoxide solution (25 g sodium dissolved in 1 L methanol) for 2 h. The reaction mixture was cooled to room temperature and neutralized by addition of acetic acid (75 ml). The mixture was evaporated to dryness and the solid was triturated in 600 ml of water, filtered and dried to provide 67.5 g (99% yield) of 4-methoxy-6-aminopyrazolo[3,4-d]pyrimidine (4).

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Abstract

The present invention provides a nucleoside comprising a pyrazolopyrimidine base and a process for producing the same. In particular, the processes of the present invention comprises using a halogenated pyrazolopyrimidine base and removing the halogen after the base is coupled to a sugar moiety. The presence of the halogen on the nucleoside base allows facile and economical production of a large quantity of nucleosides.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a process for producing pyrazolopyrimidines. In particular, the present invention relates to a process for producing a PPG phosphoramidite. BACKGROUND OF THE INVENTION [0002] PPG phosphoramidite is often used in synthesis of nucleotides and oligonucleotides containing pyrazolopyrimidine base(s). These nucleotides and oligonucleotides are useful in a variety of applications, including as crosslinkable probes for use in therapeutic and diagnostic applications. See for example PCT publication No. WO 90 / 14353, which is incorporated herein by reference in its entirety. In addition, oligonucleotides in which one or more purine residues have been replaced by pyrazolopyrimidines display enhanced duplex and triplex-forming ability and display enhanced mismatch discrimination ability. See, for example, Belousov et al., Nucleic Acids Res., 1998, 26, 1324-1328 and U.S. Pat. Nos. 5,594,121 and 6,127,121, all of which are incorporated...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07H19/04C07H19/044
CPCC07H19/044C07H19/04
Inventor DEMPCY, ROBERT O.ADAMS, A. DAVIDREED, MICHAEL W.BELOUSOV, YEVGENIY S.
Owner EPOCH BIOSCI
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