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Preparation of nucleosides ribofuranosyl pyrimidines

a technology of ribofuranosyl pyrimidine and nucleosides, which is applied in the field of preparation of nucleosides ribofuranosyl pyrimidines, to achieve the effect of efficient and scalable process

Inactive Publication Date: 2008-06-12
PHARMASSET +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015]The current invention further provides for improved procedures for the stereopecific hydroxylation of (E)-3-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-2-methyl-acrylic acid ethyl ester (22), the formation of the cyclic sulfate 26 and the ring-opening of the cyclic sulfate with a fluoride nucleophile and hydrolysis, lactonization and derivatization to afford the required lactone II (R=Ph). The latter three steps afford an efficient scalable process to prepare the requisite lactone (II).

Problems solved by technology

2-Deoxy-nucleosides afford unique problems because they lack a 2-hydroxy substituent that provides 1,2-anchiomeric assistance facilitating stereoselective β-glycosylation at the adjacent anomeric carbon.

Method used

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  • Preparation of nucleosides ribofuranosyl pyrimidines
  • Preparation of nucleosides ribofuranosyl pyrimidines
  • Preparation of nucleosides ribofuranosyl pyrimidines

Examples

Experimental program
Comparison scheme
Effect test

example 1

Benzoic acid 3-benzoyloxy-5-(4-benzoylamino-2-oxo-2H-pyrimidin-1-yl)-4-fluoro-4-methyl-tetrahydro-furan-2-ylmethyl ester (14)

[0042]

[0043]Trifluoroethanol (4.08 kg) is added slowly to a cold solution (−15° C.) of RED-AL® solution (12.53 kg) and toluene (21.3 kg) while maintaining the reaction temperature at or below −10° C. After warming up to RT (ca. 20° C.), the modified RED-AL reagent mixture (30.1 kg out of the 37.6 kg prepared) is added slowly to a pre-cooled solution (−15° C.) of fluorolactone dibenzoate 10 (10 kg) in DCM (94.7 kg) while maintaining reaction temperature at or below −10° C. After reduction of the lactone (monitored by in-process HPLC), a catalytic amount of tetrabutylammonium bromide (90 g) is added to the reaction mixture. Sulfiiryl chloride (11.86 kg) is then added while maintaining reaction temperature at or below 0° C. The reaction mixture is then heated to 40° C. until formation of the chloride is complete (ca. 4 h) or warmed to RT (20-25° C.) and stirred o...

example 2

4-Amino-1-(3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (18)

[0045]

[0046]A slurry of 14 (14.7 kg) in MeOH (92.6 kg) is treated with catalytic amounts of methanolic sodium methoxide (0.275 kg). The reaction mixture is heated to ca. 50° C. and aged (ca. 1 h) until the hydrolysis is complete. The reaction mixture is quenched by addition of isobutyric acid (0.115 kg). The resulting solution is concentrated under moderate vacuum and then residual solvents are replaced with IPA (80 kg). The batch is distilled to a volume of ca. 50 L. The resulting slurry is heated to ca. 80° C. and then cooled slowly to ca. 5° C. and aged (ca. 2 h). The precipitated product is isolated by filtration, washed with IPA (16.8 kg) and dried in an oven at 70° C. in vacuo to afford 6.26 kg (88.9%) of 18 which assayed at 99.43% pure.

example 3

(2S,3R)-3-[(4R)-2,2-dimethyl-[1,3]dioxolan-4-yl]-2,3-dihydroxy-2-methyl-propionic acid ethyl ester (24)

[0047]

[0048]A suspension of 22 (10 kg, CAS Reg. No. 81997-76-4), ethylene glycol (11.6 kg), solid NaHCO3 (11.8 kg) and acetone (150 L) is cooled to ca.-15° C. A solution of 36% aqueous NaMnO4 (19.5 kg) is charged slowly (over 4 h) to the suspension maintaining reaction temperature at or below −10° C. After stirring for 0.5 h at −10° C., an aliquot of the reaction mixture (ca. 5 mL) is quenched with 25% aqueous sodium bisulfite (ca. 15 mL). A portion of resulting slurry is filtered and submitted for GC analysis to check the progress of the reaction. When the reaction is complete, the reaction mixture is quenched by slow addition (over 40 min) of cooled (ca. 0° C.) 25% aqueous NaHSO3 (60 L). The temperature of the reaction mixture is allowed to reach 4° C. during the quench. CELITE® (ca. 2.5 kg) is then slurried in acetone (8 kg) and added to the dark brown reaction mixture. The resu...

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Abstract

The present process provides an improved method for converting 2′-deoxy-2′-fluoro-2′-methyl-D-ribonolactones derivatives to 3-fluoro-3-methyl-2-chlorofuran compounds which are useful for the synthesis of nucleosides and improved processes for the synthesis of the D-ribonolactone compounds.

Description

CROSS REFERENCE TO PRIOR APPLICATIONS[0001]This application is claims benefit of U.S. Provisional Application No. 60 / 850,962, filed Oct. 10, 2006, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention relates to an improved process for the transformation of an O-acyloxy-substituted (R)-5-methyl-dihydro-furan-2-one derivative into an O-acyloxy-substituted (R)-2-chloro-5-methyl-tetrahydro-furan. The present invention further provides a method of synthesis of cytosine and uridine derivatives utilizing the O-acyloxy-substituted (R)-2-chloro-5-methyl-tetrahydro-furan. The reaction sequence provides an improved process for the preparation of 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (18) which is a potent inhibitor of Hepatitis C Virus (HCV) NS5B polymerase. Another feature of the present invention is improved procedures for the synthesis of key lactone intermediate 1...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07H19/06C07H13/04C07D307/20
CPCC07H5/02C07H1/00C07H19/06
Inventor AXT, STEVEN D.CHUN, BYOUNG-KWONJIN, QINGWURACHAKONDA, SUGUNAROSS, BRUCESARMA, KESHABVITALE, JUSTINZHU, JIANG
Owner PHARMASSET
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