Synthesis of beta-l-2'-deoxy nucleosides

A nucleoside, a suitable technology, applied in organic chemistry, sugar derivatives, etc., can solve the problems of dioxane flammability, unsuitable industrial methods, and easy formation of peroxides

Inactive Publication Date: 2006-10-04
NOVARTIS AG
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0081] Even though McGee et al. reported that their method was scalable for industrial purposes, dioxane is known to be flammable and prone to peroxide formation, making it unsuitable for industrial use
Additionally, McGee et al. do not take into account whether their method generates the D- or L-enantiomer of 2'-deoxythymidine or requires separation of the enantiomers

Method used

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  • Synthesis of beta-l-2'-deoxy nucleosides
  • Synthesis of beta-l-2'-deoxy nucleosides
  • Synthesis of beta-l-2'-deoxy nucleosides

Examples

Experimental program
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preparation example Construction

[0174] In a first embodiment, 2'-deoxythymidine ( Figure 4 ). The synthesis method comprises: (a) first oxidizing D-xylose with aqueous bromine, then acetic acid and hydrobromic acid to form 2,5-dibromo-2,5-dideoxy-D-lyxenoic acid-1, 4-lactone (2); (b) reacting the lactone product of step (a) with potassium iodide in trifluoroacetic acid (TFA) to give the corresponding 5-iodo compound, i.e. selective removal of the C-2 bromine atom , to obtain 5-iodo-2-deoxylactone (3); (c) treating 5-iodo-2-deoxylactone with potassium hydroxide aqueous solution to obtain 4,5-epoxidized derivatives (4); (d ) Treat 4,5-epoxidized derivatives with aqueous acid to generate corresponding 2-deoxy-L-ribonolactone (5) through C-4 stereospecific conversion; (e) by combining with any protecting group such as Reaction of toluoyl chloride in TEA protects the C-3 and C-5 positions (6); (f) Selective reduction of the protected 2-deoxy-L-ribonolactone with Red-Al reducing agent gives the corresponding in...

Embodiment 1

[0250] The L-arabinose is converted to the corresponding methyloside and the 3- and 4-hydroxyl groups are protected as acetonated derivatives. The following scheme shows a method for deoxidizing the 2-hydroxyl group of compound 2 by converting the hydroxyl group to the corresponding mesylate group and subjecting the mesylate intermediate to reductive cleavage conditions to give 2-deoxy intermediate 4. See H. Urata, E. Ogura, K. Shinohara, Y. Ueda and M. Akagi, Nucleic Acids Res. 1992, 20, 3325-3332; and J.W. Pratt, N.K. Richtmyer and C.S. Hudson, J.Am.Chem.Soc .1952, 74, 2200-2205.

[0251] Start with L-arabinose

[0252]

Embodiment 2

[0254]The conversion of L-arabinose to the corresponding enose derivatives and the conversion of the resulting enose intermediates to methyl 2-deoxyribofuranosides is accomplished through key reductive elimination steps. See B. K. Shull, Z. Wu and M. Koreeda, J. Carbohydr. Chem. 1996, 15, 955-964; M. L. Sznaidman, M. R. Almond and A. Pesyan. Nucleosides, Nucleotides & Nucleic Acids 2002, 21, 155-163; and Z.-X. Wang, W. Duan, L.I. Wiebe, J. Balzarini, E.D. Clercq and E.E. Knaus, Nucleosides, Nucleotides & Nucleic Acids 2001, 20, 11-40.

[0255]

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Abstract

An improved process for the preparation of 2'-modified nucleosides and 2'-deoxy-nucleosides, such as, beta-L-2'-deoxy-thymidine (LdT), is provided. In particular, the improved process is directed to the synthesis of a 2'-deoxynucleoside that may utilize different starting materials but that proceeds via a chloro-sugar intermediate or via a 2,2' anhydro-1-furanosyl-nucleobase intermediate. Where an 2,2'-anhydro-1-furanosyl base intermediate is utilized, a reducing agent, such as Red-Al, and a sequestering agent, such as 15-crown-5 ether, that cause an intramolecular displacement reaction and formation of the desired nucleoside product in good yields are employed. An alternative process of the present invention utilizes a 2,2'-anhydro-1-furanosyl base intermediate without a sequestering agent to afford 2'-deoxynucleosides in good yields. The compounds made according to the present invention may be used as intermediates in the preparation of other nucleoside analogues, or may be used directly as antiviral and / or antineoplastic agents.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application No. 60 / 483,711, filed June 30, 2003, and US Provisional Application No. 60 / 558,616, filed April 1, 2004. field of invention [0003] The present invention belongs to the field of preparation methods of 2'-deoxy- or 2'-modified-nucleosides, especially β-L-2'-deoxythymidine. The present invention is an improved method for easy industrial scale production. The compounds prepared according to the method of the present invention are important antiviral drugs, antineoplastic drugs and intermediates in synthetic pharmaceutical compounds and compositions. Background of the invention [0004] HBV is second only to smoking as a cause of human cancer. The mechanism by which HBV induces cancer is unknown, although it is hypothesized that it may trigger tumor development directly, or through infection-re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/00
Inventor R·斯托雷尔A·穆萨J·Y·王N·乔杜里S·马蒂厄A·斯图尔特
Owner NOVARTIS AG
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