WO1993006119A1 - Derives de desoxynucleosides - Google Patents

Derives de desoxynucleosides Download PDF

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Publication number
WO1993006119A1
WO1993006119A1 PCT/GB1992/001777 GB9201777W WO9306119A1 WO 1993006119 A1 WO1993006119 A1 WO 1993006119A1 GB 9201777 W GB9201777 W GB 9201777W WO 9306119 A1 WO9306119 A1 WO 9306119A1
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WO
WIPO (PCT)
Prior art keywords
acyloxyisobutyryl
acetoxyisobutyryl
bromo
deoxy
ribonucleoside
Prior art date
Application number
PCT/GB1992/001777
Other languages
English (en)
Inventor
Pawel Jerzy Serafinowski
Original Assignee
The Institute Of Cancer Research
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB919120533A external-priority patent/GB9120533D0/en
Priority claimed from GB929207818A external-priority patent/GB9207818D0/en
Application filed by The Institute Of Cancer Research filed Critical The Institute Of Cancer Research
Publication of WO1993006119A1 publication Critical patent/WO1993006119A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to the preparation or synthesis of deoxynucleoside derivatives, and is concerned more particularly with the synthesis of 2',3'-didehydro- 2',3'-dideoxynucleosides and 2',3'-dideoxynucleosides.
  • the invention is especially, although not exclusively, concerned with the synthetic preparation of 2',3'- didehydro-2',3'-dideoxyinosine and 2',3'-dideoxyinosine from inosine (hypoxanthine ribofuranoside).
  • sugar moiety such as a selective removal of 2'(3')-0-acyl groups needed to provide the starting material for a process similar to that used for preparing a 2',3'-didehydro-2',3'-dideoxy derivative of formycin as referred to above - for this particular process it is known that a more stable protective group such as an the acyloxyisobutyryl ester is required.
  • a more stable protective group such as an the acyloxyisobutyryl ester is required.
  • the reaction of 2- acyloxyisobutyryl halides with most ribonucleosides, other than formycin has usually been found to lead to the formation of the 5'-0-dioxolano derivative, either alone or mixed in a substantial proportion with the 5'-0- acyloxyisobutyryl ester derivative.
  • the present invention is based on the finding that, contrary to expectations, reacting inosine, or certain other nucleosides (including adenosine), with 2-acyloxy- isobutyryl halides such as acetoxyisobutyryl halides in an appropriate organic solvent (preferably 2-acetoxyiso- butyryl bromide in nitromethane) under mild conditions (room temperature) can surprisingly lead to production almost exclusively of the 5'-0-(2-acyloxyisobutyryl) ester derivatives in high yield when the reaction time is sufficiently prolonged.
  • 2-acyloxy- isobutyryl halides such as acetoxyisobutyryl halides in an appropriate organic solvent (preferably 2-acetoxyiso- butyryl bromide in nitromethane) under mild conditions (room temperature)
  • This aspect of the invention has thus provided an unexpected useful and convenient new practical route to the preparation of such 5'-0-(2- acyloxyisobutyryl) ester derivatives having a high degree of purity (other than possibly being a mixture of 2' and 3' isomers) well suited for use as intermediates for subsequent production of corresponding 2',3'-didehydro- 2',3'-dideoxynucleosides and 2',3'-dideoxynucleosides, especially 2',3'-didehydro-2',3'-dideoxyinosine and 2',3'- di-eoxyinosine.
  • the 5'-0-(2-aeyloxyisobutyryl) ester derivatives so produced can then readily be selectively deacylated at the 3' or 2' positions (e.g. by the action of 8M methanolic ammonia) ready for phenoxy- thiocarbonylation (acylation) of the 2' or 3' hydroxyl groups by treatment with O-phenylchlorothionoformate in the presence of a base such as dimethylaminopyridine.
  • a base such as dimethylaminopyridine.
  • the corresponding 5'-0-(2-acyloxyisobutyryl)-2',3'-didehydro- 2',3'-dideoxynucleosides can be obtained in good yield.
  • the 5'-0-(2-acyloxyisobutyryl) protective group can be removed (e.g. 8M methanolic ammonia) to yield the 2',3'-didehydro-2',3'-dideoxynucleosides.
  • the olefinic unsaturated products may readily be hydrogenated by conventional means to provide the corresponding 2',3'- dideoxy nucleosides, if so required.
  • the invention provides a process for preparing 2',3'-didehydro-2',3'-dideoxy or 2',3'- dideoxy nucleoside derivatives from ribonucleosides that, when reacted with 2-acyloxyisobutyryl halides, tend to form 5'-0-dioxolano derivatives, said process including the steps of reacting the ribonucleoside with a 2-acyloxy- isobutyryl halide in an organic solvent for an extended time sufficient to cause substantially all the dioxolano derivative initially formed to be converted to the corresponding acyloxyisobutyryl ester, recovering the acyloxyisobutyryl ester product, and subjecting said acyloxyisobutyryl product to further treatment effective to bring about selective deacylation at the 3' and/or 2' positions and to produce the corresponding 5'-0-(2- a ⁇ yloxyisobutyryl)-2',3'-didehydro-2
  • the process according to the invention is particularly useful for preparing 2',3'-didehydro-2',3'- dideoxy and 2',3'-dideoxy derivatives of inosine.
  • the invention may also be defined as providing a process for preparing a 2',3'-dideoxy nucleoside derivative from a ribonucleoside selected from inosine and adenosine, said process being characterised in that it includes the steps of: (a) reacting the said ribonucleoside with a 2-acyloxy- isobutyryl halide in an organic solvent to form a 5'-0- dioxolano derivative or derivatives and continuing said reaction until substantially all said 5'-0-dioxolano derivative(s) becomes converted to the corresponding acyloxyisobutyryl ester 2'(3')-acyloxy-3'(2')-halo derivative(s),
  • step (c) subjecting said acyloxyisobutyryl ester recovered in step (b) to further treatment effective to bring about selective deacylation at the 3' or 2' positions and to produce the corresponding 5'-0-(2-acyloxyisobutyryl)- 2',3'-didehydro-2',3'-dideoxynucleoside, followed by
  • the acyloxyisobutyryl ester product is treated with O-phenylchlorothionoformate in the presence of an organic solvent so as to phenoxythiocarbonylate the 2' or 3' hydroxyl groups, and the products formed are then subjected to a deoxygenation reaction promoting a ⁇ - elimination of the halo, and phenoxythiocarbonyl groups.
  • the initial reaction of the ribonucleoside with the acyloxyisobutyryl halide is carried out without application of heat in nitromethane as the organic solvent, and the preferred halide used is 2'- acetoxyisobutyryl bromide.
  • the extended time for which the initial reaction is allowed to continue will be in excess of 12 hours, and preferably will be at least 20 hours, for example within the range of 24-86 hours.
  • the subsequent selective removal of the 2'(3')-0-acyl groups is carried out using 8M methanolic ammonia as the deacylating agent.
  • B represents the nucleoside base (hypoxanthine in the case of inosine, adenine in the case of adenosine).
  • ribonucleoside starting material e.g. adenosine (Compound la) or inosine
  • the deacetylated compounds 4 and 5 are then reacted with 0- phenylchlorothionoformate in the presence of an organic solvent such as dimethylaminopyridine to give inseparable mixtures of the phenoxythiocarbonylated isomers (Compounds 6 and 7).
  • an organic solvent such as dimethylaminopyridine
  • a yield in the region of 78-85% may be expected for this stage.
  • the mixture of the isomers 6 and 7 can then be deoxygenated with tributyltin hydride in the presence of 2,2'-azobis(2- methylpropionitrile), promoting a ⁇ -elimination of the halo and phenoxythiocarbonyl groups, to give the corresponding 5'-0-(2-acetoxyisobutyryl)-2',3'-didehydro- 2',3'-dideoxy nucleoside (Compound 8a or 8b) in. virtually quantitative yield.
  • the 5'-0-(2-acetoxyisobutyryl) group can be removed by further treatment with 8M methanolic ammonia as a deacetylating agent to give the 2',3'-didehydro-2',3'-dideoxy derivative ( Compound 9a or 9b).
  • this unsaturated olefinic didehydro compound can then be converted into the corresponding 2',3'-dideoxy derivative by hydrogenation using any convenient conventional hydrogenation process (see, for example, Chu, C.K. et al, J. Org. Chem. (1989), 2217). This provides an especially efficient and economical route for preparing in quantity the particularly useful compound 2',3'-dideoxyinosine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation efficace de dérivés de 2',3'-didéshydro-2',3'-didésoxynucléosides à partir de ribonucléosides, notamment l'inosine et l'adénosine. Le procédé consiste à faire réagir dans du nitrométhane le ribonucléoside initial avec du bromure de 2-acétoxyisobutyryle dans des conditions douces pour former des dérivés de 5'-O-dioxolano qui, par prolongement de la réaction, sont convertis exclusivement en dérivés de 5'-O-(2-acétoxyisobutyryl)-2'(3')acétoxy-3'(2')-bromo que l'on récupère et que l'on traite pour provoquer la désacétylation sélective dans les positions 3' et/ou 2' et la conversion en 5'-O-(2-acétoxyisobutyryl)-2',3'-didéshydro-2',3'-didésoxynucléoside correspondant. Ensuite on procède à la désacétylation desdits dérivés pour supprimer le groupe protecteur acétoxyisobutyryle dans la position 5'.
PCT/GB1992/001777 1991-09-27 1992-09-28 Derives de desoxynucleosides WO1993006119A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB919120533A GB9120533D0 (en) 1991-09-27 1991-09-27 Deoxynucleoside derivatives
GB9120533.6 1991-09-27
GB929207818A GB9207818D0 (en) 1992-04-09 1992-04-09 Deoxynucleoside derivatives
GB9207818.7 1992-04-09

Publications (1)

Publication Number Publication Date
WO1993006119A1 true WO1993006119A1 (fr) 1993-04-01

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1634882A1 (fr) * 2003-06-16 2006-03-15 Ajinomoto Co., Inc. Derive d'inosine et procede de production correspondant
CN104211746A (zh) * 2014-09-11 2014-12-17 天方药业有限公司 一种去羟肌苷的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0341704A2 (fr) * 1988-05-12 1989-11-15 F. Hoffmann-La Roche Ag Procédé pour la préparation de 2',3'-didéoxycytidines
WO1990008147A1 (fr) * 1989-01-14 1990-07-26 Boehringer Mannheim Gmbh Nucleosides de purine, leur procede de production et medicaments contenant ces composes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0341704A2 (fr) * 1988-05-12 1989-11-15 F. Hoffmann-La Roche Ag Procédé pour la préparation de 2',3'-didéoxycytidines
WO1990008147A1 (fr) * 1989-01-14 1990-07-26 Boehringer Mannheim Gmbh Nucleosides de purine, leur procede de production et medicaments contenant ces composes

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF ORGANIC CHEMISTRY. vol. 38, no. 17, 24 August 1973, EASTON US pages 3179 - 3186 T.C.JAIN ET AL. 'Reactions of 2-Acyloxyisobutyryl Halides with Nucleosides.III. Reactions of Tubercidin and Formycin.' cited in the application *
JOURNAL OF ORGANIC CHEMISTRY. vol. 39, no. 1, 11 January 1974, EASTON US pages 30 - 8 T.C.JAIN ET AL. 'Reactions of 2-Acyloxyisobutyryl Halides with Nucleosides. IV. A Facile Synthesis of 2',3'-Unsaturated Nucleosides Using Chromous Acetate.' cited in the application *
JOURNAL OF ORGANIC CHEMISTRY. vol. 54, no. 20, 29 September 1989, EASTON US pages 4780 - 5 M.M.MANSURI ET AL. 'Preparation of 1-(2,3 Dideoxy-B-D-glycero-pent-2-enofuranosyl)th ymine (d4T) and 2',3'-Dideoxyadenosine (ddA): General Methods for the Synthesis of 2',3'-Olefinic and 2',3'-Dideoxy Nucleoside Analogues Active Against HIV.' *
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. vol. 95, no. 12, 13 June 1973, GASTON, PA US pages 4025 - 4030 A.F.RUSSELL ET AL. 'Reactions of 2-Acyloxyisobutyryl Halides with Nucleosides. II. Reactions of Adenosine.' cited in the application *
SYNTHESIS. no. 5, May 1990, STUTTGART DE pages 411 - 5 P.SERAFINOWSKI 'Synthesis of 2',3'-Didehydro-2',3'-dideoxyformycin A, 2',3'-Dideoxyformycin A and 2',3'-Dideoxytubercidin.' cited in the application *
TETRAHEDRON LETTERS vol. 25, no. 4, 1984, OXFORD GB pages 367 - 370 M.J.ROBINS ET AL. 'A Mild Conversion of Vicinal Diols to Alkenes. Efficient Transformation of Ribonucleosides into 2'-ene and 2',3'-Dideoxynucleosides.' cited in the application *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1634882A1 (fr) * 2003-06-16 2006-03-15 Ajinomoto Co., Inc. Derive d'inosine et procede de production correspondant
EP1634882A4 (fr) * 2003-06-16 2008-01-09 Ajinomoto Kk Derive d'inosine et procede de production correspondant
US7816513B2 (en) 2003-06-16 2010-10-19 Ajinomoto Co., Inc. Inosine derivatives and production methods therefor
US8288526B2 (en) 2003-06-16 2012-10-16 Ajinomoto Co., Inc. Inosine derivatives and production methods therefor
CN104211746A (zh) * 2014-09-11 2014-12-17 天方药业有限公司 一种去羟肌苷的合成方法

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