WO1999009041A3 - Solution phase synthesis of oligonucleotides - Google Patents

Solution phase synthesis of oligonucleotides Download PDF

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Publication number
WO1999009041A3
WO1999009041A3 PCT/GB1998/002407 GB9802407W WO9909041A3 WO 1999009041 A3 WO1999009041 A3 WO 1999009041A3 GB 9802407 W GB9802407 W GB 9802407W WO 9909041 A3 WO9909041 A3 WO 9909041A3
Authority
WO
WIPO (PCT)
Prior art keywords
solution phase
oligonucleotides
phosphonate
phase synthesis
alcohol
Prior art date
Application number
PCT/GB1998/002407
Other languages
French (fr)
Other versions
WO1999009041A2 (en
Inventor
Colin Bernard Reese
Quanlai Song
Original Assignee
Zeneca Ltd
Colin Bernard Reese
Quanlai Song
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 to US09/485,606 priority Critical patent/US6506894B1/en
Priority to IL13451798A priority patent/IL134517A/en
Priority to KR1020007001442A priority patent/KR20010022840A/en
Priority to JP2000509720A priority patent/JP2001515086A/en
Priority to EP98938782A priority patent/EP1003758B1/en
Priority to EA200000211A priority patent/EA003091B1/en
Priority to DK98938782T priority patent/DK1003758T3/en
Application filed by Zeneca Ltd, Colin Bernard Reese, Quanlai Song filed Critical Zeneca Ltd
Priority to DE69813243T priority patent/DE69813243T2/en
Priority to NZ502684A priority patent/NZ502684A/en
Priority to CA002300874A priority patent/CA2300874A1/en
Priority to PL98338888A priority patent/PL338888A1/en
Priority to AT98938782T priority patent/ATE236916T1/en
Priority to BR9811166-3A priority patent/BR9811166A/en
Priority to AU87386/98A priority patent/AU749343C/en
Publication of WO1999009041A2 publication Critical patent/WO1999009041A2/en
Publication of WO1999009041A3 publication Critical patent/WO1999009041A3/en
Priority to NO20000690A priority patent/NO20000690L/en
Priority to US10/294,794 priority patent/US7019127B2/en
Priority to US11/167,145 priority patent/US20050240015A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
    • C07D265/33—Two oxygen atoms, in positions 3 and 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
    • C07F9/165—Esters of thiophosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
    • C07F9/165—Esters of thiophosphoric acids
    • C07F9/18—Esters of thiophosphoric acids with hydroxyaryl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
    • C07H11/04—Phosphates; Phosphites; Polyphosphates
    • 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
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • 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
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

A process for the synthesis in solution phase of a phosphorothioate triester is provided. The process comprises the solution phase coupling of an H-phosphonate with an alcohol in the presence of a coupling agent to form an H-phosphonate diester. The H-phosphonate diester is oxidised in situ with a sulfur transfer agent to produce the phosphorothioate triester. Preferably, the H-phosphonate and alcohol are protected nucleosides or oligonucleotides. Oligonucleotide H-phosphonates which can be used in the formation of phosphorothioate triesters are also provided.
PCT/GB1998/002407 1997-08-13 1998-08-10 Solution phase synthesis of oligonucleotides WO1999009041A2 (en)

Priority Applications (17)

Application Number Priority Date Filing Date Title
BR9811166-3A BR9811166A (en) 1997-08-13 1998-08-10 Process for the preparation of a phosphorothioate triester, h-phosphonate, and, process for the production of an h-phosphonate oligonucleotide
KR1020007001442A KR20010022840A (en) 1997-08-13 1998-08-10 Solution phase synthesis of oligonucleotides
JP2000509720A JP2001515086A (en) 1997-08-13 1998-08-10 Solution-phase synthesis of oligonucleotides
EP98938782A EP1003758B1 (en) 1997-08-13 1998-08-10 Solution phase synthesis of oligonucleotides
EA200000211A EA003091B1 (en) 1997-08-13 1998-08-10 Solution phase synthesis of oligonucleotides
DK98938782T DK1003758T3 (en) 1997-08-13 1998-08-10 Solution phase synthesis of oligonucleotides
CA002300874A CA2300874A1 (en) 1997-08-13 1998-08-10 Solution phase synthesis of oligonucleotides
DE69813243T DE69813243T2 (en) 1997-08-13 1998-08-10 SYNTHESIS OF OLIGONUCLEOTIDS IN SOLUTION
NZ502684A NZ502684A (en) 1997-08-13 1998-08-10 Solution phase synthesis of phosphorothioate triesters
US09/485,606 US6506894B1 (en) 1997-08-13 1998-08-10 Solution phase synthesis of oligonucleotides
PL98338888A PL338888A1 (en) 1997-08-13 1998-08-10 Method of obtaining oligonucleotides in the of their solution
AT98938782T ATE236916T1 (en) 1997-08-13 1998-08-10 SYNTHESIS OF OLIGONUCLEOTIDES IN SOLUTION
IL13451798A IL134517A (en) 1997-08-13 1998-08-10 Solution phase synthesis of oligonucleotides
AU87386/98A AU749343C (en) 1997-08-13 1998-08-10 Solution phase synthesis of oligonucleotides
NO20000690A NO20000690L (en) 1997-08-13 2000-02-11 Synthesis of solution phase oligonucleotides
US10/294,794 US7019127B2 (en) 1997-08-13 2002-11-15 Solution phase synthesis of oligonucleotides
US11/167,145 US20050240015A1 (en) 1997-08-13 2005-06-28 Solution phase synthesis of oligonucleotides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9717158.1 1997-08-13
GBGB9717158.1A GB9717158D0 (en) 1997-08-13 1997-08-13 Solution synthesis of oligonucleotides and their phosphorothioate analogues

Related Child Applications (3)

Application Number Title Priority Date Filing Date
US09/485,606 A-371-Of-International US6506894B1 (en) 1997-08-13 1998-08-10 Solution phase synthesis of oligonucleotides
US09485606 A-371-Of-International 1998-08-10
US10/294,794 Division US7019127B2 (en) 1997-08-13 2002-11-15 Solution phase synthesis of oligonucleotides

Publications (2)

Publication Number Publication Date
WO1999009041A2 WO1999009041A2 (en) 1999-02-25
WO1999009041A3 true WO1999009041A3 (en) 1999-05-06

Family

ID=10817430

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1998/002407 WO1999009041A2 (en) 1997-08-13 1998-08-10 Solution phase synthesis of oligonucleotides

Country Status (21)

Country Link
US (3) US6506894B1 (en)
EP (2) EP1003758B1 (en)
JP (1) JP2001515086A (en)
KR (1) KR20010022840A (en)
CN (1) CN1231492C (en)
AT (1) ATE236916T1 (en)
BR (1) BR9811166A (en)
CA (1) CA2300874A1 (en)
DE (1) DE69813243T2 (en)
DK (1) DK1003758T3 (en)
EA (1) EA003091B1 (en)
ES (1) ES2197491T3 (en)
GB (1) GB9717158D0 (en)
HU (1) HUP0002684A3 (en)
IL (1) IL134517A (en)
IN (1) IN190784B (en)
NO (1) NO20000690L (en)
NZ (1) NZ502684A (en)
PL (1) PL338888A1 (en)
TR (1) TR200000384T2 (en)
WO (1) WO1999009041A2 (en)

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9924285D0 (en) * 1999-10-14 1999-12-15 Avecia Ltd Process
GB0004889D0 (en) * 2000-03-01 2000-04-19 Avecia Ltd Synthesis of oligonucleotides
AU2002339175A1 (en) * 2001-11-21 2003-06-10 Avecia Biotechnology Inc. Coupling reagent for h-phosphonate chemistry
US6894158B2 (en) * 2002-02-22 2005-05-17 Honeywell International Inc. Methods of producing phosphitylated compounds
GB0209539D0 (en) * 2002-04-26 2002-06-05 Avecia Ltd Monomer Polymer and process
US20070276139A1 (en) * 2004-02-10 2007-11-29 Quanlai Song Substituted Pixyl Protecting Groups for Oligonucleotide Synthesis
JP5645840B2 (en) 2008-12-02 2014-12-24 株式会社Ｗａｖｅ Ｌｉｆｅ Ｓｃｉｅｎｃｅｓ Ｊａｐａｎ Method for synthesizing phosphorous atom-modified nucleic acid
US8272150B2 (en) * 2008-12-12 2012-09-25 Speedplay, Inc. Shoe sole mounting standard for bicycle cleat
KR20110099333A (en) 2008-12-23 2011-09-07 기린두스 아메리카 인코포레이티드 Sulfurizing reagents and their use for oligonucleotides synthesis
CN102596204B (en) 2009-07-06 2016-11-23 波涛生命科学有限公司 New nucleic acid prodrugs and using method thereof
KR20130029108A (en) 2010-06-30 2013-03-21 기린두스 아메리카 인코포레이티드 A new method of using n-thio compounds for oligonucleotide synthesis
EP2620428B1 (en) 2010-09-24 2019-05-22 Wave Life Sciences Ltd. Asymmetric auxiliary group
JP6128529B2 (en) 2011-07-19 2017-05-17 ウェイブ ライフ サイエンシズ リミテッドＷａｖｅ Ｌｉｆｅ Ｓｃｉｅｎｃｅｓ Ｌｔｄ． Methods for the synthesis of functionalized nucleic acids
WO2013017469A1 (en) 2011-07-29 2013-02-07 Girindus America, Inc. Sulfurization reagents on solid supports
AU2013287630B2 (en) 2012-07-13 2017-05-25 Shin Nippon Biomedical Laboratories, Ltd. Chiral nucleic acid adjuvant
PL2872485T3 (en) 2012-07-13 2021-05-31 Wave Life Sciences Ltd. Asymmetric auxiliary group
WO2014012081A2 (en) 2012-07-13 2014-01-16 Ontorii, Inc. Chiral control
WO2014085471A1 (en) * 2012-11-28 2014-06-05 Prognosdx Health, Inc. Acid-activated compositions for the treatment of cancers, methods of their use and methods of their preparation
WO2015108047A1 (en) 2014-01-15 2015-07-23 株式会社新日本科学 Chiral nucleic acid adjuvant having immunity induction activity, and immunity induction activator
EP3095460A4 (en) 2014-01-15 2017-08-23 Shin Nippon Biomedical Laboratories, Ltd. Chiral nucleic acid adjuvant having anti-allergic activity, and anti-allergic agent
JPWO2015108048A1 (en) 2014-01-15 2017-03-23 株式会社新日本科学 Chiral nucleic acid adjuvant and antitumor agent having antitumor activity
US10160969B2 (en) 2014-01-16 2018-12-25 Wave Life Sciences Ltd. Chiral design
WO2018215049A1 (en) * 2017-05-23 2018-11-29 F. Hoffmann-La Roche Ag Process for galnac oligonucleotide conjugates

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994015946A1 (en) * 1993-01-08 1994-07-21 Hybridon, Inc. Synthesis of dimmer blocks and their use in assembling oligonucleotides

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3444300A (en) * 1964-05-05 1969-05-13 Chevron Res N-polyhaloalkylthio compounds as fungicidal agents
FR1519704A (en) * 1967-02-14 1968-04-05 Roussel Uclaf Novel Heterocyclic Dithiocarbamic Compounds and Method of Preparation
US3546185A (en) 1968-03-20 1970-12-08 Monsanto Co Inhibiting premature vulcanization of diene rubbers
US5149798A (en) * 1989-04-06 1992-09-22 Worcester Foundation For Experimental Biology Process for synthesizing oligonucleotides and their analogs adaptable to large scale syntheses
GB9501465D0 (en) 1995-01-25 1995-03-15 King S College London Nucleoside phosphorothioate derivatives,synthesis and use thereof
GB0004889D0 (en) * 2000-03-01 2000-04-19 Avecia Ltd Synthesis of oligonucleotides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994015946A1 (en) * 1993-01-08 1994-07-21 Hybridon, Inc. Synthesis of dimmer blocks and their use in assembling oligonucleotides

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BRILL W K -D: "Thioalkylation of Nucleoside-H-phosphonates and its Application to Solid Phase Synthesis of Oligonucleotides", TETRAHEDRON LETTERS, vol. 36, no. 5, 30 January 1995 (1995-01-30), pages 703-706, XP004028873 *
DREEF C. E. ET AL.: "Phosphorylation of benzyl-protected sugar derivatives via 1-H-phosphonate intermediates: synthesis of DL-myo-inositol 1,4,5-tris-1-H-phosphonate", RECUEIL DES TRAVAUX CHIMIQUES DES PAYS-BAS, vol. 106, 1987, pages 512 - 513, XP002094936 *
GAREGG P.J. ET AL.: "Nucleoside phosphonates: part 7. Studies on the oxidation of nucleoside phosphonate esters", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANS. I, 1987, pages 1269 - 1274, XP002094938 *
SAKATSUME O. ET AL.: "Use of phosphonylating and coupling agents in the synthesis of oligodeoxyribonucleotides", TETRAHEDRON LETTERS, vol. 30, no. 46, 1989, pages 6375 - 6378, XP002094935 *
SHADID B. ; VAN DER PLAS H. C.: "The synthesis of phosphor derivatives of ribosyl zeatin", TETRAHEDRON, vol. 46, no. 6, 1990, pages 2179 - 2186, XP002094937 *

Also Published As

Publication number Publication date
EA003091B1 (en) 2002-12-26
ES2197491T3 (en) 2004-01-01
EP1325927A3 (en) 2008-07-02
EA200000211A1 (en) 2000-08-28
TR200000384T2 (en) 2000-11-21
GB9717158D0 (en) 1997-10-22
AU749343B2 (en) 2002-06-27
CN1274361A (en) 2000-11-22
NZ502684A (en) 2002-12-20
ATE236916T1 (en) 2003-04-15
US20030083490A1 (en) 2003-05-01
EP1003758B1 (en) 2003-04-09
AU8738698A (en) 1999-03-08
KR20010022840A (en) 2001-03-26
IL134517A0 (en) 2001-04-30
IN190784B (en) 2003-08-23
WO1999009041A2 (en) 1999-02-25
EP1325927A2 (en) 2003-07-09
US7019127B2 (en) 2006-03-28
BR9811166A (en) 2000-07-25
DE69813243T2 (en) 2004-01-29
CN1231492C (en) 2005-12-14
PL338888A1 (en) 2000-11-20
JP2001515086A (en) 2001-09-18
IL134517A (en) 2004-02-19
HUP0002684A2 (en) 2000-12-28
HUP0002684A3 (en) 2001-11-28
EP1003758A2 (en) 2000-05-31
US6506894B1 (en) 2003-01-14
CA2300874A1 (en) 1999-02-25
US20050240015A1 (en) 2005-10-27
NO20000690L (en) 2000-04-11
DK1003758T3 (en) 2003-07-21
NO20000690D0 (en) 2000-02-11
DE69813243D1 (en) 2003-05-15

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