+

WO1993007162A1 - Procede de preparation de derives de nucleosides - Google Patents

Procede de preparation de derives de nucleosides Download PDF

Info

Publication number
WO1993007162A1
WO1993007162A1 PCT/FI1992/000269 FI9200269W WO9307162A1 WO 1993007162 A1 WO1993007162 A1 WO 1993007162A1 FI 9200269 W FI9200269 W FI 9200269W WO 9307162 A1 WO9307162 A1 WO 9307162A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
formula
process according
protecting group
azide
Prior art date
Application number
PCT/FI1992/000269
Other languages
English (en)
Inventor
Alex V. Azhayev
Timo Korpela
Original Assignee
Leiras Oy
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
Application filed by Leiras Oy filed Critical Leiras Oy
Priority to JP5506644A priority Critical patent/JPH07500100A/ja
Publication of WO1993007162A1 publication Critical patent/WO1993007162A1/fr

Links

Classifications

    • 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
    • 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

  • the invention describes a chemical synthesis method by means of which it is possible to prepare, in a manner easier than before, deoxyribose derivatives of nucleosides, especially thymine.
  • the object of the present invention is therefore a process for the preparation of chemical derivatives of compounds formed between nucleic acid bases and ribose sugars having the formula
  • B has the meaning of a nucleobase group containing a eto group in the 2-position, especially
  • nucleoside analogues are commercially important as agents inhibiting or curing bacterial, fungal and viral diseases, as well as as cancer agents, especially in the pharmaceutical industry.
  • a very large number of low molecular nucleoside and nucleotide analogues are described in literature. These agents are subject to special interest as they often prevent the growth of bacteria, fungi, viruses and cancer cells.
  • the commercially most important nucleoside analogue is 3'-azido-3'-deoxythymidine, of the trivial name azido- thymidine, AZT, and having the commercial name of retrovir.
  • AZT is widely accepted for the treatment of the autoimmune disease (AIDS) as well as for the treatment aiming at preventing the disease from developing.
  • AZT has been a known agent already for a long time, it is still the best in the large group of tested nucleotide and nucleoside analogues. AIDS is considered to be one of the diseases most threatening to civilization, and there are no clear solu ⁇ tions in sight for the conquer thereof.
  • AZT is mainly manufactured by US Burroughs Wellcome Co. (Pharmaceutical Business News 27, April, pp. 13-16, 1990) . Irrespective of its efforts to increase its production volume, there is a continuous additional need for AZT on the world market as the number of people taken sick with AIDS and infected by AIDS grows faster. This as well as the relatively old synthesis route for AZT results in that the price of the drug raw material is high. The large number of people with AIDS in the poor developing countries makes it especially necessary to develop cheaper drugs. Although new nucleoside and nucleotide analogues are constantly synt ⁇ hesized and tested in the treatment of AIDS, the relatively few side effects of AZT make it the best known AIDS drug. Some of the side effects of AZT have been exaggerated due to over-dosing and to residues of contaminants produced by the synthesis method used.
  • the synthesis methods described for AZT and corresponding compounds use two chemical routes.
  • the first method widely in use comprises as the first step the protection of the 5'-hydroxyl group in the nucleoside with a trityl group
  • Another disclosed AZT synthesis method uses 2-chloro-l, 2- difluorotriethylamine as the cyclization agent (DE 3608606) .
  • the said reagent is not available on the market.
  • it is difficult to remove it from the mixture remaining after forming the azide of 2 , 3 '-O- anhydrothymidine.
  • X is a protecting group stable in a weakly alkaline solution, especially a pivaloyl or l-adaman oyl, or other corresponding, sterically hindered protecting group, and the dotted line together with the nitrogen atom connected thereto forms a ring corresponding to the nucleobase B defined above, is reacted in a weakly alkaline solution with sodium or potassium azide and a lithium halide, LiHal, wherein Hal means halogen, in the presence of a buffering salt, whereafter the protecting group X is removed by treating with a strong base, and recovering the desired end product of the formula I.
  • the 2,3'-anhydroderivative of the formula (II) is advantageously prepared by reacting a compound having the formula
  • X is preferably the pivaloyl group and Y is the ethanesulphonyl group.
  • Halogen means chlorine, bromine and fluorine.
  • the azide is prefera ⁇ bly sodium azide and the lithium halide is preferably lithium chloride.
  • the buffering salt advantageously ammonium chloride may be used, but also other buffering salts known to one skilled in the art can come into question, e.g. ammonium acetate.
  • a substantially simpler and more effective process of preparation of nucleoside analogues is obtained, especially as the cyclization and azide reaction is carried out in a weakly alkaline solution, where the protecting group is stable, especially at a pH value of less than appr. 11, whereby, however, the protecting group may be removed by strong alkaline treatment, preferably at a pH value over appr. 14, without degrading the product.
  • a considerable advantage is also the fact that the forma ⁇ tion of the azido group in the end product is carried out without separate synthesis of lithium azide.
  • the azide step namely has conventionally been carried out by using lithium azide which dissolves well in dimethylformamide but which is not a product easily available commercially.
  • the methods known so far have contained an additional step - the prepararion of lithium azide.
  • this additional step is avoided by simply using as a mixrure e.g. commercially available lithium chloride and sodium azide, whereby a buffering salt is present in order to neutralize the lithium and sodium ions formed during the azide reaction, which is important from the point of view of the stability of the protecting group in the 5'-position.
  • the stability of this group again is very important from the point of view of quantitative isolation of the product and its separation f om the salts.
  • the purification of the end product is simpler and does not contain chromatographic steps.
  • a nucleoside of the formula (III) When starting from a nucleoside of the formula (III) this is dissolved in an alkaline organic solvent, such as pyridine, pyrrolidone, dimethylformamide, imidazole or a corresponding solvent, or in a mixture thereof, while stirring and/or heating.
  • the organic base can also be substituted by tetrahydrofuran, which is less difficult in industrial use, and to which a small amount of a suitable base, e.g. 1-methyl-imidazole, is added.
  • a suitable base e.g. 1-methyl-imidazole
  • the reaction is allowed to proceed at a temperature of 5 to 30 °C until all the nucleoside has reacted.
  • To the reaction mixture is thereaf ⁇ ter added alkyl- or arylsulphonyl halide, such as ethane- sulphonyl-, p-toluenesulphonyl- or trifluoromethanesul- phonylchloride and the reaction is allowed to proceed at a temperature of 10 to 30 °C while stirring for 2 to 20 hours.
  • the 5'-, 3'-protected nucleoside analogue of the formula V is therafter isolated with conventional methods used in organic chemistry.
  • the base catalyzed intramolecular cyclization reaction is carried out.
  • the anhydrode- rivative protected at the 5'-group (II) is formed with a large yield.
  • the base used in this step can be, for example, an alkali metal or alkaline earth metal hydroxide or an organic nitrogen containing base, such as an alkyl- or aryl amine.
  • the protecting group of the 5'- position is base sensitive, it withstands the weak alkaline conditions of this step as well as of the next reaction step.
  • the next step comprises specifically a new reaction wherein the cyclic anhydroderivative (II) is converted with a high yield to 3 '-deoxy-3 '-azido-deoxyribose derivative (I) .
  • sodium or potassium azide is converted in situ to lithium azide in the presence of a buffering salt in a weakly alkaline solution, e.g. in dimethylformamide.
  • a buffering salt in e.g. in dimethylformamide.
  • the method according to the invention substan ⁇ tially reduces . the danger of explosion relating to the handling of azides, which is of great importance especially in the synthesis of large amounts of material.
  • the protecting group in the 5'-position is removed with a strong base, such as by treatment with an alkali or alkaline earth metal hydroxide, or an organic nitrogen containing base, such as an alkyl or aryl amine, especially with 1 to 10 N alkalimetal hydroxide.
  • a strong base such as by treatment with an alkali or alkaline earth metal hydroxide, or an organic nitrogen containing base, such as an alkyl or aryl amine, especially with 1 to 10 N alkalimetal hydroxide.
  • Thymidine (0.5 kg) is dissolved in 5 litres of pyridine.
  • Pivaloyl chloride (0.3 litres) is added while stirring to the thymidine solution at a temperature of 20 °C.
  • methanesulphonylchloride (0.24 litres) is added and the mixture stirred at a temperature of 20 °C for 5 to 10 hours.
  • the precipitated material is filtered off and to the filtrate, 0.4 kg of sucrose is added.
  • the mixture is stirred for 2 hours at a temperature of 20 °C and the pyridine is evaporated in vacuo. To the residue, ethyl acetate and water is added, and after mixing the organic layer is recovered.
  • thymidine 0.3 kg may be dissolved in a mixture of 1-methyl-imidazole (0.5 1) and tetrahydrofuran (2 1) .
  • the mixture is cooled on a ice-salt-bath and a solu ⁇ tion of pivaloyl chloride (0.19 1) in tetrahydrofuran (0.8 1) is added dropwise while stirring.
  • the mixture is stirred for 2 h on the ice-salt-bath and thereafter for 6 h at room temperature.
  • the mixture is again cooled on the ice- ⁇ alt- bath and a mixture of methanesulphonylchloride (0.25 1) and tetrahydrofuran is added while stirring.
  • the organic layer obtained by either one of the above mentioned methods is washed with a sodium bicarbonate solution.
  • the ethyl acetate solution is dried on sodium sulphate and the ethyl acetate solution is evaporated to dryness.
  • the residue is crsytallized from toluene.
  • the yield of 5'-0-pivaloyl-3'-0-methanesulphonylthymidine is 75 - 85 % of the theoretical yield calculated on the amount of thymidine.
  • the melting point of the white crystals is 140 °C (dec.)
  • the product gives a Rf-value of 0.8 in silica gel thin layer chromatography (chloroform/methanol 9:1 v/v) .
  • the absorption maximum in the ultraviolet range is 265 nm.
  • the compound formed (0.7 kg) is dissolved in dioxane cr methylene chloride (4 litres) and therein an aqueous 10 % sodium hydroxide solution is added while stirring at a temperature of 30 to 50 °C until the reaction does not proceed any longer and the pH remains at 6 to 7.5, measured with pH-reactive paper.
  • the reaction mixture is kept over night at +4 °C and the crystals are filtered off.
  • the filtrate is evaporated to dryness, whereafter to the residue chloroform is added and the mixture stirred for 30 minutes at +20 °C, wherafter it is filtered.
  • the filtrate is concentrated to a volume of about 1 liter and kept at +4 °C. When an abundance of crystals appear, these are filtered off.
  • the crystals are dried in vacuo at 50 to 60 °C, whereby 0.49 kg of 5'-0-pivaloyl-2 , 3 '-anhydrothymidine is obtained.
  • the melting point of the crystals is 216 to 217 °C (dec) .
  • silica gel thin layer chromatography chloroform/methanol 9:1 the product gives a Rf value of 0.3.
  • the UV absorption maximum in methanol is 245 nm.
  • a mixture that contains 0.53 kg of sodium azide, 0.2 kg of lithium chloride monohydrate in 6.9 litres of N,N'-dime- thylformamide is heated at reflux temperature for 1 hour while stirring.
  • the mixture is cooled to 100 to 102 °C.
  • Ammonium chloride (0.174 kg) and 0.494 kg of 5'-O-pivaloyl- 2,3'-anhydrothymidine are added.
  • the mixture is stirred for 18 to 20 hours at 100 to 105 °C and cooled to 20 °C.
  • the solid material is filtered off and the filtrate evaporated to dryness in vacuo at 50 °C.
  • the residue is treated with 2 to 5 litres of ethyl acetate and 1 to 3 litres of water.
  • the organic layer is separated, washed with water and finally the organic layer is evaporated to dryness at reduced pressure at a temperature of 40 to 45 °C.
  • the residue is dissolved in 5.7 litres of dioxane and appr. 1.25 litres of an aqueous 5M sodium hydroxide solution is added to the solution.
  • the mixture is stirred for 2 hours at a temperature of 20 °C, whereafter the solution is neutralized with the calculated equivalent amount of strong cation exchange resin (Dowex 50Wx8, 50 to 100 mesh, H ⁇ form, about 2.4 litres) to a pH value of 6.5 to 7.
  • the resin is filtered off and washed on a filter with 50% (v/v) mixture of dioxane and water.
  • the combined filtrates are evaporated to dryness under reduced pressure. Water is added to the residue and it is evaporated to dryness. This procedure is repeated 5 to 6 times.
  • the residue is dis ⁇ solved into about 10 litres of water and the solution treated with active carbon for 30 minutes at 20 °C.
  • the active carbon is filtered off and the filtrate concentrated to 1.5 litres and kept for one day at +4 °C.
  • the crystals are filtered off and dried in vacuo at 50 °C to constant weight.
  • the yield of azidothymidine is 0.365 kg, 85 %.
  • the melting point is 121-122 °C.
  • silica gel thin layer chromatography chloroform/methanol 9:1
  • the Rf-value of the product is 0.8.
  • the UV-spectrum in methanol shows a wave length maximum at 266 nm (molar absorptivity 9877 measured in a 1 cm cuvet ⁇ te) .
  • the infrared spectrum (KBr-tablet) v 2110 cm -1 (- N 3 ) .
  • the proton-NMR-spectrum (CDC1 3 ; tetramethyl silane 0 ppm) : 8.21 ppm (IH, broad singlet, 3-NH) ; 7.37 ppm (IH, dublet, 6-H) ; 6.06 ppm (IH, triplet, l'-H) ; 4.41 ppm (IH, multiplet, 3'-H) ; 4.01 ppm (IH, multiplet, 5' a-H) ; 3.9S ppm (IH, multiplet, 4'-H) ; 3.83 (IH, multiplet, 5' b-H) ; 2.57 ppm (IH, multiplet, 2' a-H) ; 2.41 ppm (IH, multiplet, 2' b-H) ; 2.37 ppm (IH, multiplet, 5'-OH) ; 1.94 (3H, investigatinget, 5-CH 3 ) .

Landscapes

  • 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 porte sur un procédé de préparation de dérivés de nucléosides et notamment l'AZT. On utilise comme point de départ un 2,3'-anhydrodérivé dudit nucléoside, qui comporte en position 5' un groupe de protection assez grand, et qui est stable en conditions faiblement alcalines mais se scinde en conditions fortement alcalines, surtout en présence de pivaloyle ou d'adamantoyle. On fait réagir ce composé avec du nitrure de sodium ou de potassium et de l'halogénure de lithium en présence d'un sel tampon, après quoi, par traitement faisant intervenir une base, on sépare le groupe de protection situé en position 5' du 3'-azido-nucléoside obtenu.
PCT/FI1992/000269 1991-10-09 1992-10-07 Procede de preparation de derives de nucleosides WO1993007162A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP5506644A JPH07500100A (ja) 1991-10-09 1992-10-07 ヌクレオシド誘導体の製造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FI914767 1991-10-09
FI914767A FI90552C (fi) 1991-10-09 1991-10-09 Menetelmä nukleosidijohdannaisten valmistamiseksi

Publications (1)

Publication Number Publication Date
WO1993007162A1 true WO1993007162A1 (fr) 1993-04-15

Family

ID=8533267

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FI1992/000269 WO1993007162A1 (fr) 1991-10-09 1992-10-07 Procede de preparation de derives de nucleosides

Country Status (6)

Country Link
JP (1) JPH07500100A (fr)
CA (1) CA2119914A1 (fr)
EE (1) EE9400304A (fr)
FI (1) FI90552C (fr)
WO (1) WO1993007162A1 (fr)
ZA (1) ZA927464B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0653437A1 (fr) * 1993-11-15 1995-05-17 Bristol-Myers Squibb Company Procédé pour la préparation d'AZT et ses dérivés
US7862552B2 (en) 2005-05-09 2011-01-04 Boston Scientific Scimed, Inc. Medical devices for treating urological and uterine conditions

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997006179A1 (fr) * 1995-08-04 1997-02-20 Kobayashi Perfumery Co., Ltd. Procede permettant de produire des derives d'azidonucleoside

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0280128A2 (fr) * 1987-02-24 1988-08-31 Bayer Ag Procédé de préparation de 1-(3-azido-2,3-didéoxy-bêta-D-érythro-pentofuranoxyl)pyrimidines et intermédiaires
WO1989006655A1 (fr) * 1988-01-19 1989-07-27 Universite Pierre Et Marie Curie (Paris Vi) Procede de synthese de l'azido-3'-desoxy-3'-thymidine et analogues
US4916122A (en) * 1987-01-28 1990-04-10 University Of Georgia Research Foundation, Inc. 3'-Azido-2',3'-dideoxyuridine anti-retroviral composition

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1575805A (en) * 1976-03-12 1980-10-01 Technicon Instr Automatic diagnostic apparatus
CA1272507A (fr) * 1984-07-10 1990-08-07 Simon John Rattle Methode de dosage a l'aide d'un compose marque retenu magnetiquement
WO1987007386A1 (fr) * 1986-05-22 1987-12-03 Unilever Plc Procede immunoanalytique en phase solide
GB8620893D0 (en) * 1986-08-29 1986-10-08 Unilever Plc Assays

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4916122A (en) * 1987-01-28 1990-04-10 University Of Georgia Research Foundation, Inc. 3'-Azido-2',3'-dideoxyuridine anti-retroviral composition
EP0280128A2 (fr) * 1987-02-24 1988-08-31 Bayer Ag Procédé de préparation de 1-(3-azido-2,3-didéoxy-bêta-D-érythro-pentofuranoxyl)pyrimidines et intermédiaires
WO1989006655A1 (fr) * 1988-01-19 1989-07-27 Universite Pierre Et Marie Curie (Paris Vi) Procede de synthese de l'azido-3'-desoxy-3'-thymidine et analogues

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J. ORG. CHEM., Vol. 40, No. 24, 1975, TADASHI SASAKI et al.: "A Convenient Synthesis of 2,3'-Imino-1-(Beta-D-Lyxofuranosyl) Uracil and its Derivatives Using Azide Ion". *
JOURNAL OF HETEROCYCLIC CHEMISTRY, Vol. 27. No. 6, 1990, BAI-CHUAN PAN et al.: "Synthesis of 5-Benzyl and 5-Benzyloxybenzyl-3' Azido-2',3'-Dideoxyuridine and their Analogues as Potential Anti-Aids Agents". *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0653437A1 (fr) * 1993-11-15 1995-05-17 Bristol-Myers Squibb Company Procédé pour la préparation d'AZT et ses dérivés
US5466787A (en) * 1993-11-15 1995-11-14 Bristol-Myers Squibb Company Process for preparing AZT
CN1047781C (zh) * 1993-11-15 1999-12-29 布里斯托尔-迈尔斯斯奎布公司 制备3'－叠氮基－3'－脱氧胸苷及其衍生物的方法
US7862552B2 (en) 2005-05-09 2011-01-04 Boston Scientific Scimed, Inc. Medical devices for treating urological and uterine conditions

Also Published As

Publication number Publication date
CA2119914A1 (fr) 1993-04-15
ZA927464B (en) 1993-04-13
FI90552B (fi) 1993-11-15
EE9400304A (et) 1996-04-15
FI914767L (fi) 1993-04-10
FI914767A0 (fi) 1991-10-09
JPH07500100A (ja) 1995-01-05
FI90552C (fi) 1994-02-25

Similar Documents

Publication Publication Date Title
CA2110335C (fr) Methode de preparation de derives de n4-acyl-5'-desoxy-5-fluorocytidine
EP0316017B1 (fr) 2',3'-Didéoxy-2'-fluoronucléosides
KR20030092006A (ko) 2',3'-디데옥시-2',3'-디데하이드로뉴클레오시드 합성 방법
US8193354B2 (en) Process for preparation of Gemcitabine hydrochloride
CA2079796A1 (fr) Derives de nucleosides
JP2005139197A (ja) ５−メチルウリジンを用いる２’，３’−ジデヒドロ−３’−デオキシチミジン（ｄ４Ｔ）の製法
CA2442979C (fr) Procede de preparation de 2'-halo beta l-arabinofuranosyl nucleosides
EP0638586B1 (fr) Dérivés de nucléosides et leur préparation
AU2002303187A1 (en) Process for the preparation of 2'-HALO-Beta-L-arabinofuranosyl nucleosides
WO1993007162A1 (fr) Procede de preparation de derives de nucleosides
EP0635517B1 (fr) Procédé pour la production des dérivés de 1-(2'-déoxy-bêta-D-érythropentofuranosyl)-5-trifluorométhyluracil
EP0311694B1 (fr) Derives de nucleosides et procede pour leur preparation
US7439351B2 (en) 2′ or 3′ -deoxy and 2′, 3′-dideoxy-β-L-pentofuranonucleo-side compounds, method of preparation and application in therapy, especially as anti-viral agents
Maruyama et al. Synthesis and Anti-HIV Activity of 6-Substituted Purine 2′-Deoxy-2′-Fluororibosides
WO2000039144A1 (fr) Procede de preparation de derives fluores de nucleosides et de sucres
Van Aerschot et al. Synthesis of 2′‐Chloro‐2′, 3′‐Dideoxy‐2′, 3′‐Didehydro Nucleosides
WO1997006179A1 (fr) Procede permettant de produire des derives d'azidonucleoside
JPH11217396A (ja) ヌクレオシド誘導体の製造方法
JPH08119989A (ja) ６−置換アミノプリン誘導体の新規な製法およびその中間体
JPH0873488A (ja) １−（２−デオキシリボフラノシル）ピリダジノン誘導体の製造法
JPH11130791A (ja) ２’，５’−ジデオキシ−５’−アジドヌクレオシド類の製造方法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA FI JP NO US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
EX32 Extension under rule 32 effected after completion of technical preparation for international publication
LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)
LE32 Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b)
WWE Wipo information: entry into national phase

Ref document number: 2119914

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 1994 211598

Country of ref document: US

Date of ref document: 19940406

Kind code of ref document: A

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载