WO2005040184A1 - Process for the preparation of doxifluridine - Google Patents
Process for the preparation of doxifluridine Download PDFInfo
- Publication number
- WO2005040184A1 WO2005040184A1 PCT/IB2004/003448 IB2004003448W WO2005040184A1 WO 2005040184 A1 WO2005040184 A1 WO 2005040184A1 IB 2004003448 W IB2004003448 W IB 2004003448W WO 2005040184 A1 WO2005040184 A1 WO 2005040184A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- process according
- compound
- reaction
- doxifluridine
- Prior art date
Links
- 0 C[C@@]([C@@]1O*)OC(*)[C@@]1O* Chemical compound C[C@@]([C@@]1O*)OC(*)[C@@]1O* 0.000 description 4
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- 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
Definitions
- the present invention relates to a process for the preparation of doxifluridine and more particularly to a process of preparation characterized by high yields and reduced formation of impurities.
- Doxifluridine or 5'-deoxy-5-fluorouridine
- antineoplastic agent Merk Index No. 3471 , 13 th Ed. 2001
- this patent describes a process for production of doxifluridine that comprises essentially the coupling reaction between a ribose derivative modified at 5" and suitably protected (III), and activated 5-fluorouracil (IV), according to the scheme:
- Said coupling reaction takes place in the presence of a Lewis acid, such as trimethylsilyltrifluoromethanesulphonate or tin tetrachloride, in an inert organic solvent, at or below room temperature, preferably cooling in ice.
- a Lewis acid such as trimethylsilyltrifluoromethanesulphonate or tin tetrachloride
- the object of the present invention is a process for the preparation of doxifluridine of formula
- R represents a linear or branched aliphatic C C 5 acyl or benzoyl, optionally substituted with C C 5 alkyls, C C 5 alkoxyls or halogens,
- R' represents R or a linear or branched C r C 5 alkyl, R and R' being identical or different,
- R" identical or different, represent a C ⁇ C ⁇ alkyl or a phenyl
- said Lewis acid is added at a temperature below 0°C, preferably below -10°C, more preferably between about -15 and -20°C.
- the reaction mixture is then maintained at the same temperature for a variable time, preferably for at least about 2 h, more preferably at least about 4 h.
- R and R' preferably represent acyl, more preferably acetyl, and IV, in which the R" are preferably identical to one another and preferably represent methyl, can be prepared according to known methods, for example as described in US4340729.
- the Lewis acid used is preferably trimethylsilyltrifluoromethanesulphonate or tin tetrachloride, more preferably tin tetrachloride.
- Inert organic solvents that are preferred according to the present invention are chlorinated solvents, preferably methylene chloride, or aromatic solvents, preferably toluene, more preferably the chlorinated solvents.
- the coupling product II of the present reaction in which R preferably represents acyl, more preferably acetyl, can then be submitted directly to the appropriate known reactions of deprotection for the removal of the specific, preselected protecting groups, for example as described in US4340729, to give doxifluridine.
- reaction carried out according to the present invention (1A) shows a surprising decrease of the main impurity (retention time 23.8 minutes) from 11 % to 1 % and, at the same time, a significant increase in the desired product II, from 70% to 90%, relative to the reaction carried out in the conditions described in the prior art (1B).
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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04791727A EP1678192A1 (en) | 2003-10-22 | 2004-10-21 | Process for the preparation of doxifluridine |
JP2006536208A JP2007509128A (en) | 2003-10-22 | 2004-10-21 | Method for producing doxyfluridine |
US10/576,598 US20070073050A1 (en) | 2003-10-22 | 2004-10-21 | Process for the preparation of doxifluridine |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT002059A ITMI20032059A1 (en) | 2003-10-22 | 2003-10-22 | PROCESS FOR THE PREPARATION OF DOXIFLURIDINE. |
ITMI2003A002059 | 2003-10-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005040184A1 true WO2005040184A1 (en) | 2005-05-06 |
Family
ID=34509454
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2004/003448 WO2005040184A1 (en) | 2003-10-22 | 2004-10-21 | Process for the preparation of doxifluridine |
Country Status (6)
Country | Link |
---|---|
US (1) | US20070073050A1 (en) |
EP (1) | EP1678192A1 (en) |
JP (1) | JP2007509128A (en) |
KR (1) | KR20060110867A (en) |
IT (1) | ITMI20032059A1 (en) |
WO (1) | WO2005040184A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2210895A1 (en) | 2009-01-27 | 2010-07-28 | F. Hoffmann-La Roche AG | Process for the recovery of beta-Acetylfuranoside |
CN108117574A (en) * | 2017-12-27 | 2018-06-05 | 连云港笃翔化工有限公司 | A kind of synthetic method of doxifluridine |
CN108558960A (en) * | 2018-05-16 | 2018-09-21 | 新乡拓新药业股份有限公司 | A kind of preparation method of tri--O- acetyl group -5- deoxidations-β of 1,2,3--D-ribose |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4340729A (en) * | 1979-06-12 | 1982-07-20 | Hoffmann-La Roche Inc. | 5'-Deoxy-5-fluorouridine |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4330729A (en) * | 1980-07-30 | 1982-05-18 | General Electric Company | Locking support arrangement for a flexible sound-generating diaphragm |
-
2003
- 2003-10-22 IT IT002059A patent/ITMI20032059A1/en unknown
-
2004
- 2004-10-21 WO PCT/IB2004/003448 patent/WO2005040184A1/en not_active Application Discontinuation
- 2004-10-21 KR KR1020067007581A patent/KR20060110867A/en not_active Application Discontinuation
- 2004-10-21 EP EP04791727A patent/EP1678192A1/en not_active Withdrawn
- 2004-10-21 JP JP2006536208A patent/JP2007509128A/en not_active Withdrawn
- 2004-10-21 US US10/576,598 patent/US20070073050A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4340729A (en) * | 1979-06-12 | 1982-07-20 | Hoffmann-La Roche Inc. | 5'-Deoxy-5-fluorouridine |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2210895A1 (en) | 2009-01-27 | 2010-07-28 | F. Hoffmann-La Roche AG | Process for the recovery of beta-Acetylfuranoside |
WO2010086247A1 (en) | 2009-01-27 | 2010-08-05 | F. Hoffmann-La Roche Ag | Process for the recovery of beta-acetylfuranoside |
CN102245621A (en) * | 2009-01-27 | 2011-11-16 | 霍夫曼-拉罗奇有限公司 | Process for the recovery of beta-acetylfuranoside |
CN108117574A (en) * | 2017-12-27 | 2018-06-05 | 连云港笃翔化工有限公司 | A kind of synthetic method of doxifluridine |
CN108558960A (en) * | 2018-05-16 | 2018-09-21 | 新乡拓新药业股份有限公司 | A kind of preparation method of tri--O- acetyl group -5- deoxidations-β of 1,2,3--D-ribose |
Also Published As
Publication number | Publication date |
---|---|
ITMI20032059A1 (en) | 2005-04-23 |
JP2007509128A (en) | 2007-04-12 |
US20070073050A1 (en) | 2007-03-29 |
KR20060110867A (en) | 2006-10-25 |
EP1678192A1 (en) | 2006-07-12 |
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