WO2007013096A1 - Improved process for the preparation of 2r, 3s-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1h-1,2,4-triazol-1-yl) butan-2-ol (voriconazole) - Google Patents
Improved process for the preparation of 2r, 3s-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1h-1,2,4-triazol-1-yl) butan-2-ol (voriconazole) Download PDFInfo
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- WO2007013096A1 WO2007013096A1 PCT/IN2006/000213 IN2006000213W WO2007013096A1 WO 2007013096 A1 WO2007013096 A1 WO 2007013096A1 IN 2006000213 W IN2006000213 W IN 2006000213W WO 2007013096 A1 WO2007013096 A1 WO 2007013096A1
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- formula
- compound
- triazol
- fluoropyrimidin
- difluorophenyl
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- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 229960004740 voriconazole Drugs 0.000 title claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 19
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 18
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-Butanol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- -1 4-chloro-6-ethyl-5-fluoropyrimidine compound Chemical class 0.000 claims description 13
- 239000007868 Raney catalyst Substances 0.000 claims description 9
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 9
- ZCSHNCUQKCANBX-UHFFFAOYSA-N Lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- LKTGVRWVTAJGMS-UHFFFAOYSA-N 4-chloro-6-ethyl-5-fluoropyrimidine Chemical compound CCC1=NC=NC(Cl)=C1F LKTGVRWVTAJGMS-UHFFFAOYSA-N 0.000 claims description 7
- 230000001476 alcoholic Effects 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- OZWKMVRBQXNZKK-UHFFFAOYSA-N Ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 claims description 3
- MIOPJNTWMNEORI-MHPPCMCBSA-N [(4R)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-MHPPCMCBSA-N 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- 125000002524 organometallic group Chemical group 0.000 claims description 3
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 2
- MIOPJNTWMNEORI-UHFFFAOYSA-M camphorsulfonate anion Chemical class C1CC2(CS([O-])(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-M 0.000 claims description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims 2
- 239000012454 non-polar solvent Substances 0.000 claims 2
- 239000003208 petroleum Substances 0.000 claims 2
- DTBVUDZWEWGJEG-UHFFFAOYSA-N zinc;propan-2-ylazanide Chemical compound [Zn+2].CC(C)[NH-].CC(C)[NH-] DTBVUDZWEWGJEG-UHFFFAOYSA-N 0.000 claims 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims 1
- FFUAGWLWBBFQJT-UHFFFAOYSA-N Bis(trimethylsilyl)amine Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims 1
- UWKKBEQZACDEBT-UHFFFAOYSA-N CCCC[Mg] Chemical compound CCCC[Mg] UWKKBEQZACDEBT-UHFFFAOYSA-N 0.000 claims 1
- VUNJVVRGYQSNQB-UHFFFAOYSA-N CCCC[Zn] Chemical compound CCCC[Zn] VUNJVVRGYQSNQB-UHFFFAOYSA-N 0.000 claims 1
- QKNDAUTYSODFJV-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;sodium Chemical compound [Na].C[Si](C)(C)N[Si](C)(C)C QKNDAUTYSODFJV-UHFFFAOYSA-N 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- 238000005695 dehalogenation reaction Methods 0.000 claims 1
- 229940093499 ethyl acetate Drugs 0.000 claims 1
- 235000019439 ethyl acetate Nutrition 0.000 claims 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- DHWFXTHZVWSSKE-UHFFFAOYSA-N magnesium;propan-2-ylazanide Chemical compound [Mg+2].CC(C)[NH-].CC(C)[NH-] DHWFXTHZVWSSKE-UHFFFAOYSA-N 0.000 claims 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims 1
- 239000011701 zinc Substances 0.000 claims 1
- 229910052725 zinc Inorganic materials 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N Diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- TUCNEACPLKLKNU-UHFFFAOYSA-N ethanone Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 3
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 3
- 229940043279 diisopropylamine Drugs 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- YEJRWHAVMIAJKC-UHFFFAOYSA-N γ-lactone 4-hydroxy-butyric acid Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 3
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 2
- 241000228212 Aspergillus Species 0.000 description 2
- 206010003486 Aspergillus infection Diseases 0.000 description 2
- 206010017533 Fungal infection Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 201000002909 aspergillosis Diseases 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 201000009910 diseases by infectious agent Diseases 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;N-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 1
- ZEMRCKIJEFNNCO-UHFFFAOYSA-N 6-ethyl-5-fluoro-1H-pyrimidin-4-one Chemical compound CCC=1NC=NC(=O)C=1F ZEMRCKIJEFNNCO-UHFFFAOYSA-N 0.000 description 1
- AARBFKKHDWSGKF-UHFFFAOYSA-N CCC(C)O.CCCCCCC Chemical compound CCC(C)O.CCCCCCC AARBFKKHDWSGKF-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N Camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- VNDYJBBGRKZCSX-UHFFFAOYSA-L Zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L Zinc chloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000001716 anti-fugal Effects 0.000 description 1
- 230000000843 anti-fungal Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- RUSXXJKVMARGOF-UHFFFAOYSA-N cyclohexane;heptane Chemical compound C1CCCCC1.CCCCCCC RUSXXJKVMARGOF-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- UJJLJRQIPMGXEZ-UHFFFAOYSA-M oxolane-2-carboxylate Chemical compound [O-]C(=O)C1CCCO1 UJJLJRQIPMGXEZ-UHFFFAOYSA-M 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003799 water insoluble solvent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The present invention relates to an improved process for the preparation of 2R, 3S-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol. It may be represented as Formula (I).
Description
Improved process for the preparation of 2R, 3S-2-(2,4-Difluorophenyl)-3-(5- fluoropyrimidin-4-yl)-l -(1H-1, 2,4- triazol-1-yl) butan-2-ol (Voriconazole)
FIELD OF THE INVENTION
The present invention relates to a improved process for the preparation of 2R, 3S-2-(2,4- Difluorophenyl)-3-(5- fluoropyrimidin-4-yl)-l -(1H-I, 2,4- triazol-1-yl) butan-2-ol It may represented as Formula ( I )
Formula ( I )
BACK GROUND OF THE INVENTION
Voriconazole exhibits excellent antifungal activity against a wide range of yeasts and filamentous fungi as demonstrated by in vitro and in vivo infection models. Viroconazole has excellent activity in vitro against Aspergillus species, shows efficacy in vivo models of aspergillosis and has demonstrated efficacy in both acute and chronic aspergillosis, with few observed side effects. Depending on the results of future clinical trials, this drug promises to become an important new agent in the treatment of invasive infections due to Aspergillus and other life- threatening fungal infections.
US 5,567,817 patent discloses relates to 2-aryl 3-(3-haloρyridin-4-yl or 5- halopyridin-4-yl)-l-(lH-l,2,4 triazol-l-yl)alkane-2ol derivatives which are useful in the treatment of fungal infections in animals,including human beings.
The US 5567817 discloses process for the preparation comprises of reacting 4- chloro-6-ethyl-5-fluoropyrimidine with l-(2,4-difluorophenyl)-2-(lH- 1 ,2,4- triazol-l-yl)ethanone in presence of Lithium diisopropy amine in Tetrahydrofuron as a solvent to get 2-(2,4-difluoroρhenyl)-3-(4-chloro-5-fluoropyrimidin-4-yl)-l- (lH-l,2,4triazol-l-yl)butan-2-ol the compound, which is further dehaloginated with 5% palladium charcol to give a Racemic Voriconazole and then resolution with camphorsufonic acid in presence of methanol medium and subsequently converted to free base with alkaline medium to give (-) Isomer of Voriconazole of Formula ( I )
Many other related patents disclose the process for the preparation of Voriconazole and its intermediates but none of those patents are related to the process of the present invention.
The prior art procedures the usage of hazardous and costly rawmaterials such as palladium on charcol and the process of the prior art reference involves a tedious work up to isolate the required product and thus results in excess time cycle which is turns resulted low yields and more scale up problems, due to that this process disclosed in the prior art become commercially not viable and not recommendable for commercial scale up.
As the Voriconazole compound of formula ( I ), which is useful in the treat ment of antigungal hence it is important to have alternate process which is cost effective and commercially viable for preparing the compound of Formula ( I ).
Therefore the main objective of the present invention is to prepare Voriconzole in improved method, which is cost effective, commercially viable and easily scalable.
The Voriconazole is prepared in the present invention, in an improved process that is cost effective and the Voriconazole obtained in this process is suitable for pharmaceutical formulations
SUMMERY OF THE INVENTION
The present invention provides an improved process for the preparation of Voriconazole and its pharmaceutically acceptable salts, the improved process of the present invention comprises, the condensation of 4-chloro-6-ethyl-5- ffluoropyrimidine with 1 -(2,4-difluorophenyl)-2-( IH- 1 ,2,4-triazol- 1 -yl)ethanone in presence of Lithium diisopropylamine as a base and n-Heptane as a solvent mixture with tetrahydrofuron to get the resulting compound 2-(2,4- difluorophenyl)-3 -(4-chloro-5-fluoropyrimidin-4-y I)- 1 -( 1 H- 1 ,2,4triazol- 1 - yl)butan-2-ol as solid. Which is then dehalogination with Raney nickel to give racemic compound of Voriconazole, which is further resolution with camphour sulfonic acid in acetone and methanol mixture to give camphor sulfonate slat of Voriconazole, which is then basified in aqueous alkaline medium and subsequent extraction with methylene chloride and distillation of solvent then isolation of the Voriconazole compound of formula ( I ) using alcohol medium as a solvent.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of 2R, 3S-2-(2,4- difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l -(1H-I, 2,4- triazol-1-yl) butan-2-ol (commonly known as Voriconazole)
The process of the present invention is schematically represented as follows.
Formula (II) (III)
Raney Nickel/Sodium aoetate/Methanol
Voriconazole Formula (I)
4-Chloro-6-ethyl-5-fluoropyrimidine (having pH above 5) reacts with 1- (2,4difluorophenyl)2-(lH-l,2,4-triazol-l-yl)ethanone in presence of Lithium diisopropylamine as a base and a mixture of n-Heptane ,n-Hexan and tetrahydrofuron as solvent medium to yield 2-(2,4 -difluorophenyl) -3-(4-chloro-5-fluoropyrimidin-4-yl)-l- ( IH-1, 2,4- l-yl)butan-2-ol Formula ( IV ).The compound of formula (IV ) is then dehalogination with Raney nickel under Hydrogen pressure in methanol as a solvent medium to give a 2R,3S/2S,3R)-2-(2,4difluoroρhenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH- l,2,4-triazol-l-yl)butan-2-ol Formula ( V ), the compound of formula (V) further resolution with R-( - ) 10- camphour sulfonic acid with the mixture of solvents Acetone and Methanol to gives an improved yields of Formula (VI) .
Accordingly, the present invention provides an improved process for the preparation of the 2R, 3S-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l -(1H-1, 2,4- triazol-1-yl) butan-2-ol (commonly known as Voriconazole)
a) Taking n-Heptane and diisopropylamine then adding n-Butylithium at below - 2O0C b) Adding 4-chloro-6-ethyl-5-fluoropyrimidine and l-(2,4-difluorophenyl)-2-(l H- 1,2,4- triazol-1-yl) ethanone in Tetrahydrofuran at a temperature of about -50 to -75°C, preferably at a temperature of about -50°C, c) Stirring the resulting reaction mixture at a temperature of about -50 to -80°C, preferably at a temperature of about -65 to -75 °C for 3 - 6 hours, d) Adding the Acetic acid at below-50°C followed by addition of water to the reaction mixture at below -10°C, e) Raising the reaction mixture temperature to 10 to 150C, f) Filtering the separated unwanted product and wash with chilled n-Heptane, g) Washing the filtrate with water 2 - 6 times, preferably 4 -5 times and separate the organic phase, h) Cooling the organic phase to -15 to -2O0C for isolation of the product i) Stirring the reaction mixture further for 1-6 hours, preferably for 2-3 hours and filter the obtained product, j) Drying the obtained wet material under vacuum at below 400C to get the compound of formula (IV)
pH of the 4-chloro-6-ethyl-5-fluoropyrimidine is checked by talcing the 1% of compound in methanol and water to the ratio of 9:1, In the same reaction, after the addition of butyl lithium to diisopropyl amine, metal exchanges can be done with Zinc chloride or with Zinc bromide as well as with magnesium halide to prepare respective organo metallic bases to get the chiral ratio in more percentage from other unwanted isomer of the title compound.
The another embodiment of present invention provides process for the preparation of compound of (2R,3S/2S,3R)-2-(2,4-difiuorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH- l,2,4-triazol-l-yl)butan-2-ol formula (V), which comprises of ;
a) Adding the compound of Formula (IV ), Raney nickel, methanol and sodium acetate in a pressure vessel, b) Maintaining the hydrogen pressure at 4-6 kg/cm2 at 40-50°C for 4-6 hours, c) After completion of the reaction filtering the raney nickel and distill the methanol, d) Basification of the obtained crude material with sodium hydroxide solution, e) Isolation of the title compound and wash with water, f) Drying the product at below 6O0C under vacuum.
Another embodiment of the present invention is to provide process for the preparation of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l(lH-l,2,4-triazol-l-yl)- butan-2-ol, R (-)-lO-camphor sulphonate compound of formula (VI) which comprises of ;
a) Dissolving the compound of formula (V) in acetone, b) Dissolving the R-(-) 10-camphorsulphonic acid in methanol, c) Adding step-b solution to step-a and stirring the reaction mixture at 5-25°C for 1- 4 hours, preferably at 15-2O0C for 2-3 hours, d) Filtering the obtained product and optionally drying the compound at 40-800C, preferably at 60-700C to give (2R,3S)-2-(2,4-difluorophenyl)-3-(5- fluoropyrimidin-4-yl)-l(lH-l,2,4-triazol-l-yl)-butan-2-ol, R (-)-lO-camphor sulphonate compound of formula (VI).
Above obtained product was carried over to next stage to obtain the product, 2R,3S-2- (254-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)- 1 -( 1 H- 1 ,2,4-triazol- 1 -yl)butan-2-ol (commonly known as Voriconazole), the process which comprises of;
a) Adjusting the pH of the compound of formula (VI) in water by treatment with an alkali or alkaline earth metal hydroxide or carbonates, preferably sodium hydroxide solution, b) Extracting the compound using water insoluble solvent, namely chloro solvents, ester solvents, less polar solvent like toluene, xylene, cyclohexane and n-heptane, preferably using chloro solvent, most preferably dichloromethane as a solvent, c) Distillation of the solvent to obtain crude Voriconazole, d) Adding alcoholic or ketonic solvent, preferably alcoholic solvent, most preferably 2-propanol to the residue, e) Stirring the reaction mixture at 0-100C for 30 miuntes to 2 hours, f) Filtering the obtained pure Voriconazole, g) Drying the Voriconazole at a temperature of about 50-80°C, preferably at a temperature of about 60-70°C.
The Voriconazole obtained in the present improved process is free flowing and non- solvated solid; hence it is well suited for pharmaceutical formulations, The process of the present invention is cost effective and getting a more yields, eco- friendly and well suited for scale up.
The examples mentioned below demonstrate specific preparations of the present invention. The examples are provided to illustrate the details of the invention and should not be construe the limit of the scope of the present invention.
EXAMPLES
Example-1 :
Preparation of 4-chloro-6-ethyI-5-fluoropyrimidine.
To a mixture of 6-ethyl-5-fluoro-4-hydroxy pyrimidine (lOOgr), dichloromethane (300ml) and triethylamine (70 gr) was slowly added phosphorous oxychloride (118 gr) over three hours stirring the reaction mixture temperature below 4O0C during the addition. The mixture was heated under reflux for 5 hours, cooled to 25 °C and cautiously quenched into 3N aqueous hydrochloric acid solution (440 ml) maintaining the temperature below 20°C during this operation layers were separated, the aqueous layer extracted with 100 ml of dichloromethane, the obtained organic layer was washed with water (250 ml) and then with 10% sodium bicarbonate solution till to get the aqueous layer pH above 7.0. stripped of the solvent under reduced pressure at below 60°C. the residue is distilled under reduced pressure (at 70-80°C, Vac 750mm/Hg) to get highly ρure 4-chloro-6-ethyl-5-fluoropyrimidine. Yield : 84 gr (Purity by HPLC : >99.0%, pH of the product 6.8).
Example -2 :
Preparation of (2R,3S/ 2S,3R): (2R,3R/2S,3S)-3-(4-chloro-5-fluoropyrimidin-6- yl)- 2-(2,4 - difluorophenyl)-l-(lH - 1,2,4-triazol-l-yI) butan-2-ol n-Heptane 112.5 ml and diisopropylamine 9.4g were taken, cooled the solution to -20 0C to - 25.O0C and then added n-Butyl lithium (41.0ml) slowly. Stirred the reaction mixture at a temperature of about -20 to -25°C for 2-4 hours. This freshly prepared lithium diisopropylamide is further cooled to -65 to -7O0C, added 4-chloro - 6- ethyl - 5- fluoropyrimidine (7.5g)(having pH range between 5 to 8) slowly to the above solution at a temperature of about -65 to -700C and then added a solution of l-(2,4-difluorophenyl)- 2-(lH-l,2,4-triazol -l-yl)ethanone (20.8grams) in Tetrahydrofuran (75.0ml) at a temperature of about -65 to -7O0C and the reaction mixture stirred at below -700C for forther 3-4 hours added acetic acid (7.5ml) to the reaction mixture at below -500C and
then added water (75.0ml) at below -10°C. Allowed the reaction mass temperature to 15°C and separated the unwanted material by filteration and collected the filtered organic layer separated the bottem aqs layer and organic layer washed with a water then cooled this organic layer to -15 to -20°C and maintained the same temperature for further 2.0hours and filtered the reaction mass and washed the material with chilled n-Heptane (7.5ml) and dried under vacuum at below 50°C to affored 5.5grams of (2R,3S/ 2S,3R): (2R,3R/2S,3S)-3-(4-chloro-5-fluoropyrimidin-6- yl)-2-(2,4 - difluorophenyl)-l-(lH - 1,2,4-triazol-l-yl) butan-2-ol (2R,3S/2S,3R isomer ratio 75% : 25%).
EXAMPLE -3:
Preparation of (2R,3S/2S,3R)-2-(2,4difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-
(lH-l,2,4-triazol-l-yI) butan-2-ol.
20.0grams of (2R, 3 S/ 2S, 3R): (2R,3R/2S,3S)-3-(4-chloro-5-fluoropyrimidin-6- yl)-2- (2,4 - difluorophenyl)-l-(lH - 1,2,4-triazol-l-yl) butan-2-ol,7.2 grams of sodium acetate ,7.0 grams of Raney nickel and 100.0ml of methanol were charged in hydrogenation vessel. Maintained Hydrogen pressure at 4-6 kg/cm2 at the temperature 40-50°C for 4-6 hours and after completion of the reaction by the TLC separated the raney nickel at 25- 350C by filteration, filterate distilled off under reduced pressure at below 70°C, 150 ml of water added to this crude and adjusted the pH between 11.0 to 12.0 with sodium hydroxide solution. Stirred the reaction mixture at 25-35°C for 90 min. Filtered the isolated solid and washed with 20 ml of water. Dry the material at 50-600C to afford 14.0 grams of (2R,3S/2S,3R)-2-(2,4difluorophenyl)-3-(5-fluoroρyrimidin-4-yl)-l-(lH- 1,2,4-triazol-l-yl) butan-2-ol. Yield : 14.0 grams.
EXAMPLE - 4:
Preparation of (2R,3S) -2-(2,4difluorophenyI )-3-(5-fluoropyrimidin-4-yl)-l-(lH~
1,2,4 triazol-1-yl) -butan-2ol R(-) -10-camphor sulphonate:
50.0 grams of (2R,3S/2S,3R)-2-(2,4difluorophenyl)-3-(5-fiuoropyriinidin-4-yl)-l-(lH- 1,2,4-triazol-l-yl) butan-2-ol dissolved in 350.0 ml of acetone and dissolved 33.2 grams of R (- ) 10 camphor sulfonic acid in 185.0 ml of Methanol and added this solution to acetone solution at 25-35°C and heated the reaction mixture to 60 to 65°C maintained for 15 to 20 min, cooled the reaction mixture to 15- 20°C and stirred for 3 hours. Filtered the separated solid and washed with 25 ml of acetone. Dried the compound at 60-70°C to afford a 30.0 grams of (2R.3S) -2-(2,4difluorophenyl )-3-(5-fluoroρyrimidin-4-yl)-l- • (1H-152,4 triazol-1-yl) -butan-2ol R(-) -10-camphor sulphonate Yield : 30.0 gr (Chiral Purity > 99.5%).
EXAMPLE - 5:
Preparation of (2R,3S) -2-(2,4difluorophenyl )-3-(5-fluoropyrimidin-4-yl)-l-(lH- 1,2,4 triazol-1-yl) -butan-2ol (Voriconazole)
To a solution of 50 grams of (2R,3S) -2-(2,4difluorophenyl )-3-(5-fluoropyrimidin-4-yl)- 1-(1H-1,2,4 triazol-l-yl) -butan-2ol R(-) -10-camphor sulphonate, 250 ml of water and 150 ml of dichloromethane is cooled to 25-35°C and adjusted the pH of the reaction mixture to 11 to 12 with sodium hydroxide solution. Separated the organic layer and washed with water. Concentrated the organic layer under reduced pressure at below 60°C. Added 200 ml of 2-propanol to the above obtained crude and cooled to 0-5°C, stirred for 3 hours. Filtered the separated solid and washed with chilled 2-propanol. Yield : 25.0 grams, HPLC Purity and chiral purity > 99.8%).
Claims
1. An improved process for the preparation of 2R, 3S-2-(2,4-Difluorophenyl)-3-(5- fluoropyrimidin-4-yl)-l -(1H-I, 2,4- triazol-1-yl) butan-2-ol (Voriconazole), which comprises:
a) Reacting 4-chloro-6-ethyl-5-fluoropyrimidine compound of formula (II) having pH range between 5 to 8,with l-(2,4-difluorophenyl)-2-(lH-l,2,4triazol-l-yl)ethanone compound of formula (III) in presence of an organo metallic base and solvent selected from non-polar solvents like n-Heptane ,n-Hexane ,cyclohexane petroleum ether, along with ethereal solvents like diethyl ether, tetrahydrofuran and mixtures thereof, gives the compound of formula (IV),
b) Dehalogenating (2R,3S/2S,3R): (2R,3R/ 2S,3S) -3-(4-chloro-5- fluoropyrimidin-6- yl)-2-(2,4-difluorophenyl)-l-(l H-l,2,4 triazol-l-yl)butane-2-ol compound of formula (IV) using a metal catalyst like Raney Nickel, Zinc/Acetic aicd in a suitable solvent selected from C1-C4 alcoholic solvents like methanol, ethanol, preferably methanol to give (2R53S/2S,3R)-2-(2,4-difluoroρhenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH- l,2,4-triazol-l-yl)butan-2-ol compound of formula (V),
c) Adding R-(-)10-Camphorsulphonic acid dissolved in C1-C4 alcohol preferably methanol to the compound of formula (V) dissolved in ketonic solvents selected from acetone, butanone, propanone and mixtures thereof, preferably acetone or adding vice versa to give (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l(lH- l,2,4-triazol-l-yl)-butan-2-ol, R (-)-lO-camphor sulphonate compound of formula (VI), d) Adjusting the pH of the compound of formula (VI) in water by treatment with an alkali or alkaline earth metal hydroxide or carbonates, preferably sodium hydroxide solution, extracting with water immiscible solvents like methylene chloride, chloroform, ethylacetate, preferably methylene chloride, isolating the Voriconazole compound of formula (I) by distillation of solvent then by adding alcoholic or ketonic solvent, preferably alcoholic solvent, most preferably 2-propanol.
2. The organo metallic base according to claim 1 a) is freshly prepared Lithium diisopropylamide, Magnesium Isopropyl amide, Zinc isopropylamide, butyl zinc, butyl magnesium, LithiuniHMDS, Sodium HMDS, Magnesium HMDS, preferably Lithium diisopropylamide and Zinc isopropyl amide, most preferably Lithium diisopropyl amide.
3. The non-polar solvent according to claim 1 a) is selected from n-Heptane ,n-Hexane, cyclohexane petroleum ether and mixtures thereof, preferably n-Heptane along with tetrhydrofuran,
4. The pH of the 4-chloro-6-ethyl-5-fluoropyrimidine according to claim 1 a) is about 5.0 to 8.0, preferably 6.0 to 7.0, more preferably 6.0.
5. Using Raney Nickel for the dehalogenation reaction of (2R,3S/2S,3R): (2R,3R/ 2S,3S) -3-(4-chloro-5- fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-l-(l H-1,2,4 triazol-1- yl)butane-2-ol, compound of formula (IV) to give (2R,3S/2S,3R)-2-(2,4- difluorophenyl)-3 -(5 -fluoropyrimidin-4-y I)- 1 -( 1 H- 1 ,2,4-triazol- 1 -yl)butan-2-ol compound of formula (V).
6. Using mixture of solvent such as acetone and methanol for the resolution of (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol- l-yl)butan-2-ol compound of formula (V) with R-(-)10-Camphor sulfonic acid to get chiral pure camphor sulfonate salt of Voriconazole.
*********
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2007132354A3 (en) * | 2006-02-01 | 2008-03-27 | Medichem Sa | Process for preparing voriconazole, new polymorphic form of intermediate thereof, and uses thereof |
WO2009020323A3 (en) * | 2007-08-06 | 2009-04-09 | Hanmi Pharm Ind Co Ltd | Process for preparing voriconazole |
WO2009053993A2 (en) * | 2007-10-22 | 2009-04-30 | Lee Pharma Limited | Process for preparation of novel salt of voriconazole oxalate form-c |
EP1828170A4 (en) * | 2004-12-14 | 2009-11-11 | Reddys Lab Ltd Dr | Process for preparing voriconazole |
KR100971371B1 (en) | 2010-02-04 | 2010-07-20 | 동국제약 주식회사 | Process for preparing voriconazole by using new intermediates |
WO2010095145A1 (en) * | 2009-02-17 | 2010-08-26 | Glenmark Generics Limited | Process for the preparation of voriconazole |
WO2010147302A2 (en) | 2009-06-17 | 2010-12-23 | 보령제약 주식회사 | Novel intermediates of voriconazole and preparation method of voriconazole using the same |
WO2011110198A1 (en) | 2010-03-10 | 2011-09-15 | Synthron B.V. | A process for making voriconazole |
CN106432198A (en) * | 2016-09-08 | 2017-02-22 | 浙江华海药业股份有限公司 | Method for preparing voriconazole resolution intermediate |
-
2006
- 2006-06-26 WO PCT/IN2006/000213 patent/WO2007013096A1/en not_active Application Discontinuation
- 2006-06-26 EP EP06780522A patent/EP1899327A1/en not_active Withdrawn
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DATABASE CAPLUS [online] XP003007869, accession no. STN Database accession no. (142:355269) * |
DATABASE CAPLUS [online] XP003007870, accession no. STN Database accession no. (142:336363) * |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
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EP1828170A4 (en) * | 2004-12-14 | 2009-11-11 | Reddys Lab Ltd Dr | Process for preparing voriconazole |
US8039619B2 (en) | 2004-12-14 | 2011-10-18 | Dr. Reddy's Laboratories Limited | Process for preparing (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol |
US8143397B2 (en) | 2006-02-01 | 2012-03-27 | Medichem S.A. | Process for preparing voriconazole, new polymorphic form of intermediate thereof, and uses thereof |
WO2007132354A3 (en) * | 2006-02-01 | 2008-03-27 | Medichem Sa | Process for preparing voriconazole, new polymorphic form of intermediate thereof, and uses thereof |
WO2009020323A3 (en) * | 2007-08-06 | 2009-04-09 | Hanmi Pharm Ind Co Ltd | Process for preparing voriconazole |
US8263769B2 (en) | 2007-08-06 | 2012-09-11 | Hanmi Science | Process for preparing voriconazole |
WO2009053993A2 (en) * | 2007-10-22 | 2009-04-30 | Lee Pharma Limited | Process for preparation of novel salt of voriconazole oxalate form-c |
WO2009053993A3 (en) * | 2007-10-22 | 2009-09-24 | Lee Pharma Limited | Process for preparation of novel salt of voriconazole oxalate form-c |
WO2010095145A1 (en) * | 2009-02-17 | 2010-08-26 | Glenmark Generics Limited | Process for the preparation of voriconazole |
US20110312977A1 (en) * | 2009-02-17 | 2011-12-22 | Glenmark Generics Limited | Process for the preparation of voriconazole |
WO2010147302A3 (en) * | 2009-06-17 | 2011-03-10 | 보령제약 주식회사 | Novel intermediates of voriconazole and preparation method of voriconazole using the same |
WO2010147302A2 (en) | 2009-06-17 | 2010-12-23 | 보령제약 주식회사 | Novel intermediates of voriconazole and preparation method of voriconazole using the same |
KR100971371B1 (en) | 2010-02-04 | 2010-07-20 | 동국제약 주식회사 | Process for preparing voriconazole by using new intermediates |
US8575344B2 (en) | 2010-02-04 | 2013-11-05 | Dongkook Pharmaceutical Co., Ltd. | Process for preparing voriconazole by using new intermediates |
WO2011110198A1 (en) | 2010-03-10 | 2011-09-15 | Synthron B.V. | A process for making voriconazole |
CN106432198A (en) * | 2016-09-08 | 2017-02-22 | 浙江华海药业股份有限公司 | Method for preparing voriconazole resolution intermediate |
CN106432198B (en) * | 2016-09-08 | 2022-10-21 | 浙江华海药业股份有限公司 | Method for preparing voriconazole split intermediate |
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WO2007013096A8 (en) | 2007-03-29 |
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