CN1488629A - Method for preparing triazole antifungal agent - Google Patents
Method for preparing triazole antifungal agent Download PDFInfo
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- CN1488629A CN1488629A CNA021292973A CN02129297A CN1488629A CN 1488629 A CN1488629 A CN 1488629A CN A021292973 A CNA021292973 A CN A021292973A CN 02129297 A CN02129297 A CN 02129297A CN 1488629 A CN1488629 A CN 1488629A
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- 238000000034 method Methods 0.000 title claims abstract description 29
- 150000003852 triazoles Chemical class 0.000 title description 11
- 239000003429 antifungal agent Substances 0.000 title description 9
- 229940121375 antifungal agent Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 238000004519 manufacturing process Methods 0.000 claims abstract 2
- 239000011737 fluorine Substances 0.000 claims description 78
- 229910052731 fluorine Inorganic materials 0.000 claims description 78
- 239000002585 base Substances 0.000 claims description 48
- 239000001257 hydrogen Substances 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 150000002431 hydrogen Chemical class 0.000 claims description 26
- 239000000460 chlorine Substances 0.000 claims description 24
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 22
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 22
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 22
- 229910052794 bromium Inorganic materials 0.000 claims description 22
- 229910052801 chlorine Inorganic materials 0.000 claims description 22
- 238000006722 reduction reaction Methods 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 12
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 11
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 11
- 239000011630 iodine Substances 0.000 claims description 11
- 229910052740 iodine Inorganic materials 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 9
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- -1 phenylsulfonyloxy Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 238000012546 transfer Methods 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 5
- 230000003197 catalytic effect Effects 0.000 claims description 5
- 230000003287 optical effect Effects 0.000 claims description 5
- XUJHKPSBHDQIOD-UHFFFAOYSA-N (2-bromo-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl)methanesulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)C(Br)C1C2(C)C XUJHKPSBHDQIOD-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 238000010537 deprotonation reaction Methods 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 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
- 150000001447 alkali salts Chemical class 0.000 claims description 3
- 239000001103 potassium chloride Substances 0.000 claims description 3
- 235000011164 potassium chloride Nutrition 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical group [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 2
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 claims description 2
- 230000005595 deprotonation Effects 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 229940071870 hydroiodic acid Drugs 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229950004288 tosilate Drugs 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 11
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims 1
- 229910000024 caesium carbonate Inorganic materials 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 229910003002 lithium salt Inorganic materials 0.000 claims 1
- 159000000002 lithium salts Chemical group 0.000 claims 1
- 239000001632 sodium acetate Substances 0.000 claims 1
- 235000017281 sodium acetate Nutrition 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 229950005953 camsilate Drugs 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241001136487 Eurotium Species 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 150000002118 epoxides Chemical class 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 241000186046 Actinomyces Species 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000005935 nucleophilic addition reaction Methods 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- ZOFJBHYCGASUQK-UHFFFAOYSA-N sodium;trimethylsilylazanide Chemical compound [Na+].C[Si](C)(C)[NH-] ZOFJBHYCGASUQK-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 description 1
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000228232 Aspergillus tubingensis Species 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061217 Infestation Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
Abstract
The invention is a method for manufacturing compound in formula (I) and the acceptable salt of the compound.
Description
Technical field
The present invention relates to prepare the novel method of antifungal drug in triazole class.
Background technology
Over past ten years, the invasive infections with fungi sickness rate continue to rise, and has become and cause the whole world one of the relative disease main causes of death that catch.The fungi infestation pathogenic agent is the most common with candidiasis, aspergillus tubigensis and cryptococcus, however clinical still do not have so far can these pathogenic agent of early detection due to aggressive easy, the noninvasive diagnostic method that infect.Existing antifungal drug is limited amount not only then, and also exists the anti-mycotic activity spectrum narrower, and pharmacokinetics character is relatively poor, and problems such as security and drug interaction are arranged, and causing now, treatment of fungal infections is subjected to the increasingly extensive attention of people.The novel antifungal drug in triazole class of this class is a big primary categories of present antifungal drug, and its representative drugs that is used for the treatment of invasive infections with fungi comprises fluconazole and itraconazole etc.
Existing document CN1109421A has reported triazole antifungal agent and preparation method thereof, but unsubstituted on its disclosed compound triazole ring, the invention discloses the new anti-mycotic agent that some triazole ring 3-positions or 5-position replace, find that wherein compound that 3-position or 5-position fluorine replace has extra high external activity to aggressive Eurotium etc., is worth further research.
Summary of the invention
The present invention relates to have the active triazole derivative of antifungal drug, its chemical structural formula is suc as formula shown in (I):
X in the formula
1And X
2Be independently selected from the group that hydrogen, C1-C4 alkyl and chlorine, bromine, iodine, fluorine or other can be removed by reduction reaction respectively; X
3Be selected from hydrogen, chlorine, bromine, iodine or fluorine;
R
1And R
2Independently be selected from the group that hydrogen, chlorine, bromine, iodine or other can be removed by the reduction reaction selectivity respectively; (a) formula (II) compound of 1 '-deprotonation form and formula (III) compound are reacted in the presence of proton-inert organic solvent, obtain formula (IA) compound
Formula (II)
Formula (III)
X in the formula
1And X
2Be independently selected from the group that hydrogen, C1-C4 alkyl, chlorine, bromine, iodine, fluorine or other can be removed by reduction reaction respectively, X
1And X
2One of them is when the hydrogen, the person is the group that chlorine, bromine, iodine, fluorine or other can be removed by reduction reaction in addition; X
3Be selected from hydrogen, chlorine, bromine, iodine or fluorine;
R
1And R
2Independently be selected from the group that hydrogen, chlorine, bromine, iodine, fluorine or other can be removed by the reduction reaction selectivity respectively.
After this reaction, as required, formula (IA) compound can be converted into its acid salt;
According to the method disclosed in the present preparation formula (I) compound, in nucleophilic addition, promptly in the step (a), because new intermediate formula (III) compound that adopts 3-position or 3-position to replace, reaction yield is up to 60-70%, and the document productive rate is less than 5%, reacting stereoselectivity in addition obviously improves, in this nucleophilic addition of the present invention, two couples of optical isomers (2R, 3S/2S, 3R): (2R, 3R/2S, 3S) ratio was brought up to 5: 1 by 1: 1, was fit to macro preparation.
Preferred formula (III) compound is selected from 6-ethyl-2,4-two chloro-5-fluorine pyrimidines, 6-ethyl-4-chloro-5-fluorine pyrimidine, 6-ethyl-2-chloro-5-fluorine pyrimidine or 4-ethyl-5-fluorine pyrimidine.
In general method, suitable alkali (as: lithium diisopropylamine or two (TMS) sodium amide or potassium) makes the deprotonation of formula (II) compound by adding about 1 equivalent, make then gained salt (preferred lithium, potassium or sodium) on the spot with formula (III) reactive ketone.Generally in suitable organic solvent (tetrahydrofuran (THF), toluene or ether), under inert atmosphere (as: nitrogen or argon), in-80 ℃ to-10 ℃, preferred-70 ℃ to-60 ℃ are reacted.
As formula (II) compound of starting raw material or known compound (referring to D.L.Cominsetal, Hetercycles,
22, 339 (1984)), or can prepare according to literature method.Maybe can be as formula (III) compound of starting raw material or known compound (referring to EP-A-44605, EP-A-69422 or GB-A-1464224) by being similar to this described method preparation.After this reaction, as required, formula (IA) compound can be converted into its pharmacologically acceptable salt; Acid salt is spirit of salt, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, methylsulfonic acid, camphorsulfonic acid, R-(-)-10-camphorsulfonic acid, (+)-3-bromo-10-camphorsulfonic acid, (-)-3-bromo-10-camphorsulfonic acid, phosphoric acid, methylsulfonic acid or tosilate, and preferred salt is the hydrogen chlorate.
(b) alkali of following formula (IV) compound or formula V compound and formula (VI) compound forms salt or reacts with formula (VI) compound in the presence of additional alkali, obtains formula (I) compound.
Formula (IV) formula V
X in the formula
1And X
2Be independently selected from the group that hydrogen, C1-C4 alkyl and chlorine, bromine, iodine, fluorine or other can be removed by reduction reaction respectively; X
3Be selected from hydrogen, chlorine, bromine, iodine or fluorine;
R
1And R
2Independently be selected from the group that hydrogen, chlorine, bromine, iodine or other can be removed by the reduction reaction selectivity respectively;
Z is chlorine, bromine, iodine, C1-C4 alkane sulfonyloxy, (replacement) phenylsulfonyloxy or other leavings group; After this reaction, as required, formula (I) compound can be converted into its pharmacologically acceptable salt; As required, formula (IA) compound can be converted into its pharmacologically acceptable salt;
The example of the suitable alkali salt of the triazole shown in the formula (VI) is a basic metal, particular certain cancers and sylvite, and tetraalkylammonium salt, preferred tetra-n-butyl ammonium salt (referring to US-A-4259505).
Adopt formula (IV) epoxide to react at last as starting raw material.If use the formula V compound in the method, reaction mechanism shows: form (being that small part forms at least) corresponding formula (IV) epoxide under this reaction conditions on the spot.This method is similar as the method for starting raw material to employing formula (IV) epoxide thus to answer this.
During the alkali salt of the triazole shown in the employing formula (VI), in the organic solvent (as: dimethyl formamide or tetrahydrofuran (THF)) that uses, under room temperature to 100 ℃, carry out this reaction.If the sodium salt of the triazole shown in the use formula (VI), preferred about 60 ℃ temperature of reaction; If adopt corresponding tetra-n-butyl ammonium salt, the temperature of reaction about then preferred room temperature.
In addition, in The suitable solvent (as: dimethyl formamide, addition or aqueous acetone), preferred 50 ℃ to 60 ℃ temperature of reaction, in the presence of additional suitable alkali (as: yellow soda ash or salt of wormwood), the triazole shown in the employing formula (VI) also can be carried out this reaction.
The preparation of intermediate formula (IV) compound and formula V compound specifically can be with reference to the method preparation of CN1040504C.
(C) with formula (IA) compound or pharmacy acceptable salt reduction, obtain formula (IB) compound.
X in the formula (IB)
1And X
2One of them is a hydrogen, the person is hydrogen, C1-C4 alkyl or fluorine in addition; X
3Be selected from hydrogen or fluorine;
R
1And R
2Independently be selected from hydrogen, fluorine respectively;
Described reduction reaction is catalytic hydrogenolysis or transfer catalysis hydrogenolysis, and particularly, catalytic hydrogenolytic cleavage is used palladium carbon catalyst, logical hydrogen, and pressurization is in case of necessity carried out described catalytic hydrogenolytic cleavage and is made formula (I) compound.Palladium carbon catalyst is for example used in the also available transfer catalysis hydrogenolysis preparation of formula (I) compound, and ammonium formate under reflux can obtain formula (I) compound.
(d) formula (I) compound and optical activity acid-respons are got diastereoisomeric salt, through fractional crystallization split the enantiomorph of formula (I) compound, wherein preferred optical activity acid is 1S-(+) or R-(-)-10-camphorsulfonic acid.
The formula that described preparation method makes (I) compound or pharmaceutically acceptable salt thereof is:
(2R, 3S)-3-(2,4-two chloro-5-fluorine pyrimidine-6-yls)-2-(2,4 difluorobenzene base)-1-(3-chloro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol (1);
(2R, 3S)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(3,5-two chloro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol (2);
(2R, 3S)-3-(2,4-two chloro-5-fluorine pyrimidine-6-yls)-2-(2,4 difluorobenzene base)-1-(3-chloro-5-fluoro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol (3);
(2R, 3S)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(3-chloro-5-ethyl-1H-1,2,4-triazol-1-yl) fourth-2-alcohol (4);
(2R, 3S)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(3-chloro-5-fluoro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol (5);
(2R, 3S)-3-(5-fluorine pyrimidine-4-yl)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl) fourth-2-alcohol (6);
(2R, 3S)-3-(5-fluorine pyrimidine-4-yl)-2-(2,4 difluorobenzene base)-1-(5-fluoro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol (7);
(2R, 3S)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(5-methyl isophthalic acid H-1,2,4-triazol-1-yl) fourth-2-alcohol (8);
(2R, 3S)-3-(5-fluorine pyrimidine-4-yl)-2-(2,4 difluorobenzene base)-1-(5-ethyl-1H-1,2,4-triazol-1-yl) fourth-2-alcohol (9).
Be dissolved among the DMSO by the reagent thing, preparation different concns sample solution joins the husky Bao Shi agar glucose base of inoculating strain subject, cultivates 37 ℃ of sons, hatches 48 hours, and the inspection that continues has or not fungal growth.Adopt Eurotium (15 strain), sufficient actinomyces (5 strain) in the test.
Table 1 target compound extracorporeal antifungal activity
MIC(μg/mL)
Compound Eurotium foot actinomyces
5 9.1 26
6 0.25 8.0
7 0.05 0.9
8 20.5 41
9 19 37
Embodiment
Embodiment 1. (2R, 3S/2S, 3R)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(3-chloro-1H-1,2,4-triazol-1-yl) fourth 2-alcohol
With two (TMS) sodium amide (the tetrahydrofuran solution 160ml of 1.0M), be added in the 350ml tetrahydrofuran (THF), in the presence of nitrogen, see that this solution is cooled to-65 ℃, 45 minutes, the 120ml tetrahydrofuran solution of adding 4-chloro-6-ethyl-5-fluorine pyrimidine (CN1040504C is seen in preparation) 25.5g.After 3 hours, the tetrahydrofuran (THF) 120ml solution with dripping 1-(2,4 difluorobenzene base)-2-(3-chloro-1H-1,2,4-triazol-1-yl) ethyl ketone 41.2g in 30 minutes, neutralizes with glacial acetic acid after 1 hour at-65 ℃ of stirring reactions-65 ℃ of stirrings.Interior temperature rise washes the separation organic layer with water after-20 ℃, and with the anti-water lift phase of ethyl acetate 200ml, merges organic layer, drying, and filtration, concentrating under reduced pressure adds the Virahol saturated solution 10ml of hydrogenchloride then, separates out white solid 45.5, productive rate 62.5%.Mass spectrum (FAB) 419 (M+1), ultimate analysis C
16H
13Cl
3F
3N
5O calculated value: C42.24% H2.86% N15.40% Cl23.43% F12.54%; Measured value: C42.39%H2.71% N15.53% Cl23.56% F12.37%.
In the three neck round-bottomed flasks of 500ml, add 40g (2R, 3S/2S, 3R)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2, the 4-difluorophenyl)-1-(3-chloro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol hydrochloride, the 100ml ethyl acetate, 200ml water, the 20g anhydrous sodium carbonate transfers to alkalescence, stir and tell organic layer after 3 hours, water layer is used ethyl acetate extraction 1 time again, merges organic layer, organic layer washing 3 times, anhydrous sodium sulfate drying filters, be concentrated into dried, 33.5g oily matter, productive rate 91%.Mass spectrum (FAB) 419 (M+1), ultimate analysis C
16H
12Cl
2F
3N
5O calculation value: C45.93% H2.87%N16.75% Cl16.99% F13.64%; Measured value: C45.70% H2.68% N16.85% Cl16.71%F13.51%.
Prepared following compounds with method:
(2R, 3S/2S, 3R)-3-(2,4-two chloro-5-fluorine pyrimidine-6-yls)-2-(2,4 difluorobenzene base)-1-(3-chloro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S/2S, 3R)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(3,5-two chloro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S/2S, 3R)-3-(2,4-two chloro-5-fluorine pyrimidine-6-yls)-2-(2,4 difluorobenzene base)-1-(3-chloro-5-fluoro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S/2S, 3R)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(3-chloro-5-ethyl-1H1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S/2S, 3R)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(3-chloro-5-fluoro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol.
Embodiment 2. (2R, 3S/2S, 3R)-3-(5-fluorine pyrimidine-4-yl)-2-(2,4 difluorobenzene base)-1-(5-fluoro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol
In the high pressure kettle, add 48g (2R, 3S/2S, 3R)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2, the 4-difluorophenyl)-1-(3-chloro-5-fluoro--1H-1,2,4-triazol-1-yl) fourth-2-alcohol, 100ml95% ethanol, the 8g sodium acetate, anhydrous, 3g palladium/carbon (10%) is till feeding hydrogen is extremely no longer inhaled hydrogen under 25 ℃ of 3-5 normal atmosphere.Filtration, filtrate is concentrated into dried, adds the dissolving of 100ml methylene dichloride, washes with water 2 times, and anhydrous sodium sulfate drying filters, and concentrates, and uses the Virahol recrystallization, gets the 38.4g white crystals, productive rate 88%, m.p.120-122 ℃.Ultimate analysis C
16H
13F
4N
5O calculated value: C55.32%H3.54% N19.07% F20.71%; Measured value: C55.27% H3.62% N19.21% F20.67%.Mass spectrum (FAB) 368 (M+1).Hydrogen nuclear magnetic resonance spectrum (DMSO-d
6) δ 9.045 (d, J=3.1Hz, 1H), 8.856 (d, J=1.7Hz, 1H), 8.244 (s, 1H), 7.279 (m, 1H), 7.194 (m, 1H), 6.923 (m, 1H), 5.987 (s, 1H), 4.827 (d, J=14.1Hz, 1H), 4.335 (d, J=14.1Hz, 1H), 3.931 (q, J=7.1Hz, 1H), 1.118 (d, J=7.1Hz, 1H).
Prepared following compounds with method:
(2R, 3S/2S, 3R)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(5-methyl isophthalic acid H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S/2S, 3R)-3-(5-fluorine pyrimidine-4-yl)-2-(2,4 difluorobenzene base)-1-(5-ethyl-1H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S/2S, 3R)-3-(5-fluorine pyrimidine-4-yl)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl) fourth-2-alcohol.
Embodiment 3. (2R, 3S)-2-(2,4 difluorobenzene base)-3-(5-fluorine pyrimidine-4-yl)-1-(5-fluoro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol R-(-)-10-camsilate
In the three neck round-bottomed flasks of 1000ml, add 15g (2R, 3S/2S, 3R)-2-(2, the 4-difluorophenyl)-3-(5-fluorine pyrimidine-4-yl)-1-(5-fluoro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol, 420ml acetone, 140ml methyl alcohol treats that solid dissolves the back fully and adds the 9.4g l-camphor sulfonic acid fast, there is a large amount of white solids to separate out, stirs after 2 hours suction filtration, with acetone/methanol (3: 1) solution washing, dry white crystals 8.6g, the productive rate 35.0% of getting, m.p.168-170 ℃, [a]
D 25-43.5 ° (2mg/ml methyl alcohol).Ultimate analysis C
26H
29F
4N
5O
5S calculated value: C52.09% H4.84%N11.69% S5.34% F12.69%; Measured value: C52.24% H4.63% N11.77% S5.43% F12.78%.Mass spectrum (FAB) 368 (M+1).
Prepared following compounds with method:
(2R, 3S)-3-(2,4-two chloro-5-fluorine pyrimidine-6-yls)-2-(2,4 difluorobenzene base)-1-(3-chloro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol R-(-)-10-camsilate;
(2R, 3S)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(3,5-two chloro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol R-(-)-10-camsilate;
(2R, 3S)-3-(2,4-two chloro-5-fluorine pyrimidine-6-yls)-2-(2,4 difluorobenzene base)-1-(3-chloro-5-fluoro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol R-(-)-10-camsilate;
(2R, 3S)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(3-chloro-5-ethyl-1H-1,2,4-triazol-1-yl) fourth-2-alcohol R-(-)-10-camsilate;
(2R, 3S)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(3-chloro-5-fluoro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol R-(-)-10-camsilate;
(2R, 3S)-3-(5-fluorine pyrimidine-4-yl)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl) fourth-2-alcohol R-(-)-10-camsilate;
(2R, 3S)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(5-methyl isophthalic acid H-1,2,4-triazol-1-yl) fourth-2-alcohol R-(-)-10-camsilate;
(2R, 3S)-3-(5-fluorine pyrimidine-4-yl)-2-(2,4 difluorobenzene base)-1-(5-ethyl-1H-1,2,4-triazol-1-yl) fourth-2-alcohol R-(-)-10-camsilate.
Embodiment 4. (2R, 3S)-2-(2,4 difluorobenzene base)-3-(5-fluorine pyrimidine-4-yl)-1-(5-fluoro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol
In the three neck round-bottomed flasks of 1000ml, and adding 10g (2R, 3S)-2-(2, the 4-difluorophenyl)-3-(5-fluorine pyrimidine-4-yl)-1-(5-fluoro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol R-(-)-10-camsilate, 100ml water, the 50ml methylene dichloride is after being stirred to solid and dissolving fully, add the 4N sodium hydroxide solution and transfer pH11, continue to stir 1 hour, take out then and tell organic layer, water layer is used dichloromethane extraction 1 time again, merge organic layer, wash anhydrous sodium sulfate drying 3 times.Filter, concentrate, the Virahol recrystallization gets the 4.8g white crystals, productive rate 78%, m.p.120-123 ℃.[a]
D 26-71 ° (1mg/ml methyl alcohol).Ultimate analysis C
16H
13F
4N
5O calculated value: C52.32% H3.54% N19.07%F20.71%; Measured value: C52.38% H3.63% N19.17% F20.86%.Mass spectrum (FAB) 368 (M+1).Hydrogen nuclear magnetic resonance spectrum (DMSO-d
6) δ 9.0551 (d, J=3.1Hz, 1H), 8.854 (d, J=1.7Hz, 1H), 8.251 (s, 1H), 7.283 (m, 1H), 7.183 (m, 1H), 6.925 (m, 1H), 6.08 (s, 1H), 4.821 (d, J=14.1Hz, 1H), 4.354 (d, J=14.1Hz, 1H), 3.943 (q, J=6.9Hz, 1H), 1.131 (d, J=6.9Hz, 1H).
Prepared following compounds with method:
(2R, 3S)-3-(2,4-two chloro-5-fluorine pyrimidine-6-yls)-2-(2,4 difluorobenzene base)-1-(3-chloro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(3,5-two chloro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S)-3-(2,4-two chloro-5-fluorine pyrimidine-6-yls)-2-(2,4 difluorobenzene base)-1-(3-chloro-5-fluoro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(3-chloro-5-ethyl-1H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(3-chloro-5-fluoro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S)-3-(5-fluorine pyrimidine-4-yl)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(5-methyl isophthalic acid H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S)-3-(5-fluorine pyrimidine-4-yl)-2-(2,4 difluorobenzene base)-1-(5-ethyl-1H-1,2,4-triazol-1-yl) fourth-2-alcohol.
Claims (11)
1. the method for preparation formula (I) compound and formula (I) compound pharmacy acceptable salt.
X in the formula
1And X
2Be independently selected from the group that hydrogen, C1-C4 alkyl and chlorine, bromine, iodine, fluorine or other can be removed by reduction reaction respectively; X
3Be selected from hydrogen, chlorine, bromine, iodine or fluorine;
R
1And R
2Independently be selected from the group that hydrogen, chlorine, bromine, iodine or other can be removed by the reduction reaction selectivity respectively; The method of said preparation formula (I) compound or its pharmaceutically useful salt comprises:
(a) formula (II) compound of 1 '-deprotonation form and formula (III) compound are reacted in the presence of proton-inert organic solvent, obtain formula (IA) compound
Formula (II)
Formula (III)
X in the formula
1And X
2Be independently selected from the group that C1-C4 alkyl, chlorine, bromine, iodine, fluorine or other can be removed by reduction reaction respectively, and X
1And X
2When one of them was hydrogen, the person then was C1-C4 alkyl, fluorine, halogens chlorine, bromine or iodine in addition;
X
3Be selected from hydrogen, chlorine, bromine, iodine or fluorine;
R
1And R
2Independently be selected from the group that hydrogen, chlorine, bromine, iodine, fluorine or other can be removed by the reduction reaction selectivity respectively.
After this reaction, as required, formula (IA) compound can be converted into its acid salt;
(b) alkali of following formula (IV) compound or formula V compound and formula (VI) compound forms salt or reacts with formula (VI) compound in the presence of additional alkali, obtains formula (I) compound.
Or
Formula (IV) formula V
Formula (VI)
X in the formula
1And X
2Be independently selected from the group that hydrogen, C1-C4 alkyl and chlorine, bromine, iodine, fluorine or other can be removed by reduction reaction respectively; X
3Be selected from hydrogen, chlorine, bromine, iodine or fluorine;
R
1And R
2Independently be selected from the group that hydrogen, chlorine, bromine, iodine or other can be removed by the reduction reaction selectivity respectively;
Z is chlorine, bromine, iodine, C1-C4 alkane sulfonyloxy, (replacement) phenylsulfonyloxy or other leavings group; After this reaction, as required, formula (I) compound can be converted into its pharmacologically acceptable salt;
(C) with formula (IA) compound or pharmacy acceptable salt reduction, obtain formula (IB) compound.
X in the formula
1And X
2One of them is a hydrogen, and the person is hydrogen, C1-C4 alkyl or fluorine in addition; X
3Be selected from hydrogen or fluorine;
R
1And R
2Independently be selected from hydrogen, fluorine respectively;
(d) formula (I) compound and optical activity acid-respons are got diastereoisomeric salt, wherein preferred optical activity acid is 1S-(+) or 1R-(-)-10-camphorsulfonic acid.
2. according to right 1 described method, wherein, described deprotonation form is lithium salts, sodium salt or the sylvite of formula (II) compound.
3. according to right 1 described method, wherein, the alkali salt of described formula (VI) compound both can be that sodium salt, sylvite also can be the tetra-n-butyl ammonium salts.
According to claim 1 and 3 described in any one described method, wherein said additional alkali is yellow soda ash, salt of wormwood or cesium carbonate.
5. according to the described method of claim 1, X
1, X
2, R
1And R
2It is the group that optionally to remove by reduction reaction.
6. according to the described method of claim 1, wherein prepared acid salt is spirit of salt, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, methylsulfonic acid, camphorsulfonic acid, R-(-)-10-camphorsulfonic acid, (+)-3-bromo-10-camphorsulfonic acid, (-)-3-bromo-10-camphorsulfonic acid, phosphoric acid, methylsulfonic acid or tosilate in the reaction process (a) and (b), and preferred salt is the hydrogen chlorate.
7. according to the described method of claim 1, wherein said reduction reaction is catalytic hydrogenolysis or transfer catalysis hydrogenolysis.
8. according to the described method of claim 7, wherein said catalytic hydrogenolysis is used palladium carbon catalyst, carries out described reduction reaction by the hydrogenolysis method.
9. wherein also there is sodium acetate in described according to Claim 8 method.
10. according to the described method of claim 7, wherein said transfer catalysis hydrogenolysis is used palladium carbon catalyst, and ammonium formiate carries out described reduction reaction.
11. according to the described method of claim 1, wherein the compound or pharmaceutically acceptable salt thereof that makes of compounds process for production thereof is:
(2R, 3S)-3-(2,4-two chloro-5-fluorine pyrimidine-6-yls)-2-(2,4 difluorobenzene base)-1-(3-chloro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(3,5-two chloro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S)-3-(2,4-two chloro-5-fluorine pyrimidine-6-yls)-2-(2,4 difluorobenzene base)-1-(3-chloro-5-fluoro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(3-chloro-5-ethyl-1H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(3-chloro-5-fluoro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S)-3-(5-fluorine pyrimidine-4-yl)-2-(2,4 difluorobenzene base)-1-(1H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S)-3-(5-fluorine pyrimidine-4-yl)-2-(2,4 difluorobenzene base)-1-(5-fluoro-1H-1,2,4-triazol-1-yl) fourth-2-alcohol;
(2R, 3S)-3-(4-chloro-5-fluorine pyrimidine-6-yl)-2-(2,4 difluorobenzene base)-1-(5-methyl isophthalic acid H-1,2,4-triazol-1-yl) fourth-2-alcohol or
(2R, 3S)-3-(5-fluorine pyrimidine-4-yl)-2-(2,4 difluorobenzene base)-1-(5-ethyl-1H-1,2,4-triazol-1-yl) fourth-2-alcohol
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|---|---|---|---|
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| CN200710079858A CN100579977C (en) | 2002-10-08 | 2002-10-08 | Method for producing antifungal drug in triazole class |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2012025506A1 (en) | 2010-08-26 | 2012-03-01 | Bayer Cropscience Ag | 5-iodo-triazole derivatives |
| US8143397B2 (en) * | 2006-02-01 | 2012-03-27 | Medichem S.A. | Process for preparing voriconazole, new polymorphic form of intermediate thereof, and uses thereof |
| CN111518041A (en) * | 2020-04-24 | 2020-08-11 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of 2'4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2545039A1 (en) | 2010-03-10 | 2013-01-16 | Synthon BV | A process for making voriconazole |
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| GB9002375D0 (en) * | 1990-02-02 | 1990-04-04 | Pfizer Ltd | Triazole antifungal agents |
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2002
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2012025506A1 (en) | 2010-08-26 | 2012-03-01 | Bayer Cropscience Ag | 5-iodo-triazole derivatives |
| US20120220638A1 (en) * | 2010-08-26 | 2012-08-30 | Bayer Cropscience Ag | 5-Iodotriazole derivatives |
| JP2013536215A (en) * | 2010-08-26 | 2013-09-19 | バイエル・インテレクチユアル・プロパテイー・ゲー・エム・ベー・ハー | 5-iodotriazole derivatives |
| US8969248B2 (en) * | 2010-08-26 | 2015-03-03 | Bayer Intellectual Property Gmbh | 5-iodotriazole derivatives |
| CN111518041A (en) * | 2020-04-24 | 2020-08-11 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of 2'4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100579977C (en) | 2010-01-13 |
| CN101003532A (en) | 2007-07-25 |
| CN100379733C (en) | 2008-04-09 |
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