CN104876872A - 一种制备1-叔丁氧基羰基-3-羟甲基吲唑的方法及应用 - Google Patents
一种制备1-叔丁氧基羰基-3-羟甲基吲唑的方法及应用 Download PDFInfo
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- CN104876872A CN104876872A CN201510197168.0A CN201510197168A CN104876872A CN 104876872 A CN104876872 A CN 104876872A CN 201510197168 A CN201510197168 A CN 201510197168A CN 104876872 A CN104876872 A CN 104876872A
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- tert
- indazole
- chloride
- butoxycarbonyl
- methylol
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- ZUTFTIKZPUYKBM-UHFFFAOYSA-N tert-butyl 3-(hydroxymethyl)indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC(C)(C)C)N=C(CO)C2=C1 ZUTFTIKZPUYKBM-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 230000002829 reductive effect Effects 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 8
- 150000002473 indoazoles Chemical class 0.000 claims description 8
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 3
- XISFOXBYRQWDNK-UHFFFAOYSA-N 2-(2-methylphenyl)propan-2-amine;hydrochloride Chemical compound [Cl-].CC1=CC=CC=C1C(C)(C)[NH3+] XISFOXBYRQWDNK-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 3
- 229960003280 cupric chloride Drugs 0.000 claims description 3
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- 229910052684 Cerium Inorganic materials 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 claims description 2
- 229910001626 barium chloride Inorganic materials 0.000 claims description 2
- 229940045511 barium chloride Drugs 0.000 claims description 2
- UUZYBYIOAZTMGC-UHFFFAOYSA-M benzyl(trimethyl)azanium;bromide Chemical compound [Br-].C[N+](C)(C)CC1=CC=CC=C1 UUZYBYIOAZTMGC-UHFFFAOYSA-M 0.000 claims description 2
- JHXKRIRFYBPWGE-UHFFFAOYSA-K bismuth chloride Chemical compound Cl[Bi](Cl)Cl JHXKRIRFYBPWGE-UHFFFAOYSA-K 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N methyl tert-butyl ether Substances COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 2
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 230000004071 biological effect Effects 0.000 abstract 1
- 125000004185 ester group Chemical group 0.000 abstract 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 abstract 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- -1 tert-butoxy carbonyl (Boc) Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000002360 preparation method Methods 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000000605 extraction Methods 0.000 description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 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 2
- 239000002585 base Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012847 fine chemical Substances 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- KPZSTOVTJYRDIO-UHFFFAOYSA-K trichlorocerium;heptahydrate Chemical compound O.O.O.O.O.O.O.Cl[Ce](Cl)Cl KPZSTOVTJYRDIO-UHFFFAOYSA-K 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种大规模制备1-叔丁氧基羰基-3-羟甲基吲唑的方法,该方法以3-吲唑甲酸酯为起始原料,用叔丁氧基羰基(Boc)保护氨基后,采用硼氢化钠和催化剂在室温下还原酯基为醇而得到1-叔丁氧基羰基-3-羟甲基吲唑;本发明具有反应试剂廉价易得,反应条件温和,操作工艺简单,后处理简便,所得产品纯度和收率高,适合工业化大规模生产等特点,本发明制得的1-叔丁氧基羰基-3-羟甲基吲唑可用于制备具有生物活性的化合物。
Description
技术领域
本发明涉及医药与精细化工领域,具体涉及1-叔丁氧基羰基-3-羟甲基吲唑的制备方法与应用。
背景技术
吲唑衍生物是一种非常重要的医药与精细化工中间体,其应用范围及其广泛。由于其独特的化学结构及理化性质,吲唑类化合物目前已被发现有多种药理活性:抗肿瘤、抗细菌、抗炎、抗病毒、抗血小板聚集和血管舒展活性、治疗糖尿病和肥胖证、治疗骨质疏松和神经退行性疾病等作用。目前,吲唑类化合物的合成备受关注,已报道了大量吲唑类化合物的合成方法。
本发明的化合物1-叔丁氧基羰基-3-羟甲基吲唑,它作为中间体,具有重要的应用价值,通过它可以合成出许多不同结构的吲唑衍生物以作生物活性筛选。
发明内容
本发明的目的是提供一种反应原料廉价易得,反应条件温和,操作工艺简单,后处理简便,所得产品纯度和收率高,可进行大规模工业化制备1-叔丁氧基羰基-3-羟甲基吲唑的方法。
本发明的上述技术目的是通过以下技术方案得以实施的:一种大规模制备1-叔丁氧基羰基-3-羟甲基吲唑(III)的方法,由如下所示步骤构成:
;
步骤一:以3-吲唑甲酸酯(Ⅰ)为原料,在溶剂存在下,用二碳酸二叔丁酯即(Boc)2O保护氨基得到化合物(Ⅱ),其中3-吲唑甲酸酯: 二碳酸二叔丁酯:碱:催化剂的摩尔比为 1:1.1~1.5:1.0~2.1:0.1~0.5,反应温度为0~50℃,反应时间为4~8小时;
步骤二:在还原剂与催化剂存在下,将化合物(Ⅱ)还原为1-叔丁氧基羰基-3-羟甲基吲唑(Ⅲ) ,其中化合物Ⅱ:还原剂:催化剂的摩尔比为1:1.1~2.8:0.01~0.2,反应温度为-10~80℃,反应时间为2~22小时。
本发明中所述步骤一中使用了溶剂,碱和催化剂,所用溶剂为四氢呋喃、二氧六环、二氯甲烷、三氯甲烷、水、甲醇、乙醇、丙酮、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺一种或两种的任意比混合物;所用碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠或三乙胺;所用催化剂为正四丁基溴化铵、正四丁基碘化铵、三甲基苄基氯化铵、三甲基苄基溴化铵、N,N-二甲基苯胺或N,N-二甲基吡啶。
本发明步骤二中使用了溶剂,还原剂和催化剂。所用溶剂为甲醇、乙醇、乙二醇、异丙醇、正丁醇、叔丁醇、乙醚、异丙醚、甲基特丁基醚、四氢呋喃、二氧六环、乙腈、甲苯、二甲苯、乙苯、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甘醇二甲醚、氮-甲基吡咯烷酮中一种或两种的任意比混合物;所用还原剂为硼氢化锂、硼氢化钠、硼氢化钾、硼氢化钙或硼氢化锌;所用催化剂为碘、硫酸、乙酸、三氟乙酸、四甲基乙二胺、N,N-二甲基苯胺、邻苯二酚、硫酸铜、氯化铜、氯化锂、氯化铋、氯化锌、氯化钴、氯化镁、氯化钙、氯化钡、氯化镍、溴化镍、氯化锡、氯化铈、七水合氯化铈、氯化锡、氯化铝、四氯化钛、四氯化锆或四异丙氧基钛。
本发明方法步骤二中所用还原剂以硼氢化钠为最优;所用催化剂以七水合氯化铈最优;反应温度优选为0~40℃。
本发明所述的1-叔丁氧基羰基-3-羟甲基吲唑的制备方法,具有反应试剂廉价易得、反应条件温和,产品后处理和提纯方法操作简便,产率和纯度高,对环境污染小,易于工业化生产等特点。
本发明的另一个目是将上述方法制得的1-叔丁氧基羰基-3-羟甲基吲唑作为中间体应用于合成具有生物活性的吲唑衍生物中。
例如,具有抗HIV-1活性的化合物3-(5-((1H-吲唑-3-基)甲氧基)-2-氯苯氧基)-5- 氯苯腈(G),一般按照如下反应路线合成(U.S. Patent 2007/0021442A1):
,
其中,从化合物A到B 的反应中,是以乙二醇为溶剂,底物A与无水肼在165℃下反应40小时得到B, 该反应存在如下问题:所用试剂无水肼在国内属于高危禁运品,易燃易爆,反应比较危险;且该反应需长时间在高温下反应,存在安全隐患,生产成本高,不适合大规模制备。
此外,从化合物C到D的反应中,副产物较多,在产物的纯化过程中需柱层析,不利于放大,而且收率较低,只有60%左右。
本发明解决上述技术问题采用的技术方案为:可以通过如下路线合成化合物3-(5-((1H-吲唑-3-基)甲氧基)-2-氯苯氧基)-5- 氯苯腈(G):
;
该技术方案采用本发明所提供的易大规模制备的1-叔丁氧基羰基-3-羟甲基吲唑为关键中间体,和化合物E经Mitsunobu反应一步生成化合物F,再脱保护得到化合物G。
与现有技术相比,本发明的优点在于,吲唑中间体廉价易得,故能方便快捷地合成多种吲唑衍生物以供活性筛选。
具体实施方式
下面通过实施例对本发明作进一步详细说明,但本发明保护范围不局限于所述内容。
实施例1: 本制备1-叔丁氧基羰基-3-羟甲基吲唑的方法,具体操作如下:
(1)1-叔丁氧基羰基-3-吲唑甲酸甲酯(化合物II)的制备
在1000mL三颈瓶中依次加入3-吲唑甲酸酯35g、N,N-二甲基吡啶4.9克、二碳酸二叔丁酯52克、三乙胺30 mL、乙腈600 mL,室温搅拌5小时后,TLC跟踪反应物3-吲唑甲酸酯消失,停止反应,将反应液倒入400 mL水中,加入300 mL乙酸乙酯,静置,分出有机层,有机层分别用水和饱和食盐水洗三次,经无水硫酸钠干燥后旋干,得白色固体52.6克,HPLC纯度98%,可直接用于下一步反应,收率:95%;熔点:122.7 ℃;1H NMR (300 MHz,CDCl3) δppm 1.75 (s, 9H, C(CH 3)3), 4.05 (s, 3H, OCH 3), 7.41-7.61 (m, 2H), 8.20-8.28 (dd, 2H);
;
(2)1-叔丁氧基羰基-3-羟甲基吲唑(III)的制备
将14克1-叔丁氧基羰基-3-吲唑甲酸甲酯溶于300 mL乙醇,加入0.4克七水合三氯化铈和3.8克硼氢化钠,室温搅拌反应,TLC跟踪约18小时原料点消失,停止反应,旋干溶剂,剩余物用100 mL 0.5 mol/L盐酸水解,用200 mL乙酸乙酯萃取3次,合并有机相,无水硫酸钠干燥,旋干得类白色固体11.2克,HPLC纯度99%,收率:90%;熔点:130.1 ℃;1H NMR (300 MHz,DMSO-d 6) δppm 1.64 (s, 9H, C(CH 3)3), 4.81 (d, 2H, J = 5.9 Hz, CH 2OH), 5.55 (t, 1H, J = 5.9 Hz, CH2OH), 7.38 (dd, 1H), 7.60 (dd, 1H), 7.96 (d, 1H, J = 7.9Hz), 8.08 (d, 1H, J = 8.3 Hz);
。
实施例2: 本制备1-叔丁氧基羰基-3-羟甲基吲唑的方法,具体操作如下:
(1)1-叔丁氧基羰基-3-吲唑甲酸甲酯(化合物II)的制备
在1000mL三颈瓶中依次加入3-吲唑甲酸酯35克、正四丁基溴化铵6.4克、二碳酸二叔丁酯48克、氢氧化钠16克、乙醇600 mL,5℃搅拌7小时后,TLC跟踪反应物3-吲唑甲酸酯消失,停止反应,旋去溶剂,剩余物加水400 mL,用300 mL乙酸乙酯萃取,分出有机层,有机层分别用水和饱和食盐水洗三次,经无水硫酸钠干燥后旋干,得白色固体48.9克,HPLC纯度98%,可直接用于下一步反应,收率:87%;熔点:122.7 ℃;1H NMR (300 MHz,CDCl3) δppm 1.75 (s, 9H, C(CH 3)3), 4.05 (s, 3H, OCH 3), 7.41-7.61 (m, 2H), 8.20-8.28 (dd, 2H);
(2)1-叔丁氧基羰基-3-羟甲基吲唑(III)的制备
将14克1-叔丁氧基羰基-3-吲唑甲酸甲酯溶于250 mL四氢呋喃,加入3.8克硼氢化钠,室温搅拌下滴入含碘2.5克的四氢呋喃溶液50 mL,滴毕继续室温下反应,TLC跟踪约15小时原料点消失,停止反应,旋干溶剂,剩余物用100 mL 0.5 mol/L盐酸水解,用200 mL乙酸乙酯萃取3次,合并有机相,无水硫酸钠干燥,旋干得类白色固体10.8克,HPLC纯度96%,收率82%;熔点:130.1 ℃;1H NMR (300 MHz,DMSO-d 6) δppm 1.64 (s, 9H, C(CH 3)3), 4.81 (d, 2H, J = 5.9 Hz, CH 2OH), 5.55 (t, 1H, J = 5.9 Hz, CH2OH), 7.38 (dd, 1H), 7.60 (dd, 1H), 7.96 (d, 1H, J = 7.9Hz), 8.08 (d, 1H, J = 8.3 Hz)。
实施例3:本制备1-叔丁氧基羰基-3-羟甲基吲唑的方法,具体操作如下:
(1)1-叔丁氧基羰基-3-吲唑甲酸甲酯(化合物II)的制备
在1000mL三颈瓶中依次加入3-吲唑甲酸酯35克、三甲基苄基氯化铵18.4克、二碳酸二叔丁酯65克、碳酸钾30克、二氯甲烷水溶液(体积浓度50%)600 mL,45℃搅拌4小时后,TLC跟踪反应物3-吲唑甲酸酯消失,停止反应,将反应液倒入200 mL水中,加入300 mL乙酸乙酯,静置,分出有机层,有机层分别用水和饱和食盐水洗三次,经无水硫酸钠干燥后旋干,得白色固体51.6克,HPLC纯度97%,可直接用于下一步反应,收率:91%;熔点:122.7 ℃;1H NMR (300 MHz,CDCl3) δppm 1.75 (s, 9H, C(CH 3)3), 4.05 (s, 3H, OCH 3), 7.41-7.61 (m, 2H), 8.20-8.28 (dd, 2H);
(2)1-叔丁氧基羰基-3-羟甲基吲唑(III)的制备
将14克1-叔丁氧基羰基-3-吲唑甲酸甲酯溶于250 mL乙醇, 0℃下加入3克硼氢化钾和0.05克氯化铜,加毕升至室温继续搅拌反应6小时,随后升温至60℃反应10小时,TLC检测原料点消失,停止反应,旋干溶剂,剩余物用100 mL 0.5 mol/L盐酸水解,用200 mL乙酸乙酯萃取3次,合并有机相,无水硫酸钠干燥,旋干得类白色固体9.6克,HPLC纯度94%,收率72%;熔点:130.1 ℃;1H NMR (300 MHz,DMSO-d 6) δppm 1.64 (s, 9H, C(CH 3)3), 4.81 (d, 2H, J = 5.9 Hz, CH 2OH), 5.55 (t, 1H, J = 5.9 Hz, CH2OH), 7.38 (dd, 1H), 7.60 (dd, 1H), 7.96 (d, 1H, J = 7.9Hz), 8.08 (d, 1H, J = 8.3 Hz)。
实施例4:本制备1-叔丁氧基羰基-3-羟甲基吲唑的方法,具体操作如下:
(1)1-叔丁氧基羰基-3-吲唑甲酸甲酯(化合物II)的制备
在1000mL三颈瓶中依次加入3-吲唑甲酸酯35克、N,N-二甲基苯胺3克、二碳酸二叔丁酯52克、碳酸氢钠35克、丙酮600 mL,回流反应8小时后,TLC跟踪反应物3-吲唑甲酸酯消失,停止反应,旋去溶剂,剩余物加水400 mL,用300 mL乙酸乙酯萃取,分出有机层,有机层分别用水和饱和食盐水洗三次,经无水硫酸钠干燥后旋干,得白色固体51克,HPLC纯度98%,可直接用于下一步反应,收率:91%;熔点:122.7 ℃;1H NMR (300 MHz,CDCl3) δppm 1.75 (s, 9H, C(CH 3)3), 4.05 (s, 3H, OCH 3), 7.41-7.61 (m, 2H), 8.20-8.28 (dd, 2H);
(2)1-叔丁氧基羰基-3-羟甲基吲唑(III)的制备
将14克1-叔丁氧基羰基-3-吲唑甲酸甲酯溶于250 mL甲苯,40℃下加入1.2克硼氢化锂和0.16克硫酸铜,加毕继续反应,TLC跟踪约18小时原料点消失,停止反应,旋干溶剂,剩余物用100 mL 0.5 mol/L盐酸水解,用200 mL乙酸乙酯萃取3次,合并有机相,无水硫酸钠干燥,旋干得类白色固体10.3克,HPLC纯度97%,收率79%,熔点:130.1 ℃;1H NMR (300 MHz,DMSO-d 6) δppm 1.64 (s, 9H, C(CH 3)3), 4.81 (d, 2H, J = 5.9 Hz, CH 2OH), 5.55 (t, 1H, J = 5.9 Hz, CH2OH), 7.38 (dd, 1H), 7.60 (dd, 1H), 7.96 (d, 1H, J = 7.9Hz), 8.08 (d, 1H, J = 8.3 Hz)。
以上所述仅是本发明的优选或部分实施方式。应当指出,对于本技术领域的普通技术人员,在不脱离本发明的前提下,还可进行若干改进和补充,这些可能的改进和补充也应视为本发明的保护范围。
Claims (4)
1.一种制备1-叔丁氧基羰基-3-羟甲基吲唑的方法,其特征在于按如下步骤进行:
(1)以3-吲唑甲酸酯为原料,在溶剂存在下,用二碳酸二叔丁酯保护氨基得到化合物Ⅱ,其中3-吲唑甲酸酯:二碳酸二叔丁酯:碱:催化剂的摩尔比为 1:1.1~1.5:1.0~2.1:0.1~0.5,反应温度为0~50℃,反应时间为4~8小时;
;
(2)在还原剂与催化剂存在下,将化合物Ⅱ还原为1-叔丁氧基羰基-3-羟甲基吲唑,其中化合物Ⅱ:还原剂:催化剂的摩尔比为1:1.1~2.8:0.01~0.2,反应温度为-10~80℃,反应时间为2~22小时;
。
2.根据权利要求1所述的制备1-叔丁氧基羰基-3-羟甲基吲唑的方法,其特征在于:步骤(1)中溶剂为四氢呋喃、二氧六环、二氯甲烷、三氯甲烷、水、甲醇、乙醇、丙酮、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺中一种或两种的混合物;碱为氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠或三乙胺;催化剂为正四丁基溴化铵、正四丁基碘化铵、三甲基苄基氯化铵、三甲基苄基溴化铵、N,N-二甲基苯胺或N,N-二甲基吡啶。
3.根据权利要求1所述的制备1-叔丁氧基羰基-3-羟甲基吲唑的方法,其特征在于:步骤(2)中溶剂为甲醇、乙醇、乙二醇、异丙醇、正丁醇、叔丁醇、乙醚、异丙醚、甲基特丁基醚、四氢呋喃、二氧六环、乙腈、甲苯、二甲苯、乙苯、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甘醇二甲醚、氮-甲基吡咯烷酮中一种或两种的混合物;还原剂为硼氢化锂、硼氢化钠、硼氢化钾、硼氢化钙或硼氢化锌;催化剂为碘、硫酸、乙酸、三氟乙酸、四甲基乙二胺、N,N-二甲基苯胺、邻苯二酚、硫酸铜、氯化铜、氯化锂、氯化铋、氯化锌、氯化钴、氯化镁、氯化钙、氯化钡、氯化镍、溴化镍、氯化锡、氯化铈、七水合氯化铈、氯化锡、氯化铝、四氯化钛、四氯化锆或四异丙氧基钛。
4.权利要求1~3中任一项所述的制备1-叔丁氧基羰基-3-羟甲基吲唑的方法制得的1-叔丁氧基羰基-3-羟甲基吲唑在制备活性吲唑衍生物中的应用。
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CN111423355A (zh) * | 2020-05-22 | 2020-07-17 | 阿里生物新材料(常州)有限公司 | 一种4-羟基-2-甲基-4,5,6,7-四氢-1h-吲哚-1-羧酸叔丁酯合成方法 |
CN111423355B (zh) * | 2020-05-22 | 2022-05-13 | 阿里生物新材料(常州)有限公司 | 一种4-羟基-2-甲基-4,5,6,7-四氢-1h-吲哚-1-羧酸叔丁酯合成方法 |
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