CN104710379B - Synthetic method for BMS-191011 - Google Patents
Synthetic method for BMS-191011 Download PDFInfo
- Publication number
- CN104710379B CN104710379B CN201510103549.8A CN201510103549A CN104710379B CN 104710379 B CN104710379 B CN 104710379B CN 201510103549 A CN201510103549 A CN 201510103549A CN 104710379 B CN104710379 B CN 104710379B
- Authority
- CN
- China
- Prior art keywords
- compound
- bms
- chloro
- synthetic method
- trifluoromethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000010189 synthetic method Methods 0.000 title claims abstract description 17
- QKOWACXSXTXRKA-UHFFFAOYSA-N 3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-one Chemical compound OC1=CC=C(Cl)C=C1CN1C(=O)OC(C=2C=CC(=CC=2)C(F)(F)F)=N1 QKOWACXSXTXRKA-UHFFFAOYSA-N 0.000 title abstract 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- GKBDXTNCBPZMFX-UHFFFAOYSA-N 4-(trifluoromethyl)benzohydrazide Chemical compound NNC(=O)C1=CC=C(C(F)(F)F)C=C1 GKBDXTNCBPZMFX-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 6
- 230000008569 process Effects 0.000 claims abstract description 3
- -1 4- (trifluoromethyl) phenyl Chemical group 0.000 claims description 43
- 229940125898 compound 5 Drugs 0.000 claims description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 20
- 229940125782 compound 2 Drugs 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- GFCZAZVHUMJMJN-UHFFFAOYSA-N (5-chloro-2-methoxyphenyl)methanol Chemical compound COC1=CC=C(Cl)C=C1CO GFCZAZVHUMJMJN-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 229940125904 compound 1 Drugs 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 5
- 230000006315 carbonylation Effects 0.000 claims description 5
- 238000005810 carbonylation reaction Methods 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 230000008859 change Effects 0.000 claims description 3
- 229940126214 compound 3 Drugs 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 238000012360 testing method Methods 0.000 claims description 3
- YRGAYAGBVIXNAQ-UHFFFAOYSA-N 1-chloro-4-methoxybenzene Chemical compound COC1=CC=C(Cl)C=C1 YRGAYAGBVIXNAQ-UHFFFAOYSA-N 0.000 claims description 2
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical group [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000005751 Copper oxide Substances 0.000 claims description 2
- 238000006751 Mitsunobu reaction Methods 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229910000431 copper oxide Inorganic materials 0.000 claims description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 2
- 150000002940 palladium Chemical class 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims 1
- 101000905241 Mus musculus Heart- and neural crest derivatives-expressed protein 1 Proteins 0.000 claims 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 claims 1
- 125000004970 halomethyl group Chemical group 0.000 claims 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 claims 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- 238000005576 amination reaction Methods 0.000 abstract 1
- 230000026030 halogenation Effects 0.000 abstract 1
- 238000005658 halogenation reaction Methods 0.000 abstract 1
- 238000005832 oxidative carbonylation reaction Methods 0.000 abstract 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 38
- 239000001257 hydrogen Substances 0.000 description 38
- 229910052739 hydrogen Inorganic materials 0.000 description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- QGRPVMLBTFGQDQ-UHFFFAOYSA-N 1-chloro-2-methoxybenzene Chemical compound COC1=CC=CC=C1Cl QGRPVMLBTFGQDQ-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 239000007788 liquid Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 150000003851 azoles Chemical class 0.000 description 4
- 230000031709 bromination Effects 0.000 description 4
- 238000005893 bromination reaction Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000002024 ethyl acetate extract Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 125000005997 bromomethyl group Chemical group 0.000 description 3
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- XEMRAKSQROQPBR-UHFFFAOYSA-N (trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=CC=C1 XEMRAKSQROQPBR-UHFFFAOYSA-N 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- AFPSETMCMFRVPG-UHFFFAOYSA-N 4-chloro-2-(hydroxymethyl)phenol Chemical compound OCC1=CC(Cl)=CC=C1O AFPSETMCMFRVPG-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 238000007445 Chromatographic isolation Methods 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000011097 chromatography purification Methods 0.000 description 2
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 229940005561 1,4-benzoquinone Drugs 0.000 description 1
- YUKILTJWFRTXGB-UHFFFAOYSA-N 1-chloro-3-methoxybenzene Chemical compound COC1=CC=CC(Cl)=C1 YUKILTJWFRTXGB-UHFFFAOYSA-N 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- XQPRBTXUXXVTKB-UHFFFAOYSA-M caesium iodide Chemical compound [I-].[Cs+] XQPRBTXUXXVTKB-UHFFFAOYSA-M 0.000 description 1
- 229910002090 carbon oxide Inorganic materials 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- KQTXIZHBFFWWFW-UHFFFAOYSA-L disilver;carbonate Chemical compound [Ag]OC(=O)O[Ag] KQTXIZHBFFWWFW-UHFFFAOYSA-L 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
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- UBXWAYGQRZFPGU-UHFFFAOYSA-N manganese(2+) oxygen(2-) titanium(4+) Chemical compound [O--].[O--].[Ti+4].[Mn++] UBXWAYGQRZFPGU-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 description 1
- 125000005546 pivalic acid group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 235000019394 potassium persulphate Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- XPDWGBQVDMORPB-UHFFFAOYSA-N trifluoromethane acid Natural products FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention relates to a synthetic method for a compound BMS-191011. The method comprises the following steps: taking 4-trifluoromethyl benzoyl hydrazine as a raw material and performing steps of oxidative carbonylation, methyl protection, halogenation, amination, deprotection and the like to prepare BMS-191011. The synthetic method adopts a CO balloon for replacing phosgene, so that the reaction toxicity is reduced and the reaction operability is improved. The method has the characteristics of simple and easily available raw materials, mild reaction conditions and simple operation process.
Description
Technical field
The present invention relates to medicine, organic chemical industry's synthesis technical field are and in particular to a kind of synthetic method of bms-191011.
Background technology
Bms-191011 is a kind of diazoles compound, its chemical entitled 3- (5- chlorine-2-hydroxyl phenyl) -5- (4- tri-
Methyl fluoride) phenyl -1,3,4- diazole -2 (3 hydrogen) -one.Its structural formula is as follows:
Bms-191011 has certain neuroprotective, can be used for treating the apoplexy diseases that cerebral ischemia leads to.
The synthetic method of the bms-191011 of document report at present, mainly has following three kinds:
A. with 4- trifluoromethylbenzoyl hydrazine as initiation material, it is passed through phosgene flow and obtains intermediate 5- (4- (trifluoromethyl)
Phenyl) -1,3,4- diazole -2 (3 hydrogen) -one, more chloro- 1- methoxybenzene or 5- chloro- 2- methoxy with 2- (halogenated methyl) -4-
Base benzyl alcohol reacts and obtains 3- (5- chloro- 2- methoxyphenyl) -5- (4- trifluoromethyl) -1,3,4- diazole -2 (3
Hydrogen) -one, after obtain bms-191011 through deprotection；
B. with 4- trifluoromethylbenzoyl hydrazine as initiation material, react with benzenyl trichloride and thionyl chloride and obtain intermediate
5- (4- (trifluoromethyl) phenyl) -1,3,4- diazole -2 (3 hydrogen) -one, the more chloro- 1- methoxybenzene with 2- (halogenated methyl) -4-
Or 5- chloro- 2- methoxy benzyl alcohol react obtain 3- (5- chloro- 2- methoxyphenyl) -5- (4- trifluoromethyl) -
1,3,4- diazole -2 (3 hydrogen) -one, after obtain bms-191011 through deprotection；
C. with 4- trifluoromethylbenzoyl hydrazine as initiation material, through three-step reaction (cs2, koh/mei/h2o2Or kmno4)
To intermediate 5- (4- (trifluoromethyl) phenyl) -1,3,4- diazole -2 (3 hydrogen) -one, then 1- chloro- with 2- (halogenated methyl) -4-
Methoxybenzene or 5- chloro- 2- methoxy benzyl alcohol react and obtain 3- (5- chloro- 2- methoxyphenyl) -5- (4- fluoroform
Base phenyl) -1,3,4- diazole -2 (3 hydrogen) -one, after obtain bms-191011 through deprotection；
Above distance has the disadvantage in that
(1) phosgene is harmful gas, and has certain unstability, using water or alcohol as medium
In the case of easily there is side reaction.
(2) although benzenyl trichloride and thionyl chloride can substitute phosgene, expensive, and thionyl chloride has very
Strong corrosivity, not easy to operate.
(3) using Carbon bisulfide and iodomethane prepare intermediate 5- (4- (trifluoromethyl) phenyl) -1,3,4- diazole -
2 (3 hydrogen) -one are although the use of toxic reagent can be avoided, but operating procedure is complicated, and synthesis is relatively costly.
Content of the invention
The present invention overcomes drawbacks described above, it is desirable to provide a kind of synthetic method of bms-191011, and the method is easy and simple to handle, ring
Border is friendly, and synthesis is with low cost.
A kind of synthetic method of bms-191011, synthetic route is as follows:
In said method, described compound 2 is intermediate 5- (4- (trifluoromethyl) phenyl) -1,3,4- diazole -2 (3
Hydrogen) -one, its synthesis is that is, the oxidized carbonylation of intermediate 4- trifluoromethylbenzoyl hydrazine is prepared by compound 1.
In said method, specifically comprise the following steps that
(1) take compound 1 in test tube, add catalyst, oxidant and accelerator, add solvent, put and be filled with one
The balloon of carbon oxide gas, stirs 1-48 hour at 50-80 DEG C, obtains compound 2；Described compound 1 is 4- trifluoromethyl
Benzoyl hydrazine；Described compound 2 is: 5- (4- (trifluoromethyl) phenyl) -1,3,4- diazole -2 (3 hydrogen) -one；
(2) take the compound 2 that step (1) obtains, add compound 4 reaction to obtain compound 5；Described compound 4 is: 2-
The chloro- 1- methoxybenzene of (halogenated methyl) -4- or 5- chloro- 2- methoxy benzyl alcohol；The group of wherein halo is-cl ,-br or-i；
Described compound 5 is: 3- (5- chloro- 2- methoxyphenyl) -5- (4- trifluoromethyl) -1,3,4- diazole -2 (3 hydrogen) -
Ketone；
(3) take the compound 5 that step (2) obtains after deprotection process, obtain bms-191011.
In said method, in step (1), described catalyst is palladium salt；Described oxidant is oxygen, 1,4-benzoquinone, titanium dioxide
Manganese, Disilver carbonate, Schweinfurt green, copper oxide or potassium peroxydisulfate, described accelerator is pivalic acid, trifluoroacetic acid or p-methyl benzenesulfonic acid, institute
State solvent and include oxolane, acetonitrile, n, n- dimethylformamide, toluene, dimethyl sulfoxide, methanol, ethanol, n, n- diethyl
One of Methanamide or Isosorbide-5-Nitrae-dioxane or more than one, preferred 50-60 DEG C of reaction temperature, carbonyl source be carbon monoxide gas
Body.
In said method, described compound 4 is the chloro- 1- methoxybenzene of 2- (halogenated methyl) -4- or 5- chloro- 2- methoxybenzene
Methanol；Wherein, the halo groups of the chloro- 1- methoxybenzene of described 2- (halogenated methyl) -4- are-cl,-br or-i.
In said method, the amount of described palladium salt is (0.05～0.5) with the mol ratio of compound 1: 1；Described oxidant
Amount is (1～4) with the mol ratio of compound 1: 1.
In said method, the amount of described accelerator is (1～5) with the mol ratio of compound 1: 1；Described CO (carbon monoxide converter) gas
Pressure be 1～100 atmospheric pressure.
In said method, the time of described oxidation carbonylation is 1～48 hour.
In said method, in step (1)-step (3), product is all isolated and purified by gained material using column chromatography；Described
Column chromatography eluent is the mixed solvent of petroleum ether and ethyl acetate, and the volume ratio between petroleum ether and ethyl acetate is 1～40:
1.
In said method, when compound 4 is the chloro- 1- methoxybenzene of 2- (halogenated methyl) -4-, the concrete system of step (2)
Preparation Method is: takes the compound 2 that step (1) obtains, adds compound 4, adds alkali using after anhydrous solvent dissolving, in 0-100
Stir 1-48 hour at DEG C, obtain compound 5；
When compound 4 is 5- chloro- 2- methoxy benzyl alcohol, the concrete preparation method of step (2) is: takes step (1) to obtain
The compound 2 arriving, carries out mitsunobu reaction and obtains compound 5.
Compared with prior art, present invention has an advantage that
(1) adopt co balloon to replace phosgene, reduce the toxicity of reaction, increased the operability of reaction.
(2) reaction raw materials directly obtain intermediate 5- (4- (trifluoromethyl) phenyl) -1,3,4- two through carbonylation
Azoles -2 (3 hydrogen) -one, reaction condition is gentle, and yield is high, and purification is convenient.
(3) intermediate 5- (4- (trifluoromethyl) phenyl) -1,3,4- diazole -2 (3 hydrogen) -one can be chloro- with intermediate 5-
Chloro- 1- methoxybenzene reacts and obtains intermediate 3- (5- is chloro- 2- methoxy benzyl alcohol respectively with intermediate 2- (halogenated methyl) -4-
2- methoxyphenyl) -5- (4- trifluoromethyl) -1,3,4- diazole -2 (3 hydrogen) -one, there is provided the multiformity of reaction and
Selectivity.
(4), in the inventive method, the key parameter of the intermediate preparation in step (1) makes reaction yield excellent, condition
Gently it is easy to operate；
(5) there is no document report before the method, there is novelty, can be around the protection of Kaiyuan research and development house journal.
Brief description
Fig. 1 is embodiment 1 gained 5- (4- (trifluoromethyl) phenyl) -1,3,4- diazole -2 (3 hydrogen) -one (compound 2)
Proton nmr spectra；
Fig. 2 is embodiment 1 gained 5- (4- (trifluoromethyl) phenyl) -1,3,4- diazole -2 (3 hydrogen) -one (compound 2)
Carbon-13 nmr spectra；
Fig. 3 is the proton nmr spectra of embodiment 6 gained bms-191011；
Fig. 4 is the carbon-13 nmr spectra of embodiment 6 gained bms-191011.
Specific embodiment
With reference to specific embodiment, the present invention is made further specifically to describe in detail, but embodiments of the present invention are not
It is limited to this, for the technological parameter especially not indicated, can refer to routine techniquess and carry out.
Embodiment 1
The synthesis of intermediate 5- (4- (trifluoromethyl) phenyl) -1,3,4- diazole -2 (3 hydrogen) -one (compound 2)
2 mMs of 4- trifluoromethylbenzoyl hydrazine, 0.1 mM of palladium trifluoroacetate, oxidation is added in the test tube of 25ml
3 mMs of copper, 6 mMs of trifluoroacetic acid, add acetonitrile as solvent, put carbon monoxide balloon as carbonyl source, take the photograph in 60
Stir under family name's degree, react about 12h.Reactant liquor is cooled to room temperature after terminating by tlc (thin layer chromatography) detection reaction, takes off an oxygen
Change carbon balloon, be slowly vented unreacted carbon monoxide.Reacting liquid filtering, filtrate decompression revolving removes solvent, then passes through post layer
Analysis isolates and purifies, and obtains target product 5- (4- (trifluoromethyl) phenyl) -1,3,4- diazole -2 (3 hydrogen) -one (compound 2),
Column chromatography eluent used is the petroleum ether of 4:1: ethyl acetate mixed solvent, yield 73% for volume ratio.
The hydrogen spectrum structural information of products obtained therefrom is as shown in figure 1, carbon spectrum is as shown in Figure 2.
Embodiment 2
The synthesis of intermediate 5- chloro- 2- methoxy benzyl alcohol
The first step: add 5 mMs of 5- chloro-salicylic aldehyde in the round-bottomed flask of 100ml, with methanol dissolving, add under zero degree
Enter 6 mMs of sodium borohydride, be transferred to stirring at normal temperature 1 hour, obtain intermediate 4- chloro- 2- hydroxymethylphenol (compound 3) 4.5
MM, yield 90%.
Second step: add intermediate 4- chloro- 2- hydroxymethylphenol (compound 3) 4.5 mmoles in the round-bottomed flask of 100ml
You, with acetone solution, add 7 mMs of potassium carbonate, 7 mMs of iodomethane, flow back under 60 degrees Celsius.Tlc detection reaction knot
After bundle, reactant liquor is cooled to room temperature, reacting liquid filtering, filtrate decompression revolving removes solvent, then passes through column chromatographic isolation and purification,
Obtain target product 5- chloro- 2- methoxy benzyl alcohol (compound 4), column chromatography eluent used is the stone of 8:1 for volume ratio
Oily ether: ethyl acetate mixed solvent, yield 80%.
Embodiment 3
The synthesis of the chloro- 1- methoxybenzene of 2- (iodo-methyl) -4-
Intermediate 5- chloro- 2- methoxy benzyl alcohol 3 mmoles that embodiment 2 prepares are added in the round-bottomed flask of 50ml
You, with acetonitrile dissolving, add 4.5 mMs of cesium iodide, 4.5 mMs of p-methyl benzenesulfonic acid, stir at room temperature, reaction is about
20min.Reactant liquor is cooled to room temperature, reacting liquid filtering after terminating by tlc detection reaction, and filtrate decompression revolving removes solvent, then
By column chromatographic isolation and purification, obtain 2.7 mMs of the chloro- 1- methoxybenzene of target product 2- (iodo-methyl) -4-, post used
Chromatographic eluate is the petroleum ether of 30:1: ethyl acetate mixed solvent, yield 90% for volume ratio.
Embodiment 4
The synthesis of the chloro- 1- methoxybenzene of 2- (chloromethyl) -4-
Take 10 mMs of cyanuric chloride, be dissolved in 2mldmf, stirring under room temperature is until there is white solid to produce, afterwards
Add 25ml dichloromethane, be stirring evenly and then adding into 9.5 mMs of 5- chloro- 2- methoxy benzyl alcohol, and stirring 4 is little under room temperature
When, add the extraction of 20ml water afterwards, take organic aqueous sodium carbonate being added to 15ml saturation, be eventually adding 1n hcl water-soluble
Liquid, through anhydrous sodium sulfate drying, obtains 7.9 mMs of the chloro- 1- methoxybenzene of 2- (chloromethyl) -4-, yield 83%.
Embodiment 5
The synthesis of the chloro- 1- methoxybenzene of 2- (bromomethyl) -4-
Take 10 mMs of cyanuric chloride, be dissolved in 2mldmf, stirring under room temperature is until there is white solid to produce, afterwards
Add 25ml dichloromethane, add 19 mMs of sodium bromide, after being stirred overnight, add 5- chloro- 2- methoxy benzyl alcohol 9.5 mmoles
You, and stir under room temperature, react about 20h, tlc detection reaction adds the extraction of 20ml water after terminating, takes and organic be added to 15ml
The aqueous sodium carbonate of saturation, is eventually adding 1n hcl aqueous solution, through anhydrous sodium sulfate drying, obtains 2- (bromomethyl) -4-
7.9 mMs of chloro- 1- methoxybenzene, yield 98%.
Embodiment 6
The synthesis of bms-191011
The first step: intermediate 3- (5- chloro- 2- methoxyphenyl) -5- (4- trifluoromethyl) -1,3,4- diazole -2
The synthesis of (3 hydrogen) -one (compound 5)
By intermediate 5- (4- (trifluoromethyl) phenyl) -1,3,4- diazole -2 (3 hydrogen) -one (embodiment 1 products obtained therefrom) 5
Person of outstanding talent mole and 5 mMs of intermediate 5- chloro- 2- methoxy benzyl alcohol (embodiment 2 products obtained therefrom), 5.5 mMs of triphenyl phosphorus in
Zero degree is dissolved in anhydrous tetrahydro furan under the protection of nitrogen stream, under agitation slowly Deca dead (azoformic acid two
Ethyl ester) 5.5 mMs, and continue stirring 24 hours under zero degree, filtration separation obtains intermediate 3- (5- chloro- 2- methoxybenzene
Base) 4.5 mMs of -5- (4- trifluoromethyl) -1,3,4- diazole -2 (3 hydrogen) -one (compound 5), yield 90%.
The synthesis of second step: bms-191011
By intermediate 3- (5- chloro- 2- methoxyphenyl) -5- (4- trifluoromethyl) -1,3,4- diazole -2 (3 hydrogen) -
2.25 mMs of ketone (compound 5) is dissolved in 55ml dichloromethane, is cooled to zero degree, adds 12ml tri- in the presence of nitrogen stream
The dichloromethane solution (1.0m) of bromination roc, stirs 18 hours under room temperature, instills 200ml saturated sodium bicarbonate water molten under zero degree
In liquid, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and obtains bms-1910112 mM, yield 90%.
The hydrogen spectrum structural information of products obtained therefrom is as shown in figure 3, carbon spectrum is as shown in Figure 4.
Embodiment 7
The synthesis of bms-191011
The first step: intermediate 3- (5- chloro- 2- methoxyphenyl) -5- (4- trifluoromethyl) -1,3,4- diazole -2
The synthesis of (3 hydrogen) -one
By intermediate 5- (4- (trifluoromethyl) phenyl) -1,3,4- diazole -2 (3 hydrogen) -one (embodiment 1 products obtained therefrom)
6.5 mMs with 6.5 mMs of the chloro- 1- methoxybenzene of intermediate 2- (bromomethyl) -4- (embodiment 5 products obtained therefrom) in nitrogen
Under the protection of stream, it is dissolved in anhydrous dmf, adds 6.5 mMs of sodium hydride, after stirring 18 hours under 60 degrees Celsius, pour into
In 100ml water, it is filtrated to get intermediate 3- (5- chloro- 2- methoxyphenyl) -5- (4- trifluoromethyl) -1,3,4- bis-
6 mMs of azoles -2 (3 hydrogen) -one (compound 5), yield 92%.
The synthesis of second step: bms-191011
By intermediate 3- (5- chloro- 2- methoxyphenyl) -5- (4- trifluoromethyl) -1,3,4- diazole -2 (3 hydrogen) -
2.25 mMs of ketone (compound 5) is dissolved in 55ml dichloromethane, is cooled to zero degree, adds 12ml tri- in the presence of nitrogen stream
The dichloromethane solution (1.0m) of bromination roc, stirs 18 hours under room temperature, instills 200ml saturated sodium bicarbonate water molten under zero degree
In liquid, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and obtains bms-1910112 mM, yield 90%.
The present embodiment structure of title compound can refer to Fig. 3 and Fig. 4.
Embodiment 8
The synthesis of bms-191011
The first step: intermediate 3- (5- chloro- 2- methoxyphenyl) -5- (4- trifluoromethyl) -1,3,4- diazole -2
The synthesis of (3 hydrogen) -one (compound 5)
By intermediate 5- (4- (trifluoromethyl) phenyl) -1,3,4- diazole -2 (3 hydrogen) -one (embodiment 1 products obtained therefrom)
6.5 mMs with 6.5 mMs of the chloro- 1- methoxybenzene of intermediate 2- (chloromethyl) -4- (embodiment 4 products obtained therefrom) in nitrogen
Under the protection of stream, it is dissolved in anhydrous dmf, adds 6.5 mMs of sodium hydride, after stirring 18 hours under 60 degrees Celsius, pour into
In 100ml water, it is filtrated to get intermediate 3- (5- chloro- 2- methoxyphenyl) -5- (4- trifluoromethyl) -1,3,4- bis-
6 mMs of azoles -2 (3 hydrogen) -one (compound 5), yield 82%.
The synthesis of second step: bms-191011
By intermediate 3- (5- chloro- 2- methoxyphenyl) -5- (4- trifluoromethyl) -1,3,4- diazole -2 (3 hydrogen) -
2.25 mMs of ketone (compound 5) is dissolved in 55ml dichloromethane, is cooled to zero degree, adds 12ml tri- in the presence of nitrogen stream
The dichloromethane solution (1.0m) of bromination roc, stirs 18 hours under room temperature, instills 200ml saturated sodium bicarbonate water molten under zero degree
In liquid, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and obtains bms-1910112 mM, yield 90%.
The present embodiment structure of title compound can refer to Fig. 3 and Fig. 4.
Embodiment 9
The synthesis of bms-191011
The first step: intermediate 3- (5- chloro- 2- methoxyphenyl) -5- (4- trifluoromethyl) -1,3,4- diazole -2
The synthesis of (3 hydrogen) -one (compound 5)
By intermediate 5- (4- (trifluoromethyl) phenyl) -1,3,4- diazole -2 (3 hydrogen) -one (embodiment 1 products obtained therefrom)
6.5 mMs with 6.5 mMs of the chloro- 1- methoxybenzene of intermediate 2- (iodo-methyl) -4- (embodiment 3 products obtained therefrom) in nitrogen
Under the protection of stream, it is dissolved in anhydrous dmf, adds 6.5 mMs of sodium hydride, after stirring 2 hours under the zero degrees celsius, pour into
In 100ml water, it is filtrated to get intermediate 3- (5- chloro- 2- methoxyphenyl) -5- (4- trifluoromethyl) -1,3,4- bis-
5 mMs of azoles -2 (3 hydrogen) -one (compound 5), yield 77%.
The synthesis of second step: bms-191011
By intermediate 3- (5- chloro- 2- methoxyphenyl) -5- (4- trifluoromethyl) -1,3,4- diazole -2 (3 hydrogen) -
2.25 mMs of ketone (compound 5) is dissolved in 55ml dichloromethane, is cooled to zero degree, adds 12ml tri- in the presence of nitrogen stream
The dichloromethane solution (1.0m) of bromination roc, stirs 18 hours under room temperature, instills 200ml saturated sodium bicarbonate water molten under zero degree
In liquid, ethyl acetate extracts, and anhydrous magnesium sulfate is dried, and obtains bms-1910112 mM, yield 90%.
The present embodiment structure of title compound can refer to Fig. 3 and Fig. 4.
Embodiment 10
The present embodiment verifies preparation 5- (4- (trifluoromethyl) phenyl) -1,3,4- diazole -2 (3 provided by the present invention
Hydrogen) -one (compound 2) method in, reaction temperature is for the impact of product yield.
Except the difference of reaction temperature, other steps are all identical with the method described in embodiment 1.Different temperatures is for 5-
The impact of (4- (trifluoromethyl) phenyl) -1,3,4- diazole -2 (3 hydrogen) -one (compound 2) yield refers to table 1.
Table 1
The data going out given in table 1 can be seen that in the temperature range value provided in the present invention, to compound 2
Yield impact plays a key effect, and the temperature parameter setting of the present invention can make reaction yield significantly improve.
The above embodiment of the present invention is only intended to clearly illustrate example of the present invention, and is not to the present invention
Embodiment restriction.For those of ordinary skill in the field, can also make on the basis of the above description
The change of other multi-forms or variation.There is no need to be exhaustive to all of embodiment.All the present invention's
Any modification, equivalent and improvement made within spirit and principle etc., should be included in the protection of the claims in the present invention
Within the scope of.
Claims (9)
1. a kind of synthetic method of bms-191011 is it is characterised in that synthetic route is as follows:
Specifically comprise the following steps that
(1) take compound 1 in test tube, add catalyst, oxidant and accelerator, add solvent, put and be filled with an oxidation
The balloon of carbon gas, stirs 1-48 hour at 50-80 DEG C, obtains compound 2；Described compound 1 is 4- trifluoromethylbenzene first
Hydrazides；Described compound 2 is: 5- (4- (trifluoromethyl) phenyl) -1,3,4- diazolones；
(2) take the compound 2 that step (1) obtains, add compound 4 reaction to obtain compound 5；In described compound 4, x represents
Group is-cl ,-br ,-i or-oh, and compound 4 is obtained by compound 3；Described compound 5 is: 3- (5- chloro- 2- methoxybenzene
Base) -5- (4- trifluoromethyl) -1,3,4- diazolones；
(3) take the compound 5 that step (2) obtains after deprotection process, obtain bms-191011；Described catalyst is palladium salt；
Described oxidant is copper oxide, and described accelerator is trifluoroacetic acid.
2. the synthetic method of bms-191011 according to claim 1 is it is characterised in that described compound 2 is intermediate
5- (4- (trifluoromethyl) phenyl) -1,3,4- diazolones, by compound 1, that is, intermediate 4- trifluoromethylbenzoyl hydrazine is through oxygen
Change carbonylation to be obtained.
3. the synthetic method of bms-191011 according to claim 1 is it is characterised in that in step (1), described solvent bag
Include oxolane, acetonitrile, n, n- dimethylformamide, toluene, dimethyl sulfoxide, methanol, ethanol, n, n- diethylformamide or
One or more of Isosorbide-5-Nitrae-dioxane, reaction temperature is 50-60 DEG C.
4. bms-191011 according to claim 1 synthetic method it is characterised in that: described compound 4 be 2- (halo
Methyl) -4- chloro- 1- methoxybenzene or 5- chloro- 2- methoxy benzyl alcohol；Wherein, the chloro- 1- methoxy of described 2- (halogenated methyl) -4-
The halo groups of base benzene are-cl ,-br or-i.
5. bms-191011 according to claim 2 synthetic method it is characterised in that: the amount of described palladium salt and compound
1 mol ratio is 0.05～0.5:1；The amount of described oxidant is 1～4:1 with the mol ratio of compound 1.
6. bms-191011 according to claim 2 synthetic method it is characterised in that: the amount of described accelerator and chemical combination
The mol ratio of thing 1 is 1～5:1；The pressure of described CO (carbon monoxide converter) gas is 1～100 atmospheric pressure.
7. bms-191011 according to claim 2 synthetic method it is characterised in that: described oxidation carbonylation
Time is 1～48 hour.
8. bms-191011 according to claim 1 synthetic method it is characterised in that: in step (1)-step (3), all
Using column chromatography, product is isolated and purified；Described column chromatography eluent is the mixed solvent of petroleum ether and ethyl acetate, petroleum ether
Volume ratio and ethyl acetate between is 1～40:1.
9. bms-191011 according to claim 1 synthetic method it is characterised in that:
When x is-cl ,-br or-i, in step (2), the concrete preparation method of compound 5 is: takes the compound that step (1) obtains
2, add compound 4, add alkali using after anhydrous solvent dissolving, stir 1-48 hour at 0-100 DEG C, obtain compound 5；
When x is-oh, in step (2), the concrete preparation method of compound 5 is: the compound 2 taking step (1) to obtain, and carries out
Mitsunobu reaction obtains compound 5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510103549.8A CN104710379B (en) | 2015-03-09 | 2015-03-09 | Synthetic method for BMS-191011 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510103549.8A CN104710379B (en) | 2015-03-09 | 2015-03-09 | Synthetic method for BMS-191011 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104710379A CN104710379A (en) | 2015-06-17 |
| CN104710379B true CN104710379B (en) | 2017-01-18 |
Family
ID=53410168
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510103549.8A Expired - Fee Related CN104710379B (en) | 2015-03-09 | 2015-03-09 | Synthetic method for BMS-191011 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104710379B (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW467902B (en) * | 1996-07-31 | 2001-12-11 | Bristol Myers Squibb Co | Diphenyl heterocycles as potassium channel modulators |
| EP1051173A4 (en) * | 1998-01-29 | 2002-07-31 | Bristol Myers Squibb Co | Derivatives of 1,3,4-oxadiazolone |
| AU736712B2 (en) * | 1998-01-29 | 2001-08-02 | Bristol-Myers Squibb Company | Benzoate derivatives of diaryl 1,3,4-oxadiazolone |
| IL144540A0 (en) * | 1999-01-29 | 2002-05-23 | Bristol Myers Squibb Co | Carbamate derivatives of diaryl 1,3,4,-oxadiazolone |
| JP6449845B2 (en) * | 2013-03-15 | 2019-01-09 | クロモセル コーポレイション | Sodium channel modulator for the treatment of pain |
-
2015
- 2015-03-09 CN CN201510103549.8A patent/CN104710379B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN104710379A (en) | 2015-06-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Mei et al. | A facile process for the asymmetric synthesis of β-trifluoromethylated β-amino ketones via addition of ketone enolates to sulfinylimine | |
| CN112778147B (en) | Preparation method of 2-amino-3-methyl-5-chlorobenzoic acid | |
| Yuan et al. | Ruthenium (ii)-catalysed selective C (sp 2)–H bond benzoxylation of biologically appealing N-arylisoindolinones | |
| CN104788360B (en) | Ketene compounds of 3 sulfuryl loop coil three and preparation method thereof | |
| CN104710379B (en) | Synthetic method for BMS-191011 | |
| Cui et al. | Direct Iodosulfonylation of Alkylynones with Sulfonylhydrazides and Iodine Pentoxide Leading to Multisubstituted α, β-Enones | |
| Gao et al. | Regioselective C–H chlorination: towards the sequential difunctionalization of phenol derivatives and late-stage chlorination of bioactive compounds | |
| CN103601717A (en) | Novel preparation method of lenalidomide | |
| CN105585540B (en) | Preparation and application of Swern reagent | |
| CN109134320A (en) | A kind of synthetic method of the sulphonyl class compound replaced containing beta-hydroxy | |
| CN103450069B (en) | Preparation method of mitiglinide calcium | |
| CN108047128A (en) | A kind of method for synthesizing (E) -2- methyl 4-phenyl -6- styryl substituted pyridine compounds | |
| CN105541738B (en) | A kind of preparation method of the acetophenone compounds of triazole substitution | |
| CN110885291B (en) | Synthetic method of 3-chloro-5- (difluoromethoxy) benzylamine | |
| CN104262159B (en) | A kind of synthetic method of ortho-nitrophenyl phenolic compound | |
| CN103408542B (en) | A kind of preparation method of highly purified Dasatinib anhydride | |
| CN106045952A (en) | Synthesizing method of benzofuranone compound containing sulfonyl | |
| CN112920030A (en) | Method for preparing dapagliflozin intermediate by one-pot method | |
| CN102079720B (en) | Method for preparing 1-benzylpiperidine-4-carboxaldehyde | |
| CN106632075B (en) | A kind of synthetic method of 2,4,6- triphenyls pyridine derivatives | |
| CN103382208B (en) | The preparation method of Arglabin | |
| CN107188843A (en) | Utilize the method for carbonylation one pot process α glucosidase inhibitors | |
| CN107935941A (en) | Treat non-small cell lung cancer, the medicine Si Dinibu of kidney and its preparation method of intermediate | |
| CN109970673B (en) | Preparation method of parecoxib sodium impurity | |
| CN107188844A (en) | Utilize the method for the enzyme inhibitors of carbonylation one pot process COX 2 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20170118 |