CN108129513A - A kind of method for synthesizing Bouguer and replacing Buddhist nun's intermediate - Google Patents
A kind of method for synthesizing Bouguer and replacing Buddhist nun's intermediate Download PDFInfo
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- CN108129513A CN108129513A CN201810104078.6A CN201810104078A CN108129513A CN 108129513 A CN108129513 A CN 108129513A CN 201810104078 A CN201810104078 A CN 201810104078A CN 108129513 A CN108129513 A CN 108129513A
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- Prior art keywords
- formula
- compound
- bouguer
- reaction
- buddhist nun
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- 238000000034 method Methods 0.000 title claims abstract description 35
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- 239000002253 acid Substances 0.000 claims abstract description 32
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 16
- 150000003863 ammonium salts Chemical class 0.000 claims abstract description 11
- 238000006482 condensation reaction Methods 0.000 claims abstract description 11
- 239000004202 carbamide Substances 0.000 claims abstract description 10
- 239000011230 binding agent Substances 0.000 claims abstract description 8
- 238000006467 substitution reaction Methods 0.000 claims abstract description 8
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- 230000009471 action Effects 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- -1 halogen acids Chemical class 0.000 claims description 22
- 230000015572 biosynthetic process Effects 0.000 claims description 21
- 238000003786 synthesis reaction Methods 0.000 claims description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 235000019441 ethanol Nutrition 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 229910052763 palladium Inorganic materials 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 239000011574 phosphorus Substances 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical class CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 2
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims 1
- HXWDNCGKKYUTTH-UHFFFAOYSA-N CN(N1CC=CC=2C=CC=NC12)C Chemical class CN(N1CC=CC=2C=CC=NC12)C HXWDNCGKKYUTTH-UHFFFAOYSA-N 0.000 claims 1
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims 1
- 239000010931 gold Substances 0.000 claims 1
- 229910052737 gold Inorganic materials 0.000 claims 1
- 230000000269 nucleophilic effect Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 6
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- 239000000047 product Substances 0.000 abstract description 4
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- 125000000714 pyrimidinyl group Chemical group 0.000 abstract description 3
- 239000007791 liquid phase Substances 0.000 abstract description 2
- 238000004064 recycling Methods 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 26
- YOTZYFSGUCFUKA-UHFFFAOYSA-N dimethylphosphine Chemical compound CPC YOTZYFSGUCFUKA-UHFFFAOYSA-N 0.000 description 23
- 238000002360 preparation method Methods 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 238000001819 mass spectrum Methods 0.000 description 16
- 238000010606 normalization Methods 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 13
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 11
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 7
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 6
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
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- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
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- 238000005292 vacuum distillation Methods 0.000 description 3
- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical class NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- UUOFSRVHZJTWDE-UHFFFAOYSA-N 3-chloro-3-oxopropanoic acid Chemical compound OC(=O)CC(Cl)=O UUOFSRVHZJTWDE-UHFFFAOYSA-N 0.000 description 2
- 101100459319 Arabidopsis thaliana VIII-2 gene Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
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- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 235000021050 feed intake Nutrition 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- PZHNNJXWQYFUTD-UHFFFAOYSA-N phosphorus triiodide Chemical compound IP(I)I PZHNNJXWQYFUTD-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- 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 2
- GIKMWFAAEIACRF-UHFFFAOYSA-N 2,4,5-trichloropyrimidine Chemical class ClC1=NC=C(Cl)C(Cl)=N1 GIKMWFAAEIACRF-UHFFFAOYSA-N 0.000 description 1
- CEJAHXLRNZJPQH-UHFFFAOYSA-N 2,5-dichloropyrimidine Chemical compound ClC1=CN=C(Cl)N=C1 CEJAHXLRNZJPQH-UHFFFAOYSA-N 0.000 description 1
- AILRADAXUVEEIR-UHFFFAOYSA-N 5-chloro-4-n-(2-dimethylphosphorylphenyl)-2-n-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine Chemical compound COC1=CC(N2CCC(CC2)N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1P(C)(C)=O AILRADAXUVEEIR-UHFFFAOYSA-N 0.000 description 1
- DHHGHQKIKXKQGJ-UHFFFAOYSA-N CP(C)(c1ccccc1N)=O Chemical compound CP(C)(c1ccccc1N)=O DHHGHQKIKXKQGJ-UHFFFAOYSA-N 0.000 description 1
- KHUKYKPHRJZTAB-UHFFFAOYSA-N Clc1nc(Cl)ncc1CC1[IH]C1 Chemical compound Clc1nc(Cl)ncc1CC1[IH]C1 KHUKYKPHRJZTAB-UHFFFAOYSA-N 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- DXRFZHILMCWCNG-UHFFFAOYSA-N N,N-dimethyl-1,8-naphthyridin-2-amine Chemical compound C1=CC=NC2=NC(N(C)C)=CC=C21 DXRFZHILMCWCNG-UHFFFAOYSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QWBAOXACRYJBED-UHFFFAOYSA-N [Cl].C1=CN=CN=C1 Chemical compound [Cl].C1=CN=CN=C1 QWBAOXACRYJBED-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 229950004272 brigatinib Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 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
- 230000009977 dual effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 208000019420 lymphoid neoplasm Diseases 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of methods for synthesizing Bouguer and replacing Buddhist nun's intermediate, include the following steps：(1) acylated condensation reaction under the action of metallic catalyst, acid binding agent is occurred into for compound of formula I and Formula II compound and obtains intermediate state formula III compound, acid adding, which is hydrolyzed, later is obtained by the reaction Formula V compound and ammonium salt IV；(2) condensation reaction is occurred into for the Formula V compound and urea and obtains VII compound of formula；(3) substitution reaction is occurred into for VII compound of formula and nucleopilic reagent and obtains VIII compound of formula, is i.e. Bouguer replaces Buddhist nun's intermediate.The present invention provides new method for Bouguer for the structure of Buddhist nun's pyrimidine ring, the generation of competitive reaction is avoided, reduces the generation of by-product, while carries out reaction process cycle to the recycling of ammonium salt, route is easy to operate, reaction step is shortened, reaction condition is mild, good reaction selectivity, overall yield is higher, product liquid phase purity is high, considerably reduces production cost, is more advantageous to industrialized production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of method for synthesizing Bouguer and replacing Buddhist nun's intermediate.
Background technology
It is a kind of completely new oral anaplastic lymphoma kinase (anaplastic developed by Ariad companies that Bouguer, which replaces Buddhist nun,
Lymphoma kinase, ALK) inhibitor, FDA listing approvals, trade name Alunbrig are obtained in April, 2017.For treating
To gram azoles for Buddhist nun do not tolerate or medication after progression of disease patient treat anaplastic lymphoma kinase (ALK) positive metastatic it is non-
Patients With Small Cell Carcinoma of The Lung, Bouguer replace Buddhist nun better than gram azoles to the selectivity of ALK for Buddhist nun, the G1202R of ALK can effectively be inhibited to be mutated.
In addition, further include fibrosarcoma, diffusivity large B cell lymphoid tumor and primary cutaneous type etc. grinding indication.Thus
It can be seen that Bouguer has good market prospects for Buddhist nun, and particularly important is just shown for the study on the synthesis of Buddhist nun to Bouguer.
Bouguer is entitled for the chemistry of Buddhist nun：The chloro- N2- of 5- [4- [(4- methylpiperazine-1-yls) piperidin-1-yl] -2- methoxybenzenes
Base]-N4- [2- (dimethyl Asia phosphono) phenyl] -2,4- pyrimidinediamines, concrete structure is as follows：
Patent WO2009143389 reports the structure and synthetic method that Bouguer replaces Buddhist nun, document (J.Med.Chem.20 for the first time
16,59,4948-4964) and patent US2015225436, WO201665028 etc. also report its synthetic method.It is reported at present
Be mainly intermediate A for the synthetic method of Buddhist nun about Bouguer and substitution reaction occurs for intermediate B, process is shown below：
Study on the synthesis at present about key intermediate A is more, (J.Med.Chem.2016,59,4948-4964) report
A kind of preparation method of intermediate A is shown in route one.This method be by 2- Iodoanilines and dimethyl phosphine palladium/
Under Xantphos catalysis, with K3PO4For acid binding agent, coupling obtains (2- aminophenyls) dimethyl phosphine, then with 2,4,5- tri-
Intermediate A (2- ((2,5- dichloro pyrimidine -4- bases) amino) phenyl) dimethyl phosphine is obtained by the reaction in chlorine pyrimidine.This method exists
The problem of be：The chlorine of 2 and 4 during 2,4,5- trichloropyrimidines and (2- aminophenyls) dimethyl phosphine replace
There are competitive reactions, lead to selective reduction；The building-up process of intermediate A reacts incomplete, post-processes purifying complex, yield not
Height, two-step reaction total recovery are only 49.9%；Operating process is complicated, is unfavorable for industrialized production.
CN107522742A discloses a kind of homogeneous " one kettle way " preparation method of intermediate A, and this method is with by route one
One pot of three kinds of raw materials feed intake and reacted, although yield slightly improves compared with route one, 2 in the synthesis process
Chlorine with 4 still has very big competitive reaction, and raw material availability is caused to reduce.Chinese journal of Medicinal Chemistry reports one simultaneously
Kind is shown in route two about the optimum synthesis method of intermediate A, although this method uses Pd (PPh3)2Cl2As catalyst instead of
The palladium of document report and Xantphos dual catalysts, but competitive reaction is equally existed, and in intermediate A and intermediate
B has used microwave heating, but this process is unfavorable for the production of industrial-scale during reacting.
To sum up, Bouguer in the synthesis of Buddhist nun there are low yield, synthesis is complicated, raw material availability is low, of high cost and be unfavorable for
The problems such as industrialization generation, and pyrimidine ring is only resided within to the research of intermediate A and is reacted with the participation of other raw materials, no
The competitive reaction of pyrimidine ring substituents is avoided that, so there is still a need for find simpler, efficient novel synthesis.
Invention content
Goal of the invention：Bouguer is prepared at present for product yield in the method for Buddhist nun is low, building-up process is complicated and gives birth in order to overcome
The defects of of high cost is produced, the present invention provides one kind there is industrialization potential and high income, by-product to recycle, product purity
Method high, synthesis step is few, simple synthesis Bouguer replaces Buddhist nun's intermediate.
Technical solution：The method that synthesis Bouguer of the present invention replaces Buddhist nun's intermediate, includes the following steps：
(1) acylated condensation reaction is occurred under the action of metallic catalyst, acid binding agent for compound of formula I and Formula II compound
Intermediate state formula III compound is obtained, acid adding, which is hydrolyzed, later is obtained by the reaction Formula V compound and ammonium salt IV；
(2) condensation reaction is occurred into for the Formula V compound and urea and obtains VII compound of formula；
(3) substitution reaction is occurred into for VII compound of formula and nucleopilic reagent and obtains VIII compound of formula, is i.e. Bouguer replaces Buddhist nun
Intermediate；
Wherein, R is selected from the linear or branched alkyl group of C1-C4, preferably methyl, ethyl, propyl, butyl, more preferable ethyl；X1
Selected from F, Cl, Br, I, preferably Cl.
In step (1), the molar ratio of compound of formula I and Formula II compound is (2-4): 1, preferably (2.5-3.5): 1.
In step (1), the metallic catalyst is aluminium chloride, one kind in iron chloride, copper chloride, palladium bichloride, palladium
Or several, preferred aluminium chloride；The molar ratio of Formula II compound and metallic catalyst is 1: (0.1-0.4), preferably 1: 0.2；
The acid binding agent is sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropyl ethyl amine, pyridine, N, N-
One or more of dimethylamino naphthyridine, N- methyl piperidines, N- methyl beautiful jades, preferably triethylamine；Formula II compound is with tiing up acid
The molar ratio of agent is 1: (0.2-1.5), preferably 1: 0.5.
In step (1), the solvent used in acylated condensation reaction is ethyl alcohol, dichloroethanes, dichloromethane, dimethylacetamide
One or more of amine, dimethyl sulfoxide (DMSO), tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, acetonitrile or toluene, preferably dichloromethane；Instead
It is 60~110 DEG C to answer temperature, preferably 60~90 DEG C, most preferably 65~80 DEG C.
In step (1), acid hydrolysis reaction acid used is hydrochloric acid, sulfuric acid, phosphoric acid, one kind in trifluoroacetic acid or several
Kind, preferably hydrochloric acid；Wherein, a concentration of 37wt% of hydrochloric acid；A concentration of 98wt% of sulfuric acid, phosphoric acid concentration 85wt%；Formula II
The molar ratio of compound and acid is 1: (1-2), preferably 1: 1.2.
In step (1), ammonium salt IV further adds alkali to generate raw material compound of formula I, recycles.The ammonium salt IV adds alkali
The alkali that generation compound of formula I is used is sodium carbonate, sodium bicarbonate, potassium carbonate, saleratus, lithium hydroxide, sodium hydroxide, hydrogen-oxygen
Change one or more of potassium, calcium hydroxide, magnesium hydroxide, barium hydroxide, preferably sodium carbonate；The throwing of IV compound of ammonium salt and alkali
It is 1 to expect molar ratio: (1-3), preferably 1: 1.5.
In step (2), the molar ratio of Formula V compound and urea is 1: (1-3), preferably 1: (1.25-2.5), it is optimal
Select 1: 1.5.
In step (2), reaction dissolvent is methanol, ethyl alcohol, n,N-Dimethylformamide, dimethylacetylamide, dimethyl are sub-
One or more of sulfone, toluene, dichloromethane, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, acetonitrile, preferably N, N- dimethyl formyls
Amine；Reaction temperature is 65~95 DEG C, preferably 80 DEG C.
In step (3), nucleopilic reagent is one or more of halogen acids, phosphorus Halides, thionyl chloride, and halogen acids is hydrogen chlorine
One or more of acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphorus Halides for phosphorus tribromide, phosphorus trichloride, phosphorus triiodide one
Kind is several.The preferred thionyl chloride of nucleopilic reagent.The molar ratio of Formula VII compound and nucleopilic reagent is 1: (1-3), preferably
1: (1.2-2), most preferably 1: 1.2.
In step (3), reaction temperature is 0~90 DEG C, preferably 60~85 DEG C.
A kind of method for synthesizing Bouguer and replacing Buddhist nun, the step of including above-mentioned VIII compound of formula, further including will be described
Formula VIII compound occurs substitution reaction with Formula IX compound and obtains Formula X compound, i.e. Bouguer replaces Buddhist nun,
The Formula VIII compound is 1 with Formula IX compound molar ratio: (1-2), preferably 1: (1.2-1.5)；Substitution
There is acid to participate in reaction in reaction, acid used is one or more of hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid, preferably trifluoro
The molar ratio of acetic acid, VIII compound of formula and acid is 1: (0.2-1.5), preferably 1: 0.5.Reaction dissolvent is methanol, ethyl alcohol, third
Alcohol, isopropanol, n-butanol, the tert-butyl alcohol, dimethylformamide, dimethylacetylamide, dimethyl sulfoxide (DMSO), toluene, dichloromethane, four
One or more of hydrogen furans, Isosorbide-5-Nitrae-dioxane, acetonitrile, preferred alcohol.Reaction temperature is 50~100 DEG C, preferably 70-90
℃。
The synthetic route of the present invention is as follows：
Wherein, R is selected from the linear or branched alkyl group of C1-C4, X1Selected from F, Cl, Br, I.
Preferably, synthesis Bouguer of the present invention includes the following steps for the method for Buddhist nun：
By compound of formula I 2- (dimethyl phosphoroso-) aniline and -1 compound of Formula II (chloroformyl) ethyl acetate in metal
Acylated condensation reaction occurs under the action of catalyst and obtains intermediate state formula III, acid adding carries out that Formula V compound 2- is obtained by the reaction later
Chloro- N- (2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides and ammonium salt IV, water phase ammonium salt add alkali to generate starting materials of formulae I chemical combination
Object recycles；
Condensation reaction is occurred into for the Formula V compound and urea VI and obtains Formula VII compound (2- ((5- chlorine-2-hydroxyls
Pyrimidine-4-yl) amino) phenyl) dimethyl phosphine；
Substitution reaction is occurred into for the Formula VII compound and nucleopilic reagent thionyl chloride and obtains -1 compound 2 of Formula VIII,
Bis- chloro- N- of 5- (2- (dimethyl Asia phosphono) phenyl) pyrimidine -4- amine；
By -1 compound of Formula VIII and Formula IX compound 2- methoxyl groups -4- [4- (4- methylpiperazine-1-yls) piperazines
Pyridine -1- bases] aniline occurs substitution reaction and obtains Formula X compound, i.e., and Bouguer replaces Buddhist nun,
Advantageous effect：Present invention synthesis Bouguer replaces the method for Buddhist nun, and relative to the prior art, the structure for pyrimidine ring provides
New method is avoided using noble metal catalyst or strong reductant reagent etc., realizes that the recycling of by-product, raw material utilizes
Rate is high, reaction condition is mild, and synthesis step is few, and good reaction selectivity, overall yield is higher, and product liquid phase purity is high, drops significantly
Low production cost, is more suitable for industrialized production.
Specific embodiment
Embodiment 1
(1) preparation of the chloro- N- of 2- (2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (V)
2- (dimethyl phosphoroso-) aniline (I) (21.12.4g, 125mmol), (chloroformyl) second are added in reaction bulb
Acetoacetic ester (II-1) (7.5g, 50mmol), aluminium chloride (1.333g, 10mmol) do catalyst, triethylamine (0.253g,
2.5mmol) do acid binding agent, dichloromethane (150mL) be solvent, be stirred to react 16h at 80 DEG C.TLC detection reactions are completed.Reaction
Terminate addition 5.8ml hydrochloric acid (concentration 37wt%) and be stirred to react 3h, make intermediate state III that reaction be hydrolyzed, 30ml is added after hydrolysis
Water makes reaction liquid layer, and aqueous phase solution makes ammonium salt be converted into raw material 2- (dimethyl by adding in sodium carbonate (7.9g, 75mmol)
Phosphoroso-) aniline (I).Organic phase after wherein hydrolyzing is washed 2 times with saturated common salt, and anhydrous sodium sulfate drying is evaporated under reduced pressure back
Solvent is received, gained concentrate ethyl acetate and n-hexane (1: 1, V/V) recrystallize to obtain compound 2- chloro- N- (2- (dimethyl
Phosphono) phenyl) -3- oxopropanamides (V) 11.2g；Yield 82%；Purity is 99.8% (HPLC area normalization methods)；Mass spectrum
(ESI)：M/z=274.04 (M+H).
(2) preparation of (2- ((5- chlorine-2-hydroxyls pyrimidine-4-yl) amino) phenyl) dimethyl phosphine (VII)
Intermediate 2- chloro- N- (2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (V) are added in reaction bulb
(10.9g, 40mmol), urea (VI) (3.6g, 50mmol), n,N-Dimethylformamide (100mL) are solvent, are stirred at 80 DEG C
Mix reaction 12h.TLC detection reactions are completed.Reaction terminates plus reaction is quenched in water 150mL, and organic phase is washed 2 times with saturated common salt,
Water phase is extracted with ethyl acetate 2 times, merges organic phase, anhydrous sodium sulfate drying, vacuum distillation recovered solvent, gained concentrate use
Petroleum ether and ethyl acetate mixed solvent column chromatography for separation obtain compound (2- ((5- chlorine-2-hydroxyls pyrimidine-4-yl) amino) benzene
Base) dimethyl phosphine (VII) 9.758g；Yield 85%；Purity is 99.8% (HPLC area normalization methods)；Mass spectrum (ESI)：m/
Z=298.05 (M+H).
Bis- chloro- N- of (3) 2,5- (2- (dimethyl Asia phosphono) phenyl) pyrimidine -4- amine 2- chloro- N- (2- (dimethyl phosphonos
Base) phenyl) -3- oxopropanamides (VIII -1) preparation
Intermediate (2- ((5- chlorine-2-hydroxyls pyrimidine-4-yl) amino) phenyl) dimethyl phosphine is added in reaction bulb
(VII) (10.4g, 35mmol) and nucleopilic reagent thionyl chloride (5g, 42mmol), 10h is stirred to react at 85 DEG C.TLC detections are anti-
It should complete.Reaction terminates plus reaction is quenched in water 150mL, and organic phase is washed 2 times with saturated common salt, and water phase is extracted with ethyl acetate 2
It is secondary, merge organic phase, anhydrous sodium sulfate drying, vacuum distillation recovered solvent, gained concentrate ethyl acetate and n-hexane (1:
1, V/V) compound 2, bis- chloro- N- of 5- (2- (dimethyl Asia phosphono) phenyl) chloro- N- (2- of pyrimidine -4- amine 2- are recrystallized to obtain
(dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (VIII -1) 10.25g；Yield 93%；(return for 99.9% by HPLC areas for purity
One method)；Mass spectrum (ESI)：M/z=313.98 (M-H).
(4) Bouguer replaces the preparation of Buddhist nun (X)
Intermediate 2 is added in reaction bulb, bis- chloro- N- of 5- (2- (dimethyl Asia phosphono) phenyl) pyrimidine -4- amine 2- is chloro-
N- (2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (VIII -1) (9.45g, 30mmol), 2- methoxyl groups -4- [4- (4-
Methylpiperazine-1-yl) piperidin-1-yl] aniline (IX) (11g, 36mmol), trifluoroacetic acid (1.7g, 15mmol), ethyl alcohol
(100mL) is solvent, and 12h, condenser pipe reflux are stirred to react at 90 DEG C.TLC detection reactions are completed.Reaction terminates plus water 150mL
Reaction is quenched, organic phase is washed 2 times with saturated common salt, and water phase is extracted with ethyl acetate 2 times, merges organic phase, anhydrous sodium sulfate
Dry, vacuum distillation recovered solvent, gained concentrate is recrystallized with n-hexane, and vacuum drying obtains white solid product cloth
Lattice replace Buddhist nun (X) 16.1g；Yield 92%；Purity is 99.8% (HPLC area normalization methods)；Mass spectrum (ESI)：M/z=584.26 (M+
H)。
Embodiment 2
(1) preparation of the chloro- N- of 2- (2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (V)
With embodiment 1, the difference lies in：Raw material compound of formula I and the molar ratio of -1 compound of Formula II are 3.5:
1, acylated condensation alkali used is pyridine, and solvent is toluene, and reaction temperature is 65 DEG C, and it is phosphoric acid (concentration to hydrolyze the acid used
85wt%).
Palladium bichloride (1.77g, 10mmol) is catalyst, the final gained chloro- N- of compound 2- (2- (dimethyl phosphine acyl group)
Phenyl) -3- oxopropanamides (V) 11.33g；Yield 83%；Purity is 99.8% (HPLC area normalization methods)；Mass spectrum (ESI)：
M/z=274.04 (M+H).
(2) preparation of (2- ((5- chlorine-2-hydroxyls pyrimidine-4-yl) amino) phenyl) dimethyl phosphine (VII)
With embodiment 1, the difference lies in：The molar ratio of Formula V compound and urea is 1: 2.5, and solvent is toluene,
Reaction temperature is 95 DEG C.
Final gained compound (2- ((5- chlorine-2-hydroxyls pyrimidine-4-yl) amino) phenyl) dimethyl phosphine (VII)
9.5g；Yield 80%；Purity is 99.8% (HPLC area normalization methods)；Mass spectrum (ESI)：M/z=298.05 (M+H).
(3) the chloro- N- of the bromo- 5- of 2- (2- (dimethyl Asia phosphono) phenyl) pyrimidine -4- amine 2- chloro- N- (2- (dimethyl phosphonos
Base) phenyl) -3- oxopropanamides (VIII-2) preparation
With embodiment 1, the difference lies in：Nucleopilic reagent is hydrobromic acid, and VII compound of formula and feeding intake for nucleopilic reagent are rubbed
, than being 1: 2, reaction temperature is 60 DEG C for you.
The final gained bromo- 5- of compound 2- chloro- N- (2- (dimethyl Asia phosphono) phenyl) chloro- N- (2- of pyrimidine -4- amine 2-
(dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (VIII-2) 9.37g；Yield 85%；Purity is 99.5% (HPLC areas
Normalization method)；Mass spectrum (ESI)：M/z=357.86 (M-H).
(4) Bouguer replaces the preparation of Buddhist nun (X)
With embodiment 1, the difference lies in：- 2 compound of Formula VIII is 1: 2 with Formula IX compound molar ratio,
Dimethyl sulfoxide (DMSO) is solvent, and used acid is hydrochloric acid, and reaction temperature is 70 DEG C.
Final gained white solid product Bouguer replaces Buddhist nun (X) 14.87g；Yield 85%；Purity is 99.8% (HPLC areas
Normalization method)；Mass spectrum (ESI)：M/z=584.26 (M+H).
Embodiment 3
(1) preparation of the chloro- N- of 2- (2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (V)
With embodiment 1, the difference lies in：(chloroformyl) ethyl acetate (II-1) replaces with (chloroformyl) acetic acid first
Ester (II-2).The molar ratio of raw material compound of formula I and -2 compound of Formula II is 2: 1.Palladium bichloride is catalyst, and Formula II -2 is changed
The molar ratio for closing object and catalyst is 1: 0.1.It is acylated to be condensed alkali used as sodium methoxide, the throwing of -2 compound of Formula II and alkali
It is 1: 0.2 to expect molar ratio.Acylated condensation reaction dissolvent used is ethyl alcohol, and reaction temperature is 60 DEG C.Acid adding water after acylated condensation
The acid that solution is used is trifluoroacetic acid, and -2 compound of Formula II is 1: 1 with sour molar ratio.
Final gained compound 2- chloro- N- (2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (V) yield 81%；
Purity is 99.8% (HPLC area normalization methods)；Mass spectrum (ESI)：M/z=274.04 (M+H).
(2) preparation of (2- ((5- chlorine-2-hydroxyls pyrimidine-4-yl) amino) phenyl) dimethyl phosphine (VII)
With embodiment 1, the difference lies in：The molar ratio of Formula V compound and urea is 1: 1, and solvent is tetrahydrochysene furan
It mutters, reaction temperature is 65 DEG C.
Final gained compound (2- ((5- chlorine-2-hydroxyls pyrimidine-4-yl) amino) phenyl) dimethyl phosphine (VII)
9.5g；Yield 81%；Purity is 99.8% (HPLC area normalization methods)；Mass spectrum (ESI)：M/z=298.05 (M+H).
(3) the chloro- N- of the fluoro- 5- of 2- (2- (dimethyl Asia phosphono) phenyl) pyrimidine -4- amine 2- chloro- N- (2- (dimethyl phosphonos
Base) phenyl) -3- oxopropanamides (VIII-3) preparation
With embodiment 1, the difference lies in：Nucleopilic reagent is hydrofluoric acid, and VII compound of formula and feeding intake for nucleopilic reagent are rubbed
, than being 1: 1, reaction temperature is 0 DEG C for you.
The final gained fluoro- 5- of compound 2- chloro- N- (2- (dimethyl Asia phosphono) phenyl) chloro- N- (2- of pyrimidine -4- amine 2-
(dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (VIII-3) yield 83%；Purity is 99.5% (HPLC area normalizations
Method)；Mass spectrum (ESI)：M/z=298.12 (M-H).
(4) Bouguer replaces the preparation of Buddhist nun (X)
With embodiment 1, the difference lies in：- 3 compound of Formula VIII is 1: 1 with Formula IX compound molar ratio,
Dichloromethane is solvent, and used acid is sulfuric acid, and reaction temperature is 50 DEG C.
Final gained white solid product Bouguer replaces Buddhist nun (X) yield 83%；Purity is 99.8% (HPLC area normalization methods)；
Mass spectrum (ESI)：M/z=584.26 (M+H).
Embodiment 4
(1) preparation of the chloro- N- of 2- (2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (V)
With embodiment 1, the difference lies in：(chloroformyl) ethyl acetate (II-1) replaces with (chloroformyl) acetic acid third
Ester (II-3).The molar ratio of raw material compound of formula I and -3 compound of Formula II is 4: 1.Palladium is catalyst, Formula II -3
The molar ratio of compound and catalyst is 1: 0.4.Acylated condensation alkali used is potassium tert-butoxide, -3 compound of Formula II and alkali
Molar ratio be 1: 0.5.Acylated condensation reaction dissolvent used is tetrahydrofuran, and reaction temperature is 110 DEG C.Acylated contracting
The acid that acid hydrolysis is used after conjunction is sulfuric acid (concentration 98wt%), and -3 compound of Formula II is 1: 2 with sour molar ratio.
Final gained compound 2- chloro- N- (2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (V) 11.33g；It receives
Rate 81.5%；Purity is 99.8% (HPLC area normalization methods)；Mass spectrum (ESI)：M/z=274.04 (M+H).
(2) preparation of (2- ((5- chlorine-2-hydroxyls pyrimidine-4-yl) amino) phenyl) dimethyl phosphine (VII)
With embodiment 1, the difference lies in：The molar ratio of Formula V compound and urea is 1: 3, and solvent is ethyl alcohol, instead
It is 80 DEG C to answer temperature.
Final gained compound (2- ((5- chlorine-2-hydroxyls pyrimidine-4-yl) amino) phenyl) dimethyl phosphine (VII) is received
Rate 82%；Purity is 99.8% (HPLC area normalization methods)；Mass spectrum (ESI)：M/z=298.05 (M+H).
(3) the chloro- N- of the iodo- 5- of 2- (2- (dimethyl Asia phosphono) phenyl) pyrimidine -4- amine 2- chloro- N- (2- (dimethyl phosphonos
Base) phenyl) -3- oxopropanamides (VIII-4) preparation
With embodiment 1, the difference lies in：Nucleopilic reagent is phosphorus triiodide, and VII compound of formula and nucleopilic reagent feed intake
Molar ratio is 1: 3, and reaction temperature is 90 DEG C.
The final gained iodo- 5- of compound 2- chloro- N- (2- (dimethyl Asia phosphono) phenyl) chloro- N- (2- of pyrimidine -4- amine 2-
(dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (VIII-4) 9.37g；Yield 82%；Purity is 99.5% (HPLC areas
Normalization method)；Mass spectrum (ESI)：M/z=405.47 (M-H).
(4) Bouguer replaces the preparation of Buddhist nun (X)
With embodiment 1, the difference lies in：- 4 compound of Formula VIII is 1 with Formula IX compound molar ratio:
1.5, tetrahydrofuran is solvent, and used acid is hydrochloric acid, and reaction temperature is 100 DEG C.
Final gained white solid product Bouguer replaces Buddhist nun (X) yield 83%；Purity is 99.8% (HPLC area normalization methods)；
Mass spectrum (ESI)：M/z=584.26 (M+H).
Claims (10)
- A kind of 1. method for synthesizing Bouguer and replacing Buddhist nun's intermediate, which is characterized in that include the following steps：(1) compound of formula I acylated condensation reaction occur under the action of metallic catalyst, acid binding agent with Formula II compound to obtain Intermediate state formula III compound, acid adding, which is hydrolyzed, later is obtained by the reaction Formula V compound and ammonium salt IV；(2) condensation reaction is occurred into for the Formula V compound and urea and obtains VII compound of formula；(3) substitution reaction is occurred into for VII compound of formula and nucleopilic reagent and obtains VIII compound of formula, i.e., Bouguer is among Buddhist nun Body,Wherein, R is selected from the linear or branched alkyl group of C1-C4；X1Selected from F, Cl, Br, I.
- 2. the method that synthesis Bouguer according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that in step (1), Formulas I The molar ratio for closing object and Formula II compound is (2-4): 1.
- 3. the method that synthesis Bouguer according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that in step (1), the gold Metal catalyst is one or more of aluminium chloride, iron chloride, copper chloride, palladium bichloride, palladium；Formula II compound is urged with metal The molar ratio of agent is 1: (0.1-0.4)；The acid binding agent for sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, Triethylamine, diisopropyl ethyl amine, pyridine, N, one kind or several in N- dimethylamino naphthyridines, N- methyl piperidines, N- methyl beautiful jades Kind, the molar ratio of Formula II compound and acid binding agent is 1: (0.2-1.5).
- 4. the method that synthesis Bouguer according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that in step (1), acylated contracting Close reaction solvent used be ethyl alcohol, dichloroethanes, dichloromethane, dimethylacetylamide, dimethyl sulfoxide (DMSO), tetrahydrofuran, 1, One or more of 4- dioxane, acetonitrile or toluene；Reaction temperature is 60~110 DEG C.
- 5. the method that synthesis Bouguer according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that in step (1), acid adding water Solution reaction acid used is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid；Formula II compound is rubbed with feeding intake for acid You are than being 1: (1-2).
- 6. the method that synthesis Bouguer according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that in step (1), ammonium salt IV Further plus alkali generates compound of formula I.
- 7. the method that synthesis Bouguer according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that in step (2), Formula V The molar ratio for closing object and urea is 1: (1-3).
- 8. the method that synthesis Bouguer according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that in step (2), reaction is molten Agent is methanol, ethyl alcohol, n,N-Dimethylformamide, dimethylacetylamide, dimethyl sulfoxide (DMSO), toluene, dichloromethane, tetrahydrochysene furan It mutters, one or more of Isosorbide-5-Nitrae-dioxane, acetonitrile；Reaction temperature is 65~95 DEG C.
- 9. the method that synthesis Bouguer according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that in step (3), nucleophilic examination Agent is one or more of halogen acids, phosphorus Halides, thionyl chloride, and the molar ratio of Formula VII compound and nucleopilic reagent is 1 ∶(1-3)。
- 10. the method that synthesis Bouguer according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that in step (3), reaction Temperature is 0~90 DEG C.
Priority Applications (1)
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019148789A1 (en) * | 2018-02-02 | 2019-08-08 | 苏州科睿思制药有限公司 | Crystal form of ap26113 and preparation method therefor |
| CN112047978A (en) * | 2019-06-05 | 2020-12-08 | 北京赛思源生物医药技术有限公司 | Novel crystal form of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine |
| CN112239422A (en) * | 2020-10-16 | 2021-01-19 | 河北化工医药职业技术学院 | Bugatinib intermediate, salt thereof, preparation method thereof and preparation method of brigatinib |
| CN112675175A (en) * | 2021-02-01 | 2021-04-20 | 天津济坤医药科技有限公司 | Application of brigatinib in preparation of medicine for treating idiopathic pulmonary fibrosis |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107522742A (en) * | 2017-10-20 | 2017-12-29 | 常州工程职业技术学院 | A kind of homogeneous " one kettle way " preparation method of Brigatinib key intermediates |
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2018
- 2018-02-01 CN CN201810104078.6A patent/CN108129513A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107522742A (en) * | 2017-10-20 | 2017-12-29 | 常州工程职业技术学院 | A kind of homogeneous " one kettle way " preparation method of Brigatinib key intermediates |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019148789A1 (en) * | 2018-02-02 | 2019-08-08 | 苏州科睿思制药有限公司 | Crystal form of ap26113 and preparation method therefor |
| CN112047978A (en) * | 2019-06-05 | 2020-12-08 | 北京赛思源生物医药技术有限公司 | Novel crystal form of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine |
| CN112239422A (en) * | 2020-10-16 | 2021-01-19 | 河北化工医药职业技术学院 | Bugatinib intermediate, salt thereof, preparation method thereof and preparation method of brigatinib |
| CN112675175A (en) * | 2021-02-01 | 2021-04-20 | 天津济坤医药科技有限公司 | Application of brigatinib in preparation of medicine for treating idiopathic pulmonary fibrosis |
| CN112675175B (en) * | 2021-02-01 | 2022-11-01 | 天津济坤医药科技有限公司 | Application of brigatinib in preparation of medicine for treating idiopathic pulmonary fibrosis |
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