WO2017016410A1 - 抗肿瘤药物ap26113的制备方法 - Google Patents
抗肿瘤药物ap26113的制备方法 Download PDFInfo
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- WO2017016410A1 WO2017016410A1 PCT/CN2016/090408 CN2016090408W WO2017016410A1 WO 2017016410 A1 WO2017016410 A1 WO 2017016410A1 CN 2016090408 W CN2016090408 W CN 2016090408W WO 2017016410 A1 WO2017016410 A1 WO 2017016410A1
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- WO
- WIPO (PCT)
- Prior art keywords
- dimethylamino
- reaction
- preparing
- aniline
- piperidin
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 9
- HOSXICNCYBUYAW-UHFFFAOYSA-N dimethylamino prop-2-enoate Chemical compound CN(C)OC(=O)C=C HOSXICNCYBUYAW-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000012320 chlorinating reagent Substances 0.000 claims abstract description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- -1 tetrafluoroborate Chemical compound 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000006482 condensation reaction Methods 0.000 claims description 10
- 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 claims description 10
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 9
- 238000007363 ring formation reaction Methods 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 8
- 238000006177 thiolation reaction Methods 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- 238000005660 chlorination reaction Methods 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- STOCRCLYMPKTEC-UHFFFAOYSA-N 1-(4-amino-3-methoxyphenyl)-n,n-dimethylpiperidin-4-amine Chemical compound C1=C(N)C(OC)=CC(N2CCC(CC2)N(C)C)=C1 STOCRCLYMPKTEC-UHFFFAOYSA-N 0.000 claims description 5
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- OHARHHSJWGEMMN-UHFFFAOYSA-N 4-dimethylphosphorylaniline Chemical compound CP(C)(=O)C1=CC=C(N)C=C1 OHARHHSJWGEMMN-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 3
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims description 2
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 2
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- SOTYGGXREPPRCJ-UHFFFAOYSA-N methyl 2-(dimethylamino)prop-2-enoate Chemical compound COC(=O)C(=C)N(C)C SOTYGGXREPPRCJ-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- JMFRHRTUYOMCSS-UHFFFAOYSA-N 2-N-[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl]-4-N-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine Chemical compound COC1=C(NC2=NC(NC3=C(C=CC=C3)P(C)(C)=O)=CC=N2)C=CC(=C1)N1CCC(CC1)N(C)C JMFRHRTUYOMCSS-UHFFFAOYSA-N 0.000 claims 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 claims 1
- 229910000071 diazene Inorganic materials 0.000 claims 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 150000003852 triazoles Chemical class 0.000 claims 1
- 238000007086 side reaction Methods 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 3
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 abstract 6
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 abstract 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 abstract 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 5
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960005061 crizotinib Drugs 0.000 description 3
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical compound [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 3
- GIKMWFAAEIACRF-UHFFFAOYSA-N 2,4,5-trichloropyrimidine Chemical compound ClC1=NC=C(Cl)C(Cl)=N1 GIKMWFAAEIACRF-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 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
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010059282 Metastases to central nervous system Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- YZMAVBGBABHUOP-UHFFFAOYSA-N aniline;benzene Chemical compound C1=CC=CC=C1.NC1=CC=CC=C1 YZMAVBGBABHUOP-UHFFFAOYSA-N 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- JODDVGWNUWGSMG-UHFFFAOYSA-N ethyl 2-(dimethylamino)prop-2-enoate Chemical compound CCOC(=O)C(=C)N(C)C JODDVGWNUWGSMG-UHFFFAOYSA-N 0.000 description 1
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- HVKPXHNOWJFJEM-UHFFFAOYSA-N methyl 3-amino-2-methylprop-2-enoate Chemical compound COC(=O)C(C)=CN HVKPXHNOWJFJEM-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
-
- 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
Definitions
- the invention belongs to the technical field of organic synthesis route design and preparation technology of raw materials and intermediates, and particularly relates to a preparation method of antitumor drug AP26113.
- AP26113 is a pilot drug developed by Ariad Pharmaceuticals that targets small molecule tyrosine kinase inhibitors to treat anaplastic lymphoma kinase-positive (ALK) metastasis resistant to crizotinib.
- ALK anaplastic lymphoma kinase-positive
- NSCLC Non-small cell lung cancer
- the drug was granted a breakthrough therapeutic drug by the US FDA in August 2014.
- Current clinical data show that AP26113 has sustained anti-tumor activity in patients with ALK-positive non-small cell lung cancer, including brain metastases.
- the inhibitory activity against ALK is about 10 times that of crizotinib, and all nine identified crizotinib-resistant ALK mutations can be inhibited.
- AP26113 5-chloro-N2-[4-[4-(dimethylamino)-1-piperidinyl]-2-methoxyphenyl]-N4-[2-(dimethyl Phosphonyl)phenyl]-2,4-pyrimidinediamine (I), the structural formula is:
- the preparation method of AP26113 has been reported.
- the preparation method of AP26113 and its raw materials A and B is reported in PCT Patent No. WO2009143389 by Ariad Company and US Patent No. 20130225527, US20130225528 and US20140066406.
- the method is to prepare the target compound AP26113 by the substitution reaction of 2,4,5-trichloropyrimidine with the starting materials A and B on the pyrimidine ring.
- the object of the present invention is to design a novel synthetic route for introducing a functional group step by step in order to avoid the occurrence of side reactions in view of the defects in the prior art.
- the preparation method of AP26113 formed by the synthetic route has the advantages of easy availability of raw materials, less side reactions, economical environmental protection, and suitability for industrial production.
- the present invention adopts the following main technical solutions: a preparation method of an antitumor drug AP26113 (I),
- the synthesis step comprises: ring formation of N-[2-methoxy-4-[4-(dimethylamino)piperidin-1-yl]aniline]anthracene (II) with N,N-dimethylamino acrylate Synthesis reaction to obtain N2-[4-[4-(dimethylamino)-1-piperidinyl]-2-methoxyphenyl]amino-4(1H)-pyrimidinone (III); N2-[4-[4-(Dimethylamino)-1-piperidinyl]-2-methoxyphenyl]amino-4(1H)-pyrimidinone (III) with 4-(dimethyl
- the condensation reaction of a phosphorous benzene aniline (A) under the action of a condensing agent and a base accelerator to obtain N2-[4-[4-(dimethylamino)-1-piperidyl]-2-methoxybenzene -N4-[2-(Dimethylpho
- the N,N-dimethylamino acrylate used in the cyclization reaction is methyl N,N-dimethylaminoacrylate or ethyl N,N-dimethylaminoacrylate.
- the starting material of the cyclization reaction is N-[2-methoxy-4-[4-(dimethylamino)piperidin-1-yl]aniline]anthracene (II) and N,N-dimethylamino acrylate
- the molar ratio of feed is 1:1-2; preferably 1:1.3-1.5.
- the solvent for the cyclization reaction is toluene, xylene, dioxane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably toluene or N. N-dimethylformamide.
- the temperature of the cyclization reaction is from 50 to 150 ° C, preferably from 110 to 140 ° C.
- the condensation agent for the condensation reaction is N,N,-dicyclohexylcarbodiimide, carbonyldiimidazole, N,N'-diisopropylcarbodiimide, 1-hydroxy-benzotriazole, O -benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-(7-azobenzotriazole)-N,N,N',N' -tetramethylurea hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate or benzotriazole-1-yloxytris(dimethyl) Aminoamino)phosphonium hexafluorophosphate, preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate or benzotriazol-1-yloxy three
- the base promoter of the condensation reaction is triethylamine, pyridine, 2,6-lutidine, 4-dimethylaminopyridine, N-methylmorpholine, N-ethylmorpholine, diisopropyl B.
- Amine 1,5-diazabicyclo[4.3.0]-non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]-undec-7-ene or 1,4 -diazabicyclo[2.2.2]octane, preferably 1,8-diazabicyclo[5.4.0]-undec-7-ene or 1,5-diazabicyclo[4.3.0] - ⁇ -5-ene or 1,4-diazabicyclo[2.2.2]octane.
- the solvent for the condensation reaction is toluene, xylene, ethyl acetate, isopropyl acetate, butyl acetate, chloroform, dimethyl sulfoxide, N,N-dimethylformamide or acetonitrile, preferably acetonitrile.
- the temperature of the condensation reaction is from 0 to 120 ° C, preferably from 50 to 60 ° C.
- the chlorinating agent for the chlorination reaction is N-chlorosuccinimide or dichlorodimethylhydantoin, preferably N-chlorosuccinimide amine.
- the solvent for the chlorination reaction is tetrahydrofuran, dioxane, acetonitrile, dichloromethane, chloroform or toluene, preferably acetonitrile.
- the temperature of the chlorination reaction is from 0 to 70 ° C, preferably from 20 to 30 ° C.
- the present invention also provides a preparation method of the raw material N-[2-methoxy-4-[4-(dimethylamino)piperidin-1-yl]aniline] ruthenium (II), that is, through 2-A
- the oxy-4-[4-(dimethylamino)piperidin-1-yl]aniline (B) is prepared by thiolation of monocyanoamine.
- the molar ratio of 2-methoxy-4-[4-(dimethylamino)piperidin-1-yl]aniline (B) to monocyanamide in the thiolation reaction is 1:1-2. Preferably, it is 1:1.2-1.6.
- the solvent for the thiolation reaction is benzene, toluene, methanol, ethanol, N,N-dimethylformamide or dioxane, preferably methanol or dioxane.
- the temperature of the thiolation reaction is from 25 to 120 ° C, preferably from 50 to 70 ° C.
- the preparation method of the AP26113(I) according to the present invention has the characteristics of easy availability of raw materials, less side reactions, and environmental protection economy, thereby facilitating the industrial production of the raw material medicine and promoting the development of its economic technology.
- Embodiment 1 is a diagrammatic representation of Embodiment 1:
- Embodiment 2 is a diagrammatic representation of Embodiment 1:
- Embodiment 3 is a diagrammatic representation of Embodiment 3
- Embodiment 4 is a diagrammatic representation of Embodiment 4:
- Embodiment 5 is a diagrammatic representation of Embodiment 5:
- DBU 1,8-diazabicyclo[5.4.0]-undec-7-ene
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Abstract
Description
Claims (10)
- 一种抗肿瘤药物AP26113(I)的制备方法,其特征在于其制备步骤包括:N-[2-甲氧基-4-[4-(二甲基氨基)哌啶-1-基]苯胺]胍与N,N-二甲氨基丙烯酸酯发生环合反应制得N2-[4-[4-(二甲基氨基)-1-哌啶基]-2-甲氧基苯基]胺基-4(1H)-嘧啶酮;所述N2-[4-[4-(二甲基氨基)-1-哌啶基]-2-甲氧基苯基]胺基-4(1H)-嘧啶酮与4-(二甲基亚磷酰)苯胺在缩合剂和碱促进剂作用下发生缩合反应制得N2-[4-[4-(二甲基氨基)-1-哌啶基]-2-甲氧基苯基]-N4-[2-(二甲基亚膦酰)苯基]-2,4-嘧啶二胺;所述N2-[4-[4-(二甲基氨基)-1-哌啶基]-2-甲氧基苯基]-N4-[2-(二甲基亚膦酰)苯基]-2,4-嘧啶二胺与氯化剂发生氯化反应制得AP26113(I)。
- 根据权利要求1所述AP26113的制备方法,其特征在于,所述环合反应原料N-[2-甲氧基-4-[4-(二甲基氨基)哌啶-1-基]苯胺]胍与N,N-二甲氨基丙烯酸酯的投料摩尔比为1∶1-2。
- 根据权利要求1所述AP26113的制备方法,其特征在于,所述环合反应溶剂为甲苯、二甲苯、二氧六环、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲亚砜。
- 根据权利要求1所述AP26113的制备方法,其特征在于,所述环合反应所使用的N,N-二甲氨基丙烯酸酯为N,N-二甲氨基丙烯酸甲酯或N,N-二甲氨基丙烯酸乙酯,所述环合反应温度为50-150℃。
- 根据权利要求1所述AP26113的制备方法,其特征在于,所述缩合反应的缩合剂为N,N,-二环己基碳二亚胺、羰基二咪唑、N,N′-二异丙基碳二亚胺、1-羟基-苯并三氮唑、O-苯并三氮唑-N,N,N′,N′-四甲基脲四氟硼酸酯、O-(7-偶氮苯并三氮唑)-N,N,N′,N′-四甲基脲六氟磷酸酯、苯并三氮唑-N,N,N′,N′-四甲基脲六氟磷酸酯或苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐。
- 根据权利要求1所述AP26113的制备方法,其特征在于,所述缩合反应的碱促进剂为三乙胺、吡啶、2,6-二甲基吡啶、4-二甲氨基吡啶、N-甲基吗啉、N-乙基吗啉、二异丙基乙胺、1,5-二氮杂二环[4.3.0]-壬-5-烯、1,8-二氮杂双环[5.4.0]-十一-7-烯或1,4-二氮杂二环[2.2.2]辛烷。
- 根据权利要求1所述AP26113的制备方法,其特征在于,所述缩合反应的溶剂为甲 苯、二甲苯、乙酸乙酯、乙酸异丙酯、乙酸丁酯、氯仿、二甲亚砜、N,N-二甲基甲酰胺或乙腈;所述缩合反应温度为0-120℃。
- 根据权利要求1所述AP26113的制备方法,其特征在于,所述氯化反应的氯化剂为N-氯琥珀亚酰胺或二氯二甲基海因。
- 根据权利要求1所述AP26113的制备方法,其特征在于,所述氯化反应的溶剂为四氢呋喃、二氧六环、乙腈、二氯甲烷、氯仿或甲苯;所述氯化反应的温度为0-70℃。
- 根据权利要求1所述AP26113的制备方法,其特征在于,所述原料N-[2-甲氧基-4-[4-(二甲基氨基)哌啶-1-基]苯胺]胍(II)通过2-甲氧基-4-[4-(二甲基氨基)哌啶-1-基]苯胺(B)与单氰胺发生胍基化反应来制备,所述胍基化反应的原料2-甲氧基-4-[4-(二甲基氨基)哌啶-1-基]苯胺(B)与单氰胺的投料摩尔比为1∶1-2,所述胍基化反应的溶剂为苯、甲苯、甲醇、乙醇、N,N-二甲基甲酰胺或二氧六环,所述胍基化反应的温度为25-120℃。
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CN113912648A (zh) * | 2015-12-02 | 2022-01-11 | 深圳市塔吉瑞生物医药有限公司 | 一种二氨基嘧啶化合物及包含该化合物的组合物 |
CN105294759B (zh) * | 2015-12-02 | 2018-01-19 | 苏州东南药业股份有限公司 | 一种抗肿瘤药物的制备方法 |
JP2020510027A (ja) * | 2017-03-08 | 2020-04-02 | アリアド ファーマシューティカルズ,インコーポレーテッド | 5−クロロ−n4−[2−(ジメチルホスホリル)フェニル]−n2−{2−メトキシ−4−[4−(4−メチルピペラジン−1−イル)ピペリジン−1−イル]フェニル}ピリミジン−2,4−ジアミンを含む医薬製剤 |
CN109748885B (zh) * | 2017-11-07 | 2020-08-11 | 新发药业有限公司 | 一种色瑞替尼中间体及色瑞替尼的制备方法 |
CN109232579B (zh) * | 2018-11-06 | 2021-07-23 | 淮海工学院 | 一种合成培美曲塞中间体培美苯甲酸的方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003000186A2 (en) * | 2001-06-21 | 2003-01-03 | Ariad Pharmaceuticals, Inc. | Novel phenylamino-pyrimidines and uses thereof |
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US20130225528A1 (en) | 2008-05-21 | 2013-08-29 | Ariad Pharmaceuticals, Inc. | Phosphorus Derivatives as Kinase Inhibitors |
US9273077B2 (en) | 2008-05-21 | 2016-03-01 | Ariad Pharmaceuticals, Inc. | Phosphorus derivatives as kinase inhibitors |
US20130225527A1 (en) | 2008-05-21 | 2013-08-29 | Ariad Pharmaceuticals, Inc. | Phosphorus Derivatives as Kinase Inhibitors |
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