CN106632244A - A novel synthetic method for preparing an anticancer medicine Niraparib - Google Patents
A novel synthetic method for preparing an anticancer medicine Niraparib Download PDFInfo
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- CN106632244A CN106632244A CN201610871851.2A CN201610871851A CN106632244A CN 106632244 A CN106632244 A CN 106632244A CN 201610871851 A CN201610871851 A CN 201610871851A CN 106632244 A CN106632244 A CN 106632244A
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- niraparib
- nitrite
- preparing
- follows
- synthesizing
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- PCHKPVIQAHNQLW-CQSZACIVSA-N niraparib Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1[C@@H]1CCCNC1 PCHKPVIQAHNQLW-CQSZACIVSA-N 0.000 title claims abstract description 47
- 229950011068 niraparib Drugs 0.000 title claims abstract description 39
- 238000010189 synthetic method Methods 0.000 title claims abstract description 6
- 239000003814 drug Substances 0.000 title description 5
- 230000001093 anti-cancer Effects 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- 239000000543 intermediate Substances 0.000 claims description 80
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 238000003786 synthesis reaction Methods 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 230000015572 biosynthetic process Effects 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 11
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 235000010265 sodium sulphite Nutrition 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- -1 nitric acid N-butyl Chemical class 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- QQZWEECEMNQSTG-UHFFFAOYSA-N Ethyl nitrite Chemical compound CCON=O QQZWEECEMNQSTG-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical group 0.000 claims description 4
- 238000005915 ammonolysis reaction Methods 0.000 claims description 4
- 238000003912 environmental pollution Methods 0.000 claims description 4
- 230000000977 initiatory effect Effects 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 3
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- RXQNKKRGJJRMKD-UHFFFAOYSA-N 5-bromo-2-methylaniline Chemical compound CC1=CC=C(Br)C=C1N RXQNKKRGJJRMKD-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 2
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 claims description 2
- GJTDJAPHKDIQIQ-UHFFFAOYSA-L barium(2+);dinitrite Chemical class [Ba+2].[O-]N=O.[O-]N=O GJTDJAPHKDIQIQ-UHFFFAOYSA-L 0.000 claims description 2
- FHIVAFMUCKRCQO-UHFFFAOYSA-N diazinon Chemical compound CCOP(=S)(OCC)OC1=CC(C)=NC(C(C)C)=N1 FHIVAFMUCKRCQO-UHFFFAOYSA-N 0.000 claims description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 claims description 2
- APNSGVMLAYLYCT-UHFFFAOYSA-N isobutyl nitrite Chemical compound CC(C)CON=O APNSGVMLAYLYCT-UHFFFAOYSA-N 0.000 claims description 2
- SKRDXYBATCVEMS-UHFFFAOYSA-N isopropyl nitrite Chemical compound CC(C)ON=O SKRDXYBATCVEMS-UHFFFAOYSA-N 0.000 claims description 2
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 150000002826 nitrites Chemical class 0.000 claims description 2
- RAFRTSDUWORDLA-UHFFFAOYSA-N phenyl 3-chloropropanoate Chemical compound ClCCC(=O)OC1=CC=CC=C1 RAFRTSDUWORDLA-UHFFFAOYSA-N 0.000 claims description 2
- 239000004304 potassium nitrite Substances 0.000 claims description 2
- 235000010289 potassium nitrite Nutrition 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- KAOQVXHBVNKNHA-UHFFFAOYSA-N propyl nitrite Chemical compound CCCON=O KAOQVXHBVNKNHA-UHFFFAOYSA-N 0.000 claims description 2
- KKKDGYXNGYJJRX-UHFFFAOYSA-M silver nitrite Chemical compound [Ag+].[O-]N=O KKKDGYXNGYJJRX-UHFFFAOYSA-M 0.000 claims description 2
- 239000013049 sediment Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000006722 reduction reaction Methods 0.000 abstract 2
- 230000009435 amidation Effects 0.000 abstract 1
- 238000007112 amidation reaction Methods 0.000 abstract 1
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 229940041181 antineoplastic drug Drugs 0.000 abstract 1
- 239000000470 constituent Substances 0.000 abstract 1
- 238000006193 diazotization reaction Methods 0.000 abstract 1
- NSLOBVGASZUPDO-UHFFFAOYSA-N methyl 3-formyl-2-nitrobenzoate Chemical compound COC(=O)C1=CC=CC(C=O)=C1[N+]([O-])=O NSLOBVGASZUPDO-UHFFFAOYSA-N 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 6
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 5
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 5
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 5
- 235000011167 hydrochloric acid Nutrition 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010064571 Gene mutation Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229940124530 sulfonamide Drugs 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 238000001238 wet grinding Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 230000005778 DNA damage Effects 0.000 description 2
- 231100000277 DNA damage Toxicity 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 150000001989 diazonium salts Chemical group 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000013517 stratification Methods 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 description 1
- DGDAVTPQCQXLGU-UHFFFAOYSA-N 5437-38-7 Chemical class CC1=CC=CC(C(O)=O)=C1[N+]([O-])=O DGDAVTPQCQXLGU-UHFFFAOYSA-N 0.000 description 1
- 108091007743 BRCA1/2 Proteins 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- KQFUDUSCWREQDD-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CC=CC=C1.N1CCNCC1 Chemical class C(C)(C)(C)OC(=O)N1CC=CC=C1.N1CCNCC1 KQFUDUSCWREQDD-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
- DEJVURNDJXNCCV-UHFFFAOYSA-N N-phenyl-N-piperidin-1-yl-1H-indazole-3-carboxamide Chemical compound N1(CCCCC1)N(C(=O)C1=NNC2=CC=CC=C12)C1=CC=CC=C1 DEJVURNDJXNCCV-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 229940127397 Poly(ADP-Ribose) Polymerase Inhibitors Drugs 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 230000004611 cancer cell death Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000010808 liquid waste Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 238000011518 platinum-based chemotherapy Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种制备抗癌药物Niraparib的新型合成方法，该方法包括起始原料3‑甲酰基‑2‑硝基苯甲酸甲酯经2位硝基还原，重氮化，还原，环化，取代，异构体拆分，酰胺化、脱BOC得到纯度达到97.51%以上的光学纯Niraparib。本发明方法简便，产率高，损耗少，易于操作，设备要求少，是一种适合工业化生产的方法。A novel synthetic method for the preparation of anticancer drug Niraparib, the method comprising the starting material 3-formyl-2-nitrobenzoic acid methyl ester through 2-nitro reduction, diazotization, reduction, cyclization, substitution, iso Constituent resolution, amidation, and de-BOC to obtain optically pure Niraparib with a purity of more than 97.51%. The method of the invention is simple, high in yield, less in loss, easy to operate and less in equipment requirement, and is a method suitable for industrialized production.
Description
Technical field
The present invention relates to the synthetic method of cancer therapy drug Niraparib, belongs to technical field of medicine synthesis.
Background technology
Niraparib chemical names are 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamides, are a kind of oral
Poly ADP-ribose polymerase (PARP) inhibitor, suppress reparation of the cell to DNA damage, for BRCA gene mutations
For cancer cell, if PARP activity is further suppressed, a large amount of DNA damages will be produced during these cell divisions, be caused
Cancer cell death.Niraparib is applied to the cancer of BRCA1/2 gene mutations, such as oophoroma and breast cancer, biological by the U.S.
Technology company Tesaro is researched and developed.The III clinical trial phases that a key name is NOVA are completed, Niraparib presents extremely good
Good curative effect.In test, researcher recruited more than 500 Jing after platinum-based chemotherapy oophoroma occur recurrence patient, and according to
Whether reproduction cell carries BRCA gene mutations, and patient has been divided into into two groups.In group of the reproduction cell with BRCA mutation, Jing
The median of patient's progression free survival phase of Niraparib treatments is crossed up to 21 months, was shown than 5.5 months of control group
Write and extend.
At present, the relevant patent document of the prior art of synthetic method in to(for) Niraparib includes Preparation of
pharmaceutically acceptable salts of(3S)-3-[4-[7-(aminocarbonyl)-2H-indazol-
2-yl] phenyl] piperidines as inhibitors of poly (ADP-ribose) polymerase (PARP),
Preparation of piperidinylphenylindazolylcarboxamide for use as poly(ADP-
Ribose) polymerase inhibitors etc., disclose a pharmaceutical chemistry synthetic route and to the discovery of Niraparib
Process has carried out detailed discussion.
The synthetic route with 3- methyl -2- nitrobenzoic acids as initiation material, by being esterified under conditions of acyl chlorides with methyl alcohol
To compound A, A is heated to reflux 12 hours in the CCl4 solution of benzoyl peroxide and NBS, and bromination obtains compound B.B and acetonitrile
And the oxidation of N-methylmorpholine-N- oxide water solutions obtains compound C.Compound C and the tert-butyl group -3- (4- aminophenyls) piperazine
Pyridine -1- carboxylic acid tert-butyl esters are stirred at reflux in ethanol solution and obtain compound D.Compound D is anti-with DMF mixtures with sodium azide
Should, cyclization formed intermediate E .. compound E be passed through in methanol solution 60 DEG C of NH3 heating it is acylated intermediate F. compound F
Hydrochloric acid is added in ethyl acetate Yu dioxane solutions, BOC groups is sloughed and is obtained intermediate G, Jing Chiralpak AS-H positives
Chiral chromatographic column splits and obtains target compound S type rotamer Niraparib.The synthetic route is longer, uses
Chiralpak AS-H positive chiral chromatographic columns split Niraparib is difficult to realize large-scale industrial production, and in reacting
Used sodium azide etc. unstable and difficult post processing raw material, limit industrialization safety in production.
The content of the invention
In order to overcome the above-mentioned deficiencies of the prior art, it is an object of the invention to provide a kind of new synthesis for preparing Niraparib
Method, route is novel, obtains multiple brand-new intermediates in building-up process, and intermediate is stable in properties, easy to operate, easily
In realizing industrialized production.
A kind of novel method for synthesizing for preparing Niraparib, synthetic route is as follows：
1) synthetic method of intermediate 1 is prepared, its structure is as follows：
Synthesis step includes:Initiation materialDo molten with acetic acid and ethanol
Agent, by 2 nitros of iron powder selective reduction on aldehyde radical without impact, generates intermediate 2, it is characterised in that iron powder density is big, easily
Precipitation, easily separated removing, environmental pollution is little.
2) structure of intermediate 2 is as follows：
Synthesis step includes：To there is diazotising in intermediate 1 anti-with concentrated hydrochloric acid into salt and natrium nitrosum
Intermediate 2 should be generated.
3) structure of intermediate 3 is as follows：
Synthesis step includes：Intermediate 2 is reacted by intermediate 3 is obtained after sodium sulfite reduction
Temperature is -10 DEG C -10 DEG C.
4) structure of intermediate 4 is as follows：Synthesis step includes：Intermediate 3 makees solvent with methyl alcohol, heating
Backflow can be cyclized as indazole ring intermediate 4 for 3 hours.
5) structure of intermediate 5 is as follows：
Synthesis step includes：The S type tert-butyl group -3- (4- bromo phenyl) piperidines -1- carboxylic acid tert-butyl esters, with
There is in the basic conditions substitution reaction in mesosome 4, then by being recrystallized to give intermediate 5.
6) structure of intermediate 6 is as follows：
Synthesis step includes：Intermediate 5 in the presence of sodium methoxide, formamide, shape after methyl esters ammonolysis
Into the amide structure of Niraparib intermediates 6.
7) structure of Niraparib compounds (I) is as follows：Synthesis step includes：Intermediate 6 is in DCM
In (dichloromethane), Niraparib compounds (I) are obtained with the de- BOC protection groups of trifluoroacetic acid reaction under room temperature.
Further detailed step is as follows：
1) preparation of intermediate 1 is prepared：3- formoxyl -2- nitrobenzene methyls are dissolved in absolute ethyl alcohol, iron is subsequently adding
Powder and acetic acid, are heated to reflux under conditions of 40 DEG C, and 2 nitros are reduced to into amino, and 3 aldehyde radicals are unaffected, in addition Fe powder
Cheap, density is big, easily precipitation, and easily separated removing, environmental pollution is little；
2) diazo-reaction can be using nitrite such as potassium nitrite, calcium nitrite, silver nitrite, natrium nitrosum, barium nitrites；
Nitrosylsulfuric acid or nitrous ether (ethyl nitrite), isoamyl nitrite, isobutyl nitrite, Isopropyl Nitrite, nitrite tert-butyl, Asia
Nitrites such as nitric acid N-butyl, n-propyl nitrite etc. and carry out.It is preferred that natrium nitrosum, intermediate 1 is with concentrated hydrochloric acid into after salt
There is diazo-reaction with natrium nitrosum and generate intermediate 2；
3) diazol that previous step is generated is added drop-wise in sodium sulfite solution and is reduced to intermediate 3；
4) intermediate 3 be heated to reflux 3h in methyl alcohol can be with cyclization as intermediate 4；
5) by the S type tert-butyl group -3- (4- bromo phenyl) piperidines -1- carboxylic acid tert-butyl esters be dissolved in 10% NaOH solution then with
Intermediate 4 reacts, and does solvent recrystallization with methyl alcohol and obtains Niraparib intermediates 5；
6) intermediate 5 forms the amide structure in intermediate 6 after ammonolysis in the presence of sodium methoxide, formamide；
7) intermediate 6 takes off BOC protection groups and obtains Niraparib compounds (I)；Solvent is made with DCM, the mol ratio of material is centre
Body：DCM：Trifluoracetic acid=1:5:1, reaction in about 3 hours is stirred at room temperature completely, it is evaporated and obtain as Niraparib compounds
(I)。
The invention has the beneficial effects as follows：
1) nitrobenzoic acid of initiation material 3- methyl -2 that the present invention is adopted synthesizes the raw material that field generally adopts for organic drug,
Low price and it is readily obtained；
2) synthesis step of the present invention is simple, and operating condition is easy to control.
3) present invention in each intermediate link only with such as：The methods of operating such as extraction, dry, filtration, crystallization and recrystallization,
Post processing is simple and convenient, is easier to realize large-scale production.
4) route of the present invention is novel, the solvent and catalyst used in building-up process it is stable in properties, it is easy to product point
From easy to operate, efficiency high, it is easy to accomplish industrialized production.
5) present invention avoids carrying out chiral resolution in final step, reduces can loss of product.
Description of the drawings
Fig. 1 is Niraparib HPLC chromatograms.
Specific embodiment
The present invention is further discussed below with reference to embodiments, but the present invention is not limited to following examples.
Embodiment
Intermediate 1Synthesis
11.2g (0.05mol) 3- formoxyl -2- nitrobenzene methyls, absolute ethyl alcohol 17ml, stirring are added in round-bottomed flask
It is allowed to add iron powder 2g (35.7mmol), acetic acid 17mL, distilled water 8.5mL to be eventually adding a drop concentrated hydrochloric acid after dissolving, 40 DEG C add
Heat backflow 15min (TLC monitoring reactions are complete) stops reaction, and suction filtration washs filter residue with water 10mL, collects filtrate with CHCl3 point
Three times extraction (3x15mL) merges organic phase, is washed with NaHCO3 (3x15mL) and distilled water (2x10mL), and standing separation is organic
Phase, anhydrous magnesium sulfate is dried, and is concentrated to give yellow oil.Column chromatography for separation [V (ethyl acetate)：V (petroleum ether)=1:9], it is dense
It is 86%. for 7.7g (0.043mol) yield that yellow oil after contracting is Niraparib intermediates 1
1HNMR(300MHz,DMSO-d6)δ(ppm):10.36(1H,s),7.97(1H,d,7.5Hz),7.85(1H,d,
7.5Hz),7.00(1H,t),6.27(2H,s),3.89(3H,s)；
13CNMR(75MHz,DMSO-d6)δ(ppm):192.8,168.5,149.1,139.0,136.3,130.5,119.1,
110.6,51.5；HRMS(ESI)for(M+H)+:calcd:179.06,found:180.06
Intermediate 2Synthesis
7.17g (0.04mol) Niraparib intermediates 1 are mixed with 16.5mL concentrated hydrochloric acids, when being cooled to 10 DEG C, to reaction bulb
In be slowly added dropwise 4.2mL30% sodium nitrite solutions (0.04mol).Excessive nitrous acid is checked with starch potassium iodide paper, really
Determine reaction end.Stirring 3h carries out diazo-reaction, is incubated stratification, and lower floor is diazonium salt solution, obtains after being dried
7.55gNiraparib intermediates 2, yield is 83.56%.
1HNMR(300MHz,DMSO-d6)δ(ppm):10.36(1H,s),8.33(1H,d,7.2Hz),8.10(1H,d,
7.2Hz),7.64(1H,t),3.89(3H,s)；13CNMR(75MHz,DMSO-d6)δ(ppm):191.0,165.9,146.3,
135.7,134.2,130.1,129.1,51.5；HRMS(ESI)for(M+H)+:calcd:226.01,found:227.01
Intermediate 3Synthesis
] 8.4mL30% sodium sulfite solutions (0.08mol) are prepared, above-mentioned diazonium salt solution is added dropwise in sodium sulfite aqueous solution,
Adjusting pH6-8. temperature with 10%NaOH solution simultaneously need to control to react 50min below 30 DEG C, then by temperature control 100
Vacuum rotary steam dehydration is carried out below DEG C, sulfonamide sodium salts A wet-milling is obtained, sulfonamide sodium salts A wet-milling is dried at less than 100 DEG C,
Sulfonamide sodium salts A dry powder is obtained, dry powder is dissolved in 15mL ethyl acetate, be cooled to 10-15 DEG C, the few drops concentrated sulfuric acid is added dropwise thereto,
The sour gas of effusion is absorbed, 35 DEG C or so insulated and stirreds 1h are warming up to after adding, be cooled to 5-10 DEG C, 10% NaOH is added dropwise
Solution to pH reaches 10, and reaction stands a point liquid after terminating, and mutually upper strata ester is removed into ethyl acetate, lower floor's water less than 50 DEG C of rotary evaporations
Phase enters purification tank for liquid waste Jing after the ethyl acetate that upper strata is reclaimed repeatedly extraction, and the ester of extraction mutually mutually merges again with upper strata ester；Will
Ester mutually removes the agitation grinding that adds water after ethyl acetate, suction filtration, washing, the finished product of gained wet-milling drying Niraparib intermediate 3
5.36g, yield 80%.
1HNMR(300MHz,DMSO-d6)δ(ppm):10.36(1H,s),8.14(1H,d,7.3Hz),8.02(1H,,7.3Hz),
7.09(1H,t),4.0(1H,s),3.89(3H,s),2.0(2H,s)；
13CNMR(75MHz,DMSO-d6)δ(ppm):192.8,168.5,144.6,138.7,136.2,127.4,119.5,
107.5,51.5；HRMS(ESI)for(M+H)+:calcd:194.07,found:195.07
Intermediate 4Synthesis
Fully dissolve after 4.27g (22mmol) Niraparib intermediates 3 are mixed with 30mL methyl alcohol, heat under conditions of 60 DEG C
Backflow 3h can obtain 3.17gNiraparib intermediates 4, and yield is 82%.
1HNMR(300MHz,DMSO-d6)δ(ppm):13.7(1H,d),7.84(1H,d,7.8Hz),7.78(1H,d,7.8Hz),
7.56(1H,t),7.55(1H,s),3.89(3H,s)；13CNMR(75MHz,DMSO-d6)δ(ppm):167.1,133.3,
132.3,128.3,125.6,51.5；HRMS(ESI)for(M+H)+:calcd:176.06,found:177.06
Intermediate 5Synthesis
Taking the 10.2g S type tert-butyl group -3- (4- bromo phenyl) piperidines -1- carboxylic acid tert-butyl esters, to be dissolved in 60mL10% NaOH molten
Liquid, in being stirred continuously lower instillation 3.17gNiraparib intermediates 4, stirs 30min, stands still for crystals suction filtration, 40 DEG C of vacuum drying
4h,
By dried compound recrystallizing methanol, the molar yield of 7.56gNiraparib intermediates 5. is obtained for 79%.
1H-NMR(300MHz,DMSO-d6)(ppm)δ:8.51 (1H, s), 8.13 (1H, d, J=7.1Hz), 7.95 (1H, d),
7.91 (2H, d, J=8.4Hz), 7.39 (2H, d, J=8.4Hz), 7.18 (1H, t, J=7.1Hz), 4.30-4.10 (2H, m),
4.00(3H,s),2.85-2.70(3H,m),2.11-2.03(1H,m),1.83-1.75(1H,m),1.73-1.53(2H,m),
1.48(9H,s).
13CNMR(75MHz,DMSO-d6)δ(ppm):167.1,153.2,145.6,136.9,128.7,124.3,120.6,
112.0,79.8,57.0,51.5,49.0,40.5,30.5,28.4,22.7；HRMS(ESI)for(M+H)+:calcd:
435.22,found:436.22
Intermediate 6Synthesis
7.4g (17mmol) Niraparib intermediates 5 are dissolved in 40mL dry DMFs at 0 DEG C, are added in this solution
10mL (252mmol) formamide, 3.0g (56mmol) sodium methoxide is warming up to 40 DEG C of reaction 3.5h.Reactant liquor is cooled to into room temperature,
In being poured into 200mL water, 1h is stirred, suction filtration is dried, and obtains the crude product 6.22g of Niraparib intermediates 6 (theoretical yield is 4.97g),
Yield is 87%.The crude product 5.0g of Niraparib intermediates 6 is added to into 40mL dioxane-water (volume ratio 8: 1) under room temperature
In mixed solvent, 101 DEG C are warming up to, complete molten rear addition 0.1g (mass fraction 2%) activated carbon of solid continues the 0.5h that flows back, and takes advantage of
Hot suction filtration, filtrate is cooled to 0 DEG C, stands 2h (precipitation white needle-like crystals), suction filtration, dry Niraparib intermediates 6.
1H-NMR(300MHz,DMSO-d6)(ppm)δ:9.04 (1H, br.s), 8.51 (1H, s), 8.31 (1H, d, J=
8.3Hz), 7.91 (1H, d, J=
8.3Hz), 7.84 (2H, d, J=8.2Hz), 7.42 (2H, d, J=8.2Hz), 7.31-7.22 (1H, m), 5.95 (1H,
br.s),4.40-4.05(2H,m),2.90-2.70(3H,m),2.15-2.00(1H,m),1.85-1.75(1H,m),1.75-
1.50(2H,m),1.48(9H,s).
13CNMR(75MHz,DMSO-d6)δ(ppm):168.0,153.2,143.2,136.9,128.7,126.7,125.0,
124.1,120.8,
115.0,79.8,57.0,49.0,30.5,40.5,28.4,22.7,HRMS(ESI)for(M+H)+:calcd:420.22,
found:421.22
Niraparib compounds (I)Synthesis
4.0gNiraparib intermediates 6 (9.3mmol) are added in 40ml dichloromethane after fully dissolving, 10mL tri- is added dropwise
Fluoroacetic acid solution, after stirring 24h, adds 20mL sodium hydrate aqueous solutions, stratification to collect organic phase, dry with anhydrous sodium sulfate
It is dry, 2.46gNiraparib is concentrated to give, the step reaction molar yield is 82.56%, and overall yield of reaction is 26.75%. Jing HPLC
It is 97.51% (chromatogram is illustrated in fig. 1 shown below) to determine Niraparib purity.
1H-NMR(300MHz,DMSO-d6)(ppm)δ:8.52 (1H, s), 8.17 (1H, br, d), 8.03 (1H, d, J=
7.2Hz), 7.66 (1H, q, J=8.4Hz), 7.54 (2H, t), 7.50 (2H, br.s), 7.30 (2H, d, J=8.4Hz), 3.15-
2.90(2H,d),2.78(1H,m),2.76-2.73(2H,t),2.0(1H,m),1.92-1.67(2H,q),1.53-1.43(2H,
m).13CNMR(75MHz,DMSO-d6)δ(ppm):168.0,143.2,136.9,128.7,126.7,125.0,124.1,
115.0,52.4,43.3,48.6,30.5,25.5,HRMS(ESI)for(M+H)+:calcd:320.16,found:321.16。
Claims (9)
1. a kind of novel method for synthesizing for preparing Niraparib, it is characterised in that synthetic route is as follows：
2. a kind of novel method for synthesizing for preparing Niraparib according to claim 1, it is characterised in that in the middle of preparing
The synthetic method of body 1, its structure is as follows：
Synthesis step includes:Initiation materialSolvent is done with acetic acid and ethanol,
By 2 nitros of iron powder selective reduction on aldehyde radical without impact, intermediate 2 is generated, it is characterised in that iron powder density is big, Yi Chen
Form sediment, easily separated removing, environmental pollution is little.
3. a kind of novel method for synthesizing for preparing Niraparib according to claim 1, it is characterised in that intermediate 2
Structure is as follows：
Synthesis step includes：There is diazo-reaction into salt and natrium nitrosum with concentrated hydrochloric acid in intermediate 1
Generate intermediate 2.
4. a kind of novel method for synthesizing for preparing Niraparib according to claim 1, it is characterised in that intermediate 3
Structure is as follows：
Synthesis step includes：Intermediate 2 after sodium sulfite reduction by intermediate 3 is obtained, and reaction is warm
Spend for -10 DEG C -10 DEG C.
5. a kind of novel method for synthesizing for preparing Niraparib according to claim 1, it is characterised in that intermediate 4
Structure is as follows：Synthesis step includes：Intermediate 3 makees solvent with methyl alcohol, and being heated to reflux 3 hours can be with ring
Turn to indazole ring intermediate 4.
6. a kind of novel method for synthesizing for preparing Niraparib according to claim 1, it is characterised in that intermediate 5
Structure is as follows：
Synthesis step includes：The S type tert-butyl group -3- (4- bromo phenyl) piperidines -1- carboxylic acid tert-butyl esters, with centre
There is in the basic conditions substitution reaction in body 4, then by being recrystallized to give intermediate 5.
7. a kind of novel method for synthesizing for preparing Niraparib according to claim 1, it is characterised in that intermediate 6
Structure is as follows：
Synthesis step includes：Intermediate 5 is formed in the presence of sodium methoxide, formamide after methyl esters ammonolysis
The amide structure of Niraparib intermediates 6.
8. a kind of novel method for synthesizing for preparing Niraparib according to claim 1, it is characterised in that Niraparib
The structure of compound (I) is as follows：Synthesis step includes：Intermediate 6 in DCM (dichloromethane), room
Temperature is lower and the de- BOC protection groups of trifluoroacetic acid reaction obtain Niraparib compounds (I).
9. a kind of novel method for synthesizing for preparing Niraparib according to claim 1, it is characterised in that detailed step
It is as follows：
1) preparation of intermediate 1 is prepared：3- formoxyl -2- nitrobenzene methyls are dissolved in absolute ethyl alcohol, iron is subsequently adding
Powder and acetic acid, are heated to reflux under conditions of 40 DEG C, and 2 nitros are reduced to into amino, and 3 aldehyde radicals are unaffected, in addition Fe powder
Cheap, density is big, easily precipitation, and easily separated removing, environmental pollution is little；
2) diazo-reaction can be using nitrite such as potassium nitrite, calcium nitrite, silver nitrite, natrium nitrosum, barium nitrites；
Nitrosylsulfuric acid or nitrous ether (ethyl nitrite), isoamyl nitrite, isobutyl nitrite, Isopropyl Nitrite, nitrite tert-butyl, Asia
Nitrites such as nitric acid N-butyl, n-propyl nitrite etc. and carry out.It is preferred that natrium nitrosum, intermediate 1 is with concentrated hydrochloric acid into after salt
There is diazo-reaction with natrium nitrosum and generate intermediate 2；
3) diazol that previous step is generated is added drop-wise in sodium sulfite solution and is reduced to intermediate 3；
4) intermediate 3 be heated to reflux 3h in methyl alcohol can be with cyclization as intermediate 4；
5) by the S type tert-butyl group -3- (4- bromo phenyl) piperidines -1- carboxylic acid tert-butyl esters be dissolved in 10% NaOH solution then with
Intermediate 4 reacts, and does solvent recrystallization with methyl alcohol and obtains Niraparib intermediates 5；
6) intermediate 5 forms the amide structure in intermediate 6 after ammonolysis in the presence of sodium methoxide, formamide；
7) intermediate 6 takes off BOC protection groups and obtains Niraparib compounds (I)；Solvent is made with DCM, the mol ratio of material is centre
Body：DCM：Trifluoracetic acid=1:5:1, reaction in about 3 hours is stirred at room temperature completely, it is evaporated and obtain as Niraparib compounds
(I)。
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108084157A (en) * | 2018-02-12 | 2018-05-29 | 安庆奇创药业有限公司 | A kind of synthetic method of Ni Lapani |
| CN110156751A (en) * | 2019-05-28 | 2019-08-23 | 江苏食品药品职业技术学院 | A new method for preparing niraparib and intermediates thereof |
| CN113637002A (en) * | 2021-08-02 | 2021-11-12 | 天津太平洋化学制药有限公司 | Preparation method of Nilaparib |
| CN115611860A (en) * | 2021-07-13 | 2023-01-17 | 上海博璞诺科技发展有限公司 | Method for synthesizing nilapanib |
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| CN106467513A (en) * | 2016-09-30 | 2017-03-01 | 陕西科技大学 | A kind of synthetic method preparing Niraparib |
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| GB0700432D0 (en) * | 2007-01-10 | 2007-02-21 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
| CN106467513A (en) * | 2016-09-30 | 2017-03-01 | 陕西科技大学 | A kind of synthetic method preparing Niraparib |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108084157A (en) * | 2018-02-12 | 2018-05-29 | 安庆奇创药业有限公司 | A kind of synthetic method of Ni Lapani |
| CN110156751A (en) * | 2019-05-28 | 2019-08-23 | 江苏食品药品职业技术学院 | A new method for preparing niraparib and intermediates thereof |
| CN115611860A (en) * | 2021-07-13 | 2023-01-17 | 上海博璞诺科技发展有限公司 | Method for synthesizing nilapanib |
| CN115611860B (en) * | 2021-07-13 | 2024-06-11 | 上海博璞诺科技发展有限公司 | Method for synthesizing nilaparib |
| CN113637002A (en) * | 2021-08-02 | 2021-11-12 | 天津太平洋化学制药有限公司 | Preparation method of Nilaparib |
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