BMN-673；LT-00673；LT-673, -Drug Synthesis Database

【结构式】

【药物名称】BMN-673；LT-00673；LT-673

【化学名称】5-Fluoro-8(S)-(4-fluorophenyl)-9(R)-(1-methyl-1H-1,2,4-triazol-5-yl)-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-3-one

【CA登记号】1207456-01-6

【分子式】C₁₉H₁₄F₂N₆O

【分子量】380.3509

【开发单位】BioMarin Pharmaceutical, Inc. (US)

【药理作用】Poly [ADP-ribose] Polymerase (PARP) Inhibitor;Oncolytic

合成路线1 合成路线2

合成路线1

Coupling of 6-fluoro-4-nitro-2-benzofuran-1(3H)-one (I) with 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (II) in the presence of Et3N in2-Me-THF affords the (Z)-alkene (III), which by reaction with MeOH in the presence of HCl affords the methyl ester (IV). Condensation of ketone (IV) with 4-fluorobenzaldehyde (V) in the presence of L-proline in DMSO at 45 °C gives the (E)-propene derivative (VI), which then cyclizes by hydrogenation over Pd/C in MeOH to yield the 3,4-dihydroquinolin-1(2H)-ol derivative (VII). Reduction of the hydroxylamine derivative (VII) by means of Fe in the presence of HCl in refluxing MeOH provides the tetrahydroquinolone derivative (VIII), which can also be obtained by reductive cyclization of the nitro derivative (VI) with Fe in the presence of HCl in refluxing MeOH . Alternatively, compound (VIII) can be obtained by reductive cyclocondensation of intermediate (IV) with 4-fluorobenzaldehyde (V) by means of either TiCl3 in THF/MeOH at 30-50 °C, Fe in the presence of HCl in MeOH/THF at 60 °C, SnCl2 in the presence of HCl in MeOH/THF at 45 ° or by hydrogenation over Pd/C in MeOH/AcOH. Chiral resolution of the methyl ester (VIII) by supercritical fluid chromatography (SFC) or simulated moving bed (SMB) unit in MeOH provides the desired (2S,3S)-isomer (IX), which finally reacts with NH2NH2·H2O in EtOH or acetonitrile or MeOH. Alternatively, cyclocondensation of the methyl ester (VIII) with NH2NH2·H2O in MeOH gives the racemate (X) , which is finally resolved through the SFC unit .

参考文献中间体

【1】 Wang, B., Chu, D., Liu, Y., Jiang, Q., Lu, L. (BioMarin Pharmaceutical, Inc.). Processes of synthesizing dihydropyridophthalazinone derivatives. EP 2533640, JP 2013518910, KR 2012125630, US 2011196153, WO 2011097602.
【2】 Wang, B., Chu, D. (LEAD Therapeutics, Inc.). Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP). CN 102171214, EP 2326650, GB 2462361, JP 2011530513, KR 2011040973, US 2010035883, US 8012976, US 2011237581, US 8420650, US 2013190306, WO 2010017055.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	68174	6-fluoro-4-nitro-2-benzofuran-1(3H)-one		C₈H₄FNO₄	详情	详情
(II)	68175	1-methyl-1H-1,2,4-triazole-5-carbaldehyde		C₄H₅N₃O	详情	详情
(III)	68176	(Z)-6-fluoro-3-((1-methyl-1H-1,2,4-triazol-5-yl)methylene)-4-nitroisobenzofuran-1(3H)-one		C₁₂H₇FN₄O₄	详情	详情
(IV)	68177	methyl 5-fluoro-2-(2-(1-methyl-1H-1,2,4-triazol-5-yl)acetyl)-3-nitrobenzoate		C₁₃H₁₁FN₄O₅	详情	详情
(V)	12337	4-fluorobenzaldehyde	459-57-4	C₇H₅FO	详情	详情
(VI)	68178	(E)-methyl 5-fluoro-2-(3-(4-fluorophenyl)-2-(1-methyl-1H-1,2,4-triazol-5-yl)acryloyl)-3-nitrobenzoate		C₂₀H₁₄F₂N₄O₅	详情	详情
(VII)	68179	methyl 7-fluoro-2-(4-fluorophenyl)-1-hydroxy-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate		C₂₀H₁₆F₂N₄O₄	详情	详情
(VIII)	68180	methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate		C₂₀H₁₆F₂N₄O₃	详情	详情
(IX)	68181	(2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate		C₂₀H₁₆F₂N₄O₃	详情	详情
(X)	68182	5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one		C₁₉H₁₄F₂N₆O	详情	详情

合成路线2

Intermediate (X) can also be prepared by coupling of 4-amino-6-fluoro-2-benzofuran-1(3H)-one (XI) with 4-fluorobenzaldehyde (V) in the presence of MgSO4 in refluxing CH2Cl2 to afford the benzylidene derivative (XII), which by cyclocondensation with 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (II) in the presence of NaOEt in ethyl propionate at 40 °C yields the tetrahydroquinolone (XIII). Finally, ethyl ester (XIII) is condensed with NH2NH2·H2O in MeOH .
Alternatively, the reaction of alkene (III) with NH2NH2·H2O in THF gives the 1,2-dihydrophthalazine derivative (XIV), which is then condensed with 4-fluorobenzaldehyde (V) in refluxing acetonitrile to yield imine (XV). Finally, intermediate (XV) is submitted to intramolecular cyclizacyclization by means of Cs2CO3 in THF at 55 °C and provides the racemate (X) .

参考文献中间体

【2】 Wang, B., Chu, D. (LEAD Therapeutics, Inc.). Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP). CN 102171214, EP 2326650, GB 2462361, JP 2011530513, KR 2011040973, US 2010035883, US 8012976, US 2011237581, US 8420650, US 2013190306, WO 2010017055.
【1】 Wang, B., Chu, D., Liu, Y., Jiang, Q., Lu, L. (BioMarin Pharmaceutical, Inc.). Processes of synthesizing dihydropyridophthalazinone derivatives. EP 2533640, JP 2013518910, KR 2012125630, US 2011196153, WO 2011097602.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	68175	1-methyl-1H-1,2,4-triazole-5-carbaldehyde		C₄H₅N₃O	详情	详情
(III)	68176	(Z)-6-fluoro-3-((1-methyl-1H-1,2,4-triazol-5-yl)methylene)-4-nitroisobenzofuran-1(3H)-one		C₁₂H₇FN₄O₄	详情	详情
(V)	12337	4-fluorobenzaldehyde	459-57-4	C₇H₅FO	详情	详情
(X)	68182	5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one		C₁₉H₁₄F₂N₆O	详情	详情
(XI)	68183	4-amino-6-fluoro-2-benzofuran-1(3H)-one		C₈H₆FNO₂	详情	详情
(XII)	68184	(E)-6-fluoro-4-((4-fluorobenzylidene)amino)isobenzofuran-1(3H)-one		C₁₅H₉F₂NO₂	详情	详情
(XIII)	68185	ethyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate		C₂₁H₁₈F₂N₄O₃	详情	详情
(XIV)	68186	5-amino-7-fluoro-4-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)phthalazin-1(2H)-one		C₁₂H₁₁FN₆O	详情	详情
(XV)	68187	(E)-7-fluoro-5-((4-fluorobenzylidene)amino)-4-((1-methyl-1H-1,2,4-triazol-5-yl)methyl)phthalazin-1(2H)-one		C₁₉H₁₄F₂N₆O	详情	详情

Extended Information