methyl 3-formyl-2-nitrobenzoate -Drug Synthesis Database

【结构式】

【分子编号】68112

【品名】methyl 3-formyl-2-nitrobenzoate

【CA登记号】　

【分子式】C₉H₇NO₅

【分子量】209.15832

【元素组成】C 51.68% H 3.37% N 6.7% O 38.25%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

Esterification of 3-methyl-2-nitrobenzoic acid (I) with MeOH in the presence of AcCl at reflux gives methyl 3-methyl-2-nitrobenzoate (II), which is then brominated with NBS in the presence of (PhCO)2O2 in refluxing CCl4 to yield methyl 3-(bromomethyl)-2-nitrobenzoate (III). Oxidation of the bromo derivative (III) with NMMO in acetonitrile leads to methyl 3-formyl-2-nitrobenzoate (IV), which is then condensed with 4-(N-Boc-3-piperidinyl)aniline (V) in refluxing EtOH to afford the corresponding imine (VI). Ring closure of the imine derivative (VI) by means of NaN3 in DMF at 90 °C provides the indazole derivative (VII), which is then treated with NH3 in MeOH at 60 °C to give the carboxamide derivative (VIII). Deprotection of compound (VIII) by means of HCl leads to the hydrochloride salt of the corresponding amine, which is finally resolved by chiral supercritical fluid chromatography (chiral SFC) and treated with HCl .
Aldehyde intermediate (IV) can be prepared in a large-scale synthesis by treatment of methyl 3-methyl-2-nitrobenzoate (II) with DMFA in DMF at 130 °C to give enamine (X), which is finally oxidized with NaIO4 in DMF/H2O .

参考文献中间体

合成目标

【1】 Jones, P., Ontoria Ontoria, J.M., Scarpelli, R., Schultz-Fademrecht, C. (Istituto di Ricerche di Biologia Molecolare P. Angeletti SpA). Amide substituted indazoles as poly(ADP-ribose)polymerase (PARP) inhibitors. EP 2109608, EP 2336120, JP 2010515715, US 2008167345, WO 2008084261.
【2】 Jones, P., Altamura, S., Boueres, J. et al. Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J Med Chem 2009, 52(22): 7170-85.
【3】 Wallace, D.J., Baxter, C.A., Brands, K.J.M. et al. Development of a fit-forpurpose large-scale synthesis of an oral PARP inhibitor. Org Process Res Dev 2011, 15(4): 831-40.

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)	68109	3-methyl-2-nitrobenzoic acid；2-Nitro-m-toluic acid	5437-38-7	C₈H₇NO₄	详情	详情
(II)	68110	methyl 3-methyl-2-nitrobenzoate；2-Nitro-3-methylbenzoic acid methyl ester;3-methyl-2-nitrobenzoic acid methyl ester	5471-82-9	C₉H₉NO₄	详情	详情
(III)	68111	methyl 3-(bromomethyl)-2-nitrobenzoate		C₉H₈BrNO₄	详情	详情
(IV)	68112	methyl 3-formyl-2-nitrobenzoate		C₉H₇NO₅	详情	详情
(V)	68113	tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate		C₁₆H₂₄N₂O₂	详情	详情
(VI)	68114	tert-butyl 3-(4-((3-(methoxycarbonyl)-2-nitrobenzylidene)amino)phenyl)piperidine-1-carboxylate		C₂₅H₂₉N₃O₆	详情	详情
(VII)	68115	methyl 2-(4-(1-(tert-butoxycarbonyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxylate		C₂₅H₂₉N₃O₄	详情	详情
(VIII)	68116	tert-butyl 3-(4-(7-carbamoyl-2H-indazol-2-yl)phenyl)piperidine-1-carboxylate		C₂₄H₂₈N₄O₃	详情	详情
(IX)	68117	2-[4-[3(S)-Piperidinyl]phenyl]-2H-indazole-7-carboxamide	1038915-64-8	C₁₉H₂₀N₄O	详情	详情
(X)	68126	(E)-methyl 3-(2-(dimethylamino)vinyl)-2-nitrobenzoate		C₁₂H₁₄N₂O₄	详情	详情
(X)	68126	(E)-methyl 3-(2-(dimethylamino)vinyl)-2-nitrobenzoate		C₁₂H₁₄N₂O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Suzuki coupling of 3-piperidinylboronic acid (X) with 1-iodo-4-nitrobenzene (XI) by means of Pd(PPh3)4 and Na2CO3 in THF , or with 1-bromo-4-nitrobenzene (XII) in the presence of PdCl2(dppf) and Na2CO3 in THF at 60 °C , gives 3-(4-nitrophenyl)piperidine (XIII), which is reduced with H2 over PtO2 in the presence of HCl in MeOH to yield 4-(3-piperidinyl)aniline (XIV) . Resolution of 4-(3-piperidinyl)aniline (XIV) with L-tartaric acid in refluxing EtOH affords 4-[3(S)-piperidinyl]aniline L-tartrate (XV), which is then N-protected by means of Boc2O in CH2Cl2, followed by basification with NH3 in MeOH to provide 4-[N-Boc-3(S)-piperidyl]aniline (XVI) . Condensation of aniline derivative (XVI) with the benzaldehyde derivative (IV) in refluxing EtOH or in MTBE at 50 °C leads to azomethine (XVII) , which then undergoes initial substitution of the nitro group and subsequent cyclization by means of NaN3 in DMF at 90 °C to result in the indazole derivative (XVIII) . Alternatively, cyclization of (XVII) with NaN3 in the presence of 2,6-lutidine in DMF at 110 °C, followed by ester hydrolysis with NaOH, affords indazole derivative (XVIII) . Amidation of methyl ester (XVIII) with NH3 in MeOH or sequential treatment with Boc2O in the presence of pyridine and reaction with NH4HCO3 gives the corresponding carboxamide (XIX) , which is finally N-deprotected with HCl in AcOEt .
Alternatively, intermediate (XVI) can be prepared by N-protection of 4-(3-piperidinyl)aniline (XIV) with Boc2O in CH2Cl2 to give tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate (V), which is finally resolved into enantiomer using chiral HPLC .

参考文献中间体

合成目标

【1】 Jones, P., Altamura, S., Boueres, J. et al. Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J Med Chem 2009, 52(22): 7170-85.
【2】 Wallace, D.J., Baxter, C.A., Brands, K.J.M. et al. Development of a fit-forpurpose large-scale synthesis of an oral PARP inhibitor. Org Process Res Dev 2011, 15(4): 831-40.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	68112	methyl 3-formyl-2-nitrobenzoate		C₉H₇NO₅	详情	详情
(V)	68113	tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate		C₁₆H₂₄N₂O₂	详情	详情
(X)	68118	(1,3-azaborinan-3-yl)methanediol		C₅H₁₂BNO₂	详情	详情
(XI)	21845	1-iodo-4-nitrobenzene	636-98-6	C₆H₄INO₂	详情	详情
(XII)	26628	1-bromo-4-nitrobenzene	99-99-0	C₆H₄BrNO₂	详情	详情
(XIII)	68119	3-(4-nitrophenyl)piperidine		C₁₁H₁₄N₂O₂	详情	详情
(XIV)	68120	4-(3-piperidinyl)aniline		C₁₁H₁₆N₂	详情	详情
(XV)	68121	4-[3(S)-piperidinyl]aniline L-tartrate		C₁₁H₁₆N₂.C₄H₆O₆	详情	详情
(XVI)	68122	tert-butyl 3(S)-(4-aminophenyl)piperidine-1-carboxylate		C₁₆H₂₄N₂O₂	详情	详情
(XVII)	68125	(E)-tert-butyl 3(S)-(4-((3-(methoxycarbonyl)-2-nitrobenzylidene)amino)phenyl)piperidine-1-carboxylate		C₂₅H₂₉N₃O₆	详情	详情
(XVIII)	68123	(S)-methyl 2-(4-(1-(tert-butoxycarbonyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxylate		C₂₅H₂₉N₃O₄	详情	详情
(XIX)	68124	tert-butyl 3(S)-(4-(7-carbamoyl-2H-indazol-2-yl)phenyl)piperidine-1-carboxylate		C₂₄H₂₈N₄O₃	详情	详情

Extended Information