1-iodo-4-nitrobenzene -Drug Synthesis Database

【结构式】

【分子编号】21845

【品名】1-iodo-4-nitrobenzene

【CA登记号】636-98-6

【分子式】C₆H₄INO₂

【分子量】249.00777

【元素组成】C 28.94% H 1.62% I 50.96% N 5.63% O 12.85%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(VI)

N-Boc-Phenylalanine (I) was treated with isobutyl chloroformate and N-methylmorpholine, and the resulting mixed anhydride (II) was coupled to 2-aminobenzophenone (III) to yield the corresponding amide (IV). After Boc deprotection of (IV) with HCl in EtOAc, the intermediate aminoketone was cyclized with NaOH to the benzodiazepine (V). This was coupled to p-iodonitrobenzene (VI) in the presence of copper and NaOAc in DMF at 150 C to give the (nitrophenyl)benzodiazepine (VII). The nitro group of (VII) was subsequently reduced with SnCl2 in boiling EtOAc to yield (VIII). Then, the resulting amine (VIII) was treated with N,N'-di-Boc-thiourea (IX) in the presence of HgCl2 to provide the diprotected guanidine (X), which was finally deprotected with trifluoroacetic acid in CH2Cl2.

参考文献中间体

合成目标

【1】 Dziadulewicz, E.K.; et al.; The design of non-peptide human bradykinin B2 receptor antagonists employing the benzodiazepine peptidomimetic scaffold. Bioorg Med Chem Lett 1999, 9, 3, 463.

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)	21835	N-(tert-butoxycarbonyl)phenylalanine	4530-18-1	C₁₄H₁₉NO₄	详情	详情
(II)	21836	N-(Tert-butoxycarbonyl)-DL-phenylalanine isobutoxycarbonyl anhydride		C₁₉H₂₇NO₆	详情	详情
(IV)	21838	tert-butyl 2-(2-benzoylanilino)-1-benzyl-2-oxoethylcarbamate		C₂₇H₂₈N₂O₄	详情	详情
(V)	21839	3-benzyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one		C₂₂H₁₈N₂O	详情	详情
(VI)	21845	1-iodo-4-nitrobenzene	636-98-6	C₆H₄INO₂	详情	详情
(VII)	21846	3-benzyl-1-(4-nitrophenyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one		C₂₈H₂₁N₃O₃	详情	详情
(VIII)	21847	1-(4-aminophenyl)-3-benzyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one		C₂₈H₂₃N₃O	详情	详情
(X)	21848	tert-butyl (Z)-[4-(3-benzyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)anilino][(tert-butoxycarbonyl)amino]methylidenecarbamate		C₃₉H₄₁N₅O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

Reaction of phosphinylmethyl phosphonate (IV) with 1-iodo-4-nitrobenzene (V) in the presence of Pd(PPh3)4 affords the nitrophenyl phosphinoyl derivative (VI). Reduction of the nitro group of (VI) to the corresponding aniline (VII) is accomplished by treatment with SnCl2 in ethanol. Then, hydrolysis of the triethyl ester (VII) under acidic conditions furnishes phosphonic acid (VIII). Displacement of the 6-chloro group of purine (III) with the aminophenyl phosphonic acid (VIII) in hot DMSO gives rise to the 6-anilino purine (IX). Finally, displacement of the remaining halogen atom of (IX) with trans-1,4-diaminocyclohexane (X) leads to the title 2,6-diaminopurine compound.

参考文献中间体

合成目标

【1】 Weigele, M.; Sawyer, T.K.; Wang, Y.; Shakespeare, W.C.; Bohacek, R.; Sundaramoorthi, R.; Metcalf, C.A. III; Dalgarno, D.C. (Ariad Pharmaceuticals Inc.); Purine derivs.. US 2002068721 .
【2】 Weigele, M.; Sawyer, T.K.; Wang, Y.; Shakespeare, W.C.; Bohacek, R.; Sundaramoorthi, R.; Metcalf, C.A. III; Dalgarno, D.C. (Ariad Pharmaceuticals Inc.); Purine derivs.. WO 0144259 .
【3】 Weigele, M.; Sawyer, T.K.; Wang, Y.; Shakespeare, W.; Bohacek, R.; Sundaramoorthi, R.; Metcalf, C.A. III (Ariad Pharmaceuticals Inc.); Novel purines. WO 0144260 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	61001	6-chloro-9-ethyl-2-fluoro-9H-purine		C₇H₆ClFN₄	详情	详情
(IV)	61002	diethyl [ethoxy(oxo)phosphoranyl]methylphosphonate		C₇H₁₈O₅P₂	详情	详情
(V)	21845	1-iodo-4-nitrobenzene	636-98-6	C₆H₄INO₂	详情	详情
(VI)	61003	diethyl [ethoxy(4-nitrophenyl)phosphoryl]methylphosphonate		C₁₃H₂₁NO₇P₂	详情	详情
(VII)	61004	diethyl [(4-aminophenyl)(ethoxy)phosphoryl]methylphosphonate		C₁₃H₂₃NO₅P₂	详情	详情
(VIII)	61005	[(4-aminophenyl)(hydroxy)phosphoryl]methylphosphonic acid		C₇H₁₁NO₅P₂	详情	详情
(IX)	61006	[{4-[(9-ethyl-2-fluoro-9H-purin-6-yl)amino]phenyl}(hydroxy)phosphoryl]methylphosphonic acid		C₁₄H₁₆FN₅O₅P₂	详情	详情
(X)	43407	4-aminocyclohexylamine; 1,4-cyclohexanediamine	3114-70-3	C₆H₁₄N₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XI)

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