2-chloroaniline; 2-chlorophenylamine -Drug Synthesis Database

【结构式】

【分子编号】35804

【品名】2-chloroaniline; 2-chlorophenylamine

【CA登记号】95-51-2

【分子式】C₆H₆ClN

【分子量】127.57308

【元素组成】C 56.49% H 4.74% Cl 27.79% N 10.98%

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：(III)

Hydrogenation of 2-nitro-5-fluorobenzoic acid (I), followed by in situ condensation with acetic anhydride produced benzoxazinone (II). Subsequent reaction of (III) with 2-chloroaniline (III) in refluxing AcOH furnished quinazolinone (IV). Treatment of (IV) with 2,6-pyridinedicarboxaldehyde (V) in the presence of ZnCl2 and Ac2O gave rise to the pyridinylvinyl derivative (VI). The title amine was finally obtained by reductive amination of aldehyde (VI) with diethylamine using NaBH(OAc)3). The two atropisomers were separated by means of preparative chiral HPLC.

参考文献中间体

合成目标

【1】 Ewing, F.E.; Welch, W.M.; Huang, J.; et al.; Atropisomeric quinazolin-4-one derivatives are potent noncompetitive alpha-amino-3-hydroxy-5-ethyl-4-isoxazolepropionic acid (AMPA) receptor antagonists. Bioorg Med Chem Lett 2001, 11, 2, 177.
【2】 Elliott, M.L.; Welch, W.M. Jr. (Pfizer Inc.); Novel 2,3 disubstd.-4(3H)-quinazolinones. EP 0901487; JP 1999514663; WO 9743276 .
【3】 Welch, W.M. Jr.; DeVries, K.M. (Pfizer Inc.); Atropisomers of 3-aryl-4(3H)-quinazolinones and their use as AMPA-receptor antagonists. EP 0968194; JP 2000509731; WO 9838173 .

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)	31962	2-Nitro-5-fluorobenzoic acid; 5-Fluoro-2-nitrobenzoic acid	320-98-9	C₇H₄FNO₄	详情	详情
(II)	38462	6-fluoro-2-methyl-4H-3,1-benzoxazin-4-one		C₉H₆FNO₂	详情	详情
(III)	35804	2-chloroaniline; 2-chlorophenylamine	95-51-2	C₆H₆ClN	详情	详情
(IV)	38463	3-(2-chlorophenyl)-6-fluoro-2-methyl-4(3H)-quinazolinone		C₁₅H₁₀ClFN₂O	详情	详情
(V)	38464	2,6-pyridinedicarbaldehyde	5431-44-7	C₇H₅NO₂	详情	详情
(VI)	38465	6-[(E)-2-[3-(2-chlorophenyl)-6-fluoro-4-oxo-3,4-dihydro-2-quinazolinyl]ethenyl]-2-pyridinecarbaldehyde		C₂₂H₁₃ClFN₃O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Condensation of malononitrile (I) with triethyl orthoacetate (II) in pyridine produced the intermediate (III), which was cyclized to pyridine (IV) by acidic treatment. Reductive dechlorination of (IV) by hydrogenation over Pd/BaCO3 afforded 2-aminopyridine-3,5-dicarbonitrile (V). Subsequent condensation of (V) with guanidine (VI) gave rise to the pyridopyrimidine system (VII). Finally, reductive amination of (VII) with 2-chloroaniline (VIII) by means of H2 and Raney-Ni afforded the title compound.

参考文献中间体

合成目标

【1】 Boutli, F.; Mourellou, O.; Avgoustinaki, N.; Zioga, M.; Rammnos, C.H.; Chin Journal of Medicinal Chemistry 1995, 5, 2, 79-85.
【2】 Gangjee, A.; Adair, O.; Queener, S.F.; Pneumocystis carinii Toxoplasma gondii dihydrofolate reductase inhibitors and antitumor agents: Synthesis and biological activities of 2,4-diamino-5-methyl-6-[(monosubstituted anilino)methyl]-pyrido[2,3-d]pyrimidines. J Med Chem 1999, 42, 13, 2447.

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)	12061	Malononitrile	109-77-3	C₃H₂N₂	详情	详情
(II)	12940	1,1-Diethoxyethyl ethyl ether; 1,1,1-Triethoxyethane; Triethyl orthoacetate	78-39-7	C₈H₁₈O₃	详情	详情
(III)	35800			C₁₃H₉N₅	详情	详情
(IV)	35801	2-amino-6-chloro-4-methyl-3,5-pyridinedicarbonitrile		C₈H₅ClN₄	详情	详情
(V)	35802	2-amino-4-methyl-3,5-pyridinedicarbonitrile		C₈H₆N₄	详情	详情
(VI)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(VII)	35803	2,4-diamino-5-methylpyrido[2,3-d]pyrimidine-6-carbonitrile		C₉H₈N₆	详情	详情
(VIII)	35804	2-chloroaniline; 2-chlorophenylamine	95-51-2	C₆H₆ClN	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

2-Chloroaniline (I) is diazotized with NaNO2/HCl and the resultant diazonium salt (II) is further coupled to 2,4-pentanedione (III) to furnish the diketo hydrazone (IV). Subsequent bromination of (IV) with Br2 in Ac2O/AcOH gives rise to the hydrazonyl bromide (V). This is finally condensed with 3-ethynylaniline (VI) in DMF to provide the corresponding aryl amidrazone.

参考文献中间体

合成目标

【1】 Wilson, D.M.; Termin, A.P.; Mao, L.; Ramirez-Weinhouse, M.M.; Molteni, V.; Gootenhuis, P.D.J.; Arylamidrazones as novel corticotropin releasing factor receptor antagonists. J Med Chem 2002, 45, 11, 2123.

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)	35804	2-chloroaniline; 2-chlorophenylamine	95-51-2	C₆H₆ClN	详情	详情
(II)	63682	2-chlorobenzenediazonium chloride		C₆H₄Cl₂N₂	详情	详情
(III)	11620	2,4-Pentanedione;acetylacetone	123-54-6	C₅H₈O₂	详情	详情
(IV)	63683	2,3,4-pentanetrione 3-[N-(2-chlorophenyl)hydrazone]		C₁₁H₁₁ClN₂O₂	详情	详情
(V)	63684	N-(2-chlorophenyl)-2-oxopropanehydrazonoyl bromide		C₉H₈BrClN₂O	详情	详情
(VI)	56445	3-Aminophenylacetylene; 3-Ethynylaniline; m-Aminophenylacetylene	54060-30-9	C₈H₇N	详情	详情

Extended Information