-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】2-[3-(Dimethylamino)-2,3-dihydro-1H-inden-5-yl]-7-methoxy-6-(5-oxazolyl)quinolin-4(1H)-one

【CA登记号】371251-98-8 ((R)-isomer), 371251-99-9 ((S)-isomer), 371249-88-6 (undefined isomer)

【分子式】C₂₄H₂₃N₃O₃

【分子量】401.46921

【开发单位】Bristol-Myers Squibb (Originator)

【药理作用】IMMUNOMODULATING AGENTS, Treatment of Autoimmune Diseases, Treatment of Transplant Rejection, Inosine 5'-Monophosphate Dehydrogenase (IMPDH) Inhibitors

合成路线1 合成路线2

合成路线1

Oxidation of 4-nitro-2-methoxytoluene (I) by means of chromic anhydride and sulfuric acid in the presence of acetic anhydride gives rise to acylal (II), which is further hydrolyzed to aldehyde (III) under acidic conditions. Reaction of aldehyde (III) with tosylmethyl isocyanide produces the 5-aryl oxazole (IV). Reduction of the nitro group of (IV) by catalytic hydrogenation yields aniline (V). Then, electrophilic iodination of amine (V) with iodine and silver triflate furnishes the aryl iodide (VI).

参考文献中间体

【1】 Pitts, W.J.; Iwanowicz, E.J.; Dhar, T.G.M.; Gu, H.H.; Watterson, S.H. (Bristol-Myers Squibb Co.); Heterocycles that are inhibitors of IMPDH enzyme. EP 1276739; JP 2003531205; WO 0181340 .

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)	39654	methyl 2-methyl-5-nitrophenyl ether; 2-methoxy-1-methyl-4-nitrobenzene	13120-77-9	C₈H₉NO₃	详情	详情
(II)	39655	(acetoxy)(2-methoxy-4-nitrophenyl)methyl acetate		C₁₂H₁₃NO₇	详情	详情
(III)	39656	2-methoxy-4-nitrobenzaldehyde		C₈H₇NO₄	详情	详情
(IV)	39657	methyl 5-nitro-2-(1,3-oxazol-5-yl)phenyl ether; 5-(2-methoxy-4-nitrophenyl)-1,3-oxazole		C₁₀H₈N₂O₄	详情	详情
(V)	39658			C₁₀H₁₀N₂O₂	详情	详情
(VI)	64043	2-iodo-5-(methyloxy)-4-(1,3-oxazol-5-yl)aniline; 2-iodo-5-(methyloxy)-4-(1,3-oxazol-5-yl)phenylamine		C₁₀H₉IN₂O₂	详情	详情

合成路线2

6-Bromo-1-indanone (VII) is reduced to alcohol (VIII) employing NaBH4. After chlorination of (VIII) with SOCl2, the resultant alkyl chloride (IX) is displaced by heating with ethanolic dimethylamine in a sealed vessel to produce the (dimethylamino)indan (X). Palladium-catalyzed coupling of aryl bromide (X) with trimethylsilyl acetylene (XI) furnishes the silyl acetylene (XII), which is then desilylated to (XIII) with Bu4NF in THF. Finally, condensation between acetylene (XIII), aryl iodide (VI) and carbon monoxide in the presence of palladium catalyst leads to the title quinolone derivative. (1,2)

参考文献中间体

【1】 Dhar, T.G.M.; Watterson, S.H.; Chen, P.; Shen, Z.; Gu, H.H.; Norris, D.; Carlsen, M.; Haslow, K.D.; Pitts, W.J.; Guo, J.; Chorba, J.; Fleener, C.A.; Rouleau, K.A.; Townsend, R.; Hollenbaugh, D.; Iwanowicz, E.J.; Quinolone-based IMPDH inhibitors: Introduction of basic residues on ring D and SAR of the corresponding mono, di and benzofused analogues. Bioorg Med Chem Lett 2003, 13, 3, 547.
【2】 Pitts, W.J.; Iwanowicz, E.J.; Dhar, T.G.M.; Gu, H.H.; Watterson, S.H. (Bristol-Myers Squibb Co.); Heterocycles that are inhibitors of IMPDH enzyme. EP 1276739; JP 2003531205; WO 0181340 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	64043	2-iodo-5-(methyloxy)-4-(1,3-oxazol-5-yl)aniline; 2-iodo-5-(methyloxy)-4-(1,3-oxazol-5-yl)phenylamine		C₁₀H₉IN₂O₂	详情	详情
(VII)	64044	6-bromo-2,3-dihydro-1H-inden-1-one		C₉H₇BrO	详情	详情
(VIII)	64045	6-bromo-2,3-dihydro-1H-inden-1-ol		C₉H₉BrO	详情	详情
(IX)	64046	6-bromo-1-chloro-2,3-dihydro-1H-indene		C₉H₈BrCl	详情	详情
(X)	64047	6-bromo-N,N-dimethyl-2,3-dihydro-1H-inden-1-amine; N-(6-bromo-2,3-dihydro-1H-inden-1-yl)-N,N-dimethylamine		C₁₁H₁₄BrN	详情	详情
(XI)	23897	ethynyl(trimethyl)silane；trimethylsilyl acetylene	1066-54-2	C₅H₁₀Si	详情	详情
(XII)	64048	N,N-dimethyl-6-[2-(trimethylsilyl)ethynyl]-2,3-dihydro-1H-inden-1-amine; N,N-dimethyl-N-{6-[2-(trimethylsilyl)ethynyl]-2,3-dihydro-1H-inden-1-yl}amine		C₁₆H₂₃NSi	详情	详情
(XIII)	64049	N-(6-ethynyl-2,3-dihydro-1H-inden-1-yl)-N,N-dimethylamine; 6-ethynyl-N,N-dimethyl-2,3-dihydro-1H-inden-1-amine		C₁₃H₁₅N	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)