MKC-1;Ro-31-7453 (former code name), -Drug Synthesis Database

【结构式】

【药物名称】MKC-1;Ro-31-7453 (former code name)

【化学名称】3-(1-Methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-1H-pyrrole-2,5-dione

【CA登记号】125313-92-0

【分子式】C₂₂H₁₆N₄O₄

【分子量】400.39722

【开发单位】Roche (Originator)

【药理作用】Breast Cancer Therapy;Antimitotic Agent;Colorectal Cancer Therapy, Lung Cancer Therapy, Oncolytic Drugs, Angiogenesis Inhibitors, Apoptosis Inducers

合成路线1 合成路线2

合成路线1

Methylation of 6-nitroindole (I) using either iodomethane and NaH or dimethyl carbonate and Na2CO3 provides 1-methyl-6-nitroindole (II), which is subsequently acylated with oxalyl chloride in CH2Cl2 to furnish the glyoxylyl chloride (III). Condensation of chloride (III) with 1-methylindole-3-acetic acid (IV) in the presence of Et3N gives the bis(indolyl)maleic anhydride (V), which is then converted to the target maleimide derivative by heating with ammonia in aqueous DMF in a sealed vessel at 140 °C .
In a related procedure, quaternization of 3-(dimethylaminomethyl)-indole (VI) with butyl bromide, followed by amine displacement with NaCN yields 2-(3-indolyl)acetonitrile (VII), which is alkylated using dimethyl carbonate and K2CO3 in hot DMF to give the 1-methylindole derivative (VIII). Treatment of compound (VIII) with isopropanol and HCl (generated from acetyl chloride and i-PrOH) affords imidate (IX), which is finally condensed with the indoleglyoxylyl chloride (III) in the presence of DIEA, followed by treatment with H2SO4 .

参考文献中间体

【1】 Davis, P.D., Hill, C.H., Lawton, G. (F. Hoffmann-La Roche AG). Substituted pyrroles. AU 8929658, EP 0328026, JP 1989233281, US 5057614.
【2】 Davis, P.D., Hill, C.H., Lawton, G. et al. Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. J Med Chem 1992, 35(1): 177-84.
【3】 Jiang, X. (F. Hoffmann La Roche AG). Methylation of indole compounds using dimethyl carbonate. CA 2405937, EP 1276721, JP 2003531192, JP 2007254487, US 6326501, WO 2001081305.

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)	39294	6-Nitroindole; 6-Nnitro-1H-indole	4769-96-4	C₈H₆N₂O₂	详情	详情
(II)	39295	1-methyl-6-nitro-1H-indole		C₉H₈N₂O₂	详情	详情
(III)	39296	2-(1-methyl-6-nitro-1H-indol-3-yl)-2-oxoacetyl chloride		C₁₁H₇ClN₂O₄	详情	详情
(IV)	39297	1-Methylindole-3-acetic acid; 2-(1-Methyl-1H-indol-3-yl)acetic acid	1912-48-7	C₁₁H₁₁NO₂	详情	详情
(V)	39298	3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-furandione		C₂₂H₁₅N₃O₅	详情	详情
(VI)	37568	N,N-Dimethyl-1H-indole-3-methanamine;Gramine;N-(1H-indol-3-ylmethyl)-N,N-dimethylamine; 3-(dimethylaminomethyl)-indole[;]1H-indol-3-yl-N,N-dimethylmethanamine	87-52-5	C₁₁H₁₄N₂	详情	详情
(VII)	44291	3-Indolylacetonitrile;3-Cyanomethyl-1H-indole;3-(Cyanomethyl)indole;Indole-3-acetonitrile;3-Indoleacetonitrile;2-(3-indolyl)acetonitrile;2-(1H-indol-3-yl)acetonitrile;2-(1H-Indol-3-yl)acetonitrile; 3-Indolylacetonitrile	771-51-7	C₁₀H₈N₂	详情	详情
(VIII)	69305	1-Methylindole-3-acetonitrile;1-Methylindole-3-acetonitrile;N-Methylindole-3-acetonitrile;3-(Cyanomethyl)-1-methylindole;2-(1-methyl-1H-indol-3-yl)acetonitrile	51584-17-9	C₁₁H₁₀N₂	详情	详情
(IX)	69306	isopropyl 2-(1-methyl-1H-indol-3-yl)acetimidate hydrochloride		C₁₄H₁₈N₂O.HCl	详情	详情

合成路线2

6-Nitroindole (I) was methylated using iodomethane and NaH and the resulting 1-methyl-6-nitroindole (II) was acylated with oxalyl chloride in dichloromethane to furnish the glyoxylyl chloride (III). Subsequent condensation of (III) with 1-methylindole-3-acetic acid (IV) in the presence of Et3N gave the bisindolylmaleic anhydride (V). This was finally converted into the target maleimide by heating with ammonia in aqueous DMF in a sealed vessel at 140 C.

参考文献中间体

【1】 Hill, C.H.; Wilkinson, S.E.; Hurst, S.A.; Lawton, G.; Keech, E.; Davis, P.D.; Nixon, J.S.; Turner, S.E.; Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. J Med Chem 1992, 35, 1, 177.
【2】 Davis, P.D.; Hill, C.H.; Lawton, G. (F. Hoffmann-La Roche AG); Substd. pyrroles. AU 8929658; EP 0328026; JP 1989233281; US 5057614 .

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)	39294	6-Nitroindole; 6-Nnitro-1H-indole	4769-96-4	C₈H₆N₂O₂	详情	详情
(II)	39295	1-methyl-6-nitro-1H-indole		C₉H₈N₂O₂	详情	详情
(III)	39296	2-(1-methyl-6-nitro-1H-indol-3-yl)-2-oxoacetyl chloride		C₁₁H₇ClN₂O₄	详情	详情
(IV)	39297	1-Methylindole-3-acetic acid; 2-(1-Methyl-1H-indol-3-yl)acetic acid	1912-48-7	C₁₁H₁₁NO₂	详情	详情
(V)	39298	3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-furandione		C₂₂H₁₅N₃O₅	详情	详情
(VI)	29841	Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride	79-37-8	C₂Cl₂O₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)