Sunitinib Malate, PNU-290940AD, SU-010398, SU-011248 L-malate salt, Sutent, -Drug Synthesis Database

【结构式】

【药物名称】Sunitinib Malate, PNU-290940AD, SU-010398, SU-011248 L-malate salt, Sutent

【化学名称】(Z)-N-[2-(Diethylamino)ethyl]-5-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide

【CA登记号】326914-13-0, 342641-94-5 (undefined isomer)

【分子式】C₂₂H₂₇FN₄O₂

【分子量】398.48449

【开发单位】Pfizer (Originator), Sugen (Originator)

【药理作用】Gastric Cancer Therapy, Leukemia Therapy, Myeloid Leukemia Therapy, Oncolytic Drugs, Renal Cancer Therapy, Angiogenesis Inhibitors, Flt3 (FLK2/STK1) Inhibitors, Inhibitors of Signal Transduction Pathways, PDGFRbeta Inhibitors, VEGFR-1 (Flt-1) Inhibitors, VEGFR-2 (FLK-1/KDR) Inhibitors

合成路线1 合成路线2

合成路线1

Nitrosation of tert-butyl acetoacetate (I) with NaNO2/AcOH produces the oximino ester (II). Reductive cyclization of (II) with ethyl acetoacetate (III) in the presence of Zn/AcOH leads to the pyrrole dicarboxylate (IV). Selective decarboxylation of the t-butyl ester of (IV) under acidic conditions, followed by Vilsmeier formylation of the intermediate ethyl 2,4-dimethylpyrrole-3-carboxylate furnishes the pyrrole aldehyde (V). Alternatively, this compound is directly obtained from (IV) upon treatment with trimethyl orthoformate and trifluoroacetic acid. Basic hydrolysis of the ethyl ester group of (V) yields the pyrrolecarboxylic acid (VI). This is coupled to 2-(diethylamino)ethylamine (VII) to afford the corresponding amide (VIII).

参考文献中间体

【1】 Sun, L.; Liang, C.; Shirazian, S.; Zhou, Y.; Miller, T.; Ciu, J.; Fukuda, J.Y.; Chu, J.-Y.; Nematalla, A.; Wang, X.; Chen, H.; Sistla, A.; Luu, T.C.; Tang, F.; Wei, J.; Tang, C.; Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine. J Med Chem 2003, 46, 7, 1116.
【2】 Wei, C.C.; Miller, T.; Tang, P.C.; Nematalla, A.S.; Li, X.; Liang, C.; Shirazian, S.; Su, L.; Vojkovsky, T. (Sugen, Inc.); Pyrrole substd. 2-indolinone protein kinase inhibitors. EP 1255752; US 2002156292; US 6573293; WO 0160814 .
【3】 Shenoy, N.; Sorasuchart, W. (Sugen, Inc.); Formulations for pharmaceutical agents ionizable as free acids or free bases. JP 2003514851; WO 0137820 .

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)	27907	Acetoacetic acid tert-butyl ester;3-Oxo-butanoic acid 1,1-dimethylethyl estertert-butyl 3-oxobutanoate	1694-31-1	C₈H₁₄O₃	详情	详情
(II)	63353	1,1-dimethylethyl 2-(hydroxyimino)-3-oxobutanoate	14352-65-9	C₈H₁₃NO₄	详情	详情
(III)	11819	ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate	141-97-9	C₆H₁₀O₃	详情	详情
(IV)	63354	2-(1,1-dimethylethyl) 4-ethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate	86770-31-2	C₁₄H₂₁NO₄	详情	详情
(V)	60381	ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylate	2199-59-9	C₁₀H₁₃NO₃	详情	详情
(VI)	60382	5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid	253870-02-9	C₈H₉NO₃	详情	详情
(VII)	12420	N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine	100-36-7	C₆H₁₆N₂	详情	详情
(VIII)	63355	N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide	356068-86-5	C₁₄H₂₃N₃O₂	详情	详情

合成路线2

5-Fluoroisatin (IX) is heated with neat hydrazine hydrate to produce 2-amino-5-fluorophenylacetic hydrazide (X), which, upon acidic treatment cyclizes to 5-fluorooxindole (XI). Subsequent condensation of oxindole (XI) with the formylpyrrole carboxamide (VIII) in the presence of piperidine in hot EtOH leads to the title compound. In an alternative procedure, oxindole (XI) is condensed with the formylpyrrole carboxylic acid (VI) giving (XII), which is further coupled with 2-(diethylamino)ethylamine (VII) in the presence of EDC/HOBt to yield the target carboxamide.

参考文献中间体

【1】 Sun, L.; Liang, C.; Shirazian, S.; Zhou, Y.; Miller, T.; Ciu, J.; Fukuda, J.Y.; Chu, J.-Y.; Nematalla, A.; Wang, X.; Chen, H.; Sistla, A.; Luu, T.C.; Tang, F.; Wei, J.; Tang, C.; Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine. J Med Chem 2003, 46, 7, 1116.
【2】 Wei, C.C.; Miller, T.; Tang, P.C.; Nematalla, A.S.; Li, X.; Liang, C.; Shirazian, S.; Su, L.; Vojkovsky, T. (Sugen, Inc.); Pyrrole substd. 2-indolinone protein kinase inhibitors. EP 1255752; US 2002156292; US 6573293; WO 0160814 .
【3】 Shenoy, N.; Sorasuchart, W. (Sugen, Inc.); Formulations for pharmaceutical agents ionizable as free acids or free bases. JP 2003514851; WO 0137820 .

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)	60382	5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid	253870-02-9	C₈H₉NO₃	详情	详情
(VII)	12420	N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine	100-36-7	C₆H₁₆N₂	详情	详情
(VIII)	63355	N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide	356068-86-5	C₁₄H₂₃N₃O₂	详情	详情
(IX)	21552	5-fluoro-1H-indole-2,3-dione	443-69-6	C₈H₄FNO₂	详情	详情
(X)	63356	2-(2-amino-5-fluorophenyl)acetohydrazide	356068-89-8	C₈H₁₀FN₃O	详情	详情
(XI)	60384	5-fluoro-1,3-dihydro-2H-indol-2-one	56341-41-4	C₈H₆FNO	详情	详情
(XII)	60386	5-[(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid	356068-93-4	C₁₆H₁₃FN₂O₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(3)