5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】60382

【品名】5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid

【CA登记号】253870-02-9

【分子式】C₈H₉NO₃

【分子量】167.1644

【元素组成】C 57.48% H 5.43% N 8.38% O 28.71%

与该中间体有关的原料药合成路线共 5 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

该中间体在本合成路线中的序号：(VI)

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

合成目标

【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

该中间体在本合成路线中的序号：(VI)

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

合成目标

【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

合成路线3

该中间体在本合成路线中的序号：(III)

Vilsmeier formylation of ethyl 2,4-dimethylindole-3-carboxylate (I) by means of POCl3 and DMF leads to aldehyde (II). Subsequent ester group hydrolysis in (II) under alkaline conditions furnishes acid (III), which is then coupled to N-(2-aminoethyl)pyrrolidine (IV) employing EDC/HOBt to afford the corresponding amide (V). Chemoselective reduction of the 3-carbonyl group of 5-fluoroisatin (VI) upon heating with hydrazine hydrate gives rise to 5-fluorooxindole (VII). Finally, condensation of (VII) with aldehyde (V) under Knoevenagel conditions provides the title compound

参考文献中间体

合成目标

【1】 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 .

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)	60380	ethyl 2,4-dimethyl-1H-pyrrole-3-carboxylate	2199-51-1	C₉H₁₃NO₂	详情	详情
(II)	60381	ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylate	2199-59-9	C₁₀H₁₃NO₃	详情	详情
(III)	60382	5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid	253870-02-9	C₈H₉NO₃	详情	详情
(IV)	18161	2-(1-pyrrolidinyl)ethylamine; 2-(1-pyrrolidinyl)-1-ethanamine; 1-Pyrrolidineethanamine	7154-73-6	C₆H₁₄N₂	详情	详情
(V)	60383	5-formyl-2,4-dimethyl-N-[2-(1-pyrrolidinyl)ethyl]-1H-pyrrole-3-carboxamide		C₁₄H₂₁N₃O₂	详情	详情
(VI)	21552	5-fluoro-1H-indole-2,3-dione	443-69-6	C₈H₄FNO₂	详情	详情
(VII)	60384	5-fluoro-1,3-dihydro-2H-indol-2-one	56341-41-4	C₈H₆FNO	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

In a related, scale-up procedure, 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (I) is condensed to 5-fluorooxindole (II) in the presence of pyrrolidine and AcOH to furnish adduct (III). This is then condensed with N-(2-aminoethyl)pyrrolidine (IV) in the presence of BOP to produce the target amide

参考文献中间体

合成目标

【1】 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 .

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)	60382	5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid	253870-02-9	C₈H₉NO₃	详情	详情
(II)	60384	5-fluoro-1,3-dihydro-2H-indol-2-one	56341-41-4	C₈H₆FNO	详情	详情
(III)	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
(IV)	18161	2-(1-pyrrolidinyl)ethylamine; 2-(1-pyrrolidinyl)-1-ethanamine; 1-Pyrrolidineethanamine	7154-73-6	C₆H₁₄N₂	详情	详情

合成路线5

该中间体在本合成路线中的序号：(VII)

参考文献中间体

合成目标

【1】 Jin QW, Mnuragis MA, May PD. 2003. Process for preparing aminocarbonylpyrrolylmethylideneindolinones from indolinones, imidazolcarbonylpyrrolecarboxaldehydes, and amines. W0 2003070725
【2】 Manley JM, Kalman MJ, Conway BG, et al. 2003. Early amidation approach to 3-[(4-anudo)pyrrol-2-yl]-2-indolinones. J Org Cbem, 68(16):6447～6450
【3】 Sun L, Liang C, Shirazian S, et aL. 2003. Discovery of 5-[5-Fluoro-2-oxo-l,2-dihydroindol-(3Z)-ylidenemethyl}2,4一dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med Chem, 46(7): 1116～1119

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	63353	1,1-dimethylethyl 2-(hydroxyimino)-3-oxobutanoate	14352-65-9	C₈H₁₃NO₄	详情	详情
(VIII)	14754	ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine	107-15-3	C₂H₈N₂	详情	详情
（IX）	66753	(E)-N-(2-(diethylamino)ethyl)-5-(((2-(diethylamino)ethyl)imino)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide		C₂₀H₃₇N₅O	详情	详情
(X）	60384	5-fluoro-1,3-dihydro-2H-indol-2-one	56341-41-4	C₈H₆FNO	详情	详情
(XI）	66752	(Z)-N-[2-(Diethylamino)ethyl]-5-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide	326914-13-0	C₂₂H₂₇FN₄O₂	详情	详情
(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
(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)	60380	ethyl 2,4-dimethyl-1H-pyrrole-3-carboxylate	2199-51-1	C₉H₁₃NO₂	详情	详情
(VI)	60381	ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylate	2199-59-9	C₁₀H₁₃NO₃	详情	详情
(VII)	60382	5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid	253870-02-9	C₈H₉NO₃	详情	详情

Extended Information