Indole-3-acetamide;3-Indoleacetamide;2-(1H-indol-3-yl) -Drug Synthesis Database

【结构式】

【分子编号】48682

【品名】Indole-3-acetamide;3-Indoleacetamide;2-(1H-indol-3-yl)

【CA登记号】879-37-8

【分子式】C₁₀H₁₀N₂O

【分子量】174.20228

【元素组成】C 68.95% H 5.79% N 16.08% O 9.18%

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：(XII)

A new strategy for the synthesis of a key intermediate in the preparation of LY-333531 has been described: Condensation of indole (I) with the tosylate (II) by means of NaH in DMF gives 4-(1-indolyl)butane-1,2-diol (III), which is monotritylated with trityl bromide yielding ether (IV). Alkylation of compound (IV) with tert-butyl bromoacetate (V) and NaH in THF affords the hydroxyacetic derivative (VI), which is reduced with LiBH4 in THF/EtOH to provide the carbinol (VII). Reaction of compound (VII) with Ms2O and pyridine in THF gives the mesylate (VIII), which is condensed with oxalyl chloride (IX) in ethyl ether to yield the oxoacetyl chloride (X). The alcoholysis of (X) with NaOMe in methanol affords the oxoacetate (XI), which is finally cyclized with 2-(3-indolyl)acetamide (XII) by means of NaH in DMF to provide the target intermediate (XIII).

参考文献中间体

合成目标

【1】 Faul, M.M.; Kumrich, C.A.; Cyclization strategies for the synthesis of macrocyclic bisindolylmaleimides. J Org Chem 2001, 66, 6, 2024.

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)	15292	Indole; 1H-indole	120-72-9	C₈H₇N	详情	详情
(II)	48674	2-(2,2-diethyl-1,3-dioxolan-4-yl)ethyl 4-methylbenzenesulfonate		C₁₆H₂₄O₅S	详情	详情
(III)	48675	4-(1H-indol-1-yl)-1,2-butanediol		C₁₂H₁₅NO₂	详情	详情
(IV)	48676	4-(1H-indol-1-yl)-1-(trityloxy)-2-butanol		C₃₁H₂₉NO₂	详情	详情
(V)	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(VI)	48677	tert-butyl 2-[3-(1H-indol-1-yl)-1-[(trityloxy)methyl]propoxy]acetate		C₃₇H₃₉NO₄	详情	详情
(VII)	48678	2-[3-(1H-indol-1-yl)-1-[(trityloxy)methyl]propoxy]-1-ethanol		C₃₃H₃₃NO₃	详情	详情
(VIII)	48679	2-[3-(1H-indol-1-yl)-1-[(trityloxy)methyl]propoxy]ethyl methanesulfonate		C₃₄H₃₅NO₅S	详情	详情
(IX)	29841	Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride	79-37-8	C₂Cl₂O₂	详情	详情
(X)	48680	2-[3-[3-(2-chloro-2-oxoacetyl)-1H-indol-1-yl]-1-[(trityloxy)methyl]propoxy]ethyl methanesulfonate		C₃₆H₃₄ClNO₇S	详情	详情
(XI)	48681	methyl 2-[1-[3-[2-[(methylsulfonyl)oxy]ethoxy]-4-(trityloxy)butyl]-1H-indol-3-yl]-2-oxoacetate		C₃₇H₃₇NO₈S	详情	详情
(XII)	48682	Indole-3-acetamide;3-Indoleacetamide;2-(1H-indol-3-yl)	879-37-8	C₁₀H₁₀N₂O	详情	详情
(XIII)	48683	18-[(trityloxy)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione		C₄₅H₃₇N₃O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXV)

The 2,3-disubstituted maleimide intermediate (X) is prepared by N-alkylation of 1,2,3,4-tetrahydroquinoline (XIX) with ethyl 3-bromopyruvate (XX) in THF to give ethyl 3-(3,4-dihydro-2H-quinolin-1-yl)-2-oxopropionate (XXI), which by intramolecular cyclocondensation by means of MgCl2 in 2-methoxyethanol at 125 °C affords ethyl 5,6-dihydropyrrolo[3,2,1-ij]quinoline-1-carboxylate (XXII). Hydrolysis of ethyl ester (XXII) with NaOH in EtOH/H2O provides the corresponding carboxylic acid (XXIII), which is then decarboxylated to 5,6-dihydropyrrolo[3,2,1-ij]quinoline (lilolidine) (XVII) by heating to 185 °C in quinoline in the presence of CuO·Cr2O3 . Acylation of lilolidine (XVII) with (COCl)2 in Et2O, and subsequent quenching of the resulting glyoxylyl chloride with MeOH or NaOMe/MeOH affords the oxoester (XXIV), which is finally cyclocondensed with indole-3-acetamide (XXV) in the presence of t-BuOK in THF .

参考文献中间体

合成目标

【1】 Li, C.J., Ashwell, M.A., Hill, J., Moussa, M.M., Munshi, N. (ArQule, Inc.). Maleimide derivatives, pharmaceutical compositions and methods for treatment of cancer. CN 10194970, EP 1846406, EP 2289892, JP 2008530026, US 2006223760, US 7713969, WO 2006086484.
【2】 Chan, T.C.K., France, D.S., Ishii, K. (ArQule, Inc.; Kyowa Hakko Kirin Co., Ltd.). Combinational compositions and methods for treatment of cancer. KR 2011118817, US 2010297075, WO 2010093789.
【3】 Reed, D.P., Barnes, N.R., Kane, J.C., Lee, C.A., Chen, J.-X., Redmon, M.P.(ArQule, Inc.). Purified pyrroloquinolinyl-pyrrolidine-2,5-dione compositions and methods for preparing and using same. US 201116022, WO 2011079142.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	68960	3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione		C₂₃H₁₇N₃O₂	详情	详情
(XVII)	68966	5,6-dihydropyrrolo[3,2,1-ij]quinoline;5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline;1,7-Trimethyleneindol;1,8-Trimethyleneindole	5840-01-7	C₁₁H₁₁N	详情	详情
(XIX)	23859	1,2,3,4-tetrahydroquinoline	635-46-1	C₉H₁₁N	详情	详情
(XX)	25183	ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate	70-23-5	C₅H₇BrO₃	详情	详情
(XXI)	68968	ethyl 3-(3,4-dihydro-2H-quinolin-1-yl)-2-oxopropionate		C₁₄H₁₇NO₃	详情	详情
(XXII)	68969	ethyl 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylate		C₁₄H₁₅NO₂	详情	详情
(XXIII)	68970	5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid		C₁₂H₁₁NO₂	详情	详情
(XXIV)	68971	methyl 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-2-oxoacetate		C₁₄H₁₃NO₃	详情	详情
(XXV)	48682	Indole-3-acetamide;3-Indoleacetamide;2-(1H-indol-3-yl)	879-37-8	C₁₀H₁₀N₂O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XXV)

The allyl-indole intermediate (XII) is obtained by acylation of 1-allyl-7-bromoindole (XXVI) with (COCl)2 in CH2Cl2, followed by treatment with NaOMe to afford the oxoester (XXVII), which upon cyclocondensation with (3-indolyl)acetamide (XXV) in the presence of t-BuOK in THF furnishes the pyrrole-2,5-dione derivative (XXVIII). Finally, the maleimide derivative (XXVIII) is reduced by means of Mg in refluxing MeOH .

参考文献中间体

合成目标

【1】 Li, C.J., Ashwell, M.A., Hill, J., Moussa, M.M., Munshi, N. (ArQule, Inc.). Maleimide derivatives, pharmaceutical compositions and methods for treatment of cancer. CN 10194970, EP 1846406, EP 2289892, JP 2008530026, US 2006223760, US 7713969, WO 2006086484.
【2】 Chan, T.C.K., France, D.S., Ishii, K. (ArQule, Inc.; Kyowa Hakko Kirin Co., Ltd.). Combinational compositions and methods for treatment of cancer. KR 2011118817, US 2010297075, WO 2010093789.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	68962	(±)-trans-(3R,4R)-3-(1-allyl-7-bromo-1H-indol-3-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione		C₂₃H₁₈BrN₃O₂	详情	详情
(XXV)	48682	Indole-3-acetamide;3-Indoleacetamide;2-(1H-indol-3-yl)	879-37-8	C₁₀H₁₀N₂O	详情	详情
(XXVI)	68972	1-allyl-7-bromoindole;1-allyl-7-bromo-1H-indole		C₁₁H₁₀BrN	详情	详情
(XXVII)	68973	methyl 2-(1-allyl-7-bromo-1H-indol-3-yl)-2-oxoacetate		C₁₄H₁₂BrNO₃	详情	详情
(XXVIII)	68974	3-(1-allyl-7-bromo-1H-indol-3-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione		C₂₃H₁₆BrN₃O₂	详情	详情

Extended Information