3-methyl-1H-indole -Drug Synthesis Database

【结构式】

【分子编号】63428

【品名】3-methyl-1H-indole

【CA登记号】

【分子式】C₉H₉N

【分子量】131.1772

【元素组成】C 82.41% H 6.92% N 10.68%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：

Thermal cyclization of the azidocinnamate (II), obtained from O-benzylsalicylaldehyde (I) by methoxide condensation with ethyl azidoacetate, provides methyl 4-benzyloxyindol-2-carboxylate (III). Debenzylation by catalytic hydrogenolysis and alkylation of the phenol with (2S)-glycidyl tosylate gives the chiral oxirane (IV). Ring opening of (IV) followed by protection of the secondary amine by reaction with di-tert-butyldicarbonate and saponification of the methyl ester gives the key (S)-beta-blocker synthon (V). The required ACE inhibitor svnthon (VIII) is assembled from tert-butyl-N'-benzyloxycarbonyl-(S)-lysinate (VI). Alkylation of the alpha-amino group with the triflate of methyl (R)-lactate and saponification of the methyl ester gives N-[5-benzyloxycarbonylamino-1-(S)-tert-butyloxycarbonylpent-1-yl-(S)-alanine (VII). Condensation of (VII) with tert-butyl-(S)-prolinate. mediated by dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, followed by hydrogenolytic removal of the benzyloxycarbonyl group, provides tert-butyl-N-[5-amino-1-(S)-tert-butyloxycarbonylpent-1-yl]-(S)-alanyl-(S)-prolinate (VIII). Coupling of (V) with (VIII) using dicyclohexylcarbodiimide-1-hydroxybenzotriazole and removal of the tert-butyl protecting groups by acidolysis in trifluoroacetic acid, with ethyl methyl sulfide as a scavenger, gives crude BW-8385C as the bistrifluoroacetate salt. Purification is achieved by ion exchange chromatography on DE52 cellulose, followed by reverse-phase desalting to provide pure BW-B385C as the zwitterionic trihydrate.

参考文献中间体

合成目标

【1】 Allan, G.; Hardy, G.W.; BW-B385C. Drugs Fut 1988, 13, 3, 203.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	16242	(2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate	113826-06-5	C₁₀H₁₂O₄S	详情	详情
	19832	tert-butyl (2S)-2-pyrrolidinecarboxylate		C₉H₁₇NO₂	详情	详情
	23933	2-Propanamine; Isopropylamine	75-31-0	C₃H₉N	详情	详情
	32916	ethyl 2-azidoacetate	637-81-0	C₄H₇N₃O₂	详情	详情
	63428	3-methyl-1H-indole		C₉H₉N	详情	详情
(I)	21874	2-(benzyloxy)benzaldehyde	5896-17-3	C₁₄H₁₂O₂	详情	详情
(II)	21875	methyl (Z)-2-azido-3-[2-(benzyloxy)phenyl]-2-propenoate		C₁₇H₁₅N₃O₃	详情	详情
(III)	21876	methyl 4-(benzyloxy)-1H-indole-2-carboxylate		C₁₇H₁₅NO₃	详情	详情
(IV)	21877	methyl 4-[(2R)oxiranylmethoxy]-1H-indole-2-carboxylate		C₁₃H₁₃NO₄	详情	详情
(V)	21878	4-([(2S)-3-[(tert-butoxycarbonyl)(isopropyl)amino]-2-hydroxypropyl]oxy)-1H-indole-2-carboxylic acid		C₂₀H₂₈N₂O₆	详情	详情
(VI)	21879	tert-butyl (2S)-2-amino-6-[[(benzyloxy)carbonyl]amino]hexanoate		C₁₈H₂₈N₂O₄	详情	详情
(VII)	21880	(2S)-2-[[(1S)-5-[[(benzyloxy)carbonyl]amino]-1-(tert-butoxycarbonyl)pentyl]amino]propionic acid		C₂₁H₃₂N₂O₆	详情	详情
(VIII)	21881	tert-butyl (2S)-1-((2S)-2-[[(1S)-5-amino-1-(tert-butoxycarbonyl)pentyl]amino]propanoyl)-2-pyrrolidinecarboxylate		C₂₂H₄₁N₃O₅	详情	详情
(IX)	21882	tert-butyl (2S)-1-((2S)-2-[[(1S)-1-(tert-butoxycarbonyl)-5-([[4-([(2S)-3-[(tert-butoxycarbonyl)(isopropyl)amino]-2-hydroxypropyl]oxy)-1H-indol-2-yl]carbonyl]amino)pentyl]amino]propanoyl)-2-pyrrolidinecarboxylate		C₄₂H₆₇N₅O₁₀	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The target compound has been obtained by condensation of 3.3-dimethylindoline-1-carbonyl chloride (IV) with endo-8-methyl-8-azabicyclo[3.2.1]octan-3-amine (II) by means of triethylamine followed by salification with HCl. The intermediates (II) and (IV) have been obtained as follows: A) The metthylation of 3-methylindole (III) with methylmagnesium iodid / methyl iodid, followed by hydrogenation with H2/Pt in acetic acid gives 3,3-dimethylindoline (I), which is then treated with phosghene / Et3N to afford intermediate (IV). B) The reductocondensation of 8-methyl-para-bicyclo[3.2.1]octan-3-one (V) with benzylamine and H2/Pt gives the secondary benzylamine (VI), which is finally deprotected by hydrogenation over Pd/C to give intermediate (II).

参考文献中间体

合成目标

【1】 Archer, S.; Lewis, T.R.; Unser, M.J.; 3alpha-(2-Diethylaminoethyl)-aminotropane and related compounds. J Am Chem Soc 1957, 79, 4194-8.
【2】 Miyasaka, T.; Mutai, M.; Nokata, K.; Sawada, S.; Sugino, E. (Yakult Honsha Co., Ltd.); New camptothecin derivs. and process for preparing same. EP 0137145; JP 1985019790 .
【3】 Joiner, K.A.; King, F.D. (SmithKline Beecham plc); Certain 2,3-dihydro-indole-1-carboxamido-N-[8-azabicyclo(3.2.1)octan-3-yl] derivatives having 5-HT-antagonist activity. EP 0363466; JP 1990503569; US 4871744; US 5049556; WO 8909217 .
【4】 Blackburn, T.; King, F.; BRL46470A. Drugs Fut 1992, 17, 11, 987.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	12411	3,3-Dimethylindoline	C₁₀H₁₃N	详情	详情
(II)	12412	(1R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine; (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]oct-3-ylamine	C₈H₁₆N₂	详情	详情
(III)	63428	3-methyl-1H-indole	C₉H₉N	详情	详情
(IV)	12414	3,3-Dimethyl-1-indolinecarbonyl chloride	C₁₁H₁₂ClNO	详情	详情
(V)	16443	(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-one	C₈H₁₃NO	详情	详情
(VI)	12413	N-Benzyl-N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amine; (1R,5S)-N-Benzyl-8-methyl-8-azabicyclo[3.2.1]octan-3-amine	C₁₅H₂₂N₂	详情	详情

Extended Information