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

【结构式】

【分子编号】28747

【品名】2-methyl-1H-indole

【CA登记号】95-20-5

【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 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：(I)

The condensation of 2-methyl-3-(1H-imidazol-1-ylmethyl)indole (III) with acrylonitrile (IV) by means of benzyltrimethylammonium hydroxide (B) in dioxane gives 1-(2-cyanoethyl)-2-methyl-3-(1H-imidazol-1-ylmethyl)indole (V), which is then hydrolyzed with KOH in water. The reaction of compound (III) with methyl acrylate (VI) in the same conditions as before gives 1-(2-methoxy-carbonylethyl)-2-methyl-3-(1H-imidazol-1-ylmethyl)indole (VII), which is also hydrolyzed. Compound (III) can be obtained from 2-methylindole (I).

参考文献中间体

合成目标

【1】 Cross, P.E.; Dickinson, R.P.; Randall, M.J.; Parry, M.J.; K-38485, a novel, selective thromboxane synthetase inhibitor with prolonged activity in vivo. N Am Med Chem Symp 1982, 68.
【2】 Cross, P.E.; Dickinson, R.P. (Pfizer Inc.); Inhibition of thromboxane synthetase by 3-(1-imidazolylalkyl)indoles. NL 8001351 .
【3】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Grau, M.; UK-38485. Drugs Fut 1983, 8, 11, 947.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	10255	Imidazole; 1H-Imidazole	288-32-4	C₃H₄N₂	详情	详情
(B)	36194	N,N,N-trimethyl(phenyl)methanaminium	4525-46-6	C₁₀H₁₆N	详情	详情
(I)	28747	2-methyl-1H-indole	95-20-5	C₉H₉N	详情	详情
(II)	36192	N,N-dimethyl-N-[(2-methyl-1H-indol-3-yl)methyl]amine; N,N-dimethyl(2-methyl-1H-indol-3-yl)methanamine		C₁₂H₁₆N₂	详情	详情
(III)	36193	3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indole		C₁₃H₁₃N₃	详情	详情
(IV)	10847	Acrylonitrile	107-13-1	C₃H₃N	详情	详情
(V)	36195	3-[3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indol-1-yl]propanenitrile		C₁₆H₁₆N₄	详情	详情
(VI)	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(VII)	36196	methyl 3-[3-(1H-imidazol-1-ylmethyl)-2-methyl-1H-indol-1-yl]propanoate		C₁₇H₁₉N₃O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

This compound can be obtained by two related ways: 1) The condensation of 2-methylindole (I) with 2-morpholinoethyl chloride (II) by means of KOH in hot DMSO gives 1-(2-morpholinoethyl)-2-methylindole (III), which is then submitted to a Friedel-Craft's reaction with 4-methoxybenzoyl chloride (IV) by means of AlCl3 in dichloromethane or ethylene dichloride. 2) The condensation of indole (I) with acyl chloride (IV) by means of methylmagnesium bromide in anhydrous ethyl ether gives 2-methyl-3-(4-methoxy benzoyl)indole (V), which is then condensed with morpholine (II) by means of K2CO3 in DMF.

参考文献中间体

合成目标

【1】 Bell, M.R. (Sanofi-Synthelabo); 3-Carbonyl-1-aminoalkyl-1H-indoles useful as analgesics and preparation thereof. AU 8545764; EP 0171037; ES 8609246; ES 8800149; ES 8800901; ES 8800902; ES 8801203; JP 1986047463 .
【2】 Castaner, R.M.; Castaner, J.; Serradell, M.N.; WIN-48098. Drugs Fut 1987, 12, 9, 867.

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)	28747	2-methyl-1H-indole	95-20-5	C₉H₉N	详情	详情
(II)	27355	4-(2-chloroethyl)morpholine	3647-69-6	C₆H₁₂ClNO	详情	详情
(III)	28748	4-[2-(2-methyl-1H-inden-1-yl)ethyl]morpholine		C₁₆H₂₁NO	详情	详情
(IV)	22671	4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride	100-07-2	C₈H₇ClO₂	详情	详情
(V)	28749	(4-methoxyphenyl)(2-methyl-1H-indol-3-yl)methanone		C₁₇H₁₅NO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

2-Methylindole (I) was nitrated employing NaNO3 in H2SO4 and the resultant 5-nitroindole (II) was further reduced to the corresponding indoline (III) by means of NaBH3CN in the presence of HOAc. Catalytic hydrogenation of the nitro group of (III) over Pd/C furnished diamine (IV), which was converted to the bis-carbamate (V) by treatment with benzyl chloroformate. Oxazolidinone (VII) was then obtained by condensation of carbamate (V) with (R)-glycidyl butyrate (VI) in the presence of BuLi at -78 C. After conversion of alcohol (VII) to the corresponding nosylate (VIII), displacement of its sulfonate group with ammonium hydroxide gave rise to the primary amine (IX). Acetylation of amine (IX), followed by hydrogenolysis of the remaining N-benzyloxycarbonyl group, yielded acetamide (X). The indoline N of (X) was then acylated by acetoxyacetyl chloride (XI) to produce amide (XII). The title compound was then obtained by smooth hydrolysis of the acetoxy group of (XII) with K2CO3, followed by separation of the resultant mixture of diastereoisomers by chiral HPLC.

参考文献中间体

合成目标

【1】 Genin, M.J.; Barbachyn, M.R.; Grega, K.C.; et al.; The potentiating effect of remote chirality on the antibacterial activity of a series of 2-substituted indolinyl phenyloxazolidinones. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1042.
【2】 Hester, J.B. Jr.; Barbachyn, M.R.; Johnson, P.D.; Genin, M.J. (Pharmacia Corp.); Bicyclic oxazolidinones as antibacterial agent. EP 1181288; US 6387896; WO 0073301 .

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)	28747	2-methyl-1H-indole	95-20-5	C₉H₉N	详情	详情
(II)	55948	2-methyl-5-nitro-1H-indole; 2-Methyl-5-nitroindole	7570-47-0	C₉H₈N₂O₂	详情	详情
(III)	55949	2-methyl-5-nitroindoline		C₉H₁₀N₂O₂	详情	详情
(IV)	55950	2-methyl-2,3-dihydro-1H-indol-5-ylamine; 2-methyl-5-indolinamine		C₉H₁₂N₂	详情	详情
(V)	55951	benzyl 5-{[(benzyloxy)carbonyl]amino}-2-methyl-1-indolinecarboxylate		C₂₅H₂₄N₂O₄	详情	详情
(VI)	18385	(2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate	60456-26-0	C₇H₁₂O₃	详情	详情
(VII)	55952	benzyl 5-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-methyl-1-indolinecarboxylate		C₂₁H₂₂N₂O₅	详情	详情
(VIII)	55953	benzyl 2-methyl-5-[(5R)-5-({[(3-nitrophenyl)sulfonyl]oxy}methyl)-2-oxo-1,3-oxazolidin-3-yl]-1-indolinecarboxylate		C₂₇H₂₅N₃O₉S	详情	详情
(IX)	55954	benzyl 5-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-methyl-1-indolinecarboxylate		C₂₁H₂₃N₃O₄	详情	详情
(X)	55955	N-{[(5S)-3-(2-methyl-2,3-dihydro-1H-indol-5-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide		C₁₅H₁₉N₃O₃	详情	详情
(XI)	10456	Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate	13831-31-7	C₄H₅ClO₃	详情	详情
(XII)	55956	2-(5-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl acetate		C₁₉H₂₃N₃O₆	详情	详情

Extended Information