2-Ethyl-2-chloro-1 - indole

The diketoindoles 777 were prepared in three steps starting from indol-3-ylacetic acid (680) and 5-chloro indol-3-ylacetic acid (774) in 75% and 66% overall yield, respectively. The indole acids 680 and 774 were converted into Weinreb amides 775, followed by reaction with ethyl Grignard reagent to afford the corresponding indol-3-yl ketones 776. In order to introduce the second carbonyl moiety, the 3-substituted... 

CN l-[2-[4-[5-chloro-l-(4-fluorophenyl)-l//-indol-3-yl]-l-piperidinyl]ethyl]-2-imidazolidinone... 

CN 5-[2-[4-(l,2-Benzisothiazol-3-yl)-l-piperazinyl]ethyl]-6-chloro-l,3-dihydro-2//-indol-2-one hydrochloride hydrate... 

Recently, SB-269970 (l-[3-hydroxy-phenyl-sulphonyl]-2-[2-(4-methyl-l-piperidinyl)-ethyl] pyrrolidine) and SB-656104 (6-((R)-2- 2-[4-(4-chloro-phenoxy)-piperidin-l-yl]-ethyl pyrrolidine-l-sulphonyl)-lH-indole) have been reported to be potent 5-HT7 receptor antagonists (Hagan et al., 2000 Forbes et al., 2002). Selective 5-HT7 receptor agonists are not available at the present time. Systemic administration of SB-269970 or SB-656104 to rats at the beginning of the light period has been shown to reduce the total amount of REMS and to increase REMS latency. Values of W and SWS were not significantly modified (Hagan et al., 2000 Thomas et al., 2003). Hedlund et al. (2005) established that 5-HT7... 

Dialkylindolines and 1,3-dialkylindoles are formed in poor yield (<10%) from the reaction of ethyl- or phenymagnesium bromide with 2-chloro-N-methyl-N-allylaniline in the presence of catalytic quantities of (bistriphenylphosphine)nickel dichloride.72 In a modification of this procedure, the allyl derivatives can be converted by stoichiometric amounts of tetrakis(triphenylphosphine)nickel into 1,3-dialkylindoles in moderate yield72 (Scheme 43) an initial process of oxidative addition and ensuing cyclization of arylnickel intermediates is thought to occur. In contrast to the nickel system,72 it has proved possible to achieve the indole synthesis by means of catalytic quantities of palladium acetate.73 It is preferable to use... 

Azatricyclo[2.2.1.02 6]hept-7-yl perchlorate, 2368 f Azetidine, 1255 Benzvalene, 2289 Bicyclo[2.1.0]pent-2-ene, 1856 2-/ert-Butyl-3-phenyloxaziridine, 3406 3 -Chloro-1,3 -diphenyleyclopropene, 3679 l-Chloro-2,3-di(2-thienyl)cyclopropenium perchlorate, 3388 Cyanocyclopropane, 1463 f Cyclopropane, 1197 f Cyclopropyl methyl ether, 1608 2,3 5,6-Dibenzobicyclo[3.3.0]hexane, 3633 3,5 -Dibromo-7-bromomethy lene-7,7a-dihy dro-1,1 -dimethyl-1H-azirino[l,2-a]indole, 3474 2.2 -Di-tert-butyl-3.3 -bioxaziridinc, 3359 Dicyclopropyldiazomethane, 2824 l,4-Dihydrodicyclopropa[ >, g]naphthalene, 3452 iV-Dimethylethyl-3,3-dinitroazetidine, 2848 Dinitrogen pentaoxide, Strained ring heterocycles, 4748 f 1,2-Epoxybutane, 1609 f Ethyl cyclopropanecarboxylate, 2437 2,2 -(l,2-Ethylenebis)3-phenyloxaziridine, 3707 f Methylcyclopropane, 1581 f Methyl cyclopropanecarboxylate, 1917 f Oxetane, 1222... 

Generally, however, lithium aluminium hydride reduction is used to convert isatins to indoles. Thus, 4,5,6-trimethoxyisatin,251 5-bromo-isatin,252 5-chloro-6-methoxy-l-methylisatin,253 1-ethyl- and 1-methyl-isatin,254 and 4,6-dimethoxyisatin94 all gave the corresponding indoles. 

The 3-chloro-l-(4-indolyloxy)-2-propanol is dissolved in 50 ml of toluene and 50 ml of isopropylamine and heated to the boil for 45 h. Evaporation to dryness is effected in a vacuum, the residue is shaken out thrice between ethyl acetate and a 1 N tartaric acid solution and a 5 N sodium hydroxide solution is then added to the combined tartaric acid phases until an alkaline reaction is obtained. The alkaline solution is shaken out thrice with 50 ml of methylene chloride, the extracts are dried over magnesium sulfate and the solvent evaporated in vacuum. The residue is crystallized from ethyl acetate/ether to give the 4-(2-hydroxy-3-isopropylaminopropoxy)indole. 

The water phase was extracted with further 15 L dichloromethane. The combined dichloromethane phases were dried with Na2S04 and were evaporated. The product was flushed off with 5 L acetone, 35 L acetone was added and the suspension was heated until reflux. The crystallised product did not dissolve completely. Heating was discontinued and the mixture was left over night with gentle cooling. The crystallised l-[2-[4-[5-chloro-l-(4-flourophenyl)-lH-indol-3-yl]-l-piperidinyl]ethyl]-2- imidazolidinone was isolated on a notch, washed with further 5 L acetone and dried over night under air stream at 60°C. Yield 4.90 kg (83.2%), melting point 154.7°C. 

A clean and dry 20-gallon reactor was charged with 17.4 gallons of deionized water and 4.44 L of concentrated hydrochloric acid, to give a 0.77 M solution. To the solution was added 4.44 kg of the anhydrous 5-(2-(4-(l,2-benzisothiazol-yl)-l-piperazinyl)-ethyl)-6-chloro-l,3-dihydro-2H-indol-2-one free base. The slurry was warmed to 65°C and held for 18 hours. The slurry was cooled to room temperature. The product was filtered and washed with 2x5-gallon portions of deionized water, and then air dried at 50°C for 30 hours. The dried product contained 4.4% water and the x-ray diffraction method confirmed that the desired product was obtained. 

Ethyl 4-methyl-7-azaindole-3-acetate (155, R = H), obtained from the attempted cyanomethylation of the indole, was hydrolyzed to the 3-acetic acid (156, R = H) (54%), which was treated in succession by thionyl chloride and ammonia to give the 3-acetamide (157) (78%). Reduction with lithium aluminium hydride gave the azatryptamine (150, R = R = R" = H) in 94% yield. The 6-chloro ester (155, R = Cl) was hydrolyzed also to the acid (156, R = Cl.) ... 

Indol 4-Chlor-l-(2-cyan-ethyl)-E6b/2, 1127 (NH - N-R) Pyrimidin 2-Benzyl-4-chloro- E9b/2,... 

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