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ChemicalBook CAS DataBase List Ramelteon
196597-26-9

Ramelteon synthesis

6synthesis methods
Vilsmeier-Haack reaction on benzofuran 112 provided aldehyde 113 (100%), which was converted to olefin 114 (88%) by Horner-Emmons reaction with triethylphosphonoacetate, and was followed by hydrogenation of the olefin to give ester 115 (100%). In order to avoid the cyclization of the acid chloride intermediate into the wrong position, the benzene ring was protected by bromination. Both bromination and hydrolysis of the ester is accomplished in a single pot to give acid 116. Thus the ester is brominated with bromine in sodium acetate and acetic acid at 0°C and RT for several hours followed by quenching of remaining bromide by sodium thiosulfate. The resulting acidic solution was taken up in acetonitrile and refluxed for 2hr to provide the acid 116 in 73% yield. The conversion of the acid to acid chloride was done by reacting with thionyl chloride in odichlorobenzene at 40°C for 30 to 40 min after which the reaction was cooled to 0°C . Aluminum trichloride was added and the reaction mixture was stirred at 0°C for 30 min to deliver cyclized ketone 117 in 92% yield. After completion of the cyclization, the bromines are removed by hydrogenation (86%) and resulting ketone 118 was then reacted under Horner-Emmons condition with diethyl cyano phosphonate to give vinyl nitrile 119 in 84% yield. Selective reduction of the nitrile was accomplished by hydrogenation under basic condition (sodium hydroxide in toluene) in the presence of the activated cobalt at 25-50°C for 6.5 hr. The amine was recovered as hydrochloride salt 120 (99% yield) by treating the amine with HCl in methanol. In the next step, the amine salt 120 was taken up in toluene and treated with sodium hydroxide followed by hydrogenation of the mixture with [RuCl(benzene)(R)-BINAP]Cl as catalyst to provide chiral amine 121, after several work up and palladium catalyzed hydrogenations, in 73% overall yield. Final acylation of the amine with propionyl chloride in the presence of aqueous sodium hydroxide in THF at room temperature gave the desired product ramelteon (XVI), after crystallization, in 97% yield.

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Yield:196597-26-9 86%

Reaction Conditions:

Stage #1: methanesulfonyl chloride;(S)-N-[2-(6-hydroxy-7-(2-hydroxyethyl)-2,3-dihydro-1H-inden-1-yl)ethyl]propionamidewith pyridine at -10 - -5; for 0.833333 h;
Stage #2: with triethylamine in ethyl acetate;Heating;Further stages.;

References:

Uchikawa, Osamu;Fukatsu, Kohji;Tokunoh, Ryosuke;Kawada, Mitsuru;Matsumoto, Kiyoharu;Imai, Yumi;Hinuma, Shuji;Kato, Koki;Nishikawa, Hisao;Hirai, Keisuke;Miyamoto, Masaomi;Ohkawa, Shigenori [Journal of Medicinal Chemistry,2002,vol. 45,# 19,p. 4222 - 4239]

1185516-79-3 Synthesis
(S)-2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl)acetonitrile

1185516-79-3
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