Benzyl Alcohol → 1H-Indole-2-carboxylic acid, octahydro-, phenylmethyl ester, hydrochloride (1:1), (2S,3aR,7aS)-

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Reaktionsschritte

Additionally, as depicted in FIG. 3, the production of (2S,3aR,7aS)-benzyl octahydro-1H-indole-2-carboxylate hydrochloride salt (3), a key intermediate in the production of trandolaprilat and trandolapril, may be produced using a starting material of crystalline ((1S,2S)-2-((S)-1-phenylethylamino)cyclohexyl)methanol (11). The first step of the process involves reaction with a catalyst including, but not limited to, palladium on carbon or palladium hydroxide on carbon in the presence of an alcohol such as methanol to produce ((1S,2S)-2-aminocyclohexyl)methanol (17). The remaining steps in the conversion of compound (17) to the hydrochloride salt, and eventual conversion to (2S,3aR,7aS)-benzyl octahydro-1H-indole-2-carboxylate hydrochloride salt (3) are based upon the teachings of U.S. Pat. No. 4,879,392, which is fully incorporated herein by reference. Generally, the remaining steps can be described as follows. Compound (17) is subjected to treatment with sodium cyanide in the presence of formaldehyde to produce compound (18), as illustrated in FIG. 3. Subsequently, compound (18) is first reacted with trimethylsilyl chloride, and then the product of that reaction is treated with benzyl chloride to produce compound (19). Further, compound (19) is then subjected to three sequential reactions to produce compound (20) as illustrated in FIG. 3. Specifically, compound (19) is first subjected to treatment with hydrochloric acid. Subsequently, methanesulfonyl chloride is added to the reaction mixture. Thereafter, potassium hydroxide is added to the reaction to produce compound (20). After compound (20) is produced, the compound is treated with aqueous mineral acid to produce the hydrochloride salt of compound (5), as disclosed previously. As described previously, compound (5) may then be treated with thionyl chloride, benzyl alcohol, and dichloromethane to produce (2S,3aR,7aS)-benzyl octahydro-1H-indole-2-carboxylate hydrochloride salt (3).

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