July 22, 2013

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The following patent record is from the CAplusSM database.


Patent Number: US 8431733
Title: Process for the preparation of (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyalkanamide derivatives in the absence of cyclopropylisonitrile and their use in the synthesis peptidyl HCV and cathepsin inhibitors
Inventor(s): Dener, Jeffrey
Patent Assignee(s): ViroBay, Inc., USA
Source: PCT Int. Appl., 38pp. CODEN: PIXXD2
Language: English

The invention is related to a process for the prepn. of (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyalkanamide derivs. I [R = C1-6 alkyl optionally substituted by C3-6 cycloalkyl] via amidation of acids II with N,O-dimethylhydroxylamine hydrochloride, redn. of the Weinreb amides with LAH, one pot addn. of sodium bisulfite to the aldehydes in an inert org. solvent/treatment of bisulfite adduct with NaCN, conversion of the cyanohydrines III to hydroxyacids IV in the presence of a strong acid, coupling of the acids with cyclopropylamine and debenzylation, and to the use of I in the first step of the synthesis of HCV and cathepsin inhibitors, such as HCV inhibitor V.  The invention allows prepn. of I in the absence of cyclopropylisonitrile via stable, in some steps, solid intermediates which are easily purified by recrystn.  Thus, benzylation of L-norvaline with benzyl bromide in the presence of NaOH/K2CO3 in water, sapon. of the benzyl ester, activation of (S)-2-(dibenzylamino)pentanoic acid with HOBt/EDCI and treatment of the activated acid with N,O-dimethylhydroxylamine hydrochloride in the presence of N-methylmorpholine, redn. of (S)-2-(dibenzylamino)-N-methoxy-N-methylpentanamide with LAH, addn. of sodium bisulfite to (S)-2-(dibenzylamino)pentanal and treatment of the reaction mixt. contg. the bisulfite adduct with NaCN in water, conversion of (2S,3S)-3-(dibenzylamino)-2-hydroxyhexanenitrile to (2S,3S)-3-(dibenzylamino)-2-hydroxyhexanoic acid in the presence of HCl, purifn. of the crude acid via salt formation with ((S)-a-methylbenzyl)amine, amidation of the acid with cyclopropylamine in the presence of HOBt/EDCI and debenzylation by hydrogenolysis gave I [R = Pr-n].  Amidation of (2S,4R)-1-(tert-butoxycarbonyl)-4-[[7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yl]oxy]pyrrolidine-2-carboxylic acid with amine I·HCl [R = Pr-n] in the presence of diisopropylethylamine and HATU in CH2Cl2/DMF, cleavage of the tert-butoxycarbonyl group, amidation of (R)-2-(3-tert-butylureido)-3,3-dimethylbutanoic acid with the resulting pyrrolidinium chloride in the presence of diisopropylethylamine and HATU in DMSO and Dess-Martin oxidn. gave peptide deriv. V.

Please note:  Abstracts and Titles for patent records in CAplus are routinely enhanced to better describe the claimed invention.

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