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Process for preparing (2R, 5R)-1, 6-diphenylhexane-2, 5-diamine

IP.com Disclosure Number: IPCOM000245328D
Publication Date: 2016-Mar-01
Document File: 4 page(s) / 125K

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Process for preparing (2R, 5R)-1, 6-diphenylhexane-2, 5-diamine

    Provided herein is a process for preparing (2R, 5R)-1, 6-diphenylhexane-2, 5-diamine, referred herein as Compound I. The process is described in Example 1. Compound I may be used for preparing 1,3-thiazol-5-ylmethyl-[(2R,5R)-5-{[(2S)-2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl} carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate.

Compound - I

    Adipic acid was identified as a suitable starting material for the synthesis of Compound I. The synthesis was initiated with the esterification of adipic acid with various alcohols (alkyl, cycloalkyl, aryl-alkyl) under acidic conditions (HBr, HCl, H2SO4, TsOH, SOCl2 etc.,) following the procedure cited for example in Organic synthesis, collective volume-2, 264. Di-Benzylation of the ester with benzyl hailde such as (Benzyl chloride, Benzyl bromide, Benzyl iodide, Benzyl chloride/NaBr or NaI) was then carried out under basic conditions (NaOMe, NaOEt, NaH, t-BuONa, t-BuOK, etc.,) in a suitable solvent (Toluene, THF, acetonitrile, etc.,) under heating for example as reported in Di- benzylation: US 2014/0051888.

    Compound 3 was isolated as a mixture of isomers (meso and racemic mixture) in ratio 1:1. Separation of the meso isomer, from the racemic mixture was accomplished in two ways (Scheme-I & Scheme-II).

    In one procedure (Scheme-I), meso isomer of the ester was separated by crystallization at the ester stage using alcoholic solvent (MeOH, EtOH, IPA etc.). Isolation of the desired (R, R) isomer from the racemic mixture was accomplished by hydrolysis of the racemic ester, obtained from the crystallization from alcohol solvents, followed by chiral resolution using chiral amine base. The meso- diester isomer -8, thus separated, can be recycled via its epimerization to a mixture of meso and racemic isomers under basic conditions using organic or inorganic base preferred alkoxide base such


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as (MeONa, EtONa, t-BuONa, etc.,) or hydroxide base (NaOH, KOH, LiOH, etc.,) in a suitable solvent such as THF, toluene, MeOH, EtOH, t-BuOH, etc., under heating. However, presumably due to the moisture, hydrolysis ensued with epimerization and led to the formation of compound 9 as a mixture of isomers (meso and racemic). Separation of the racemic mixture from the compound-9 was achieved by sequential crystallization first using toluene/alcohol mixture to separate the meso isomer (Purity: 89 %) and racemate isomer (Purity: 91%), followed by classical resolution using chiral amine base to isolate the desired (R, R) isomer 6 (scheme-I).

Scheme - I

    An alternative procedure (Scheme-II) involve...