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    Processes and intermediates for the preparation of protease inhibitors
    56.
    发明专利
    Processes and intermediates for the preparation of protease inhibitors 未知

    公开(公告)号：NZ595817A

    公开(公告)日：2014-03-28

    申请号：NZ59581710

    申请日：2010-04-27

    Applicant: VERTEX PHARMA

    Inventor： LOOKER ADAM ,  CHEN MINZHANG ,  JURKAUSKAS VALDAS ,  TANOURY GERALD J ,  COCHRAN JOHN E

    IPC: C07D209/52 ,  A61K31/403 ,  C07D471/08 ,  C07K7/02

    Abstract: 595817 Disclosed herein are processes for preparing a mixture of cis- and trans-octctahydropenta[c]pyrrole-1-carboxylic acids of formula 7, wherein R’ substituents are described in the specification, comprising carboxylation of an azabicyclooctane of formula 6, and equilibrating in the presence of a suitable base wherein the trans-/cis-ratio is greater than 80 to 20, or 90 to 10 or 98 to 2. Also disclosed herein are processes for preparing a compound of formula 4, comprising providing a compound of Formula 7 forming a salt with an optically active amine; crystallizing the salt; esterifying the acid provided in step iii); removing the N-alkoxycarbonyl group to produce (1S,3aR,6aS)-t-butyl-octahydrocyclopenta[c]pyrrole-1-carboxylate, t-butyl ester; reacting the bicyclic aminoester of step v) with a protected amino acid of Formula 26, wherein Z is an amine protecting group, in the presence of a coupling reagent, to produce an amide-ester of Formula 27; removing the protecting group Z from the amide-ester of step vi) to produce the amino compound of Formula 28; reacting the amino compound of Formula 28 with a protected amino acid of Formula 29in the presence of a coupling reagent to produce a tripeptide of Formula 30; removing the protecting group Z in the tripeptide of Formula 30 to produce a free amino-tripeptide of Formula 31; reacting the amino-tripeptide of Formula 31 with pyrazine-2-carboxylic acid in the presence of a coupling reagent to produce an amide-tripeptide ester of Formula 33; hydrolyzing the ester of the amide-tripeptide ester of Formula 33 to produce an amide-tripeptide acid of Formula 34; reacting the amide-tripeptide acid of Formula 34 with an aminohydroxy-amide of Formula 18in the presence of a coupling reagent to produce a hydroxy-tetrapeptide of Formula 35; and oxidizing the hydroxy group of Formula 35 to produce the compound of Formula 4.

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