Several
publications and patents including process patents
describing the preparation of key fragments and a full synthesis of boceprevir, have been published. Retrosynthetically, the
drug can be broken down into 3 or 4 key fragments and assembled
in a convergent synthesis as depicted in the scheme.
Synthesis of t-butyl urea fragment 55 began with esterification
of t-butyl amino acid 58 with TMSCl and triethylamine to give silyl
ester 59. Silyl ester 59 was then reacted with t-butyl isocyanate 60
to provide urea 55 in 74¨C89% (2-steps).
Although several routes for the preparation of the azbicyclo[
3.1.0]hexane ester 56 have been disclosed, the most recent
process-scale synthesis of this heterocyclic core was accomplished
using enzymatic desymmetrization of readily available azabicyclo[
3.1.0]hexane 61(the scheme). This was accomplished through
the enzymatic oxidation of 61 followed by trapping of the resulting
imine 62 with bisulfate to give the corresponding sulfonate 63. Sulfonate
63 was attained under manufacturing conditions in 95% and
99% ee. Without isolation, the sulfonate salt was reacted with sodium
cyanide in cyclopentyl methyl ether providing trans nitrile
64 in 90% yield from 61, presumably through an elimination of
the sulfonate to regenerate imine 62, followed by addition of the
nitrile group from the opposite face of the dimethylcyclopropyl
group. Nitrile 64 was reacted under Pinner conditions (HCl, MeOH) to give ester salt 56 in 56% overall yield with greater than 99% ee
after recrystallization from MTBE.
Although several preparations of cyclobutyl amides 57 have
been disclosed, the process scale preparation is described
in the scheme. Benzophenone-derived imine 65 was alkylated
with bromomethylcyclobutane in the presence of base to give
the alkylated intermediate, which was immediately treated
in situ with HCl to furnish aminoester 66. This aminoester was
then protected as the Boc-carbamate 67 prior to reduction of the
ester to provide the corresponding alcohol 68 after crystallization
from heptane in 43% overall yield. This alcohol was then oxidized
with TEMPO, sodium bromide and sodium hypochlorite in DCM
at 5 to 0C to give aldehyde 69 in 91% yield. After exchanging solvents,
aldehyde 69 was treated with acetone cyanohydrin at room
temperature to provide intermediate 70 which, after treatment with potassium carbonate to wash off excess cyanohydrin, was
hydrolyzed with hydrogen peroxide at 40C to give 90% of amide
71. Hydroxyl amide 71 was deprotected under acidic conditions
to give the hydrochloride salt 73. Alcohol 71 was also oxidized
using EDCI, DMSO and dichloroacetic acid in ethyl acetate to afford
the keto amide 72 in 70% yield. Subsequent treatment with HCl in
isopropyl alcohol provided salt 57 in 91% yield.
With all four key fragments in hand, the final target was rapidly
assembled in a convergent manner as described in the scheme. Carboxylic acid fragment 55 was first coupled to azbicyclo[
3.2.1]cyclohexane amine ester salt 56 using EDCI as the coupling
reagent under basic conditions to give amide 74. Hydrolysis
of the methyl ester with lithium hydroxide followed by salt formation
gave rise to carboxylate salt 75 in 90% overall yield. Under
acidic conditions, salt 75 was coupled directly with cyclobutyl keto amide salt 57 in the presence of EDCI, HOBt and N-methylmorpholine
in acetonitrile to give, after acidic and basic work-ups, boceprevir
(VII) in 85¨C90% yield. Alternatively, salt 75 could be
coupled with the cyclobutyl alcohol amide salt 73 using EDCI,
HOBt and diisopropylethyamine (DIPEA) to give alcohol 76 in
90% yield after acid and base work-ups and crystallization. Oxidation
of alcohol intermediate 76 with TEMPO and NaOCl in the presence
of KBr also furnished boceprevir (VII) in 93% yield.
