A practical, enantioselective synthesis of cis-2,5-disubstituted pyrrolidine is described. Application of an enzymatic DKR reduction of a keto ester, which is easily accessed through a novel intramolecular N→C benzoyl migration, yields syn-1,2-amino alcohol in >99% ee and >99:1 dr. Subsequent hydrogenation of cyclic imine affords the cis-pyrrolidine in high diastereoselectivity. By integrating biotechnology into organic synthesis and isolating only three intermediates over 11 steps, the core scaffold of β3-AR agonists is synthesized in 38% overall yield.
A practical asymmetric synthesis of the estrogen receptor beta selective agonist (7β-9aβ)-1,4-dichloro-2-hydroxygibba-1(10a),2,4,4b-tetraen-6-one (1), proceeding by way of six isolated intermediates and without recourse to chromatography, is described. Highlights of the process route developed are two chemoselective chlorinations, a lithiated hydrazone alkylation and an asymmetric Michael addition of indanone 11 to methyl vinyl ketone (using 15 mol % of cinchonine-derived catalyst 20g) to set the all-carbon quaternary asymmetric stereocenter. The challenges addressed in scaling the latter heterogeneous biphasic phase transfer reaction to 44 mol (14 kg) scale are discussed in detail. Overall, the chemistry developed has been used to prepare >6 kg of drug candidate 1 in 18% overall yield and with >99% ee.
The development of
a scalable asymmetric route to a new calcitonin
gene-related peptide (CGRP) receptor antagonist is described. The
synthesis of the two key fragments was redefined, and the intermediates
were accessed through novel chemistry. Chiral lactam 2 was prepared by an enzyme mediated dynamic kinetic transamination
which simultaneously set two stereocenters. Enzyme evolution resulted
in an optimized transaminase providing the desired configuration in
>60:1 syn/anti. The final chiral
center was set via a crystallization induced diastereomeric transformation.
The asymmetric spirocyclization to form the second fragment, chiral
spiro acid intermediate 3, was catalyzed by a novel doubly
quaternized phase transfer catalyst and provided optically pure material
on isolation. With the two fragments in hand, development of their
final union by amide bond formation and subsequent direct isolation
is described. The described chemistry has been used to deliver over
100 kg of our desired target, ubrogepant.
The development of a practical synthesis of the hepatitis C virus polymerase inhibitor 1 was necessary to support preclinical safety and human clinical studies. Significant challenges face the process chemist in developing a route to 1 that is amenable to multikilogram operation. In particular, an efficient construction of the eight-membered dihydroindolobenzoxazocine ring and enantioselective synthesis of the secondary amine stereocenter are required. This article describes our process development of a Mitsunobu protocol to achieve the latter goal which uses diphenylphosphoryl azide at ambient temperature to invert a scalemic secondary alcohol. The hazard evaluation performed to establish the safety of this protocol and allow pilot-plant introduction at >8.0 kg scale is discussed. Overall, an enantioselective synthesis of 1 by way of seven isolated intermediates in 32% overall yield was developed from commercially available materials. This allowed us to prepare over 3 kg of the targeted drug candidate.
Two new routes to
a pyrimidyl tetrazole intermediate are described.
The first-generation route featured an iron-catalyzed cross-coupling
between 4-butenylmagnesium bromide and a 4-chloropyrimidine derivative
to afford an alkene-bearing pyrimidine intermediate. A subsequent
intramolecular Heck cyclization afforded the desired bicyclic core,
which was subsequently converted to the corresponding carboxylic acid
via hydroboration and oxidation. This route was rapidly defined and
used to prepare the initial 0.3 kg of the pyrimidyl tetrazole intermediate,
which supported early toxicology and clinical studies of a drug candidate.
A second-generation, eight-step route to the pyrimidyl tetrazole intermediate
was defined and demonstrated on multikilogram scale in a 21% overall
yield. The key transformation in this sequence was a copper(I) mediated
cyclization of an iodopyrimidine, affording the bicyclic core of the
target in quantitative yield. Due to the larger scale involved for
the second-generation approach, significant process safety evaluation
was undertaken for a number of steps in this route, and the highlights
of these studies are presented.
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