11 research outputs found
Studies toward the Total Synthesis of Parvifolals A/B: An Intramolecular oâQuinone Methide [4 + 2]-Cycloaddition To Construct the Central Tetracyclic Core
Total Synthesis of (±)-Allocolchicine and Its Analogues Using Co-Catalyzed Alkyne [2 + 2 + 2]-Cyclotrimerization
The total synthesis
of (±)-allocolchicine has been completed
by employing cobalt-catalyzed alkyne [2 + 2 + 2]-cyclotrimerization
as the key reaction. The essential diyne has been synthesized from
easily available 3,4,5-trimethoxybenzaldehyde following simple chemical
transformations. In general, the cycloaddition gave a mixture of C(9)
and C(10) isomers thus allowing the synthesis of both allocolchicine
and its C(10)-carboxylate. Because this cycloaddition was employed
at the penultimate stage, it allowed the synthesis of various analogues
having the diverse functionality at C(9) and/or C(10) of ring C
Ruthenium(II)-Catalyzed C3 Arylation of 2âAroylbenzofurans with Arylboronic Acids/Aryltrifluoroborates via Carbonyl-Directed CâH Bond Activation
The
RuÂ(II)-catalyzed carbonyl-directed CâH activation with
(hetero)Âarylboron reagents has been executed for the synthesis of
2-aroyl-3-(hetero)Âarylbenzofurans. A hypothesis founded upon the involvement
of an active carbonatorutheniumÂ(II) complex for a coordinative insertion
and the aerobic oxidation of the <i>in situ</i> generated
Ru(0) to RuÂ(II), to continue the catalytic cycle, has been extended
Toward a Practical, Two-Step Process for Molnupiravir from Cytidine
A two-step synthesis of molnupiravir (1) is presented. This work focuses on the development of
practical reaction and purification conditions toward a manufacturing
route. The sequence commences from
highly available cytidine (2), and
molnupiravir is formed through direct hydroxamination of the cytosine ring and
esterification of the sugarâs primary alcohol without use of protecting or
activating groups. A highly crystalline
hydrate of N-hydroxycytidine (3) resulted in an easily purified
intermediate, and a practical, off-the-shelf enzyme was selected for the
acylation. The yield was increased
through a chemically-promoted, selective ester cleavage which converted a by-product,
molnupiravir isobutyryl oxime ester (4),
into the final API. Both reactions
proceed in >90% assay yield and crystallization procedures are used to
afford intermediate and active pharmaceutical ingredient in purities above 99%
with an overall yield of 60%. Excellent
throughput and sustainability is achieved by limiting the total concentration
to 7 volumes of solvent in the course of the two reactions with an overall PMI
of 41 including work-up and isolation. Environmentally
friendly solvents, water and 2-methyl tetrahydrofuran, enhance sustainability
of the operation. </p
Toward Secure Supply of Remdesivir via a 2-Pot Triazine Synthesis: Supply Centered Synthesis
Pyrrolotriazine 1
is an important precursor to Remdesivir, and an efficient synthesis is disclosed. This
route features atom economy and reduced derivatization of starting materials,
by making use of highly abundant, commoditized raw material inputs. The yield of triazine was doubled from 31% to
59%, and the synthetic step count was reduced from 4 to 2. A one-pot cascade sequence was developed for
direct cyanation of pyrrole. Amination
and cyclization with formamidine acetate complete the synthesis. The
problematic nature of typically dilute electrophilic aminations was solved with
semi-continuous processing. Moreover,
development of a continuous platform afforded access to the ideal yet
non-commercial aminating reagent, monochloramine. These efforts help to secure the Remdesivir
supply chain
A Concise Route to MK-4482 (EIDD-2801)
A two-step route to MK-4482 (EIDD-2801, 1) was developed consisting of an
esterification and hydroxamination of cytidine.
The reactions can be conducted in either order with overall yields of
67% (first stepâesterification) and 37% (first stepâhydroxamination). Selective
esterification of the nucleosideâs primary alcohol by enzymatic means
eliminated the need for diol protection/deprotection, and direct transamination
with hydroxylamine precluded the necessity of activating the nucleobase for
amine coupling. This results in a significant
advancement over the reported synthesis which is formed in at best 17%
yield. The step count is reduced from
five transformation to two, and the more expensive uridine is replaced with the
more available cytidine
A concise route to MK-4482 (EIDD-2801) from cytidine
© The Royal Society of Chemistry. A two-step route to MK-4482 (EIDD-2801, 1) was developed consisting of an esterification and hydroxamination of cytidine. The selective acylation and direct amination eliminate the need for protecting and activating groups and proceed in overall yield of 75%, a significant advancement over the reported yield of 17%. The step count is reduced from five transformations to two, and expensive uridine is replaced with the more available cytidine. This journal i
An Efficient Synthesis of Tenofovir (PMPA): A Key Intermediate Leading to Tenofovir-Based HIV Medicines
Abstract: Herein, we report further
improvements to the synthesis of tenofovir 1,
the precursor to tenofovir disoproxil fumarate and tenofovir alafenamide
fumarate. Starting from acyclic precursor
diaminomalononitrile 12, a four-step
protocol to tenofovir 1 will allow
for vertical integration for more manufacturers. The key transformation is a more convergent
one step procedure from 6 as
compared to the current commercial process, with an improved yield from 59% (two
steps) to 70%. Further improvements
include eliminating the need for problematic magnesium tert-butoxide (MTB) and significant solvent reduction by
eliminating the need for an intermediate workup. With the costs of HIV/AIDS
treatments remaining a barrier for those most in need, lowering the raw
material/processing costs and increasing the security of supply can increase
patient access.</p
Adagrasibâs Second-Generation Synthesis: Transitioning from Route Scouting to Optimization
Process optimization details are disclosed following
the completion
of process design for a second-generation manufacturing route of adagrasib.
Key objectives for development included control of difficult-to-purge
impurities in the key starting materials (KSMs), enhanced scalability
of the KSM, improved pyrimidone formation of the core, increased robustness
of oxidation, enhanced stability of the step 3 intermediate, removal
of the halogenated solvent in the fourth step, and implementation
of single crystallization of the final API. These improvements led
to more efficient production of adagrasib and a further reduction
in the cost of goods by approximately 50%