4 research outputs found
Development of a Continuous Schotten–Baumann Route to an Acyl Sulfonamide
The development and scale-up of a synthetic route to
tasisulam
sodium (5-bromo-thiophene-2-sulfonic acid 2,4-dichlorobenzoylamide
sodium salt, hereafter referred to as tasisulam) utilizing continuous
Schotten–Baumann reaction conditions is disclosed. A new synthetic
route for the cytotoxic API amenable to continuous processing was
envisioned that would minimize potential worker exposure by reducing
the number of unit operations and would allow commercial-scale API
production in laboratory fume hoods with inexpensive glassware. The
developed Schotten–Baumann conditions contained fewer unit
operations than the existing batch process by utilizing the direct
formation of the final sodium salt from a sulfonamide and acid chloride
without isolation of the free acyl sulfonamide. Batch development,
continuous proof of concept studies, 5.2 g/h lab-scale demonstration
and 5 kg/day commercial-scale runs will be discussed. Very stringent
release specifications were in place for the tasisulam API batch process,
and the challenges of meeting these requirements for the continuous
process are detailed. Finally, the quality of material generated during
startup and shutdown transitions will be addressed
How to Convert a Walk-in Hood into a Manufacturing Facility: Demonstration of a Continuous, High-Temperature Cyclization to Process Solids in Flow
An intramolecular thermal cyclization
protocol was developed in
a flow reactor to take advantage of the high pressures and temperatures
that are easily obtained in small scale autoclave reactors that have
been modified to handle slurries. This reactor was equipped with a
fill/empty pumping system to enable easy and nearly complete transfer
of slurries. The reaction conditions were designed to take advantage
of the insolubility of the product in order to separate it from residual
starting material by filtration after short reaction times. Recycling
of the filtrate maximized the yield and throughput while minimizing
decomposition. Recycles were accomplished using a strip to dryness
protocol that was easily performed in a rotary evaporator. This new
equipment set was designed with lab-hood manufacturing in mind, a
minimized footprint, and the system was completely automated for charging,
emptying, rinsing, and reacting. Additional efforts for quick screening
and alternate modes of addition were also investigated
Mechanistic Study of Diketopiperazine Formation during Solid-Phase Peptide Synthesis of Tirzepatide
This study focused on investigating diketopiperazine
(DKP) and
the formation of associated double-amino-acid deletion impurities
during linear solid-phase peptide synthesis (SPPS) of tirzepatide
(TZP). We identified that the DKP formation primarily occurred during
the Fmoc-deprotection reaction and post-coupling aging of the unstable
Fmoc-Pro-Pro-Ser-resin active pharmaceutical ingredient (API) intermediate.
Similar phenomena have also been observed for other TZP active pharmaceutical
ingredient (API) intermediates that contain a penultimate proline
amino acid, such as Fmoc-Ala-Pro-Pro-Pro-Ser-resin, Fmoc-Pro-Pro-Pro-Ser-resin,
and Fmoc-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-resin, which are
intermediates for both hybrid and linear synthesis approaches. During
post-coupling aging, it is found that Fmoc deprotection can proceed
in dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), and acetonitrile (ACN) solvents without
any piperidine addition. Density functional theory (DFT) calculations
showed that a peptide that has a penultimate proline stabilizes the
transition state through the C–H···π interaction
during Fmoc decomposition, which causes those peptides to be more
prone to cascade-deprotection reactions. Pseudo-reaction pathways
are then proposed, and a corresponding macrokinetics model is developed
to allow accurate prediction of the TZP peptide intermediate self-deprotection
and DKP formation rate. Based on those studies, control strategies
for minimizing DKP formation were further investigated and an alternative
to Fmoc protection was identified (Bsmoc-protected amino acids), which
eliminated the formation of the DKP byproducts. In addition, the use
of oxyma additives and lower storage temperature was demonstrated
to markedly improve the peptide intermediate stability to DKP degradation
pathways
Development and Manufacturing GMP Scale-Up of a Continuous Ir-Catalyzed Homogeneous Reductive Amination Reaction
The design, development,
and scale up of a continuous iridium-catalyzed
homogeneous high pressure reductive amination reaction to produce <b>6</b>, the penultimate intermediate in Lilly’s CETP inhibitor
evacetrapib, is described. The scope of this report involves initial
batch chemistry screening at milligram scale through the development
process leading to full-scale production in manufacturing under GMP
conditions. Key aspects in this process include a description of drivers
for developing a continuous process over existing well-defined batch
approaches, manufacturing setup, and approaches toward key quality
and regulatory questions such as batch definition, the use of process
analytics, start up and shutdown waste, “in control”
versus “at steady state”, lot genealogy and deviation
boundaries, fluctuations, and diverting. The fully developed continuous
reaction operated for 24 days during a primary stability campaign
and produced over 2 MT of the penultimate intermediate in 95% yield
after batch workup, crystallization, and isolation