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
Continuous Platform To Generate Nitroalkanes On-Demand (in Situ) Using Peracetic Acid-Mediated Oxidation in a PFA Pipes-in-Series Reactor
The synthetic utility
of the aza-Henry reaction can be diminished
on scale by potential hazards associated with the use of peracid to
prepare nitroalkane substrates and the nitroalkanes themselves. In
response, a continuous and scalable chemistry platform to prepare
aliphatic nitroalkanes on-demand using the oxidation of oximes with
peracetic acid and direct reaction of the nitroalkane intermediate
in an aza-Henry reaction is reported. A uniquely designed pipes-in-series
plug-flow tube reactor addresses a range of process challenges, including
stability and safe handling of peroxides and nitroalkanes. The subsequent
continuous extraction generates a solution of purified nitroalkane,
which can be directly used in the following enantioselective aza-Henry
chemistry to furnish valuable chiral diamine precursors with high
selectivity, thus completely avoiding isolation of the potentially
unsafe low-molecular-weight nitroalkane intermediate. A continuous
campaign (16 h) established that these conditions were effective in
processing 100 g of the oxime and furnishing 1.4 L of nitroalkane
solution
Development of an Intermittent-Flow Enantioselective Aza-Henry Reaction Using an Arylnitromethane and Homogeneous Brønsted Acid–Base Catalyst with Recycle
A stereoselective aza-Henry reaction
between an arylnitromethane
and Boc-protected aryl aldimine using a homogeneous Brønsted
acid–base catalyst was translated from batch format to an automated
intermittent-flow process. This work demonstrates the advantages of
a novel intermittent-flow setup with product crystallization and slow
reagent addition which is not amenable to the standard continuous
equipment: plug flow tube reactor (PFR) or continuous stirred tank
reactor (CSTR). A significant benefit of this strategy was the integration
of an organocatalytic enantioselective reaction with straightforward
product separation, including recycle of the catalyst, resulting in
increased intensity of the process by maintaining high catalyst concentration
in the reactor. A continuous campaign confirmed that these conditions
could effectively provide high throughput of material using an automated
system while maintaining high selectivity, thereby addressing nitroalkane
safety and minimizing catalyst usage
Route Design and Development of a MET Kinase Inhibitor: A Copper-Catalyzed Preparation of an <i>N</i>1<i>-</i>Methylindazole
The synthesis of
a MET kinase inhibitor in an overall yield of
22% was achieved over eight steps starting with 3-hydroxybenzaldehyde,
an improvement from the initial 12-step process with a 5.4% yield.
Highlights of the process chemistry design and development are a Cu-catalyzed
cyclization to form an important <i>N</i>1-methylindazole
ring, a selective nitro reduction in the presence of an aryl bromide,
a late-stage Suzuki cross-coupling, and a base-promoted Boc deprotection
to form the desired drug candidate