Increasing global access to the high-volume HIV drug nevirapine through process intensification

Article abstract of DOI:10.1039/c7gc00937b

Access to affordable medications continues to be one of the most pressing issues for the treatment of disease in developing countries. For many drugs, synthesis of the active pharmaceutical ingredient (API) represents the most financially important and technically demanding element of pharmaceutical operations. Furthermore, the environmental impact of API processing has been well documented and is an area of continuing interest in green chemical operations. To improve drug access and affordability, we have developed a series of core principles that can be applied to a specific API, yielding dramatic improvements in chemical efficiency. We applied these principles to nevirapine, the first non-nucleoside reverse transcriptase inhibitor used in the treatment of HIV. The resulting ultra-efficient (91% isolated yield) and highly-consolidated (4 unit operations) route has been successfully developed and implemented through partnerships with philanthropic entities, increasing access to this essential medication. We anticipate an even broader global health impact when applying this model to other active ingredients.

Full text of DOI:10.1039/c7gc00937b

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DOI: 10.1039/C7GC00937B
Green Chemistry
Paper
Increasing Global Access to the High-Volume HIV Drug Nevirapine
through Process Intensification
a†
a†
a
a
a
b
Jenson Verghese , Caleb J. Kong , Daniel Rivalti , Eric C. Yu , Rudy Krack , Jesus Alcázar , Julie B.
Received 00th January 20xx,
Accepted 00th January 20xx
c
d
a
a
a
Manley , D. Tyler McQuade , Saeed Ahmad *, Katherine Belecki *, and B. Frank Gupton *
DOI: 10.1039/x0xx00000x
Access to affordable medications continues to be one of the most pressing issues for the treatment of disease in developing
countries. For many drugs, synthesis of the active pharmaceutical ingredient (API) represents the most financially important
and technically demanding element of pharmaceutical operations. Furthermore, the environmental impact of API
processing has been well documented and is an area of continuing interest in green chemical operations. To improve drug
access and affordability, we have developed a series of core principles that can be applied to a specific API, yielding dramatic
improvements in chemical efficiency. We applied these principles to nevirapine, the first non-nucleoside reverse
transcriptase inhibitor used in the treatment of HIV. The resulting ultra-efficient (91% isolated yield) and highly-consolidated
www.rsc.org/
(4 unit operations) route has been successfully developed and implemented through partnerships with philanthropic
entities, increasing access to this essential medication. We anticipate an even broader global health impact when applying
this model to other active ingredients.
platforms can yield significant improvements to API production
3
Introduction
Synthetic processes for active pharmaceutical ingredients
costs and efficiency. Based on these observations, we have
established a set of core principles for API process
development, which are derived from fundamental elements of
process intensification that are commonly known but often
neglected. These principles include (a) implementation of
innovative chemical methodologies and new manufacturing
platforms, (b) consolidation of high-yielding reactions into a
minimal number of unit operations with common solvents and
limited intermediate isolations, and (c) vertical integration of
advanced starting materials prepared from commodity
(
APIs) often evolve directly from medicinal chemistry routes
that are designed to access a variety of structural analogs, with
limited regard for commercial consideration. In many cases,
1
early routes can help define the final process for a drug in order
to expedite commercial implementation. However, legacy API
processes are also frequently carried forward into the product
lifecycle post-patent expiration, impacting the cost structure of
many generic and global health drugs. In both cases, the Small
Molecule API cost represents 65 to 75% of the total drug
product cost. As a result, these sub-optimal synthetic routes
can have a major impact on affordability and subsequent access
to medicines. In the case of the global healthcare supply, the
resulting high cost often necessitates that API purchases be
underwritten by philanthropic organizations in order to
increase patient access.
1c, 2
We and others have demonstrated that new approaches
using state-of-the-art chemical methods and novel reactor
a.Department of Chemistry and Department of Chemical and Life Science
Engineering, Virginia Commonwealth University, 601 W. Main St. Richmond, VA
2
3220 USA, Email: sahmad@vcu.edu, kbelecki@vcu.edu, bfgupton@vcu.edu
b.
Neuroscience Medicinal Chemistry, Janssen Research and Development, Jarama
7
5A, 45007 Toledo, Spain
c.
Guiding Green LLC, 457 E. Mier Rd. Sanford. MI 48657 USA
Florida State University, Department of Chemistry and Biochemistry, 95 Chieftan
Way, Tallahassee, FL 32306, USA, Present address: Defense Sciences Office,
Defense Advanced Research Projects Agency (DARPA), 675 North Randolph
Street, Arlington, VA 22203, United States
d.
†
Authors contributed equally to this article
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Green Chemistry
chemicals. Assessment of cost drivers guides the initial infected patients and is a high volume component of HIV
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4
DOI: 10.1039/C7GC00937B
development plan for a target molecule. Sub-optimal portions combination drug therapies. Two commercial processes have
of the existing route are identified and alternative reaction been reported by Boehringer Ingelheim (B.I.), both of which
conditions are developed that are both high yielding and construct the central diazapine ring system from two multi-
chemically compatible with the overall synthetic sequence. This functional pyridines, 2-chloro-3-amino-4-picoline (CAPIC,
2
) and
approach allows for process consolidation to reduce a nicotinic acid derivative, either
3
or
4
(Fig. 1), as the registered
5
intermediate isolations.
starting materials. These processes provide moderate yields,
Incorporation of commodity chemicals often has the but require multiple synthetic steps, solvent exchanges, and
greatest impact when applied to the vertical integration of intermediate isolations that add to process complexity and
registered starting materials that tend to be complex and highly waste generation. In order to iteratively score and identify
functionalized, and thus represent a major expense. The cost process improvement opportunities, routes are not only
driver analysis during our initial evaluation highlights those API evaluated by yield and unit operations, but also by chemical
precursors of greatest impact, and significant effort is then efficiency using Process Mass Intensity (PMI, total mass of all
placed on the use of commodity chemicals to prepare these materials used in the process to produce 1 kg of product), a
compounds using our process principles. Cost drivers are metric that has been widely accepted by the pharmaceutical
6
further intensified as the potential increase in process industry. With emphasis placed on value and efficiency rather
complexity resulting from additional transformations is offset than quantifying waste, PMI has been used to motivate and
by telescoping reaction steps.
evaluate process improvements of various pharmaceuticals and
7
For our initial application of these core principles we pharmaceutically-relevant building blocks. In our case, PMI is
selected nevirapine (
, as our target. Nevirapine is the first non-nucleoside reverse generated by telescoping reactions in a common solvent
transcriptase inhibitor approved for the treatment of HIV- system.
1), a widely-prescribed treatment for HIV- an especially appropriate metric, as it emphasizes the value
1
Fig. 1. Prior commercial nevirapine process routes. Conditions: i. SOCl
diglyme vii. NaH, diglyme. 2-CNA = 2-chloronicotinic acid, 2-CAN = 2-(cyclopropylamino)nicotinic acid, CYCLOR = N-(2-chloro-4-methylpyridin-3-yl)-2-
cyclopropylamino)nicotinamide
2 2
, PhMe ii. cyclopropylamine (CPA), diglyme iii. NaH, diglyme iv. dimethyl formamide v. SOCl vi.
(
2
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Green Chemistry
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DOI: 10.1039/C7GC00937B
Fig. 2. Our optimized nevirapine process and comparative metrics. Conditions: i. NaH, diglyme 65 °C ii. NaH, diglyme 115 °C. MeCAN = methyl 2-
(
cyclopropylamino)nicotinate
We now report a scalable, streamlined process route to
nevirapine that results directly from the application of our core
principles. This improved route, which uses CAPIC ( ) and
methyl 2-(cyclopropylamino)nicotinate (MeCAN, ) as starting
2
5
materials for the registered portion of the synthesis, is marked
by use of high atom-economy transformations and a high-
throughput design that minimizes waste generation and
maximizes product yield (Fig. 2). Furthermore, the ability to
achieve high yields in each individual reaction allowed us to
directly recycle a major portion of the solvent distillate, which
was not possible with the previous commercial routes due to
by-product impurities resulting from low-yielding reaction
steps. Moreover, this new process has been applied in both
batch and continuous synthesis regimes. Overall, the impact of
these process improvements on yield, unit operations, and
waste generation are profound (Fig. 2). The most noteworthy
improvement was observed in the product yield of 91%,
compared to 1st and 2nd generation process yields of 59% and
6
3%, respectively. This parameter is particularly important
because it directly impacts the other two metrics and
represents a major underpinning of our core process
intensification principles.
Results and Discussion
Our route to nevirapine (Fig. 2) relies on a new strategy for
construction of the 7-membered central lactam ring. By using
in place of the free carboxylate , amide bond formation with
could be telescoped with the final S Ar conversion to produce
5
2
1
4
N
in a streamlined, one-pot process. Accordingly, we additionally
decreased the PMI associated with the preparation of
by starting from commodity raw materials.
2
and
5
Scheme 1. Optimized routes towards 5 and 2. CYCIC = 2-chloro-4-
methylnicotinonitrile, COMAD
= 2-chloro-4-methylnicotinamide, IPA =
isopropyl alcohol, Ac2O = acetic anhydride, DMF-DMS = dimethylformamide
dimethylsulfate
Our efficient synthesis of MeCAN included process
improvements for the preparation of (Scheme 1a). Using only
4
Techno-economic projections indicated that CAPIC (2)
one equivalent of cyclopropylamine, we achieved 98%
conversion by pressurizing the reaction vessel to 10 psi with
nitrogen. Moreover, we identified conditions for the sequential
comprises 64% of the production cost of the nevirapine API. We
previously reported a novel approach to build from the
commodity-based raw materials acetone ( ) and malononitrile
(10) . While our previously reported route was a significant
2
9
one-pot amination and nitrile hydrolysis, furnishing
4
in higher
yields (91% vs 70% for the B.I. process). Esterification of with
thionyl chloride in methanol afforded in 95% yield, resulting
in an overall yield of 86 %, a PMI of 12, and a total number of 8
unit operations from to MeCAN ( ).
3e, 8
5
d
4
advance, we found additional improvements including
reduction of waste by maximizing reaction concentrations and
optimizing relative reagent input (Scheme 1b). We iteratively
5
8
5
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Green Chemistry
re-evaluated cost drivers for new opportunities and found that synthesis, these reactions typically possess poor atom
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1
0
DOI: 10.1039/C7GC00937B
dimethyl formamide-dimethyl acetal (DMF-DMA) became the
economy. Recent reports of lithium hexamethyldisilazide
HMDS) facilitating amide bond formation between anilines and
(
11
esters inspired our efforts to form intermediate
from and . As an improvement over the B.I. processes, this
strategy presented an opportunity to telescope the reaction
sequence, converting to nevirapine without isolation. Indeed,
sodium HMDS-mediated amide formation provided high
conversions of (Table 1, entry 1).
We then evaluated sodium hydride as a cost- and atom-
economical alternative to achieve 95% conversion to using 1.7
7 directly
Table 1. Optimization of the batch process for 1.
2
5
7
7
7
equivalents of sodium hydride. (Table 1, entry 2). Moreover,
upon treatment with additional base at an elevated
temperature,
, entry 3). After optimization (Table 1, entries 3-6), near-
quantitative conversion to was achieved, affording an isolated
yield of 91% for the overall process. This streamlined synthesis
not only improved the overall yield, but also cut the number of
7 could be converted to 1 without isolation (Table
1
Conversion[a]
1
Base
[equiv]
Step A
Base
[equiv]
Step B
5
Entry
Base
[
equiv]
to 7
95
95
94
99
99
99
to 1
unit operations in half and reduced the PMI dramatically from
1
2
3
4
5
6
1.0
1.05
1.05
1.0
NaHMDS
NaH
1.7
1.7
2.0
2.0
1.8
1.8
-
-
nd
4
6 (2 generation B.I. process) to 11 (our process, Fig. 2).
-
-
70
Solvent losses to waste typically represent one of the largest
contributors to high PMI values in API processes, and solvent
recycling was prohibitive in both B.I. processes due to elevated
impurity levels in the reaction mixtures. However, the yield
improvements realized from the new process provided the
additional benefit and opportunity to recover and recycle 80%
of the diglyme solvent, which is reflected in our PMI. Nevirapine
produced by this method exceeded the purity of prior
processes.
NaH
1.0
2.0
1.8
1.7
NaH
97
1.05
1.05
NaH
97
NaH
97 (91[b]
)
[
a] Conversions determined by HPLC. [b] Yield (wt%) of isolated product.
Having established a highly-consolidated batch process for
, nevirapine became an ideal candidate for a continuous
most expensive reagent in our improved route, leading to the
replacement of DMF-DMA with dimethyl formamide-dimethyl
sulfate (14) as a surrogate formylating agent. This air-stable
reagent was formed quantitatively from commodity chemicals
and was introduced directly into our process with equivalent
performance. With these improvements, we were able to
increase the isolated yield of 12 to 85% over three telescoped
1
9
manufacturing platform. While API manufacturing relies
predominantly on batch reactor technology, continuous
manufacturing of APIs has recently seen a surge of interest.
Continuous chemical operations not only provide exceptional
control of critical reaction parameters and minimize process
12
safety hazards but also provide access to short-lived
intermediates , minimize by-product and waste formation, and
steps, providing CAPIC (
acetone.
2) in an overall yield of 80% from
6
b, 12b, 12c, 13
increase overall productivity.
With optimized processes for the key nevirapine starting
materials in hand, we applied our core principles to the
preparation of the nevirapine API. While amide bond formation
is one of the most important chemical transformations in drug
For the continuous preparation of nevirapine, we
envisioned a system that would be capable of safely handling
14
solid sodium hydride as well as the off-gassing of hydrogen
required to drive both reactions to completion. Thus, a
Scheme 2. Continuous process for 1.
4
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Green Chemistry
Paper
continuous, thin-film reactor was used as sodium hydride (2M
suspension) and (3M solution) were delivered to the reactor
simultaneously and the resulting salt was fed into a continuous
stirred tank reactor containing , affording conversion to
Scheme 2). This intermediate was directed to a packed bed
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2
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(
manufacturing
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for
essential
medicines,
reactor of sodium hydride to affect the diazepine ring formation
with high conversion as the packed bed system provided
7
excellent
stoichiometric
leverage,
maximizing
the
15
instantaneous solid-solution phase concentrations.
2
of the continuous process, our group has elected to adopt the
measure of Volume-Time Output (VTO). Briefly, VTO measures
throughput in the context of reactor space and is an excellent
indicator of the intrinsic economy of a particular manufacturing
platform. The overall continuous process provided excellent
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throughput with a volume-time output (VTO) of 7.01 x 10 m
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1
manufacturing processes strive to reach a VTO of <1.1b
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Conclusions
Integrating principles derived from the basic tenets of process
intensification, we have demonstrated a process development
model that has been successfully applied to the preparation of
nevirapine and its starting materials. We streamlined routes to
both API starting materials by pinpointing conditions that
minimize unit operations while incorporating commodity
chemicals as raw materials into the consolidated process. In
doing so, we were able to increase the isolated yield of
nevirapine from 63% to 91% while reducing the PMI value for
the process from 46 to 11. The details of this streamlined
nevirapine batch process were transferred to the Clinton Health
Access Initiative (CHAI) and rapidly adopted by their supply
chain network. CHAI estimates that implementation of our
optimized process will result in a minimum of 30% savings in
nevirapine cost of goods.
1
263.
5
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Boswell and B. Gupton, Y. Lo, US Patent 5569760, 2004.
. (a) C. Jimenez-Gonzalez, C. S. Ponder, Q. B. Broxterman and J. B.
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6
Furthermore, we successfully transitioned our streamlined
synthesis into a continuous process, demonstrating high
conversions and throughput in a consolidated reactor space
3
3
-1
(
7.01 x 10-
m hr kg ). We anticipate that this process 7. (a) F. Gallou, M. Seeger-Weibel and P. Chassagne, Org. Process
intensification model will serve as a template for the
optimization of other drugs that support the global healthcare
network, providing the greatest impact in areas where access to
essential medications is limited.
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Baloglu, D. Bauer, A. Becker, N. Chaudhuri, G. M. Latham, J. Li, S.
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(
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1
Acknowledgements
7
We are grateful for the support and partnership of the Bill and
Melinda Gates Foundation (OPP1108573) and the Clinton Health
Shukla, J. P. Adams and G. Sandford, Green Chem., 2016, 18,
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Access Initiative. We would also like to thank Dr. Tom Roper and 8. (a) A. R. Longstreet, B. S. Campbell, B. F. Gupton and D. T.
Dr. Frank Roschangar for their critical readings of the manuscript.
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