Investigating the continuous synthesis of a nicotinonitrile precursor to nevirapine

Article abstract of DOI:10.3762/bjoc.9.292

2-Chloro-3-amino-4-picoline (CAPIC) is a strategic building block for the preparation of nevirapine, a widely-prescribed nonnucleosidic reverse transcriptase inhibitor for the treatment of HIV-infected patients. A continuous synthesis to the bromo derivative of a CAPIC intermediate, 2-bromo-4- methylnicotinonitrile, that terminates in a dead-end crystallization is described. The route uses inexpensive, acyclic commodity-based raw materials and has the potential to enable lower cost production of nevirapine as well as other value added structures that contain complex pyridines. The route terminates in a batch crystallization yielding high purity CAPIC. This outcome is expected to facilitate regulatory implementation of the overall process.

Full text of DOI:10.3762/bjoc.9.292

Investigating the continuous synthesis of a
nicotinonitrile precursor to nevirapine
Ashley R. Longstreet1, Suzanne M. Opalka1, Brian S. Campbell1,
B. Frank Gupton2 and D. Tyler McQuade*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2570–2578.
1Department of Chemistry and Biochemistry, Florida State University,
95 Chieftan Way, Tallahassee, FL 32306, United States and
2Department of Chemistry, Virginia Commonwealth University, 1001
West Main Street, P.O. Box 842006 Richmond, Virginia 23284, United
States
doi:10.3762/bjoc.9.292
Received: 14 July 2013
Accepted: 14 October 2013
Published: 20 November 2013
Email:
This article is part of the Thematic Series "Chemistry in flow systems III".
Guest Editor: A. Kirschning
D. Tyler McQuade* - mcquade@chem.fsu.edu
* Corresponding author
© 2013 Longstreet et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
continuous; flow chemistry; HIV; Knoevenagel; nevirapine;
nicotinonitriles
Abstract
2-Chloro-3-amino-4-picoline (CAPIC) is a strategic building block for the preparation of nevirapine, a widely-prescribed non-
nucleosidic reverse transcriptase inhibitor for the treatment of HIV-infected patients. A continuous synthesis to the bromo deriva-
tive of a CAPIC intermediate, 2-bromo-4-methylnicotinonitrile, that terminates in a dead-end crystallization is described. The route
uses inexpensive, acyclic commodity-based raw materials and has the potential to enable lower cost production of nevirapine as
well as other value added structures that contain complex pyridines. The route terminates in a batch crystallization yielding high
purity CAPIC. This outcome is expected to facilitate regulatory implementation of the overall process.
Introduction
Nevirapine (3) was the first commercially available non-nucleo- viable NNRT substitutes for nevirapine are available, nevi-
side reverse transcriptase inhibitor (NNRTI), and has remained rapine manufacturing requirements will remain high because
an important medicine in the management of human immunode- clinicians are reluctant to change treatment once a successful
ficiency virus (HIV) [1,2]. Nevirapine combined with lamivu- combination therapy is identified and many remain healthy with
dine (3TC) and azidothymidine (AZT) or tenofovir (TDF) is the nevirapine based combinations. Furthermore, the recent
one of the preferred first-line combination drug therapies development of an extended release dosage form of nevirapine
recommended by the World Health Organization (WHO) [3-5]. that enables once a day administration is expected to further
WHO initiatives are expected to increase the demand for nevi- increase market demand [6-8]. The high demand coupled with
rapine over the next 10 years (Figure 1) [6]. Although several the financial burden associated with long-term HIV treatments
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has resulted in shortages and patients opting to reduce dosing synthesis telescopes three steps using substantially less expen-
which increases development of resistant strains [9-12]. This sive starting materials.
confluence of increased demand and cost provides an opportu-
nity to reevaluate both the chemistry as well as the manufac- Flow or continuous chemistry is alternative to batch chemistry
turing platforms by which this drug can be produced.
where reactions are performed by passing reagents through
devices containing small-dimensional channels as opposed to
using batch reactors [15-17]. Flow reactors are particularly ad-
vantageous in multistep syntheses where telescoping steps
avoids isolation of dangerous and/or unstable intermediates and
reduces solvent usage and waste production incurred through
intermediate purifications [18-27]. The large surface to volume
ratios found in the small channels allow for more efficient
mixing and heat transfer often resulting in shorter contact times
[28,29]. Consequently, flow chemistry allows chemists to
expand their window of process operability by working at
elevated temperatures and pressures to increase reaction rates
and decrease catalyst loadings [30-33]. Unlike scaling-up batch
reactions, which requires additional optimization, scaling-up
flow processes only requires implementing multiple reactors to
work in parallel [29].
Figure 1: The estimated demand of for nevirapine until 2015 [6].
The two key Food and Drug Administration (FDA) registered We have recently developed a method to synthesize polysubsti-
starting materials in the commercial nevirapine process are tuted 2-halonicotinonitriles in high yields via enamine inter-
2-chloro-3-amino-4-picoline (CAPIC) (1a) and 2-cyclopropyl- mediates 5 by reacting alkylidene malononitriles in the pres-
aminonicotinic acid (2-CAN) (2) (Scheme 1) [13]. The CAPIC ence of acetic anhydride with N,N-dimethylformamide dimethyl
process comprises approximately 64% of the total production acetal (DMF-DMA) [34]. Previous attempts to synthesize the
cost. Based on our previous experience with the development of nicotinonitriles via enamines resulted in poor yields due to
the current commercial batch processes for nevirapine [13] and dimerization of the starting alkylidene malononitrile [35-37]. A
its pyridine precursors [14], we have started a program to define high yield enamine approach allows us to begin the synthesis
lower costs nevirapine processes. After a cost of goods analysis, from the commodity chemicals (acetone and malononitrile) and
we have come to the conclusion that the most promising cost bypass the pyridone intermediate used in the original CAPIC
saving path forward is through the use of acyclic, commodity- synthesis (Scheme 2a) by effecting the ring closure under
based starting materials in the assembly of the active pharma- Pinner reaction conditions (Scheme 2b) [14].
ceutical ingredient (API) (analysis will be included on future
publications). We hypothesized that by both reducing the cost We set out to investigate the possibility of performing a contin-
of goods via chemistry changes and reducing the unit opera- uous synthesis of 2-bromo-4-methylnicotinonitrile starting from
tions the most significant cost reduction could be achieved. acetone and malononitrile (Scheme 3) using the Vapourtec R
Herein, we demonstrate a proof of concept flow synthesis of the series reactor system [38]. The batch synthesis commences with
key intermediate used to produce the bromo derivative of the a Knoevenagel reaction condensing malononitrile and acetone
CAPIC precursor, 2-bromo-4-methylnicotinonitrile (6b). The catalyzed by aluminum oxide producing isopropylidene-
malononitrile (4) [39,40]. The penultimate enamine 5 results by
treating 4 with DMF-DMA in the presence of acetic anhydride,
and ultimately 2-bromo-4-methylnicotinonitrile (6b) is
produced after 5 is treated with HBr in acetic acid. Transferring
the batch synthesis into a semi-continuous process requires one
to consider solvent exchanges and byproducts that might
complicate downstream operations.
We immediately recognized the water formed in the Knoeve-
nagel condensation would quench the DMF-DMA in the second
Scheme 1: Commercial building blocks to nevirapine.
step. In addition, our batch Knoevenagel condensation was base
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Scheme 2: a) Current commercial process to CAPIC and b) newly developed batch synthesis to CAPIC and its bromo derivative.
Scheme 3: Proposed synthesis to 2-bromo-4-methylnicotinonitrile using a continuous approach with the considerations for each reaction. i. Knoeve-
nagel condensation to produce the isopropylidenemalononitrile (4). ii. Reaction of the isopropylidenemalononitrile with DMF-DMA to produce an
enamine (5). iii. Dead end cyclization to the desired 2-bromo-4-methylnicotinonitrile (6b) using HBr.
catalyzed and we discovered that base increased dimer byprod- these and other considerations, we designed the process shown
ucts in the enamine step. Therefore, we chose to employ a solid in Scheme 3 with a summary of considerations for each step.
basic reagent that would simultaneously catalyze the Knoeve-
nagel reaction and confine the reagent to the first step, as well Results and Discussion
as a solid desiccant to remove the water. Previously we have We began our investigation by optimizing the enamine forma-
used solid catalysts and/or solid reagents in a number of contin- tion (5, Figure 2) because we predicted that success with this
uous processes [41-44]. Another challenge was the need to central step would help define the flanking reactions. Initial
increase the rate of enamine 5 formation. Under some condi- batch studies revealed that the reaction occurred rapidly (1 h) in
tions, the enamine step required up to 24 hours [34]. Factoring toluene (1.0 M) heated to 45 °C to produce 4 in 94% yield [34],
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Figure 2: a) Flow scheme to produce the enamine intermediate 5 from isopropylidenemalononitrile (4) (see Supporting Information File 1 for details).
b) Coil temperature effect on yield at a 0.10 M reaction concentration with a 2 min residence time.
but the product precipitated and these conditions were rejected 2 min residence time. In comparison, our batch method with
to avoid reactor clogging. Based on literature precedent and our similar concentration conditions in toluene was complete in 1 h
own screening, we discovered that DCM solubilized 4, 5, and with 94% yield [34]. These flow conditions were high yielding
6b (Scheme 3). In batch, use of DCM would require non-tradi- in one thirtieth of the reaction time. This example underscores
tional glassware because temperatures exceeding the standard the benefit of operating outside of normal process windows
boiling point at atmospheric pressure were required to avoid [45]. Attempts to increase the reaction concentration beyond
unwanted dimer formation unless low reaction concentrations 1.0 M led to reactor clogging due to the limited of solubility of
(0.10 M) were used. A flow reactor is ideal for performing reac- 5.
tions well outside of normal operating conditions and we
pushed forward seeking high temperature conditions using
DCM [45].
We proceeded to develop a continuous process by coupling the
enamine step with the Knoevenagel condensation (Scheme 4).
To achieve this, we included two columns: a packed-bed of
When screening conditions, we initially investigated the effect Al2O3 to catalyze the reaction and a packed bed of 3 Å molec-
temperature had on the reaction at a 0.10 M concentration ular sieves to absorb water before the addition of DMF-DMA
(Figure 2b). Placing backpressure regulators after the heated (Scheme 4). The mass of each solid used (2.00 g of Al2O3 and
coil allowed the temperature of the reactor coil to be raised far 1.50 g molecular sieves) was chosen based on the size of the
above the boiling point of DCM. As shown in Figure 2b, available columns. Assuming that the Knoevenagel conden-
increasing the temperature to 80 °C provided 67% yield with a sation occurred primarily in the Al2O3 column, we only varied
2 min residence time. We then examined reaction concentra- the temperature of the Al2O3 column. The Al2O3 column
tions to reduce the volume of DCM (Table 1). We were not temperature was initially set to 25 °C which yielded 91% of 5
only able to increase the concentration to 1.0 M by heating to from acetone and malononitrile (Table 2, entry 2). We observed
95 °C, but were also able to increase yields to >93% with a that the Al2O3 column reactor temperature increased during the
Table 1: Concentration screen for enamine formation.
Entry
Reaction concentration (M)
Residence time (min)
Coil temperature (°C)
Yield (%)a
1
2
3
4
5
6
0.10
0.20
0.40
0.60
0.80
0.98
2
2
2
2
2
2
100
95
95
95
95
95
68
93
96
98
97
97
aDetermined by GC analysis using mesitylene as an internal standard. See Figure 2a for flow scheme.
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Scheme 4: Flow scheme to produce the enamine 5 starting from acetone and malononitrile (See Supporting Information File 1 for details).
Table 2: Screened conditions for formation of 5 starting from acetone and malononitrile.
Entry Al2O3 column temperature (°C)
3 Å MS column temperature (°C)
Residence time of coil (min)a
Yield (%)b
1
2
3
4
5
6
7
8
9
25
25
20
10
35
50
75
95
95
20
20
25
25
20
20
20
20
20
2
4
4
4
4
4
4
4
6
NAc
91
91
92
88
88
84
81
81
aCoil temperature was 95 °C. bDetermined by GC analysis using mesitylene as an internal standard. cThe fast flow rates needed for this residence
time caused the pressure of the system to exceed the maximum limit. See Scheme 4 for flow scheme.
reaction and thus examined the use of temperatures below supported by the increased production of 7 when excess
25 °C. Cooling the column did not provide any observable malononitrile reacts with DMF-DMA (Scheme 5). Heating the
improvement (Table 2, entries 3 and 4) prompting us to exam- column to 95 °C allowed the Al2O3 column to remain activated
ine higher temperatures. Heating the column past 25 °C longer. Despite the fact that higher alumina column tempera-
increased the byproduct formation which lowered the yield tures result in less than optimal yields of the enamine, we exam-
(Table 2, entries 5–8). Increasing the residence time through the ined the system stability at 95 °C. As can be seen in Figure 3,
alumina column had no positive impact on yield (Table 2, entry increasing the alumina column temperature provides improved
9).
stability compared to 25 °C; however, the column performance
exhibits shallow decline over the first 37 min and then fails
The successful combination of the Knoevenagel/enamine steps rapidly beyond 37 min. The fact that we can resurrect the
prompted us to evaluate the stability of this two-step system. column performance somewhat suggests that this stability issue
We often find that when multisteps are combined the system can be addressed when and if this process is implemented on
stability can become an issue. To measure the stability, we ran scale. To demonstrate that further gains in stability are possible,
the reaction under the optimized conditions and monitored the we examined the impact of reaction concentration on column
product distribution. When the aforementioned optimized stability.
column temperatures were used (20 °C Al2O3 column, 25 °C
3 Å MS column), the alumina column begins to fail (Figure 3). Process chemists often seek the highest operating concentra-
At a collection time of 12 min (Table 2, entry 3), the yield is at tions to reduce solvent costs. Recognizing this aspiration, we
its maximum at 91%. However, by ~17 min, the yield drops to performed the aforementioned Knoevenagel reaction at 2.0 M.
48%. We speculate that at high reactant concentrations the Considering that many process reactions run at 0.20 M, this
water produced fouls the Al2O3 column. This conjecture is starting concentration was high. The high starting concentra-
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Figure 3: Comparing the long-term stability of the Al2O3 and 3 Å MS columns when the Al2O3 column temperature (20 °C and 95 °C) and Knoeve-
nagel reaction concentration (2.0 M and 0.50 M) are varied. The time between 0 and 13 min was the equilibration period.
Scheme 5: Several byproducts were observed when producing 5 starting from acetone and malononitrile. 7 is formed from excess malononitrile when
the Knoevenagel reaction does not go to completion. The formation of dimers 8a and 8b can begin at any point during the reaction.
tion also allowed us to realize a 1.0 M reaction concentration concentrations high lowering the Knoevenagel concentration
once addition of the acetic anhydride and DMF-DMA only results in the enamine concentration decreasing by factor
(Scheme 4). While the higher the concentration the better, our of 1.25 (0.40 M). As shown in Figure 3, reducing the
prior efforts have revealed that packed-bed catalyst stability can Knoevenagel to 0.50 M and heating the alumina column
rapidly decline at high concentrations while at lower concentra- to 95 °C results in a dramatic improvement in system stability.
tions can run for an extended length of time [44]. With this in The output of the enamine, however, remains similar. The reac-
mind, we lowered the Knoevenagel concentration to 0.50 M. tion at a 1 M concentration would produce approximately 7 g of
This setup also resulted in the residence time in the Al2O3 enamine product within the 24 min window and at a 0.4 M
column and 3 Å MS to reduce from 2.88 min and 2.72 min to concentration approximately 5.8 g in the 42 min window. While
0.90 min and 0.85 min respectively. The faster residence time we are bolstered by these improvements, we suggest that a
could account for less water absorption in the Al2O3 column. commercial version of this process must address how to achieve
Because we can still hold the acetic anhydride/DMF-DMA long-term stability at the higher concentrations.
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Creating a chemical process for an active pharmaceutical ingre- trile 6b crystallized out of solution in 81% overall yield
dient is a careful integration of chemical and regulatory chal- (2-steps, Scheme 6). While our intent was not to create a
lenges. While from an academic standpoint a completely completely continuous process at this time, commercially avail-
continuous process provides the opportunity to advance process able reactors that can handle strong acid are available and this
chemistry/technology, a new process can often require signifi- step could easily be achieved in flow (for an example of an
cant investment for regulatory validation. We wish to imple- strong acid resistant reactor, see reference [38]).
ment our technology as quickly as feasible and to do so we want
to avoid potential regulatory problems. Therefore, we have We completed the process by integrating all three steps together
opted to carry out the Pinner cyclization as terminal cyclization/ using the lower concentration Knoevenagel condensation
crystallization step where the already validated material could (0.50 M) with the heated Al2O3 column at 95 °C due to its long-
be collected. To optimize the cyclization step, we combined term stability (Scheme 7). We ran 100 mL of material through
only the enamine/cyclization steps to reduce system complexity. the process and after simple trituration with water 69% (5.4 g
When we subjected 25 mL of the enamine 5 output to a solu- for 100 mL) of the desired 2-bromo-4-methylnicotinonitrile
tion of HBr in AcOH for 45 min (55 °C) the desired nicotinoni- (6b) was obtained and was analytically pure as determined by
Scheme 6: Flow scheme to produce 2-bromo-4-methylnicotinonitrile (6b) in 81% yield from 4 with a 1 M concentration and 2 min residence time in
the coil (See Supporting Information File 1 for further details).
Scheme 7: Reactor scheme for the continuous synthesis of 2-bromo-4-methylnicotinonitrile (6b) with an average of 69% yield. The reaction concen-
tration within the columns was 0.50 M, while the reaction concentration in the coil was 0.40 M. The residence time in the Al2O3 column was 0.90 min,
in the 3 Å MS column 0.85 min, in the coil 4 min, and the reaction time for the cyclization to occur to produce 6b was 45 min (See Supporting Informa-
tion File 1 for further details).
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cyclization using HCl instead of HBr and have produced the
registered chloride in 81% yield [34].
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