Development of an NH4Cl-Catalyzed Ethoxy Ethyl Deprotection in Flow for the Synthesis of Merestinib

Article abstract of DOI:10.1021/acs.oprd.5b00240

An NH₄Cl-catalyzed ethoxy ethyl deprotection was developed for the synthesis of merestinib, a MET inhibitor. Alternative reactor technologies using temperatures above the solvent boiling point are combined with this mild catalyst to promote the deprotection reaction. The reaction is optimized for flow and has been used to synthesize over 100 kg of the target compound. The generality of the reaction conditions is also demonstrated with other compounds and protecting groups.

Full text of DOI:10.1021/acs.oprd.5b00240

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Communication
Development of an NH4Cl-Catalyzed Ethoxy Ethyl
Deprotection in Flow for the Synthesis of Merestinib
Michael O Frederick, Joel R. Calvin, Richard F Cope, Michael E LeTourneau, Kurt Thomas
Lorenz, Martin D Johnson, Todd D Maloney, Yangwei Pu, Richard D. Miller, and Lauren E Cziesla
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00240 • Publication Date (Web): 23 Sep 2015
Downloaded from http://pubs.acs.org on September 26, 2015
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Development of an NH Cl-Catalyzed Ethoxy Ethyl
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Deprotection in Flow for the Synthesis of Merestinib
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Michael O. Frederick*, Joel R. Calvin, Richard F. Cope, Michael E. LeTourneau, Kurt T. Lorenz,
Martin D. Johnson, Todd D. Maloney, Yangwei John Pu, Richard D. Miller, Lauren E. Cziesla
Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, United
States
*
Corresponding Author
frederickmo@lilly.com
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TABLE OF CONTENTS GRAPHIC
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ABSTRACT: An NH Clꢀcatalyzed ethoxy ethyl deprotection was developed for the synthesis of
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merestinib, a MET inhibitor. Alternative reactor technologies using temperatures above the solvent
boiling point are combined with this mild catalyst to promote the deprotection reaction. The reaction is
optimized for flow, and has been used to synthesize over 100 kg of the target compound. The generality
of the reaction conditions is also demonstrated with other compounds and protecting groups.
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KEYWORDS: Merestinib, ethoxy ethyl deprotection, flow chemistry, scaleꢀup, ammonium chloride
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INTRODUCTION: MET kinase inhibitors are a class of small molecules that inhibit the enzymatic
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activity of MET tyrosine kinase and may have therapeutic applications for the treatment of various types
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of cancers. Merestinib (1, Figure 1) is one such molecule and is currently undergoing earlyꢀphase
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clinical studies in cancer patients.
A synthesis of 1 has been previously described which relied on a Bocꢀprotected penultimate
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compound (2). Although successful, lability concerns with the Boc group led us to explore alternative
protecting groups. After evaluation of different commercially available protected boronic ester
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pyrazoles, it was decided that an ethoxy ethyl (EE) protecting group would be explored, as it was
believed that it would withstand the desired chemistry, while also being able to be deprotected in high
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,6
yields. Retrosynthetically, merestinib (1) can be deconstructed in two ways, the first of which
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involves breaking the amide bond of 3 to give known carboxylic acid 4 and aniline 5. The aniline
would then be derived from EEꢀprotected pinacol boronic ester 7 and previously described aryl bromide
3
8
. The second synthetic option would use the same building blocks, but the first retrosynthetic
disconnection would break the aryl bond into EEꢀprotected pinacol boronic ester 7 and aryl bromide 9.
Bromide 9 would be split into carboxylic acid 4 and aryl bromide 8.
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Figure 1. Retrosynthesis of merestinib 1 through two routes starting from common intermediate 8. pin =
pinacol.
RESULTS AND DISCUSSION:
Routes to penultimate compound 3:
3
The first route explored mirrored the previously disclosed route, which entailed a nitro
reduction of compound 8 followed by amide bond formation to give 9 (Scheme 1). A Suzuki coupling
worked very well with EEꢀprotected pyrazole 7 (similar to previously used Bocꢀprotected pyrazole 6).
Using the previously developed conditions [Pd(dtbpf)Cl , K PO , THF, H O, 40 °C], provided
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penultimate compound 3 in 96% yield, leaving the deprotection to be explored (vide-infra).
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Scheme 1. Reagents and Conditions: 7 (1.2 equiv.), K PO (2.0 equiv.), Pd(dtbpf)Cl (0.012 equiv.),
3
4
2
THF, H O, 40 °C, 15 hr, 96%. dtbpf = bis(diꢀtertꢀbutylphosphino)ferrocene.
2
The second route used similar chemistry, but in a different order (Scheme 2). Pinacol boronate 7
was joined with bromide 8 [Pd(dtbpf)Cl , K PO , THF, H O, 50 °C], to form the biaryl bond of 10 in
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8
7% yield. Performing the Suzuki coupling first was advantageous over the previous route as it removed
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the risk of debromination during hydrogenation. As a result, simple nitro reduction with 5% Pd/C
worked well to afford aniline 5 in 92% yield. Finally, amide bond formation was accomplished by
addition of aniline 5 to the freshly prepared mixed anhydride [4, iBuC(O)Cl], to give penultimate
compound 3 in 86% yield.
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Scheme 2. Reagents and Conditions: a) 7 (1.2 equiv.), K PO (2.2 equiv.), Pd(dtbpf)Cl (0.012 equiv.),
3
4
2
THF, H O, 50 °C, 3.5 hrs, 87%; b) 5% Pd/C (55% H O by wt, 0.09 wt%), Et N (1.5 equiv.), 2ꢀMeTHF,
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H (50 psi), 45 °C, 4.5 hr, 92%; c) 4 (1.1 equiv.), NMM (2.5 equiv.), 2ꢀMeTHF, 0 °C, 15 min;
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iBuC(O)Cl (1.3 equiv.), 0 °C, 4 hr; 11 (1.0 equiv.), 0 °C, 3 hr, 86%. NMM = Nꢀmethylmorpholine.
EE deprotection in batch:
Although the EEꢀprotected compound 3 could be successfully prepared through two similar, but
separate routes, a deprotection still needed to be developed. We first explored acid catalyzed removal of
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the EE group in 3. A mix of THF:H O was used as the solvent for the reaction as they provided the best
2
solubility (maximum solubility for both starting material 3 and product 1 is between 10 and 20
volume% water in THF). Finding an appropriate acid was less straightforward. Weak acids result in
very slow reactions, while stronger acids lead to amide bond hydrolysis. Methanesulfonic acid gave the
desired balance between rate and stability; however, the reaction would stall with 1–5% of the starting
EEꢀprotected compound (3) remaining. As starting material 3 is not efficiently removed by
crystallization, the purity of target compound 1 was unacceptable. The stalling of the reaction could be
overcome by removing acetaldehyde during the reaction through distillation. Unfortunately, the
prolonged reaction time would result in further cleavage of the amide bond in 1 affording aniline 11 and
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carboxylic acid 4 (Scheme 3). Although the amounts of 11 were low (roughly 1%), aniline 11 is a
mutagen that needed to be controlled to below 80 ppm in 1, and it rejects poorly during crystallization.
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As a result, another solution was needed for the deprotection.
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OEt
MSA,
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NH2
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HN
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Scheme 3. Reagents and Conditions: MSA (1.0 equiv.), THF, H O, reflux, 3 hr, 92% with 1% 11. MSA
2
=
methanesulfonic acid.
EE deprotection in flow:
To avoid the amide bond cleavage, alternative reactor technologies were explored including the
possibility of a tubular plugꢀflow reactor that is capable of heating to higher temperatures, within a
8
shorter period of time. Heating a reaction with various additives (see Table 1) to 200 °C for 30 minutes
9
showed this to be an effective way to synthesize the product. The formation of minimal product for a
reaction with no additive (entry 1) clearly demonstrates that the deprotection is not simply thermally
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driven. Not surprisingly, protic acids were effective (entries 2–5), but as with reactions at lower
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temperatures, there was a balance between reaction rate and formation of the undesired aniline.
Fortunately, NH Cl looked very promising. Interestingly, aprotic additives were also effective in the
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reaction (entries 6–10).
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Table 1. Reactions run on 0.1 mmol scale with 1 mL high pressure batch reactors in 85:15 THF:H O
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(15 volumes).
Although NH Cl was ultimately selected for this reaction, the aprotic additive results led to a
4
better understanding of how the reaction was taking place. Instead of the normally accepted protic acidꢀ
mediated mechanism of EEꢀdeprotections, it is believed that this reaction occurs through a Krapchoꢀ
1
1
type mechanism, which could involve a nucleophilic displacement at two sites on the EE group
Scheme 4). The halogen could displace the ethoxy group affording haloꢀaminal 15. The halide would
(
then get pushed out by electrons on the nitrogen pyrazole making the reaction catalytic in the halide and
providing the deprotected pyrazole 17 after liberation of acetaldehyde from 16. Similarly, and perhaps
more likely, ethyl halide could be formed along with intermediate 18. It should be noted that ethyl
chloride is not detected during our reaction, but due to the large excess of water and high temperatures,
it would be expected to convert to ethanol and HCl very quickly. After expulsion of acetaldehyde from
1
8, anion 19 could be quickly protonated to form deprotected 17.
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R
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N
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+
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5
14
18
H O
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EtOH
+
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Scheme 4. Krapchoꢀtype mechanism for the EE deprotection.
For scaling up, a feed solution was created that contained all components: starting material 3,
THF, H O, and NH Cl. The feeds were pumped through a 12 L coiled tube reactor at 150 °C with 250
2
4
psi of back pressure to keep the contents liquid at a flow rate that would provide a two hour residence
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time. Once the product for one batch was collected, it was worked up in batch. In addition to analysis
of the collected final product, onꢀline HPLC was also in place to monitor the reaction in realꢀtime and
be able to respond to any departures from the expected reaction profile (see Experimental Section for
more detail about the onꢀline HPLC). Figure 2 shows the output of the onꢀline HPLC with area% of
starting material (3) plotted over time. The results were very consistent across the 90 hours, representing
1
4
the first of 4 batches. In total, over 100 kg was made in this way with a total yield of 94% and greater
than 99.8% purity (Scheme 5).
Figure 2. Onꢀline HPLC data of wt% starting material (3) remaining over time.
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Scheme 5. Reagents and Conditions: NH Cl (0.05 equiv.), THF, H O, 150 °C, 2 hr, 94%.
4
2
Substrate generality:
To further explore the generality of the reaction, a variety of substrates were explored (Table 2).
Aliphatic EEꢀprotected alcohols were cleanly deprotected at 150 °C over one hour (entry 1), as well as
phenolic (entry 2), primary benzylic (entry 3) and secondary benzylic (entry 4) EEꢀprotected alcohols.
Other protecting groups (triethyl silyl, tꢀbutyldimethylsilyl, and tetrahydropyranyl) could also be
removed with slightly higher temperatures (200 °C) and longer reaction times (2 h), further
demonstrating the generality of the reaction.
Entry
1
Substrate
Temp.
Time
1 h
Conversion
100%
CholesterolꢀOEE 150 °C
OEE
2
3
150 °C
1 h
1 h
100%
100%
OEE
150 °C
OEE
4
5
6
7
150 °C
1 h
2 h
2 h
2 h
100%
100%
100%
100%
OTES
200 °C
OTBS
200 °C
OTHP
200 °C
Table 2. Reactions on 0.1 to 1.0 mmol scale in 1 mL high pressure batch reactors with NH Cl (5 mol%)
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in 85:15 THF:H O (10 volumes) as the solvent composition.
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Conclusions: In conclusion, a new deprotection for ethoxy ethyl protecting groups was developed and
applied to the synthesis of more than 100 kg of merestinib (1). Although high temperatures (150 °C)
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were required, the conditions (catalytic NH Cl) are relatively mild and tolerant of a wide variety of
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substrates. The methodology was further applied to other protecting groups, demonstrating further
generality.
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Experimental Section:
OnꢀLine HPLC Description
The automated sampling/dilution system takes a precise volume sample from a continuous
process, dilutes it with a precise volume of diluent, mixes the diluted sample, and then parks it at a
desired location, for example an injection loop or an overflow Tee 200 feet away.
The dilution factor for this system can be changed from 20 X to 200 X by changing the size of
the diluent measureꢀout zone. There are no automated valves or sample loops in the main process flow
path so that this system does not interfere with the flow chemistry process. This system is not designed
for slurries; only homogeneous solutions. The process is sampled by using gravity and automated block
valves. Sample size is 2 mL. The system operates at ambient temperature. The system uses 15–45 psig
N for the mixing and pushing to the LC. The system is electrically classified to reside in the plant
2
module at the reactor outlet tubing, and it pushes the diluted sample to the onꢀline HPLC in an adjacent
laboratory.
The 2 mL sample is taken from an overflow Tee by gravity. The minimum size tubing and
fittings are selected so that the sample collection zone is selfꢀventing. Liquid must flow down into the
sample zone by gravity only, meaning that the displaced vapor from the sample zone must bubble up.
The sample zone is the space between two standard 1/2” block valves. The top valve opens and closes,
then the bottom valve opens and closes, which drops a 2 mL sample by gravity into a lower sample
chamber. The fittings and tubing below the valve must be at least 1 cm inside diameter, with no smaller
internal restrictions, or else the 2 mL sample may not gravity flow down to the lower zone when the
valve opens. This depends on the surface tension of the fluid.
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The vertical dilution solvent measure out zone fills from bottom up, and empties from top down.
1
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This ensures that it gets completely liquid filled with no gas pockets, and that it subsequently
completely empties, with only a few surface drops remaining. The dilution solvent measure out zone
uses four automated block valves, two at the top and two at the bottom, so that it can overflow back to
the solvent vessel while filling, and then push with nitrogen to the mixing vessel after filled.
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Pressurized nitrogen pushes the dilution solvent through the lower sample zone, which pushes
the sample into the bottom of a mixing chamber. The mixing chamber is typically 5X larger volume
than the sum of dilution solvent plus sample. The nitrogen bubbling action into the bottom of the mixing
chamber thoroughly mixes the diluted sample. The nitrogen bubbling happens after all of the sample
and dilution solvent has been pushed into the mixing chamber, and the nitrogen continues to blow
through the valves to pressure up the mixing chamber. This nitrogen pressure in the mixing chamber
subsequently serves to push the diluted sample to the onꢀline HPLC through 200 feet of tubing. There
are two automated block valves at the bottom of the mixing chamber, one to allow flow into the
chamber from the sample zone, and one to allow flow out of the chamber to the onꢀline HPLC. The
digital control system runs the sequence for all of the automated block valves. It typically takes about 2–
10 minutes for this system to go through the entire automated sequence, depending on how far it is
pushing the diluted sample to the onꢀline HPLC, the internal diameter of the tubing, and viscosity and
volume of the diluted sample solution. If a PATROL onꢀline HPLC system (see description below) is
used, then it sips the diluted sample from the bottom of an overflow Tee 200 feet away in an adjacent
laboratory.
PATROL Description
A PATROL onꢀline HPLC was coupled to the process via the automated sampling/dilution
15
system described above. The automated sampling/dilution system delivers a sample to the overflow
Tee every 30 min for the PATROL to sample. The process sampling valve on the PATROL was
connected to the overflow Tee by a 1 meter long segment of 1/16” o.d. x 0.030” i.d. PTFE tubing. The
PATROL sips the diluted sample from the bottom of the overflow Tee to ensure only liquid is drawn
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into the instrument. When the PATROL run sequence is initiated the PATROL draws 2 mL of sample
from the overflow Tee at a flow rate of 4 mL/min. The duration of sampling ensures there is a minimal
amount of diluted sample remaining in the overflow Tee between samples being delivered from the
automated sampling/dilution system. The 2 mL of sample drawn also flushes the sample fluidic train
within the PATROL, ensuring it is flushed with representative material from the process and reducing
instrument carryover in the process sample pump. Once this cycle is completed the PATROL performs a
secondary dilution on the process sample (5X) by metering the process sample pump in parallel with a
diluent pump filled with acetonitrile. The combined effluent from these pumps fills a loop (2 ꢁL) that is
injected on column. For this process the PATROL delivered a sample from the overflow tee and
performed the analysis every 30 min.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
In addition to online sampling, the PATROL has a standard autosampler carousel which enables
injection of method calibration samples. Before process startꢀup a series of method calibration samples
were injected to ensure method performance and enable quantitation via external standard method. Over
the course of the campaign the method calibration sample was injected atꢀline daily to demonstrate the
method was performing acceptably.
Chemistry Procedures
General Procedure for Table 2, entry 4.
To a 1 mL high pressure batch reactor in a glove box was added 1ꢀ(1ꢀethoxyethoxy)ethylbenzene (50
mg, 0.26 mmol, 1.0 equiv.), THF (0.425 mL, 8.5 volumes), water (0.075 mL, 1.5 volumes) and NH Cl
4
(0.69 mg, 0.013 mmol, 0.05 equiv.). The reactor connector was sealed by screwing the lid on tight and
then heated in an oven at 150 °C for 1 hour. The reactor connector was then allowed to cool to ambient
temperature and was sampled by HPLC for conversion.
N-(4-((6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-1-methyl-1H-indazol-5-yl)oxy)-3-fluorophenyl)-1-(4-
fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (3, Suzuki Coupling).
To a 1000 gal glassꢀlined reactor was added 9 (138.8 kg, 238.9 mol, 1.0 equiv.), 7 (76.6 kg, 287.7 mol,
1
.2 equiv.), K PO (102.0 kg, 480.5 mol, 2.0 equiv.), followed by THF (1044 L, 7.5 volumes) and H O
3
4
2
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Organic Process Research & Development
(
410 L, 3 volumes). The biphasic mixture was stirred at 25 °C until complete dissolution was observed.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
To the biphasic mixture was then charged Pd(dtbpf)Cl (1.88 kg, 2.88 mol, 0.012 equiv.) and the
2
solution was heated to 40 °C for 15 hours at which point the reaction was complete by HPLC. The
stirring was then stopped and the biphasic mixture was allowed to separate completely over 30 minutes
1
6
at 40 °C. The aqueous layer was removed and 41 kg of Silicaꢀthiol Pdꢀscavenging resin was added to
the organic layer. The slurry was heated to 60 °C for 6 hours and the resin was removed by filtration.
The filtrate was concentrated by vacuum distillation at 30–35 °C to get to a final volume of 870 L
(approximately 6 Volumes relative to 3). To the solution was added seed of 3 (1.62 kg) and the slurry
was cooled to 20–25 °C where it was stirred for 10 hours. The slurry was further cooled to 0–5 °C
where it was held for another 6 hours. The solid was collected by filtration and the wet cake was dried
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
under vacuum at 55 °C for 60 hours to obtain 3 (136 kg, 208.8 mol, 96% yield) as a yellow solid. 3: H
NMR (400 MHz, DMSOꢀd ): δ = 11.88 (s, 1 H), 8.43 (d,
J
= 7.6 Hz, 1 H), 8.26 (s, 1 H), 7.99 (s, 2 H),
6
7
.93 (dd,
J
= 13.6, 2.4 Hz, 1 H), 7.89 (s, 1 H), 7.46–7.37 (m, 4 H), 7.27 (s, 1 H), 7.19 (d, = 9.2 Hz, 1
J
H), 6.80 (t,
J
= 9.2 Hz, 1 H), 6.66 (d,
J
= 8.0 Hz, 1 H), 5.53–5.50 (m, 1 H), 4.05 (s, 3 H), 3.35–3.32 (m,
13
1
H), 3.08–3.03 (m, 1 H), 2.03 (s, 3 H), 1.55 (d,
J
= 6.0 Hz, 3 H), 0.94 (t,
J
= 7.2 Hz, 3 H) ppm; C
NMR (100 MHz, DMSOꢀd ): δ = 163.4, 161.9, 161.2, 153.7, 151.3, 147.7, 144.4, 140.4, 138.5, 137.7,
6
1
1
34.9, 134.8, 134.5, 132.4, 130.5, 127.5, 124.0, 122.4, 120.0, 118.3, 117.4, 117.1, 116.9, 116.4, 109.5,
+
4
09.0, 108.9, 108.2, 86.8, 63.4, 36.0, 22.1, 21.7, 15.1 ppm; HRꢀMS [ESI]: Calcd for C H F N O [M
3
4
31
2
6
+
+ H ]: 625.2369, found 625.2353.
-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazole (10).
To a 250 mL 3N flask was added 8 (5.0 g, 13.6 mmol, 1.0 equiv.), THF (60 mL, 12 volumes), K PO
6
3
4
(6.56 g, 30.3 mmol, 2.22 equiv.) in 26 mL of water and 7 (4.36 g, 16.4 mmol, 1.2 equiv.). To this
mixture was added Pd(dtbpf)Cl (140 mg, 21 µmoles, 0.02 equiv.). The mixture was heated to 50 °C
2
where it became a clear dark brown solution, and then became a slurry. After 3.5 hours, the reaction was
complete (HPLC analysis). To the slurry was added THF (10 mL, 2 volumes) and the reaction
temperature was raised to 70 °C. The mixture became a dark solution and the aqueous layer was
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removed. The organic layer was cooled to 21 °C and stirred for 12 hours at which time product
precipitated. The resulting slurry was filtered and rinsed with 30 mL of THF. The wet cake was dried in
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
a vacuum oven at 45 °C to give 10 (5.05 g, 11.8 mmol, 87% yield) as a grey solid. 10: H NMR (400
MHz, DMSOꢀd ): δ = 8.27 (dd, J = 11.2, 2.4 Hz, 1 H), 8.15 (s, 1 H), 8.04 (s, 1 H), 8.02 (s, 1 H), 7.89 (d,
6
J
= 11.2 Hz, 1 H), 7.86 (s, 1 H), 7.67 (s, 1 H), 6.74 (t,
J
= 8.8 Hz, 1 H), 5.49–5.45 (m, 1 H), 4.09 (s, 3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
H), 3.28–3.23 (m, 1 H), 2.89–2.84 (m, 1 H), 1.51 (d,
J
= 6.0 Hz, 3 H), 0.87 (t, J = 7.2 Hz, 3 H) ppm; C
NMR (100 MHz, DMSOꢀd ): δ = 152.2, 151.8, 149.7, 144.8, 141.9, 138.6, 138.3, 132.8, 127.2, 124.6,
6
122.6, 121.7, 117.8, 116.7, 113.4, 109.8, 86.8, 63.3, 36.1, 21.6, 14.9 ppm; HRꢀMS [ESI]: Calcd for
+
+
C H FN O [M + H ]: 426.1565, found 426.1572.
21
21
5
4
4
-((6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-1-methyl-1H-indazol-5-yl)oxy)-3-fluoroaniline (5).
To a 1 L pressure parr reactor was added 10 (40.6 g, 95.4 mmol, 1.0 eq), 5% Pd/C (55% water content,
.61 g, 0.09% w/w), Et N (14.7 g, 146 mmol, 1.53 equiv.) and 2ꢀMeTHF (525 mL, 13 volumes). The
1
3
reactor was sealed and the reaction mixture was heated to 45 °C under 50 psi of H pressure. The
2
reaction was complete after 4.5 hours (HPLC analysis) and was filtered through Celite (9.4 g), rinsed
16
with 175 mL of 2ꢀMeTHF. The filtrate was heated to 70 °C with 12 g of SiliaMet S Thiol for 7 hours
and cooled to 21 °C. The resulting slurry was filtered and rinsed with 100 mL of 2ꢀMeTHF. The filtrate
was concentrated to ~400 mL volume and to the solution was added heptane (400 mL) dropwise. After
~55 mL of heptane was added, the reaction solution was seeded with 118 mg of seed and then the
remainder of the heptane was added. The light tan slurry was filtered and rinsed with 100 mL of 40%
v/v 2ꢀMeTHF/heptane. The wet cake was dried in a vacuum oven at 45 °C to give 5 (35.8 g, 87.8 mmol,
1
9
2% yield) as a light tan solid. 5: H NMR (400 MHz, DMSOꢀd ): δ = 8.33 (s, 1 H), 8.06 (s, 1 H), 7.94
6
(s, 1 H), 7.82 (s, 1 H), 6.94 (s, 1 H), 6.82 (t,
J = 8.8 Hz, 1 H), 6.49 (dd, J = 8.8, 2.4 Hz, 1 H), 6.35 (dd, J
=
8.8, 2.4 Hz, 1 H), 5.59–5.55 (m, 1 H), 5.25 (s, 2 H), 4.02 (s, 3 H), 3.43–3.38 (m, 1 H), 3.21–3.17 (m, 1
1
3
H), 1.59 (d,
J = 6.0 Hz, 3 H), 1.01 (t, J = 7.2 Hz, 3 H) ppm; C NMR (100 MHz, DMSOꢀd ): δ = 155.8,
6
153.4, 150.6, 147.5, 138.7, 137.0, 132.5, 132.1, 127.6, 123.3, 122.3, 118.7, 110.4, 108.3, 105.3, 102.2,
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Organic Process Research & Development
+
+
8
3
6.8, 63.4, 35.9, 21.7, 15.2 ppm; HRꢀMS [ESI]: Calcd for C H FN O [M + H ]: 396.1822, found
21 23 5 2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
96.1830.
-(4-((6-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-1-methyl-1H-indazol-5-yl)oxy)-3-fluorophenyl)-1-(4-
N
fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide
Coupling).
(3,
Mixed
Anhydride
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
To a 25 mL roundꢀbottom flask was added 4 (0.7 g, 2.78 mmol, 1.1 equiv.), 2ꢀMeTHF (5 mL, 7
volumes) and NMM (0.64 g, 6.3 mmol, 2.5 equiv.). The orange slurry was stirred and cooled to 0–5 °C.
Then isobutyl chloroformate (0.45 g, 3.3 mmol, 1.3 equiv.) was added dropwise. After 4 hours of
stirring at 0–5 °C, to the reaction was added 5 (1 g, 2.53 mmol, 1.0 equiv.). The thin slurry was stirred at
0–5 °C for 3 hours and then warmed to 21 °C. To the resulting slurry was added 10 mL of water and the
resulting biphasic mixture was heated to 50 °C. To the biphasic mixture was added 5 mL of sat. brine
and the aqueous layer was removed. To the organic layer was slowly added heptane (10 mL) over 45
min at 21 °C. The resulting slurry was filtered and rinsed with 10 mL of 50% w/w 2ꢀMeTHF/heptane.
The wet cake was dried in a vacuum oven at 75 °C to afford 3 (1.35 g, 2.18 mmol, 86% yield) as a light
tan solid.
Merestinib (1).
MSA Reaction:
To a 50 mL roundꢀbottom flask equipped with a stir bar, Dean–Stark trap and reflux condenser was
charged: 3 (1 g, 1.46 mmol, 1.0 equiv.), THF (13 mL, 13 volumes) and H O (2 mL, 2 volumes). The
2
reaction was heated to reflux and to the solution was charged methanesulfonic acid (96 ꢁL, 1.46 mmol,
1.0 equiv.). Five mL of solution was allowed to collect in the Dean–Stark trap at which time the reaction
was complete (analysis by HPLC, approximately 3 hours). The solution was allowed to return to
ambient temperature by removing the heat source. The reaction solution was quenched by the addition
of Et N (244 ꢁL, 1.75 mmol, 1.2 equiv.) which resulted in the homogeneous solution separating into
3
two layers. The biphasic mixture was poured into a separatory funnel and the aqueous layer was
removed. The organic layer was transferred to a 50 mL roundꢀbottom flask with a distillation head. 10
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mL EtOH was added to the solution and then 10 mL of solution was removed by vacuum distillation. 10
mL of EtOH was added a second time and 10 mL more of solution was removed by vacuum distillation.
During the second distillation, product started to precipitate. 10 mL of EtOH was added a third time and
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
10 mL more of solution was removed by vacuum distillation. The solution was allowed to cool to
ambient temperature and the product was collected by vacuum filtration and washed with 2 mL of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
EtOH. The wet cake was dried in a vacuum oven for 16 hours to afford 1 (0.72 g, 1.31 mmol, 90%
1
yield) as a white solid (approximately 1% of aniline 11 present). 1: H NMR (500 MHz, DMSOꢀd ): δ =
6
13.00 (s, 1 H), 11.93 (s, 1 H), 8.45 (d,
d, = 2.2 Hz, 1 H), 7.91 (d, = 2.6 Hz, 1 H), 7.50–7.46 (m, 2 H), 7.43–7.40 (m, 2 H), 7.27 (s, 1 H),
.26–7.25 (m, 1 H), 6.86 (t,
NMR (125 MHz, DMSOꢀd ): δ = 163.0, 161.5, 161.0, 153.2, 152.2, 147.5, 144.0, 140.1, 138.0, 137.3,
J = 7.5 Hz, 1 H), 8.17 (s, 1 H), 8.05 (s, 1 H), 8.01 (s, 1 H), 7.97
(
J
J
1
3
7
J = 9.0 Hz, 1 H), 6.67–6.65 (m, 1 H), 4.08 (s, 3 H), 2.03 (s, 3 H) ppm; C
6
1
1
34.5, 134.1, 132.0, 130.1, 127.4, 124.2, 121.8, 119.8, 117.0, 116.8, 116.6, 116.1, 108.9, 108.6, 108.2,
+
3
+
07.8, 35.5, 21.7 ppm; HRꢀMS [ESI]: Calcd for C H F N O [M + H ]: 553.1794, found 553.1793.
30 23
2
6
NH Cl Reaction:
4
To a 250 gal stainless steel tank was charged 3 (31 kg, 49.7 mol, 1.0 equiv.), NH Cl (132 g, 2.49 mol,
4
0
.05 equiv.), THF (395 L, 12.75 volumes), and H O (70 L, 2.25 volumes). The solution was then fed
2
through a 12 L Hastelloy® tube heated to 150 °C at a rate which corresponds to a residence time of 2
hours, with a back pressure of 250 psi. The solution was collected into 50 gal stainless steel tanks on the
other side of the tube and combined for workꢀup in batch.
The combined solution for one batch was transferred to a 250 gal stainless steel tank. The solution was
heated to reflux at atmospheric pressure and concentrated from approximately 460 L to a total volume
of 260 L (9.5 volumes based on the expected amount of 1). To the solution was charged 150 L of IPA
(5.6 volumes based on expected amount of 1) and the solution was concentrated through atmospheric
distillation to a total volume of 260 L. The solution temperature was lowered to a few degrees below the
boiling point (approximately 65 °C) and to the heated solution was charged a slurry of 1 seed (250 g, 1
mol% of expected amount of 1) in IPA (50 L, 1.9 volumes). To the slurry was charged IPA (100 L, 3.7
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Organic Process Research & Development
volumes) and the slurry was heated to reflux and concentrated to a total volume 260 L (9.5 volumes
based on expected amount of 1), representing the third distillation. To the slurry was charged IPA (100
L, 3.7 volumes) and the slurry was heated to reflux and concentrated to a total volume 260 L (9.5
volumes based on expected amount of 1), representing the fourth distillation. To the slurry was charged
IPA (100 L, 3.7 volumes) and the slurry was heated to reflux and concentrated to a total volume 260 L
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(9.5 volumes based on expected amount of 1), representing the fifth distillation. To the slurry was
charged IPA (100 L, 3.7 volumes) and the slurry was heated to reflux and concentrated to a total volume
1
7
250 L (9 volumes based on expected amount of 1), representing the sixth and final distillation.
The slurry was cooled to 23 °C, and the solid was collected by filtration. The wet cake was washed with
IPA (110 L, 4 volumes based on expected amount of 1). The wet cake was dried by vacuum at 55 °C for
6 hours to obtain 1 (26.7 kg, 48.2 mol, 94% yield) as a white solid.
ACKNOWLEDGEMENT: The authors thank David Myers and Cynthia Hammill for analytical
support.
References
1
Liu, X.; Newton, R. C.; Scherle, P. A. Expert Opin. Invest. Drugs 2011, 20, 1225.
2
Yan, S. B.; Peek, V. L.; Ajamie, R.; Buchanan, S. G.; Graff, J. R.; Heidler, S. A.; Hui, Y.; Huss, K. L.;
Konicek, B. W.; Manro, J. R.; Shih, C.; Stewart, J. A.; Stewart, T. R.; Stout, S. L.; Uhlik, M. T.; Um, S.
L.; Wang, Y.; Wu, W.; Yan, L.; Yang, W. J.; Zhong, B.; Walgren, R. A. Invest. New Drugs 2013, 31
,
833.
3
Kallman, N. J.; Liu, C.; Yates, M. H.; Linder, R. J.; Ruble, J. C.; Kogut, E. F.; Patterson, L. E.; Laird,
D. L. T.; Hansen, M. M. Org. Process Res. Dev. 2014, 18, 501.
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Some include: Boc, Bn, Me and THP protected boronate pyrazoles.
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Lin, Q.; Meloni, D.; Pan, Y.; Xia, M.; Rodgers, J.; Shepard, S.; Li, M.; Galya, L.; Metcalf, B.; Yue, T.ꢀ
Y.; Liu, P.; Zhou, J. Org. Lett. 2009, 11, 1999.
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Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3 ed. Wiley: New York,
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999.
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Reduction of nitro compound 8 required the addition of poisons to minimize the amount of protoꢀ
debromination (see Reference 3).
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a) Baxendale, I. R.; Braatz, R. D.; Hodnett, B. K.; Jensen, K. F.; Johnson, M. D.; Sharratt, P.;
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Sherlock, J.ꢀP.; Florence, A. J. J. Pharm. Sci. 2015, 104, 781. b) Baxendale, I. R. J. Chem. Technol.
Biotechnol. 2013, 88, 519. c) Hartman, R. L.; McMullen, J. P.; Jensen, K. F. Angew. Chem. Int. Ed.
2011, 50, 7502.
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Reactions were screened by dissolving contents into a 1 mL high pressure batch reactor and heating in
a GC oven. For reactor description, see supporting information in: White, T. D.; Alt, C. A.; Cole, K. P.;
Groh, J. M.; Johson, M. D.; Miller, R. D. Org. Process Res. Dev. 2014, 18, 1482.
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The discovery of this reaction was actually quite serendipitous as the reaction worked initially without
additives. It was only found after going to subsequent batches of starting materials that trace metals
were present in the original batch that helped catalyze the reaction and when they were no longer
present, the reaction would not proceed.
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a) Krapcho, A. P.; Glynn, G. A.; Grenon, B. J. Tetrahedron Lett. 1967, 8, 215. b) Krapcho, A. P.;
Lovey, A. J. Tetrahedron Lett. 1973, 14, 957. c) Krapcho, A. P.; Jahngen, E. G. E.; Lovey, A. J.
Tetrahedron Lett. 1974, 15, 1091.
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The reaction is heated above the solvents boiling point, so back pressure must be applied to ensure the
contents stay a liquid. The equipment used must be able to withstand pressures above those needed, in
this case 250 psi.
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The reaction was one continuous feed from start to finish, but the product was worked up in 4
batches. In order to keep the reaction continuous, it is necessary that the workꢀup (solvent swap into
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IPA/crystallization, filtration and drying) take less time than the following portion of the solution takes
to flow through the tube, which was accomplished in this reaction.
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The small gaps are where the onꢀline HPLC system stopped working and is not indicative of poor
quality.
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The PATROL system is developed by Waters Corporation (Milford, MA), www.waters.com.
Obtained from Silicycle: www.silicycle.com.
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A THFꢀsolvate and monohydrate form of 1 are known. The six distillations assure that only the
desired nonꢀsolvated form is obtained while also increasing the yield.
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