Development and kilogram-scale synthesis of mGlu5 negative allosteric modulator VU0424238 (auglurant)

Article abstract of DOI:10.1016/j.tetlet.2017.07.100

This communication details the kilogram-scale synthesis of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (VU0424238, auglurant), a novel mGlu₅ negative allosteric modulator (NAM) developed as an alternative treatment for depression. The process highlights a challenging pyridine N-oxidation sequence, an S_NAr reaction, and the elimination of all chromatography steps (required in the medicinal chemistry route) with replacement by highly efficient recrystallizations (save one silica plug). The improved process was utilized for the preparation of a 1.2 kg toxicology batch, as well as a 2.82 kg GMP batch to support the Phase I trial, in very high purity (99.8%).

Full text of DOI:10.1016/j.tetlet.2017.07.100

Accepted Manuscript
Development and Kilogram-Scale Synthesis of mGlu5 Negative Allosteric Mod-
ulator VU0424238 (Auglurant)
Thomas K. David, Nayak K Prashanth, M Rajendraswami, Devendrareddy
Pallalu, Arlindo L. Castelhano, Michael J. Kates, Anna L. Blobaum, Carrie K.
Jones, Kyle A. Emmitte, P. Jeffrey Conn, Craig W. Lindsley
PII:
S0040-4039(17)30968-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.100
TETL 49182
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 July 2017
26 July 2017
28 July 2017
Please cite this article as: David, T.K., Prashanth, N.K., Rajendraswami, M., Pallalu, D., Castelhano, A.L., Kates,
M.J., Blobaum, A.L., Jones, C.K., Emmitte, K.A., Conn, P.J., Lindsley, C.W., Development and Kilogram-Scale
Synthesis of mGlu5 Negative Allosteric Modulator VU0424238 (Auglurant), Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.07.100
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Development and Kilogram-Scale Synthesis of mGlu5 Leave this area blank for abstract info.
Negative Allosteric Modulator VU0424238 (Auglurant)
Thomas K. David, Prashanth Nayak K, Rajendraswami M, Devendrareddy Pallalu, Arlindo L. Castelhano,
Michael J. Kates, Anna L. Blobaum, Carrie K. Jones, Kyle A. Emmitte, P. Jeffrey Conn and Craig W. Lindsley

1
Tetrahedron Letters
Development and Kilogram-Scale Synthesis of mGlu5 Negative
Allosteric Modulator VU0424238 (Auglurant)
Thomas K. David,ψ Prashanth Nayak K,ψ Rajendraswami M,ψ Devendrareddy Pallalu,ψ Arlindo L.
Castelhano,¥ Michael J. Kates,¥ Anna L. Blobaum,ǂ Carrie K. Jones,ǂ Kyle A. Emmitte,Φ P. Jeffrey Connǂ
and Craig W. Lindsleyǂ*
ψAnthem Biosciences Private Limited No. 49, Bommasandra Industrial Area, Bommasandra , Bangalore – 560 099 Karnataka, INDIA
¥DavosPharma, A Davos Chemical Company, 600 East Crescent Ave., Upper Saddle River, NJ 07458, U.S.A.
ΦDepartment of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, 76107, U.S.A.
ǂDepartment of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232-6600, U.S.A.
ARTICLE INFO
ABSTRACT
This communication details the kilogram-scale synthesis of N-(5-fluoropyridin-2-yl)-6-methyl-
4-(pyrimidin-5-yloxy)picolinamide (VU0424238, auglurant), a novel mGlu5 negative allosteric
modulator (NAM) developed as an alternative treatment for depression. The process highlights
a challenging pyridine N-oxidation sequence, an SNAr reaction, and the elimination of all
chromatography steps (required in the medicinal chemistry route) with replacement by highly
efficient recrystallizations (save one silica plug). The improved process was utilized for the
preparation of a 1.2 kg toxicology batch, as well as a 2.82 kg GMP batch to support the Phase I
trial, in very high purity (99.8%).
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Pyridine N-oxide
recrystallization
mGlu5 NAM
SNAr
2017 Elsevier Ltd. All rights reserved.
The class C G protein-coupled receptor (GPCR) metabotropic
glutamate receptor subtype 5 (mGlu5) is one of eight mGluRs
toxicology studies as well as drug product for a human Phase I
clinical trial.
activated by glutamate (L-glutamic acid).1
Due to high
evolutionary conservation of the orthosteric glutamate binding
site and the physiochemical challenges with glutamate analogs,
drug discovery efforts have largely focused on allosteric
modulation (negative allosteric modulation (NAM) or positive
allosteric modulation (PAM)) as the desired mode of
pharmacology for these GPCRs.2-5 Decades of preclinical
evidence provide strong support for the therapeutic utility of
mGlu5 NAMs for the potential treatment of major depressive
disorder, anxiety, fragile X syndrome, Parkinson’s disease,
autism and Alzheimer’s disease.6-16
Derived from the first
mGlu5 NAM MPEP (1), several mGlu5 NAMs 2-4, based on a
conserved phenyl/heteroaryl acetylene chemotype, have entered
Phase II clinical trials, but none have made it to market launch
(Figure 1).18-26
Our mGlu5 NAM effort departed from the prototypical
phenyl/heteroaryl acetylene chemotype by virtue of a high-
throughput screen that identified fundamentally new chemical
matter devoid of the prototypical aryl/heteroaryl acetylene
motif.27-30
During the course of our discovery effort, we
identified VU0424238 (5), later named auglurant, as a clinical
candidate with all of the requisite pharmacological and DMPK
properties for advancement into IND-enabling studies.30 Herein,
we report on the development of an efficient process route for the
multi-kilogram production of VU0424238 to support both GLP
Figure 1. Structures of prototypical and clinical mGlu5 NAMs: MPEP (1),
mavoglurant (2), basimglurant (3), dipraglurant (4) and the atypical, non-
acetylenic VU0424238/auglurant (5).

2
Tetrahedron
The medicinal chemistry route developed to prepare N-(5-
Following these temperature guidelines, the process resulted in
no thermal stability/safety issues in the subsequent IND-
toxicology and GMP batch. However, this was a major concern
for the large scale production of 5, and the concern was realized.
Beyond safety assessment concerns, initial development
work echoed earlier considerations on the high aqueous solubility
and polarity of 7, rendering product extraction and isolation
tedious. Pilot chemistry indicated that the equivalents of H2O2-
urea adduct (2.0 equiv.) and TFAA (2.2 equiv.), relative to 1.0
equivalents of 6 were indeed optimal; however, reduction of the
solvent volume of THF proved fruitful. In the medicinal
chemistry route, 40 V of THF was employed, but this
complicated product extraction on large scales. We were able to
progressively lower the amount of THF to only 15 V (~63%
reduction), which greatly enhanced product extraction. Beyond
the reduction in THF, the reaction was quenched with 10%
sodium thiosulfate, the aqueous layer saturated with NaCl and
extracted with CH2Cl2, followed by washing with saturated
potassium carbonate to remove excess TFAA and TFA. These
modifications provided the desired N-oxide 7 in average purity of
97.6% (plus 1.2% 6) reproducibly from 25 g to 4.25 kg scale
batches, and avoided the need for HPLC purification. For both
the toxicology batch and GMP batches, 7 was advanced without
additional purification (>97.6% purity, with <1.5% of 6), and the
residual 6 would be removed at a later purification step (Scheme
2).
fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide
(5, VU0424238, auglurant) was a five step linear sequence
(Scheme 1) that proceeded in 33.9% overall yield, and involved
five HPLC purification steps.30 Moreover, this route was adapted
from 10 mg scale to a maximum of ~17 g in the medicinal
chemistry laboratory.
peroxide-urea complex in trifluoroacetic anhydride in dilute THF
(40 V), while maintained at 0 C, delivered the pyridine N-oxide
7 in 99% yield. Note, due to potential thermal stability concerns
In short, treatment of pyridine 6 with
o
of the crude pyridine N-oxide, the temperature was maintained at
0 C for these scale reactions.30 The pyridine N-oxide 7 is also
o
highly water soluble; thus, we were concerned about both the
isolation of 7 and the thermal stability of pyridine N-oxide
generation on kilo scale. Cyanation proceeded smoothly
affording 8, which then underwent an SNAr reaction with 5-
hydroxypyrimidine to deliver 10 in 77% yield after HLPC
purification. Hydrolysis of the nitrile provided acid 11 in near
quantitative yield, and a subsequent POCl3-mediated amide
coupling with 2-amino-5-fluoropyridine 12 gave the candidate 5
in 60% yield after HLPC purification. While this route provided
the quantity of material needed to evaluate and select 5 as a
preclinical development candidate, there were a number of issues
and concerns to be addressed prior to efficient scale-up of
toxicology and GMP batches in the pilot plant: (a) Step 1, the
pyridine N-oxidation sequence (exotherm risk) and water
solubility of the product; (b) Step 3, the SNAr reaction; (d) the
final amide coupling reaction (only 60% on small scale), and (c)
the elimination of all HPLC purification steps and replacement
with high yielding recrystallization protocols. Moreover, pilot
dose efficacy and toxicology escalation studies required
extensive pharmaceutical sciences intervention and formulation
studies. Ultimately, a spray-dried dispersion (SDD) formulation
was developed (12.5% VU0424238
Scheme 2. Synthesis of pyridine N-oxide 7.
Scheme 1. Original Medicinal Chemistry Route to 5 (VU0424238).
The cyanation of 7 to provide 8 also required revision of the
original medicinal chemistry route.30 Here, the equivalents of
both TMSCN and dimethylcarbamoyl chloride (DMCC) were
increased from 1.2 equivalents to 2.6 equivalents, while reducing
the DCM solvent volume to 20 V and lowering the reaction
o
temperature to 0 C. On scale, the optimal reaction time for
>80% conversion, as judged by HPLC, was 36 hours. For the
pilot chemistry (10-500 g scales) as well as the toxicology and
GMP batches, filtration through a silica plug and recrystalization
from n-heptane afforded 50-52% isolated yields of 8 with HPLC
purities >99.75%. Moreover, these conditions afforded no trace
of the N-oxide 7 and DMCC content was <110 ppm (Scheme 3).
While finding an alternative to DCM would ideally be
environmentally attractive, project timelines required pushing
forward.
Scheme 3. Synthesis of cyanide 8.
Pilot chemistry was performed at multiple scales (10 g, 25 g,
100g and 500 g) to assess and optimize reaction conditions prior
to committing to the 1.2 kg IND-toxicology and 2.82 kg GMP
batch. The initial focus was on safety assessment and reaction
optimization of step 1, the formation of the pyridine N-oxide 7.
Due to the potential for thermal instability of both crude and
purified pyridine N-oxide 7, a differential scanning calorimetry
(DSC) study and safety evaluation was performed on both crude
and purified N-oxide 7. In the event, DSC thermogram of
The SNAr reaction between 8 and 5-hydroxypryimidine 9
was also revised.30 We were pleased to find that we could
reduce the equivalents of 5-hydroxypryimidine 9 from 2.2 to 1.2
equivalents with no diminution in yields.
chromatography was also avoided. In the event, 5-
hydroxypryimidine (1.2 equiv.) and potassium carbonate (3.0
o
purified 7 displayed a strong exotherm at 121 C, with heat
evolution of 1,495J/g, and the crude 7 lesser so, at 431 J/g!
Based on the DSC data, the temperature of the reaction, as well
as of the jacket/heating media during reaction concentration,
Moreover,
o
must not exceed 30 C at any point to maintain a safety margin.

3
equiv.) in DMF (10V) was treated with 8 at room temperature
and subsequently heated to 80 C for 40 h (>94% conversion by
chemistry team was replaced by
a
highly efficient
o
recrystallization from ethyl acetate (Scheme 6). This protocol
afforded 5, N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-
yloxy)picolinamide (VU0424238, auglurant), in yields averaging
50% and with high purities >99.5% by HPLC (no single impurity
was >0.05% and total impurities 0.19%).31 Release testing of the
GMP batch by validated analytical methods revealed a purity of
the API of 99.8%, Total impurities of 0.19% with individual
impurities at 0.02-0.07%, 0.08% residue on ignition, 0.52% water
content by KF and a clean melt at 167.25o (by DSC). Residual
solvents, metals and microbial analysis met specified guidelines.
A portion of the GMP batch was spray dried with HPMCAS-M
yielding a stable, amorphous 12.5% SDD that was then
incorporated into a blend formulation and encapsulated in 5 and
20mg capsule strengths. Stability studies of the VU0424238 API
and SDD Tox batches at 6 months under normal and
forced/accelerated conditions show very stable products with no
change in quality attributes. Overall, the process route (here
highlighting the final GMP process and data) proceeded in five
steps with an overall yield of 17.5% (cf with 33.9% via the
HPLC). At this point, the reaction was cooled to room
temperature, and the solid was filtered and washed with DMF.
o
The filtrate was then cooled to 0 C, and purified water was
added dropwise over 1 hour, forming a white precipitate. The
precipitate was washed with purified water (10 V) and dried to
afford 80-85% isolated yield of 10 in >99.7% purity, without the
need for chromatography (Scheme 4).
Scheme 4. SNAr reaction to afford 10.
The hydrolysis of nitrile 10 to the carboxylic acid 11
afforded three impurities not observed via the reaction scales and
conditions of the medicinal chemistry route (Scheme1).30 Pilot
scale-up chemistry noted the formation of the primary
carboxamide 13 (~1% ) and two acrolein impurities 14 and 15 (6-
9% combined by HPLC) due to the harsh 90 oC hydrolysis
conditions (Figure 2); however, all three Impurities could be
eliminated or greatly reduced in the work-up procedure (note, 15
is present in final 5 at ~0.05%).
medicinal
chemistry scales),
eliminated
all
HPLC
chromatography purifications (save one slicia plug), and is a
scalable process of high purity (99.8%).
Scheme 6. Synthesis of 5 (VU0424238, auglurant).
A scalable approach to the novel mGlu5 NAM 5 (VU0424238,
auglurant) has been successfully developed and adapted to multi-
kilo scale. The developed process is scalable and provided
kilogram quantities of material for GLP tox studies formulated as
a 12.5% SDD, and GMP material for drug product manufacture
of clinical studies.. Notably, we found an initial safety concern
with N-oxide production 7, and observed a large exotherm at 121
oC, with heat evolution of 1,495J/g, requiring stringent control of
temperature. The yields achieved with this optimized GMP route
are comparable to the original medicinal chemistry route, but all
HPLC purification has been replaced with aqueous work-ups and
highly efficient recrystallization procedures affording product of
high purity.
Figure 2. Impurities 13-15 generated under the harsh amide
hydrolysis conditions.
In the event, hydrolysis of 10 with 2 N NaOH (10 V) in 1,4-
o
dioxane (15 V) at 90 C for 6 hours afforded conversion to 11
(with low levels of 13-15). Dilution with DCM and subsequent
washing of the aqueous layer with DCM, afforded an aqueous
solution that was acidified to pH 3-4 using 6 N HCl. The
aqueous layer was then evaporated, resuspended in 10%
MeOH/DCM (50 V) and stirred at 50-55 oC for 1 h. The
undissolved solid was filtered and the solvent evaporated to
afford acid 11 in 75-80% isolated yield and in purities ranging
from 94.4 to 99.7% (Scheme 5).
Acknowledgments
Financial support from the Warren Family and Foundation is
gratefully acknowledged and for establishing the William K.
Warren, Jr. Chair in Medicine.
Scheme 5. Nitrile hydrolysis to afford 11.
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31. Large scale synthesis of 5. Synthesis of 4-chloro-2-methylpyridine-N-
oxide (7). To a solution of 4-chloro-2-methyl pyridine (4.0 kg, 31.32 mol) in
tetrahydrofuran (40.0 L, 10 V), hydrogen peroxide-urea adduct (588 kg, 62.7
mol) was added lot wise at 25 to 30 °C. The reaction mass was stirred at 25-
30°C for about 10-15 minutes and cooled the reaction mass to 0-5°C. A
solution of trifluoroacetic anhydride (14.48 kg, 68.9 mol) in THF (20.0 L, 5
V) was added drop wise to the reaction mass over a period of 2-3 h
maintaining the temperature between 0-5°C. The reaction was slowly
allowed to attain 25-30°C and stirred for 18 h. The reaction was monitored
by HPLC (Int 1 NMT 5.0 % by HPLC). Reaction mass was cooled to 0-5°C
and quenched with 10% sodium thiosulphate solution (40.0 L, 10 V) over a
period of 1 h maintaining temperature between 0-5°C. The reaction mass was
diluted with dichloromethane (8.0 L, 2 V) and the temperature was slowly
allowed to attain 25-30°C and stirred for 10 minutes at 25 to 30°C. The layers
were separated; aqueous layer was saturated with sodium chloride (14.0 kg,
3.5 w/w on SM) [M R Fine chem, Assay by titrimetry - 99.9 % w/w] and
extracted with dichloromethane (20.0 L, 5 V x 3). To the combined organic
layer was added aqueous saturated potassium carbonate solution (20.0 L, 5.0
V) [Chemielink, Assay by titrimetry - 99.8 % w/w] at 25-30°C and stirred for
15 minutes. The layers were separated; aqueous layer was extracted
with dichloromethane (20.0 L, 5 V x 2). The combined organic layer was
dried over sodium sulfate (0.8 kg, 0.2 w/w) and concentrated under vacuum
to obtain crude Int 2 (4.32 kg, 96%) as pale yellow oil which was taken as
such for next step without purification. 1H NMR (400 MHz, DMSO-d6) δ
8.23 (d, J = 7.0 Hz, 1H), 7.66 (d, J = 3.0 Hz, 1H), 7.40 (dd, J = 7.0, 3.0 Hz,
1H), 2.32 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 149.53, 139.78, 128.73,
126.41, 124.17, 17.09 ppm; LCMS (Method 1): RT = 0.302 min, m/z = 144.2
[M+H]+; HRMS, calc’d for C6H6ClNO [M], 143.0138; found
143.0139.Synthesis of 4-chloro-6-methylpicolinonitrile (8). To a solution
of 4-chloro-2-methylpyridine-N-oxide (7, 4.3 kg, 29.94 mol) in
dichloromethane (64.5 L, 15 V) was added trimethyl silyl cyanide (9.76 L,
77.83 mol) at 25-30 °C over a period of 30 minutes and further stirred for 15
minutes. Reaction mass was cooled to 0-5 °C. N,N-Dimethylcarbamoyl
chloride (7.17 L, 77.83 mol) was added drop wise over a period of 1h. The
reaction mass was slowly warmed to 25-30 °C and stirred for 36 h. Reaction
was monitored by HPLC [7 NMT 1.0 %]. The reaction mass was cooled to 0-
5 °C. The reaction was quenched with 10% aqueous potassium carbonate
solution until the pH of aqueous layer was about 9-10. The temperature of
reaction mass was allowed to attain 25-30 °C and the layers were separated.
The aqueous layer was extracted with dichloromethane (8.6 L, 2 V). The
combined organic layer was washed with 0.5 N HCl solution (21.5 L, 5 V)
followed by brine solution (21.5 L, 5 V), dried over anhydrous sodium sulfate
and concentrated under vacuum. The residue was chased twice with n-
heptane (2 x 17.2 L). The crude product was diluted with 2 % ethyl acetate
[Ashok alco-chem limited, Purity (area %) by GC - 100 %] in hexanes (43 L,
10 V) and filtered through silica plug (21.5 kg, 5 % w/w on SM, 230-400
mesh) and silica plug was washed with 10% ethyl acetate in hexanes till the
product was completely eluted (300 L, 69 V). Combined fractions were
concentrated and residue was chased twice with n-heptane (2 x 17.2 L).
Resulting mass was stirred in n-heptane (21.5 L, 5 V) at 0-5 °C for 1h and
filtered. Solid was washed with cold n-heptane (4.3 L, 1 V) and dried to get 8
as off white solid (2.32 kg, 51 %). . 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d,
J = 1.6 Hz, 1H), 7.82 (d, J = 1.7 Hz, 1H), 2.52 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ = 161.99, 144.13, 133.01, 127.65, 126.40, 116.60, 23.57 ppm;
LCMS (Method 1): RT = 0.715 min, m/z = 153.2 [M+H]+; HRMS, calc’d for
C7H5ClN2 [M], 152.0141; found 152.0139. Synthesis of 6-methyl-4-
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U.; Pähler, A.; Peters, J. U.; Petersen, A.; Prinssen, E.; Ricci, A.;
Rueher, D.; Rueher, M.; Schneider, M.; Spurr, P.; Stoll, T.;
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Lindemann, L. J. Med. Chem. 2015, 58, 1358-1371.
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Funk, C.; Hartung, T.; Gloge, A.; Mallalieu, N. L. Xenobiotica
2017, 47, 144-153.
24. Quiroz, J. A.; Tamburri, P.; Deptula, D.; Banken, L.; Beyer, U.;
Rabbia, M.; Parkar, N.; Fontoura, P.; Santarelli, L. JAMA
Psychiatry 2016, 73, 675-684.
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Tison, F.; Rascol, O.; Poli, S. M. Mov. Disord. 2014, 29, 1074-
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Eggert, K.; Lew, M.; Isaacson, S.; Bezard, E.; Poli, S. M.; Goetz,
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995-1003.
(pyrimidin-5-yloxy)picolinonitrile (10). To
a
solution of 5-
hydroxypyrimidine (9, 1.73 kg, 18.08 mol) in DMF (23.0 L, 10 V), potassium
carbonate (6.25 kg, 45.21 mol) was added followed by 4-chloro-6-
methylpicolinonitrile (8, 2.3 kg, 15.07 mol) at 25-30°C. The reaction mass
was heated at 75-80 °C for 36 h. The reaction was monitored by HPLC 8
NMT 2.0 % by HPLC). Reaction mass was cooled to 25-30 °C. The solid
was filtered and washed the solid with DMF (4.6 L, 2.0 V). The filtrate was
cooled to 0-5 °C and purified water (27.6 L, 12 V) was added drop wise over
a period of 1 h. The solid precipitated was filtered and washed with purified
water (2.3 L, 10 V) to afford 10 as off white solid (2.62 kg, 82.1%). 1H NMR
(400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.85 (s, 2H), 7.74 (d, J = 2.4 Hz, 1H),
7.32 (d, J = 2.3 Hz, 1H), 2.48 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ =
28. Zhang, L.; Balan, G.; Barreiro, G.; Boscoe, B. P.; Chenard, L. K.;
Cianfrogna, J.; Claffey, M. M.; Chen, L.; Coffman, K. J.; Drozda,
S. E.; Dunetz, J. R.; Fonseca, K. R.; Galatsis, P.; Grimwood, S.;
Lazzaro, J. T.; Mancuso, J. Y.; Miller, E. L.; Reese, M. R.;
Rogers, B. N.; Sakurada, I.; Skaddan, M.; Smith, D. L.; Stepan, A.
F.; Trapa, P.; Tuttle, J. B.; Verhoest, P. R.; Walker, D. P.; Wright,
A. S.; Zaleska, M. M.; Zasadny, K.; Shaffer, C. L. J. Med. Chem.
2014, 57, 861-877.

5
164.04, 162.28, 155.51, 150.02, 148.75, 133.54, 117.05, 115.59, 115.04,
23.82 ppm; LCMS (Method 1): RT = 0.535 min, m/z = 213.2 [M+H]+; HRMS,
calc’d for C11H8N4O [M], 212.0698; found 212.0697. Synthesis of 6-methyl-
4-(pyrimidin-5-yloxy)picolinic acid (11). To a solution of 6-methyl-4-
(pyrimidin-5-yloxy) picolinonitrile (10, 2.6 kg, 12.25 mol) in 1,4-dioxane
(39.0 L, 15 V) [Synergy chemicals, Purity (area %) by GC - 99.7 %], 2N
aqueous NaOH solution (26.0 L, 10 V) was added at 25-30°C. The reaction
mixture was heated at 85-90°C for 6 h. Reaction was monitored by HPLC,
reaction mass was cooled to 25-30 °C and diluted with DCM (26.0 L, 10 V).
The layers were separated, aqueous layer was washed with DCM (26.0 L, 10
V), cooled the aqueous layer to 0-5°C and adjusted the pH to 3-4 using 6N
aqueous HCl solution. The aqueous layer was evaporated under vacuum, the
crude product obtained was suspended in 10 % methanol in dichloromethane
(130.0 L, 50 V) and stirred at 45-50 °C for 1 h. The un-dissolved solid was
filtered and filtrate was evaporated under vacuum. Residue was chased with
DCM (2 X 7 V), stirred with DCM: n-heptane (1:1, 10 V), filtered and dried
to afford 11 as off white solid (2.22 kg, 78.4 %). Synthesis of N-(5-
Fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (5).
A
solution of 6-methyl-4-(pyrimidin-5-yloxy)pyridine-2-carboxylic acid (11,
2.2 kg, 9.51 mol) in pyridine (33.0 L, 15 V) was stirred at 25-30 °C for 15-20
minutes. 5-fluoro-2-aminopyridine (12, 1.386 kg, 12.36 mol) was added to
the reaction mass at 25-30 °C and stirred at 25-30 °C for 45 minutes.
Reaction mass was cooled to 0-5 ºC, phosphorus oxychloride (1.33 L, 14.27
mol) was added drop wise over a period of 1 h by maintaining the
temperature between 0-5 ºC. The reaction mass was stirred at 10-15°C for 30
min. The reaction completion was monitored by HPLC. After reaction
completion, reaction mass was quenched with water (44.0 L, 20 V) and
neutralized with 10% potassium carbonate solution (22.0 L, 10 V) at 0-5 °C.
The suspension was stirred at 0-5 °C for 1h. Solid was filtered, washed with
water (22.0 L, 10 vol.) and dried under vacuum. Crude material was dissolved
in DCM (22.0 L, 10 vol.) and washed with water (6 x 10 V) to remove
pyridine traces. Organic layer was dried over sodium sulfate and evaporated
1
under vacuum to get desired product as beige solid (1.8 kg, 58.2 %). H NMR
(400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.18 (s, 1H), 8.88 (s, 2H), 8.40 (d, J =
3.0 Hz, 1H), 8.27 (dd, J = 9.2 Hz, 4.10 Hz, 1H), 7.86 (td, J = 8.6, 3.1 Hz, 1H),
7.55 (d, J = 2.3 Hz, 1H), 7.29 (d, J = 2.3 Hz, 1H), 2.58 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) δ = 165.15, 161.11, 160.57, 156.12 (d, J(C,F) = 249.0
Hz), 155.41, 150.29, 150.07, 149.01, 146.92 (d, J(C,F) = 2.1 Hz), 135.94 (d,
J(C,F) = 25.5 Hz), 125.83 (d, J(C,F) = 19.9 Hz), 114.56, 114.27 (d, J(C,F) =
4.7 Hz), 108.01, 23.84 ppm; LCMS (Method 2): RT = 0.727 min, m/z = 326.2
[M+H]+; HRMS, calc’d for C16H12FN5O2 [M], 325.0975; found 325.0979.
AUTHOR INFORMATION
Corresponding Author
* E-mail: craig.lindsley@vanderbilt.edu
Phone: 615-322-8700, fax: 615-343-3088

6
Tetrahedron
Scalable 5 step GMP synthesis of Auglurant in
Highlights




>99.8% purity
Elimination of chromatography steps and
replacement with recrystallizations
Addressed thermal instability of pyridine N-
oxide
Efficient cyanation and SNAr reactions