Process Development and Multikilogram-Scale Synthesis of a TRPV1 Antagonist

Article abstract of DOI:10.1021/op400304h

The process development and multikilogram preparation of a TRPV1 antagonist, 1, is described. Pyrido[2,3-b]pyrazine 1 was prepared in a convergent manner by the coupling of two key fragments, glyoxal 2 and diamine 3. Glyoxal 2 was synthesized in six chemical steps in 20% overall yield, the key step being a challenging Grignard reaction to install the glyoxalate moiety. Diamine 3 was also prepared in six chemical steps in 46% overall yield, exploiting a regioselective nucleophilic aromatic substitution to obtain the key nitrodiamine intermediate 19.

Full text of DOI:10.1021/op400304h

Article
pubs.acs.org/OPRD
Process Development and Multikilogram-Scale Synthesis of a TRPV1
Antagonist
Ed Cleator,* Jeremy P. Scott,* Paulo Avalle, Matthew M. Bio, Sarah E. Brewer, Antony J. Davies,
Andrew D. Gibb, Faye J. Sheen, Gavin W. Stewart, Debra J. Wallace, and Robert D. Wilson.
Global Process Chemistry, Merck Sharp and Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU,
U.K.
ABSTRACT: The process development and multikilogram preparation of a TRPV1 antagonist, 1, is described. Pyrido[2,3-
b]pyrazine 1 was prepared in a convergent manner by the coupling of two key fragments, glyoxal 2 and diamine 3. Glyoxal 2 was
synthesized in six chemical steps in 20% overall yield, the key step being a challenging Grignard reaction to install the glyoxalate
moiety. Diamine 3 was also prepared in six chemical steps in 46% overall yield, exploiting a regioselective nucleophilic aromatic
substitution to obtain the key nitrodiamine intermediate 19.
unsuitable as elevated temperatures were required to drive the
reaction to completion, which led to significant decomposition
products. Alternatively, acetonitrile buffered with disodium
hydrogen phosphate at 80 °C gave an acceptable reaction
profile, but a white solid sublimed onto the nearest cool surface.
The formation of this solid was attributed to the interaction of
hydrogen bromide with acetonitrile. On scale, the reaction was
performed in a closed system to prevent the blockage of plant
vessel valves by this sublimation byproduct. The crude reaction
mixture was cooled and filtered, and the solvent was switched
to isopropyl alcohol to crystallize 7, which was isolated in 69%
yield over the two steps.
Conversion of bromide 7 to iodide 8 was necessary in order
to improve the efficiency of the halogen−metal exchange
reaction to form glyoxal fragment 2. Iodide 8 was stable under
the conditions required to form 9, so a telescoped process from
7 to 9 was developed. Bromide 7 was converted to 8 using
sodium iodide and acetic acid in acetonitrile at 65 °C. Iodide 8
was obtained in >95% assay yield, and after an aqueous workup,
a solvent switch to toluene was performed. The solution of 8
was then treated with concentrated sulfuric acid and heated to
50 °C to hydrolyze the nitrile, affording amide 9. An extractive
workup was developed, beginning with an inverse quench into a
sodium hydroxide solution (1 M). Amide 9 was isolated in 85%
yield over the two steps following extraction of the aqueous
phase with methyl tert-butyl ether and a solvent switch to
toluene.
INTRODUCTION
■
The transient receptor potential cation channel, subfamily V,
member 1 (TRPV1) is a nonselective cation channel which is
activated by a wide range of stimuli, such as capsaicin, acid, or
heat.1 Recently, selective antagonists of TRPV1 activation have
been investigated in attempts to identify new treatments for
pain.2 Our interest in this field instigated a multikilogram
preparative campaign of pyrido[2,3-b]pyrazine 1.3 The original
route for the preparation of 1 was sufficient for gram quantities
but not scalable to the kilogram level. Because of the length of
the synthesis and a number of challenging and/or low-yielding
steps, we designed and implemented a new synthesis. Our
synthetic strategy was based upon a disconnection approach
giving two divergent fragments, glyoxal 2 and diamine 3
(Scheme 1), which could be coupled under acidic conditions at
a late convergent stage of the synthesis. Herein we describe the
process development and preparation of 1 on a pilot-plant
scale.
RESULTS AND DISCUSSION
■
Synthesis of Glyoxal Fragment 2. The synthesis of
glyoxal fragment 2 began from commercially available 2-
hydroxy-3-(trifluoromethyl)pyridine (4) (Scheme 2). Iodina-
tion of 4 with N-iodosuccinimide (NIS) in acetic acid was
complete in 5 h at 65 °C. The product could be crystallized
directly from the reaction mixture by the addition of aqueous
sodium thiosulfate followed by additional water, affording 5 in
86% yield. Rosenmund−von Braun cyanation4 of 5 with
copper(I) cyanide in DMF gave 6, which was not isolated
because of thermal stability concerns. After removal of the
copper salts by filtration and aqueous washes with N-(2-
hydroxyethyl)ethylenediaminetriacetic acid and water to ensure
complete removal of DMF, the crude stream was taken directly
onto the bromination step to form 7.
In order to complete the synthesis of glyoxal 2, several
kilograms of electrophile 10 (Scheme 3) had to be prepared.
Initially, during our development phase, the piperidine
analogue of 10 was synthesized using a literature procedure.5
The preparation of the piperidine derivative was deemed
unsatisfactory to be run on larger scale because of long reaction
times, elevated temperatures, and the need for vacuum
distillation to purify the product. A more attractive alternative
for the synthesis of 10 was identified by using a literature
Phosphorous oxybromide was found to be the only reagent
which could effectively brominate 6. Although the yields were
high, several issues needed to be addressed before we could run
the reaction on scale. The only compatible solvents were
chlorobenzene and acetonitrile. Chlorobenzene was deemed
Received: October 24, 2013
Published: November 21, 2013
© 2013 American Chemical Society
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Scheme 1. Retrosynthetic Strategy for Target 1
a
Scheme 2. Synthesis of Glyoxal Fragment 2
a
Reagents and conditions: (a) NIS, AcOH/MeCN, 65 °C, 86%; (b) CuCN, DMF, 120 °C, 85−88% by assay; (c) POBr3, MeCN, 80 °C, 69%
isolated yield over two steps; (d) NaI, AcOH, 65 °C; (e) conc. H2SO4, toluene, 50 °C, 85% isolated yield over two steps; (f) NaH, THF, TMEDA,
i
then 10 in THF, cool to T < −60 °C, then PrMgCl, 39%.
a
procedure for the formation of similar amides using Grignard
reagents.6 This allowed us to substitute piperidine with
diethylamine (Scheme 3). Thus, amide 11 was prepared from
diethylamine by the addition of isopropylmagnesium chloride
in tetrahydrofuran (THF) and subsequently added to ethyl
acetal 12. Following a quench and aqueous extraction, the
organic phase was concentrated in vacuo to give a 78% yield of
10 in suitable purity to be used directly in downstream
chemistry.
Scheme 3. Preparation of Glyoxal Acetal Electrophile 10
a
Reagents and conditions: (a) THF, T < 25 °C, 78%.
Synthesis of Diamine Fragment 3. The synthesis of
diamine 3 (Scheme 4) was initiated from commercially
available dihydroxypyridine 13. Selective nitration of 13 at
the 3-position of the pyridine ring has been reported in the
literature.11−13 Slight modifications to this protocol allowed the
reaction to proceed efficiently using lower reagent volumes.
The optimized conditions for the reaction at 0 °C, with three
volumes of concentrated sulfuric acid and 1.6 equiv of fuming
nitric acid, gave 14 in 98% yield.
Dichlorination of 14 was initially explored as a one-pot
process using phosphorus oxychloride;11 however, significant
charring and high temperatures were observed, which required
us to explore alternative reagents. A high-yielding, one-pot
dichlorination was found to proceed with either phenyl
dichlorophosphate or phenylphosphoric dichloride; however,
because of extended lead times for these reagents, a two-step
procedure was developed. Initial chlorination with freshly
prepared Vilsmeier reagent in acetonitrile selectively chlori-
nated the 4-position of 14 at ambient temperature with assay
yields greater than 90%. Isolation was achieved by a solvent
switch into water, which provided 15 in 91% yield.
The coupling of 9 and 10 to prepare glyoxal 2 proceeded via
halogen−metal exchange of 9 (Scheme 2), which proved
challenging. There are several examples of acylation reactions of
this type using organolithium reagents derived from 2-
bromopyridines.7,8 The lithiation of 2-bromo-3-
(trifluoromethyl)pyridine9 and the magnesium−halogen ex-
change of 2-iodo-5-cyanopyridine10 are also outlined in the
literature. When we applied these conditions to our system, we
found that proton transfer from the amide was a significant
issue, as only modest yields of 2 were observed. Optimisation of
this reaction was demanding; treatment of 9 with sodium
hydride prior to organometallic generation was found to inhibit
proton transfer and increase the amount of desired 2 formed.
The evaluation of a protecting group strategy for the amide
moiety, which would obviate the need to use NaH, ultimately
offered no advantage over the optimized sodium hydride
conditions and would have increased the step count in the
longest linear sequence. The results were further improved
when isopropylmagnesium chloride was added to a mixture of
deprotonated 9 and 10 to initiate the magnesium−halogen
exchange in situ. Glyoxal 2 was then separated from the
undesired deiodinated analogue of 9 by selective aqueous
extraction with hydrochloric acid and subsequent crystalliza-
tion, giving an isolated yield of 39%.
The second chlorination required more strenuous con-
ditions. Following a screen of reagents, neat phosphorus
oxychloride at elevated temperatures proved the most effective.
The rate of conversion to 16 was improved by charging lithium
chloride and hydrochloric acid into the reaction mixture at
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a
Scheme 4. Synthesis of Diamine 3 from Pyridine 13
a
Reagents and conditions: (a) H2SO4/HNO3, 0 °C, 98%; (b) (COCl)2, DMF, MeCN, 20 °C, 91%; (c) POCl3, LiCl, HCl added portionwise, 105
°C, 88%; (d) NH3, 91 °C, 94%; (e) DMPU, NaOt-Bu, 55 °C, 68%; (f) Pd/C (5 wt %), EtOAc, H2 (50 psi) then AcOH, 91%.
a
Scheme 5. Coupling of Glyoxal Fragment 2 and Diamine Fragment 3
a
Reagents and conditions: (a) NMP, 4 M HCl, 45−50 °C; (b) CDI, NH3, THF, 52 °C, 74% over two steps; (c) EtOH/water 4:1, 45 °C, 95%.
hourly intervals. It is proposed that these additives maintained
the level of chloride ion in the reaction mixture, enabling the
reaction to go to completion. At the end of the reaction,
acetonitrile was added to homogenize the reaction mixture
before a controlled quench with water. The acetonitrile was
then removed by distillation, and 16 crystallized directly from
the reaction mixture in 88% yield.
Amination of dichloride 16 was achieved using aqueous
ammonia in a sealed vessel at 91 °C (the internal pressure
reached 4090 mbar during this reaction), and 17 could be
simply filtered from the crude stream on cooling. This reaction
gave diamine 17 in 94% yield. Development showed that the
SNAr displacement of 18 was selective at the 4-position of 17
when performed in polar aprotic solvents.14 Deprotonation was
required for the reaction to proceed, and screening several
bases showed that sodium was a better counterion than
potassium or cesium in these reactions. As a result, sodium tert-
butoxide was chosen. Initial solvent screening showed that
good conversion was observed when dimethyl sulfoxide
(DMSO) was used, although isolation of the product was
troublesome. N,N-Dimethylacetamide (DMAc) and N,N-
dimethylformamide (DMF) acylated the free amine at the 2-
position and were therefore unsuitable. N,N′-Dimethyl-N,N-
isopropyleneurea (DMPU) gave reproducible results and was
inert to the reaction conditions. A bis-substituted byproduct,
20, (Scheme 4) was observed as the major impurity formed
under these conditions and proved difficult to reject at high
levels. Further investigations showed that the formation 20
could be minimized by slow addition of the base. Under these
conditions, the formation of 20 could be successfully reduced
to less than 1 mol %. When the reaction was complete, 19 was
crystallized from 1:1 ethanol/acetic acid in 68% isolated yield.
Finally, reduction of the nitro group completed the synthesis of
diamine 3. During the development phase of this reaction,
although the assay yields were high, it became apparent that
high levels of 3 (up to 20%) remained attached to the catalyst
after the reaction, giving yields that were lower than anticipated.
Using ethyl acetate as the solvent improved the recovery of 3,
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as only 5% of the material was lost to the catalyst. The free base
was found to be unstable, so a suitable salt was sought to
facilitate the isolatation of 3. The monoacetate salt was
identified, and the filtrate of the reaction mixture post
palladium removal could be treated directly with acetic acid,
allowing crystallisation of the salt from the crude reaction
stream to give 3·AcOH in 91% isolated yield with a residual
palladium level of 8 ppm. The nitro-reduced analogue of
impurity 20 was found to be completely rejected in the liquors.
Fragment 3 was therefore produced on scale in six steps from
commercially available materials in 46% overall yield.
Final Coupling and Isolation. The coupling of glyoxal 2
and diamine 3 proceeded under acidic conditions in a variety of
solvents (Scheme 5). During the course of initial experimenta-
tion, significant quantities of acid 22 were produced in addition
to deazadenine byproduct 21 (identified by high-resolution MS
and subsequently confirmed by synthesis); therefore, our
process development focused on reducing the formation of
these byproducts in order to maximize the overall yield of 1.
A screen of the reaction for improved conditions was
initiated, and this highlighted that hydrochloric acid in N-
methylpyrrolidine (NMP) at 45 °C for 50 h was optimal. When
applied, this protocol allowed the level of acid 22 to be lowered
to 5%, and deazaadenine 21 was formed in only trace
quantities. Separation of 22 from 1 was problematic, and the
easiest solution was to convert 22 into 1 by treatment with 1,1-
carbonyldiimidazole (CDI) and ammonia. A purity upgrade of
1 from this two-step protocol was achieved using tetrahy-
drofuran (THF), and as a result, 1 could be crystallized as a
THF solvate by the addition of water in 74% yield, containing
0.26 A% acid 22 by HPLC. The monohydrate of 1 had been
identified as the desired crystalline form, and a process for its
conversion from the THF solvate of 1 was developed. Thus, a
suspension of the THF solvate of 1 in 20 mL/g of a 4:1 mixture
of water and ethanol followed by heating of the mixture to 45
°C effected the desired turnover to the monohydrate of 1 in
95% isolated yield.
followed by water (22 kg); the temperature was allowed to fall
during the addition. The slurry was cooled to room
temperature, filtered, and washed with water (8 kg). After
overnight drying at 50 °C under vacuum, 5 was isolated as a
pale-yellow solid (6.33 kg, 96.4 wt %, 96.3 A%) in 86% yield.
1H NMR (400 MHz, CDCl3): δ 13.33 (br s, 1H), 7.98 (d, J = 2
Hz, 1H), δ 7.85 (d, J = 2 Hz, 1H). 13C NMR (400 MHz,
CDCl3): δ 159.8, 147.8 (q, J = 5 Hz), 144.1, 121.8 (q, J = 32
Hz), 121.3 (q, J = 272 Hz), 62.8. HRMS (EI): calcd 289.9290
for C6H4F3INO (M + H), found 289.9294. Mp 195−196 °C.
6-Bromo-5-trifluoromethylnicotinonitrile (7). 2-Hydroxy-3-
trifluoromethyl-5-iodopyridine (5) (12.33 kg, 42.67 mol) and
copper(I) cyanide (4.01 kg, 44.80 mol) were heated at 120 °C
in DMF (52 kg) for 16 h. The batch was then cooled to
ambient temperature and filtered through a closed filter to
remove copper(I) iodide, and the cake was washed with DMF
(11 kg). The filtrate and wash were stirred vigorously with N-
(2-hydroxyethyl)ethylenediaminetriacetic acid (55 kg of a 35 wt
% solution in water) for 1 h, and the solution was acidified to a
pH in the range 5.5 to 6 using 4 M HCl. Water was then added
such that the total charge of water and 4 M HCl constituted 60
kg (5 mL/g w.r.t. 5). Isopropyl acetate (85 kg) was charged,
and the phases were separated. The aqueous (lower) phase was
back-extracted with isopropyl acetate (53 kg), and the
combined organic layers were washed with lithium chloride
(3 × 24.5 kg of a 5 wt % solution in water) and once with water
(24.5 kg). The organic phase was then switched to acetonitrile
(final volume ∼70 L) by vacuum distillation. HPLC assay of
this layer showed 6.9 kg of 6 (86% assay yield). Disodium
hydrogen phosphate (2.7 kg, 19.0 mol) was added to the
acetonitrile solution of 6, followed by phosphorous oxybromide
(12.1 kg, 42.4 mol). The mixture was heated to 80 °C for 16 h,
with the vessel sealed apart from some venting during the heat
up. The batch was cooled to ambient temperature and filtered,
and the cake was washed with acetonitrile (22 L). The
combined filtrate and wash were switched to 2-propanol (final
volume 22−25 L) by vacuum distillation, the batch self-seeding
upon cooling. Water (20 L) was added over 1 h, and the slurry
was filtered and washed with 2:1 water/IPA (10 L). The solid
was dried under vacuum to give 7 as a pale-pink solid (7.4 kg,
99.3 wt %, 99.1 A%) in 69% yield over the two steps. 1H NMR
(400 MHz, CDCl3): δ 8.54 (d, J = 2 Hz, 1H), 7.95 (d, J = 2 Hz,
1H). 13C NMR (100 MHz, CDCl3): δ 154.2, 143.8, 138.6 (q, J
= 5 Hz), 128.5 (q, J = 34 Hz), 121.0 (q, J = 274 Hz), 114.2,
111.4. Anal. Calcd for C7H2BrF3N2: C, 33.5; H, 0.80; N, 11.16.
Found: C, 33.39; H, 0.77; N, 10.97. Mp 71 °C.
CONCLUSION
■
In summary, we developed a new synthesis of the TPVR1
antagonist 1 which was implemented on multikilogram scale.
Our new synthesis allows this target to be prepared in 14%
overall yield with the longest linear sequence consisting of nine
steps, including a form change to the desired monohydrate 1.
EXPERIMENTAL SECTION
6-Iodo-5-trifluoromethylnicotinamide (9). 6-Bromo-5-tri-
fluoromethylnicotinonitrile (7) (7.2 kg, 29.08 mol) was
dissolved in acetonitrile (34.4 kg), and sodium iodide (21.8
kg, 145.4 mol) and glacial acetic acid (8.73 kg, 145.4 mol) were
added. The slurry was heated to 65 °C for 15 h and then cooled
to ambient temperature. Sodium thiosulfate solution (1.1 kg in
22 L of water), K2CO3 solution (1.1 kg in 22 L of water), and
toluene (19 kg) were added, and the phases were cut. The
aqueous layer was back-extracted with toluene (19 kg), and the
combined organic phases were washed with saturated NaHCO3
(2.2 kg in 22 L of water). The organic phase was reduced by
vacuum distillation (T < 45 °C) to a volume of 15 L and
warmed to 50 °C, and concentrated H2SO4 (40.8 kg) added
over 30 min, keeping T < 60 °C. The mixture was aged for 2 h
at 50 °C and then cooled to 40 °C and quenched into 1 M
NaOH(aq) (110 L), keeping T < 25 °C and rinsing the batch
in with water (20 L). The quenched batch was agitated for 30
■
General. Starting materials were obtained from commercial
suppliers and used without further purification. Melting points
were obtained using a Stuart Scientific SMP3 capillary melting
point apparatus and are uncorrected. NMR data were obtained
using a Bruker 400 MHz instrument. HPLC analyses were
performed on a Hewlett-Packard Series 1100 system eluting
with acetonitrile/0.1% aqueous H3PO4 in varying gradients.
Reported yields are corrected for weight percent purity based
on analytical standards, unless otherwise noted.
Syntheses. 2-Hydroxy-3-trifluoromethyl-5-iodopyridine
(5). 2-Hydroxy-3-trifluoromethylpyridine (4) (4.0 kg, 24.52
mol) was slurried in acetonitrile (11 kg), and glacial acetic acid
(1.55 kg, 25.75 mol) was added, followed by N-iodosuccini-
mide (6.62 kg, 29.43 mol). The resultant slurry was heated to
65 °C for 5 h. The slurry was cooled to 40 °C, and 10 wt %
sodium thiosulfate solution (16 kg) was charged over 30 min,
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min, and then MTBE (108 kg) was added. The phases were
cut, and the aqueous layer was extracted twice with MTBE (108
kg then 88 kg). The combined MTBE extracts were washed
with saturated NaHCO3 (22 L) and water (30 kg) and
switched to toluene by vacuum distillation (T < 45 °C, final
volume 23 L). The batch self-seeded during the solvent switch
and was then cooled to 20 °C, filtered, and washed with toluene
(20 L). After drying overnight at 40 °C under vacuum, 9 was
obtained as a white solid (7.79 kg, 99.6 A%, 99.6 wt %) in 85%
MHz, CDCl3): δ 9.21 (d, J = 2 Hz, 1H), 8.56 (d, J = 2 Hz, 1H),
6.8 (br s, 1H), 6.6 (br s, 1H), 5.75 (s, 1H), 3.78 (m, 2H), 3.68
(m, 2H), 1.19 (t, J = 7 Hz, 6H). 13C NMR (100 MHz, CDCl3):
δ 195.0, 165.6, 155.9 (q, J = 2 Hz), 149.9, 134.8 (q, J = 5 Hz),
130.2, 125.1 (q, J = 35 Hz), 122.4, (q, J = 273 Hz), 99.2, 63.3,
15.0. HRMS (EI): calcd 343.0882 for C13H15F3N2NaO4 (M +
Na), found 343.0894. Mp 112−113 °C.
3-Nitropyridine-2,4-diol (14). 2,4-Dihydroxypyridine (13)
(4.95 kg, 43.2 mol) was added portionwise to cooled (0−20
°C) concentrated sulfuric acid (15 L). The reaction was aged
for 35 min. Fuming nitric acid (2 L) was added at a rate to
maintain the internal temperature below 5 °C (addition time
4.5 h). Cold water (6 L) was added, keeping the internal
temperature below 5 °C (addition time 2.6 h). The remaining
54 L of water was added at a rate which allowed the internal
temperature to increase to 15 °C (addition time 1.25 h). The
reaction was seeded with 50 g of 14, and a liquor assay was
obtained. The slurry was cooled to 8 °C, and a second liquor
assay was obtained. The batch was filtered (2 h) and washed
with water (2 × 20 L). The solid was dried under nitrogen in a
vacuum oven at 75 °C to give 14 (6.82 kg, 97.0 wt %, 100A%)
1
yield over the two steps. H NMR (400 MHz, DMSO-d6): δ
8.97 (d, J = 2 Hz, 1H), 8.41 (d, J = 2 Hz, 1H), 8.39 (br s, 1H),
7.85 (br s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 164.9,
152.8, 134.8 (q, J = 5 Hz), 130.3 (q, J = 32 Hz), 129.0, 123.0
(q, J = 273 Hz), 20.4. HRMS (EI): calcd 316.9399 for
C7H5F3IN2O (M + H), found 316.9391. Mp 186 °C.
2,2-Diethoxy-N,N-diethylacetamide (10). Isopropylmagne-
sium chloride (26.56 kg of a 2 M solution in THF, 54.48 mol)
was cooled to 12 °C, and diethylamine (4.15 kg, 56.75 mol)
was added over 2.5 h at T < 25 °C. The resultant grey solution
was aged for 40 min and then was added to cold (2 °C) ethyl
diethoxyacetate (8.0 kg, 45.40 mol) over 100 min at T < 25 °C.
Fifteen minutes after the end of addition, glacial acetic acid
(6.83 kg, 112.5 mol) was added over 60 min at T < 25 °C.
Water (20 kg) and isopropyl acetate (14 kg) were then added,
and the phases were cut. The organic phase was washed with 1
M HCl (8 kg), three times with NaHCO3 (9 wt %, 3 × 16 kg),
and water (4 kg). The organic phase was reduced in vacuo to a
minimum volume, and heptane (11 kg) was added. The
distillation was continued to a minimum volume to give 10 as a
light-brown mobile oil (7.39 kg, 98.3 A%, 97.0 wt %) in 78%
1
in 98% yield. H NMR (400 MHz, DMSO-d6): δ 12.45 (br s,
1H), 11.91 (br s, 1H), 7.44 (d, J = 7.3 Hz, 1H), 6.04 (d, J = 7.3
Hz, 1H). Other data were consistent with those previously
reported.11,12
4-Chloro-3-nitropyridin-2-ol (15). DMF (4.76 L) was
charged into the vessel followed by acetonitrile (51 L). A
solution of oxalyl chloride (8.3 kg, 65.3 mol) in acetonitile
(10.3 L) was added to this solution over 1 h and aged for a
further 10 min. 2,4-Dihydroxy-3-nitropyridine (14) (6.79 kg,
43.6 mol) was added, and the reaction was stirred for a further
30 min. HPLC analysis confirmed reaction completion. Water
was charged (60.9 L), and the acetonitrile was evaporated
under vacuum at 30 °C until the supernatant contained 3.6% of
the product. Water (60.9 L) was added, and the slurry was
filtered and washed with water (16.6 L). The solid was dried
under vacuum at 55 °C to provide 15 (6.72 kg, 100 wt %, 99.3
1
yield. H NMR (400 MHz, CDCl3): δ 5.00 (s, 1H), 3.76 (m,
2H), 3.63 (m, 2H), 3.56 (q, J = 7 Hz, 2H), 3.39 (q, J = 7 Hz,
2H), 1.29 (t, J = 7 Hz, 6H), 1.21 (tr, J = 7 Hz, 3H), 1.18 (tr, J =
7 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 166.5, 100.7, 62.6,
40.5, 39.8, 14.8, 12.3, 13.8. HRMS (EI): calcd 226.1419 for
C10H21NNaO3 (M + Na), found 226.1413.
6-Diethoxyacetyl-5-trifluoromethylnicotinamide (2). So-
dium hydride (60 wt %, 1.17 kg, 29.2 mol) was charged into
a clean, dry vessel under N2. THF (68.5 kg) and TMEDA (17.9
kg) were charged, and the resultant slurry was cooled to 10 °C.
A solution of 6-iodo-5-trifluoromethylnicotinamide (9) (7.7 kg,
24.34 mol) in THF (72.5 kg) was added over 30 min whilst the
batch temperature was maintained between 10 and 15 °C. After
15 min of stirring, electrophile 10 (5.1 kg, 24.34 mol) in THF
(3.4 kg) was charged, and the batch was cooled to −70 °C.
Isopropylmagnesium chloride (19 kg of a 2 M solution in THF,
38.9 mol) was added over 1 h at T < −55 °C. After a 15 min
age at −70 °C < T < −60 °C, ethanol (2.8 kg, 60.9 mol) was
added over 20 min at T < −55 °C. The batch was then aged at
−60 °C for 1 h and subsequently warmed to −40 °C over 45
min. HCl (6 M) was prepared by mixing conc. HCl (37 wt %,
46.8 kg) and water (37.1 kg), degassed, and cooled to 5 °C.
The batch was added to the 6 M HCl over 35 min at T < 20
°C, rinsing in with THF (3 kg). Isopropyl acetate (134 kg) was
added, and the layers were cut. The organic layer was washed
twice with 4 M HCl (2 × 90.4 kg) and once with NaHCO3 (5
wt %, 48 kg). The organic phase was then switched to toluene
by vacuum distillation (T < 45 °C, final volume 15 L). Heptane
(20.4 kg) was charged over 30 min, and the resultant slurry was
stirred overnight at room temperature, filtered, washed with
toluene/heptane (2.2 kg of toluene, 5.3 kg of heptane), and
dried under vacuum at 55 °C to give 2 as a yellow solid (3.23
kg, 91.8 A%, 93.7 wt %) in 39% corrected yield. 1H NMR (400
1
A%) in 91% yield. H NMR (400 MHz, DMSO-d6): δ 13.12
(br s, 1H), 7.78 (d, J = 7.0 Hz, 1H), 6.60 (d, J = 7.0 Hz, 1H).
Other data were consistent with those previously reported.11,13
2,4-Dichloro-3-nitropyridine (16). Phosphorus oxychloride
(29.4 kg, 191.9 mol) was charged into a vessel, and 4-chloro-3-
nitropyridinyl-2-ol (15) (6.72 kg, 38.4 mol) was added,
followed by lithium chloride (1.7 kg). The reaction mixture
was heated to 105 °C for 2.5 h and then cooled to 89 °C, and a
sample was analysed by HPLC assay. Hydrochloric acid (70 g,
37%) was added, and the reaction was reheated to 105 °C for 1
h. The reaction mixture was then cooled 88 °C, treated with
hydrochloric acid (80 g, 37%), and then reheated to 105 °C
and stirred for 1 h. Another 2 portions of hydrochloric acid
were added to the batch in this way until <5% of the starting
material remained. The reaction mixture was cooled to 44 °C,
and acetonitrile (43.2 L) was added. The batch was stirred at
ambient temperature overnight. It was then cooled to 0 °C.
Water (4 × 0.25 L, 18 × 1 L) was added to the batch, ensuring
that the temperature remained between 22 and 28 °C
throughout the addition. The reaction mixture was stirred for
5.5 h before the acetonitrile was removed by vacuum distillation
at 28 °C, generating a slurry. The slurry was filtered, and the
solid was washed with water (16.7 L). The wet cake was dried
under vacuum overnight at 55 °C to give 16 (7.36 kg, 88 wt %,
100 A%) in 88% yield. 1H NMR (400 MHz, DMSO-d6): δ 7.78
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Organic Process Research & Development
Article
(d, J = 7.0 Hz, 1H), 6.61 (d, J = 7.1 Hz, 1H). Other data were
consistent with those previously reported.12
salt 3 (4.23 kg, 12.9 mol) was charged, followed by 4 M HCl
(12 L). The batch was then heated to 45 °C for 40 h and 50 °C
for a further 8 h and then cooled to 12 °C overnight. Water (15
L) was added over 1.5 h, and the slurry was aged for 30 min
and then filtered. The cake was washed with 1:1 THF/water (2
× 11.8 L). Drying overnight at 45−50 °C under vacuum
afforded the product 1 as a yellow solid (3.73 kg, 86.7 wt %,
89.4 A%). Crude 1 (3.73 kg, 6.95 mol) was slurried in THF (28
kg) and heated to 52 °C. 1,1′-Carbonyldiimidazole (1.13 kg,
6.95 mol) was charged portionwise over 10 min, and the batch
was heated to 55 °C for 1 h and then 58 °C for 3 h. The slurry
was cooled to 15 °C, and aqueous ammonium hydroxide (1.67
kg of a 16 M solution, 29.66 mol) was added over 15 min,
keeping T < 25 °C. The batch was then heated to 45 °C, and
water (44.5 kg) was charged over 1.5 h to crystallize the
product, which was filtered and washed with 3:1 water/THF
(14.8 L). Drying at 50 °C under vacuum gave the product 1·
THF solvate as a yellow solid (3.38 kg, 98.7 A%, 96.1 wt %) in
74% yield.
3-Nitropyridine-2,4-diamine (17). 2,4-Dichloro-3-nitropyr-
idine (16) (6.4 kg, 33.6 mol) was charged into the vessel, and
an aqueous ammonia solution (35.5 kg, 25%) was added. The
mixture was heated at 91 °C for 7 h while an internal pressure
of 4090 mbar was maintained. The reaction mixture was cooled
to ambient temperature and filtered under vacuum. The solid
was washed with water (2 × 15 L) and dried in the vacuum
oven at 55 °C to yield 17 (4.83 kg, 101 wt %, 99 A%) in 94%
yield. 1H NMR (400 MHz, DMSO-d6): δ 8.00 (s, 2H), 7.76 (s,
2H), 7.57 (d, J = 5.7 Hz, 1H), 6.08 (d, J = 5.7 Hz, 1H). Other
data were consistent with those previously reported.13
3-Nitro-N4-[(trifluoromethyl)pyridin-2-yl]pyridine-2,4-dia-
mine (19). 2-Chloro-5-(trifluoromethyl)pyridine (18) (3.02 kg,
16.6 mol) was melted in a water bath at 50 °C, and DMPU (2
L) was added. 3-Nitropyridine-2,4-diamine (17) (2.35 kg, 15.1
mol) and DMPU (11.6 L) were charged into a 50 L vessel,
followed by the solution of 18. The reaction was heated to 55
°C. NaOt-Bu (4.16 kg, 43.3 mol) was added in 0.32 kg portions
(addition time 5 h). The batch was quenched by the addition of
ethanol (14 L). Acetic acid (2.55 L in 25 L of water) was then
added, maintaining an internal temperature of 65 °C (addition
time 1 h). The reaction was stirred for 30 min and then cooled
to room temperature. The slurry was filtered, and the filter cake
was washed with ethanol/water (24 L). The wet cake was dried
in a vacuum oven at 50 °C to give the title compound 19 as a
5-Trifluoromethyl-6-(8-{[5-trifluoromethyl)pyridine-2-yl]-
amino}pyrido{2,3-b]pyrazin-3-yl)nicotinamide Monohydrate
(1·H2O). The THF solvate of 1 (3.73 kg, 96.1 wt %) was
slurried in an ethanol/water mixture (10.7 kg of ethanol, 53.9
kg of water) and heated to 47 °C for 17 h. The resultant slurry
was cooled to 23 °C and filtered, washing with an ethanol/
water mix (1.4 kg of ethanol, 13.5 kg of water). Drying for 18 h
at 40 °C under vacuum afforded 1·H2O as a yellow solid (3.19
1
1
kg, 99.5 A%, 100 wt %) in 95% yield. H NMR (400 MHz,
yellow solid (3.5 kg, 90.5 LCWP, 97 LCAP) in 70% yield. H
DMF-d6): δ 10.85 (br s, 1H), 9.76 (d, J = 1 Hz, 1H), 9.64 (s,
1H), 9.31 (d, J = 5 Hz, 1H), 9.26 (d, J = 5 Hz, 1H), 9.13 (d, J =
1 Hz, 1H), 9.02 (d, J = 2 Hz, 1H), 8.92 (br s, 1H), 8.39 (dd, J =
2 Hz, 9 Hz, 1H), 8.20 (br s, 1H), 8.18 (d, J = 9 Hz, 1H). 13C
NMR (400 MHz, DMF-d6): δ 165.1, 157.8, 156.5, 155.2, 154.0,
151.8, 149.8, 145.2 (q, J = 4 Hz), 144.8, 143.5, 135.5 (q, J = 5
Hz), 135.2 (q, J = 3 Hz), 130.5, 129.5, 125.3 (q, J = 34 Hz),
124.8 (q, J = 271 Hz), 123.8 (q, J = 274 Hz), 119.1 (q, J = 33
Hz), 114.4, 110.3. HRMS (EI): calcd 480.1008 for (M + H),
found 480.0996. Mp: Loss of water with Tmax of 155 °C,
followed by two further events at 232 and 318 °C.
NMR (400 MHz, DMSO-d6): δ 10.47 (s, 1H), 8.60 (s, 1H),
8.09 (dd, J = 2.3, 2.3 Hz, 1H), 8.04 (d, J = 5.6 Hz, 1H), 7.51 (s,
2H), 7.39 (d, J = 5.7 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H). 13C
NMR (100 MHz, DMSO-d6): δ 155.3, 153.8, 151.9, 145.3,
144.3, 135.84, 119.3, 114.3, 105.2. Anal. Calcd for
C11H8F3N5O2: C, 44.16; H, 2.69; N, 23.41. Found: C, 44.06;
H, 2.63; N, 23.13. Mp 244.6 °C.
N4-[4-(Trifluoromethyl)pyridin-2-yl]pyridine-2,3,4-triamine
Acetate (3·AcOH). 3-Nitro-N4-[(trifluoromethyl)pyridin-2-yl]-
pyridine-2,4-diamine (19) (6.7 kg) was charged into the vessel,
and ethyl acetate (95.5 L) was added. Pd/C (5 wt %, 670 g)
suspended in ethyl acetate (5 L) was added, followed by ethyl
acetate (20.6 L). The mixture was stirred at 28 °C under a
hydrogen pressure of 50 psi for 18 h. The reaction mixture was
filtered, washing the catalyst with ethyl acetate (14.9 L). The
filtrate was transferred to a second vessel, and acetic acid (1.5
L) was added over 30 min. The resulting slurry was stirred at
ambient temperature for 12 h. The slurry was filtered, and the
solid was washed with ethyl acetate (14.9 L). The solid was
dried at 40 °C in a vacuum oven to give 3·AcOH (6.03 kg, 99
wt %, 100 A%) in 91% yield. 1H NMR (400 MHz, DMSO-d6):
δ 8.69 (s, 1 H), 8.42 (s, 1H), 7.83 (dd, J = 2.4, 2.4 Hz, 1H),
7.29 (d, J = 5.5 Hz, 1 H), 6.84 (d, J = 8.8 Hz, 1 H) 6.80 (d, J =
5.5, 1H), 5.51 (bs, 2 H), 1.90 (s, 3H). 13C NMR (100 MHz,
DMSO-d6): δ 172.8, 159.0, 150.3, 145.8, 135.7, 134.9 (m),
130.39, 125.0 (q, J = 269.9 Hz), 121.95, 115.45 (q, J = 32.1
Hz), 110.8−108.2 (m, 2C, two overlapping quartets, J = 26 and
52.1 Hz), 21.73. Anal. Calcd for C13H14F3N5O2: C, 47.42; H,
4.29; N, 21.27. Found: C, 47.47; H, 4.35; N, 20.78. Mp: 183.2
°C.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: edward_cleator@merck.com.
*Fax: +44 1992 452581. Phone: +44 1992 452179. E-mail:
jeremy_scott@merck.com.
Notes
The authors declare no competing financial interest.
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