Development of a Scalable Synthesis of the Small Molecule TGFβR1 Inhibitor BMS-986260

Article abstract of DOI:10.1021/acs.oprd.0c00232

A scalable route to the small molecule TGFβR1 inhibitor BMS-986260 (1) was developed. This alternative approach circumvented the purification of intermediates by column chromatography and provided access to multikilogram quantities of the key intermediate

Full text of DOI:10.1021/acs.oprd.0c00232

pubs.acs.org/OPRD
Article
Development of a Scalable Synthesis of the Small Molecule TGFβR1
Inhibitor BMS-986260
Muthalagu Vetrichelvan, Souvik Rakshit, Sathishkumar Chandrasekaran, Karthikeyan Chinnakalai,
Chetan Padmakar Darne, Dyamanna Doddalingappa, Indasi Gopikumar, Anuradha Gupta,
Arun Kumar Gupta, Ananta Karmakar, Thirumalai Lakshminarasimhan, David K. Leahy, Senthil Palani,
Vignesh Radhakrishnan, Richard Rampulla, Antony Savarimuthu, Varadharajan Subramanian,
Upender Velaparthi, Jayakumar Warrier, Martin D. Eastgate, Robert M. Borzilleri, Arvind Mathur,
and Rajappa Vaidyanathan*
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ABSTRACT: A scalable route to the small molecule TGFβR1 inhibitor BMS-986260 (1) was developed. This alternative approach
circumvented the purification of intermediates by column chromatography and provided access to multikilogram quantities of the
key intermediate, 6. The safety aspects of the synthetic approach to the other fragment of the API (TosMIC 10) were critically
evaluated, and a robust process for its large-scale synthesis was successfully demonstrated.
KEYWORDS: TGFβR1 inhibitor, imidazo[1,2-b]pyridazine, TosMIC, AKTS software, Van Leusen imidazole synthesis
condensation with dimethyl formamide−dimethyl acetal
(DMF−DMA) and subsequent base-mediated cyclization of
the intermediate enamine 3 with bromoacetonitrile. Stille
coupling of 4 with tributyl(vinyl)stannane followed by osmium
tetroxide-mediated oxidative cleavage of the resultant vinyl
compound 5 afforded the key aldehyde 6. Treatment of
aldehyde 6 with ethanolamine led to aldimine 7, which was
subjected to the Van Leusen imidazole synthesis13 with the
TosMIC reagent 10 (synthesized in two steps from aldehyde 8)
to furnish the desired API 1.
INTRODUCTION
■
The imidazo[1,2-b]pyridazine scaffold has been successfully
utilized in the discovery of a number of therapeutic agents.1−10
Compound 1 (BMS-986260, Figure 1), an imidazo[1,2-
While this approach allowed medicinal chemistry researchers
to access small quantities of 1 for early evaluation, it was clear
that the route needed modification prior to further scale up: (i)
the use of tributyl(vinyl)stannane and osmium tetroxide had to
be avoided during the synthesis of larger quantities of API
because of the well-documented hazards of these reagents and
their remnants;14−18 (ii) the synthesis of TosMIC reagent 10
was low yielding and warranted improvement; and (iii) most of
the intermediates in the medicinal chemistry approach were
purified by column chromatography, which was clearly not the
preferred purification method on a large scale. However, we also
recognized that the existing chemistry to convert aldehyde 6 to
API 1 could be scaled up with minor improvements in the
isolation conditions. Thus, the primary focus of the next
Figure 1. Structure of 1 (BMS-986260).
b]pyridazine-containing molecule, was identified as a potent
and selective TGFβR1 inhibitor.11,12 As the molecule was
gearing up to progress into development, we required a safe and
robust process that could deliver significant quantities of the
drug substance to fund the pre-clinical and early clinical needs of
this program. Herein, we report the process development efforts
to synthesize kilogram quantities of 1 that represented a
significant improvement over the Medicinal Chemistry route.
Received: May 17, 2020
RESULTS AND DISCUSSION
■
First-Generation Synthesis of 1. The medicinal chemistry
approach to 1 involved eight steps starting from 6-bromo-
pyridazine-3-amine 2 (Scheme 1).12 The imidazopyridazine
intermediate 4 was obtained in two steps from pyridazine 2 via
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© XXXX American Chemical Society
A

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Scheme 1. First-Generation Synthesis of 1 (BMS-986260)
Scheme 2. Attempts to Synthesize 6 from 4
generation efforts was twofoldto develop a robust synthesis of
aldehyde 6, which avoids the pitfalls of the medicinal chemistry
route, and to streamline the process toward the synthesis of the
TosMIC component 10.
Scheme 3. Retrosynthetic Analysis of Aldehyde 6
While initial attempts to circumvent the use of tin by replacing
the Stille coupling reaction with a Suzuki coupling reaction in
the conversion of 4 to 5 seemed to be encouraging,19 the
substitution of the OsO4-mediated oxidative cleavage of 5 to 6
with more benign alternatives (such as ruthenium chloride in the
presence of bulk oxidants)20−22 was not successful (Scheme 2).
Similarly, several direct formylation conditions (either metal-
mediated formylations, or metalation/formylation conditions)
attempted on bromide 4 provided poor yields (<20%) of the
desired aldehyde 6. This prompted us to explore de novo routes
to 6, vide infra.
Second-Generation Synthesis of Aldehyde 6. We
envisioned that the imidazopyridazine aldehyde 6 could be
synthesized via two approaches, namely, route A and route B
(Scheme 3). Route A involved the formation of pyridazine ester
12 from 6-oxo-1,6-dihydropyridazine-3-carboxylic acid 13.
Subsequent cyclization to form the imidazopyridazine ring
followed by ester reduction would furnish aldehyde 6.
Alternatively, 6-methylpyridazin-3-amine 16 could be converted
to the imidazopyridazine core 15. Enamine (14) formation via
homologation of the benzylic methyl group in 15 followed by
oxidative cleavage of the enamine functionality would produce
aldehyde 6 (route B, Scheme 3). Both of these routes were
evaluated in parallel and our results are summarized herein.
B
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Scheme 4. Synthesis of Intermediate 12 (Route A)
Scheme 5. Proof-of-Concept for Route B
Scheme 6. Telescoped Synthesis of 15
Route A. Commercially available 6-oxo-1,6-dihydropyrida-
zine-3-carboxylic acid 13 was converted to the corresponding
methyl ester 17 via treatment with SOCl2/MeOH (Scheme 4).
Chlorination of 17 with neat POCl3 provided the aryl chloride
18. Our attempts to convert 18 to the corresponding amine 12
by treatment with an ammonia surrogate (such as benzophe-
none imine or LiHMDS) under Buchwald−Hartwig conditions
provided very little conversion (<5%) to the desired product.
This transformation has been reported in the literature using
sodium azide at 120 °C followed by a Staudinger reduction using
PPh3.23 While we were able to successfully reproduce these
conditions on a laboratory scale, we were unable to accomplish
this reaction under milder conditions.24,25 Our inability to effect
the amination under benign conditions, the hazards associated
with handling azides especially at elevated temperatures, and the
success we attained in our simultaneous efforts on route B (vide
infra) prompted us to halt further work on route A.
Route B. The key transformation in the synthesis of aldehyde
6 via route B was the conversion of the methyl group at the 6-
position of the imidazopyridazine 15 to enamine 14. Compound
15 was synthesized in two steps from commercially available 6-
methylpyridazin-3-amine 16 by treatment with DMF−DMA
followed by cyclization of the intermediate amidine 19 with
bromoacetonitrile (Scheme 5).26 Treatment of 15 with DMF−
DMA provided enamine 14, which was oxidatively cleaved with
sodium periodate to furnish aldehyde 6.27−29 We were able to
rapidly achieve proof-of-concept on this route, which enabled
our route-selection efforts. The next section describes the
development of this synthetic route into a scalable process.
In step 1, the reaction of 6-methylpyridazin-3-amine 16 with
DMF−DMA proceeded smoothly in toluene to afford the
desired amidine 19. While clean conversion to 19 was achieved
in the reaction, the noncrystalline nature of 19 created problems
during isolation. In our initial attempts, treatment of crude 19
with bromoactonitrile and NaHCO3 in 2-propanol led to
imidazopyridazine 15, which was isolated by the addition of
water (antisolvent), and recrystallized using MTBE.
We sought to streamline this process further by addressing
two main concerns namely, the noncrystalline nature of 19, and
the need to recrystallize 15. Gratifyingly, the amidine formation
reaction (step 1) worked well in 2-propanol,30,31 paving the way
for the development of a one-pot telescoped process.32 At the
end of the step 1 reaction, bromoacetonitrile was charged into
the reaction mixture, and heated to 80 °C to achieve the
cyclization reaction. Interestingly, this reaction proceeded in the
absence of an external base, and the product crystallized out
upon the addition of aqueous NaHCO3. This two-step, one-pot
telescoped process worked well on a multikilogram scale to
furnish compound 15 as a crystalline solid in 73% yield and >99
area % purity by HPLC (Scheme 6).
The next step in the sequence was synthesis of enamine 14 via
homologation of the Me group at the 6-position. Based on the
literature precedent for these kinds of reactions, N,N-
diisopropylethylamine was used as the base in the presence of
5 equiv of DMF−DMA.33 Under these conditions, the reaction
stalled at 67 area % product after 15 h at 115 °C (Figure 2). We
screened several bases (n-Bu3N, 2,6-lutidine, DABCO, and
DBU, 5 equiv each) in an attempt to push the reaction to
C
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number of small peaks in the chromatogram. In addition,
differential scanning calorimetry (DSC) studies on the reaction
mixture indicated a significant thermal event with an onset of
∼66 °C, and an energy release of 470 J/g (Figure 3A). We
attempted to lower the reaction temperature to 0−5 °C in order
to provide a wider safety margin to carry out the reaction, but a
significant amount of starting material remained unreacted
(Table 1, entry 2). We, therefore, screened alternative solvent
systems in an effort to increase both the conversion as well as the
onset temperature, and a few representative conditions are
presented in Table 1. While the conversions were low to modest
in most of the solvents screened (Table 1, entries 3−7),38 it was
gratifying to note that methanol provided ∼83 area % product at
ambient temperature (Table 1, entry 8).28 Interestingly, the
addition of 10% v/v water to the methanol reaction pushed the
reaction to 96 area % product (Table 1, entry 9). The addition of
water facilitated the reaction presumably by increasing the
solubility of NaIO4 in the reaction medium.
DSC studies with NaIO4 (in the absence of substrate 14)
revealed a substantially lower energy release under the aqueous
MeOH conditions (99.7 J/g, Figure 3D) than the aqueous THF
conditions (555 J/g, Figure 3C). Furthermore, the reaction
mixture (with substrate 14) in aqueous methanol exhibited a
significantly higher onset of decomposition (∼178 °C), and a
relatively low decomposition energy (267 J/g) by DSC (Figure
3B) in comparison to the aqueous THF conditions (Figure 3A),
providing a wider thermal window for carrying out the reaction.
While the aqueous methanol conditions provided high
conversions, the isolation of pure aldehyde 6 proved challenging
primarily because of its high solubility in aqueous media. In
general, aqueous solutions of reducing agents such as sodium
thiosulfate and sodium bisulfite are used to quench residual
oxidizing agents. However, under these conditions, it was
extremely difficult to extract the product from the aqueous phase
because of the high solubility of aldehyde 6 in water.39 We
addressed this challenge by developing a nonaqueous workup
protocol wherein upon reaction completion, the reaction
mixture was filtered to remove insoluble inorganics (such as
excess NaIO4 and its byproducts). The filter cake was separately
quenched with aqueous Na2S2O3 and discarded. The product-
rich filtrate was treated with excess solid Na2S2O3, and the
residual inorganic solids were separated by filtration and
discarded. The methanol in the filtrate was replaced with
methylene chloride, and the solution was treated with neutral
alumina and filtered. The filtrate was concentrated, and the
product was crystallized from toluene/n-heptane (1:2) to
provide 6 in 56% yield and ∼96 area % purity on a multikilogram
scale.
Figure 2. Step 3 conversions as a function of base used.
completion. While the reaction proceeded to ca. 80% conversion
with most of the other bases, the reaction with DBU provided 99
area % of product 14 after 15 h even with only 3 equiv of the
base. After completion of the reaction, the crude product was
precipitated by the addition of aqueous NH4Cl. The crude
product was dissolved in 2-MeTHF and treated with neutral
alumina to remove color and insoluble inorganics. Addition of n-
heptane as the antisolvent furnished exclusively the E-isomer 14
in 71% yield and >98 area % purity.
Our initial proof-of-concept conditions to synthesize small
quantities (<5 g) of aldehyde 6 by the sodium periodate-
mediated oxidative cleavage of enamine 14 involved the use of
THF−H2O as the solvent system at ambient temperature.34−37
The reaction produced ∼75 area % of the product by HPLC
analysis (Table 1, entry 1), but was accompanied by a significant
Table 1. Screening of Oxidative Cleavage of Enamine 14
Using NaIO4
in-process
area %
Large-Scale Synthesis of TosMIC 10. The medicinal
chemistry synthesis of TosMIC 10 was accomplished in two
steps starting from 3-chloro-4-fluorobenzaldehyde 8 (Scheme
1).12 The first step involved treatment of benzaldehyde 8 with
formamide, chlorotrimethylsilane (TMSCl), and 4-methylben-
zenesulfinic acid (TolSO2H) in acetonitrile to yield the
substituted formamide 9. After purification by column
chromatography, intermediate 9 was dehydrated using POCl3
in the presence of 2,6-lutidine to produce the TosMIC reagent
10 in 47% overall yield from 8.
As we considered increasing the yield and throughput in this
sequence, one obvious area for improvement was the avoidance
of purification by column chromatography. Furthermore,
TolSO2H was prepared by acidification of the corresponding
commercially available sodium salt (sodium p-toluenesulfinate,
equiv of
NaIO4
temp
time
(h)
entry
1
solvent (vol)
(°C)
6
14
3.0
3.0
1.5
1.5
THF/water
(10:10)
THF/water
(10:10)
2-MeTHF/water
(20:5)
MeCN/water
(20:5)
DMF (20)
2-PrOH (20)
EtOH (20)
MeOH (20)
MeOH/water
(30:3)
23
1
3
3
3
74.6
0
2
3
4
0−5
0−5
0−5
67.9
76.5
40.9
18.8
2.6
1.5
5
6
7
8
9
2.0
2.0
2.0
2.0
2.0
23
23
23
23
23
1
1
1
2
2
0
0
20.3
83.2
96.1
100
100
75.5
2.7
0.2
D
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Figure 3. DSC thermograms of: (A) reaction mass in THF/water; (B) reaction mass in MeOH/water; (C) NaIO4 in THF/water; and (D) NaIO4 in
MeOH/water.
TolSO2Na) using HCl and isolated prior to use in the first
step.40 We determined that the reaction proceeded smoothly
even with TolSO2Na, and thus we were able to circumvent the
extra protonation step. Upon completion of the reaction under
these modified reaction conditions (Scheme 7), the crude
Scheme 8. Synthesis of TosMIC 10
Scheme 7. Synthesis of TosMIC Precursor 9
product was precipitated by the addition of water, but was found
to be contaminated with ca. 15 area % of byproduct 20.
Compound 20 presumably arises out of a disproportionation of
TolSO2Na, and was purged effectively by slurrying the crude
product with MTBE. This protocol worked very well on a
multikilogram scale to furnish 9 in 73% yield and >92 area %
purity by HPLC.
The dehydration reaction to prepare TosMIC 10 from 9
worked best when using 3 equiv of POCl3 in the presence of 2,6-
lutidine (12 equiv). Of the bases surveyed, 2,6-lutidine
performed best, and the reactions routinely proceeded to >90
area % product by HPLC. While the reaction itself worked well,
we encountered two major challenges during work up and
isolation:41,42 (1) TosMIC 10 was prone to hydrolysis (to give
precursor 9) during the addition of water to quench the excess
POCl3 at the end of the reaction (the pH at the end of the water
addition was ∼5.5), and (2) isolated TosMIC 10 exhibited a
sharp exothermic event by DSC (Tonset 94 °C, ΔH = −425 J/g),
suggesting that its decomposition could be autocatalytic,43
which necessitated certain controls during workup, isolation,
and drying. Both of these issues needed to be addressed prior to
scale up.
slowly hydrolyzed to starting material 9 (Scheme 8). After an
extractive workup (EtOAc/H2O) and charcoal treatment, the
product was isolated as a pale brown solid in 85% yield and 97.5
area % purity by crystallization from n-heptane in the
temperature range 15−25 °C. Because of the safety concerns
associated with the isolation of TosMIC 10 (vide infra), we
attempted to telescope the crude solution after the charcoal
treatment into the subsequent Van Leusen reaction with
aldimine 7. The poor yields obtained in this approach suggested
that the purity of TosMIC 10 was critical for the success of the
final Van Leusen reaction, and therefore, we focused our efforts
on defining safe operating parameters for the isolation of 10.
While TosMIC 10 was isolable, the low onset temperature
(94 °C) necessitated a study of the decomposition kinetics of
the material in order to establish a safe operating window for
concentration and drying operations on scale. Kinetic analysis of
the heat data obtained from a series of dynamic DSC runs using
the AKTS software predicted the ADT24 to be 50 °C. As
suspected, the AKTS model also predicted significant
decomposition under isothermal conditions (above 50 °C)
beyond 40 h (Figure 4). Furthermore, TosMIC 10 also
exhibited a strong autocatalytic behavior as evidenced by the
long induction time to decomposition. On the basis of these
studies, we decided to restrict the maximum operating
temperature to 45 °C during concentration and drying. The
AKTS model also predicted the self-accelerating decomposition
temperature to be 29 °C. Therefore, the compound was stored
at 2−8 °C, and processed to the next step within two weeks.
The problem of hydrolysis of 10 during the aqueous quench
of the excess POCl3 was addressed by a systematic screening of
bases. While carbonate bases led to frothing and some
hydrolysis, it was found that a 10% aqueous NaH2PO4 quench
at 0−15 °C suppressed the hydrolysis (Scheme 8). Stability
studies indicated that the mixture after the NaH2PO4 quench
(pH 7−8) was stable for 9 h. Beyond that time, product 10 was
E
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Figure 4. Predicted decomposition of TosMIC 10 under isothermal conditions using AKTS software.
Scheme 9. End Game
Scheme 10. Summary of the Second-Generation Route to 1
During this period, no significant loss of purity or potency was
observed by HPLC analysis.
>99.9 area % purity after crystallization from CH2Cl2/n-heptane
(2:3).
End Game. With both aldehyde 6 and TosMIC 10 in hand,
we turned our attention to the assembly of the API. Aldehyde 6
was converted to the corresponding aldimine 7 via a reaction
with 2-aminoethanol in the presence of 4 Å molecular sieves
(Scheme 9). The reaction furnished a single imine isomer of an
undetermined configuration, and the product was isolated in
Aldimine 7 was treated with TosMIC 10 in the presence of
K2CO3 in DMF to effect the Van Leusen imidazole synthesis
reaction.12 The reaction proceeded cleanly at ambient temper-
ature. A detailed safety evaluation revealed that the reaction was
accompanied by a modest adiabatic temperature rise of 35 °C,
and the total heat was released at a steady rate over ∼7−8 h.
F
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Furthermore, the reaction mixture at the end of the reaction as
well as the product 1 were stable under the reaction conditions
with no significant thermal events up to 200 °C.
After an extractive workup with CH2Cl2, a solvent exchange
with MTBE led to the precipitation of the crude product. The
isolated crude API 1 was dissolved in CH2Cl2, decolorized with
activated charcoal, and crystallized using CH2Cl2/n-heptane
(1:4) to furnish the API 1 in 99.8 area % purity (Scheme 9).44
completion, the mass was cooled to 5−10 °C and 10% aqueous
NH4Cl (36 L) was added maintaining the temperature below 30
°C. The resulting slurry was allowed to granulate at 5−10 °C for
1 h, filtered, and the wet cake was washed with water (9 L). The
wet solid was deliquored in the temperature range 20−25 °C
under vacuum for 5 h. The solid was dissolved in 2-MeTHF (27
L), dried over Na2SO4 (4.5 kg), filtered, and washed with 2-
MeTHF (5.5 L). The filtrate and washes were combined and
treated with neutral alumina (2 kg) in the temperature range
20−25 °C. The alumina was removed by filtration through
Celite, and the obtained cake was washed with 2-MeTHF (5 L).
The combined filtrate was distilled under vacuum at <55 °C to
∼5 L, cooled to 20−25 °C, and n-heptane (36 L) was added over
∼0.5 h. The resulting slurry was stirred for 0.5 h at ambient
temperature, and filtered. The wet cake was washed with n-
heptane (5 L) and deliquored for 5 h. The filtered solid was
dried in the temperature range 50−55 °C under vacuum for 14 h
to afford (E)-6-(2-(dimethylamino)vinyl)imidazo[1,2-b]-
pyridazine-3-carbonitrile 14 as a pale brown solid (0.86 kg,
CONCLUSION
■
An improved process for the large-scale synthesis of BMS-
986260 (1) was developed (Scheme 10). The modified route to
the key aldehyde fragment 6 avoided the use of osmium
tetroxide and vinyl(tributyl)tin. A systematic study of the safety
aspects of the process to access the TosMIC coupling partner
helped define the operating parameters for this step. The
second-generation process described herein was a significant
improvement over the first-generation route, and provided the
API in 99.8% purity without recourse to chromatographic
purification of any of the intermediates.
1
98.5 HPLC area % purity, 71% yield). H NMR (400 MHz,
DMSO-d6): 8.25 (s, 1H), 7.95 (d, 1H, J = 9.6 Hz), 7.62 (d, 1H, J
= 13.6 Hz), 7.53 (d, 1H, J = 10.0 Hz), 5.17 (d, 1H, J = 13.6 Hz),
2.95 (s, 6H). 13C NMR (75 MHz, DMSO-d6): 156.1, 147.8,
147.7, 140.3, 140.1, 124.9, 120.3, 111.7, 101.3, 90.7 (2C).
6-Formylimidazo[1,2-b]pyridazine-3-carbonitrile (6).
To a solution of (E)-6-(2-(dimethylamino)vinyl)imidazo[1,2-
b]pyridazine-3-carbonitrile 14 (4.7 kg, 22.0 mol, 1.0 equiv) in
MeOH (141 L) and water (15 L) in a C22-Hastelloy reactor,
NaIO4 (14.2 kg, 66.4 mol, 3.0 equiv) was charged slowly
maintaining the internal temperature below 35 °C (NaIO4 is a
strong oxidant; adequate safety studies need to be completed
prior to its use). The reaction mass was stirred for 2 h in the
temperature range 20−25 °C. Upon reaction completion, the
mixture was filtered, and washed with CH2Cl2 (38 L). The
filtered solid contained inorganic residues including NaIO4, and
was quenched in a separate vessel using excess aqueous Na2S2O3
solution, and discarded. The combined product-containing
filtrate was quenched with solid Na2S2O3 (2.8 kg) and was
stirred for 0.5 h in the temperature range 20−25 °C. The slurry
was filtered, and the filtered cake was washed with CH2Cl2 (38
L). The combined filtrate was distilled to ∼14 L under vacuum
below 55 °C. CH2Cl2 (47 L) was added, and the mixture was
distilled to ∼14 L. This operation was repeated one more time to
remove residual MeOH (<1% by GC). The resulting slurry was
dissolved in CH2Cl2 (118 L) in the temperature range 20−25
°C, and dried over Na2SO4 (23.5 kg). The inorganic solids were
filtered, and the filtered cake was washed with CH2Cl2 (38 L).
The combined filtrate was treated with neutral alumina (14.1
kg) in the temperature range 20−25 °C for 2 h, filtered through
Celite, and the cake was washed with CH2Cl2 (38 L). The
combined filtrate was distilled to ∼14 L under vacuum below 55
°C. Toluene (47 L) was added and the mixture was distilled to
∼35 L. The mass was cooled to 20−25 °C, and n-heptane (94 L)
was added over a period of 0.5 h. The mixture was stirred for 0.5
h and filtered. The wet cake was washed with n-heptane (38 L),
and deliquored in the temperature range 20−25 °C under
vacuum for 1 h. The filtered solid was dried in the temperature
range 55−60 °C under vacuum for 12 h to afford 6-
formylimidazo[1,2-b]pyridazine-3-carbonitrile 6 as a pale
brown solid (2.1 kg, 95.7 HPLC area % purity, 56% yield). 1H
NMR (400 MHz, CDCl3): 10.15 (d, 1H, J = 0.8 Hz), 8.42 (s,
1H), 8.24 (dd, 1H, J = 9.6, 0.8 Hz), 7.89 (d, 1H, J = 9.2 Hz). 13C
EXPERIMENTAL SECTION
■
General Information. All reagents, starting materials, and
solvents (laboratory grade or anhydrous grade) were used as
received. Purity was determined using reverse-phase HPLC.
Chemical shifts (δ) for protons and carbon are reported in parts
per million (ppm) referenced to tetramethylsilane (δH = 0.00, δC
= 0.00) or to residual proton or carbon in the NMR solvent
(CDCl3: δH = 7.26 ppm, δC = 77.2 ppm; DMSO-d6: δH = 2.50
ppm, δC = 39.5 ppm).
6-Methylimidazo[1,2-b]pyridazine-3-carbonitrile (15).
To a solution of 6-methylpyridazin-3-amine 16 (3.0 kg, 27.5
mol, 1.0 equiv) in 2-propanol (30 L) in a glass reactor, DMF−
DMA (5.2 kg, 43.6 mol, 1.6 equiv) was charged in the
temperature range 20−35 °C under a nitrogen atmosphere. The
reaction was stirred in the temperature range 70−80 °C for 3 h.
Once the reaction was deemed complete by HPLC (<2.0 area %
of 16 remaining), 2-bromoacetonitrile (5.2 kg, 43.4 mol, 1.6
equiv) [Caution: lachrymator] was charged under a nitrogen
atmosphere maintaining the temperature in the range 40−50
°C. The reaction was stirred in the temperature range 70−80 °C
for 15 h. Upon reaction completion, the mixture was distilled to
∼9 L under vacuum at 55 °C, and then cooled to 20−25 °C. The
mass was quenched with 10% aqueous NaHCO3 (9 L), and
further diluted with purified water (42 L). The mixture was
cooled to 0−10 °C and stirred for 2 h. The resulting slurry was
filtered, and the wet cake was washed with water (12 L). The
filtered solid was deliquored under vacuum for 3 h, and dried in
the temperature range 60−70 °C under vacuum for 14 h to
afford 6-methylimidazo[1,2-b]pyridazine-3-carbonitrile 15 as a
pale brown solid (3.2 kg, 99.3 HPLC area % purity, 73% yield).
1H NMR (400 MHz, CDCl3): 8.18 (s, 1H), 7.96 (d, 1H, J = 9.6
Hz), 7.17 (d, 1H, J = 9.2 Hz), 2.69 (s, 3H). 13C NMR (100 MHz,
DMSO-d6): 155.6, 142.0, 140.7, 126.5, 124.1, 111.2, 101.8, 21.6.
(E)-6-(2-(Dimethylamino)vinyl)imidazo[1,2-b]-
pyridazine-3-carbonitrile (14). To a solution of 6-
methylimidazo[1,2-b]pyridazine-3-carbonitrile 15 (0.9 kg, 5.7
mol, 1.0 equiv) in DMF (9 L) in a glass reactor, DBU (2.6 kg,
17.1 mol, 3.0 equiv) and DMF−DMA (3.5 kg, 29.0 mol, 5.1
equiv) were added in the temperature range 20−25 °C under a
nitrogen atmosphere. The reaction mixture was stirred in the
temperature range 105−115 °C for 15 h. Upon reaction
G
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NMR (100 MHz, CDCl3): 188.3, 149.2, 143.6, 141.6, 127.3,
117.2, 109.1, 104.1.
(m, 3H), 7.26−7.23 (m, 1H), 7.16 (t, 1H, J = 8.4 Hz), 5.57 (s,
1H), 2.47 (s, 3H). 13C NMR (75 MHz, CDCl3): 167.2, 159.5 (d,
J = 252.8 Hz), 147.1, 130.9, 130.5, 130.0, 129.8, 128.5 (d, J = 8.0
Hz), 123.8 (d, J = 3.9 Hz), 122.0 (d, J = 18.3 Hz), 117.1 (d, J =
21.8 Hz), 75.1, 21.8. 19F NMR (376 MHz, CDCl3): −110.99.
6-(((2-Hydroxyethyl)imino)methyl)imidazo[1,2-b]-
pyridazine-3-carbonitrile (7). To a solution of 6-
formylimidazo[1,2-b]pyridazine-3-carbonitrile 6 (1.7 kg, 9.6
mol, 1.0 equiv) in CH2Cl2 (63 L) in a glass reactor, 2-
aminoethanol (1.3 kg, 21.4 mol, 2.2 equiv) was added in the
temperature range 20−25 °C under a nitrogen atmosphere and
stirred for 1 h. 4 Å molecular sieves (3.3 kg) were added and the
slurry was stirred for 10 h in the temperature range 20−25 °C
under a nitrogen atmosphere. Upon reaction completion,
activated charcoal (0.5 kg) was added, and the slurry was stirred
for 1 h in the temperature range 20−25 °C. The slurry was
filtered through Celite and washed with CH2Cl2 (2 × 16 L). The
combined filtrate was distilled under vacuum below 55 °C to
∼16 L. The mass was cooled to 20−25 °C and n-heptane (25 L)
was added slowly into the mass over about 1 h. The resulting
slurry was stirred for 0.5 h and filtered. The wet cake was washed
with n-heptane (2 × 16 L) and filtered. The wet solid was
deliquored in the temperature range 20−25 °C under vacuum
for 1 h, and dried in the temperature range 60−65 °C under
vacuum for 15 h to afford 6-(((2-hydroxyethyl)imino)methyl)-
imidazo[1,2-b]pyridazine-3-carbonitrile 7 as a yellow solid (1.3
kg, >99.9 HPLC area % purity, 62% yield). 1H NMR (400 MHz,
DMSO-d6): 8.63 (s, 1H), 8.45 (s, 1H), 8.39 (d, 1H, J = 9.6 Hz),
7.98 (d, 1H, J = 9.6 Hz), 4.72 (br s, 1H), 3.83−3.80 (m, 2H),
3.74−3.72 (m, 2H). 13C NMR (100 MHz, DMSO-d6): 158.8,
151.6, 143.3, 141.9, 127.3, 119.3, 110.9, 102.7, 63.4, 60.6.
6-(4-(3-Chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-
1H-imidazol-5-yl)imidazo[1,2-b]pyridazine-3-carboni-
trile (BMS-986260) (1). To a solution of 6-(((2-
hydroxyethyl)imino)methyl)imidazo[1,2-b]pyridazine-3-car-
bonitrile 7 (1.2 kg, 5.6 mol, 1.0 equiv) in DMF (22 L) in a glass
reactor, K2CO3 (1.1 kg, 8.0 mol, 1.4 equiv) and 2-chloro-1-
fluoro-4-(isocyano(tosyl)methyl)benzene 10 (2.2 kg, 6.8 mol,
1.2 equiv) were added in the temperature range 20−25 °C under
a nitrogen atmosphere. The mixture was stirred for 15 h in the
temperature range 20−25 °C. Upon reaction completion, water
(38 L) and CH2Cl2 (38 L) were added and the layers were
separated. The aqueous layer was back-extracted with CH2Cl2
(38 L). The combined organic layers were washed sequentially
with water (2 × 38 L) and 30% aqueous NaCl (2 × 38 L). The
organic phase was distilled to ∼1.5 L under vacuum below 55
°C. MTBE (6 L) was added and the mixture was distilled to ∼1.5
L. This operation was repeated one more time to remove any
residual CH2Cl2. The mixture was diluted with MTBE (27 L)
and the resulting slurry was stirred in the temperature range 20−
30 °C for 1 h. The mass was filtered and the wet cake was washed
with MTBE (2 × 9 L). The wet solid was deliquored under
vacuum for 1 h, and was dissolved in CH2Cl2 (55 L) in the
temperature range 20−25 °C. Activated charcoal (0.4 kg) was
added; the slurry was stirred for 1 h in the temperature range
20−25 °C, filtered through Celite, and the filtered cake was
washed with CH2Cl2 (2 × 22 L). The combined filtrate was
charged into a clean glass reactor through a 0.2 μm cartridge
filter, and distilled under vacuum to ∼17 L. The solution was
cooled to 20−25 °C, and n-heptane (70 L) was added over
about 0.5 h. The resulting slurry was stirred in the temperature
range 20−30 °C for 0.5 h and filtered. The wet cake was washed
with n-heptane (2 × 9 L). The wet solid was deliquored under
N-((3-Chloro-4-fluorophenyl)(tosyl)methyl)-
formamide (9). To a solution of 3-chloro-4-fluoro-benzalde-
hyde 8 (1.8 kg, 11.4 mol, 1.0 equiv) in MeCN (14 L) in a glass
reactor, formamide (1.3 kg, 28.9 mol, 2.5 equiv), TolSO2Na (3.0
kg, 17.0 mol, 1.5 equiv), and TMSCl (3.0 kg, 27.6 mol, 2.4
equiv) were charged in the temperature range 20−25 °C under a
nitrogen atmosphere. The reaction mixture was heated to 45−
55 °C and stirred for 5 h. Upon reaction completion, the mass
was cooled to 20−25 °C and purified water (36 L) was added to
the reaction mixture over a period of 1 h and stirred for another 1
h. The resulting slurry was filtered and the wet cake was washed
sequentially with water (9 L) and n-heptane (36 L). The wet
cake was deliquored under vacuum for 2 h. The filtered solid was
reslurried in MTBE (18 L) at 0−10 °C for 2 h. The slurry was
filtered and the wet cake was washed with MTBE (9 L) and
deliquored under vacuum for 2 h. The filtered solid was dried in
the temperature range 50−60 °C for 12 h to afford N-((3-
chloro-4-fluorophenyl)(tosyl)methyl)formamide 9 as a white
1
solid (2.9 kg, 92.0 HPLC area % purity, 73% yield). H NMR
(400 MHz, CDCl3): 8.11 (s, 1H), 7.71 (d, 2H, J = 8.0 Hz),
7.53−7.46 (m, 2H), 7.33−7.25 (m, 3H), 7.12 (t, 1H, J = 8.4
Hz), 6.31 (d, 1H, J = 10.4 Hz), 2.41 (s, 3H). 13C NMR (75 MHz,
DMSO-d6): 162.9 (d, J = 275.1 Hz), 160.2, 144.8, 133.3, 131.6
(d, J = 8.5 Hz), 129.7, 129.6, 129.2, 129.1, 126.7, 115.2 (d, J =
21.6 Hz), 69.4, 21.1. 19F NMR (376 MHz, DMSO-d6): −114.94.
2-Chloro-1-fluoro-4-(isocyano(tosyl)methyl)benzene
(TosMIC) (10). To a solution of N-((3-chloro-4-fluorophenyl)-
(tosyl)methyl)formamide 9 (1.6 kg, 4.7 mol, 1.0 equiv) in THF
(12 L) in a glass reactor, POCl3 (2.2 kg, 14.1 mol, 3.0 equiv) was
charged at 0−10 °C under a nitrogen atmosphere over 15 min. A
solution of 2,6-lutidine (6.0 kg, 56.4 mol, 12.0 equiv) in THF (3
L) was charged at 0−15 °C over a period of 15 min. The reaction
mixture was stirred in the temperature range 20−25 °C for 16 h.
Upon reaction completion, EtOAc (16 L) and 10% aqueous
NaH2PO4 (13 L) were added sequentially to the reaction vessel
maintaining the internal temperature between 0 and 15 °C. The
mixture was allowed to warm to ambient temperature, and the
layers were separated. The organic layer was washed sequentially
with water (13 L) and 15% aqueous NaCl (13 L) in the
temperature range 20−25 °C. The organic layer was dried over
Na2SO4 (3.2 kg) and filtered. The filtrate was treated with
activated charcoal (0.4 kg) and stirred in the temperature range
20−25 °C for 1 h. The slurry was filtered through Celite and
washed with EtOAc (19 L). The combined filtrate was distilled
to ∼14 L under vacuum maintaining the temperature below 35
°C (Caution: higher temperature leads to product decom-
position, see the manuscript text for thermal hazards associated
with 10). n-Heptane (16 L) was then charged to the vessel, and
the distillation was continued until a final volume of ∼14 L. The
n-heptane addition and distillation sequence was repeated twice
to ensure that the EtOAc levels at the end of the distillation were
<0.5% v/v by GC. To the clear solution, n-heptane (16 L) and
the 2-chloro-1-fluoro-4-(isocyano(tosyl)methyl)benzene 10
seed (32 g, 0.2 w/w % w.r.t. 9) were charged sequentially, and
the resulting slurry was allowed to granulate for 1 h at ambient
temperature. The slurry was cooled to ambient temperature, and
the solid was filtered. The wet cake was washed with n-heptane
(8 L), and deliquored for 1 h to get the desired 2-chloro-1-
fluoro-4-(isocyano(tosyl)methyl)benzene 10 as a light brown
1
solid (1.3 kg, 97.5 HPLC area % purity, 85% yield). H NMR
(400 MHz, CDCl3): 7.64 (dd, 2H, J = 6.8, 1.6 Hz), 7.38−7.35
H
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vacuum for 1 h, and dried in the temperature range 60−65 °C
under vacuum for 20 h to afford 6-(4-(3-chloro-4-fluorophen-
yl)-1-(2-hydroxyethyl)-1H-imidazol-5-yl)imidazo[1,2-b]-
pyridazine-3-carbonitrile 1 as a white solid (1.4 kg, 99.8 HPLC
area % purity, 66% yield). 1H NMR (400 MHz, DMSO-d6): 8.63
(d, 1H, J = 6.0 Hz), 8.35 (d, 1H, J = 9.6 Hz), 8.03 (s, 1H), 7.77
(dd, 1H, J = 7.2, 2.4 Hz), 7.48−7.42 (m, 1H), 7.42 (d, 1H, J = 5.2
Hz), 7.33 (t, 1H, J = 8.8 Hz), 4.97 (t, 1H, J = 5.6 Hz), 4.32 (t, 2H,
J = 5.2 Hz), 3.76−3.73 (m, 2H). 13C NMR (100 MHz, DMSO-
d6): 157.1 (d, J = 245.9 Hz), 147.2, 142.6, 141.5, 140.6, 140.1,
132.2 (d, J = 3.7 Hz), 129.7, 128.5 (d, J = 7.2 Hz), 127.2, 124.6,
123.3, 120.2 (d, J = 17.8 Hz), 117.3 (d, J = 20.9 Hz), 111.0,
102.9, 61.0, 48.7. 19F NMR (376 MHz, DMSO-d6): −118.07.
Vignesh Radhakrishnan − Department of Discovery Synthesis,
Biocon Bristol-Myers Squibb Research and Development Center,
Bangalore 560099, India
Richard Rampulla − Small Molecule Drug Discovery, Bristol
Myers Squibb Research and Early Development, Princeton, New
Jersey 08543-4000, United States
Antony Savarimuthu − Chemical Development and API Supply,
Biocon Bristol-Myers Squibb Research and Development Center,
Bangalore 560099, India
Varadharajan Subramanian − Chemical Development and API
Supply, Biocon Bristol-Myers Squibb Research and Development
Center, Bangalore 560099, India
Upender Velaparthi − Small Molecule Drug Discovery, Bristol
Myers Squibb Research and Early Development, Princeton, New
Jersey 08543-4000, United States; orcid.org/0000-0002-
3000-9255
Jayakumar Warrier − Medicinal Chemistry, Biocon Bristol-Myers
Squibb Research and Development Center, Bangalore 560099,
India
Martin D. Eastgate − Chemical Process Development, Bristol-
Myers Squibb, New Brunswick, New Jersey 08903, United States;
orcid.org/0000-0002-6487-3121
Robert M. Borzilleri − Small Molecule Drug Discovery, Bristol
Myers Squibb Research and Early Development, Princeton, New
Jersey 08543-4000, United States
AUTHOR INFORMATION
■
Corresponding Author
Rajappa Vaidyanathan − Chemical Development and API
Supply, Biocon Bristol-Myers Squibb Research and Development
Center, Bangalore 560099, India; orcid.org/0000-0002-
2236-5719; Email: vaidy@bms.com
Authors
Muthalagu Vetrichelvan − Department of Discovery Synthesis,
Biocon Bristol-Myers Squibb Research and Development Center,
Bangalore 560099, India; orcid.org/0000-0001-7201-4143
Souvik Rakshit − Chemical Development and API Supply, Biocon
Bristol-Myers Squibb Research and Development Center,
Bangalore 560099, India
Arvind Mathur − Small Molecule Drug Discovery, Bristol Myers
Squibb Research and Early Development, Princeton, New Jersey
08543-4000, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00232
Sathishkumar Chandrasekaran − Chemical Development and
API Supply, Biocon Bristol-Myers Squibb Research and
Development Center, Bangalore 560099, India
Karthikeyan Chinnakalai − Chemical Development and API
Supply, Biocon Bristol-Myers Squibb Research and Development
Center, Bangalore 560099, India
Chetan Padmakar Darne − Small Molecule Drug Discovery,
Bristol Myers Squibb Research and Early Development, Princeton,
New Jersey 08543-4000, United States
Dyamanna Doddalingappa − Department of Discovery
Synthesis, Biocon Bristol-Myers Squibb Research and
Development Center, Bangalore 560099, India
Indasi Gopikumar − Department of Discovery Synthesis, Biocon
Bristol-Myers Squibb Research and Development Center,
Bangalore 560099, India
Anuradha Gupta − Department of Discovery Synthesis, Biocon
Bristol-Myers Squibb Research and Development Center,
Bangalore 560099, India; orcid.org/0000-0002-4211-1441
Arun Kumar Gupta − Department of Discovery Synthesis, Biocon
Bristol-Myers Squibb Research and Development Center,
Bangalore 560099, India
Ananta Karmakar − Department of Discovery Synthesis, Biocon
Bristol-Myers Squibb Research and Development Center,
Bangalore 560099, India; orcid.org/0000-0003-3795-5807
Thirumalai Lakshminarasimhan − Chemical Development and
API Supply, Biocon Bristol-Myers Squibb Research and
Development Center, Bangalore 560099, India
David K. Leahy − Chemical Process Development, Bristol-Myers
Squibb, New Brunswick, New Jersey 08903, United States;
orcid.org/0000-0003-4128-7792
Author Contributions
M.V. and S.R. contributed equally. The manuscript was written
with contributions from all authors. All authors have given
approval to the final version of this manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Jayaprakash Karamil and Sabuj Mukherjee for their
helpful suggestions during the execution of this project.
Analytical support from Rajendran Ashok Kumar and Santosh
Gandhi is gratefully acknowledged. Process Safety and Engineer-
ing support was provided by Durga Prajapati, Somprabha Sidar,
Arun Vinodini, and Aravind Gangu. Scale-up support from the
BCDL and S14 operating staff is gratefully acknowledged. Our
sincere thanks to David Kronenthal and Robert Waltermire for
their support of this work.
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K
https://dx.doi.org/10.1021/acs.oprd.0c00232
Org. Process Res. Dev. XXXX, XXX, XXX−XXX