Development of an alternate synthesis for a key JAK2 inhibitor intermediate via sequential c-h bond functionalization

Article abstract of DOI:10.1021/op300344m

The development of an alternative synthetic route to a functionalized imidazopyridazine which strategically streamlines the synthesis and avoids a number of problematic reagents is described. Key to the success of this alternative route is the use of two

Full text of DOI:10.1021/op300344m

Article
pubs.acs.org/OPRD
Development of an Alternate Synthesis for a Key JAK2 Inhibitor
Intermediate via Sequential C−H Bond Functionalization
Alison N. Campbell,* Kevin P. Cole, Joseph R. Martinelli, Scott A. May, David Mitchell,
Patrick M. Pollock, and Kevin A. Sullivan
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
*
S Supporting Information
ABSTRACT: The development of an alternative synthetic route to a functionalized imidazopyridazine which strategically
streamlines the synthesis and avoids a number of problematic reagents is described. Key to the success of this alternative route is
the use of two C−H functionalization reactions: a Pd-catalyzed direct benzylation reaction to functionalize a C−H bond with a
substituted benzyl group and a V-catalyzed NMO addition reaction to install a benzylic morpholine moiety.
INTRODUCTION
historically challenging component of the synthesis. A
vanadium-catalyzed NMO addition reaction was previously
developed to install this functionality (Scheme 1, step 4), and
in our current synthesis, we sought to implement a similar set
of conditions.
■
Myeloproliferative disorders are a group of blood cell cancers in
which the bone marrow cells that produce the body’s blood
cells develop and function abnormally; these chronic disorders
are associated with splenomegaly and the development of
4
1
We envisioned installing the benzyl group of 2 in one of two
ways: either via a direct C−H benzylation reaction or by a
decarboxylative benzylation. The efficiency and high-atom
economy of these metal-catalyzed transformations made them
leukemia. LY2784544 (1) has been identified as a highly
selective inhibitor of JAK2-V617F, the most common
molecular abnormality found in BCR/ABL-negative myeloid
proliferative neoplasms, and is currently undergoing clinical
trials for the treatment of several myeloproliferative disorders.
2
9
3
attractive approaches. While both direct and decarboxylative
1
0
couplings have received considerable attention in the
A practical synthesis of 1 has been previously reported and is
2
2
4
literature as atom-economical means of achieving sp −sp
shown in Scheme 1. Several liabilities were identified in this
2
3
bond formation (e.g., direct arylation), sp −sp coupling
synthesis, particularly en route to the key late-stage
intermediate 2. First, the amino acetal used to form the
pyridazine framework (step 1) was not readily available. Long
lead times were required to secure the desired amounts for
active pharmaceutical ingredient (API) synthesis campaigns,
and a wide range of purity profiles were observed due to
1
1,12
reactions are notably more scarce.
However, we believed
that one of these methods could serve as a viable and efficient
means of installing the benzylic functionality, and the
development of this approach is discussed herein.
As exemplified in Scheme 2, there are several possible orders
in which the key steps can be performed. The final order of the
steps was the result of analyzing several possible substrates for
each reaction with a focus on maximizing the yield, product
quality, and manufacturability of 2. The development of each
step is discussed in turn, and considerations related to route
selection (e.g., yield, impurity control, scalability) are detailed.
Imidazopyridazine Formation. Construction of the 6-
chloro-2-methyl-imidazopyridazine core can be accomplished
through the coupling of 3-amino-6-chloropyridazine (3) with
either chloroacetone (CAUTION: highly irritating and a strong
lachrymator) or ethyl 2-chloroacetoacetate to give 4 or 5,
5
residual methanol. Second, the ketone deoxygenation step,
which utilized trifluoroacetic acid (TFA) and triethylsilane, was
a liability from a waste disposal perspective. Incineration of
fluoride-containing waste is known to corrode waste inciner-
ators and reduces the useful life of incinerator refractory
6
,7
brick.
Silicon dioxide which results from triethylsilane
incineration leads to particulate agglomeration on the heat
transfer media of regenerative thermal oxidizers. The
8
challenges associated with the route shown in Scheme 1 led
us to pursue a diverse, alternative synthesis to access 2 which
avoids the use of the undesirable TFA and silane reagents and
shares no common intermediates with the previous route. We
report herein our efforts directed toward the development of a
new synthetic route to 2.
13
respectively (Scheme 3). The literature reports on formation
of these imidazopyridazines are plagued by low yields and poor
14
conversion of the starting materials. A broad screen of
solvents revealed that DMF, MeCN, and EtOH each gave the
15
RESULTS AND DISCUSSION
desired product in ∼50% yield. Further improvement to the
■
yield was realized by the addition of substoichiometric NaBr
Overview of Targeted Route. The route selection and
development described in this report were focused on the
following two key retrosynthetic disconnections of 2: at the
benzylic morpholine substituent and at the benzyl moiety
and several equivalents of H O to reactions run in DMF (Table
2
16
1
). The use of such additives in MeCN or EtOH did not
(
Scheme 2). Installation of the benzylic morpholine moiety
Received: November 30, 2012
Published: January 12, 2013
onto the 8-position of the imidazopyridazine core had been a
©
2013 American Chemical Society
273
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Scheme 1. Route to LY2784544
Scheme 2. Key retrosynthetic disconnections of 2
Scheme 3. Synthesis of imidazopyridazine
Table 1. Additive effects on the synthesis of 5 from 3 and
ethyl 2-chloroacetoacetate
a
entry
solvent
NaBr (equiv)
H O (equiv)
5
(%)
52
2
1
2
3
4
5
6
7
MeCN
EtOH
DMF
DMF
DMF
DMF
DMF
1.2
1.2
−
1.7
3.4
−
−
4
51
52
66
73
84
91
1.2
−
1.2
0.7
result in similar improvements to the reaction yield (Table 1,
entries 1−2).
Optimized conditions employed 0.7 equiv NaBr and 4 equiv
4
4
a
HPLC area %.
H O in DMF and achieved 91% conversion of 3 (Table 1, entry
2
7). Addition of water to the crude reaction mixture, isolation of
2
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the resulting solids, and crystallization from ethyl acetate/n-
heptane resulted in isolation of 5 in 62% yield and with 99.3%
relative HPLC area. Similar conditions were applied to the
synthesis of 4, but the reaction was not clean with only 60%
formation of the desired product and only a 41% isolated yield.
Although the use of 4 eliminates a decarboxylation step
downstream, 5 was the preferred intermediate since the yield
was higher and chloroacetone was eliminated. Additionally, the
presence of the electron-withdrawing ester group improved
reactivity in downstream chemistry (vide infra).
be improved to 9:1 using a 9 h addition time. Although the
reaction times were long (48 h) and conversion reached only
88%, 6 with 96% relative HPLC area could be crystallized from
the crude reaction mixture by addition of water, albeit in ∼45%
yield. Unfortunately, DMAc appears to be uniquely successful
in facilitating the transformation in the presence of aqueous
NMO. While DMAc has been historically considered an
undesirable but acceptable solvent, there is now growing
concerns associated with its use, particularly in the European
Union (EU) where it has been identified as a substance of very
high concern (SVHC) and is now a candidate on the REACH
Installation of Benzylic Morpholine. Installation of the
benzylic morpholine functionality had been historically
21
list. Given the incomplete conversion, very long reaction time,
and concerns associated with the use of DMAc, we turned our
attention to developing an alternative, cost-efficient source of
anhydrous NMO.
challenging, and the development of a VO(acac) -catalyzed
2
NMO addition reaction in the previous route to 2 greatly
4
facilitated this functionalization (Scheme 1, step 4). On the
basis of previous success with the VO(acac) -catalyzed process,
2
In order to utilize the inexpensive and widely available 50%
aqueous solution of NMO, a dehydration method was
necessary to satisfy the requirements of the chemistry.
Azeotropic water removal from a refluxing biphasic mixture
of NMO and toluene under reduced pressure (130 mmHg) was
effective in removing the water level near that of the
monohydrate, but the resultant monohydrate crystallized as a
solid mass (mp 76−78 °C) during the reflux, and removal of
the water below the monohydrate level proved to be impossible
we sought to develop a similar process for functionalization of
5
. Starting with analogous conditions, treatment of 5 with 10
equiv anhydrous NMO and 20 mol % VO(acac) in EtOH at
2
4
0 °C led to 73% conversion of the starting material but
surprisingly gave a 3:1 mixture of the exo and endo addition
products (respectively 6 and 7, Scheme 4). In an effort to
17
Scheme 4. Vanadium-catalyzed NMO addition reaction
22
with this technique. Azeotropic water removal using alcoholic
solvents (EtOH, i-PrOH, n-PrOH, n-BuOH) was an improve-
ment over toluene because the polar solvent was able to keep
the N-oxide in solution; however, these solvents were similarly
unable to remove water below the monohydrate level.
Subsequent investigation focused on the direct distillation of
water after addition of a cosolvent with a very high boiling
point that would be able to provide ample hydrogen bonding
for the strongly polar N-oxide. Preliminary studies utilized one
equivalent of ethylene glycol relative to NMO and were simply
performed on a rotary evaporator at full house vacuum (∼20
mbar) and 80 °C. These studies showed great promise, but a
switch to propylene glycol (PG) solvent was made due to
toxicity concerns over the large-scale use of ethylene glycol.
Larger-scale batch distillations of water showed the tendency
for the NMO solution to become darker in color upon
prolonged heating, and there was some concern over the large-
scale high-temperature distillation for safety reasons, despite a
measured decomposition onset temperature of >140 °C. This
prompted us to investigate a continuous method for the
dehydration, which could utilize a short contact time of the
hydrated solution to a high temperature.
improve both reaction yield and selectivity for the desired exo
product 6, various reaction parameters were screened.
Incremental improvements in selectivity could be made by
altering the reaction concentration in ethanol (15 vol EtOH,
3
:1; 20 vol EtOH, 4.1:1 ratio of 6:7), but changes to reaction
time, temperature, solvent, catalyst, and additives failed to
18
improve the reaction conversion or selectivity. Success in
affecting the exo:endo selectivity toward the desired product
could be achieved by slow addition of the NMO. Maximum
selectivity for the exo product (5.9:1) was achieved by addition
of 15 equiv NMO over 18 h, but the reaction was sluggish,
19
requiring 43 h to reach 93% conversion of starting material.
While these conditions provided a small-scale solution to
install the benzylic morpholine, the continued use of anhydrous
solid NMO was not viewed as an acceptable long-term
approach. Due to its large-scale commercial use in the Lyocell
Wiped-film evaporation (WFE) was identified as a suitable
technology for this application. Initial studies were highly
successful, and it was rapidly determined that house vacuum
2
0
process, the 50 wt % aqueous solution of NMO is more
readily available and less expensive than anhydrous NMO. The
high stoichiometry of NMO required in the transformation led
to efforts to develop a system which used NMO as a 50 wt %
aqueous solution. In EtOH, the reaction was poor when
aqueous NMO was used, stalling at 40% conversion. During a
solvent screen with anhydrous NMO, a particularly fast
transformation in dimethylacetamide (DMAc) had been
previously noted. Replacing anhydrous NMO with aqueous
NMO in a DMAc solvent led to 55% conversion in 16 h;
however, the selectivity for the desired isomer was poor (1.9:1
of 6:7). Adding 1,2-propanediol as a cosolvent and
implementing the NMO slow addition protocol used in the
EtOH system (vide supra), the selectivity of the reaction could
(
∼20 mbar), a WFE jacket temperature of 100−110 °C, and a
flow rate of ∼1600 mL/h were suitable conditions for the
dehydration of aqueous NMO to which one equivalent of PG
(
23
relative to NMO) had been added. This method of
distillation minimized color formation while producing a very
consistent water level (2−4% by KF). The NMO in PG
produced in this manner was found to perform in the reaction
as well as or better than solid “anhydrous” NMO (in EtOH,
24
97% conversion, 3.1:1 ratio of 6:7). This was viewed as an
easily scalable operation with minimal engineering require-
ments and was used to prepare >75 kg of the NMO in PG
solution, which assayed at 59−62 wt % NMO by Q-NMR. We
believe that both the hydrogen bond-donating ability of the PG
2
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and the high temperature during the WFE are responsible for
the successful dehydration of NMO.
Scheme 5. Attempted decarboxylative coupling to form 2
Again taking advantage of the improvement in selectivity
when NMO is added slowly to the reaction, an 18 h addition of
1
%
3 equiv of 60 wt % NMO in PG to a solution of 5 and 20 mol
VO(acac) in EtOH resulted in installation of the benzylic
2
morpholine functionality with >95% conversion of SM and an
1:1 ratio of 6:7 in 48 h. Addition of water to the crude
1
reaction mixture led to an efficient crystallization of the desired
product which could be isolated with good purity (97.5%). The
major impurities were starting material (5) and the endo isomer
(
7), which were rejected in downstream isolations. Vanadium
was well rejected (<10 ppm). This reaction was successfully
carried out on a 400 g scale with 55% yield and 97.2% relative
HPLC area of the isolated material. The main impurities were 5
(
0.4%) and 7 (0.6%).
It should be noted that two other substrates were considered
in the development of this step as a means of ultimately
accessing 2. However, functionalization of either 8 or 4 (Chart
Scheme 6. Saponification of 6
1) gave incomplete conversion of starting material and required
Chart 1. Substrates for the V-catalyzed NMO addition
reaction
metric Cu or Ag have been more commonly reported in the
26
decarboxylative coupling literature. Unfortunately, in this
case, the bimetallic systems led to mixtures which largely
contained decarboxylated starting material (13) and benzyl
ester, 12, and only traces of 2.
In order to pursue direct C−H benzylation as an alternate
way of accessing 2, acid hydrolysis and decarboxylation of the
ester group of 6 were carried out. This transformation was quite
straightforward and involved treatment of an aqueous
suspension of 6 with 4 equiv H SO for 24 h at reflux followed
2
4
by neutralization and isolation of the resulting precipitate which
afforded 13. The reaction was carried out on a 165 g scale to
give 13 in 91% yield with 99% relative HPLC area. (Scheme 7).
longer reaction times and higher stoichiometry of NMO. The
data at hand suggest that substrates with electron-withdrawing
groups in the 3-position (e.g., 5 and 9) are more reactive in the
V-catalyzed NMO addition reaction than substrates without
electron-withdrawing groups in the same position (8 and 4).
Given the improved reactivity of 5 as well as the benefits of
having an ester group present in the synthesis of the
imidazopyridazine core (4 vs 5), we chose to pursue
development of 5 and 6.
Scheme 7. Decarboxylation of 6
Decarboxylation. Early efforts to complete the synthesis of
focused on a decarboxylative coupling between the potassium
2
salt of 6 (11) and benzyl chloride 10 (Scheme 5). Although
2
2
successful decarboxylative aryl (sp −sp ) couplings have been
10
reported in the literature, there are no reported examples of
Palladium-Catalyzed Direct Benzylation. Key to the
design of the aforementioned route was the use of a Pd-
catalyzed direct benzylation to install the benzylic functionality
at the C-3 position on the imidazopyridazine. While direct
arylation of C−H bonds has received extensive attention in the
recent literature as an efficient, atom-economical method of
12
intermolecular decarboxylative benzylations of heteroarenes.
However, because of the high efficiency such a transformation
would afford to our process, we explored the reactivity of our
imizadopyridazine under decarboxylative conditions.
Saponification of 6 under basic conditions readily afforded
the potassium salt 11 (Scheme 6). Treatment of 11 with benzyl
chloride 10 in the presence of monometallic Pd-catalyst
9
cross-coupling, direct benzylation reactions are notably more
11
scarce. However, the success of direct benzylation reactions,
particularly on heterocyclic substrates, suggested that the
desired transformation may be obtainable under the right
conditions. An additional challenge in designing any C−H
activation process is the presence of multiple C−H bonds in
2
5
systems led to exclusive formation of the benzyl ester (12,
Scheme 5). Even under harsh conditions (150−200 °C), the
benzyl ester did not decarboxylate. Bimetallic systems
containing a Pd-catalyst together with catalytic or stoichio-
2
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the substrate. In the case of 13, we hypothesized that the more
Scheme 9. Proposed mechanism for the formation of 2 from
10 and 13
nucleophilic C-3 position would preferentially undergo the
27
desired activation and reaction.
Preliminary screening of reaction conditions in 1,4-dioxane
indicated that C−H activation of 13 did occur and was
exclusive to the C-3 position. A wide range of ligands and bases
2
8
were screened, and results indicated that PPh was the
3
optimal ligand and that K CO was a superior choice of base for
2
3
the reaction (Scheme 8).
Scheme 8. Palladium-catalyzed direct benzylation
A broader screen of Pd sources led to insight into the
mechanism of C−H activation (Table 2) which in this case can
Table 2. Palladium source screening for the synthesis of 2
stoichiometric base, K CO , with NaOAc led to almost no
2
3
a
entry
Pd source
additive
none
2
(%)
70
product formation (4% as compared to 70%), likely due to
poisoning of the Pd center with excess acetate. In fact, even the
addition of catalytic PivOH (10 or 30 mol %), which has been
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(TFA)2
Pd(OPiv)2
PdCl2
none
33
51
19
70
4
31
shown to be beneficial in promoting some CMD reactions,
none
was detrimental in this case, resulting in a decrease in the in situ
yield from 70% to 38%. Clearly, the reaction is highly sensitive
to the stoichiometry of carboxylate ligands.
none
PdCl2
10% NaOAc
none
Pd dba
2
3
Although the Pd(OAc) /PPh /K CO /dioxane system iden-
Pd dba
10% NaOAc
none
60
24
56
2
3
2
3
2
3
b
b
tified through the screening reaction detailed above did provide
an appreciable amount of desired product, the reaction stalled
at 70% yield and 85% conversion of 13 and did not proceed
further with longer reaction times (up to 72 h) even though
both starting materials remained; such a scenario suggested
catalyst decomposition. Increasing the catalyst loading to 10
mol % led to complete consumption of 13, but the in situ yield
of 2 remained 70% due to increased formation of a number of
byproducts. The mechanism of the catalyst deactivation
remains unclear at this point. Experiments in which product
and impurity-rich filtrate were spiked into a catalytic reaction
showed no difference in the reaction performance (Figure 1),
suggesting that catalyst poisoning does not occur by simple
coordination of a reaction product or byproduct to the Pd
center.
(PPh ) Pd
3
4
(PPh ) Pd
10% NaOAc
3
4
a
b
Based on HPLC wt % of 2. No additional PPh was added. Separate
control experiments indicated that, after 16 h, up to a 6-fold excess of
3
PPh relative to Pd had no effect on the reaction.
3
be well-rationalized within the context of a concerted
metalation deprotonation (CMD) mechanism (Scheme 9).
CMD is commonly proposed in the recent C−H activation
literature and requires the presence of a basic, anionic ligand on
the palladium center capable of assisting in the deprotonation
of the C−H bond. Examining the present data (Table 2),
Pd(TFA) was clearly inferior to Pd(OAc) , likely because the
29
2
2
TFA anion is less basic. Pd(OPiv) performed moderately well
2
and led to only a slightly lower yield than Pd(OAc) . Palladium
Another notable concern with the process was the use of
2
32
sources which did not contain a basic anionic ligand (Table 2,
entries 4, 6, and 8) gave low yields of 2. However, when these
catalysts were used in combination with 10% NaOAc (2 equiv
relative to Pd), the reactions performed nearly as well as when
dioxane, a suspect carcinogen, as the solvent. In an effort to
both replace dioxane and improve the overall yield of the
reaction, a number of alternative reaction solvents (toluene,
CPME, t-AmOH, THF, 2-MeTHF, anisole, MTBE, 2-BuOH,
DME, diglyme; see Table S6 in Supporting Information) were
screened. Unfortunately, no improvement in yield was
Pd(OAc) was used as the catalyst, emphasizing the importance
2
30
of the basic, anionic ligand. Interestingly, replacement of the
2
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synthesis of the imidazopyridazine core is accomplished in a
single step and circumvents the use of the amino acetal
(
Scheme 1, step 1) which had required long lead times to
secure. The Pd-catalyzed direct benzylation is one of the most
complex examples of this type of reaction reported to date and
exemplifies the potential of this powerful but underdeveloped
methodology as well as its scalability. The route described in
this report shares no common intermediates with the previous
route and is one step shorter. However, while there are several
key advantages to the route described in this report, because
several of the steps have only moderate yields, the overall yield
4
is lower than that of the previous route (16% vs 35%). The
demonstrated synthesis offers future suppliers of our key
building block an alternative for manufacture, and continued
reaction optimization and development, particularly to the
vanadium- and palladium-catalyzed steps, may help to realize a
more competitive route.
Figure 1. Reaction time course for the conversion of 13 to 2 for a
reaction run under standard conditions (red ■) or with impurity-rich
filtrate added (blue ●).
achieved, although anisole, with 61% yield, showed promise as a
suitable replacement for dioxane.
EXPERIMENTAL SECTION
■
Product Isolation. We next turned our attention to
isolation of 2 from the crude reaction mixture. Addition of
toluene and water to the crude reaction followed by addition of
concentrated HCl to pH <0.5 led to a scenario in which
compounds containing the imidazopyridazine core were
protonated and in the aqueous phase, whereas nonbasic
General Considerations. Reactions were monitored by
reverse-phase HPLC using a Zorbax SB-C18 4.6 mm × 75 mm
column with 3.5 μm particle size. Solvent A was a 0.1% solution
of TFA in water, and solvent B was a 0.1% solution of TFA in
CH CN. The flow rate was 1.0 mL/min with a column
3
temperature of 40 °C. The gradient method is given in Table 3.
HPLC retention times for the given conditions are given in
Table 4.
impurities (10, PPh O, etc.) were readily removed by
3
separation of the organic layer and repeated washing of the
acidic aqueous layer with toluene. Subsequent adjustment of
the pH of the aqueous solution to ∼1.0 allowed for direct
crystallization of 2 as the HCl salt with good rejection of
Table 3. HPLC gradient elution conditions
time (min)
0
% A
% B
remaining 13. Freebasing of the HCl salt in 2-MeTHF/H O
2
95
20
20
95
5
80
80
5
followed by a toluene/heptane crystallization allowed for
isolation of 2 in 50% yield with 96.9% relative HPLC area
when the reaction was carried out on a 235 g scale (Scheme 8).
This material was carried on to prepare 1 with quality
comparable to that of material prepared via the route in
Scheme 1.
1
1
2
5
6
0
6-Chloro-2-methylimidazo[1,2-b]pyridazine (4). A
slurry of 3 (10.1 g, 78.0 mmol), NaBr (5.56 g, 1.73 mmol),
DMF (60 mL), water (5.6 mL, 311 mmol), and chloroace-
CONCLUSIONS
■
33
In summary, a synthesis for 2 was developed (Scheme 10)
which avoids the major challenges associated with the previous
route, namely fluoride and silane waste incineration (Scheme
tone (3.75 mL, 46.2 mmol) was heated to 100 °C. After 4 h,
additional chloroacetone (3.75 mL, 46.2 mmol) was added over
10 min, and the reaction was then stirred at 100 °C for an
additional 10 h. The reaction was cooled to 20 °C, and water
1
). Furthermore, using the route described in this report, the
Scheme 10. Alternative route to 2
2
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Table 4. Relevant HPLC retention times
t = 3.36 min (254 nm); ESI-HRMS calc’d for C H ClN O
3
R
13 16
4
+
(
M + 2H − K) 311.0905, found 311.0903.
cmpd
HPLC retention time (min)
4
-((6-Chloro-2-methylimidazo[1,2-b]pyridazin-8-yl)-
2
3
4
5
6
7
9.95
1.67
3.59
8.25
6.40
6.67
12.74
3.36
4.81
methyl)morpholine (13). A solution of water (400 mL),
sulfuric acid (203.6 g, 1.95 mol), and 6 (165 g, 0.49 mol) was
heated to 100 °C and stirred for 24 h after which time it was
cooled to rt and water added (3.2 L). Sodium hydroxide (50 wt
%, 314 g, 3.9 mol) was added slowly to bring the pH to >9. The
resulting solids were isolated via filtration and washed with
1
1
1
0
1
3
water (3 × 200 mL) to afford 11 as a beige powder in 91% yield
1
(
119 g) after drying under vacuum; mp = 136−137 °C; H
NMR (CDCl ): δ 7.68 (s, 1H), 7.19 (s, 1H), 3.96 (d, 2H, J =
3
1
(
.2 Hz), 3.77 (t, 4H, J = 4.4 Hz), 2.59 (t, 4H, J = 4.4 Hz), 2.47
s, 3H). 13C NMR (CDCl ): δ 146.6, 144.0, 138.1, 115.7,
3
(
210 mL) was charged over 60 min. After stirring for 12 h at 20
1
14.9, 67.1, 56.1, 54.0, 15.0. HPLC t = 4.81 min (235 nm);
R
°
C, the solids were isolated by filtration and dried to afford 4 as
a tan solid (5.39 g, 41% yield). H and C NMR match
+
ESI-HRMS calc’d for C H ClN O (M + H) 267.1007, found
1
13
12 16
4
2
67.1004.
-((6-Chloro-3-(4-chloro-2-fluorobenzyl)-2-
methylimidazo[1,2-b]pyridazin-8-yl)methyl)morpholine
2). To a mixture of Pd(OAc) (10.0 g, 44.5 mmol), PPh (23.4
14c
previously reported data. HPLC t = 3.59 min (220 nm).
R
4
Ethyl 6-Chloro-2-methylimidazo[1,2-b]pyridazine-3-
carboxylate (5). A slurry of 3 (1.20 kg, 9.26 mol), NaBr
(
2
3
(
672 g, 6.53 mol), DMF (7.2 L), water (672 mL, 37.3 mol),
g, 89.5 mmol), K CO (185 g, 1.35 mol), and 13 (237 g, 0.889
2
3
and ethyl 2-chloroacetoacetate (762 mL, 5.6 mol) was heated
to 100 °C. After 4 h, additional ethyl 2-chloroacetoacetate (762
mL, 5.6 mol) was added over 1 h, and the reaction was then
stirred at 100 °C for an additional 10 h. The reaction was
cooled to 20 °C, and water (25 L) was charged over 2 h. After
stirring for 1 h at 20 °C, the slurry was filtered. The resulting
wet cake was dissolved in ethyl acetate (21.6 L) at 60 °C. The
organic solution was washed with water (2 × 6 L) and then
concentrated to 3.6 L. n-Heptane (6 L) was then charged to the
reactor. The solids were isolated by filtration and dried to afford
mol) was added anhydrous dioxane (1.90 L) and 10 (241 g,
.35 mol). The reaction mixture was thoroughly inerted with a
1
nitrogen atmosphere and then heated to reflux (101 °C) for 16
h. The mixture was cooled to rt, and toluene (1 L) and water (1
L) were added. Concentrated HCl (435 mL) was added over
3
0 min to adjust the pH to <0.5. The layers were separated, and
the acidic aqueous layer was subsequently washed with toluene
(3 × 500 mL). The pH of the resulting aqueous solution was
adjusted to 1.0 by addition of 50% NaOH (178 mL) and the
resulting slurry stirred at rt overnight. Filtration of the solids,
washing with water, and drying under vacuum afforded 2·HCl.
2-MeTHF (3.0 L) and water (1.0 L) were added to 2·HCl. To
reach a pH of 10−12, 50% NaOH (35 mL) was added. The
layers were separated, and the aqueous layer was extracted with
1
13
5
as a tan solid (1.38 kg, 61% yield). H and C NMR match
14b
previously reported data. HPLC t = 8.25 min (254 nm).
R
Ethyl 6-Chloro-2-methyl-8-(morpholinomethyl)-
imidazo[1,2-b]pyridazine-3-carboxylate (6). A solution of
5
(400 g, 1.67 mol), VO(acac) (88.5 g, 0.33 mol), and EtOH
2
(
4.0 L) was heated to 40 °C with stirring. A 60 wt % solution of
2
-MeTHF (500 mL). The combined organics were dried over
NMO in 1,2-propanediol (4.6 kg, 23.5 mol) was added over 18
h, and the reaction mixture was then stirred for an additional 24
h at 40 °C. Addition of water (3.2 L) over 2 h, cooling to 20
Na SO and filtered, and the 2-MeTHF was removed by rotary
2
4
evaporation. The resulting residue was dissolved in PhMe (1.0
L) at 60 °C, n-heptane (3.0 L) was added over 5 h, and the
resulting slurry was slowly cooled to rt. After stirring at rt
overnight, the slurry was cooled to 5 °C and stirred for 3 h.
Filtration of the solids and washing with n-heptane (2 × 300
mL) afforded 2 (199 g, 50% yield) as an off-white powder after
°
C, seeding with 6 (4.0 g, 16.7 mmol), and then cooling to 0−5
°
C resulted in crystallization of 6. The solids were isolated via
filtration and washed with water (4 × 800 mL) to afford 6 as a
tan powder in 56% yield (315 g) after drying under vacuum;
mp = 285 °C dec; H NMR (CDCl ): δ 7.38 (s, 1H), 4.43 (q,
2
1
1
13
4
3
drying. H and C NMR match previously reported data.
H, J = 7.2 Hz), 3.96 (d, 2H, J = 1.2 Hz), 3.76 (t, 4H, J = 4.8
HPLC t = 9.95 min (220 nm).
R
Hz), 2.70 (s, 3H), 2.58 (t, 4H, J = 4.8 Hz), 1.42 (t, 3H, J = 7.2).
Wiped-Film Evaporation to Prepare NMO in 1,2-
Propanediol. The distillation was carried out in a Sambay
WFE. The material feed was performed with a Telab 2500
pump set to 1625 mL/h. The jacket temperature was set to 130
1
3
C NMR (CDCl ): δ 159.5, 151.2, 147.9, 139.0, 138.6, 118.7,
3
6
7.0, 61.0, 56.0, 53.9, 16.8, 14.5. HPLC t = 6.40 min (254
R
+
nm); ESI-HRMS calc’d for C H O N Cl (M + H) 399.1218,
1
5
20
3
4
found 399.1217.
Potassium 6-Chloro-2-methyl-8-(morpholinomethyl)-
°
C. The heating device for the glass bridge to the distillate
vessel was set to 110 °C to ensure that the water would not
condense and flow back into the product. The distillate was
condensed at 2 °C and the distillation performed at 20 mbar.
The wiper rotation speed was set to 590 rpm. In a typical
distillation, 50 wt % aqueous NMO (6.41 kg, 27.3 mol NMO)
and 1,2-propanediol (2.14 kg, 27.6 mol) were combined, and
the water was distilled to afford a ∼60 wt % solution of NMO
in 1,2-propanediol (5.12 kg, 26.1 mol NMO, 96% recovery of
NMO) as determined by quantitative 11H NMR. The water
content in this solution was 2% which met the specification of
<5% (by KF).
imidazo[1,2-b]pyridazine-3-carboxylate (11). A slurry of 6
(
1.08 g, 3.19 mmol) in isopropanol (12.5 mL) was heated to 50
°C at which point a solution formed. Powdered KOH (322 mg,
5
3
.74 mmol) was added, and the resulting slurry was stirred for
0 min after which time the reaction was cooled to rt. The
solids were isolated by filtration, washed with isopropanol (3 ×
5
mL), and dried under vacuum to afford 12 in 86% yield (955
1
mg); mp = 111−113 °C; H NMR (CD OD): δ 7.36 (s, 1H),
3
3
2
1
.92 (d, 2H, J = 0.8 Hz), 3.74 (t, 4H, J = 4.4 Hz), 2.66 (s, 3H),
.59 (t, 4H, J = 4.4 Hz). C NMR (CD OD): δ 166.8, 148.1,
47.3, 138.8, 138.1, 118.8, 111.6, 68.0, 56.9, 55.0, 15.5. HPLC
1
3
3
2
79
dx.doi.org/10.1021/op300344m | Org. Process Res. Dev. 2013, 17, 273−281

Organic Process Research & Development
Article
(
2
i) Mai, W.; Yuan, J.; Li, Z.; Yang, L.; Xiao, Y.; Mao, P.; Qu, L. Synlett
ASSOCIATED CONTENT
■
012, 23, 938−942.
*
S
Supporting Information
(12) There are no reported examples of (hetero)arene decarbox-
1
H and 13C NMR spectra and additional experimental data
ylative benzylation. For other examples of decarboxylative benzylation,
see: (a) Torregrosa, R. R. P.; Ariyarathna, Y.; Chattopadhyay, K.;
Tunge, J. A. J. Am. Chem. Soc. 2010, 132, 9280−9282. (b) Zhang, W.-
W.; Zhang, X.-G.; Li, J.-H. J. Org. Chem. 2010, 75, 5259−5264.
(c) Weaver, J. D.; Recio, A.; Grenning, A. J.; Tunge, J. A. Chem. Rev.
(
Tables S1−S6). This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
E-mail: campbell_alison_nicole@lilly.com
■
*
2
011, 111, 1846−1913. (d) Recio, A., III; Heinzman, J. D.; Tunge, J.
A. Chem. Commun. 2012, 48, 142−144.
13) Both chloroacetone and ethyl 2-chloroacetoactate are
(
Notes
commercially available in bulk quantities, whereas the chloroaceto-
phenone used in the previous route to prepare the imidazopyridazine
necessitates an additional synthetic step (Scheme 1, step 2).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(14) (a) Stanovnik, B.; Tisler, M. Tetrahedron 1967, 23, 2739−46.
■
(b) Abignente, E.; Arena, F.; Luraschi, E.; Saturnino, C.; Rossi, F.;
We thank John Howell, C. Brad Held, and Michele Lake for
their contributions to this work. We are grateful to Jared
Fennell and Utpal Singh for helpful discussions.
Berrino, L.; Cenicola, M. L. Farmaco 1992, 47, 931−944. (c) Pevarello,
P.; Garcia, C. A. M.; Rodriguez, H. A.; Saluste, C.-G. P.; Ramos, L. F.
J.; Gonzalez, C. E.; Oyarzabal, S. J. Preparation of imidazo[1,2-b]
pyridazines as protein kinase inhibitors. U.S. Pat. Appl. Publ. US/
0046127, 2011; A1 741765, 2010. (d) Banno, H.; Hirose, M.;
Kurasawa, O.; Langston, S. P.; Mizutani, H.; Shi, Z.; Visiers, I.; Vos, T.
J.; Vyskocil, S. Heteroaryls as PI3K and/or mTOR inhibitors and their
preparation and use in the treatment of diseases. U.S. Pat. Appl. Publ.
US/0256172, 2010; A1 657801, 2010.
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should be used with caution.
2
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