Scalable synthesis of a cis-substituted cyclobutyl-benzothiazole pyridazinone: Process development of an efficient copper catalyzed C-N cross-coupling reaction

Article abstract of DOI:10.1021/op3002883

A scalable process for the preparation of 2-(2-(cis-3-(piperidin-1-yl) cyclobutyl)benzothiazol-6-yl)pyridazin- 3(2H)-one in multi-kilogram amounts and in high purity has been developed. The key features of this synthesis are the coppercatalyzed C-N cross-

Full text of DOI:10.1021/op3002883

Article
pubs.acs.org/OPRD
Scalable Synthesis of a Cis-Substituted Cyclobutyl-Benzothiazole
Pyridazinone: Process Development of an Efficient Copper Catalyzed
C−N Cross-Coupling Reaction
Jeffrey M. Kallemeyn,* Yi-Yin Ku, Mathew M. Mulhern, Richard Bishop, Agnes Pal, and Legi Jacob
Process Research, AbbVie, 1401 North Sheridan Road, North Chicago, Illinois 60064, United States
ABSTRACT: A scalable process for the preparation of 2-(2-(cis-3-(piperidin-1-yl)cyclobutyl)benzothiazol-6-yl)pyridazin-
3(2H)-one in multi-kilogram amounts and in high purity has been developed. The key features of this synthesis are the copper-
catalyzed C−N cross-coupling reaction and the development of a highly diastereoselective reductive amination using
NaBH(OPiv)3 as a reducing agent. Controls were implemented to minimize both base- and acid-catalyzed isomerization of the
1,3-cis-substituted cyclobutane ring.
multi-kilogram quantities of 1. First, it would be desirable to
avoid the use of the toxic OsO4 during the synthesis of 6.
Second, removal of the reduction and oxidation steps, which
were used as a protecting group strategy to minimize impurity
formation in the cross-coupling reaction, would afford a
significant increase in efficiency. Finally, we identified a
stereoselective reductive amination as being the pivotal step
to set the desired cis-stereochemistry, improve the yield, and
avoid a tedious chromatography.7,8 This stereoselective
reductive amination could occur either early in the reaction
sequence as a way to avoid the reduction and subsequent
oxidation of the cyclobutanone (via intermediate 10) or as the
last step (via intermediate 9) (Scheme 2). This led to
identification of the key intermediate 6, which would serve as
precursor to both routes.
INTRODUCTION
■
A number of histamine-3 (H3) antagonists have in recent years
entered and completed clinical trials for the treatment of central
nervous system (CNS) disorders such as attention deficit
hyperactivity disorder (ADHD), Alzheimer’s disease (AD), and
the cognitive deficits of schizophrenia (CDS).1−4 Compound 1
(Figure 1) exhibits potent and selective binding to human and
Figure 1. Structure of API 1.
rat H3 receptors, where it acts as a competitive antagonist. In
order to further evaluate its effectiveness and profile in
extended studies, a large quantity of the drug substance was
required. The process research and development efforts
resulted in a reliable and scalable synthesis to provide multi-
kilogram quantities of 1 in high purity.
DISCUSSION AND RESULTS
■
To quickly determine the feasibility of the proposed routes and
identify which one showed more promise, the key experiments
were performed first. Compound 10 was prepared in a 97:3 dr
after purification and was subjected to the CuCl catalyzed
cross-coupling with 7 to afford 1 in 99% conversion.
Surprisingly, 1 was obtained in a 79:21 dr as both 10 and 1
were observed to isomerize over the course of the reaction. A
series of control studies shows that the isomerization of 1 is
catalyzed by CuCl under the reaction conditions. Modification
of the reaction conditions by varying the catalyst loading and
lowering reaction temperature helped attenuate the isomer-
ization to less than 5% but resulted in longer reaction times or
lower conversions. The propensity of the isomerization to
occur under a variety of reaction conditions led us to abandon
this route and focus on improving the route via intermediate 9.
As in the initial route, the synthesis of 6 began with the
hydrolysis of 2 to the aminothiol 3 in aqueous NaOH. After
The key structural features of 1 are the 1,3-cis-substitution of
the benzothiazole and piperidine substituents on the cyclo-
butane ring as well as the pyridazinone heterocycle.5,6 The
initial synthesis (Scheme 1) begins by hydrolysis of the
commercially available 6-bromo-2-benzothiazolinone (2), fol-
lowed by construction of the benzothiazole heterocycle via
condensation of the aryl aminothiol 3 and cyclobutene
substituted acid chloride 4 promoted by Et3N and pyridinium
p-toluenesulfonate. Oxidative cleavage of the cyclobutene 5 to
the ketone 6 followed by reduction and copper-catalyzed C−N
cross-coupling with pyridazinone 7 affords alcohol 8. Oxidation
of 8 to ketone 9 followed by reductive amination with sodium
cyanoborohydride, NaBH3CN, afforded a mixture of the cis-
and trans-isomers, 1 and trans-1. These isomers could be
separated by SiO2 chromatography, affording a 35% yield of 1.
The initial synthesis provided 1 in seven steps with an overall
yield of 12%.5,6
Special Issue: Transition Metal-Mediated Carbon-Heteroatom Cou-
pling Reactions
On analysis of this synthesis, several scale-up concerns and
areas of improvement were identified to develop a synthesis of
Received: October 12, 2012
© XXXX American Chemical Society
A
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Scheme 1. Initial Route
substrate was air sensitive and required sparging of solvents and
reaction vessels prior to hydrolysis and during isolation. The
isolated product 3 was also susceptible to oxidation to the
disulfide; however, drying and keeping the solid under a N2
atmosphere minimized the amount of oxidation which
occurred.9
Scheme 2. Retrosynthesis
To avoid the OsO4 oxidative cleavage, condensation of 3
with the commercially available cyclobutanone carboxylic acid
11 was studied (Scheme 3). This condensation proceeded by
activating the carboxylic acid with N,N′-carbonyldiimidazole
(CDI)10 followed by slow addition of the activated carboxylic
acid intermediate to 3 ,which resulted in reaction at either the
amine or the thiol functionality to afford a mixture of
intermediates 12 and 13. Slow addition of 1.05 equiv of the
activated carboxylic acid intermediate minimized the formation
of the bis-acylated impurity, which did not undergo further
conversion to 6. Addition of HCl to the reaction mixture
promoted the condensation of 12 and 13 to the benzothiazole
to form the key intermediate 6 (12 converted at rt; however, 13
required mild heating to 45 °C for the condensation to occur).
It was found that the cyclobutanone could be efficiently
protected as the dimethyl ketal 14 by addition of MeOH to the
acidification, the product precipitated from the reaction mixture
and was isolated by filtration to afford a 96% yield of 3. This
Scheme 3. Synthesis of 6 and 14
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acidic reaction mixture after the condensation to form
intermediate 6 was complete. This telescoped process resulted
in the isolation of 14 as a crystalline solid in an 84% overall
yield from 3.
Table 2. Base Optimization
Intermediates 6 and 14 were both evaluated in the C−N
cross-coupling reaction with 7. Direct cross-coupling of
intermediate 6 with 7 resulted in the formation of a number
of impurities, which had been addressed in the initial route by
using the reduction/oxidation sequence. Conversely, the
intermediate 14 was found to undergo smooth C−N cross-
coupling reaction with 7 so the reaction conditions for the
copper-catalyzed cross-coupling were then further optimized.
The commonly used 1,10-phenanthroline ligand11 resulted in
low conversion to product 15 (Table 1, entry 1) whereas
entry
base
conversion, %
16, %
1
2
3
4
K2HPO4
K2CO3
10%
100%
98%
ND
1%
6%
8%
K3PO4
KOTMS
92%
the product through a toluene/heptane recrystallization. This
procedure provided crystalline 15 in an 84% yield with >98%
purity and <20 ppm of residual copper.
The ketal protecting group could be efficiently removed by
treating 15 with aqueous HCl in CH3CN to provide the desired
ketone 9 in 92% yield and >98% purity.
Table 1. Ligand and Solvent Optimization
To set the key cis-stereochemistry on the cyclobutane ring, a
variety of reductive amination procedures were investigated.7
Using NaBH3CN, the same reductant as for the initial route,
gave a poor cis/trans ratio as well as significant alcohol side-
product, 8 (Table 3, entry 1). Switching reducing agent to
NaBH(OAc)3 greatly improved the reaction profile by lowering
the amount of impurity 8 and improving the diastereoselectivity
(entry 2). To further increase the diastereoselectivity, more
hindered reducing agents were prepared by reaction of NaBH4
with a variety of carboxylic acids.14 While increasing the
substituent size from Me to Et to i-Pr had little improvement in
selectivity, the t-Bu substituent in the prepared NaBH(OPiv)3
resulted in a significant increase in cis to trans selectivity as well
as a decrease in the amount of alcohol side-product formed.
Further modification of solvent and temperature to toluene at
10 °C resulted in a 55:1 diastereoselectivity.
The NaBH(OPiv)3 reagent is conveniently prepared by
addition of pivalic acid to NaBH4 in THF in a 3.0:1.0 molar
ratio, and it can be used directly in solution or isolated as a
white solid after concentration of the THF and precipitation
with heptane. In the course of determining the robustness of
this reagent for the reductive amination, the equivalents of
pivalic acid to NaBH4 were varied from 2.7 to 3.3 equiv. To our
surprise, no reaction occurred when 2.7 equiv was employed,
and a significant rate increase was observed with 3.3 equiv of
pivalic acid, reducing the reaction time from 16 h to as little as 2
h with no impact to yield or diastereoselectivity. Increasing the
pivalic acid to 4.0 equiv resulted in no further increase in
reaction rate. The excess pivilac acid may be catalyzing the
formation of the iminium intermediate. The initial preparation
of the NaBH(OPiv)3 using a 3.0:1.0 ratio may have had
sufficient acid catalyst present for the reaction to proceed, albeit
at a slower rate, whereas with preparation of the reagent using a
2.7:1.0 ratio, no acid catalyst was present, resulting in no
conversion. To ensure the reaction proceeded on scale, a
3.3:1.0 ratio of pivalic acid/NaBH4 was used and 1 was isolated
in 99% yield in a 98:2 cis/trans ratio.
entry
ligand
solvent
conversion, %
47%
1
2
3
4
5
6
7
1,10-phenanthroline
8-hydroxyquinoline
DMEDA
NMP
NMP
NMP
a
100%
24%
b
DMEDA
pyridine
100%
DMEDA
toluene
15%
5%
DMEDA
dioxane
DMEDA
5:1 toluene/pyridine
75%
a
b
Peak area purity of 85% Peak area purity of 96%.
employment of 8-hydroxyquinoline12 in NMP (entry 2) or
N,N′-dimethylethylene diamine (DMEDA)13 in pyridine (entry
4) resulted in complete conversion of the starting material. On
closer evaluation of the 8-hydroxyquinoline reaction, up to 15%
of an impurity arising from a cross-coupling reaction between
14 and ligand was observed, which was difficult to remove by
crystallization from the desired product. This low purity led to
the choice of DMEDA as the preferred ligand. A 2:1 loading of
ligand/catalyst was found to result in the fastest reaction, and a
solvent survey found pyridine to be the most effective solvent
for this conversion (entries 3−7).
To complete the optimization of the C−N cross-coupling
step, a number of bases were screened. K2CO3 was found to
give the highest conversion while minimizing the amount of
ligand cross-coupled impurity 16 (Figure 2). The use of other
Figure 2. Impurity 16.
bases was inferior, such as K2HPO4, which resulted in poor
conversion to product (Table 2, entry 1) or K3PO4 or KOTMS,
which resulted in significant formation of 16 (entries 3, 4).
Effective removal of the residual copper from the reaction
mixture was achieved by a 5% NH4OH wash. It was found that
only minimal product was lost to the first 5% NH4OH wash;
additional washes resulted in significant loss of product due to
the pyridine solvent. It was found that a solvent switch from
pyridine to toluene followed by additional washes minimized
the loss of product as well as providing a convenient isolation of
To further improve the cis/trans ratio and for pharmaceutical
formulation purposes, preparation of a salt was explored. Both
succinate and hydrochloride salts were shown to have
acceptable physical properties, and upon crystallization, the
ratio of cis/trans could be improved to >99.5:<0.5. However,
high levels of trans-1 were observed in the mother liquor of the
succinate salt recrystallization process, and a mass balance
calculation corresponded to rejection of 2.8% of trans isomer,
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Table 3. Optimization of Reductive Amination
entry
R
time, h
solvent
temp, °C
cis/trans
8, %
40
3.5
1
NaBH3CN
Me
8
0.5
0.5
0.5
0.5
3
MeOH
THF
22
22
22
22
22
0
7:1
17:1
13:1
17:1
30:1
36:1
12:1
31:1
25:1
41:1
55:1
55:1
2
3
Et
THF
5.6
0.3
4
i-Pr
THF
5
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
THF
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
0.8
6
THF
7
2
CH3CN
CH2Cl2
IPA
22
22
22
22
0
8
2
9
18
2
10
11
12
toluene
toluene
toluene
24
16
10
0.3
and not the 1.8% as anticipated. To understand the origin of
this high level of trans-isomer, a series of control studies were
performed. Both the succinate and HCl salts of 1 were
dissolved in water and stirred at 60 °C. Heating of the succinate
salt resulted in an increase of trans-1 to 4.5% overnight, whereas
heating of the HCl salt resulted in no significant increase of
trans-1. Due to the slightly lower solution pH of the succinate
salt solution (pH = 4.5) compared to the HCl salt solution (pH
= 6.0), owing to a free carboxylic acid in the succinate, an acid-
catalyzed isomerization was hypothesized. This was confirmed
by heating 1·Succinate in 0.5 M HCl, which resulted in
formation of 20.4% of trans-1 overnight (Chart 1).
4). After 2 h, an 85:15 mixture of the cis/trans isomers had
formed. The cis-isomer had 15% deuterium incorporation
whereas the trans-isomer contained 100% deuterium, indicating
1
that an equilibrium was not yet established. H NMR analysis
of trans-1 showed that all of the proton adjacent to the
benzothiazole ring had been exchanged for deuterium. These
results clearly indicated that the isomerization occurred at the
carbon adjacent to the benzothiazole ring.
The free base of 1 was not isolated after the reductive
amination workup but was carried directly into the salt
formation. To minimize the amount of isomerization on salt
formation, 0.95 equiv of HCl was used in the crystallization to
ensure the acid-catalyzed isomerization did not occur.
Recrystallization from toluene/MeOH afforded an 86% yield
of 1·HCl with 99.6:0.4 dr (Scheme 5). A total of 4.3 kg of 1 was
prepared using this process.
To determine the site of isomerization, a deuterium exchange
reaction was performed by heating 1 in DCl and D2O (Scheme
Chart 1. pH Dependence on Isomerization
CONCLUSION
■
We have developed an efficient and scalable six-step process for
the synthesis of 1 in high purity with an improved overall yield
of 53% versus 12% in the initial process. The improved process
successfully overcomes the drawbacks associated with the initial
route involving an undesirable OsO4 oxidative cleavage
reaction, an inefficient cyclobutaneketone reduction−oxidation
sequence and the nonstereoselective reductive amination
reaction. The scalable process features a highly diastereose-
lective reductive amination reaction of the cyclobutaneketone
to set the key cis stereochemistry and an optimized copper-
catalyzed C−N cross-coupling reaction. Mechanistic under-
standing of the potential isomerization of the product 1
catalyzed by both acid and base led to development of
conditions to produce 1 in a 99.6:0.4 dr. This improved column
chromatograph-free process involved several simple workup
and purification procedures and several new crystalline
intermediates which allow purification by crystallization, and
it was successfully demonstrated on scale to produce 4.3 kg of
high purity product 1.
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Scheme 4. Deuterium Incorporation
Scheme 5. Synthesis of 1·HCl
(5% EtOAc/95% heptane to 100% EtOAc) provided analyti-
cally pure 17. mp: 122−125 °C. 1H NMR (400 MHz, CDCl3):
δ 7.28−7.21 (m, 4H), 6.63−6.57 (m, 2H), 4.30 (bs, 4H). 13C
NMR (101 MHz, CDCl3): δ 147.15, 138.18, 134.15, 119.60,
116.37, 108.73. IR (KBr): 3415 (w), 3295 (w), 3185 (w, br),
1624 (w, br), 1471.2 (s), 1387 (w), 1294 (w), 1244 (w), 1152
(w), 1107 (w), 1075 (w), 884 (w), 845 (w), 819 (s), 722 (w),
644 (w), 615 (m), 551(m). MS (ESI+): 406.8 (100) [M+ + H].
97.3 A% purity (HPLC Method 1). Anal. Calcd for
C12H10Br2N2S2: C, 35.49; H, 2.48; N, 6.90. Found: C, 35.32;
H, 2.17; N, 6.81.
EXPERIMENTAL SECTION
■
HPLC analyses were conducted on an Agilent 1100 series
HPLC using the following methods. HPLC Method 1: Zorbax
RX-C8, Isocratic 70% (0.1% H3PO4/acetonitrile)/(0.1%
H3PO4/water), col temp 35 °C, 1.5 mL/min, 10 min, 254
nm, tR: 3, 2.58 min; 17, 3.78 min; 6, 2.87 min; 14, 3.66 min.
HPLC Method 2: Gemini C18, 4.6 × 150 3 μm column, 70%
to 10% 0.15% NH4OH, 30% to 90% ACN over 10 min, hold 5
min, 3 min equilibration, 1.0 mL/min, col temp 35 °C, 254 nm,
tR: 15, 5.59 min; 9, 3.35 min; 1, 13.0 min; trans-1, 11.9 min. 1H
and 13C NMR spectra were collected on a Varian Mercury 400
1
3-(6-Bromobenzothiazol-2-yl)cyclobutanone (6). To a
solution of 1,1′-carbonyldiimidazole (CDI, 65.1 g, 0.402 mol,
1.05 equiv) in nitrogen-sparged NMP (100 mL) was slowly
added a nitrogen sparged solution of 3-oxocyclobutane
carboxylic acid (11; 48 g, 0.421 mol, 1.1 equiv) in NMP
(100 mL) over 15 min to control the gas evolution at <25 °C.
The activated carboxylic acid solution was mixed for 30 min at
25 °C. A solution of 2-amino-5-bromobenzenethiol (3; 78 g,
0.383 mol, 1.0 equiv) in nitrogen-sparged NMP (200 mL) was
cooled to 0 °C while maintaining a nitrogen sparge. To this
solution was added the activated acid solution over 20 min at
<10 °C. The mixture was agitated at 10 °C for 30 min until the
reaction was complete (<1 A% 3 by HPLC). The mixture was
cooled to 0 °C, and 4 M HCl in 1,4-dioxane (301 g, 1.148 mol,
3.0 equiv) was slowly added over 1 h at <10 °C. The mixture
was agitated at 10 °C for 30 min until 12 had been converted to
6 (<1 A% 12 by HPLC). The mixture was then agitated at 50
°C for 16 h until 13 had been converted to 6 (<1 A% 13 by
HPLC). The solution was cooled to 22 °C and was used
directly in the next step. This afforded 900 g of a 10.75% (w/w)
solution of 6 in NMP (96.75 g of 6, 89.5% yield). A small
amount of 6 was isolated by precipitation with water (1 L) and
purified by silica chromatography (Biotage 40 + S, 5% ethyl
acetate/heptane to 100% ethyl acetate) to provide analytically
NMR (400 MHz for H and 100 MHz for 13C).
2-Amino-5-bromobenzenethiol (3). A mixture of 6-
bromobenzothiazolinone (2; 100 g, 0.435 mol, 1.0 equiv) and
nitrogen-sparged water (500 mL) was heated to 90 °C while
maintaining a continuous nitrogen sparge. To the slurry was
added nitrogen sparged 26% sodium hydroxide solution (674 g,
4.35 mol, 10.0 equiv). The resulting solution was stirred at
reflux for 16 h and monitored by HPLC until starting material
had been consumed (<3 A% 2 by HPLC). After the solution
was cooled to 0 °C, the pH was adjusted to 3 with concentrated
HCl (350 mL) at <35 °C [Note: As the hydrochloric acid was
added, off-gassing occurred, and solids formed as the pH
approached 7]. The product was collected by filtration, washed
with water (500 mL), and dried under vacuum/nitrogen to
afford 85 g (96%) of 3 as a light yellow solid. The crude 3 was
1
used directly in the next step. HPLC and H NMR were
collected for 3, and additional analytical data were collected
after complete conversion to 2,2′-disulfanediylbis(4-bromoani-
line) (17). 91.7 A% purity (HPLC Method 1). H NMR (400
MHz, D6-DMSO) δ 7.12 (bs, 2H), 6.61 (bs, 1H), 5.38 (bs,
3H).
1
2,2′-Disulfanediylbis(4-bromoaniline) (17). A mixture
of 6-bromobenzothiazolinone (2; 5 g, 21.74 mmol, 1.0 equiv),
water (10 mL), and 50% NaOH (34.8 g, 434.78 mmol, 20
equiv) was heated to reflux for 16 h. The reaction was
monitored by HPLC until starting material had been consumed
(<3 A% 2 by HPLC). After cooling the solution to 0 °C, the
pH was adjusted to pH 7 with concentrated HCl (35 mL) at
<35 °C. [Note: As the hydrochloric acid was added, off-gassing
occurred, and solids formed as the pH approached 7].
Methanol (30 mL) was added, and the suspension was stirred
at 0 °C. NaClO2 (80%, 1.83 g, 16.30 mmol, 0.75 equiv) in
water (4 mL) was slowly added. After 30 min, the product was
collected by filtration, washed with water (20 mL), and dried
under vacuum/nitrogen to afford 4.45 g of 2,2′-disulfanediylbis-
(4-bromoaniline) (17). Purification by silica chromatography
1
pure 6. mp: 93−96 °C. H NMR (400 MHz, CDCl3): δ 7.99
(dd, J = 1.9, 0.5, 1H), 7.83 (dd, J = 8.6, 0.5, 1H), 7.58 (dd, J =
8.6, 1.9, 1H), 4.09−3.97 (m, 1H), 3.74−3.55 (m, 4H). 13C
NMR (101 MHz, CDCl3): δ 202.92, 172.41, 151.52, 136.48,
129.52, 123.92, 123.74, 118.52, 54.68, 27.96. IR (KBr): 1783
(s), 1587 (w), 1541 (w), 1513 (w), 1440 (w), 1395 (w), 1371
(w), 1302 (w), 1269 (w), 1164 (w), 1117 (m), 1102 (m), 1086
(m), 1037 (w), 945 (w), 863 (w), 817 (s), 745 (w), 712 (w),
668 (w), 563 (w). MS (ESI+): m/z 283.7 (100) [M+ + H].
99.1 A% purity (HPLC Method 1). Anal. Calcd for
C11H8BrNOS: C, 46.82; H, 2.86; N, 4.96. Found: C, 46.71;
H, 2.63; N, 4.99.
E
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6-Bromo-2-(3,3-dimethoxycyclobutyl)benzothiazole
(14). In a 3-L 3-necked round-bottomed glass flask equipped
with a mechanical stirrer was charged 900 g of a 10.75 wt %
solution of 6 in NMP (96.75 g of 6, 0.295 mol, 1.0 equiv)
followed by MeOH (1.56 L) at 22 °C. The solution was stirred
for 16 h until the reaction was complete (<2% area 6 by
HPLC). The resulting slurry was cooled to 15 °C, and 50%
NaOH (46 g, 0.575 mol, 1.9 equiv) and water (80 mL) were
added. The pH was adjusted to 7 with the addition of 50%
NaOH (50 g, 0.625 mol, 2.1 equiv). To this mixture was added
water (1.1 L), and the resulting solids were collected by
filtration, washed with water (500 mL), and dried in a vacuum
oven at 50 °C to afford 112 g of crude 14 (83.8% w/w by
HPLC analysis) as a light grey solid.
(dd, J = 0.4, 8.7, 1H), 7.90 (dd, J = 1.7, 3.8, 1H), 7.68 (dd, J =
2.1, 8.7, 1H), 7.25 (dd, J = 3.8, 9.5, 1H), 7.06 (dd, J = 1.7, 9.5,
1H), 3.80−3.66 (m, 1H), 3.24 (s, 3H), 3.20 (s, 3H), 2.87−2.75
(m, 2H), 2.64−2.53 (m, 2H). 13C NMR (101 MHz, CDCl3) δ
176.07, 159.64, 152.31, 137.77, 136.44, 134.88, 131.01, 130.84,
123.36, 122.36, 118.46, 99.64, 49.01, 48.69, 39.46, 29.84. IR
(KBr): 3026 (w), 2949 (w), 2928 (w), 1658 (s), 1585 (m),
1519 (m), 1457 (m), 1272 (m), 1228 (w), 1150 (s), 1047 (m),
860 (m), 828 (s). MS (DCI): 344 (M + H, 100), 312 (M −
31). 97.8 A% purity (HPLC Method 2). Anal. Calcd for
C17H17N3O3S: C, 59.46; H, 4.99; N, 12.24. Found: C, 59.44; H,
4.80; N, 12.25.
2-(2-(3-Oxocyclobutyl)benzothiazol-6-yl)pyridazin-
3(2H)-one (9). To a mixture of 15 (4.7 kg, 13.7 mol, 1.0
equiv), CH3CN (27.8 kg), and H2O (2.5 kg, 140 mol, 10
equiv) was added concentrated HCl (410 g, 4.2 mol, 0.30
equiv). The reaction mixture was heated to 35 °C and held at
35 °C for 1.5 h. The reaction mixture was then heated to 70 °C,
and H2O (64.8 kg) was added over 40 min. The product slurry
was cooled to −7 °C over 3.5 h and held at −7 °C for 15.75 h.
The product was collected by filtration, washed with H2O (30
kg), and dried in a vacuum oven to afford 3.75 kg (92%) of 9 as
an off-white solid. mp: >200 °C. 1H NMR (400 MHz, CDCl3):
δ 8.19 (d, J = 2.1, 1H), 8.07 (d, J = 8.8, 1H), 7.93 (dd, J = 1.7,
3.8, 1H), 7.74 (dd, J = 2.1, 8.8, 1H), 7.28 (dd, J = 3.7, 9.5, 1H),
7.08 (dd, J = 1.7, 9.5, 1H), 4.08 (tt, J = 6.9, 8.9, 1H), 3.92−3.41
(m, 4H). 13C NMR (101 MHz, CDCl3): δ 202.99, 173.53,
159.56, 152.02, 138.09, 136.52, 134.84, 130.98, 130.89, 123.66,
122.49, 118.49, 54.65, 28.01. IR (KBr): 1781 (s), 1671 (s),
1656 (s), 1591 (m), 1519 (w), 1461 (m), 1415 (w), 1373 (w),
1315 (w), 1305 (w), 130 (m), 862 (m), 822 (s). MS (DCI):
298 (M + H, 100). 98.8 A% purity (HPLC Method 2). Anal.
Calcd for C15H11N3O2S: C, 60.59; H, 3.73; N, 14.13. Found: C,
60.42; H, 3.52; N, 14.22.
Preparation of NaBH(OPiv)3 in Toluene. A mixture of
NaBH4 (0.915 kg, 24.2 mol, 1.0 equiv) and THF (35 kg) was
cooled to 0 °C, and a solution of pivalic acid (7.46 kg, 73.0 mol,
3.02 equiv) in THF (21 kg) was added over 2 h. The reaction
was warmed to 25 °C and stirred under N2 for 6 h. The THF
solvent was then exchanged to toluene by continuous
distillation at 38 L, adding 130 kg of toluene as needed to
maintain the 38 L distillation volume. The clear, colorless
toluene solution was transferred to a tared drum, and the
reactor was rinsed with toluene (10 kg). This afforded 53.4 kg
of a clear, colorless, nominally 15.3% (w/w) solution of
NaBH(OPiv)3 in toluene.
2-(2-(cis-3-(Piperidin-1-yl)cyclobutyl)benzothiazol-6-
yl)pyridazin-3(2H)-one (1). A mixture of 9 (3.75 kg, 12.6
mol, 1.0 equiv), pivalic acid (0.365 kg, 3.6 mol, 0.3 equiv),
toluene (53 kg), and piperidine (1.6 kg, 18.6 mol, 1.5 equiv)
was cooled under N2 to 5 °C. The toluene solution of
NaBH(OPiv)3 (15.3% w/w, 33.4 kg, 15.1 mol, 1.2 equiv) was
added over 20 min. The reaction mixture was stirred at 5 °C for
16 h, at which time HPLC analysis showed complete
consumption of 9. The product was extracted with 0.5 M
sodium succinate solution buffered at pH 5.0 (60 kg, 2 × 28
kg). To the combined aqueous layers was added toluene (60
kg), and the pH was adjusted to 9.7 using 50% NaOH (3.8 kg).
The resulting two-layer mixture was filtered through an in-line
filter, and the lower aqueous layer was removed and extracted
with toluene (38 kg). The combined organic layers were
washed with water (39 kg), distilled to approximately 100 L,
and transferred to a tared drum. This gave 72.5 kg of a light
To half of the crude 14 (56 g) was added EtOAc (1.07 L),
and the mixture was stirred for 16 h at 22 °C. After filtration of
an insoluble material, the filtrate was concentrated to dryness,
diluted with methanol (800 mL), and heated to reflux to afford
a light yellow solution. Water (100 mL) was added while
maintaining the temperature above 60 °C. The solution was
slowly cooled to −5 °C over 4 h and held at −5 °C for 1 h. The
resulting solid was collected by vacuum filtration and dried in a
vacuum oven at 50 °C to afford 46.9 g (93% yield, 95.5% w/w
by HPLC analysis) of 14 as an off-white solid. To obtain an
analytically pure sample, a small amount of 14 was purified by
silica chromatography (5% ethyl acetate/heptane to 100% ethyl
1
acetate). mp: 116−118 °C. H NMR (400 MHz, CDCl3): δ
7.96 (d, J = 1.9, 1H), 7.80 (d, J = 8.6, 1H), 7.53 (dd, J = 8.7, 2.0,
1H), 3.75−3.63 (m, 1H), 3.23 (s, 3H), 3.19 (s, 3H), 2.84−2.74
(m, 2H), 2.60−2.51 (m, 2H). 13C NMR (101 MHz, CDCl3): δ
174.91, 151.70, 136.50, 129.14, 123.81, 123.53, 118.02, 99.63,
49.02, 48.70, 39.42, 29.70. IR (KBr): 2953 (w), 2830 (w), 1587
(w), 1510 (w), 1438 (w), 1408 (w), 1393 (w), 1301 (w), 1270
(s), 1226 (w), 1198 (w), 1149 (s), 1125 (w), 1095 (m), 1078
(w), 1037 (m), 1018 (w), 932 (w), 850 (m), 821 (w), 809 (m),
747 (w), 709 (w), 566.8 (w). MS (ESI+): m/z 327.8 (100)
[M+ + H]. 100 A% purity (HPLC Method 1). Anal. Calcd for
C13H14BrNO2S: C, 47.57; H, 4.30; N, 4.27. Found: C, 47.43;
H, 3.98; N, 4.30.
2-(2-(3,3-Dimethoxycyclobutyl)benzothiazol-6-yl)-
pyridazin-3(2H)-one (15). A flask containing 14 (13.2 g, 40.2
mmol, 1.0 equiv), 7 (5.79 g, 60.2 mmol, 1.5 equiv), K2CO3
(11.1 g, 80.4 mmol, 2.0 equiv), and CuCl (0.597 g, 6.03 mmol,
0.15 equiv) was sequentially evacuated and backfilled with N2
three times. A nitrogen sparged solution of pyridine (80 mL)
and N,N′-dimethylethylenediamine (1.30 mL, 12.1 mmol, 0.30
equiv) was added. The dark yellow mixture was heated to reflux
under N2. After 16.5 h, the reaction was shown to be complete
by HPLC analysis. After cooling the reaction to 40 °C, 5%
NH4OH (80 g) was added, and the resulting solution was
stirred for 30 min. Toluene (172 g) was added, the upper
organic layer was isolated, and pyridine was removed by
continuous distillation while adding toluene (320 mL) as
needed to maintain a 200-mL distillation volume. This toluene
solution was washed with 5% NH4OH (80 g), concentrated to
approximately 66 mL, and then heated to 68 °C. Heptane (110
g) was added via addition funnel over 20 min, which resulted in
crystallization of the product. The slurry was cooled to 30 °C
over 1 h and then placed in an ice bath, where it was stirred for
45 min. The product was collected by vacuum filtration, washed
with heptanes (58 mL), and dried in a vacuum oven to afford
11.55 g (84%) of 15 as a light yellow solid. mp: 117−118 °C.
1H NMR (400 MHz, CDCl3) δ 8.14 (dd, J = 0.4, 2.1, 1H), 8.03
F
dx.doi.org/10.1021/op3002883 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
(8) Hutchins, R. O.; Su, W. Y.; Sivakumar, R.; Cistone, F.; Stercho, Y.
P. J. Org. Chem. 1983, 48, 3412.
(9) Formation of the disulfide of the isolated solid was observed to
occur at a rate of 0.5%/day under a N2 atmosphere and 10%/day open
to air.
yellow solution, whose concentration was determined to be
6.3% w/w of 1 (4.57 kg, 99% yield) by quantitative HPLC
analysis versus an external standard. This solution was used
directly in the HCl salt formation.
2-(2-(cis-3-(Piperidin-1-yl)cyclobutyl)benzothiazol-6-
yl)pyridazin-3(2H)-one Hydrochloride (1·HCl). The 6.3%
w/w solution of 1 in toluene (72.5 kg, 12.5 mol) was
concentrated to approximately 55 L, methanol (10.6 kg) was
added, and the solution was heated to 55 °C. A solution of
13.3% w/w anhydrous HCl in EtOH (3.22 kg, 11.7 mol, 0.94
equiv) was added. The reaction solution was cooled to 45 °C
over 1 h and held at this temperature for 2 h, and toluene (53
kg) was added over 1 h. The resulting mixture was cooled to 5
°C over 4 h and held at 5 °C for 14 h. The solid was collected
by filtration and was washed with toluene (20 kg). The wet
cake was dried in a vacuum oven and afforded 4.3 kg (86%) of
1·HCl as an off-white crystalline solid. mp: >200 °C. 1H NMR
(400 MHz, CDCl3) δ 12.76 (s, 1H), 8.13 (d, J = 2.1, 1H), 7.98
(d, J = 8.8, 1H), 7.90 (dd, J = 1.7, 3.8, 1H), 7.69 (dd, J = 2.1,
8.7, 1H), 7.25 (dd, J = 3.8, 9.5, 1H), 7.05 (dd, J = 1.7, 9.5, 1H),
3.80−3.62 (m, 1H), 3.57−3.36 (m, 3H), 3.35−3.17 (m, 2H),
2.92−2.75 (m, 2H), 2.59−2.44 (m, 2H), 2.40−2.24 (m, 2H),
1.99−1.76 (m, 3H), 1.50−1.30 (m, 1H). 13C NMR (101 MHz,
CDCl3) δ 202.99, 173.53, 159.56, 152.02, 138.09, 136.52,
134.84, 130.98, 130.89, 123.66, 122.49, 118.49, 54.65, 28.01.
MS (DCI): 367 (M + H, 100). IR (KBr): 3064 (w), 3030 (w),
2977 (w), 2440 (w), 1660 (s), 1588 (m), 1517 (w), 1456 (m),
1330 (w), 1303 (w), 1142 (w), 846 (m), 826 (s), 714 (w). 99.3
A% purity, 0.5 A% trans-1 (HPLC Method 2). Anal. Calcd for
C20H23ClN4OS: C, 59.62; H, 5.75; N, 13.90. Found: C, 59.50;
H, 5.75; N, 13.83.
(10) Barkalow, J. H.; Breting, J.; Gaede, B. J.; Haight, A. R.; Henry,
R.; Kotecki, B.; Mei, J.; Pearl, K. B.; Tedrow, J. S.; Viswanath, S. K.
Org. Process Res. Dev. 2007, 11, 693.
(11) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett.
1999, 40, 2657.
(12) Pu, Y.-M.; Ku, Y.-Y.; Grieme, T.; Henry, R.; Bhatia, A. V.
Tetrahedron Lett. 2005, 47, 149.
(13) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727.
(14) Burks, J. E.; Espinosa, L.; LaBell, E. S.; McGill, J. M.; Ritter, A.
R.; Speakman, J. L.; Williams, M.; Bradley, D. A.; Haehl, M. G.;
Schmid, C. R. Org. Process Res. Dev. 1997, 1, 198.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Jeff.Kallemeyn@abbvie.com. Telephone: +1-847-935-
1242.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by AbbVie. The authors thank Dr. Ian
Marsden for NMR analysis and Dr. Ashok Bhatia for helpful
discussions.
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dx.doi.org/10.1021/op3002883 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX