Process Development of an Efficient Kilogram-Scale Preparation of a Preferential Dopamine D3 versus D2 Receptor Antagonist SIPI 6398 as a New Antipsychotic Candidate

Article abstract of DOI:10.1021/acs.oprd.9b00182

Herein we describe the development of a kilogram-scale preparation of a preferential dopamine D₃ versus D₂ receptor antagonist SIPI 6398 (1) as a new alternative treatment for schizophrenia. Modification and optimization of the route includes one-pot synthesis of a trans/cis mixture of cyclohexyl ethyl acetate 19, direct crystallization of cyclohexyl acetic acid 21 in trans configuration, avoidance of hazardous reagents to obtain mesylate 24, and a salinization and recrystallization protocol to efficiently remove the olefinic impurity 31 from 12 (free base of 1). Ultimately these improvements led to the successful and facile preparation of 2.7 kg of SIPI 6398 in nine steps with an HPLC purity of >99.9%.

Full text of DOI:10.1021/acs.oprd.9b00182

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Full Paper
Process Development of an Efficient Kilogram-scale
Preparation of a Preferential Dopamine D3 versus D2 Receptor
Antagonist SIPI 6398 as a New Antipsychotic Candidate
Ainan Zhou, Xiaowen Chen, Yangli Qi, Gengli Duan, and Jianqi Li
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00182 • Publication Date (Web): 11 Jun 2019
Downloaded from http://pubs.acs.org on June 11, 2019
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Process Development of an Efficient Kilogram-scale Preparation of a
Preferential Dopamine D versus D Receptor Antagonist SIPI 6398 as a New
3
2
Antipsychotic Candidate
Ai-Nan Zhou,†,‡,1 Xiao-Wen Chen, Yang-Li Qi, Geng-Li Duan, Jian-Qi Li
‡,1
†‡
*,†
*,‡
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†School of Pharmacy, Fudan University, 220 Handan Rd, Shanghai 200433, PR China
‡Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of
Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 285
Gebaini Rd, Shanghai 201203, PR China
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ABSTRACT: Herein we describe the development of a kilogram-scale preparation of
a preferential dopamine D versus D receptor antagonist SIPI 6398 (1) as a new
3
2
alternative treatment for schizophrenia. Modification and optimization of the route
includes one-pot synthesis of a trans/cis mixture of cyclohexyl ethyl acetate 19, direct
crystallization of cyclohexyl acetic acid 21 in trans configuration, avoidance of
hazardous reagents to obtain mesylate 24, and a salinization and recrystallization
protocol to efficiently remove the olefinic impurity 31 from 12 (free base of 1).
Ultimately these improvements led to the successful and facile preparation of 2.7
kilogram of SIPI 6398 in nine steps with HPLC purity of > 99.9%.
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Keywords: schizophrenia, D /D receptor preferential antagonist, practical preparation,
3
2
crystallization
INTRODUCTION
Schizophrenia is among the most severe and debilitating of the brain disorders and
affects nearly 1% of the world's population.1,2 The symptoms of schizophrenia fall
into three main categories: a) positive b) negative and c) cognitive. Most clinically
available antipsychotic agents effectively alleviate positive and negative symptoms,
but are ineffective at managing cognitive impairment. Therefore, antipsychotic agents
with cognitive improvement efficacy represent an urgent clinical need for
schizophrenic patients.
Preferential D versus D receptor antagonists enhance frontocortical cholinergic
3
2
transmission and improve social cognition, which may be beneficial in alleviating
3
cognitive impairment in schizophrenia. Our research team has been devoted to the
discovery of potential atypical antipsychotics with D versus D receptor subtype
3
2
selectivity. Recently we discovered
a
series of novel and potent
N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amides
exhibiting this binding profile.4,5 Among these compounds, SIPI 6398 (1; Figure 1)
was identified as our preferential D versus D receptor (22-fold) antagonist candidate
3
2
4
showing cognitive improvement in animal models. To support its preclinical
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development and investigational new drug (IND) application, it is necessary to
develop an efficient, practical and kilogram-scale process for the preparation of SIPI
6
398.
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Figure 1. Structure of SIPI 6398 (1).
The initial synthetic route for SIPI 6398 (Scheme 1) possesses some major
drawbacks upon scale-up, specifically (i) low yield in the preparation of
-((2-hydroxyethyl)cyclohexyl)acetamide 8; (ii) use of hazardous reagents such as
4
methylsulfonyl chloride; and (iii) the difficult hydrolysis of N-acetyl for the synthesis
of cyclohexan-1-amine 11. Therefore, a second generation synthesis of SIPI 6398
should be envisaged.
Scheme 1. Initial synthetic route of SIPI 6398a
aReagents and conditions: (i) Triethyl phosphonoacetate, tBuOK, THF, 0~5 °C,
82-88%; (ii) H , 10%Pd/C, EA, rt, 89-92%; (iii) LiOH.H O, THF, H O, 40 °C,
2
2
2
80-85%; (iv) DMF, recrystallization, 50-55%; (v) EtOH, conc. H SO , reflux,
2
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3-87%; (vi) NaBH , MeOH, THF, reflux, 50-60%; (vii) Et N, MsCl, CH Cl ,
4 3 2 2
~5 °C, 81-86%; (viii) 3-(piperazin-1-yl)benzo[d]isothiazole, Na CO , KI, CH CN,
2
3
3
reflux, 54-61%; (ix) 5%HCl, reflux, 80-85%; (x) 2-furoyl chloride, Et N, CH Cl ,
3
2
2
0
~5 °C, 89-92%; (xi) EtOH, 10%HCl, reflux, 80-84%.
Second-Generation Synthesis. Using N-(4-oxocyclohexyl)acetamide (2,
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Scheme 1) as the starting material resulted in water soluble product 8 bearing both
acetamido and hydroxy substituents. Intermediate 8 was achieved through a tedious
operation (three to four extractions) in acetone with low yield (50-60%) after
concentration of the reaction mixture. Another shortcoming of using 2 as the starting
material was that the N-acetyl was difficult to remove in the hydrolysis step to prepare
6
1
1. Therefore, our first focus was to identify a starting material containing a more
hydrophilic and readily removable protective group that was commercially available
on a large scale. Boc-4-aminocyclohexan-1-one 13 was selected as shown in Scheme
2.
First, two synthetic protocols were envisioned to prepare 1 (Scheme 2). In
protocol 1, 1 was synthesized via steps similar to the initial synthetic route. Although
the primary alcohol 15 could be obtained via facile extraction as well as easy
deprotection of the Boc group to afford 11, the key intermediate 14 was inefficiently
6
obtained, which aborted this protocol. Our tentative experiments showed that the
early introduction of the furoyl group produced positive results, and protocol 2
(Scheme 2) was worthy of further scale-up study.
One-pot Synthesis of a Trans/cis Mixture of Cyclohexyl Ethyl Acetate 19.
The same reaction solvent (THF) used in the Wittig-Horner reaction (step 1) and
hydrogenation (step 2) enabled one-pot synthesis of
-(4-((tert-butoxycarbonyl)amino)cyclohexyl)acetate 17 as a trans/cis mixture
2
(
trans/cis isomer ratio, 1.51:1.0, GC method A) accompanied by higher isolated yield
enhanced from 81% to 90%) compared to the stepwise process. N-Boc deprotection
(
with TFA in CH Cl (step 3) to obtain 18 (trans/cis isomer ratio, 1.6:1.0, GC method
2
2
B) followed by acylation with 2-furoyl chloride in CH Cl afforded 19 (step 4,
2
2
trans/cis isomer ratio, 1.67:1.0, HPLC method A). Similarly, one-pot operation of
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steps 3 and 4 was implemented using CH Cl as the reaction solvent with improved
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isolated yield (enhanced from 70% to 85%). By virtue of CH Cl used during the
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posttreatment of hydrogenation for the preparation of 17, the two one-pot steps were
incorporated into a one-step operation to synthesize 19 in the same solvent. Thus, the
synthetic route was shortened to three steps. The improved and facile operation
facilitated high overall yield (70%, four steps) and work up of 19 at a scale of over 11
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Scheme 2. Second-generation synthesis of SIPI 6398a
aReagents and conditions: (i) Triethyl phosphonoacetate, tBuOK, THF, 0~5 °C; (ii)
H , 5%Pd/C-53%water, THF, rt; (iii) TFA, CH Cl , rt; (iv) 2-furoyl chloride, Et N,
2
2
2
3
CH Cl , 0~5 °C; (v) LiOH.H O, THF, H O, 40 °C; (vi) CH CN, recrystallization;
2
2
2
2
3
(
vii) EtOH, EDC.HCl, DMAP, rt; (viii) NaBH , MeOH, THF, reflux; (ix) Et N, MsCl,
4
3
CH Cl , 0~5 °C; (x) 3-(piperazin-1-yl)benzo[d]isothiazole, Na CO , KI, CH CN,
2
2
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reflux; (xi) EtOH, 10%HCl, reflux.
Direct
Recrystallization
Method
to
Prepare
2
-(trans-4-(Furan-2-carboxamido)cyclohexyl)acetic Acid 21. In the initial
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synthetic route, the key intermediate 6 was obtained in trans configuration using
direct recrystallization. We envisioned a similar protocol to achieve acid 21 in trans
configuration. The trans/cis mixture of acid 20 was synthesized after hydrolysis of 19
using lithium hydroxide monohydrate in THF/H O. Then, a direct recrystallization
2
was used to efficiently obtain 21 by solvent screening (Table 1). The purity was
monitored by HPLC.
The results from Table 1 showed that the initial trans/cis isomer ratio (entry 1)
was 3.6:1.0. Several solvents were screened, and ethanol (74.2:1.0) and
dichloromethane (43.7:1.0) were ineffective. 2-Butanone (184.1:1.0), tetrahydrofuran
(242.9:1.0) and isopropanol (237.1:1.0) exhibited moderate effects. Acetone
(665.7:1.0), ethyl acetate (499.0:1.0), isopropyl acetate (402.8:1.0) and acetonitrile
(525.3:1.0) gave the best results. Finally, acetonitrile was chosen as the optimal
solvent considering both high yield (58%) and relatively low solvent usage (21
volumes). The direct recrystallization method using acetonitrile as the solvent was
applied to produce 21 at multiple kilogram-scale.
Table 1. Screening of recrystallization solvents to prepare 21
trans/cis ratiob
c
entry
20 (g)
solvent /20
/a
yield (%)
1
2
3
4
5
3.6:1.0
74.2:1.0
665.7:1.0
184.1:1.0
242.9:1.0
5
4
5
3
EtOH (5)
34
52
48
33
Acetone (22)
2-Butanone (36)
THF (8)
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Isopropanol (8)
Ethyl acetate (42)
Isopropyl acetate (56)
237.1:1.0
40
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82d
499.0:1.0
402.8:1.0
525.3:1.0
43.7:1.0
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CH CN (21)
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CH Cl (60)
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Before recrystallization. b The trans/cis isomer ratio was determined by HPLC. c
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Isolated yield. Insoluble in CH Cl .
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2
Condition Optimization for the Synthesis of Mesylate 24. With 21 in hand,
mesylate 24 was achieved by three further steps: esterification under
EDC.HCl/DMAP conditions (22, 95% isolated yield), reduction by NaBH -MeOH
4
(
23, 90% isolated yield), and methylation by methanesulfonyl chloride (90% isolated
yield). The hazardous and expensive transportation of methanesulfonyl chloride limits
its use at large scale. We further investigated 4-methylbenzensulfonate and
halogenated (Cl, Br and I) derivatives (compounds 25-28) as substitute for
methanesulfonyl chloride. Our tentative explorations showed that all four derivatives
were obtained in low isolated yield (Scheme 3) by chromatography attributed to
massive unconverted 23 (TLC analysis). Methanesulfonic anhydride was chosen as
the alternative acylating agent due to the characteristics of good reactivity, low
volatilization, and convenient transportation and storage. After investigation of bases
(
Na CO , NaOH, ammonium hydroxide, diisopropylethylamine and triethylamine),
2 3
equivalent DMAP and anhydride, solvent (acetonitrile, ethyl acetate, CH Cl and
2
2
DMF),
and
triethylamine/DMAP/methanesulfonic
anhydride
(equivalent,
2
.5:0.2:1.5)/DMF conditions displayed the highest isolated yield (88%) (Table 2,
entry 8). The optimizations facilitated the work-up of 24 through simple operation
without chromatography under mild conditions.
Scheme 3. Synthesis of derivatives of 24
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Table 2. Sulfonylation conditions for preparing 24
DMAP
base
anhydride temp yield
entry
solvent
(equivalent) (equivalent) (equivalent) (°C)
(%)b
28
a
1
2
CH CN
0.5
0.5
Na CO (2.0)
1.7
1.5
1.5
0-5
0-5
3
2
3
a
CH Cl
NaOH (2.0)
NaOH (2.0)
51
2
2
Ethyl
3
0.3
0-10
39
acetatea
a
4
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CH Cl
0.5
0.5
0.3
0.5
0.2
0.2
0.1
Et N (3.0)
1.6
1.5
1.5
2.0
1.5
1.4
1.5
0-5
0-5
62
87
83
81
88
83
79
2
2
3
DMF
DMF
DMF
DMF
DMF
DMF
Et N (2.0)
3
DIPEA (2.5)
0-10
0-15
0-5
NH OH (3.0)
4
Et N (2.5)
3
Et N (2.5)
0-5
3
1
0
Et N (2.5)
0-5
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Insoluble in 30 volumes of solvent. Isolated yield.
Removal of the Olefinic Impurity 31. The synthesis of the free base of SIPI
6
3
398 (12) was then completed by the S 2 coupling of 24 and
N
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-(piperazin-1-yl)benzo[d] isothiazole under mild basic conditions. The HPLC purity
of crude product 12 was 98.5%, and the content of the main impurity was 1.5%
HPLC) (Table 3, entry 1). The results from LC/MS analysis showed that the
(
molecular weight of the main impurity was 436, two units less than that of 1,
indicating the existence of an olefinic moiety (29 or 31, Scheme 4). We proposed the
possible process of forming the impurity: unconverted 16 during the hydrogenation
step took part in the following steps to form the exocyclic olefin compound 29; or the
Wittig-Horner reaction byproduct 30 (Scheme 5) joined in similar steps to form the
endo olefin compound 31 (Scheme 4). 16 was not detected in 17 by HPLC analysis,
7
discrediting the existence of 29. 31 was obtained by a preparative separation method
from crude product 12. We then focused on the removal of 31.
Table 3. Purification of 1
e
entry substrate
recrystallization
12 or 1
(area %)d
98.50
31
(area %) d
1.50
yield (%)
solvent
/
1
2
3
4
5
6
7
12
1
/
EtOH/H O
99.08
0.92
85
81
62
46
86
58
2
a
1
MeOH/H O
99.31
0.69
2
b
1
MeOH/H O
99.39
0.61
2
c
1
MeOH/H O
99.45
0.55
2
1
CH CN/H O
99.17
0.83
3
2
1
AcOH
98.89
1.01
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1
DMF/H O
99.20
0.80
65
2
a
b
c
d
e
Once. Twice. Three times. Determined by HPLC analysis. Isolated yield.
Scheme 4. Formation of the impurity
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5. Proposed mechanism for the formation of byproduct 30
Serious regulations and quality control are necessary to be considered an API
(
Active Pharmaceutical Ingredient). To obtain the API in high quality, the aim was to
decrease the content of 31 to less than 0.1%. Our tentative experiments showed that
the following salt formation step to prepare 1 under EtOH/10% HCl aqueous solution
condition and further recrystallization from EtOH and water was inefficient at
improving the purity (entry 2, HPLC 99.08%). Investigation of alternative
recrystallization solvents (acetonitrile, methanol, DMF, etc.) and the number of
recrystallizations failed to remove 31 (entries 3-8). Thus, we envisioned two possible
methods to conduct scrupulous impurity control of 12.
Method 1–Recrystallization of 12. The direct recrystallization method was
applied to remove 31 from 12. Unexpectedly the purity was barely improved after
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
screening of several solvents (Table 4, entries 1-4). The inefficient recrystallization
method was attributed to the similar polarities of 12 and 31 observed from HPLC
result.
Method 2–Salt Formation Screening of 12 and recrystallization. Considering
the potential solubility difference between 12 and 31 after acidifying with acids,
several acids (oxalic acid, methanesulfonic acid, fumaric acid, etc.) were screened.
The results from Table 4 (entries 7-11) showed that methanesulfonic acid (31, 0.55%
HPLC), fumaric acid (31, 0.53% HPLC), succinic acid (31, 0.73% HPLC), acetic acid
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(31, 0.81% HPLC) and lactic acid (31, 0.66% HPLC) were ineffective. Both oxalic
acid (entry 5, 31, 0.08% HPLC) and maleic acid (entry 6, 31, 0.29% HPLC) were
efficient. Oxalic acid was chosen as the optimal acid because of its purity (99.92%
HPLC) and yield (80% isolated yield).
Table 4. Salt formation screening of 12
entry
acid
recrystallization
solvent
12
31
Yieldb
(area % (area % (%)
)a
)a
1
2
3
4
5
6
7
8
/
CH CN/MeOH
98.59
98.72
98.68
98.69
99.92
99.71
99.45
99.47
1.41
1.28
1.32
1.31
0.08
0.29
0.55
0.53
72
75
80
88
80
72
81
75
3
/
Acetone/MeOH
Ethyl acetate /MeOH
Ethyl acetate /CH Cl
/
/
2
2
Oxalic acid
Maleic acid
Methanesulfonic acid
Fumaric acid
MeOH/H O
2
MeOH/H O
2
MeOH/H O
2
MeOH/H O
2
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Succinic acid
Acetic acid
Lactic acid
MeOH/H O
99.27
99.19
99.34
0.73
0.81
0.66
77
83
80
2
1
0
1
MeOH/H O
2
1
MeOH/H O
2
a
b
Determined by HPLC analysis.
Isolated yield (three steps: salinization,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
recrystallization and neutralization).
The successful optimization was applied for the scale up of 12 with high HPLC
purity (> 99.9%) at > 4-kg scale.
Ultimately, treatment of 12 with 10%HCl aqueous solution in EtOH furnished
the crude product of 1 which was further slurried in EtOH to successfully prepare 1 as
a white solid at 2.7-kilogram scale in 15% overall yield with high purity (> 99.9%,
HPLC). The trans configuration of SIPI 6398 (1) was assigned via an X-ray
crystallographic study (Figure 2).8
Figure 2. ORTEP diagram of 1 with 30% thermal ellipsoid plot for non hydrogen
atoms with atom labeling
CONCLUSION
In summary, a practical and kilogram-scale preparation of preferential D3 versus
D2 receptor antagonist SIPI 6398 (1) has been developed (Scheme 6). The new
process addressed the main issues encountered in the original synthesis by changing
the starting material and optimizing the conditions. In particular, 21, the key
intermediate in constructing the trans configuration of 1, was facilely prepared using a
direct crystallization method. Furthermore, a salinization and recrystallization
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8
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
protocol to efficiently remove the olefinic impurity 31 guaranteed the quality of the
API. Finally, these improvements led to the successful and easy preparation of 2.7
kilograms of SIPI 6398 in nine steps with high HPLC purity (99.94%).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 6. Final process route for the synthesis of SIPI 6398
EXPERIMENTAL SECTION
All solvents and reagents were used without further purification, unless otherwise
stated. Melting points were determined on an electrothermal melting point apparatus
and are uncorrected. NMR spectra were recorded on a Bruker AVANCE II 400 (400
MHz) with TMS as an internal standard in CDCl or DMSO solution. Chemical shifts
3
are given in δ values (ppm) and coupling constants (J values) are given in Hz. ESI
mass spectra was acquired on a Waters ZQ2000 spectrometer. HRMS was performed
on a Q-Tof micro spectrometer. Gas chromatography (GC) and high-performance
liquid chromatography (HPLC) data were obtained using the following methods: GC
method A: GC-FID DB-5 (30 m, 0.25 μm × 320 μm); split ratio: 20:1; temperature
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programming: temp 70 °C for 3 min, temp 250 °C for 10 min; carrier gas: N ; flow
2
rate = 1.0 mL/min; temp 250 °C. GC method B: GC-FID DB624 (30 m, 1.4 μm × 250
μm); split ratio: 20:1; temperature programming: temp 50 °C for 3 min, temp 250 °C
for 10 min; carrier gas: N ; flow rate = 1.0 mL/min; temp 250 °C. HPLC method A:
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Phenomenex Luna PFP (2) (5 μm, 4.6 mm × 250 mm); mobile phase A (CH CN) and
3
B (10 mM K HPO (pH = 3.0)), from 20:80 A/B to 80:20 A/B over 45 min; detection
2
4
at 254 nm; flow rate = 1.0 mL/min; temp 30 °C. HPLC method B: Waters Sunfire
C18 column, C18 (5 μm, 250 mm ×4.6 mm); mobile phase A (MeOH) and B (20 mM
K HPO (pH = 5.5)), from 70:30 A/B to 10:90 A/B over 80 min; detection at 230 nm;
2
4
flow rate = 1.0 mL/min; temp 30 °C.
Ethyl 2-(trans/cis-4-(furan-2-carboxamido)cyclohexyl)acetate (19). To a
stirred solution of potassium tert-butanolate (8.8 kg, 78.8 mol) in THF (53 L) was
added dropwise triethyl phosphonoacetate (13.9 kg, 61.9 mol) in THF (35 L) at
0-5 °C, and the solution was then stirred at room temperature for 1 h. A suspension of
tert-butyl (4-oxocyclohexyl) carbamate (13) (12.0 kg, 56.3 mol) in THF (60 L) was
added dropwise to the solution at 0-5 °C. The resulting solution was stirred for
another 5 h at room temperature and subsequently quenched with water (30 L). The
resultant mixture was extracted with THF (2 × 10 L) after separation.
5
%Pd/C-53%water (702 g) was added to the organic layer and hydrogenation was
conducted with ambient temperature and pressure conditions. The resulting solution
was stirred for 20 h and filtered. The filtrate was evaporated in vacuo to give a
colorless semisolid. The residue was dissolved in dichloromethane (60 L) followed by
washing with water (10 L) and brine (10 L). To the organic layer at room temperature
was added TFA (19.3 kg, 168.9 mol) followed by stirring for 12 h. The resulting
mixture was evaporated in vacuo to remove most of the TFA. CH Cl (50 L) and 20%
2
2
aqueous sodium hydroxide (14 kg) were added to the residual at 0-10 °C, stirred for
.5 h and separated. After separation, another portion of 20% aqueous sodium
0
hydroxide (12 kg) was added to the organic layer at room temperature, followed by a
dropwise addition of 2-furoyl chloride (7.3 kg, 56.3 mol) in CH Cl (8 L) at 0-5 °C
2
2
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1
1
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1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
4
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5
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and stirring at room temperature for 4 h. The resulting mixture was separated, and the
organic layer was washed with water (20 L), brine (20 L), dried over anhydrous
sodium sulfate and evaporated in vacuo to give 19 (11.0 kg, 70%) as a white
semisolid. MS m/z 280.2 [M + H]+.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
5
6
7
8
9
0
2
-(trans-4-(Furan-2-carboxamido)cyclohexyl)acetic acid (21). A mixture of
1
9 (10.0 kg, 35.8 mol), lithium hydroxide monohydrate (3.5 kg, 82.3 mol), water (25
L) and THF (100 L) was stirred at 40 °C for 19 h. The resulting solution was
evaporated in vacuo to remove most of the THF and acidified by hydrochloric acid
(6.0 mol/L, 41 L) at 0-5 °C followed by stirring at room temperature for 5 h. The
resulting mixture was filtered and washed with water (5 L) to yield a white solid,
which was further recrystallized from CH CN (110 L) to yield 21 (4.6 kg, 51%) as a
3
white solid with the trans/cis isomer ratio of 517.4:1.0 (HPLC method A, t = 13.8
R
1
min). Mp 185-187 °C; H NMR (400 Hz, DMSO-d ) δ 12.09 (br, 1H), 8.11-8.10 (m,
6
1H), 7.80 (d, J = 0.8 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.60 (dd, J = 2.0, 0.8 Hz, 1H),
3.69-3.66 (m, 1H), 2.11 (d, J = 4.4 Hz, 2H), 1.79-1.73 (m, 4H), 1.61-1.59 (m, 1H),
1
3
1.38-1.32 (m, 2H), 1.08-1.01 (m, 2H); C NMR (100 MHz, DMSO-d ) δ 174.21,
6
157.35, 148.58, 145.14, 113.53, 112.18, 47.99, 41.54, 34.05, 32.35, 31.58; MS m/z
252.1 [M + H]+.
Ethyl 2-(trans-4-(furan-2-carboxamido)cyclohexyl)acetate (22). To a mixture
of 21 (4.5 kg, 17.9 mol) and ethanol (5.2 kg) in CH Cl (14 L),
2
2
1
4
-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.1 kg, 21.5 mol) and
-dimethylaminopyridine (1.7 kg, 14.3 mol) in CH Cl (18 L) were added at room
2
2
temperature. The resulting mixture was stirred at room temperature for 3 h and water
5 L) was added. The resulting solution was separated and washed with water (5 L),
(
hydrochloric acid (2.0 mol/L, 11 L), brine (5 L); dried over anhydrous sodium sulfate;
and evaporated in vacuo to yield 22 (4.7 kg, 95%) as a white solid in 97.2% purity
1
(
HPLC method A, t = 31.7 min). Mp 104-106 °C; H NMR (400 Hz, DMSO-d ) δ
R
6
8
.10 (d, J = 1.6 Hz, 1H), 7.80 (s, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.60 (dd, J = 2.0, 1.6
Hz, 1H), 4.06 (q, J = 4.8 Hz, 2H), 3.68-3.67 (m, 1H), 2.19 (d, J = 4.8 Hz, 2H),
1
.79-1.77 (m, 2H), 1.70-1.72 (m, 2H), 1.68-1.61 (m, 1H), 1.37-1.34 (m, 2H), 1.18 (t, J
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=
4.8 Hz, 3H), 1.09-1.05 (m, 2H); C NMR (100 MHz, DMSO-d ) δ 172.56, 157.35,
6
1
48.57, 145.14, 113.54, 112.18, 60.12, 47.92, 41.23, 34.20, 32.29, 31.56, 14.63; MS
m/z 280.2 [M + H]+.
N-(trans-4-(2-Hydroxyethyl)cyclohexyl)furan-2-carboxamide (23). A mixture
of 22 (4.5 kg, 16.1 mol), sodium borohydride (3.0 kg, 80.5 mol) and THF (36 L) was
stirred under reflux for 0.5 h, and then methanol (9 L) was added dropwise to this
mixture for 2 h at room temperature under the condition of a nitrogenous atmosphere.
The resulting solution was stirred under reflux for 12 h and quenched with
hydrochloric acid (6.0 mol/L, 27 L) at 0-35 ℃. The resulting mixture was stirred for 1
h and alkalized with 50% sodium hydroxide solution (11 L). The resultant mixture
was extracted with dichloromethane (2 × 24 L). The combined organic extracts were
dried over anhydrous sodium sulfate and evaporated in vacuo to yield 23 (3.4 kg,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
0%) as a white solid in 97.7% purity (HPLC method A, t = 16.2 min). Mp
R
1
135-137 °C; H NMR (400 Hz, DMSO-d ) δ 8.09 (d, J = 1.2 Hz, 1H), 7.79 (s, 1H),
6
7.08 (d, J = 2.0 Hz, 1H), 6.60 (dd, J = 2.0, 1.2 Hz, 1H), 4.33 (t, J = 3.2, 1H),
3.68-3.66 (m, 1H), 3.43 (dd, J = 7.2, 4.0 Hz, 2H), 1.79-1.74 (m, 4H), 1.34-1.30 (m,
1
3
5H), 0.98-0.96 (m, 2H); C NMR (100 MHz, DMSO-d ) δ 157.33, 148.61, 145.11,
6
113.49, 112.17, 58.99, 48.36, 33.51, 32.61, 32.16; MS m/z 238.1 [M + H]+.
2
-(trans-4-(Furan-2-carboxamido)cyclohexyl)ethyl methanesulfonate (24).
To a solution of 23 (3.3 kg, 13.9 mol) and triethylamine (3.5 kg, 34.7 mol) in DMF
13.2 L), methanesulfonic anhydride (3.6 kg, 20.8 mol) in DMF (7 L) was added
(
dropwise at 0~5 °C, and the resulting mixture was stirred for 3 h at ambient
temperature. The resultant mixture was supplemented with water (80 L) and extracted
with dichloromethane (2 × 8 L). The combined organic extracts were washed with
water (2 × 5 L) and brine (10 L) and then dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure to give crude 24, which was further
slurried in petroleum ether/ethyl acetate (1:1, 32 L) under reflux to afford 24 (3.9 kg,
1
1
2.2 mol) as a colorless solid in 98.2% purity (HPLC method A, t = 40.9 min). Mp
R
1
40-142 °C; H NMR (400 Hz, DMSO-d ) δ 8.10 (d, J = 5.6 Hz, 1H), 7.80 (d, J = 1.2
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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5
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Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.60 (dd, J = 2.4, 1.2 Hz, 1H), 4.24 (t, J = 4.4, 2H),
3
3
1
.70-3.66 (m, 1H), 3.17 (s, 3H), 1.80-1.76 (m, 4H), 1.60-1.57 (m, 2H), 1.37-1.32 (m,
1
3
H), 1.06-1.00 (m, 2H); C NMR (100 MHz, DMSO-d ) δ 157.35, 148.58, 145.14,
6
13.54, 112.19, 69.15, 48.15, 37.00, 35.82, 33.32, 32.38, 31.62; MS m/z 316.1 [M +
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H]+.
N-(trans-4-(2-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-l)ethyl)cyclohexyl)fura
n-2-carboxamide (12). mixture of 24 (3.6 kg, 11.4 mol),
-(piperazin-1-yl)benzo[d]isothiazole (2.4 kg, 10.9 mol), sodium carbonate (2.9 kg,
7.3 mol), potassium iodide (9.0 g, 54.5 mmol), and CH CN (72 L) was stirred under
A
3
2
3
reflux for 24 h. The resulting solution was cooled to ambient temperature and filtered
and then washed with CH CN (2 × 3 L). The filter cake was slurried in CH Cl (15 L)
3
2
2
and water (20 L) and then separated. The organic layer was washed with water (5 L)
and brine (5 L) and concentrated under reduced pressure to yield crude product 12
(3.8 kg, 80%) as a colorless solid. To a stirred solution of oxalate dihydrate (1.2 kg,
9.5 mol) in MeOH (77 L) and water (11 L) was added crude 12 (3.8 kg, 8.7 mol). The
mixture was stirred under reflux for 1 h after clarification, cooled to room temperature
and filtered. The obtained solid was recrystallized from MeOH/water (8:1) and
alkalized with 10% sodium hydroxide solution in CH Cl . The organic layer was
2
2
washed with water (5 L) and brine (5 L) and then concentrated under reduced pressure
to afford 12 (3.1 kg, 80%) as a white solid with 99.92% purity (HPLC method B, t =
R
1
6
1.7 min). Mp 188-190 °C; H NMR (400 Hz, DMSO-d ) δ 8.15-8.11 (m, 3H), 7.81
6
(s, 1H), 7.60 (t, J = 4.8 Hz, 1H), 7.48 (t, J = 4.8 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H),
6
3
1
1
1
.60 (t, J = 0.8 Hz, 1H), 4.08-4.06 (m, 2H), 3.60-3.58 (m, 1H), 3.50-3.48 (m, 2H),
.27-3.25 (m, 2H), 3.21-3.18 (m, 4H), 1.82-1.77 (m, 4H), 1.68-1.65 (m, 2H),
1
3
.38-1.36 (m, 3H), 1.07-1.05 (m, 2H); C NMR (100 MHz, DMSO-d ) δ 162.70,
6
57.39, 152.62, 148.58, 145.17, 128.62, 127.45, 125.12, 124.50, 121.69, 113.55,
12.19, 54.38, 50.97, 48.14, 46.89, 34.81, 32.30, 31.72, 30.32; MS m/z 439.2 [M +
+
+
H] ; HRMS (ESI) m/z calcd for C H N O S [M + H] 439.2168, found 439.2271.
2
4
31
4
2
N-(trans-4-(2-(4-(Benzo[d]isothiazol-3-yl)piperazin-1-l)ethyl)cyclohexyl)fura
n-2-carboxamide hydrochloride (SIPI 6398). A mixture of 12 (3.0 kg, 6.8 mol),
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EtOH (30 L) and 10% aqueous hydrochloric acid solution (7.5 mol) was stirred under
reflux for 1 h. The resulting mixture was cooled to room temperature and filtered to
yield a white solid, which was slurried in ethanol (24 L) at 60 °C and filtered to afford
2
.7 kg of SIPI 6398 with 99.94% purity (HPLC method B, t = 61.7 min) as a white
R
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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8
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0
solid (85% yield). Mp > 270 °C; Anal.Calcd for C H N O S.HCl: C, 60.68; H, 6.58;
2
4
30
4
2
N, 11.79. Found: C, 60.60; H, 6.61; N, 11.74.
AUTHOR INFORMATION
Corresponding Author
Jianqi Li.
*
Telephone: +86 21 20572000. E-mail: lijianqb@126.com.
Gengli Duan.
*
Telephone: +86-21-54237208. E-mail: glduan@shmu.edu.cn.
Authors Ai-Nan Zhou and Xiao-Wen Chen contributed equally.
1
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work is supported by National Natural Science Foundation of China (Grant No.
8
1803371), Key Technologies R&D Program of Shanghai Municipal Science and
Technology Commission (Grant No. 17431903800), Shanghai Rising-Star Program
(
Grant No. 19QB1406200), and the National Science and Technology Major Project
Grant No. 2018ZX09301028-002).
(
REFERENCES
1) Saha, S.; Chant, D.; Welham, J.; McGrath. A Systematic Review of the Prevalence
of Schizophrenia. PLoS Med. 2005, 2 (5), 413-433.
2) Chong, HY.; Teoh, SL.; Wu, DBC.; Kotirum, S.; Chiou, CF.; Chaiyakunapruk, N.
(
(
Global Economic Burden of Schizophrenia: A Systematic Review. Neuropsychiatr.
Dis. Treat. 2016, 12, 357-373.
(3) Millan, M.J.; D.C.ra, B.; Dekeyne, A.; Panayi, F.; D.G.oote, L.; Sicard, Dée.;
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Cistarelli, L.; Billiras, R.; Gobert, A. Selective Blockade of Dopamine D versus D
3
2
Receptors Enhances Frontocortical Cholinergic Transmission and Social Memory in
Rats: A Parallel Neurochemical and Behavioural Analysis. J. Neurochem. 2007, 100
(4), 1047-1061.
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(4) Chen, X. W.; Sun, Y. Y.; Fu, L.; Li, J. Q. Synthesis and Pharmacological
Characterization
of
Novel
N-(trans-4-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amides as
Potential Multireceptor Atypical Antipsychotics. Eur. J. Med. Chem. 2016, 123,
3
32-353.
5) Li, J. Q.; Chen, X. W.; Ma, Z. L.; Zhang, L.; Cui, N. Preparation of
benzoisothiazole compounds as antipsychotic drugs. US9550741B2, 2017.
6) Chen, X. W.; Ni, F.; Liu, Y.; Fu, L.; Li, J. Q. A New and Practical Synthesis of
Cariprazine via the Facile Construction of
(
(
2-(trans-4-(3,3-Dimethylureido)cyclohexyl)acetic acid. Synthesis. 2016, 48 (18),
3120-3126.
(7) The impurity 31 was isolated by preparative separation method (Instrument:
Shimadzu LC-20AP*3 Prep HPLC (PrepL-GB); Column: Ximate C18, 5 µm, 150 ×
25 mm I.D.; Mobile phase: A for H O (0.05% ammonia hydroxide) and B for MeOH;
2
Gradient: B 65% in 13 min linearly; Flow rate: 35 mL/min; Column temperature:
R.T.; Wavelength: 220 nm; Sample preparation: Compound dissolved in MeOH with
1
1
0 mg/mL concentration; Injection: 500 μL per injection.) and confirmed by H
1
NMR, MS and HRMS. Mp 152-154 °C; H NMR (400 Hz, CDCl ) δ 7.89-7.82 (m,
3
2
2
1
H), 7.49 (t, J = 5.2 Hz, 1H), 7.43-7.39 (m, 1H), 7.36 (d, J = 5.2 Hz, 1H), 7.11 (d, J =
.0 Hz, 1H), 6.49 (dd, J = 2.0 Hz, 0.8 Hz, 1H), 6.37 (d, J = 5.2 Hz, 1H), 5.47-5.46 (m,
H), 4.28-4.26 (m, 1H), 3.77 (brs, 4H), 3.77 (brs, 4H), 2.78-2.74 (m, 2H), 2.48-2.38
(m, 3H), 2.18-2.15 (m, 2H), 1.97-1.94 (m, 2H), 1.76-1.74 (m, 1H); MS m/z 437.2 [M
+
+
+
H] ; HRMS (ESI) m/z calcd for C H N O S [M + H] 437.2011, found 437.2018.
24 29 4 2
(8) Crystallographic data for SIPI 6398 have been deposited with the Cambridge
Crystallographic Data Centre (CCDCꢀ1907982). Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
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(fax: +44-(0) 1223-336033 or e-mail: deposit@ccdc.cam.ac.Uk).
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