Industry-Oriented Route Evaluation and Process Optimization for the Preparation of Brexpiprazole

Article abstract of DOI:10.1021/acs.oprd.8b00438

Efforts toward route evaluation and process optimization for the preparation of brexpiprazole (1) are described. Starting from commercially available dihydroquinolinone 11, a three-step synthesis route composed of O-alkylation, oxidation, and N-alkylation was selected for industry-oriented process development aiming to reduce side reactions and achieve better impurity profiles. The reaction conditions of the three steps were investigated, and the control strategy for the process-related impurities was established. The optimized process was validated on the kilogram scale and now is viable for commercialization, with the results of not less than 99.90% purity of 1 (by HPLC) and not more than 0.05% of persistent impurities 15 and 16.

Full text of DOI:10.1021/acs.oprd.8b00438

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Full Paper
Industry Oriented Route Evaluation and Process
Optimization for the Preparation of Brexpiprazole
Weiming Chen, Jin Suo, Yongjian Liu, Yuanchao Xie, Mingjun Wu,
Fuqiang Zhu, Yifeng Nian, Haji Akber Aisa, and Jingshan Shen
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00438 • Publication Date (Web): 08 Mar 2019
Downloaded from http://pubs.acs.org on March 9, 2019
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Industry Oriented Route Evaluation and Process Optimization for the
Preparation of Brexpiprazole
Weiming Chen,† Jin Suo, Yongjian Liu, Yuanchao Xie, Mingjun Wu, Fuqiang Zhu, Yifeng
,
‡
§
‡
§
§
Nian, Haji A. Aisa, and Jingshan Shen*, ‡
§
*,†
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†
Key Laboratory of Plant Resources and Chemistry in Arid Regions, Xinjiang Technical Institute
of Physics and Chemistry, Chinese Academy of Sciences, South Beijing Road 40–1, Urumqi,
Xinjiang 830011, P. R. China.

University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, P. R.
China.
CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese
‡
Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
§Topharman Shanghai Co., Ltd., Building 1, No.388 Jialilue Road, Zhangjiang Hitech Park,
Shanghai 201209, P. R. China.
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ABSTRACT
Efforts toward route evaluation and process optimization for the preparation of brexpiprazole (1)
are described. Starting from the commercially available dihydroquinolinone 11, a three-step
synthetic route composed of O-alkylation, oxidation and N-alkylation was selected for industry
oriented process development aiming to reduce side reactions and achieve better impurity profiles.
The reaction conditions of the three steps were investigated and the control strategy for the
process-related impurities was established. The optimized process was validated at kilogram scale
and now is viable for commercialization, with the results of not less than 99.90% purity of 1 (by
HPLC) and not more than 0.05% of the persistent impurities 15 and 16.
0
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0
Keywords: brexpiprazole; route evaluation; process optimization; impurity control strategy
INTRODUCTION
Brexpiprazole (1), discovered by Otsuka Pharmaceutical Co., Ltd. and approved by FDA in 2015,
is an antipsychotic drug for the treatment of schizophrenia and also used as adjunctive therapy for
1-2
the treatment of major depressive disorder (MDD) . Brexpiprazole is considered to be a possible
successor of Otsuka's top-selling antipsychotic drug aripiprazole.3
Many synthetic strategies have been reported for the preparation of 1,1-2, 4-10 however, as
11
commented recently by Micro Labs, most of the reported synthetic routes were feasible from an
academic perspective, but of limited practical value. We herein report our results from the R&D
campaign of route evaluation and the process optimization in pursuit of a commercially viable
process.
RESULTS AND DISCUSSION
As shown in scheme 1, the original route accomplished by Yamashita and coworkers was
suggested to be feasible for commercialization.1, 11 Quinolinone 2 was O-alkylated with
1
-bromo-4-chlorobutane 3 to afford chlorobutoxy-quinolinone 412 and followed by N-alkylation
1
3
with arylpiperazine 5 to give 1.
In the first O-alkylation step, the bromo-substituted impurity 4a was considered to be the
equivalents of 4 for it was also transformed to 1 in the following step, but formation of significant
1
4
amounts of the dimeric impurity 6 was unavoidable. Moreover, two major side-products 7 and 8
15
generated from quinolinone 2 under basic conditions, which have also been reported recently by
Micro Labs,11 were a significant concern during the manufacturing process. These two
side-products were unavoidable in the intermediate 4 despite extensive optimization, and formed
the downstream impurities 9 and 10 in the subsequent N-alkylation reaction. 11
Scheme 1. Original Route to Brexpiprazole: O-Alkylation and N-Alkylation
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N
S
Cl
O
HN
Br
N
S
3
HCl
5
Cl
N
O
N
OH
N
O
O
N
O
KOH, MeOH
0oC
H
K2CO3, NaI, DMF
H
H
5
80 C
(N-Alkylation)
o
2
4
Brexpiprazole (1)
(O-Alkylation)
N-Alkylation
Br
Brexpiprazole (1)
6 (Unchanged)
O
N
H
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
4
4
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4
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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
4a
H
O
N
O
O
N
H
O
O
N
OH
H
2
+
Side reactions
6
Cl
Br
S
N
N
S
3
Cl
Cl
O
N
O
N
N
O
N
O
7
9
N
S
Cl
N
O
N
O
N
O
N
O
S
Cl
N
8
10
Our lab investigated an alternate route (Scheme 2) in which O-alkylation of dihydroquinolinone
11 produced chlorobutoxy-dihydroquinolinone 12,16 which was then oxidated to
chlorobutoxy-quinolinone 4. This route has greater commercial potential due to improved control
of the impurities described above.
Scheme 2. Revised Route to Brexpiprazole: O-Alkylation, Oxidation and N-Alkylation
N
S
3
, K2CO3
DDQ
5, K2CO3
Cl
Cl
N
O
N
OH
O
N
O
O
N
O
O
N
O
H
O-Alkylation
H
Oxidation
H
N-Alkylation
H
11
12
4
1
For the first O-alkylation step (Scheme 3), the bromo-analogue 12a was unavoidable, but
formation of the dimeric impurity 13 was minimal. Moreover, because of the relatively high pKa
value of dihydroquinolinone 11 as well as the weak nucleophilicity of the 2-oxygen atom under
basic conditions, only the N,O-dialkylated impurity 14 was observed, and the O,O-dialkylated
impurity 14a was not found in the reaction mixture. Due to the weaker nucleophilicity of the
nitrogen atom compared with that of quinolinone 2, the level of impurity 14 (below 0.5% in the
reaction mixture) was lower than that of the corresponding impurity 8 (more than 1.0%) in the
original route. Impurity 14 was proved to be an oil that was readily purged during the isolation and
purification of 12.
The following oxidation step with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) produced
the key intermediate 4,17 accompanied with its bromo-analogue 4a and the unchanged impurity
6
.18 The unavoidable impurities 9 and 10 in the original route were not formed at all in the final
N-alkylation step owing to the absence of the dehydrogenated impurities 7 and 8 in the revised
route.
Scheme 3. Major Side Reactions in Revised Route
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DDQ
K2CO3
Br
Brexpiprazole
6 (Unchanged )
Br
O
N
O
N-Alkylation
O
N
O
Oxidation
H
H
1
2a
4a
H
N
H
O
O
O
N
O
O
N
H
O
N
O
N
OH
Cl
O
N
O
H
H
1
1
Side Reactions
K2CO3
13
6
+
Br
Cl
O
O
3
8 (Not observed)
0
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0
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1
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0
1
2
3
4
5
6
7
8
9
0
Cl
14 (Purged completely )
Cl
Cl
O
N
O
7 (Absent)
1
4a (Absent)
A comparison of the impurity profile between the revised route and the original route is shown
in Table 1. The revised route produced the improved purity profiles at both intermediate 4 and
brexpiprazole, with dimer 6 being the sole observed impurity in the final product.
Table 1. Improved Impurity Profile of Revised Route in Comparison with that of Original
Route
Brexpiprazole
Stage
Intermediate 12
Intermediate 4
(N-Alkylation)
Revised route
Original route
12a, 13, 14 (O-Alkylation) 4a, 6 (Oxidation)
6
-
4a, 6, 7, 8 (O-Alkylation) 6, 9, 10
Based on our initial evaluation, the revised route starting from dihydroquinolinone 11 appeared
to have improved the efficiency. Further optimization of the process was then conducted in order
to control side reactions and optimize charges of starting materials.
O-Alkylation Optimization (step 1)
In the initial stage of the lab work, up to 10.5% and 13.8% of 12a was found in the reaction of
1
1 with 1-bromo-4-chlorobutane 3 using K CO /DMF and KOH/DMF, respectively (Table 2,
2 3
entries 1–2). Using i-PrOH or EtOH/H O instead of DMF at relatively higher temperatures, a
2
higher level of impurity 13 (Table 2, entries 3–4) was observed. The impurity had poor solubility
in commonly used solvents, and was difficult to separate from intermediate 12. DMF gave a
relatively small amount of 13, so it was chosen for further condition optimizations.
With respect to the reaction temperature, as shown in entries 5–6, lower levels of 13 and 12a
were observed at 10–20 °C but longer reaction times were required. With decreased molar ratio of
K CO (Table 2, entry 7), 11 was not consumed completely and there was no significant decrease
2
3
in the level of 12a.
,4-Dichlorobutane was also investigated as the alkylating agent. As expected, bromo impurity
2a was not observed and low levels of N-alkylated impurity 14 were formed. However, side
1
1
product 13 was produced at unacceptably high levels (up to 6%) regardless of conversion.
As shown in entries 9–10, the level of impurity 13 was correlated with the equivalents of
1
-bromo-4-chlorobutane. Increasing the amount of 1-bromo-4-chlorobutane produced lower levels
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of 13. For instance, 3.0 equiv of the halogenated reagent led to a level of 0.72%, but further
increase of the charge was not explored in consideration of the cost.
Table 2. Trials for the O-Alkylation Step
HPLC purity in reaction mixture (%)b,c
Temp
(oC)
Entry
Basea
Solvent (5V)
3 (equiv)
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
12
11
12a
Imp 13
0.89
0.87
2.51
1.41
0.82
0.75
0.89
5.93
1.10
0.72
Imp 14
0.35
0.45
0.63
0.17
0.33
0.25
0.12
0.11
0.18
0.25
1
2
3
4
5
6
7
8
9
K
2
CO
3
DMF
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5g
2.0
3.0
30–40
20–30
82–84
50–60
20–30
10–20e
20–30
40–45
20–30
20–30
85.16
83.26
91.79d
89.82d
93.10
95.25
87.13
51.38
93.44
94.33
0.43
0.40
0.15
0.10
0.13
0.08
8.01
41.05
0.32
0.15
10.52
13.80
2.80
5.79
3.98
2.91
3.12
-
KOH
DMF
K
2
K
2
K
2
K
2
K
2
K
2
K
2
K
2
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
i-PrOH
EtOH/H
2
O(1:1)
DMF
DMF
f
DMF
DMF
DMFh
DMFh
4.13
3.69
1
0
a
The molar ratio of base was 1.5 times unless otherwise mentioned; b HPLC analysis after checking the
reaction endpoint by TLC (about 24 hours unless otherwise noted); c Calculated from the HPLC area; d
e
f
performed for 15 hours; The reaction was finished after more than 40 hours; The molar ratio was 1.2 times;
g
h
1,4-dichlorobutane was used; 4V DMF was used.
Utilizing the optimized conditions (1.5 times moles ratio of K CO , 3.0 equiv of
2
3
o
1
-bromo-4-chlorobutane and 4V DMF, 20–30 C), three batches were performed and the above
side reactions were well controlled. After a general work-up procedure and slurry with t-butyl
methyl ether, the O-alkylated intermediate 12 was obtained with consistent quality and more than
90% yield at 720 g scale (Table 3). Additionally, the levels of impurity 13 were acceptable and
impurity 14 was not detected.
Table 3. The Impurity Profile of Three Batches for the O-Alkylation Step
Batch No.a
12 (%)b
93.02
95.57
92.56
95.60
93.21
95.69
12a (%) 13 (%)
14 (%)
Reaction mixture
3.90
3.65
3.89
3.56
3.59
3.42
0.62
0.58
0.70
0.67
0.63
0.61
0.22
1st
N.D.c
Purified intermediate
Reaction mixture
0.28
N.D.
0.25
N.D.
2nd
Purified intermediate
Reaction mixture
3rd
Purified intermediate
a
Performed at 720 g scale of 11 per batch; b Calculated from the HPLC area; c Not detected.
Oxidation Optimization (step 2)
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6
The oxidation was initially performed with DDQ in 1,4-dioxane (Table 4, entry 1). Considering
19
the potential carcinogenicity of 1,4-dioxane, alternative solvents such as acetonitrile, 2-MeTHF,
2
0
and CPME were investigated, but 12 was not consumed completely, even at higher temperature
or over prolonged reaction time (Table 4, entries 2–4). The reaction in THF gave lower levels of
residual 12 as entry 5, but when DDQ was reduced to 1.1 equiv, 7% of intermediate 12 was not
consumed in reaction mixture after 4 hours (Table 4, entry 6) and no further decrease was
observed even if prolonging the reaction time. The harmful and environmentally unfriendly
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
2
1
byproduct 4,5-dichloro-3,6-dihydroxyphthalonitrile (DDHQ) could be recovered and oxidized to
DDQ with concentrated nitric acid as in Walker’s method.22
Table 4. Solvent Screening for the Oxidation Stepa
HPLC purity in reaction mixture (%)b
DDQ
equiv)
Temp
(oC)
Reaction
time
3h
Entry
Solvent
4 + 4ac
98.84
96.43
53.43
86.86
96.07
96.42
98.93
90.96
Residual 12
0.05
(
1
2
3
1.2
1.2
1.2
1,4-dioxane
Acetonitrile
2-MeTHF
50–60
20–30
20–30
30–40
20–30
4h
1.71
4h
42.63
11.55
2.52
6hd
4
1.2
CPME
4h
6hd
2
0–30
2.44
5
6
1.2
1.1
THF
THF
20–30
20–30
4h
4h
0.16
7.07
a
Unless otherwise indicated, DDQ was added in portions into the solution of 4 in 5-fold volume of solvent.
The reaction was stirred for 4 hours and monitored by TLC prior to HPLC analysis; b Calculated from the
HPLC area; c 4a was calculated together with 4; d The reaction was performed for additional 6 hours after
o
stirring for 4 hours at 20–30 C.
In the oxidation step performed in THF, no further impurity apart from bromo-analogue 4a and
impurity 6 was observed. After slurrying in hot ethyl acetate, off-white intermediate 4 was
obtained with the result of at least 95.9% purity and 3.1~3.5% of 4a, as shown in Table 5.
Table 5. The Impurity Profile of Three Batches for the Oxidation Step
Batch No.a
4 (%)b,c
4a (%)
3.46
3.46
3.30
3.34
3.17
3.18
6 (%)
0.56
0.34
0.58
0.39
0.60
0.38
Reaction mixture
95.39
95.95
93.91
96.04
95.30
96.34
1st
Purified intermediate
Reaction mixture
2nd
Purified intermediate
Reaction mixture
3rd
Purified intermediate
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a
Performed at 1 kg scale 12 per batch; b Calculated from the HPLC area; c DDHQ and residual
DDQ in the reaction mixture were not calculated from the HPLC area.
N-Alkylation Optimization (step 3)
For the N-alkylation step, besides the carry-over impurity 6 mentioned above, two additional
process-related impurities (15 and 16) were observed in accordance with the results of the original
route (Figure 1).11, 18 These impurities were consistently observed and the next goal of our
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
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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
optimization efforts was to establish a robust control strategy for their levels in brexpiprazole.
H
O
N
O
O
N
O
H
6
N
S
N
S
N
H
N
O
N
O
O
N
O
O
O
N
H
O
N
O
16
15
Figure 1. Process-related Impurities of the N-Alkylation Step
Firstly, the reaction was conducted using 2.1 times molar ratio of K CO in heated DMF to give
2
3
the two impurities at a very high level (Table 6, entry 1). When the molar ratio of base was
reduced to 1.2 times, lower levels of the impurities were obtained but the reaction ran slowly
(
Table 6, entries 2–3). Though the reaction was accelerated in the presence of catalytic potassium
4
iodide, 15.4% of intermediate 4 was left after 15 hours.
2
When EtOH/H O (1:1) was utilized, impurities 15 and 16 were obtained at the levels of 0.56%
2
and 0.25%, respectively (Table 6, entry 4). Then, a significant decrease of the two impurities was
observed by modifying the ratio of ethanol and water to 1:2.5, as shown in entry 5.
It was also discovered that the two impurities were further reduced by increasing the
equivalents of arylpiperazine 5 (Table 6, entries 6–7). However, when the loading was up to 1.2
equiv, the impurity profile was not significantly altered, compared with that of the use of 1.1
equivalents. Finally, the conditions were defined as 1.1 equiv of arylpiperazine 5 and 1.2 times
molar ratio of K CO in EtOH/H O (1:2.5).
2
3
2
Table 6. Trials for the N-Alkylation Stepa
HPLC purity in reaction mixture (%)c
2 3
K CO (times
Entry
5 (equiv)
Solventb
molar ratio)
Brexpiprazole (1) Imp 15 Imp 16
1
2
3
4
5
6
1.03
1.03
1.03e
1.03
1.05
1.1
2.1
1.2
1.2
1.2
1.2
1.2
DMF
DMF
DMF
66.67
55.77d
69.03f
84.62
9.75
0.47
0.19
0.56
0.27
0.15
3.32
0.16
0.15
0.25
0.21
0.08
EtOH/H
EtOH/H
EtOH/H
2
O (1:1)
2
2
O (1:2.5) 88.59
O (1:2.5) 88.61
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a
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The reactions were performed at 80–85 C for 15 hours and monitored by TLC prior to HPLC analysis;
b
The volume was 10-fold of 4; c Calculated from the HPLC area; TLC indicated that high level of 4 was
d
not consumed after 15 hours. After additional 15 hours, 22.12% of 4 was still left in reaction mixture by
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HPLC; 0.1 equiv of KI was used as catalyst; 15.45% of 4 was left.
Following work-up, the crude product was purified by means of an acid-base treatment
salt-formation with hydrochloric acid, re-crystallization, and basification with sodium
(
hydroxide).2, 23 According to the optimized conditions and purification method, three batches of
final API were obtained at kilogram scale, and the impurities 15 and 16 were controlled to below
0
.05% along with the absence of impurity 6, as shown in Table 7.
Table 7. The Impurity Profile of Three Batches for the N-Alkylation Step
Batch No.a
Brexpiprazole (%)b
88.62
6 (%) 15 (%)
16 (%)
0.08
Reaction mixture
0.22
0.16
1st
Final API
99.90
N.D.c 0.03
0.01
Reaction mixture
Final API
87.88
0.21
N.D.
0.28
N.D.
0.16
0.03
0.16
0.04
0.08
2nd
N.D.d
99.95
Reaction mixture
Final API
88.32
0.09
0.01
3rd
99.90
a
b
Performed at 800 g scale of 4 per batch; Calculated from the HPLC area;
c.
d
Not detected (Limit of Detection = 0.004%); Not detected (Limit of Detection = 0.003%).
CONCLUSION
In summary, an industry oriented route consisting of O-alkylation, oxidation, and N-alkylation to
brexpiprazole was established by exploring the reaction conditions of each step in conjunction
with detailed analysis of the in-process impurity profiles. The major side reactions of three steps
were investigated, and as a result the process-related impurities were avoided or well-controlled.
After the process was optimized and finalized, three validation batches were performed to obtain
high quality of brexpiprazole with not more than 0.10% of total impurities and not more than
0
.05% of impurities (15 and 16) at kilogram scale. From a commercial perspective, the present
work has provided viable solutions for the preparation of brexpiprazole.
EXPERIMETNAL SECTION
General Information. All commercially available materials and solvents were used directly
without further purification unless otherwise noted. TLC analyses were performed on silica gel 60
F254 plates. The process mass intensity (PMI) was defined as the total mass of materials used to
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produce a specified mass of product (PMI=Σ mass of materials/ mass of product). Materials
included reactants, reagents, solvents used for reaction, workup and purification.24 The ESI mass
1
13
spectra were determined on a THERMO LTQ. H NMR and C NMR data were recorded with a
Bruker spectrometer using TMS as internal standard and reported relative to residual solvent
signals and are reported as follows: chemical shift (δ ppm), multiplicity, coupling constant (Hz),
and integration. The multiplicities are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; br, broad.
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O-Alkylation (Step 1): Preparation of chlorobutoxy-dihydroquinolinone 12 from 11.
K CO (913 g, 6.60 mol) and dihydroquinolinone 11 (720 g, 4.41 mol) were mixed in DMF (2880
2
3
mL). 1-bromo-4-chlorobutane 3 (2270 g, 13.24 mol) was charged and the mixture was intensively
o
stirred with a mechanical agitator at 20–30 C for 24 hours. The reaction was monitored the
endpoint by TLC prior to HPLC analysis until the starting material 11 was below 0.5% by HPLC
(24–30 hours). The reaction mixture was added into water (10 L) with stirring. The crude product
o
was collected by filtration and slurried in t-butyl methyl ether (1440 mL) below 30 C for 1–2
hours. The isolated material was dried to give 1044 g of purified 12 (4.11mol, 93.2% yield) with
PMI data 17. HPLC analysis showed that the purity of 12 was 95.6% with 3.6% of 12a.
1
ESI-MS: m/z = 254.11 [M+H]. H NMR (500 MHz, DMSO-d6) δ (ppm): 10.00 (s, 1H), 7.04 (d,
J = 8.2 Hz, 1H), 6.48 (dd, J = 8.2, 2.4 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 3.92 (t, J = 6.0 Hz, 2H),
1
3
3
.70 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 7.5 Hz, 2H), 2.41 (t, J = 7.5 Hz, 2H), 1.91–1.74 (m, 4H). C
NMR (125 MHz, DMSO-d ) δ (ppm): 170.39, 157.85, 139.30, 128.49, 115.69, 107.57, 101.82,
6
66.78, 45.28, 30.84, 28.99, 26.26, 24.09.
Oxidation (step 2): Preparation of chlorobutoxy-quinolinone 4 from 12. To the solution of
intermediate 12 (1010 g, 3.98 mol) in THF (5050 mL) was added DDQ (1085 g, 4.78 mol) in
o
portions. During the addition, the temperature was allowed to go up to 35 C. The reaction was
stirred for 4 hours and monitored the endpoint by TLC prior to HPLC analysis. The reaction was
stirred until residual 12 was below 0.5% by HPLC (4–6 hours). The reaction mixture was
concentrated and the residue was dispersed into water (5.05L), then the solution of sodium
bicarbonate (685 g, 8.15 mol) in water (5.05 L) was added carefully. The mixture was stirred at
o
20–30 C for 2 hours. After filtration, the wet material was purified with hot ethyl acetate (3.03 L).
The dry 810 g of 4 (3.22 mol, 80.9% yield) was obtained as a light yellow solid with PMI data 25.
HPLC analysis showed that the purity of 4 was 96.0% with 3.3% of 4a.
1
ESI-MS: m/z = 250.20 [M-H]. H NMR (500 MHz, DMSO-d6) δ (ppm): 11.61 (s, 1H), 7.81 (d,
J = 9.4 Hz, 1H), 7.56 (d, J = 9.3 Hz, 1H), 6.80 (m, 2H), 6.31 (d, J = 9.4 Hz, 1H), 4.05 (t, J = 5.8
Hz, 2H), 3.72 (t, J = 5.8 Hz, 2H), 1.95–1.78 (m, 4H). 13C NMR (125 MHz, DMSO-d ) δ (ppm):
6
1
62.34, 160.40, 140.73, 140.10, 129.35, 118.64, 113.43, 110.85, 98.72, 67.08, 45.25, 28.92, 26.16.
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N-Alkylation (step 3): Preparation of Brexpiprazole (1).
Preparation of crude 1: The intermediate 4 (800 g, 3.18 mol) was charged into the suspension
of K CO (526.3 g, 3.81 mol) and arylpiperazine 5 (890.7 g, 3.50 mol) in the solution of ethanol
2
3
and water (1:2.5 by volume, 8.0 L). Under nitrogen atmosphere, the mixture was heated to reflux
0
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for 15 hours and monitored by TLC prior to HPLC analysis. When the un-reacted 4 was below
o
2
.0% by HPLC (15–20 hours), the heterogeneous reaction mixture was cooled to 20–30 C. The
crude product was filtered and dried to give 1374g (3.17 mol, ~100% yield) as a light yellow
solid.
Salt-formation and purification: The crude product (1354g, 3.12 mol) was added into the
solution of ethanol (27.08 L) and glacial acetic acid (1625 mL). When a solution was given after
heating, concentrated hydrochloric acid (35%, ~342 mL, 3.28 mol) was added drop-wise
o
successively. The mixture was cooled to below 20 C and filtered to give brexpiprazole
hydrochloride, which was dried to obtain 1435g (3.05 mol, 97.7% yield) as an off-white solid.
The hydrochloride salt (1435g, 3.05 mol) was added into the solution of ethanol (12.9 L) and
water (8.6 L). After the mixture was heated to obtain a solution, activated carbon (114 g) was
o
added and stirred for 1–2 hours at refluxing temperature. The mixture was filtered over 70 C and
o
the filtrate was cooled to below 20 C. Then filtered and dried to give 1176 g of purified
brexpiprazole hydrochloride (2.50 mol, 81.9% yield).
Basification to 1: The purified salt (1156 g, 2.46 mol) was dissolved in the solution of ethanol
(
10.4 L) and purified water (6.9 L) at refluxing temperature. The solution of NaOH (108 g, 2.70
mol) in purified water (346 mL) was added drop-wise and kept refluxing for 30–60 minutes. Then
o
the mixture was cooled to 30–40 C, filtered and washed with purified water. The wet product was
dried to obtain the purified API (987g, 2.28 mol) with 92.7% yield and 99.95% HPLC purity.
The PMI of this N-alkylation step was 73. For the entire process, the PMI of the three steps
from starting material 11 was 103, 45% of which was recyclable solvent (ethyl acetate, t-butyl
methyl ether and ethanol) and 40% of water.
1
ESI-MS: m/z = 434.22 [M+H]. H NMR (500 MHz, DMSO-d6) δ (ppm): 11.61 (s, 1H), 7.80 (d,
J = 9.4 Hz, 1H), 7.69 (d, J = 5.5 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 9.4 Hz, 1H), 7.40
(d, J = 5.5 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.84 – 6.78 (m, 2H), 6.30 (d,
J = 9.4 Hz, 1H), 4.05 (t, J = 6.4 Hz, 2H), 3.06 (brs, 4H), 2.61 (brs, 4H), 2.43 (t, J = 7.1 Hz, 2H),
13
1
.86 – 1.75 (m, 2H), 1.69–1.57 (m, 2H). C NMR (125 MHz, DMSO-d ) δ (ppm): 162.35, 160.55,
6
148.36, 140.76, 140.49, 140.12, 133.47, 129.34, 125.92, 125.19, 121.99, 118.57, 116.73, 113.36,
12.11, 110.96, 98.68, 67.71, 57.47, 53.08, 51.83, 26.66, 22.81.
1
ASSOCIATED CONTENT
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Supporting Information
Experimental and/or spectroscopic data for the compounds (12, 4 and 1) and the impurities (4a, 6,
, 8, 12a, 13, 14, 15 and 16) (PDF)
7
The Supporting Information is available free of charge on the ACS Publications website at DOI:
XXXXX.
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AUTHOR INFORMATION
Corresponding Authors
*
*
Tel: +86-0991-3835679. Fax: +86-0991-3835679. E-mail: haji@ms.xjb.ac.cn.
Tel: +86-21-20231000-2407. Fax: +86-21-20231000-2407. Email: shenjingshan@simm.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors acknowledge the support from the National Science Foundation for Young Scientists
of China (Grant No. 21502209) and thank Topharman Shanghai Co., Ltd. for their helpful support.
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Table of Contents Graphic
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69x58mm (300 x 300 DPI)
ACS Paragon Plus Environment