A Simple and Commercially Viable Process for Improved Yields of Metopimazine, a Dopamine D2-Receptor Antagonist

Article abstract of DOI:10.1021/acs.oprd.7b00052

An efficient, practical, and commercially viable manufacturing process was developed with ≥99.7% purity and 31% overall yield (including four chemical reactions and one recrystallization) for an active pharmaceutical ingredient, called Metopimazine (1), an antiemetic drug used to prevent emesis during chemotherapy. The development of two in situ, one-pot methods in the present synthetic route helped to improve the overall yield of 1 (31%) compared with earlier reports (<15%). For the first time, characterization data of API (1), intermediates, and also possible impurities are presented. The key process issues and challenges were addressed effectively and achieved successfully.

Full text of DOI:10.1021/acs.oprd.7b00052

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Full Paper
A simple and commercially viable process for improved
yields of Metopimazine, a dopamine D2-receptor antagonist
Venumanikanta Karicherla, Kumar Phani, Mohan Reddy Bodireddy,
Kumar Babu Prashanth, Madhusudana Rao Gajula, and Kumar Pramod
Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 27 Apr 2017
Downloaded from http://pubs.acs.org on April 27, 2017
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A simple and commercially viable process for improved yields of
Metopimazine, a dopamine D2-receptor antagonist
7
Venumanikanta Karicherla, Kumar Phani, Mohan Reddy Bodireddy, Kumar Babu Prashanth,
8
Madhusudana Rao Gajula,* Kumar Pramod *
9
Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43-45, KIADB Industrial Area, 4th
phase, Bommasandra-Jigani Link Road, Bommasandra, Bangalore-560 105, Karnataka, India.
Corresponding Authors: gmadhusudanrao@yahoo.com, pramodkumar@microlabs.in
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Abstract: An efficient, practical and commercially viable manufacturing process was
developed with ≥99.7% purity and 31% overall yield (including four chemical reactions and
one recrystallization) for an active pharmaceutical ingredient, called Metopimazine (1), an
antiemetic drug used to prevent emesis during chemotherapy. The development of two in situ
one-pot methods in the present synthetic route helped to improve the overall yield of 1 (31%)
compared to earlier reports (<15%). For the first time characterization data of API (1),
intermediates and also possible impurities are presented. The key process issues and
challenges were addressed effectively and achieved successfully.
Key words: Commercial process, Metopimazine, antiemetic, cancer treatment,
phenothiazine, pharmaceutical industry
INTRODUCTION
There is an increasing demand for antiemetic agents owing to most troublesome adverse
effects of chemotherapy induced nausea and emesis during cancer treatment.1 However, the
objective of complete prevention of emesis in all patients remains elusive. Therefore, there is
a great demand for both development of i) new antiemetic agents2 and ii) new manufacturing
processes for existing antiemetic agents. Metopimazine is an existing dopamine D2-receptor
antagonist3 with potent antiemetic properties.4-6 It is chemically known as l-(3-[2-
(Methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-piperidinecarboxamide
(1)
which
belongs to nitrogen- and sulfur-containing tricyclic compounds (phenothiazine class of drugs)
with interesting biological and pharmacological activities.7 Recently, it has been found that
Metopimazine plays a key role as an alternative to Ondansetron in the prevention of delayed
chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderate to high
emetogenic non-cisplatin-based chemotherapy.8-13 It has been used in France for many years
for the prevention and treatment of nausea and vomiting under the brand name of Vogalene®.
Extensive literature search revealed that most of the reported methods for the preparation of 1
suffer from many disadvantages which include i) overall lower yields (10-15%), ii) use of
toxic reagents and catalysts, iii) inadequate discussion and optimization of reaction
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conditions, iv) lack of study on impurity profile (evaluation of possible impurities, their
control and also their elimination) in the process of Metopimazine (1) and v) unavailability of
characterization data of intermediates and possible impurities. To overcome the above said
drawbacks and also to develop industrially viable process, it is planned to conduct a detailed
study.
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HISTORICAL DEVELOPMENT
In 1883, Bernthsen reported the first synthesis of 10H-dibenzo-(b,e)-1,4-thiazine, a
phenothiazine.14 Many methods for the synthesis of phenothiazines were reported.15,16
Interestingly, only three types of synthetic routes were reported for the synthesis of
Metopimazine (1), a drug which belongs to phenothiazine family.
In 1959, the first synthesis and manufacture process of Metopimazine (1) was reported by
17
Jacob et al (Scheme 1). The synthesis starts from the protection of 2-(Methylsulfanyl)-
10H-phenothiazine (2) followed by selective oxidation of methyl sulphur and deprotection of
3 provided compound 4e. Subsequent reaction of 4e with 1-bromo-3-chloropropane provided
intermediate 5 which on condensation with 4-piperidinecarboxamide gave metopimazine (1).
The major disadvantages associated with this process include i) difficulties in handling of
strong base (NaNH2) in a large scale process, ii) formation of by-products due to high
basicity of NaNH2 and iii) complications in removal of meta-chlorobenzoic acid, a by-
product generated during oxidation stage.
O
H
N
H
N
O
S
O
S
S
N
S
3
O
m-CPBA
NaOH
NaNH2
Ac2O
S
S
4e
2
Br
Cl
NaNH2
NH2
Cl
N
O
S
O
S
O
O
Na2CO3
N
S
N
O
H
N
S
1
5
NH2
Scheme 1. First synthesis of Metopimazine (1).
Later, in 1990, Sindelar et al.18 reported a modified process (Scheme 2) which starts from
synthesis of 4-(2-fluorophenylthio)-3-nitrophenylmethylsulfone (2a) by condensation of 2-
fluorothiophenol and 4-chloro-3-nitrophenyl methyl sulfone. The reduction of compound 2a
to amine derivative (2b) followed by cyclization provided 2-(methylsulfonyl)phenothiazine
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(4e). The subsequent condensation of compound 4e with 1-(3-chloropropyl)-4-
piperidinecarboxamide (2c) provided the target metopimazine (1). The major disadvantages
include i) harsh reaction conditions, ii) lower yields were reported in most of the steps, and
iii) the process is lab scale only (not commercial level).
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O
S
O
S
O
S
O
O
O
SH
F
K2CO3
FeCl3
NH2NH2
(94%)
+
S
Cl
DMF
(63%)
S
F
NO2
NO2
F
NH2
2b
2a
NaH
Xylene
Cl
(65%)
S
N
O
S
N
S
O
O
+
NaH
N
S
DMSO
(25%)
O
H
4e
N
H2N
O
2c
H2N
1
O
Overall yield: 9.6%
Scheme 2. Sindelar’s approach for the synthesis of Metopimazine (1).
In 2010, Satyanarayana Reddy et al.19 reported a modified synthetic route (Scheme 3) which
starts from either N-protection using acetyl chloride or N-alkylation using dihalopropane of
2-(methylsulfanyl)-10H-phenothiazine (2).
O
O
NH2
O
NH2
X
N
H2O2
Ammonium
molybdate
NaOH
O
H
N
O
S
O
S
N
H
O
S
O
X
O
Base
PTC
N
S
N
S
N
PTC
Et3N
IPA
S
S
CHCl3
X
S
3
5
1
[121% (crude)]
(34%)
4e
(29.7%)
Toluene
CH3COCl
Overall yield: 10.5%
(86%)
H
N
S
S
2
Toluene
O
NH2
(98%)
X
X
NH2
H2O2
Aq. base
X
X
N
Ammonium
molybdate
PTC
O
S
N
H
O
O
O
N
HS
N
S
CHCl3
S
N
(95%)
Et3N
IPA
S
S
1
2d
X = Cl, Br
5
(4.6%)
Overall yield: 4.3%
Scheme 3. Satyanarayana Reddy’s approach for the synthesis of Metopimazine (1).
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In one of the routes, protection of 2-(methylsulfanyl)-10H-phenothiazine (2) using acetyl
chloride and then selective oxidation of methyl sulphur of compound 3 followed by
deprotection yield compound 4e and subsequent N-alkylation using dihalopropane provided
compound 5. Then, the condensation of compound 5 with 4-piperidinecarboxamide provided
the target Metopimazine (1). In another route, the synthesis starts from N-alkylation of 2
using dihalopropane followed by selective oxidation of 2d provided intermediate 5. Finally,
condensation of compound 5 with 4-piperidinecarboxamide provided target Metopimazine
(1) as depicted in above scheme. The notable drawbacks of this process include i) use of
ammonium molybdate which causes health hazards; ii) CHCl3 was used as solvent (class 2),
and iii) lower yields of products were reported.
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The following challenges are to be addressed to overcome the disadvantages of existing
processes, i) improved yields in each and every step; ii) avoid the tedious work-up procedures
by enhancing the robustness throughout the synthesis by testing and optimization of critical
parameters, iii) reduce or replace toxic chemicals with green reagents or solvents, iv)
characterization of intermediates (3, 4 and 5) and process impurities, and v) aiming to
develop practical and commercial synthetic route with detailed study of impurities profile.
Herein we report an improved synthetic route for the synthesis of Metopimazine (1) with high
purity (≥99.7%), improved yields (31% of overall yield), easy work-up, simple isolation and
purification of intermediates as well as final product.
RESULTS AND DISCUSSION
A modified process was designed and developed to achieve improved yields of
Metopimazine drug compared to existing processes as shown in scheme 4.
O
O
O
H
N
O
S
O
S
O
O
b
i
S
S
N
N
N
S
ii
a
93%
85%
S
2
S
3
S
4
4a
O
O
c
60%
NH2
Cl
N
O
S
O
S
O
O
N
d
N
65%
S
S
1
5
Overall yield: 30.8 %
Reaction conditions: a) Acetyl chloride, toluene, 20-30 °C, 1h; b) i) Oxone, H2O-Acetonitrile
(7:10 ratio) at 20-30 °C, 2h, ii) Zn powder, Lactic acid, acetonitrile, 60-70 °C, 3h; c) Powdered
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KOH, 1-bromo-3-chloropropane, acetone, 50-60 °C, 3h; d) 4-piperidinecarboxamide, K2CO3, toluene-
DMF (8:2 ratio), 90-100 °C, 8h.
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Scheme 4. Improved process for the synthesis of Metopimazine (1).
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The synthesis of the target Metopimazine (1) starts by the protection of compound 2 using
acetyl chloride and it provided compound 3. Then, the oxidation of compound 3 using oxone
provided compound 4a and successive in-situ selective reduction of compound 4a using Zn-
lactic acid provided compound 4 in one-pot. The deprotection and subsequent in situ N-
alkylation of compound 4 in presence of powdered KOH using dihalopropane in one-pot
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provided compound 5. Finally, the condensation of compound
5
with 4-
piperidinecarboxamide in presence of K2CO3 provided the final Metopimazine (1) as shown
in scheme 4.
With an objective to develop a commercially viable process for the manufacture of 1, the
reaction conditions were well optimized in each and every step as discussed below.
Improved process conditions for 1-[2-(methylsulfanyl)-10H-phenothiazin-10-
yl]ethanone (3) derivative:
Synthesis of 1-[2-(methylsulfanyl)-10H-phenothiazin-10-yl]ethanone (3) involves protection
of compound 2. Two methods were reported for protection of compound 2. The method
reported by Jacob et al17 involve N-acetylation using acetic anhydride in presence of NaNH2
without any quality profile. But this method suffers from formation of by-products due to
high basicity of NaNH2 and difficulties in handling of NaNH2.
Recently, a new method was published in a patent19 which reported N-acetylation using 8.0
eq. of acetyl chloride in toluene at 50-55 °C provided compound 3 in 86.7% yield without
any quality data. The isolation of compound 3 was carried out by adding cyclohexane which
is not preferable at production scale. The equivalents of acetyl chloride are also very high
(8.0 eq.).
With an aim of reducing the acetyl chloride quantity, we conducted the same experiment with
1.0, 2.5, 5.0, 7.5 and 10 equivalents of acetyl chloride both at 20-30 °C and 50-60°C and the
obtained results were presented in Table 1. The study establishes 2.5 equivalents of acetyl
chloride as the best option at 20-30 °C for maximum formation (95%) of compound 3
compared to at 50-60°C (92%) [entry 2, Table 1 and Figure S5, supplementary information].
The same reaction either with low or high amount of acetyl chloride provided lower yields of
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compound 3 (entries 1, 3-5, Table 1). The same acetylation reaction was unsuccessful with
inorganic (Na2CO3, K2CO3) and organic bases (Et3N, piperidine) due to incompatibility of
acetyl chloride with bases.20 In this conversion, incremental scale-up and close monitoring of
the reaction disclosed that the production is possible without difficulties.
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Table 1. Effect of acetyl chloride amount and temperature on N-acetylation.a
Yield (%)b of
Product 3
Entry
Acetyl
Time Tempꞌ
(% by HPLC)
chloride (eq.)
(h)
(°C)
product 3
2
2
61
56
20-30
50-60
52
41
1
2
3
4
1
1
1
95
92
20-30
50-60
93
90
2.5
5
1
1
95
89
20-30
50-60
87
79
1
1
94
88
20-30
50-60
85
76
7.5
1
1
92
86
20-30
50-60
81
72
5
10
aReaction conditions: Compound 2 (10 g, 0.04 mol), acetyl chloride, toluene (60 mL).
bIsolated yield.
cRemaining unreacted substrate.
The purity of crude compound 3 is low (<95.5%). The compound 3 was isolated in different
solvents to improve the quality by recrystallization in different solvents like methanol,
ethanol, isopropanol and ethyl acetate and the obtained results were presented in Table 2. It
was found that isopropanol was the best option to improve the quality (up to 97%) with good
isolated yield (93%) [entry 3, Table 2, Figure S6, supporting information].
Table 2. Selection of suitable solvent for isolation of compound 3.
Yieldb
S. No
Solvent
Purity
(%)
80
(% by HPLC)
1.
2.
3.
4.
Methanol
Ethanol
98
98
97
93
82
Isopropanol
Ethyl acetate
93
72
aReaction conditions: Crude compound 3 (10 g, 0.034 mol) in solvent (30 mL), at reflux
temperature (clear solution) for 30 min, cool to 10-15 °C, stir for 1h and filter the solid.
bIsolated yield.
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New process conditions for 1-[2-(methylsulfonyl)-5-oxido-10H-phenothiazin-10-
yl]ethanone (4) derivative:
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The reported chemoselective oxidation methods provided low yields (up to 35%)17, 19 of
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compound 4 due to the formation of 1-[2-(methylsulfonyl)-5-oxido-10H-phenothiazin-10-
ylethanone
(4a)
[2-(methylsulfinyl)-10H-phenothiazin-10-yl]ethanone
(4b),
2-
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(methylsulfinyl)-10-oxo-10H-phenothiazin-10-ium (4c) and 1-[2-(methylsulfonyl)-5,5-
dioxido-10H-phenothiazin-10-yl]ethanone (4d) are unavoidable by-products (scheme 5).
For example, in recent patent,19 the selective oxidation of 3 using H2O2 was presented, but
there were several difficulties, for instance i) large quantity of H2O2 was required, ii) toxic
metal catalysts are needed,19 and iii) huge amount of solvents are required for the purification
of crude mass. In addition, the isolated yields were low (≤34%). In another patent,17 m-
CPBA (meta-chloro perbenzoic acid) was applied and the obtained yield was low. The by-
product, meta-chlorobenzoic acid is difficult to remove and it affects the yield and purity of
compound 4. At the same time, the m-CPBA is expensive and its storage is difficult.
O
O
O
O
S
O
O
S
O
O
N
S
N
N
O
+
+
+
S
S
4
S
S
N
Oxidation
4a
O
4b
O
S
3
O
O
S
O
O
N
S
N
+
S
S
O O
O
4c
4d
Scheme 5: Formation of possible products during oxidation of 3 using oxidising agents.
It is planned to develop one-pot method which consists of preparation of compound 4a
exclusively by minimizing the formation of by-products such as 4b, 4c and 4d and
subsequent in-situ reduction of compound 4a to generate desired compound 4 in high yield
compared to literature reported low yields. Towards this direction, screening of a series of
oxidizing agents in a variety of solvents was planned.
Initially, different types of oxidising agents were applied for the oxidation of compound 3, for
example peracetic acid, m-CPBA, magnesium monoperoxyphthalate (MMPP) and oxone.
The formation of compound 4a with the above said oxidising agents was 10%, 14%, 52% and
85% in a mixture of H2O-Acetonitrile (7:10 ratio) (entries 1-4, Table 3). The formation of
impurities increased with oxidising agents other than oxone. For example, 12-48% of
impurity 4b, 7-27% of impurity 4c, 6-15% of impurity 4d were formed along with 5-14% of
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desired compound 4 (entries 1-3). In addition, the formation of impurity 4d was increased
exponentially with increase of amount of oxidising agent (more than 2.0 equivalents). The
study revealed that the formation of compound 4a was good (85%) using oxone (entry 4,
Table 3 and Figure S10, supplementary information) compared to other oxidising agents
(entries 1-3). As a result, the oxone was selected for the optimization of other reaction
conditions. In addition, oxone is a green oxidising agent with good stability, it is easy to
handle, non-toxic nature and low cost.21, 22 Moreover, the by-products of oxone (inorganic
salts) are harmless to environment thus encouraging us to utilize it as a reagent for the present
route of synthesis. Additionally literature also revealed that oxone can be efficiently used as
an oxidising agent in the conversion of sulphide to sulfone.24
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Table 3. Screening of appropriate oxidising agent for oxidation.a
Selectivityb by HPLC
Entry
Oxidising
agent
Time Product
(h)
4
4a
4b
4c
4d
1
2
3
Peracetic acid
m-CPBA
4
3
5
05
08
14
10
14
52
42
48
12
25
27
07
12
15
06
4a
4a
4a
Magnesium
monoperoxy
phthalate
4
Oxone
2
0.2
85
0.8
0
12
4a
aReaction conditions: Compound 3 (10 g, 0.034 mol), Oxidising agent (0.069 mol) in H2O-
Acetonitrile (7:10 ratio) (170 mL) at 20-30 °C.
bRemaining unreacted substrate.
Further, the effect of various solvents on the course of oxidation was studied, for example
dichloromethane, methanol, ethanol, THF, DMF and DMSO provided compound 4a in the
range of 10-15% only (entries 1-6, Table 4). It is due to insolubility of oxone in these
solvents. Hence, it was planned to study the effect of mixture of water and organic solvents.
For example in H2O: Dichloromethane and H2O:Ethyl acetate (in presence of PTC), 67% and
38% of compound 4a was (entries 7 and 8) formed, respectively. In H2O: Dichloromethane in
presence of PTC (Tetra-butyl ammonium bromide), 67% of compound 4a and 5% of
impurity 4b was formed (entry 7). The conversion (67%) was good, but the 5% of impurity
4b was difficult to remove in further stages up to the limits of specification of API.
To improve the yield further, the same reaction was carried out in H2O:Methanol,
H2O:Ethanol, H2O:THF and H2O:Acetonitrile (7:10 ratio) and 52%, 55%, 46% and 85% of
compound 4a was formed (entries 9-12, Table 4), respectively. The oxidation in H2O-
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Methanol/Ethanol, the formation of impurity 4d increased up to 35% and 39% (entries 9 and
10). In H2O:DMF and H2O:DMSO (8:2 ratio), 60% and 58% of compound 4a was formed
(entries 13 and 14), respectively.
7
8
9
Interestingly, in case of mixture of H2O-Acetonitrile (7:10 ratio), 85% of compound 4a and
0.8% of impurity 4b was formed. The formation of impurity 4d was increased to 12% which
easily gets removed during purification process. The results reveal that mixture of H2O-
Acetonitrile (7:10 ratio) is the best option for maximum conversion (85%) and exercise good
control on potential impurities (entry 12, Table 4, and Figure S10, supplementary
information).
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15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Selection of suitable solvent for oxidation using Oxonea
Selectivityb by HPLC
Entry
Solvent
Time
(h)
24
24
24
24
24
24
6
Product
4
4a
4b
4c
4d
02
1
2
Dichloromethane
Methanol
05 10
06 12
07 13
04 11
08 15
07 14
11 67
07 38
02 52
02 55
03 46
0.2 85
07 60
08 58
02
01
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
03
03
02
02
02
05
04
03
02
03
0.8
02
02
02
02
03
01
02
06
05
04
04
05
0
01
01
02
02
01
09
04
39
35
04
12
02
03
3
Ethanol
4
THF
5c
DMF
6c
DMSO
7d, e
8d, e
9e
H2O:Dichloromethane
H2O:Ethyl acetate
H2O:Methanol
H2O:Ethanol
H2O:THF
8
3
10e
11e
12e
13f
14f
3
7
H2O:Acetonitrile
H2O:DMF
2
3
01
01
H2O:DMSO
4
aReaction conditions: Compound 3 (10 g, 0.034 mol), Oxone (42.7 g, 0.069 mol) in organic
solvent (10 vol)/Mixture of aqueous organic solvent at 20-30 °C.
bRemaining unreacted substrate.
cSolvent (3 vol).
dIn presence of PTC (tetrabutyl ammonium bromide).
eMixture of solvents (7:10 ratio) [170 mL, 17 vol].
fMixture of solvents (8:2 ratio) [100 mL, 10 vol].
Then, the effect of temperature on the course of oxidation was studied in H2O-Acetonitrile
(7:10 ratio), for instance oxidation at 20-30 °C provided 85% (4a) conversion in 2 h. The
same reaction at >30 °C, the percentage of formation of impurity 4d increased exponentially
with the increase of temperature.
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Finally the effect of load of oxone was studied on the course of oxidation, for example 1.0,
2.0 and 3.0 eq. of oxone provided 40%, 85% and 64% of compound 4a (entries 1, 3, 4, Table
5). In case of 1.0 eq. of oxone, 40% of compound 4a, 43% of impurity 4b and 14% of
impurity 4c were formed (entry 1). Use of 2.0 eq. of oxone provided 85% of compound 4a
and impurity 4d in 12% (entry 3). When 3.0 eq. of oxone was applied, low formation (64%)
of compound 4a and high (32%) formation of impurity 4d was observed (entry 4). To reduce
the load of oxone, 1.5 eq. of oxone was used, but the conversion was low (55%) and the
formation of impurities (27% of 4b and 5% of 4c) was increased (entry 2, Table 5). The study
disclosed that 2.0 eq. of oxone is optimum for maximum formation (85%) of compound 4a
and 12% of impurity 4d in H2O-Acetonitrile (7:10 ratio) at 20-30 °C (entry 3, Table 5 and
Figure S10, supplementary information). The study was also evident with report from the
literature.24
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14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. Effect of load of oxone.a
Selectivityb by HPLC
Entry
Load of
Time Product
(h)
Oxone (eq.)
4
4a
4b
4c
4d
1
2
3
4
1
1.5
2
1
02
40
43
14
01
4a
4a
4a
4a
1.5
2
04
0.2
05
55
85
64
27
0.8
0.4
5
0
08
12
32
3
2.5
0.5
aReaction conditions: Compound 3 (10 g, 0.034 mol), Oxone in H2O-Acetonitrile (7:10
ratio) (170 mL) at 20-30 °C.
bRemaining unreacted substrate.
Then, it was planned to conduct in situ reduction of compound 4a to generate desired
compound 4 in one-pot using the process reported in literature.25Accordingly, compound 4a,
Zn powder and acetic acid in DMF were stirred at 60-70 °C and 68% isolated yield of
compound 4 was obtained (entry 1, Table 6).
There are a few disadvantages with this process at commercial level, for example i) the
contamination of effluent with acetic acid and DMF, ii) difficult to remove DMF from the
reaction mass, and iii) large amount of water is required to isolate compound 4. To overcome
these issues, it was planned to replace acetic acid with lactic acid and also DMF with
acetonitrile. Accordingly, the same reaction was carried out in acetonitrile using Zn/lactic
acid as selective reducing agent and the conversion increased up to 83% (4) (entry 2, Table
6). In addition, the lactic acid is environmentally benign, non-volatile and biodegradable
green reagent.26, 27 The solvent, acetonitrile was recovered after the completion of reaction
and it is one of the added advantages over DMF.
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With the help of modified process, the inevitable compound 4a that was formed in oxidation
process was successfully converted into the desired compound 4 using reduction process.
This modification provided improved yield (85%) of compound 4 compared to previously
reported chemoselective oxidation methods.17, 18, 19 The study disclosed that the conversion of
compound 4a to compound 4 was good in Zn/lactic acid/acetonitrile system (entry 2, Table 6,
and Figure S16, supplementary information).
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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31
32
33
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35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
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60
Table 6. Screening of suitable acid during reduction.a
Selectivityc by HPLC
Entry
Acid
Time Product Yield
(h)
1
(%)b
68
4
4a
4b
4d
1d
2e
Acetic acid
Lactic acid
68
0.8
0.5
12
4
4
3
85
83
0.1
0.4
11
aReaction conditions: Compound 4a crude (10 g, 0.034 mol), Zn (3.76 g, 0.057 mol ), Lactic
acid (20 mL) in solvent (70 mL, 7 vol) at 60-70 °C.
bIsolated yield without purification.
cRemaining unreacted substrate.
dReaction was carried out in DMF.
eReaction was carried out in acetonitrile.
New process conditions for 10-(3-chloropropyl)-2-(methylsulfonyl)-10H-phenothiazine
(5) derivative:
The conversion of 1-[2-(methylsulfonyl)-5-oxido-10H-phenothiazin-10-yl]ethanone (4) to
10-(3-chloropropyl)-2-(methylsulfonyl)-10H-phenothiazine (5) in presence of base using 1-
bromo-3-chloropropane was achieved through deprotection followed by in situ N-alkylation
as shown in scheme 6.
O
S
O
S
Cl
N
O
O
S
Base
O
S
O
O
S
O
O
N
Br
Cl
N
S
O
N
S
+
N
S
S
Solvent
+
S
O
4
5a
5
5b
Scheme 6: Formation of possible products during deprotection and in situ N-alkylation.
The reaction of compound 4 in presence of KOH using 1-bromo-3-chloropropane in
dichloromethane at reflux temperature provided 40% of compound 5 through deprotection
followed by in situ N-alkylation in one-pot (entry 1, Table 7) along with 15% of impurity 5a
and 3% of impurity 5b. To improve the conversion further, the same reaction was carried out
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at 50-60 °C using ethyl acetate, acetone, acetonitrile, THF, DMSO and DMF and 35%, 84%,
42%, 35%, 61% and 64% of compound 5 was formed, respectively (entries 2, 3 and 7-10,
Table 7). In ethyl acetate, acetonitrile and THF, 35%, 42% and 35% of compound 5 was
formed (low conversion) and 25%, 31% and 38% of impurity 5a was formed, respectively
(entries 2, 7 and 8). In acetone, 84% of compound 5 along with 9% of impurity 5a and 1.5%
of impurity 5b were formed (entry 3). In DMSO and DMF, the formation of compound 5 was
low, 61% and 64%, respectively, but the formation of impurities were more (18% and 20% of
impurity 5a and 4% and 5% of impurity 5b were formed in DMSO and DMF, respectively)
[entries 9 and 10]. The solvent study confirmed that acetone is the best option for maximum
formation (84%) of compound 5 (entry 3, Table 7 and Figure S40, supplementary
information). In solvents other than acetone (reported in Table 7), it was observed that the
reaction was not proceeded at 20-30 °C and the formation of impurity 5a increased
exponentially with increase of temperature >60 °C.
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17
18
19
20
21
22
23
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32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To study the effect of NaOH on the course of the reaction, the same reaction was carried out
in presence of NaOH, but the formation of compound 5 was low (68%) even after 6 h with
increased formation of impurities (10% of 5a and 8% of 5b) compared to the reaction in
KOH.
Table 7. Selection of suitable solvent for deprotection and in situ N-alkylationa
Selectivityc by HPLC
Entry
Solvent
Time
(h)
8
Tempˈ
(°C)
Product
5
5a
15
25
9
5b
03
06
1.5
01
02
04
08
06
04
05
1
2
Dichloromethane
Ethyl acetate
Acetone
30-35
50-60
50-60
20-30
30-40
40-50
50-60
50-60
50-60
50-60
40
35
84
20
35
66
42
35
61
64
5
5
5
5
5
5
5
5
5
5
5
3
3
4
24
15
6
03
05
10
31
38
18
20
5
6
7
Acetonitrile
THF
4
8
5
9d
DMSO
DMF
3
10d
2
aReaction conditions: Compound 4 (10 g, 0.031 mol), powdered KOH (5.26 g, 0.094 mol),
1-bromo-3-chloropropane (14.6 g, 0.094 mol) in solvent (10 vol) at 50-60 °C.
bIsolated yield after isolation and purification in Methanol.
cRemaining unreacted substrate.
dSolvent (3 vol).
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It was planned to study the effect of temperature on the course of reaction, for example 20-30
°C, 30-40 °C and 40-50 °C in acetone, 20%, 35% and 66% of compound 5 was formed,
respectively (entries 4-6, Table 7). The study disclosed that the optimum temperature for
maximum formation (84%) of compound 5 was 50-60 °C (entry 3, Table 7 and Figure S40,
supplementary information)
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17
18
19
20
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Then, the effect of load of powdered KOH on the course of the reaction was studied in
acetone, for example 1.0, 2.0, 3.0 and 4.0 eq. of powdered KOH, 4%, 20%, 84% and 69% of
compound 5 was formed, respectively. In 1.0 eq. of KOH, low formation of compound 5 was
observed. The de-protection of compound 4 was completed, but N-alkylation was not
proceeding due to insufficient KOH. In case of 2.0 eq. of KOH, the same situation was
observed but the formation of 5 was increased (20%) slightly. The same reaction in presence
of 4.0 eq. of KOH, the formation of 5 decreased (69%) as the formation of impurities
increased (20% of 5a and 4% of 5b). The study revealed that 3.0 eq. of powdered KOH in
acetone provided the maximum formation of 5 (84%) along with 9% of impurity 5a and 1.5%
of impurity 5b (Figure S40, supplementary information).
The formation of potential impurity (5a) was in high level (9%) (entry 3, Table 7), which
affects severely in producing required quality of final API. Hence, its removal is mandatory
up to the level of not more than 2.5%. So it is planned to improve the quality of compound 5
by isolating in different solvents, for example acetone, methanol, ethanol, acetonitrile and
ethyl acetate and the obtained results were presented in Table 8 (entries 1-5). The study
disclosed that methanol was the best option to isolate the desired compound 5 and also to
remove the potential impurity 5a up to the process capability level (<2.5%) [entry 2, Table 8
and Figure S41, supplementary information)
Table 8. Selection of suitable solvent for isolation of compound 5a
Yieldb
(%)
65
Purity (% by HPLC)
Entry
Solvent
Product
5
5a
05
02
04
06
07
5b
01
1.2
01
01
01
1
2
3
4
5
Acetone
Methanol
89
96
91
90
89
5
5
5
5
5
60
Ethanol
64
Acetonitrile
Ethyl acetate
66
68
aReaction conditions: Crude compound 5 (10 g, 0.031 mol) in solvent (100 mL) at reflux
temperature for 30 min, cool to 20-30 °C, stir for 1h and filter the solid.
bIsolated yield.
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New process for the preparation of 1-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-
yl]propyl) 4-piperidinecarboxamide (1), Metopimazine:
6
7
8
9
The synthesis of final Metopimazine (1) was achieved by the reaction of compound 5 with 4-
piperidinecarboxamide in presence of base as shown in scheme 7, Note: The 4-
piperidinecarboxylic acid is a common impurity in 4-piperidinecarboxamide. This impurity
content should be less than 2%, if it is beyond 2%, the formation of both impurity 1a and 1b
increase exponentially.
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17
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19
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36
37
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42
43
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50
51
52
53
54
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58
59
60
O
O
S
O
NH2
Base
S
N
S
N
N
N
O
S
O
S
S
O
S
N
O
S
+
O
O
O
Solvent
+
N
H
+
O
O
N
N
S
N
S
H2N
HO
Cl
5
O
1
O
1a
1b
O
Scheme 7: Formation of possible products during N-alkylation of compound 5.
Initially, a reaction of compound 5 with 4-piperidinecarboxamide was carried out in
dichloromethane in presence of K2CO3 at reflux temperature, the reaction was unsuccessful
(entry 1, Table 9). The same reaction was carried out in ethyl acetate, acetone and methanol
at reflux temperature, but the reaction was unsuccessful (entries 2-4). It is due to inadequate
temperature. Then, the same reaction was conducted in toluene at reflux temperature, 50% of
compound 1 and 1% of impurity 1a and 2% of impurity 1b were formed (entry 5).
The same reaction was carried out in alcoholic solvents and also in acetonitrile at reflux
temperature, the formation of compound 1 was low (43-47%) along with 1-2% of impurity 1a
and 1-3% of impurity 1b (entries 6-9, Table 9). Interestingly, in DMAc the conversion was
very low (30%) with 1% of impurity 1a and 2% of impurity 1b (entry 10). But in case of
DMSO and DMF, 51% and 63% of compound 1 was formed, respectively (entries 11 and 12)
in presence of K2CO3 at 90-100°C. In DMSO and DMF, 2% of impurity 1a and 1% and 12%
impurity 1b was formed, respectively. It is found that in DMF, the conversion was good
(63%) [entry 12]. It was observed that both in toluene (entry 5) and DMF (entry 12), the
conversion was good compared to other single solvents (entries 1-4 and 6-11). This
encouraged us to study the effect of mixture of Toluene and DMF, for example mixture of
toluene-DMF in 4:6, 5:5, 6:4, 7:3, 8:2 and 9:1 ratio, 63%, 68%, 70%, 72%, 81% and 73% of
compound 1 was formed, respectively (entries 13-17 and 24, Table 9). On decrease of DMF
ratio, for example on decrease from 6 to 2 ratio, the formation of impurity 1a also decreased
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from 5% to 1.5% and impurity 1b also decreased from 11% to 8% (entries 13-17).
Interestingly, further decrease of DMF ratio leads to increase of impurities (3% of 1a and
10% of 1b) [entry 24].
7
8
9
The study revealed that the formation of compound 1 (81%) was good and impurities profile
(1.5% of 1a and 8% of 1b) is also tolerable in 8:2 ratio of toluene-DMF mixture (entry 17,
Table 9 and Figure S59, supplementary information).
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11
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13
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17
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19
20
21
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23
24
25
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30
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33
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35
36
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38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 9. Effect of solvent for the synthesis of Metopimazine (1) from compound 5.a
Time (h)
Selectivityb by
HPLC
Entry Solvent
Tempˈ
(°C)
Base
Product
1
1a
1b
1
2
3
4
5
6
7
Dichloromethane
24
24
24
24
24
24
24
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
-
-
-
1
1
1
1
1
1
1
Ethyl acetate
Acetone
-
-
-
-
-
-
Methanol
Toluene
-
-
-
50
43
45
01
02
02
02
03
01
Ethanol
Isopropanol
8
n-Butanol
Acetonitrile
DMAc
11
24
7
90-100°C
Reflux
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
47
44
30
51
63
63
01
02
01
02
02
05
02
03
02
01
12
11
1
1
1
1
1
1
9
10
11
12
13
90-100°C
90-100°C
90-100°C
90-100°C
DMSO
10
7
DMF
Toluene-DMF
(4:6 ratio)
6
14
15
16
Toluene-DMF
(5:5 ratio)
6
7
8
90-100°C
90-100°C
90-100°C
K2CO3
K2CO3
K2CO3
68
70
72
04
03
02
10
09
08
1
1
1
Toluene-DMF
(6:4 ratio)
Toluene-DMF
(7:3 ratio)
17
18
19
20
21
22
23
24
Toluene-DMF
(8:2 ratio)
8
90-100°C
90-100°C
90-100°C
K2CO3
Na2CO3
Et3N
81
67
31
37
-
1.5
04
04
01
-
08
07
04
02
-
1
1
1
1
1
1
1
1
12
24
24
24
24
24
8
90-100°C Piperidine
20-30 °C
50-60 °C
70-80 °C
90-100°C
K2CO3
K2CO3
K2CO3
K2CO3
42
01
02
03
10
53
73
01
03
Toluene-DMF
(9:1 ratio)
aReaction conditions: Compound 5 (10 g, 0.028 mol), 4-piperidinecarboxamide (5.43 g,
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5
0.042 mol), Base (0.07 mol) in solvent (100 mL, 10 vol).
bRemaining unreacted substrate.
6
7
8
9
Then, the effect of base on the course of reaction was studied, for example Na2CO3, Et3N and
piperidine in toluene-DMF (8:2 ratio), the conversion was 67%, 31% and 37%, respectively
(entries 18-20, Table 9). The formation of impurities in presence of K2CO3 was low (1.5% of
1a and 8% of 1b) compared to Na2CO3 and Et3N. In presence of piperidine, the conversion
was not acceptable (37%), but the formation of impurities was very less (1% of 1a and 2%
1b). The investigation revealed that K2CO3 is suitable base for the maximum conversion
(81%) with acceptable impurities profile (entry 17, Table 9 and Figure S59, supplementary
information).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Then, the effect of temperature on the course of reaction was studied in toluene-DMF (8:2
ratio). Accordingly, a reaction of compound 5 with 4-piperidinecarboxamide in presence of
K2CO3 was carried out at 20-30 °C, but the reaction was not proceeded (entry 21, Table 9).
The same reaction at 50-60 °C and 70-80 °C, the conversion was 42% and 53%, respectively
(entries 22 and 23). The formation of impurity 1b (2-3%) was low and unreacted substrate 5
(5-15%) was more when reaction was conducted at <90 °C. The conversion was decreased
(60-70%) and the formation of impurity 1a (4-8%) and impurity 1b (15-20%) was increased
when reaction was carried out at >100 °C. The study disclosed that 90-100 °C is the optimum
temperature for maximum conversion (81%) (entry 17, Table 9 and Figure S59,
supplementary information).
Finally, the effect of base concentration was studied, for example 1.0, 2.0, 3.0 and 4.0 eq. of
K2CO3, 52%, 66%, 75% and 72% of compound 1 was formed, respectively. In 1.0 eq. of
K2CO3, 40% of the unreacted compound 5 was formed and impurities formation was usual
even after 24 h. The same reaction was completed in 12 h with 2.0 eq. of K2CO3, but 6-7% of
substrate 5 was unreacted. In case of 3.0 and 4.0 eq., the formation of impurity 1a was
increased up to 15-25%. Hence, it is planned to conduct the same reaction using 2.5 eq. of
K2CO3, the reaction completed in 8 h with 1.5% of impurity 1a and 8% of impurity 1b. The
study disclosed that maximum formation (81%) of compound 1 was observed in presence of
2.5 eq. of K2CO3 in toluene-DMF (8:2 ratio) at 90-100 °C (Figure S59, supplementary
information).
The purity of crude Metopimazine (1) did not comply with the specifications of API. Hence,
it was planned to isolate in different solvents to improve the quality, to remove potential
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impurities such as 1a and 1b and also other carryover impurities. Initially, the purification
was conducted using single solvent system (toluene, methanol, isopropanol and ethyl
acetate), but the impurities were not eliminated completely. Then, mixture of solvents such as
Toluene-DMF, Toluene-Methanol, Toluene-Ethyl acetate and Methanol-DMSO (8:2 ratio)
[entries 1-4, Table 10) were used and the obtained results were presented in Table 10. The
study disclosed that Toluene-DMF (8:2 ratio) is the best option for the purification to achieve
the desired quality of Metopimazine (API) (1) [entry 1, Table 10 and Figure S60,
supplementary information].
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Table 10. Selection of suitable solvent for purification of compound 1a
Yieldb
(%)
Entry
Solvent
Product
Purity by HPLC
5a
0.01 0.01 0.06
1
1a 1b
5
5b Unknown
1
2
Toluene-DMF
(8:2 ratio)
Toluene-
Methanol
(8:2 ratio)
Toluene-
Ethyl acetate
(8:2 ratio)
Methanol-
DMSO
65
1
1
99.7
0
0
0.05
60
64
66
99.0 0.2 0.5 0.02 0.03 0.1
98.4 0.5 0.8 0.02 0.05 0.2
99.0 0.2 0.5 0.02 0.03 0.1
0.15
1
3
4
0.16
0.15
1
(8:2 ratio)
aReaction conditions: Crude compound 1 (9.5 g, 0.031 mol) in mixture of solvents (8:2
ratio) [50 mL, 5 vol] at 60-70 °C for 1h, cool to 20-30 °C and stir for 30 min and filter the
solid.
bIsolated yield.
EXPERIMENTAL SECTION.
The solvents and reagents were obtained from commercial sources and were used without
purification. Nuclear magnetic resonance (NMR) spectra of the synthesized compounds were
recorded on AscendTM Bruker 400 (Bruker, Fallanden, Switzerland) instrument and operating
1
at 400 MHz for H NMR and 100 MHz for 13C NMR using either CDCl3 or DMSO-d6
solvent and tetramethylsilane (TMS) as internal standard. Spin multiplicities are given as s
(singlet), d (doublet), dd (doublet of doublet), t (triplet), and m (multiplet) as well as brs
1
(broad singlet). The H chemical shift values were reported on δ scale in ppm, relative to
TMS (δ = 0.00 ppm) and in the 13C chemical shift values were reported relative to DMSO-d6
(δ = 39.5 ppm). The ESI/MS experiments were performed on a Velos Pro ion trap mass
spectrometer from Thermo Scientific (San Jose, CA, USA).
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Synthesis of 1-[2-(methylsulfanyl)-10H-phenothiazin-10-yl]ethanone (3):
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In a 2 litre RB flask, 2-(methylsulfanyl)-10H-phenothiazine (1) [200 g, 0.81 mol] in toluene
(1200 mL, 6 vol) was charged and acetyl chloride (160 g, 2.02 mol) was added slowly at 20-
30 °C. The reaction mass was stirred at 20-30 °C for 1h. After completion of the reaction as
per reaction monitoring by HPLC, the reaction mass was cooled to 0-5 °C and water (800
mL, 4 vol) was added slowly. Then, the temperature of the reaction mass was raised to 20-30
°C. The layers were separated and the organic layer was collected and it was washed with 5%
aqueous NaHCO3 solution (15 g in 300 mL water). Again layers were separated and the
organic layer was collected. The organic layer was washed with water (600 mL, 3 vol). The
organic layer was collected and the solvent was evaporated under vacuum at 45 °C.
Isopropanol (600 mL) was added to the crude mass and the temperature was raised to reflux
(clear solution). At reflux temperature, the reaction mass was stirred for 15 min and then
cooled to 10-15 °C and maintained for 1h. The solid was filtered and washed with (100 mL,
0.5 vol) isopropanol. The compound was dried under vacuum at 60-65 °C for 8h.
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Off-white solid, yield. 93% (218 g), m. p. 223-226 °C.
1H NMR (400 MHz, CDCl3, δ/ppm): 7.49 (d, 1H, arom H, J = 7.6 Hz), 7.46-7.42 (m, 2H,
arom H), 7.36-7.32 (m, 2H, arom H), 7.28-7.22 (m, 1H, arom H), 7.13 (dd, 1H, arom H, J =
8.0 Hz and 1.6 Hz), 2.51 (s, 3H, -SCH3), 2.23 (s, 3H, -COCH3).
13C NMR (100 MHz, DMSO-d6, δ/ppm): 168.36, 139.19, 138.52, 137.74, 132.05, 128.07,
127.97, 127.78, 127.44, 127.19, 126.94, 124.60, 124.51, 22.71, 14.88.
MS m/z (ESI): 288.04 (M+H)+.
Kilogram scale: The same reaction carried out in kilogram scale with compound 1 (6.5 kg,
26.49 mol, 1.0 equiv.), acetyl chloride (5.2 kg, 66.2 mol, 2.5 equiv.), toluene (39 L, 6 vol)
and obtained 6.98 Kg of compound 3 (Yield: 91.8%).
Synthesis of 1-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]ethanone (4):
In a 3 litre RB flask, 1-[2-(methylsulfanyl)-10H-phenothiazin-10-yl]ethanone (3) [150 g, 0.52
mol] was charged at 20-30 °C in acetonitrile [1500 mL, 10 vol]. The oxone [641.3 g, 1.04
mol] in water (1050 mL, 7 vol) was added slowly. The reaction mass stirred at 20-30 °C for 2
h. After completion of the reaction as per reaction monitoring by HPLC, the reaction mass
was quenched with sodium thiosulphate solution (75 g in 300 mL water, 2 vol).
Dichloromethane (DCM) (750 mL) was added and stirred for 10 min. Layers were separated,
the organic layer was collected in the same pot and the solvent was evaporated under
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vacuum. To the crude mass (4a), Zn powder (56.5 g, 0.86 mol) in acetonitrile (1050 mL, 7
vol) and lactic acid (300 mL, 2 vol) were added and stirred at 60-70 °C for 3h. After
completion of the reaction as per reaction monitoring by HPLC, the reaction mass was cooled
to 20-30 °C. Charged dichloromethane (750 mL, 5 vol) as the compound 4 has poor solubility
in acetonitrile. The reaction mass stirred for 30 min and filtered through hyflo bed at 20-30
°C. The filtrate was transferred into 2 litre RB flask and the solvent was removed under
reduced pressure at 40-45 °C. The reaction mass was cooled to 20-30 °C and water (750 mL,
5 vol) was added slowly and then stirred for 30 min. The precipitated solid was filtered and
washed with water (300 mL, 2 vol). The solid product 4 was dried in hot air oven at 50 °C for
10 h.
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Off-white solid, yield. 85% (142 g), m. p. 90-97 °C.
1H NMR (400 MHz, DMSO-d6, δ/ppm): 8.13 (s, 1H, arom H), 7.86-7.81 (m, 2H, arom H),
7.69 (d, 1H, arom H, J = 7.6 Hz), 7.60 (d, 1H, arom H, J = 8.0 Hz), 7.48-7.44 (m, 1H, arom
H), 7.38-7.34 (m, 1H, arom H), 3.25 (s, 3H, -S-CH3), 2.17 (s, 3H, -COCH3), 1.8 (s, 3H, -
COCH3 of acetic acid impurity).
13C NMR (100 MHz, DMSO-d6, δ/ppm): 168.43, 139.48, 138.66, 138.55, 137.95, 130.80,
128.69, 128.06, 127.88, 127.45, 127.40, 125.70, 125.06, 43.43, 22.54.
MS m/z (ESI): 320.05 (M+H)+.
Characterization data of 1-[2-(methylsulfonyl)-5-oxido-10H-phenothiazin-10-ylethanone
(4a):
1H NMR (400 MHz, DMSO-d6, δ/ppm): 8.37 (s, 1H, arom H), 8.10-8.05 (m, 2H, arom H),
7.93 (dd, 1H, arom H, J = 6.4 Hz and 2.0 Hz), 7.64-7.56 (m, 3H, arom H), 3.14 (s, 3H, -SO2-
CH3), 2.40 (s, 3H, -COCH3).
MS m/z (ESI): 336.01 (M+H)+.
Kilogram scale: The same reaction carried out in kilogram scale with compound 3 (6.3 kg,
21.92 mol, 1.0 equiv.) in acetonitrile [63 L, 10 vol], oxone [26.93 kg, 43.8 mol, 2.0 equiv.] in
water (44.1 L, 7 vol), dichloromethane (31.5 L), Zn powder (2.36 kg, 36.0 mol, 1.65 equiv.)
in acetonitrile (44.1 L, 7 vol) and lactic acid (12.6 L, 2 vol) and obtained 5.91 Kg of
compound 4 (Yield: 84.4 %).
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Synthesis of 10-(3-chloropropyl)-2-(methylsulfonyl)-10H-phenothiazine (5):
In a 2 litre RB flask, 1-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]ethanone (4) [100 g,
0.313 mol] in acetone (1000 mL, 10 vol) and powdered KOH (52.6 g, 0.94 mol) was added
(Note: The colour of the reaction mass was changed from grey yellow to dark pink). Then, 1-
bromo-3-chloropropane [148 g, 0.94 mol] was added slowly at 20-30 °C. The reaction mass
temperature increased to 50-60 °C and stirred at the same temperature for 3h. After
completion of the reaction as per reaction monitoring by HPLC, the reaction mass was cooled
to 20-30 °C and water (500 mL, 5 vol) was added. The formed product was extracted using
dichloromethane (500 mL, 5 vol). The organic solvent was collected and evaporated under
vacuum. To the obtained crude mass, methanol (500 mL, 5 vol) was added. The reaction
mass temperature increased to 60-65 °C and maintained for 30 min. Then, the reaction mass
was cooled to 20-30 °C and stirred for 1h at 20-30 °C. The reaction mass was filtered and
washed with methanol (50 mL, 0.5 vol). The obtained compound 5 was dried in vacuum oven
at 50 °C for 10h.
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Yellow color solid, yield. 60% (67 g), m. p. 122-127 °C.
1H NMR (400 MHz, CDCl3, δ/ppm): 7.49 (dd, 1H, arom H, J = 8.0 Hz and1.6 Hz), 7.40 (d,
1H, arom H, J = 1.6 Hz), 7.32-7.28 (m, 1H, arom H), 7.24-7.22 (m, 1H, arom H), 7.17 (dd,
1H, arom H, J = 7.6 Hz and 1.2 Hz), 7.04-7.0 (m, 1H, arom H), 6.96 (d, 1H, arom H, J = 8.0
Hz), 4.15 (t, 2H, -NCH2-, J = 6.4 Hz), 3.68 (t, 2H, -CH2Cl, J = 6.0 Hz), 3.06 (s, 3H, -
SO2CH3), 2.26 (quintet, 2H, -CH2-).
13C NMR (100 MHz, DMSO-d6, δ/ppm): 145.29, 143.53, 140.24, 131.13, 128.16, 127.75,
127.46, 123.52, 122.81, 120.98, 116.51, 113.43, 43.67, 43.43, 42.52, 29.04.
MS m/z (ESI): 354.04 (M+H)+.
Kilogram scale: The same reaction carried out in kilogram scale with compound 4 (5.5 kg,
17.2 mol, 1.0 equiv.) in acetone (55 L, 10 vol), powdered KOH (2.893 kg, 51.6 mol, 3.0
equiv.]), 1-bromo-3-chloropropane [8.14 kg, 51.7 mol, 3.0 equiv.]] and obtained 3.73 Kg of
compound 5 (Yield: 61.2 %).
Synthesis
of
1-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-
piperidinecarboxamide (1)-Metopimazine:
In a 2 litre RB flask, mixture of 10-(3-chloropropyl)-2-(methylsulfonyl)-10H-phenothiazine
(5) [100 g, 0.282 mol], 4-piperidinecarboxamide [54.21 g, 0.42 mol] and K2CO3 (97.63 g,
0.706 mol) in toluene-DMF (8:2 ratio) (1000 mL, 10 vol) were stirred at 90-100 °C for 8h.
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After completion of the reaction as per reaction monitoring by HPLC, cooled to 25-30 °C.
Toluene (1000 mL, 10 vol) was added to the reaction mass and stirred for 30 min. The
reaction mass was filtered and washed with toluene (100 mL, 1 vol). Water (1000 mL, 10
vol) was added to the wet material and stirred for 1 h at 20-30 °C, filtered the solid and dried
at 60-65 °C for 5 h. The crude material (95 g) in toluene-DMF (8:2 ratio) (500 mL, 5 vol)
were stirred at 60-70 °C for 1 h. Then, the reaction mass was cooled to 20-30 °C and stirred
for 30 min. The formed solid was filtered and washed with toluene (100 mL, 1 vol). The
obtained compound (1) was dried in hot air oven at 50 °C.
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Pale yellow color solid, yield. 65% (82 g), DSC 189 °C.
1H NMR (400 MHz, DMSO-d6, δ/ppm): 7.44 (d, 1H, arom H, J = 8.8 Hz), 7.37 (d, 2H, arom
H, J = 8.0 Hz), 7.24 (t, 1H, arom H, J = 7.6 Hz), 7.16 (m, 2H, -NH2), 7.1 (d, 1H, arom H, J =
8.4 Hz), 6.99 (t, 1H, arom H, J = 7.6 Hz), 6.68 (s, 1H, arom H), 3.99 (t, 2H, -NCH2, J = 6.4
Hz), 3.23 (s, 3H, -S-CH3), 2.8-2.73 (m, 2H, -CH2-), 2.36 (t, 2H, -CH2-, J = 6.8 Hz), 2.02-1.96
(m, 1H, -CH-), 1.84-1.78 (m, 4H, 2-CH2-), 1.61-1.58 (m, 2H, -CH2-), 1.48-1.44 (m, 2H, -
CH2-).
13C NMR (100 MHz, DMSO-d6, δ/ppm): 176.52, 145.41, 143.5, 140.12, 130.47, 128.03,
127.50, 127.25, 123.23, 122.16, 120.59, 116.38, 113.24, 54.82, 52.97, 44.64, 43.47, 41.7,
28.59, 23.52.
MS m/z (ESI): 446.21 (M+H)+.
Powder XRD data: The crystalline form of Metopimazine was characterized by PXRD
(Powder XRD) and it showed peaks at 4.43, 8.81, 9.84, 11.37, 13.21, 16.57, 17.64, 19.09,
19.72, 19.99, 20.62, 21.68, 22.07, 24.39, 24.77, 26.42, 27.76, 30.82, 32.02 degrees 2θ.
Kilogram scale: The same reaction carried out in kilogram scale with compound 5 [3.5 kg,
9.89 mol, 1.0 equiv.], 4-piperidinecarboxamide [1.9 kg, 14.8 mol, 1.5 equiv.] and K2CO3
(3.42 kg, 24.74 mol, 2.5 equiv.) in toluene-DMF (8:2 ratio) (35 L, 10 vol) and obtained 2.81
Kg of Metopimazine API (1) (Yield: 63.8 %); HPLC purity:99.9% and the related substances
and individual unknown impurities are within the limit of the specifications.
Synthesis and characterization data of possible impurities: All the possible impurities
were identified, synthesized and characterized. The details are as below.
Synthesis of 1-[2-(methylsulfinyl)-10H-phenothiazin-10-yl]ethanone (4b):
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In a 2 litre RB flask, 1-[2-(methylsulfanyl)-10H-phenothiazin-10-yl]ethanone (3) [50 g, 0.174
mol] was charged at 20-30 °C in dichloromethane [500 mL, 10 vol]. Then, oxone [13.24 g,
0.087 mol, 0.5 equiv.] in water (750 mL, 15 vol) and PTC (tetrabutyl ammonium bromide)
[5.6 g, 0.0173 mol, 0.1 eq.] were added. The reaction mass was stirred at 30-40 °C for 6 h.
After completion of the reaction as per TLC, cooled to 20-30 °C and the reaction mass was
quenched in sodium thiosulphate solution (25.0 g in 100 mL water, 2 vol). Layers were
separated, the organic layer was collected and the solvent was evaporated under vacuum. The
crude mass was purified over column filled with silica gel (60-120 mesh) using 20% ethyl
acetate in hexane. The solid product 4b was dried in hot air oven at 50 °C. Weight = 8.8 g.
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1H NMR (400 MHz, DMSO-d6, δ/ppm): 7.94 (s, 1H, arom H), 7.76 (d, 1H, arom H, J = 8.4
Hz), 7.67 (d, 1H, arom H, J = 8.0 Hz), 7.62-7.58 (m, 2H, arom H), 7.46-7.42 (m, 1H, arom
H), 7.36-7.32 (m, 1H, arom H), 2.78 (s, 3H, -SO-CH3), 2.17 (s, 3H, -COCH3).
13C NMR (100 MHz, DMSO-d6, δ/ppm): 168.37, 145.59, 138.96, 138.21, 134.87, 131.33,
128.50, 127.97, 127.59, 127.41, 127.24, 122.48, 122.01, 43.15, 22.62.
MS m/z (ESI): 303.98 (M+H)+.
Synthesis of 1-[2-(methylsulfinyl)-5-oxido-10H-phenothiazin-10-yl]ethanone (4c):
In a 1 litre RB flask, 1-[2-(methylsulfanyl)-10H-phenothiazin-10-yl]ethanone (3) [25g, 0.087
mol] was charged at 20-30 °C in dichloromethane [250 mL, 10 vol]. Then, oxone [53.4g,
0.087mol, 1.0 equiv.] in water (375 mL, 15 vol) and PTC (tetrabutyl ammonium bromide)
[2.8g, 0.0087 mol, 0.1 eq.) were added. The reaction mass was stirred at 30-40 °C for 6 h.
After completion of the reaction as per TLC, cooled to 20-30 °C and the reaction mass was
quenched in sodium thiosulphate solution (12.5 g in 50 mL water, 2 vol). Layers were
separated, the organic layer was collected and the solvent was evaporated under vacuum. The
crude mass was purified over column filled with silica gel (60-120 mesh) using 20% ethyl
acetate in hexane. The solid product 4c was dried in hot air oven at 50 °C. Weight = 12 g.
1H NMR (400 MHz, DMSO-d6, δ/ppm): 8.18 (br, 1H, arom H), 8.00 (t, 1H, arom H, J = 7.2
Hz), 7.89 (t, 1H, arom H, J = 8.0 Hz), 7.85 (d, 2H, arom H, J = 8.0 Hz), 7.67 (t, 1H, arom H,
J = 7.2 Hz), 7.60 (t, 1H, arom H, J = 7.2 Hz), 2.82 (s, 3H, -SO-CH3), 2.33 (s, 3H, -COCH3).
13C NMR (100 MHz, DMSO-d6, δ/ppm): 168.48, 150.20, 142.12, 139.57, 132.11, 131.54,
129.16, 128.25, 125.03, 123.10, 123.02, 122.62, 122.56, 43.57, 23.71.
MS m/z (ESI): 320.07 (M+H)+.
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Synthesis of 1-[2-(methylsulfonyl)-5,5-dioxido-10H-phenothiazin-10-yl]ethanone (4d):
In a 1 litre RB flask, 1-[2-(methylsulfanyl)-10H-phenothiazin-10-yl]ethanone (3) [10g, 0.034
mol] was charged at 20-30 °C in acetic acid [100 mL, 10 vol]. Then, 30% solution of H2O2
[100 mL] was added slowly. The reaction mass stirred at 20-30 °C for 24h. After completion
of the reaction as per TLC, the reaction mass was filtered and washer with water (20 mL,
2V). The crude mass was purified over column filled with silica gel (60-120 mesh) using
20% ethyl acetate in dichloromethane. The solid product 4d was dried in vacuum oven at 50
°C. Weight = 2.3 g.
1H NMR (400 MHz, DMSO-d6, δ/ppm): 8.53 (s, 1H, arom H), 8.30 (d, 1H, arom H, J = 8.0
Hz), 8.16 (dd, 1H, arom H, J = 8.0 Hz and 1.6 Hz), 8.09-8.03 (m, 2H, arom H), 7.84 (t, 1H,
arom H, J = 6.8 Hz), 7.68 (t, 1H, arom H, J = 7.6 Hz), 3.35 (s, 3H, -SO2-CH3), 2.36 (s, 3H, -
COCH3).
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13C NMR (100 MHz, DMSO-d6, δ/ppm): 168.71, 144.98, 140.30, 139.57, 138.11, 134.41,
133.77, 128.62, 128.47, 127.06, 126.47, 125.21, 124.26, 43.50, 23.93.
MS m/z (ESI): 308.00 (M+H)+.
Synthesis of 2-(methylsulfonyl)-10-(prop-2-en-1-yl)-10H-phenothiazine (5a):
In a 100 mL RB flask, 1-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]ethanone (4) [5g, 0.015
mol] in acetone (50 mL, 10 vol) and powdered KOH (2.63g, 0.047 mol) were added at 20-30
°C (Note: The color of the reaction mass was changed from grey yellow to dark pink). Then,
allyl bromide [4.3g, 0.035 mol] was added slowly at 20-30 °C. The reaction mass stirred at
50-60 °C for 3h. After completion of the reaction as per TLC, the reaction mass was cooled
to 20-30 °C. The dichloromethane (100 mL, 20 vol) was added to the crude reaction mass
and stirred for 30 min. The solid was filtered and it was dried in vacuum oven at 50 °C.
1H NMR (400 MHz, CDCl3, δ/ppm): 7.41 (dd, 1H, arom H, J = 8.0 Hz and 1.6 Hz), 7.34 (d,
1H, arom H, J = 8.0 Hz), 7.27 (s, 1H, arom H), 7.20-7.16 (m, 1H, arom H), 7.12 (dd, 1H,
arom H, J = 7.6 Hz and 1.2 Hz), 6.95 (q, 2H, arom H, J = 7.6 Hz), 5.99-5.93 (m, 1H, -
CH=CH2), 5.31 (dd, 1H, J=12 Hz and J=1.2 Hz, -CH=CH2), 5.20 (dd, 1H, J=18.4 Hz and
J=1.2 Hz, -CH=CH2), 4.58 (t, 2H, -CH2-, J = 2.0 Hz), 3.18 (s, 3H, -SO2CH3).
13C NMR (100 MHz, DMSO-d6, δ/ppm): 144.38, 143.03, 139.86, 132.57, 129.08, 128.03,
127.10, 126.79, 123.28, 120.83, 120.59, 117.49, 116.07, 113.16, 50.21, 43.51.
MS m/z (ESI): 316.98 (M+H)+.
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Preparation of 2‐methanesulfonyl‐10‐[3‐(2‐methanesulfonyl‐10H‐phenothiazin‐10‐yl)
propyl]‐10H‐phenothiazine (5b): The mother liquor of 10-(3-chloropropyl)-2-
(methylsulfonyl)-10H-phenothiazine (5) was taken and concentrated. The crude mass was
purified over column filled with Silica gel using 10% ethyl acetate in hexane and the desired
impurity 5b was collected.
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1H NMR (400 MHz, CDCl3, δ/ppm): 7.27-7.24 (m, 4H, arom H), 7.50-7.00 (m, 4H, arom H),
6.96 (dd, 2H, arom H, , J = 7.6 Hz and 1.2 Hz), 6.84 (t, 2H, arom H, J = 7.6 Hz), 6.77 (d, 2H,
arom H, J = 8.0 Hz), 4.07-4.01 (m, 4H, 2 -CH2-, aliphatic), 2.95 (s, 6H, -CH3, -SO2CH3),
2.10-2.05 (m, 2H, -CH2-).
13C NMR (100 MHz, CDCl3, δ/ppm): 146.06, 143.10, 139.42, 133.47, 127.84, 127.76, 127.64,
124.43, 123.66, 121.11, 116.41, 113.88, 53.44, 44.59, 43.46, 23.30, 19.17.
MS m/z (ESI): 595.10 (M+H)+.
Synthesis
of
1-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-piperidine
carboxylic acid (1a):
In a 100 mL RB flask, Metopimazine (1) [5g, 0.011 mol], conc. HCl [12.5 mL] were stirred
at 70-80 °C for 10 h. After completion of the reaction as per TLC, cooled to 20-30 °C and
water (50 mL, 5 vol) was added. Then dichloromethane (100 mL, 20 vol) was added. The
layers were separated and the organic layer was collected and washed with water (10 mL, 2
vol). The organic layer was collected, dried over Na2SO4 and the solvent was evaporated
under vacuum. The ethyl acetate was added (15 mL, 3 vol) to the crude compound and stirred
for 1h at 20-30 °C. The solid was filtered and washed with ethyl acetate (5 mL, 1 vol). The
solid 1a was dried under vacuum at 30-35 °C for 8h.
1H NMR (400 MHz, DMSO-d6, δ/ppm): 7.49-7.43 (m, 3H, arom H), 7.28 (t, 1H, arom H, J =
7.2 Hz), 7.24-7.21 (m, 1H, arom H), 7.14 (d, 1H, J = 8.4 Hz), 7.03 (t, 1H, arom H, J = 7.6
Hz), 4.07 (t, 2H, -NCH2-, J = 6.8 Hz), 3.26 (br s, 6H, -alky H), 3.00 (br, 2H, -CH2-), 2.75 (br
s, 2H, -CH2-), 2.46 (br s, 1H, -CH-), 2.08 (br s, 2H, -CH2-), 1.92 (m, 2H, -CH2-), 1.79 (br m,
2H, -CH2-).
13C NMR (100 MHz, DMSO-d6, δ/ppm): 175.33, 145.81, 143.93, 140.71, 131.56, 128.66,
128.23, 127.96, 124.04, 123.27, 121.47, 117.11, 114.06, 55.39, 53.99, 51.50, 44.59, 43.99,
38.38, 25.94, 21.95, 21.55.
MS m/z (ESI): 447.08 (M+H)+.
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Bis-{(1-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-piperidine
carboxamide)} (1b):
In a 2 litre RB flask, mixture of 10-(3-chloropropyl)-2-(methylsulfonyl)-10H-phenothiazine
(5) [10 g, 0.0282 mol], 4-piperidinecarboxylic acid [5.47 g, 0.042 mol] and K2CO3 (9.76 g,
0.07 mol) in toluene-DMF (8:2 ratio) (1000 mL, 10 vol) were stirred at 90-100 °C for 8 h.
After completion of the reaction as per TLC, the reaction mass was cooled to 20-30 °C. Then,
toluene (100 mL, 10 vol) was added and stirred for 30 min. The reaction mass was filtered
and washed with toluene (20 mL, 2 vol). The crude material was collected and purified over
column filled with Silica gel using 5% ethyl acetate in dichloromethane.
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1H NMR (400 MHz, DMSO-d6, δ/ppm): 7.45-7.36 (m, 6H, arom H), 7.23 (t, 2H, arom H, J =
8.0 Hz), 7.17 (t, 2H, arom H, J = 6.8 Hz), 7.09 (t, 2H, J = 7.6 Hz), 6.99 (m, 2H, arom H),
4.07 (m, 4H, -NCH2), 3.98 (t, 2H, -CH3, J = 7.6 Hz), 3.21 (s, 6H, -CH2-), 2.62 (br s, 2H, -
CH2-), 2.32 (br, 2H, -CH-), 2.17 (br t, 2H, -CH2-, J = 10.8 Hz), 1.99 (br t, 2H, -CH2-, J = 6.4
Hz ), 1.88-1.75 (br m, 4H, -CH2-), 1.60 (br, 2H, -CH2-), 1.34 (q, 2H, -CH2-, J = 10.4 Hz).
13C NMR (100 MHz, DMSO-d6, δ/ppm): 174.32, 145.43, 145.28, 143.57, 143.44, 140.19,
140.12, 130.94, 130.52, 128.09, 128.05, 127.64, 127.55, 127.38, 127.29, 123.42, 123.26,
122.60, 122.22, 120.85, 120.63, 116.44 (2C), 113.35, 113.31, 61.09, 54.65, 52.36 (2C),
44.57 (2C), 43.46, 43.43, 43.14, 27.87 (2C), 25.10, 23.48.
MS m/z (ESI): 764.14 (M+H)+.
CONCLUSION
In the present work, we have demonstrated the commercially viable and practical process for
the preparation of Metopimazine (1), an antiemetic drug. Important intermediates (3, 4 and 5)
and impurities (4b-d, 5a, 5b and 1a, 1b) were well characterized by 1H, 13C NMR and Mass
spectral data. The major advantages of the present process include i) improved commercial
process with well optimized reaction conditions, ii) use of green chemicals, iii) operational
friendly process (simple, scalable and practical ) with improved yields (overall yield ≈ 31%)
compared to previously reported processes (<15%). In the present process i) two new
impurities (5b and 1b) are found and reported with characterization data; ii) the concept of
green chemistry was achieved partially with the use of green reagents like oxone and lactic
acid. In addition, the present work is highly helpful in commercialization of the
Metopimazine drug throughout the world which is now limited to France.
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AUTHOR INFORMATION
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Corresponding Author
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Dr. Pramod Kumar
Senior Vice-President
API R&D Centre
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Micro Labs Ltd.
Tel. No. 0811 0415647, Ext. No. 245
Mobile No. +91 9008448247
E-mail: pramodkumar@microlabs.in
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors are thankful to the management of Micro Labs limited for financial support for
this research work (No. MTO/2015-16). We are grateful to colleagues in the Analytical
Research Division, API R&D Centre, Micro Labs Limited, Bangalore., for their support and
special thanks to Dr. R.V. Jayanth Kasyap, Assistant Professor, Department of English, Yogi
Vemana University for English language corrections.
ASSOCIATED CONTENT
Supporting Information: Copies of relevant 1H, 13C NMR and mass spectra and also HPLC
chromatograms are available in the supporting data.
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Graphical Abstract
165x106mm (300 x 300 DPI)
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