Magic Bullet! Rebamipide, a Superior Anti-ulcer and Ophthalmic Drug and Its Large-Scale Synthesis in a Single Organic Solvent via Process Intensification Using Krapcho Decarboxylation

Article abstract of DOI:10.1021/acs.oprd.7b00382

Rebamipide (1) is a superior drug compared to existing drugs for use in healing of peptic ulcers, gastrointestinal bleeding, and dyspepsia. It is also useful as an ophthalmic drug for the treatment of dry eye syndrome. Process intensification for its synthesis was achieved by (i) averting uncontrollable frothing using Krapcho decarboxylation instead of conventional acid hydrolysis, where uncontrollable frothing became chaotic, (ii) minimizing organic waste generation by using a single organic solvent, and (iii) avoiding anti-foaming agents (n-octanol, acetophenone) and acetic acid. With these trifling modifications, the overall yield of active pharmaceutical ingredient (API) was ≥83% with excellent purity (≥99.89%), and the process meets the metrics of "green" chemistry with an E-factor = 11.5. The developed hassle-free commercial process is viable for multi-kilogram synthesis of Rebamipide (1) as the key step, Krapcho decarboxylation is safe to run at 130-140 °C in DMSO, and it was proved to be effective by differential scanning calorimetry thermal screening studies. The characterization data of intermediates, process-related impurities, and API are reported. The carryover and process-related impurities were controlled efficiently. The present work can enhance the scope and worldwide adoptability of Rebamipide (1), which is currently limited to Asian countries.

Full text of DOI:10.1021/acs.oprd.7b00382

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Full Paper
Magic Bullet! Rebamipide, a Superior Antiulcer and Ophthalmic
Drug and Its Large-Scale Synthesis in a Single Organic Solvent
via Process Intensification Using Krapcho Decarboxylation
Prashanth Kumar Babu, Mohan Reddy Bodireddy, Reshma Choudlu Puttaraju, Dnyaneshwar
Vagare, Raghu Nimmakayala, Naresh Surineni, Madhusudana Rao Gajula, and Pramod Kumar
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00382 • Publication Date (Web): 31 May 2018
Downloaded from http://pubs.acs.org on May 31, 2018
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Magic Bullet! Rebamipide, a Superior Antiulcer and Ophthalmic Drug and Its Largeꢀ
Scale Synthesis in a Single Organic Solvent via Process Intensification Using Krapcho
Decarboxylation
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Prashanth Kumar Babu, Mohan Reddy Bodireddy, Reshma Choudlu Puttaraju.,
Dnyaneshwar Vagare, Raghu Nimmakayala, Naresh Surineni, Madhusudana Rao
Gajula,* and Pramod Kumar*
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Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43ꢀ45, KIADB
Industrial Area, 4th phase, BommasandraꢀJigani Link Road, Bommasandra, Bangaloreꢀ560
105, Karnataka, India.
Eꢀmail: pramodkumar@microlabs.in
Abstract: The Rebamipide (1) is a superior drug in healing of peptic ulcers, gastrointestinal
bleeding and dyspepsia compared to existing drugs. In addition, it is also useful as
ophthalmic drug for the treatment of dry eye syndrome. The process intensification was
achieved by i) averting uncontrollable frothing using Krapcho decarboxylation instead of
conventional acid hydrolysis where uncontrollable frothing became chaotic, ii) use of single
organic solvent was minimized the organic waste generation, and iii) avoided antifoaming
agents (nꢀoctonol, acetophenone) and acetic acid. With these trifling modifications the overall
yield of API was ≥83% with excellent purity of API (≥99.89%) and the process meets the
metrics to “green” chemistry with EꢀFactor =11.5. The developed hassle free commercial
process is viable for multiꢀkilogram synthesis of Rebamipide (1) as the key step, Krapcho
decarboxylation is safe to run at 130ꢀ140 °C in DMSO and it was proved by DSC
(differential scan calorimetry) thermal screening studies. The characterization data of
intermediates 4, 5, 6 and 7, process related impurities (1a, 1b 1c, 8a and 8b) and API (1) is
reported. The carryover and process related impurities were controlled efficiently. The
present work can enhance the scope and world wide adoptability of Rebamipide (1) which is
now limited to Asian countries.
Key words: Rebamipide, Process intensification, Frothing free, Ulcer healing, ophthalmic,
Eꢀfactor
INTRODUCTION
The peptic ulcer disease1 is a disorder of the upper gastrointestinal tract caused by various
noxious agents,2 for example hypoacidity,3 Helicobacter pylori4 and use of certain drugs
(captopril, gold salts, nicorandil, phenobarbitol, piroxicam), especially NSAIDS, such as
ibuprofen and aspirin,5 or other things that cause breaks in mucosa. The development of
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ulcers can lead to serious complications such as bleeding, perforation, abdominal pain,
burning sensation, vomiting, and a lifeꢀthreatening condition that require emergency surgery.6
Hence, there is a great demand for new drugs which prevent the formation of ulcers as the
existing drugs are only inhibitors of gastric acid secretion and none of the available
medications prevent the formation of peptic ulcer. The unresolved problem was solved with
the invention of a magic bullet in 1980.7 The magic bullet was named as Rebamipide which
is superior drug to treat gastric ulcers, acute gastritis, exacerbated chronic gastritis, whereas
other existing drugs are futile, for example Cetraxate.8 It was also found that it can also be
used as ophthalmic drug for the treatment of dry eye syndrome.9 Rebamipide is chemically
called as (±)–2–(4–Chlorobenzoylamino)–3–[2(1H)–quinolinon–4–yl] propionic acid. The
precise mode of action of Rebamipide is unknown.10ꢀ17
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Process intensification can be understood as a portfolio for the development of new process
approaches resulting in “substantially smaller, cleaner, safer and more efficient process
methods.”11, Unfortunately, the reported methods for the production of Rebamipide (1) suffer
from one or more disadvantages,14–16 for example, expensive starting material and reagent,
sudden bumping of reaction mass, fast refluxing conditions, requisite quick removal of byꢀ
products (ethanol, ethyl acetate and CO2), increased utility cost and removal of traces
amounts of some catalysts/reagents in API is difficult to meet the ICH guidelines, and huge
organic waste generation. The extensive literature search revealed that uncontrollable
frothing is chaotic during the synthesis of Rebamipide (1).12, 13 The uncontrollable frothing or
foaming or agglomerate or bubbles is one of the most problematic conditions not only in
pharmaceutical industry, for example in production of Rebamipide,14 but also in most of the
other industries.21 The major disadvantages include i) requirement of 10 times big reactor
than usual with regard to batch size, ii) inefficiency of process involving expensive costs ,
iii) runꢀoff of the reaction mass along with froth; iv) operational unfavourable and chaotic, v)
reduction in product yield, and vi) sudden bumping of the reaction mass. The situation
become worse when the reaction mass is handled at higher temperature. Hence, there is a
great demand for the innovative process that is free from such uncontrollable frothing or
bubbles in the production of Rebamipide drug. The messy problems were addressed in the
present work by the application of Krapcho decarboxylation.17
The one–pot operation was reported first by Robinson nearly 100 years ago.18 It has received
great attention as it can minimize the number of reaction steps, cost, development time,
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execution time, and environmental impact of synthesis.19 In continuation of our interest in
developing one–pot reactions20 to meet the metrics to green chemistry, herein, we report a
new synthetic method for the production of Rebamipide (1) starting from the reaction of 4–
(bromomethyl)quinolin–2(1H)–one (2) with diethyl–(acetylamino) propanedioate (3) in
presence of aqueous NaOH solution offered diethyl (acetylamino)[(2–oxo–1,2–
dihydroquinolin–4–yl)methyl]propanedioate (4) followed by decarboxylation using Krapcho
conditions [DMSO–H2O–NaBr (in situ)] provided mixture of ethyl 2–(acetylamino) –3–(2–
oxo–1,2–dihydroquinolin–4–yl)propanoate (5) as major and 2–(acetylamino)–3–(2–oxo–1,2–
dihydroquinolin–4–yl)propanoic acid (6) as minor in DMSO as single organic solvent. The
acid hydrolysis of compounds 5 and 6 offered compound 7 which further reacts with 4ꢀ
chlorobenzoyl chloride (8) to produce Rebamipide (1) as shown in scheme 1.
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O
HN
O
O
O
O
O
i.
HO
O
O
Krapcho
decarboxylation
DMSOꢀH2Oꢀ
O
Br
O
O
O
NH
NH
NH
O
O
O
3
NaBr (in situ
)
+
DMSO
N
H
O
ii. Aq. NaOH
iii. Filtration and
water wash
N
H
O
O
N
H
4
N
H
O
5
2
6
iv. Collect solid
i. Dil. HCl
ii. Filtration
iii. Collect solid
O
HO
O
O
HO
N
H
NH2
i. 25% Aq. NaOH
ii. 4ꢀchlorobenzoyl
Cl
chloride (8) in acetone
.2H2O.2HCl
O
N
H
O
iii. Acidify using dil. HCl
iv. Filtration
v. Purification in
N
H
1
7
DMSOꢀH2OꢀMeOH
Scheme 1: Synthesis of Rebamipide (1)
RESULTS AND DISCUSSION
In the initial stage of development, the synthesis of Rebamipide was carried out by aiming to
develop frothing free costꢀeffective process as the reported literature methods suffer from few
disadvantages at bulk scale as discussed in above sections. As a result, it is planned to focus
on Krapcho decarboxylation17 to avert conventional acid hydrolysis of compound 4 where
uncontrollable frothing is hectic.14 Accordingly, the Krapcho decarboxylation was preceded
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well without any frothing in presence of DMSO–H2O–NaBr (in situ). Secondly, we focused
on optimization of unit operations, such as work–up(s), distillation(s), and filtration(s). For
instance, we have avoided the isolation and workꢀup operations by the development of one–
pot operation. Thirdly, we focused on impurity profile, for example source of carryover,
process related impurities and development of control strategies for those impurities. The
intermediates (4, 5, 6 and 7) and API (1) are soluble in DMSO, DMF and DMAc and they
have poor solubility in other common organic solvents. This directs that the purification
process could only be developed within certain confines to meet the specification criteria of
API. Accordingly, DMSO–H2O–MeOH solvent system was developed to remove the
potential impurities. The desired quality and nature of API was achieved.
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The hassle free and improved commercial process was designed and developed by aiming to
achieve improved yields with desired quality (≥99.89%) of Rebamipide (1) drug as shown in
Scheme 1. In each and every step, the reaction conditions were optimized well as discussed in
below sections.
Ideal process conditions for the synthesis of diethyl(acetylamino)[(2–oxo–1,2–
dihydroquinolin–4–yl)methyl]propanedioate (4): Initially, a reaction was carried out using
4ꢀ(bromomethyl)quinolin–2(1H)–one (2) with diethyl–(acetylamino)propanedioate (3) in
presence of NaOH in DMF (as the compound 2 is soluble only in DMF, DMSO and DMAc)
at 0–10 °C and the formation of compound 4 was 97% where as at 20–30 °C, slight low
formation (94%) was observed (entry 1, Table 1). Most of the literature methods reported use
of NaOH in DMF (anhydrous conditions).21 If the same was followed at production scale,
some amount of NaOH was settled down at the bottom of the reactor which leads to
inconsistent results and also choking at the bottom valve of the reactor. To overcome the
problem, the same reaction was carried out by dissolving NaOH in water (used 0.5 vol of
water with respect to batch size) and obtained similar results (98%) (entry 1). The success of
aqueous NaOH solution encouraged us to replace DMF with DMSO. The same reaction was
carried out using DMSO at 20–30 °C and 98% formation of product 4 in presence of aqueous
NaOH solution (entry 2) was observed. When the same reaction was carried out in DMAc,
the formation was decreased (75% at 0–10 °C and 52% at 20–30 °C) (entry 3).
Further, the effect of various bases, for example KOH, Na2CO3, K2CO3 (aqueous solution)
and Et3N and piperidine was studied and obtained 78%, 11%, 19%, 22% and 20% formation
of compound 4, respectively (entries 4–8, Table 1).
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The study disclosed that both DMF at 0–10 °C (entry 1, Table 1) and DMSO at 20–30 °C
(entry 2 and Figure S6 in the Supporting Information) are the best solvents for maximum
formation of compound 4 (~95%) in presence of aqueous NaOH solution. We have selected
DMSO as preferable solvent for further studies of Krapcho reaction telescopically as the
reaction proceeds well in DMSO.
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Table 1: Effect of reaction conditions on formation of compound 4a
S. No.
Base
Solvent Time Tempˈ Product
Product
(% by HPLC)
(°C)
(h)
1
NaOH
DMF
3
0–10
97
94
98c
98
4
2
20–30
Aq. NaOH
3
3
0–10
20–30
2
3
Aq. NaOH DMSOb
4
4
Aq. NaOH DMAc
1
0–10
20–30
20–30
20–30
20–30
20–30
20–30
75
52
78
11
19
22
20
4
5
Aq. KOH
DMSO
1
6
5
4
4
4
4
4
4
4
Aq. Na2CO3 DMSO
Aq. K2CO3 DMSO
6
7c
8c
Et3N
DMSO
Piperidine
DMSO
aReaction conditions: Substrate 2 (10.0 mmol), compound 3 (11.0 mmol), Base (10.0
mmol), organic solvent (3.0 vol) and water (0.5 vol).
bReaction conducted at 20ꢀ30 °C as DMSO freezing point is 19 °C.
cWater was not used.
New process conditions for the synthesis of ethyl 2–(acetylamino)–3–(2–oxo–1,2–
dihydroquinolin–4–yl)propanoate
(5)
and
2–(acetylamino)–3–(2–oxo–1,2–
dihydroquinolin–4–yl) propanoic acid (6): Initially, we attempted the conventional
decarboxylation of compound 4 to prepare compound 7 directly using conc. HCl, an
uncontrollable frothing was observed with 98% of product (7) formation (entry 1, Table 2).14
The major problems faced during acid hydrolysis at production level include i) 10 times big
reactor required than usual with respect to batch size, ii) run–off of the reaction mass along
with foam, and iii) sudden bumping of the reaction mass cause operational unfavourable and
chaotic. The situation became awful when the same reaction was carried out at higher
temperature (>97 °C is compulsory).
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Then, we conducted the same reaction using antifoaming agents (nꢀoctonol, acetophenone
and acetic acid) and the conversion is ≥94% (entries 2–4). The major issues associated with
this method include sudden bumping of the reaction mass, unpredictable time line for the
completion of the reaction, vigorous reflux conditions and removal of by–products of the
reaction, and operational hazard at high temperature, organic waste generation, and their
carryover up to API.
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To get rid from these hassles, our attention turned towards Krapcho decarboxylation which
was well documented in literature.17 The Krapcho method is excellent when NaCN and KCN
were used, but we have avoided them because of their heavy toxicity. Initially, a reaction was
carried out using DMSO–H2O–NaCl at 130–140 °C and the conversion was 97% (64% of
compound 5 and 33% of compound 6) (entry 6). The same reaction was carried out using
NaBr instead of NaCl and the conversion was 96% (62% of compound 5 and 34% of
compound 6) (entry 7). The success of Krapcho reaction in DMSO–H2O–NaBr system (entry
7) encouraged us to conduct the same experiment without addition of external NaBr as it was
generated in situ during the conversion of compound 2 to compound 4 (scheme 1) and the
formation of compound was good 95% (62% of compound 5 and 33% of compound 6 within
7 h (entry 8). It was observed that the unreacted substrate (4) (~2%) was converted to desired
compound 7 during acid hydrolysis in the next stage.
The study disclosed that Krapcho reaction [DMSO–H2O–NaBr (in situ)] at 130–140 °C is
good for maximum conversion (96%) and safe operation without frothing (entry 8, Table 2
and Figure S17 in the Supporting Information)
Table 2: Effect of reaction conditions on decarboxylation of compound 4.a
Entry
Conditions
Time Tempˈ Product Selectivity
Remarks
(h)
(°C)
(% by HPLC)
5:6:7
1b
dil. HCl
11
>97
00:0.3:98 a. Uncontrollable
frothing
7
7
b. Sudden bumping
c. runꢀoff
of
the
reaction mass along
with foam
2c
dil. HCl and nꢀ 10–14
octonol
>97
00:02:96 a. Sudden bumping
b. Vigorous
conditions
reflux
c. Required
quick
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3c
dil. HCl and 10–14 >97
acetophenone
00:03:94
00:0.1:98
removal
products
azeotropically
d. Carryover
antifoaming agents
up to API
e. More organic waste
(in case of acetic
acid)
of
byꢀ
of
7
7
4c, d dil. HCl and 10–14 >99
acetic acid
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f. Unpredictable
timeline
5
6e
DMSO–H2O
24 130–140
–
–
No reaction
DMSO–H2Oꢀ
NaCl
10 130–140 5 & 6
64:33:00 a. Free from frothing
helped to escape
7e
8f
DMSO–H2O–
NaBr
8
7
130–140 5 & 6
130–140 5 & 6
62:34:00
from frothing related
troubles
b. Conversion
good
was
DMSO–H2O–
NaBr (in situ)
62:33:00
aReaction conditions:
bConventional process (15.0 vol of 20% HCl)
cAntifoaming agents are used (10.0 vol of 20% HCl and 0.5 vol of antifoaming agent)
dAcetic acid (10.0 vol of 20% HCl and 3.0 vol of acetic acid)
eKrapcho process was applied [DMSO (3.0 vol)–H2O (0.5 vol)–NaCl (1.0 equiv)]
fKrapcho process was applied, one–pot operation
Evaluation of Process safety by Thermal Screening with DSC: The decomposition of
DMSO at lower temperatures (<189 °C) is a common problem under reaction conditions
compared to the boiling point temperature of DMSO alone. But, sometimes it cause serious
explosion in chemical and pharmaceutical industry.22 Hence, the reactions in DMSO need to
carryout thermal screening using DSC and ARC etc. as a process safety issue. To ensure the
safety of present developed process, we have planned to explore the decomposition of
reactants/products in the present reaction conditions at 130ꢀ140 °C using DSC (differential
scan calorimetry). It was found that there was no decomposition of either DMSO or
reactants/products at this temperature (Figure 1). The exothermic onset decomposition at
186°C with heat evolution of 250 J/g of sample is due to decomposition of DMSO. The same
trend was observed and found on bulkꢀscale synthesis.
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Figure 1: Differential scan calorimetry (DSC) chart of Krapcho decarboxylation (4.5 mg
reaction mixture)
Optimum process conditions for the synthesis of 2ꢀaminoꢀ3ꢀ(2ꢀoxoꢀ1,2ꢀdihydroquinolinꢀ
4ꢀyl)propanoic acid dihydrochloride dihydrate (7): The conventional ester hydrolysis and
deprotection of compound(s) 5 and 6 was carried out at 80–90 °C14 and obtained 95% of
compound 7 (Figure S27 in the Supporting Information).
Optimum process conditions for the synthesis of Rebamipide (1): The synthesis of
Rebamipide (1) from compound 7 was carried out as per literature process.12, 14 Accordingly,
a reaction was carried out by dissolving compound 7 in 25% aqueous NaOH solution
followed by addition of 4–chlorobenzoyl chloride (8) and desired compound 1 was formed
about 98% (Figure S35 in the Supporting Information).
The HPLC purity of crude Rebamipide (1) did not fulfil the specifications stipulated for the
API (Figure S36 in the Supporting Information). Hence, it was planned to develop efficient
purification method to remove the impurities and to increase the purity of API (1).
Accordingly, the crude compound 1 was dissolved in DMSO, DMF and DMAc at 60–70 °C
and cooled the reaction mass up to room temperature followed by addition of water. The
compound 1 was precipitated during addition of water. The major problems associated with
this purification method include i) sticky nature of compound 1 and ii) very slow filtration
(entries 1–3, Table 3). To overcome these problems at production scale, we have developed a
new solvent system, mixture of DMSO–water–MeOH. The fast filtration and free flow solid
nature was observed by the purification of this new solvent system.
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The study disclosed that purification in a mixture of DMSO–water–MeOH (1:3:0.1 ratio)
provided excellent purity (99.89%) with excellent yield (95%) (entry 4 and Figure S37 in the
Supporting Information).
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Table 3: Selection of suitable solvent system for the purification of Rebamipide (1).
Timee
Yieldf
(%)
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Entry
Solvent
system
Product
Purity
(% by HPLC)
(h)
1
7
1c
8a
8b
ꢀ
Total
unknown
0.13
1a, c
2a, c
3a, c
4b, d
DMSO–H2O
(1:3 ratio)
DMF–H2O
(1:3 ratio)
DMAc–H2O
(1:3 ratio)
DMSO–H2O– 0.5
MeOH
2.5
2
94
93
88
95
99.84
ꢀ
ꢀ
0.03
0.06
0.03
1
1
1
1
99.82 0.01
99.80 0.03
ꢀ
ꢀ
0.11
0.14
0.04
2
ꢀ
ꢀ
99.89
ꢀ
0.02 0.03 0.02
(1:3:0.1ratio)
Reaction conditions:
aCompound 1 (10.0 mmol) in solvent (3.0 vol) at 60–70 °C for 1 h, cooling to 20–30 °C,
water (6.0 vol) was added, stirred for 1 h, and filtration of the solid.
bCompound 1 (10.0 mmol) in DMSO (3.0 vol) at 60–70 °C, clear solution, cooling to
20ꢀ30 °C, added to mixture of waterꢀmethanol (9.0 vol of water and 0.3 vol methanol),
stirring for 1 h, and filtration of the solid.
cVery slow filtration, sticky nature and wet weight 3 times with regard to input batch size.
dFast filtration and the wet weight 1.5 times with regard to input batch size.
eTime duration for filtration
fIsolated yields
Formation of probable impurities: The formation of impurities was observed during the
preparation of Rebamipide (1) from compound 7. The impurities 1a and 1b were formed
when 4–chlorobenzoyl chloride (8) contains trace amounts of either 2–chloro or 3–
chlorobenzoyl chloride otherwise they are not formed in final API (entries 1–3, Table 3).
COCl
H
O
O
O
O
O
HO
O
O
Cl
N
H
COOMe
COOH
N
H
Cl
NH2
Cl
8
.2H2O.2HCl
+
N
H
O
+
+
25% aq. NaOH
solution
N
H
O
N
H
O
Cl
Cl
1c
8b
8a
1 = 4ꢀCl
1a = 2ꢀCl
1b = 3ꢀCl
7
Scheme 2: Formation of probable impurities during the preparation of Rebamipide (1).
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The formation of impurities 1c, 8a and 8b was observed in final API (entries 1–3). The
process related impurities 1c, 8a and 8b were removed efficiently during purification in a
mixture of DMSO–water–MeOH (1:3:0.1 ratio) system.
8
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EXPERIMENTAL SECTION
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The solvents and reagents were obtained from commercial sources and were used without
any purification. Nuclear magnetic resonance (NMR) spectra of the synthesized compounds
were recorded on Ascend Bruker 400(Bruker, Fallanden, Switzerland) instrument and
1
operating at 400 MHz for H NMR and 100 MHz for 13C NMR using either CDCl3 or
DMSOꢀd6 solvent and tetramethylsilane (TMS) as internal standard. Spin multiplicities are
given as s (singlet), d (doublet), dd (doublet of doublet), qd (quartet of doublet), t (triplet),
1
and m (multiplet) as well as brs (broad singlet). The H chemical shift values were reported
13
on δ scale in ppm, relative to TMS (δ = 0.00 ppm) and in the C chemical shift values were
reported relative to DMSOꢀd6 (δ = 39.5 ppm). The ESI/MS experiments were performed on a
Velos Pro Ion Trap mass spectrometer from Thermo Scientific (San Jose, CA, U.S.A.). The
DSC study was performed in a Gold plated high pressure crucible at heating rate of 4 °C per
minute on a METTLER TOLEDO (Greifensee, Switzerland).
Synthesis
yl)propanoic acid (1): In a 50 L reactor, diethylꢀ(acetylamino)propanedioate (3) (5.0 kg,
23.0 mol) in DMSO (15 L) and 4–(bromomethyl)quinolin–2(1 )–one (2) (5.0 kg, 21.0 mol)
of
2–[(4–chlorobenzoyl)amino]–3–(2–oxo–1,2–dihydroquinolin–4–
H
were charged sequentially. The sodium hydroxide solution (0.84 Kg, 21.0 mol, dissolved in
2.5 L water) was added drop wise into the reaction mass at 20–30 °C and maintained for 2 h.
After completion of the reaction as per reaction monitoring by HPLC, the temperature of the
reaction mass was increased to 130–140 °C and maintained at the same temperature for 7 h.
After completion of the reaction as per reaction monitoring by HPLC, the reaction mass was
cooled to below 60 °C and slowly added water (12.5 L) followed by Conc. HCl (12.5 L).
Again, the temperature of the reaction mass was raised to 80–90 °C and stirred for 2h. After
completion of the reaction as per reaction monitoring by HPLC, the reaction mass was cooled
to 20ꢀ30 °C and stirred for 1h at 20–30 °C. The solid was filtered, washed with cold 1N HCl
(2.5 L) followed by water (1 L) and suck dried the material for 1h. The aqueous NaOH
solution (2.94 kg of NaOH, 73.5 mol, dissolved in 25 L water) was taken in reactor and the
wet material (7) was charged at 20–30 °C. The reaction mass was cooled to 5–10 °C and 4ꢀ
chlorobenzoylchloride (8) (4.4 Kg, 25.2 mol) was added slowly into the reaction mass at 0–
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10 °C and maintained at the same temperature for 30 minutes at 0ꢀ10 °C. After completion of
reaction as per reaction monitoring by HPLC, the pH of the reaction mass was adjusted to pH
1.0–3.0 using HCl solution (~2.5 L) at 20–30 °C and maintained at the same temperature for
30 minutes. The reaction mass was filtered and washed with water (2.5 L). The obtained solid
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product 1 was dried under vacuum at 60−65 °C and obtained 6.85 kg (88% of yield) of
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compound 1 with HPLC purity of 99.31% (before purification).
Purification of compound 1: In a 50 L reactor, crude compound 1 (6.0 kg) was dissolved in
DMSO (18 L) at 60–70 °C and stirred for 30 min at the same temperature. Then, the reaction
mass was cooled up to 20–30 °C, filtered through sparkler and it was added slowly in to the
mixture of water (54 L) and methanol (1.8 L) in 100 L reactor. The reaction mass was stirred
for 1 h at 20–30 °C, filtered and washed with water (3 L) and obtained 5.7 kg (95%) of pure
Rebamipide (1) after drying with an HPLC purity of 99.89%. The overall yield is 83.6%
(after purification).
CHARACTERIZATION DATA
Diethyl– (acetylamino)[(2–oxo–1,2–dihydroquinolin–4–yl)methyl] propanedioate (4) :
(Figures S1ꢀS6). 1H NMR (400 MHz, DMSOꢀd6, δ/ppm): 11.76 (s, 1H, arom –NH–); 8.33 (s,
1H, aliphatic –NH); 7. 47–7.52 (m, 1H, arom H), 7.30 (d, 1H,
1H, = 7.6 Hz, arom H); 6.13 (s, 1H, arom H), 4.17–4.09 (m, 4H, 2 –CH2–); 3.67 (s, 2H, –
CH2–), 1.8 (s, 3H, –CH3), 1.16 (t, 6H,
= 7.2 Hz, 2 –CH3).; 13C NMR (100 MHz, DMSOꢀd6,
J = 8.0 Hz, arom H), 7.16 (t,
J
J
δ/ppm): 170.03, 166.81 (2C), 160.99, 145.64, 138.81, 130.40, 124.09, 123.04, 121.44,
119.42, 115.67, 66.56, 62.02 (2C), 32.88, 22.05, 13.72 (2C).; MS m/z (ESI): 375.12 (M+H) +.;
HPLC purity: 98.34%
Ethyl 2–(acetylamino)–3–(2–oxo–1,2–dihydroquinolin–4–yl)propanoate (5): (Figures S7ꢀ
1
S11). H NMR (400 MHz, DMSOꢀd6, δ/ppm): 11.71 (s, 1H, arom –NH–); 8.47 (d, 1H,
J =
8.0 Hz, arom H); 7.76 (d, 1H,
1H, = 8.0 Hz, arom H), 7.23 (t, 1H,
(d, 1H, = 4.8 Hz, –CH–), 4. 05ꢀ4.10 (m, 2H, –CH2–), 3.27 (dd, 1H,
Hz, –CH– geminal), 3.06 (dd, 1H, = 14.0 Hz and = 9.2 Hz, –CH– geminal), 3.01 (s, 3H, –
J
= 8.4 Hz, arom H); 7.51 (t, 1H,
= 7.6 Hz, arom H), 6.38 (s, 1H, aliphatic –NH–), 4.54
= 14.0 Hz and = 5.6
J = 7.6 Hz, arom H); 7.33 (d,
J
J
J
J
J
J
J
CH3), 1.14 (t, 3H,
J
= 6.8 Hz, –CH3).; 13C NMR (100 MHz, DMSOꢀd6, δ/ppm): 171.26,
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169.53, 161.31, 146.72, 138.94, 130.37, 124.00, 121.91, 121.89, 118.47, 115.83, 60.79,
4
5
51.56, 33.30, 22.23, 13.94.; MS m/z (ESI): 303.15 (M+H) +.
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7
8
9
2–(acetylamino)–3–(2–oxo–1,2–dihydroquinolin–4–yl)propanoic acid (6): (Figures S12ꢀ
1
S17). H NMR (400 MHz, D2O, δ/ppm): 7.74 (d, 1H,
J
= 8.0 Hz, arom H), 7.47 (t, 1H,
=9.2 Hz,
= 3.6 Hz, –CH–), 2.87 (dd, 1H, =13.2
= 10.0 Hz, –CH–), 1.74 (s, 3H, –CH3).; 13C NMR (100 MHz, DMSOꢀd6, δ/ppm):
J =
6.8 Hz, arom H), 7.17–7.27 (m, 2H, arom H), 6.31 (s, 1H, arom H), 4.42 (dd, 1H,
J
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11
12
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J
= 4.0 Hz, –CH–), 3.38 (dd, 1H,
J
=13.6 Hz and
J
J
Hz,
J
174.61, 169.07, 162.19, 149.67, 139.27, 130.24, 125.11, 121.94, 121.67, 119.89, 116.06,
54.60, 35.98, 23.26, 22.70.; MS m/z (ESI): 275.19 (M+H) +.
2ꢀaminoꢀ3ꢀ(2ꢀoxoꢀ1,2ꢀdihydroquinolinꢀ4ꢀyl)propanoic acid dihydrochloride dehydrate
1
(7): (Figures S18ꢀS27). H NMR (400 MHz, D2O, δ/ppm): 7.90 (d, 1H,
J
= 8.0 Hz, arom H),
7.60 (t, 1H,
J
= 7.6 Hz, arom H), 7.49 (d, 1H,
J
= 8.0 Hz, arom H), 7.31 (t, 1H, J= 7.6 Hz,
1
arom H), 4.20 (t, 1H, aliphatic –CH–), 3.39ꢀ3.50 (m, 2H, aliphatic –CH2–).; H NMR (400
+
MHz, DMSOꢀd6, δ/ppm): 12.06 (br s, 1H, –COOH), 8.83 (br, 3H, –NH3 Clꢀ), 7.93 (d, 1H,
J
=
8.0 Hz, arom H), 6.66–7.79 (m, 8H= 3H of arom H+5H of 2H2O and HCl), 6.59 (s, 1H, arom
H), 4.13 (d, 1H, = 5.6 Hz, –CH–), 3.48–3.53 (m, 1H, –CH(H)– geminal), 3.36ꢀ3.41 (m, 1H,
J
–CH(H)–, geminal).; 13C NMR (100 MHz, DMSOꢀd6, δ/ppm): 169.98, 161.33, 144.84,
139.16, 130.54, 124.27, 123.22, 122.03, 118.43, 115.96, 51.54, 32.51.; MS m/z (ESI): 233.05
(M+H) +.; HPLC purity:
1
Rebamipide (1): (Figures S28ꢀS35). H NMR (400 MHz, DMSOꢀd6, δ/ppm): 13.10 (br, 1H,
–COOH), 11.66 (s, 1H, arom –NH–), 8.92 (d, 1H,
J
= 8.0 Hz, aliphatic –NH–), 7.82–7.85 (m,
= 8.4 Hz, arom H), 7.24 (t, 1H, J=
3H, arom H), 7.49–7.56 (m, 3H, arom H) 7.32 (d, 1H,
J
7.6 Hz, arom H), 6.45 (s, 1H, arom H), 4.71–4.77 (m, 1H, aliphatic –CH–), 3.47–3.52 (m,
1H,–CH(H)–, geminal), 3.20–3.26 (m, 1H, –CH(H)– geminal).; 13C NMR (100 MHz,
DMSOꢀd6, δ/ppm): 172.90, 166.08, 161.94, 148.14, 138.98, 136.92, 132.64, 130.90, 129.61
(2C), 128.88 (2C), 124.40, 122.62, 121.86, 118.96, 116.33, 52.27, 33.23.; MS m/z (ESI):
371.15 (M+H) +.
2–(2–chlorobenzamido)–3–(2–oxo–1,2–dihydroquinolin–4–yl)propanoic
(Figures S38ꢀS42). 1H NMR (400 MHz, DMSOꢀd6, δ/ppm): 11.68 (s, 1H, arom –NH–), 8.88
(d, 1H, = 8.4 Hz, arom H), 7.83 (d, 1H, = 8.0 Hz, aliphatic –NH–), 7.18–7.54 (m, 7H,
acid
(1a):
J
J
arom H), 6.49 (s, 1H, arom H), 4.68–4.74 (m, 1H, aliphatic –CH–), 3.46–3.51 (m, 2H, –CH2–
, geminal), 3.07–3.13 (m, 1H, –CH–, geminal).; 13C NMR (100 MHz, DMSOꢀd6, δ/ppm):
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172.87, 166.75, 161.82, 147.37, 139.47, 136.7, 131.43, 130.72, 130.43, 130.14, 129.27 (2C),
127.45 (2C), 124.47, 122.61, 122.37, 119.02, 116.29, 52.04, 33.53.; MS m/z (ESI): 371.14
(M+H) +.
2–(3–chlorobenzamido)–3–(2–oxo–1, 2–dihydroquinolin–4–yl)propanoic acid (1b):
1
9
(Figures S38ꢀS47). H NMR (400 MHz, DMSOꢀd6, δ/ppm): (Figures S43ꢀS47). 13.12 (s, 1H,
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–COOH), 11.70 (s, 1H, arom –NH–), 9.02 (d, 1H,
(m, 1H, arom H), 7.79 (d, = 8.0 Hz, arom H), 7.62 (dq, 1H,
H), 7.51 (t, 1H, = 7.6 Hz, arom H), 7.34 (d, 1H, = 8.0 Hz, arom H), 7.23ꢀ7.27 (m, 1H,
J
= 8.0 Hz, aliphatic –NH–), 7.84–7.86
J
J
= 8.0 Hz and = 2.0 Hz, arom
J
J
J
arom H), 6.47 (s, 1H, arom H), 4.73–4.79 (m, 1H, aliphatic –CH–), 3.48–3.53 (m, 1H, –CH–,
13
geminal), 3.27 (dd, 1H,
J
= 14.4 Hz and
J
= 10.8, –CH–, geminal).; C NMR (100 MHz,
DMSOꢀd6, δ/ppm): 172.54, 165.04, 161.34, 147.36, 138.96, 135.60, 133.21, 131.41, 130.42,
130.33, 127.09, 126.14, 124.03, 121.93, 121.68, 118.54, 115.87, 51.96, 32.79.; MS m/z (ESI):
371.07 (M+H) +.
Methyl–2–(4–chlorobenzamido)–3–(2ꢀoxo–1, 2–dihydroquinolin–4–yl)propanoate (1c):
(Figures S48ꢀS52). 1H NMR (400 MHz, DMSOꢀd6, δ/ppm): 11.70 (br, 1H, –COOH), 9.08 (d,
1H,
J
=8.0 Hz, arom –NH–), 7.81–7.84 (m, 3H, arom H), 7.49–7.57 (m, 3H, arom H), 7.33
= 8.4 Hz, arom H), 7.21–7.26 (m, 1H, arom H), 6.45 (s, 1H, arom H), 4.78–4.83(m,
(d, 1H,
J
1H, aliphatic –CH–), 3.69 (s, 3H,–CH3), 3.46ꢀ3.51 (m, 1H, –CH(H)–, geminal), 3.25–3.32
(m, 1H, –CH(H)–, geminal).; 13C NMR (100 MHz, DMSOꢀd6, δ/ppm): 171.58, 165.44,
161.27, 147.12, 138.92, 136.51, 132.1, 130.39, 129.30 (2C), 128.49 (2C), 124.01, 121.97,
121.71, 118.52, 115.92, 52.30, 51.96, 32.54.; MS m/z (ESI): 385.11 (M+H) +.
CONCLUSION
In the present work, we have developed bulk scale synthesis of Rebamipide (1) using
Krapcho method using DMSO–H2O–NaBr (in situ) system at 130–140 °C to arrest the
chaotic uncontrollable frothing. Several process issues were addressed effectively and
efficiently to achieve the goal of development of multikilogram–scale process for production
of Rebamipide (1). New intermediates (5 and 6) were isolated and characterized for the first
time. The major advantages of the present developed commercial process include i)
excluding the use of antifoaming agents as well as conventional process for decarboxylation.
In addition, it was found that Krapcho reaction was useful to arrest the uncontrollable
frothing, ii) avoided step–by–step process to save process time cycle, drying and analysis,
utility cost and averting the loss of compound during isolation of intermediates and
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purification, iii) purification of API in DMSO–H2Oꢀmethanol solvent system was utilized to
remove the impurities and to achieve desired quality (≥99.89%) and nature, and iv) E–Factor
of the developed process is 11.5 (excluded water) which meets the metrics to “green”
chemistry. We are hopeful that the use of Krapcho reaction conditions in the present work
may be helpful in the development of efficient processes for other drugs also as it is safe to
run at 130ꢀ140 °C (confirmed by DSC thermal screening studies). Our mission and vision is
that the present work can help in adoption and use of Rebamipide (1) as safe antiulcer and
ophthalmic drug worldwide which is now limited to Asian countries.
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ASSOCIATED CONTENT
1
Copies of relevant H, 13C NMR, and mass spectra, powder XRD data, and HPLC
chromatograms can be found in supporting information.
ACKNOWLEDGMENTS
The authors are thankful to the management of Micro Labs Limited for financial support of
this research work (REB/2016–17). We are grateful to colleagues in the Analytical Research
Division, API R&D Centre, Micro Labs Limited, Bangalore. Our special thanks are extended
to Dr. R. V. Jayanth Kasyap and Ridhima Kochar for their support.
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