Old is Gold? Nefopam Hydrochloride, a Non-opioid and Non-steroidal Analgesic Drug and Its Practical One-Pot Synthesis in a Single Solvent for Large-Scale Production

Article abstract of DOI:10.1021/acs.oprd.7b00228

Nefopam hydrochloride is extensively used in most of the European countries until today as an analgesic because of its non-opiate (non-narcotic) and non-steroidal action with fewer side effects compared with opioid and other analgesics, which cause more troublesome side effects. A multikilogram synthesis of nefopam hydrochloride has been achieved in one pot using a single solvent (toluene). A ≥99.9% purity of the active pharmaceutical ingredient (API) was achieved in excellent overall yield (≥79%). The one-pot, five-step synthetic process involves formation of an acid chloride (3) from benzoylbenzoic acid (2) followed by amidation (4), reduction (5), cyclization (6), and formation of the hydrochloride salt (1). The major advantages include (i) use of a single solvent, (ii) >90% conversion in each step, (iii) a cost-effective and operationally friendly process, (iv) averting the formation of genotoxic impurities, and (v) improved overall yield (≥79%) provided by the one-pot operation. For the first time, we report the characterization data of API 1, intermediates 3, 4, and 5, and also a possible impurity (5a).

Full text of DOI:10.1021/acs.oprd.7b00228

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Full Paper
Old is Gold? Nefopam Hydrochloride, a Non-opioid and
Non-steroidal Analgesic Drug and its Practical One-pot
Synthesis in a Single Solvent for Large-Scale Production
Mohan Reddy Bodireddy, Kiran Krishnaiah, Prashanth Kumar Babu,
Chaithanya Bitra, Madhusudana Rao Gajula, and Pramod Kumar
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00228 • Publication Date (Web): 19 Oct 2017
Downloaded from http://pubs.acs.org on October 20, 2017
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Old is Gold? Nefopam Hydrochloride, a Non-opioid and Non-steroidal Analgesic Drug
and its Practical One-pot Synthesis in a Single Solvent for Large-Scale Production
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Mohan Reddy Bodireddy, Kiran Krishnaiah, Prashanth Kumar Babu, Chaithanya
Bitra, Madhusudana Rao Gajula,* and Pramod Kumar *
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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.
Abstract: Nefopam hydrochloride is extensively used in most of the European countries till
today as an analgesic, owing to its non-opiate (non-narcotic) and non-steroidal action with
fewer side-effects compared with opioid and other analgesics which causes more troublesome
side-effects. A multi-kilogram synthesis of Nefopam hydrochloride has been achieved in one-
pot using single solvent (toluene). The purity of API was achieved ≥99.9% with excellent
overall yield (≥79%). The one-pot multistep (five steps) synthetic process involves formation
of acid chloride (3) from benzoylbenzoic acid (2) followed by amidation (4), reduction (5),
cyclization (6) and hydrochloride salt (1) formation. The major advantages include i) use of
single solvent, ii) >90% conversion in each step, iii) cost-effective and operational friendly
process, iv) averting the formation of genotoxic impurities and v) one-pot operation provided
improved overall yield (≥79%). For the first time, we report the characterization data of API
(1), intermediates (3, 4 and 5) and also possible impurity 5a.
Keywords: Nefopam, one-pot, single solvent, toluene, vitride, analgesic
Introduction
Any kind of pain has a significant impact on quality of life.1 Human being always try to get
rid from pain immediately which leads to extensive consumption of analgesic drugs,2-4
especially easily available opioid and steroidal analgesics which cause troublesome side-
effects and increased death rates from overdose. The study is aimed to overcome such
troublesome side-effects by focussing attention on use of Nefopam hydrochloride5 drug as an
alternative to opioid and steroidal analgesics because of its superior advantages, for example
it is i) central analgesic6 with non-opiate action,7 ii) non-steroidal analgesic,8 iii) effectiveness
in post-cardiac operative analgesia,9 iv) superior than aspirin,10 v) less side-effects,11 vi)
incompetence of respiratory depression12 compared with morphine13 and oxycodone,14 and v)
less probability of common death from overdose compared with opioid analgesic drugs.15
Interestingly, Nefopam hydrochloride16 was developed in the early 1960 and its consumption
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was limited to European countries where it is widely used for the prevention of post-operative
shivering,17 severe hiccups,18 post-trauma and post-operative pain,19 dental pain,20 and renal
colic pain.21 At the same time practical commercial process with good yield and purity is
found to be essential for its quick adoptability throughout the world which is now limited to
France, the U. K22 and few other European countries.
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The extensive literature search revealed that the reported processes23-27 for the synthesis of
Nefopam hydrochloride suffer from one or more disadvantages such as i) multi-step synthesis
involving isolation, drying and analysis increases cycle time, labour and utility costs and also
compromising in yield, ii) cumbersome workup procedure, iii) lack of practicality and
viability, and iv) use of industrially undesired solvents such as low boiling and chlorinated
solvents. In addition, it was observed that none has been reported about i) characterization
and purity of API, intermediates and impurities, ii) comprehensive results and discussion of
the reported processes and iii) commercial feasibility to prepare desired quality of API. The
above mentioned process problems and metrics to ‘green’ chemistry28 encouraged us to
develop a practical one-pot multi-step process involving proper selection of synthetic route,
reagents, bases, acids, catalysts and use of single solvent for five steps.
Herein, we report a commercially viable process for the multi-kilogram synthesis of Nefopam
hydrochloride (1). The one-pot synthesis starts from formation of acid chloride (3) from
benzoylbenzoic acid (2) followed by amidation (4), reduction (5), cyclization (6) and
hydrochloride salt formation (1) in toluene as shown in Scheme 1.
OH
i. Et3N
O
OH
O
Cl
NH
O
N
O
O
ii.
i. SOCl2,
OH
O
Toluene
Cat. DMF
iii. Water and NaHCO3
Toluene
ii. Codistilation
with toluene
wash
iv. Remove aqueous
4
2
3
i. Vitride
iv. Add toluene and basify
with aq. NaOH
Remove aqueous
ii. Quench with aq. NaOH
Remove aqueous
iii. Acidify with dil. H2SO4
Remove toluene
v. Water wash
OH
O
. HCl
N
S OH
O
i.
N
N
Purge HCl
Toluene
OH
O
O
ii. Add water
Remove toluene
iii. Add toluene and basify
with aq. NaOH
Remove aqueous
iv). Water wash
5
1
6
Scheme 1: One-pot Synthesis of Nefopam Hydrochloride (1) from Benzoylbenzoic Acid (2).
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Results and Discussion
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The major fundamental components in the optimization of process are i) reducing the number
of different operations in the selected synthetic route of synthesis.29 In the present work,
higher yield was achieved (≥79%) with the run of multiple reactions in a single vessel (one-
pot), ii) coordinating solvents, in general solvents need to be changed between steps in multi-
step process. It was achieved by selection of toluene as a single solvent which is compatible
with five steps, thus reducing waste and cost in multi-step sequences28 iii) selection and use
of reagents to run the process safely at production level as plant safety is the most important
concern always. It was achieved by the use of vitride30 instead of LiAlH4 and borane
dimethylsulfide (BH3.SMe2). In some patents, NaBH4 was also reported, however it was
unfruitful in our study, iv) impurities control strategy: selection of suitable reagents,
temperature, mode of addition, order of reagents addition, and workup procedures play a vital
role in control of impurities and overall yield of API with desired quality. The control of
impurities in line with ICH guidelines is the major task in the design of efficient process that
is capable in removal of carryover or metallic impurities (formed from unreacted substrates,
byproducts and reagents) wherever possible during workup. It was accomplished in the
present process in each and every stage as discussed in the below sections and v) control or
avoid of genotoxic impurities based on dosage of API is one of the key points in design of
process. It was accomplished with the use of toluene as solvent instead of alcoholic solvents
during hydrochloride salt formation.
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Optimum Process Conditions for the Synthesis of 2-Benzoyl-N-(2-hydroxyethyl)-N-
methylbenzamide (4): The synthesis of compound 4 involves preparation of compound 3
from compound 2 using SOCl2 followed by reaction of compound 3 with 2-
(methylamino)ethanol. The preparation of acid chloride (3) is well known process.31 Initially,
the compound 2 was treated with SOCl2 in dichloromethane in presence of catalytic quantity
of dimethylformamide at 20-30 °C to prepare compound 3. The conversion was good (94%),
however the removal of unreacted SOCl2 becomes difficult at kilogram scale by codistillation
using dichloromethane and it is undesired solvent at commercial level. In the next step, the
presence of unreacted SOCl2 affected the formation (88%) of compound 4. Hence we planned
to improve the formation of compound 4 by carrying out a reaction in toluene at 20–30 °C.
The reaction was completed in 5 h with 94% conversion (entry 1, Table 1). Hence, it was
aimed to reduce the duration of reaction time and improve the conversion. Accordingly, the
same reaction was carried out at 30–40 °C, 40–50 °C and 50–60 °C and the reaction was
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completed in 3 h, 1 h and 40 min with the conversion of 95%, 98% and 97%, respectively
(entries 2–4). The study revealed that 40–50 °C is ideal temperature for maximum formation
of compound 3 with in 1 h (entry 3, Table 1, and Figure S6, Supporting Information). The
removal of volatiles from the reaction mass by codistillation using toluene under vacuum
helped to improve formation (98%) of compound 4.
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The preparation of amide from organic acid using different methods were reported, however
the preparation via acid chlorides is one of the simple and most economical methods.32 The
major problems associated with acid chlorides during amide formation include racemization,
hydrolysis, deprotection, and other side reactions.33 Hence, we planned to optimize the
reaction conditions in a systematic approach. The reaction of compound 3 with 2-
(methylamino)ethanol in toluene in presence of Na2CO3 at 20–30 °C offered moderate
conversion (72%) (entry 5, Table 1). The same reaction with K2CO3 and Et3N offered 76%
and 81%, respectively (entries 6 and 7). The same reaction at low temperature offered
improved conversion (up to 98%) (entry 9). The effect of order of addition of reagents was
also studied. For example, if the order of addition, i) 2-(methylamino)ethanol followed by
addition of Et3N at 0–10 °C offered moderate conversion (77%) (entry 9, conversion in
parenthesis, Table 1) and the unreacted substrate (3) was more (22%) and ii) addition of Et3N
followed by 2-(methylamino)ethanol at 0–10 °C offered maximum conversion (98%) (entry
9, Table 1 and Figure S12 & S13, Supporting Information). The conformational isomerism
(rotamers) was found in compound 4 as per characterization data (Figure S14–S17,
Supporting Information).
Table 1: Effect of Reaction Conditions for the Preparation of Compound 4a
entry tempˈ
(°C)
time
(h)
base
mole
ratio
product
Product
(% by HPLC)b
3
4
1
2
3
4
20–30
30–40
40–50
50–60
5
-
-
-
-
-
-
-
-
94
-
3
3
3
3
3
1
95
98
97
-
-
-
40 min
5
6
7
20–30
20–30
20–30
1
1
1
Na2CO3
K2CO3
Et3N
3.0
3.0
3.0
-
-
-
72
76
81
4
4
4
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10–20
0–10
1
Et3N
Et3N
3.0
3.0
4
4
-
95
98 (77)c
-
1.5
aReaction conditions: compound 2 (10.0 mmol), SOCl2 (12.0 mmol), base, 2-
(methylamino)ethanol (11.0 mmol) in toluene at specified temperature.
bOrder of addition: 2-(methylamino)ethanol followed by Et3N at 0–10 °C.
cOrder of addition: Et3N followed by 2-(methylamino)ethanol at 0–10 °C.
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Optimum
Process
Conditions
for
the
Synthesis
of
2-[{2-
[Hydroxy(phenyl)methyl]benzyl}(methyl)amino]ethanol (5): Direct conversion of amides
to the corresponding amines is not as facile as it seems. Even though many procedures were
reported for the reduction of both amide to amine and ketone to 2˚ alcohol of compound 4,
the efficient reagents are Lithium Aluminum Hydride (LiAlH4),34 diborane or borane
complex,35 and others reducing agents such as DIBAL–H,36 NaBH4–TFA and NaBH4–
TFAA,37 NaBH4–I2,38 LiH3BNMe2.39 Most of the reported reducing agents are good to reduce
ketone to 2˚ alcohol, however most of them are not suitable for the reduction of amide to
amine of compound 4 at production level because of their i) probability of ignition that cause
safety concerns, ii) requirement of more quantity of reducing agent or in combination with
other reagents affects cost, handling and isolation, iii) handling and personal safety problems,
and iv) less stability at higher temperature.
The reduction of compound 4 was reported in many patents with good yields using LiAlH4.40
However, LiAlH4 possess major drawbacks. For example i) it is expensive and its handling is
very risky compared with other reagents, ii) it reacts violently with water and even a little
humidity in the working surroundings or in the solvents can produce hydrogen and it causes
ignition.41 Some patents reported use of borane dimethylsulfide (BH3.SMe2) to reduce amide
to amine24 of compound 4. The same reagent was applied in our laboratory, the conversion
was low (68%) compared with reported yields even after 24 h with 4.0 equiv of reagent. The
drawbacks associated with BH3.SMe2 reagent is that it is expensive and flammable as it reacts
readily with water to produce a flammable hydrogen gas. The reduction of amide
functionality of compound 4 was tested with NaBH4 and DIBAL–H, however the reactions
were not successful. The literature search revealed that vitride (Red–Al),30 chemically known
as sodium bis(2–methoxyethoxy)aluminumhydride is the best option among the available
reagents for reduction of both amide to amine and ketone to 2˚ alcohol of compound 4 at
production level. Because vitride i) does not have inconvenient pyrophoric nature and short
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shelf-life, ii) reacts with air and moisture exothermically however does not ignite, iii)
tolerates higher temperatures, and iv) soluble in aromatic solvents. Interestingly, in one
patent, the reduction of amide and ketone functionalities of compound 4 using vitride was
reported.25 The same reaction was carried out in our laboratory using 1.5 eq. of vitride (70%
in toluene) and low formation (52%) of compound 5 (entry 1, Table 2) was observed. To
improve the conversion and to make the process cost effective, reaction conditions were
optimized in a systematic way. Initially, the reduction was carried out using 2.0, 3.0, 4.0, 5.0
and 6.0 equiv of vitride and the conversion was 58%, 64%, 71%, 80% and 92%, respectively
(entries 2–6, table 2) at 20–30 °C. To reduce the consumption quantity of vitride and to
achieve cost effective process, the same reaction was carried out at higher temperatures as the
vitride reagent tolerate high temperatures. For example, 2.0, 2.5, 3.0 equiv of vitride offered
72%, 95% and 94% of compound 5 (entries 7–9, table 2) at 90-100 °C. The study disclosed
that 2.5 equiv. of vitride offered excellent formation (95%) of compound 5 at 90–100 °C
(entry 8). To study further the effect of temperature on the course of the reaction, the same
reaction was carried out at 60–70 °C, 70–80 °C and 80–90 °C and the conversion was 67%,
73% and 78%, respectively (entries 11–13). The study disclosed that the formation of
compound 5 from compound 4 was excellent (>90%) both at 20–30 °C with 6.0 equiv. of
vitride (entry 6) and at 90–100 °C with 2.5 equiv. of vitride (entry 8).
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Interestingly, it is found that the dilution of the reaction mass has significant effect on the
course of the reduction. For example, compound 5 (82%) (entry 8, conversion in parenthesis,
table 2), impurity 5a (8%) and impurity 5b (0.1%) were formed in 5 vol. of toluene solvent
using 2.5 equiv. of vitride at 90–100 °C (scheme 2). The same reaction in 2 vol. of toluene
provided maximum formation (95%) of compound 5 (entry 8, table 2) and impurities 5a
(0.03%) and 5b (0.01%) were formed. The same reaction on increase of further dilution (10
vol. of toluene as solvent) the formation of compound 5 was decreased (66%) and impurities
5a (18%) and 5b (0.25) were formed more. The study revealed that the reduction of 4 was not
effective at high dilution. Further, the same reaction was offered low conversion (52%)
(entry 15) without toluene. The study disclosed that 2.5 equiv of vitride reagent (70% in
toluene) in 2 vol. of toluene at 90–100 °C provided maximum formation (95%) of compound
5 (entry 8, Table 2 and Figure S23, Supporting Information). The impurity 5b was not formed
at higher level in the present reaction conditions, so it was not isolated. But the impurity 5a
was carried up to API. Hence, impurity 5a was isolated and characterized (Scheme 2 and
Figure S24–S33, Supporting Information).
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OH
OH
OH
5
6
7
8
O
N
N
O
N
O
O
OH
Vitride
9
Toluene
+
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4
5a
5b
Scheme 2: Formation of probable impurities during reduction of compound 4.
Table 2: Effect of Reaction Conditions on Reduction of Compound 4.a
entry
equiv. of
Reducing
agent
tempˈ
(°C)
volume
of
toluene
time
(h)
product
Product 5
(% by HPLC)b
1
2
1.5
20–30
20–30
2
9
52
58
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
2.0
3.0
4.0
5.0
6.0
2.0
2.5
3.0
2.5
2.5
2.5
2.5
2.5
2.5
2
7
3
20–30
2
6
64
4
20–30
2
5
71
5
20–30
2
3
80
6
20–30
2
2
92
7
90–100
90–100
90–100
100–110
60–70
2
3
72
8
2 (5)b
1.5
95 (82%)b
9
2
2
1
94
10
11
12
13
14
15c
30 min
83
2
4
3
67
70–80
2
73
80–90
2
2.5
6
78
90–100
10
66
90–100
-
1
52
aReaction conditions: compound 4 (10.0 mol), Vitride in toluene at specified temperature.
bConversion when 5.0 vol of toluene was applied
cNeat reaction
Optimum Process Conditions for the Synthesis of 5-Methyl-1-phenyl-3,4,5,6-tetrahydro-
1H-2,5-benzoxazocine (6) via Intramolecular Cyclization:
The formation of 8-membered ring via intramolecular cyclization is a central issue as several
methods failed to get high yield with minimum reaction time. The catalysts reported for the
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cyclization are not viable at production level, for example in few patents p-toluenesulfonic
acid was reported for intramolecular cyclization for the formation of compound 6.26 But, the
major drawbacks associated with this method include i) difficulty to stir the reaction mass as
it is in semi-solid form and it leads to unfavorable for production in plant, and ii) the
percentage of unreacted substrate (5) is also more (25–40%) [entry 1, Table 3).
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The drawbacks associated with p-toluenesulfonic acid encouraged us to search for catalyst
with almost similar chemical features. In this thirst we found that methanesulfonic acid is one
of the best options available because of its efficiency in cyclization reactions as reported in
literature.42 As expected, it offered 76% formation of compound 6 in 24 h at 100–110 °C in
presence of 1.0 equiv. of methanesulfonic acid (entry 2, Table 3). To increase the conversion
further and to reduce the duration of reaction time, the same reaction was carried out
azeotropically to remove the water, a byproduct of the reaction, amazingly the reaction
completed in 1.5 h with 96% formation of 6 in presence of 2.0 equiv. of methanesulfonic acid
(entry 3). The same reaction in presence of 3.0 equiv. of methanesulfonic acid offered 93% of
compound 6 (entry 4). The same reaction in presence of polyphosphoric acid, it was observed
that the reaction mass was dark in color, moderate conversion (73%) and poor appearance of
API even after carbon treatment (entry 5). The same reaction in presence of hydrobromic
acid26 provided low formation (66%) of compound 6 (entry 6).
The study disclosed that 2.0 equiv of methanesulfonic acid offered excellent formation (96%)
of 8-membered ring compound 6 (Figure S34, Supporting Information).
Table 3: Effect of Reaction Conditions on Intramolecular Cyclization to Prepare 8-
Membered Ring Compound (6):
entry
Catalyst
equiv.
time
(h)
product
Product 6
(% by HPLC)b
61
1
2
3
4
5
6
p-toluenesulfonic acid
2.0
1.0
2.0
3.0
2.0
2.0
24
6
6
6
6
6
6
methanesulfonic acid
6
1.5
1
76
96
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polyphosphoric acid
hydrobromic acid
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aReaction conditions: compound 5 (10.0 mol), catalyst, toluene (5 vol) and acidic catalyst at
100–110 °C.
bRemaining unreacted substrate
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Optimum Process Conditions for the Synthesis of 5-Methyl-1-phenyl-3,4,5,6-tetrahydro-
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1H-2,5-benzoxazocine hydrochloride (1):
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The hydrochloride salt formation (1) of compound 6 was carried out in different solvents, for
example acetone, methanol, ethanol and isopropyl alcohol offered lower yields 71%, 76%,
80% and 85%, respectively with purity ≥98% except in isopropyl alcohol (97%). The
formation of genotoxic impurities (alkyl chlorides and alkyl methanesulfonate etc) is the
major problem with alcoholic solvents. To avoid the formation of genotoxic impurities, the
same reaction was carried out in toluene at 0–10 °C. The formed product 1 was in viscid
nature even after 6 h stirring at 0–10 °C. To avoid formation of 1 with viscid nature, the same
salt formation was carried out by purging dry HCl gas into reaction mass (compound 6 in
toluene) at 0–10 °C and the product was obtained with ≥97% purity.
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The HPLC data of crude Nefopam hydrochloride (1) revealed that it did not fulfil the
specifications of API (Figure S35, Supporting Information). Hence, it was planned to
recrystallize in different alcoholic solvent systems, for example, methanol, ethanol and
mixture of aqueous alcoholic solvent system (H2O:methanol in 1:1 ratio) as the compound 1
was practically insoluble in other solvents. The results obtained were presented in Table 4.
The study disclosed that the methanol provided excellent purity >99.9% with excellent yield
(95%) (entry 1, Table 4 and Figure S46, Supporting Information). Before the finalization of
alcoholic solvents for purification of compound 1, the content of methanesulfonic acid was
checked as its presence forms the genotoxic impurities (alkyl methanesulfonates).
Interestingly, the analysed crude compound 1 did not have any methanesulfonic acid which
helped to avoid the formation of such genotoxic impurities.
Table 4. Selection Suitable Solvent for the Purification of Nefopam Hydrochloride (1)a
yieldb
(%)
entry
solvent
product
purity (% by HPLC)
5a unknown
1
2
4
5
1
2
3
methanol
ethanol
95
1
1
1
99.96 0.02 0.00 0.00 0.00
99.50 0.20 0.10 0.02 0.03
99.41 0.10 0.2 0.06 0.03
0.01
0.15
0.2
96
water:methanol
(1:1 ratio)
82
aReaction conditions: crude compound 1 (10 g, 0.031 mol) in solvent (100 mL] at 60–65 °C
for 1h, cool to 0–10 °C, stir for 2 h and filter the solid.
bIsolated yield.
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Experimental
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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
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1
operating 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 (broad singlet). The 1H 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, U.S.A.). The CHN analyses were
recorded on a Vario EL analyser.
Synthesis of 5-Methyl-1-phenyl-3,4,5,6-tetrahydro-1H-2,5-benzoxazocine hydrochloride
(1).
In a 50 L reactor, benzoylbenzoic acid (2) (2.0 kg, 8.841 mol), toluene (10 L), DMF (60 mL)
and thionyl chloride (1.26 kg, 10.609 mol) were charged and maintained at 40–50 °C for 1 h.
After completion of the reaction, the volatiles were distilled out under vacuum at 40-50 °C
and chased out with toluene (4 L). The toluene (20 L) and Et3N (2.68 kg, 26.523 mol) were
charged and 2-(methylamino)ethanol solution (0.730 kg, 9.725 mol, in 4 L toluene) was
added slowly at 0–10 °C. The temperature of the reaction mass was increased to 20–30 °C
and maintained for 1 h. After completion of the reaction, water (6 L) was added and the
product (4) was extracted (toluene layer) at 50–60 °C and washed with 5% aq. NaHCO3
solution (6 L) followed by water (6 L). The solvent was evaporated from the organic layer (4)
until reaction mass became 2–3 vol and vitride (70% in toluene) (6.38 kg, 22.102 mol) was
added slowly at 0–15 °C followed by maintenance at 90–100 °C for 1.5 h. After completion
of the reaction, toluene (10 L) was charged and quenched the reaction mass using aq. NaOH
solution (0.6 kg NaOH, 15.00 mol, in 20 L water) at 0–15 °C. The product toluene layer (5)
was collected at 40–50 °C and to this added dil. H2SO4 (1.0 kg H2SO4, 10.167 mol, in 10 L
water) at 5–15 °C. The aqueous layer was collected and added fresh toluene (14 L) followed
by basification using aq. NaOH solution (0.884 kg NaOH, 22.1 mol, in 6 L water) at 5–15 °C.
The organic layer was collected and washed with water (6 L) at 40–50 °C. The solvent was
evaporated until reaction mass became 4–5 vol followed by addition of methanesulfonic acid
(1.7 kg, 17.682 mol ) at 20–30 °C. The reaction was maintained at 100–110 °C for 1.5 h by
collecting water azeotropically. After completion of the reaction, water (10 L) was added at
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20–30 °C. The aqueous layer was collected and added toluene (10 L) followed by basification
using aq. NaOH solution (0.99 kg NaOH, 24.755 mol, in 6 L water) at 5–15 °C. The organic
layer (6) was collected and washed twice with water (2x4 L). The HCl gas was purged slowly
into the reaction mass at 0–10 °C for 30 min and stirred at the same temperature for 1 h. The
reaction mass was filtered, washed with toluene (2 L). The obtained solid product (1) was
dried under vacuum at 50–55 °C. Yield = 2.15 kg. The yield of compound 1 is 84% with
purity 98.06% (Before purification).
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Purification of 5-Methyl-1-phenyl-3,4,5,6-tetrahydro-1H-2,5-benzoxazocine
hydrochloride (1).
In a 2 L RB flask, compound 1 (2.0 kg) in methanol (20 L) was heated to 60–65 °C and
stirred at the same temperature until clear solution was obtained. The activated carbon (100
g) was charged and stirred for 30 minutes. The reaction mass was filtered through hyflo bed
and washed with methanol (2 L). The filtrate was collected and the solvent was evaporated
under vacuum until the reaction mass became 3–4 vol. The reaction mass was cooled to 0–10
°C and stirred for 2 h at 0–10 °C. The reaction mass was filtered and washed with methanol
(1 L).
Yield = 1.9 kg (95%) with HPLC purity 99.96%. The overall yield is 79.8% (after
purification).
Characterization data:
2-Benzoylbenzoyl chloride (3) [Figure S1–S6, Supporting Information):
1H NMR (400 MHz, CDCl3, δ/ppm): 7.91 (d, 1H, arom H, J = 7.6 Hz), 7.78 (t, 1H, arom H, J
= 7.6 Hz), 7.69–7.66 (m, 3H, arom H), 7.60 (t, 1H, arom H, J = 7.6 Hz), 7.42-7.38 (m, 3H,
arom H).
13C NMR (100 MHz, CDCl3, δ/ppm): 167.1, 151.3, 138.2, 135.5, 130.8, 130.0, 129.7, 128.8,
128.5, 125.9, 125.8, 123.6, 123.5, 99.9
MS m/z (ESI): 209.06 (M+.)
2-Benzoyl-N-(2-hydroxyethyl)-N-methylbenzamide (4) [Figure S7–S13, Supporting
Information]:
1H NMR (400 MHz, CD3OD, recorded at 55 °C, δ/ppm): 7.77 (d, 2H, arom H, J = 7.6 Hz),
7.64 (t, 2H, arom H, J = 7.6 Hz), 7.60–7.49 (m, 5H, arom H), 3.69 (t, 2H, –CH2–O–, J = 7.6
Hz), 3.52 (t, 1H, –CH(H)–), 3.37 (t, 1H, –CH(H)–), 2.99 (s, 3H, –CH3).
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13C NMR (100 MHz, DMSO–d6, recorded at 90 °C, δ/ppm): 195.5, 168.9, 137.1, 136.7, 136.6,
3
4
5
6
132.4, 130.2, 128.9 (2C), 128.6, 127.9, 127.8 (2C), 126.7, 58.0, 45.5, 32.0
7
8
MS m/z (ESI): 284.15 (M+H) +.
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2-[{2-[Hydroxy(phenyl)methyl]benzyl}(methyl)amino]ethanol (5) [Figure S18–S23,
Supporting Information]:
1H NMR (400 MHz, CDCl3, δ/ppm): 8.68 (s, 1H, –CH–O–), 7.41–7.33 (m, 4H, arom H),
7.31–7.25 (m, 3H, arom H), 7.21 (t, 2H, arom H, J = 7.6 Hz), 3.72–3.62 (m, 2H, –CH2–),
3.44 (d, 1H, –CH(H)–, J = 12.4 Hz), 3.36 (d, 1H, –CH(H)–, J = 12.4 Hz), 3.04 (s, 1H, –OH),
2.65–2.51 (m, 2H, –CH2–), 2.21 (s, 3H, –CH3).
13C NMR (100 MHz, CDCl3, δ/ppm): 144.1, 143.3, 135.8, 132.0, 130.0, 128.2, 127.9 (2C),
127.5, 126.7, 126.0 (2C), 75.5, 61.4, 59.2, 59.0, 41.5
MS m/z (ESI): 272.22 (M+H) +.
5‐Methyl‐1‐phenyl‐3,4,5,6‐tetrahydro‐1H‐2,5‐benzoxazocine hydrochloride (1) [Figure
S37–S49, Supporting Information]:
[ ]
White crystalline solid, m. p. 248–251 °C, = -0.016 (c 1.0, H2O).
1H NMR (400 MHz, D2O, δ/ppm): 7.36–7.25 (m, 6H, arom H), 7.21–7.18 (m, 2H, arom H),
7.12–7.10 (m, 1H, arom H), 5.89 (s, 1H, Aryl–CH–Aryl), 5.45 (d, 1H, Aryl–CH(H)–N–, J =
12.8 Hz), 4.34–4.27 (m, 1H, –CH(H)–O–), 4.21 (d, 1H, Aryl–CH(H)–N–, J = 13.2 Hz),
4.05–4.00 [m (dt), 1H, –CH(H)–O–, J = 6.8 Hz and J = 3.6 Hz], 3.30-3.23 (m, 1H, –CH(H)–
N–), 3.08–3.02 [m (dt), 1H, –CH(H)–N–, J = 7.2 Hz and J = 3.6 Hz), 2.87 (s, 3H, –CH3).
13C NMR (100 MHz, D2O, δ/ppm): 142.4, 141.1, 134.3, 130.5, 129.1, 129.0 (2C), 128.7,
128.4, 127.7 (2C), 125.3, 85.3, 64.9, 58.3, 50.5, 41.6
MS m/z (ESI): 254.20 (M+H) +.
CHN analysis data (%/w): Anal. Calcd. for C17H19NO.HCl or C17H20NOCl: C, 70.46; H,
6.96; N, 4.83; Found: C, 70.39; H, 7.25; N, 4.49; S, not found.
Isolation of (2-{[(2-Hydroxyethyl)(methyl)amino]methyl}phenyl)(phenyl)methanone
(5a): The mother liquor (100 mL) of 5‐Methyl‐1‐phenyl‐3,4,5,6‐tetrahydro‐1H‐2,5‐
benzoxazocine hydrochloride (1) was taken and concentrated. The crude mass was purified
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over column filled with Silica gel using 10% EA in hexane. The obtained impurity 5a (850
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6
mg) was characterized.
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1H NMR (400 MHz, CDCl3, δ/ppm): 9.24 (bs, 1H, –OH), 7. 75–7.64 (m, 6H, arom H), 7.61–
7.57 (m, 1H, arom H), 7.49 (t, 2H, arom H, J = 7.6 Hz)), 4.49 (d, 1H, Aryl–CH(H)–N–, J =
12.8 Hz), 4.29 (d, Aryl–CH(H)–N–, J = 12.8 Hz), 4.04–3.91 (m, –N–CH2–), 3.51–3.45 (m,
1H, –CH(H)–O–), 3.33 (d, 1H, –CH(H)–O–), 2.94 (s, 3H, –CH3).
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13C NMR (100 MHz, CDCl3, δ/ppm): 200.0, 138.0, 136.7, 134.5, 134.4, 133.4, 133.2, 131.0
(2C), 130.3, 129.9, 128.8 (2C), 60.2, 57.4, 55.3, 39.3
MS m/z (ESI): 270.15 (M+H) +.
Conclusion
A versatile one-pot method using single solvent has been developed for the manufacture of
Nefopam hydrochloride (1) with excellent purity (≥99.9%) and overall yield (≥79%). The
present work addressed several process issues to make the entire mechanism operational
friendly for multi-kilogram scale production. The optimization of reaction conditions during
reduction of both amide and ketone functionalities using minimum quantity (2.5 equiv) of
vitride is one of the key success in the present process. In addition, the process impurity 5a
and carryover impurities (2, 4 and 5) are efficiently removed during purification process. The
formation of genotoxic impurities (alkyl chlorides and alkyl methanesulfonates) was
eliminated by using toluene as solvent instead of alcoholic solvents during hydrochloride salt
(1) formation. The concept of green chemistry was also achieved partially by developing one-
pot multi-step synthetic strategy (avoided step by step process) using single solvent (toluene).
Our team hoping that the present work can help both in focussing and adopting Nefopam
hydrochloride as alternative safe analgesic to the rest of the countries which is now limited to
United Kingdom, France and few other European countries.
Corresponding author
Dr. Pramod Kumar
Senior Vice-President ,
API R&D Centre, Micro Labs Ltd., Bangalore.
Tel. No. 0811 0415647, Ext. No. 245
Mobile No. +91 9008448247
E-mail: pramodkumar@microlabs.in
Notes
The authors declare no competing financial interest.
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Acknowledgments
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The authors are thankful to the management of Micro Labs Limited for financial support for
this research work (No. NEF/2016-17). We are grateful to colleagues in the Analytical
Research Division, API R&D Centre, Micro Labs Limited, Bangalore. Our special thanks to
Dr. R. V. Jayanth Kasyap and Ridhima Kochar for their support.
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Supporting information
Copies of relevant 1H, 13C NMR, DEPT-135, mass spectra, CHN analyses, Powder XRD and
also HPLC chromatograms are available in the supporting information.
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coated
tablets
(PL
41830/0014
and
PL
41830/0034):
5
6
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http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con534711.pdf
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