Nitro-Aldol Approach for Commercial Manufacturing of Fenspiride Hydrochloride

Article abstract of DOI:10.1021/acs.oprd.9b00022

An efficient, short manufacturing process for fenspiride hydrochloride is reported. Nitro-aldol condensation is the key reaction in the developed process. Improved routes to key building blocks are demonstrated by expedient multikilogram production. Hazardous reactions are avoided. API produced following this new route meets the quality requirement NLT 99.70% purity by HPLC with any individual impurity NMT 0.10% with very good yield.

Full text of DOI:10.1021/acs.oprd.9b00022

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Communication
Nitro-Aldol approach for commercial
manufacturing of Fenspiride Hydrochloride
Chinmoy Pramanik, Kiran Bapat, Pradip Patil, Sandeep kotharkar, Yogesh More, dinkar
gotrane, Sudhir Panditrao Chaskar, Ulhas Supadu Mahajan, and Narendra K Tripathy
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00022 • Publication Date (Web): 09 May 2019
Downloaded from http://pubs.acs.org on May 9, 2019
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Nitro-Aldol approach for commercial manufacturing of Fenspiride
Hydrochloride
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Chinmoy Pramanik†*, Kiran Bapat†§, Pradip Patil†, Sandeep Kotharkar†, Yogesh More†, Dinkar
Gotrane†, Sudhir P. Chaskar†§, Ulhas Mahajan†, Narendra K. Tripathy†§.
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†API R&D Centre, Emcure Pharmaceuticals Ltd., ITBT Park, Phase-II, MIDC, Hinjewadi,
Pune-411057, India
§Department of Chemistry, Sabitribai Phule Pune University, Ganeshkhind, Pune, Maharashtra,
411007
*Fax: +91-20-39821445.E-mail: chinmoy.pramanik@emcure.co.in
Abstract: An efficient, short manufacturing process for Fenspiride hydrochloride is reported.
Nitro-Aldol condensation is the key reaction in the developed process. Improved routes to key
building blocks are demonstrated by expedient multi-kilogram production. Hazardous reactions
are avoided. API produced following this new route meets the quality requirement NLT 99.70%
with any individual impurity NMT 0.10% with very good yield.
Keywords: Fenspiride Hydrochloride, Active Pharmaceuticals Ingredients, ICH guidelines,
Commercial Manufacturing, Nitro-Aldol Condensation.
Introduction: Fenspiride{8-(2-phenylethyl)-1-oxa-3,8-diazaspiro[4,5]decan-2-oneHCl} is a non-
steroidal compound with a number of mode of action and end-organ effects. It has been shown to
be antiinflamatory, antiallergic and antioxidant. It is an effective drug in case of acute and
chronic inflammatory diseases of otolaryngological system and respiratory tracts. It is also used
as a complex therapy for bronchial asthma, allergic rhinitis and other symptoms of allergy within
otolaryngological system and respiratory tracts, respiratory manifestations of measles, flu and
symptomatic therapy of whooping cough.1
.
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O
NH
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O
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9
N
.HCl
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1
Figure-1: Fenspiride Hydrochloride.
Although it is a very old drug, detailed review of literature revealed that there are very few
processes available for the synthesis of Fenspiride hydrochloride (1). Initially, Gilbert et. al.2,
reported the synthesis of 1 (US 3399192), starting with 1-phenethyl-4-hydroxy-4-aminomethyl
piperidine (4) [prepared according to the British Patent No. 1100281, from piperidone (2) via
cyanohydrin (3) and subsequent reduction] (scheme-1).
Scheme-1
O
NH
O
O
NH2
NH
O
HO
CN
LAH
HO
O
N
1.Diethyl
Carbonate
5
H
KCN
1. NaOMe
2. HCl
N
N
N
N
Br
.HCl
2. Ethyl
acetate-HCl
2
3
4
1
6
o
Cyclization of 4 was affected with ethyl carbonate under reflux at 80 C in presence of freshly
prepared sodium methoxide. They also reported an alternative synthesis starting from
spiro(4,5)decane derivative (5) and coupling with Bromo derivative (6) (scheme-1)3.
Later, Ida Taccone reported the synthesis of Fenspiride (US 4028351)4, starting from N-
substituted-4 Piperidone (2) which was reacted in an appropriate solvent or solvent mixture with
an alpha halogen ester in the presence of activated zinc.
Scheme-2
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Route -A
H2NHN
O
COOEt
HO
HO
7
8
9
NH2NH2
N
N
NaNO2, HCl
Ethyl
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Bromoacetate
O
7
8
NH
O
ZnCl2
O
N
N
.HCl
SiMe3
NH2
2
NC
O
HO
Me3SiCN
ZnI2
1
LAH
Triphosgene
N
N
9
4
Route-B
The resulting beta-hydroxy ester (7) was then reacted with an excess of hydrazine to afford beta
hydroxy hydrazide (8) which was then subjected to a Curtius transposition5 with excess nitrous
acid (scheme-2, route A) to afford Fenspiride.
Somanathan et al6. reported an alternative synthesis (scheme-2, route B) by starting with N-(2-
phenylethyl)-4-piperidone (2) which was treated with trimethylsilylcyanide in presence of ZnI2,
followed by LAH reduction to arrive at intermediate 4. Finally, cyclization of aminol 4 using
triphosgene afforded Fenspiride HCl (1).
All the above described methods are associated with serval shortcomings for tones scale
production owing to its huge annual consumption i.e. involves highly toxic cyanide reaction, use
of hazardous reagents like LAH, sodium metal, use of Class-I solvent like benzene and highly
flammable diethyl ether, low yield etc.
In an effort to avoid all these limitations, earlier a commercial scale process was developed by
our team7 (scheme-3). Piperidone 2 on Corey-Chaykovsky8 epoxide formation using trimethyl
sulfoxonium iodide in DMSO in presence of sodium hydroxide as base, resulted in epoxide 10 in
o
good yield. In-situ epoxide opening using sodium azide in DMSO at 45-50 C afforded azido
intermediate 11.
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Scheme-3
5
6
7
8
HO
NH2
HO
N3
Hydrazine
O
O
N
TMSI
NaOH
DMSO
NaN3
Hydrate
9
N
N
N
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5-30 oC
50-55 oC
DMSO
45-50 oC
85% for two steps
4
11
10
2
O
O
NH
NH
O
O
CDI
Ethyl acetate-HCl
95%
N
N
.HCl
75% for two steps
12
1
Reduction of azide (11) was best affected under hydrogenation condition using hydrazine
hydrate under heating to arrive at amine 4. The final oxazolidone formation was accomplished
using carbonyl diimidazole (CDI) under basic medium to arrive at Fenspiride free base (12)
followed by salt formation using HCl-EtOAc which provided the target molecule Fenspiride HCl
with high HPLC purity (>99.7%) complying to ICH guidelines. The above process is being used
for the commercial manufacturing of Fenspiride on 40-50 Kg scale. Even though, the yields in
each step is reasonable to high, and produce high quality API, the process turns out to be non-
profitable in highly competitive generic market because of the use of costly reagent TMSI
(trimethyl -sulfoxonium iodide) for long term manufacturing. Also, owing to the risk/safety
factor associated with use of NaN3 along with its effluent treatment after reaction, the process
couldn’t be scaled up further.
As part of our ongoing efforts towards developing efficient, commercially viable process of
generic drugs, we decided to look for a better process involving simpler reagents/reaction
conditions with cost-reduction/much more economical.
For manufacturing of Fenspiride HCl, we came up with a strategy starting from piperidone-2 via
Nitro-derivative 13 which could be easily converted to the critical/penultimate amine
intermediate 4, and subsequently to Fenspiride HCl following known routes as shown in retro-
synthetic scheme (Scheme 4). This NO2 approach to access the Amine 4 is the simplest.
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Scheme 4: Retrosynthetic presentation of proposed route
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O
NH
NH2
NO2
O
N
O
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HO
HO
N
N
N
.HCl
4
2
1
13
Accordingly, for Piperidione derivative (2), we have redeveloped the reported process for big
scale manufacturing as shown in scheme-5.
Scheme-5: Preparation of compound 2
O
O
O
O
N
O
N
O
O
O
O
Sodium
methoxide
NH3
Methanol
dil-HCl
N
O
overall 77%
2
15
16
17
18
Following the reported procedure, condensation of 2-phenyl ethyl amine (15) with excess methyl
acrylate (16) at room temperature provided compound 17. Compound 17 on base promoted
Dieckmann condensation followed by acidic hydrolysis and concomitant decarboxylation
provided compound 2 with good quality and yield (scheme 4). Using this route, we have
manufactured the piperidone derivative (2) on 150 Kg scale.
The nitro aldol condensation (Henry reaction) which mainly involves the coupling of a nitro
alkane with a carbonyl group is an important C-C bond forming reaction in organic chemistry
giving a nitroalkanols, which are useful versatile intermediates in synthetic organic chemistry.
As per our retrosynthetic strategy, Nitro-aldol of piperidone 2 with nitromethane was affected
under mild conditions using potassium carbonate as base in DMSO at room temperature9 to
furnish β-nitroalcohol (13) with excellent yield and high purity. Considering the process safety
assessment, Nitromethane is a flammable liquid with a closed cup flash point of 96°F (36°C). Its
vapor has a lower explosive limit of 7.3% by volume at atmospheric pressure and at 91°F
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(33°C). It does not form explosive mixtures with air at room temperature and below, when
unconfined. Nitromethane can be handled safely as long as its hazardous properties are
2
understood and unsafe conditions are avoided during its use. Considering all the safety
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precautions, in our process, nitromethane is used at very low temperature (0 to 5 C). As
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genotoxicity of nitro compounds and their control are a critical subject for the API process
development, genotoxicity data of nitromethane and intermediate 13 were also evaluated with
Mcase software. The data revealed that, both these compounds are non-genotoxic in nature.
Initially, the reduction of Nitro-group was affected by hydrogenation using Pd/C to arrive at
aminol 4 and finally converted into Fenspiride using similar conditions used in our Azido-route.
Scheme-6
O
NH
NH2
1. CDI/Triphosgene
2. HCl
NO2
O
N
O
HO
HO
Pd/C
H2
Nitromethane
81%
N
N
N
.HCl
4
2
13
1
Zn,HCl
O
78%
O
HN
HO
1. (Boc)2O, K2CO3
2. HCl
4
N
14
Later to avoid the use of Pd (contributing towards the overall cost even with recovery), the
reduction was affected by using Zn/HCl in IPA, but the isolation of the free amine after aqueous
work up was found to be tedious. So, we decided to protect the in-situ formed amine 4 as its Boc
derivative (14) for its easier isolation by extraction. The hidden idea behind the Boc-protection
was to attempt the cyclization (isoxazolidone formation) of intermediate 14 under basic
condition which would directly provide us the desired Fenspiride free base thus avoiding the
additional cyclization step using triphosgene/CDI/alkylcarbonates. Accordingly, after the
reduction of the Nitro-intermediate, the in-situ amino-group (without actually isolating the amine
4) was protected as its Boc derivative in aqueous medium to afford the Boc-derivative 14. As
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predicted, the isolation was easy (extraction in MDC) and provided highly pure product in high
yield. Although the cost for the Zn is very less, but considering the scale of Zn used, one can
recover Zn from the aqueous layer of the reaction mixture based on the reported literature
methods.10 The final cyclization of the Boc-derivative was efficiently affected by using NaOtBu
in toluene at 80oC to afford Fenspiride free base >99.7% by HPLC which was converted into the
desired Hydrochloride salt using HCl-EtOAc with >99.9% HPLC purity.
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Conclusion: In conclusion we have developed a new process for the large scale manufacturing
of fenspiride hydrochloride involving simple process reagents/conditions. Considering the safety
concerns related to the use of sodium azide and azide intermediate or the use of KCN and LAH,
these reagents were avoided in our process. We have also avoided the use of costly reagents like
Trimethylsulfoxonium iodide, which was used in the earlier routes to prepare the epoxide 10
from ketone 2 (scheme 3), thus making our route cost effective and commercially viable.
Considering the operational simplicity in industrial scale, all the chemicals/reagent which are
used in the present route are very easy to handle in large scale.
Acknowledgment
The authors wish to thank Mr. Samit Mehta, our management and ARD group of Emcure
Pharmaceuticals Ltd. for their willing support and constant encouragements.
Experimental:
All materials were purchased from commercial suppliers. Unless specified otherwise, all
1
13
reagents and solvents were used as supplied by manufacturers. H NMR spectra and C NMR
spectra were recorded on a Varian 400 MR spectrometer in CDCl3 and DMSO-d6, and mass
spectra were determined on an API-2000LCMS mass spectrometer from Applied Biosystems.
Elemental Analysis was done with a VarioEL III instrument.
Preparation of Intermediate 13:
To a solution of nitromethane (1.5 lit) in DMSO (2 lit), was added potassium carbonate (815.6 g,
5.9 mol) at room temperature. The reaction mixture was cooled to 0 to 5 oC and was added 1-(2-
o
Phenylethyl)-4-piperidone (2, 1.0 kg, 4.9 mol). The reaction mixture was stirred at 0 to 5 C for
1h. After completion of the starting material (monitored by HPLC), reaction mixture was diluted
o
with water (5 lit) at below 15 C and allowed to stir for 1 h. The precipitated solid was filtered;
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the residue was slurry washed with water followed by cyclohexane (5.0 lit). Finally, the solid
o
1
was dried in an oven at 35-40 C under vacuum to obtain 13 (1.05 kg, 81%). H NMR (CDCl3,
400 MHz) δ (ppm): 1.54 (bs, 1H), 1.73-1.75 (m, 4H), 2.45-2.52 (m, 2H), 2.62-2.66 (m, 2H),
7
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13
2.73-2.82 (m, 4H), 4.44 (s, 2H), 7.18-7.20 (m, 3H), 7.25-7.30 (m, 2H), C NMR: (CDCl3, 100
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MHz) δ (ppm): 33.75, 34.64, 48.49, 60.22, 68.86, 84.78, 126.09, 128.41, 128.66, 140.22,
Calculated Mass for C14H20N2O3 (M+) = 264.1, Obtained Mass: 265.1 (M+1). Melting Point: 112
oC to 117 oC
Preparation of Fenspiride Hydrochloride (1):
o
To a cold (0 to 5 C) solution of 13 (1.0 kg, 3.8 mol) in isopropanol (5.0 lit), was added dil-
hydrochloric acid (6(N), 5.0 lit). Zinc powder (1.24 kg, 19.0 mol) was added into the reaction
o
o
mixture at 0 to 5 C lot wise and reaction mixture was stirred for 1h at 15 to 20 C. After
complete consumption of the starting material (monitored by HPLC), dil aq. Sodium hydroxide
o
solution (1.40 kg dissolved in 2.8 lit water) was added at below 30 C. Then di-tert-butyl
dicarbonate (1.0 kg, 4.58 mol) was added into the reaction mixture and stir for 1 h. The reaction
mixture was diluted with water (7.0 lit) and filtered through a pad of hyflo. From filtrate, organic
layer was separated and concentrated. To the concentrated reaction mass, toluene (6.0 lit) was
added and followed by addition of sodium tert-butoxide (365 g, 3.8 mol) and reaction mixture
o
was heated to 55 to 60 C for 1 h. After completion of the reaction (monitored by HPLC),
reaction mixture was diluted with water (5.0 lit) and ethyl acetate (7.0 lit). Product was extracted
with ethyl acetate. The organic layer was concentrated to obtain a crude residue. Ethyl acetate
o
(3.0 lit) was added into the residue and reaction mass was heated at 70 C for 1h. Reaction
mixture was then cooled at 0-5 oC, stirred for 2 h and filtered to obtain Fenspiride free base (12)
with > 99.7% purity. The free base (12) was converted to its hydrochloride salt (1, 880 g, 78%)
1
by treatment with ethyl acetate-HCl. H NMR (CDCl3, 400 MHz) δ (ppm): 2.13-2.17 (m, 2H),
2.73-2.81 (m, 2H), 3.11-3.21 (m, 4H), 3.26-3.3 (m, 2H), 3.47 (S, 2H), 3.54-3.57 (m, 2H), 5.15 (s,
13
1H), 7.24-7.36 (m, 5H), 12.97 (s, 1H), C NMR: (CDCl3, 100 MHz) δ (ppm): 30.24, 32.64,
48.84, 50.49, 58.56/58.62, 77.52, 127.49, 128.62, 129.12, 135.68, 156.92/156.95. Calculated
Mass for C15H20N2O2 (Free base, M+) = 260.2, Obtained Mass: 261.2 (M+1). Melting point:
238.0°C to 242.0°C.
Supporting Information.
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Spectral data of selected intermediates and final compound. This information is available
free of charge via the Internet at http://pubs.acs.org/.
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References:
1. i). Romanet, P, Stewart, A. G. Value of Fenspiride in the Treatment of Inflammation
Diseases in Otorhinolaryngology, Eur Respir Rev 1991, 1, 105–110. ii) Pidpruzhnykov, Y.
V.; Sabko, V. E.; Lurchenko, V. V.; Zupanets, I. A. UPLC-MS/MS Quantification of
Fenspiride in Human Plasma, J Bioequiv Availab 2013, 5(4), 185-190. iii) Khawaja, A.
M.; Liu, Y. C.; Rogers, D. F. Effect of Fenspiride, a Non-steroidal Antiinflammatory
agent, on Neurogenic Mucus secretion in Ferret Trachea in Vitro, Pulmonary
Pharmacology & Therapeutics 1999, 12, 363-368. iv) Volkova, L. I.; Budkova, A.A.;
Filonova, N. N.; Khristolyubova, E. I.; Kutuzova, E. B.; Koroleva, N, V.; Radzivil, T. T.;
Aminova, Z. R.; Chuchalin, A. G. Effeciency of Supplemental Anti-Inflammatory
Therapy with Fenspiride in Chronic Obstructive and Nonobstructive Bronchitis, Clin.
Drug Invest. 2005, 25, 257-264.
2. Regnier, G.; canevari, R., 1-Oxa-2-oxo 3,8-diazaspiro (4,5) decanes, US 3399192,
August 27, 1968.
3. Duhault, J.; Lonchampt, M.; Regnier, G.; Guillonneau, C., Spiro (4,5) decanes US
4824836, April 25, 1989.
4. Taccone, I., Method for the Preparation of Derivatives of Spiro (4, 5)-decanes and
Derivatives Thus Obtained, US 4028351, June 7, 1977.
5. Keicher, T.; Loebbecke, S., In Organic Azides: Syntheses and Applications; Braese, S.,
Banert, K., Eds.; Wiley: New York, 2009.
6. Somanathan, R.; Rivero, I. A.; Nuñez, G. I.; Hellberg, L. H. Convenient Synthesis of 1-
Oxa-3,8-diazaspiro [4,5] Decan-2-ones, Synth. Commun. 1994, 24, 1483-1487.
7. Gurjar, M. K; Maikap, G. S.; Mahajan, U. S.; Shinde, S. N.; Patil, D. B.; Mehta, S. S.,
Process for Preparation of Fenspiride, 1554/MUM/2011.
8. Corey E. J.; Chaykovsky, M., Dimethylsulfonium Methylide, a Reagent for Selective
Oxirane Synthesis from Aldehydes and Ketones, J. Am. Chem. Soc. 1962, 84 (19), 3782–
3783.
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9. Tripathy, N. K.; More, Y. P.; Patil, P. N.; Gotrane, D. M.; Kotharkar, S. A.; Pramanik, C.
M., Fenspiride Hydrochloride Process, 2635/MUM/2013.
10. i) Alagusundarm. R.; Narayanan, A.; Alagappan, A. L.; Warrier, P. C. and
Vijayavalli, R., Processing of industrial by product zinc compounds to recover
zinc by suspension electrolysis method. Trans. SAEST, 1975, 10, 225-225. ii).
Basha, C. A.; Warrier, P. C.; Alagappan, A. L.; Vasudeva Rao, P. V. and
Venkateshwaran, K. V. Production of zinc from industrial by product zinc
compounds. J. Electroanal. Interfacial Chem., 1981, 118, 365-365. iii)
Basha., C. A.; Warrier, P. C.; Alagappan, A. L.; Vasudeva Rao, P. V. and
Venkateshwaran, K.V. Industrial production of zinc from byproduct zinc
compounds by suspension electrolysis. Proceedings of National Seminor
on Zinc Waste and Their Utilization Technical Papers, Organized by
Indian Lead Zinc Information Centre, 1980, New Delhi, 2-11. iv) Jha, M.
K.; Kumar, V. and Singh, R. J. Review of hydrometallurgical recovery of
zinc from industrial wastes. 2000.Resour. Conserve. Recycling, 33, 1-22.
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Organic Process Research & Development
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