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Cite This: Org. Process Res. Dev. 2019, 23, 1252−1256
Nitro-Aldol Approach for Commercial Manufacturing of Fenspiride Hydrochloride Chinmoy Pramanik,*,† Kiran Bapat,†,§ Pradip Patil,† Sandeep Kotharkar,† Yogesh More,† Dinkar Gotrane,† Sudhir P. Chaskar,†,§ Ulhas Mahajan,† and Narendra K. Tripathy†,§ †
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, India
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S Supporting Information *
Cyclization of 4 was affected with ethyl carbonate under reflux at 80 °C in the 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. 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 al.6 reported an alternative synthesis (Scheme 2, route B) by starting with N-(2-phenylethyl)-4piperidone (2) which was treated with trimethylsilylcyanide in the 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 several shortcomings for large-scale production owing to its huge annual consumption, i.e. involving 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 the presence of sodium hydroxide as base resulted in epoxide 10 in good yield. In situ epoxide opening using sodium azide in DMSO at 45−50 °C afforded azido intermediate 11. 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 yield in each step is reasonable to high
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 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. KEYWORDS: fenspiride hydrochloride, active pharmaceuticals ingredients, ICH guidelines, commercial manufacturing, nitro-aldol condensation
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INTRODUCTION Fenspiride{8-(2-phenylethyl)-1-oxa-3,8-diazaspiro[4,5]decan2-oneHCl} (Figure 1) is a nonsteroidal compound with a
Figure 1. Fenspiride hydrochloride.
number of modes of action and end-organ effects. It has been shown to be anti-inflamatory, 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 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 1phenethyl-4-hydroxy-4-aminomethylpiperidine (4) [prepared according to the British Patent No. 1100281, from piperidone (2) via cyanohydrin (3) and subsequent reduction] (Scheme 1). © 2019 American Chemical Society
Received: January 17, 2019 Published: May 9, 2019 1252
DOI: 10.1021/acs.oprd.9b00022 Org. Process Res. Dev. 2019, 23, 1252−1256
Organic Process Research & Development
Communication
Scheme 1
Scheme 2
Scheme 3
Scheme 4. Retrosynthetic Presentation of Proposed Route
As part of our ongoing efforts toward developing efficient, commercially viable process of generic drugs, we decided to look for a better process involving simpler reagents/reaction conditions that results in cost reduction and is 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
and produces high quality API, the process turns out to be nonprofitable 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 could not be scaled up further. 1253
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Scheme 5. Preparation of Compound 2
Scheme 6
Mcase software. The data revealed that both of these compounds are nongenotoxic in nature. Initially, reduction of the nitro group was affected by hydrogenation using Pd/C to arrive at aminol 4 and finally converted into fenspiride using conditions similar to those used in our azido-route. Later, to avoid the use of Pd (contributing toward 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 conditions, which would directly provide us the desired fenspiride free base, thus avoiding the additional cyclization step using triphosgene/CDI/alkylcarbonates. Accordingly, after 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 predicted, the isolation was easy (extraction in MDC) and provided highly pure product with high yield. Although the cost for the Zn is much 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 80 °C 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.
amine intermediate 4 and subsequently to fenspiride HCl following known routes as shown in the retro-synthetic scheme (Scheme 4). This NO2 approach to access the amine 4 is the simplest. Accordingly, for piperidione derivative (2), we redeveloped the reported process for big scale manufacturing as shown in Scheme 5. 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 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 nitroalkanols, which are useful versatile intermediates in synthetic organic chemistry. Pursuant to 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 (Scheme 6). 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 (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 understood and unsafe conditions are avoided during its use.2 Considering all the safety precautions, in our process, nitromethane is used at very low temperature (0−5 °C). As 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
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CONCLUSION In conclusion, we 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 1254
DOI: 10.1021/acs.oprd.9b00022 Org. Process Res. Dev. 2019, 23, 1252−1256
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process. We 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 and reagents which are used in the present route are very easy to handle in large scale.
3.3 (m, 2H), 3.47 (S, 2H), 3.54−3.57 (m, 2H), 5.15 (s, 1H), 7.24−7.36 (m, 5H), 12.97 (s, 1H), 13C 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 to 242.0 °C.
EXPERIMENTAL SECTION All materials were purchased from commercial suppliers. Unless specified otherwise, all reagents and solvents were used as supplied by manufacturers. 1H NMR spectra and 13C 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 °C and was added 1-(2Phenylethyl)-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 with water (5 lit) at below 15 °C and allowed to stir for 1 h. The precipitated solid was filtered; the residue was slurry washed with water followed by cyclohexane (5.0 lit). Finally, the solid was dried in an oven at 35−40 °C under vacuum to obtain 13 (1.05 kg, 81%). 1H 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), 2.73−2.82 (m, 4H), 4.44 (s, 2H), 7.18−7.20 (m, 3H), 7.25−7.30 (m, 2H), 13C NMR: (CDCl3, 100 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 to 117 °C Preparation of Fenspiride Hydrochloride (1). 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 mixture at 0−5 °C lot wise, and the reaction mixture was stirred for 1 h at 15−20 °C. After complete consumption of the starting material (monitored by HPLC), dil aq. sodium hydroxide solution (1.40 kg dissolved in 2.8 lit water) was added at below 30 °C. Then, ditert-butyl dicarbonate (1.0 kg, 4.58 mol) was added into the reaction mixture and stirred 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 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 (3.0 lit) was added into the residue, and reaction mass was heated at 70 °C for 1 h. Reaction mixture was then cooled at 0−5 °C, 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%) by treatment with ethyl acetate-HCl. 1H 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−
* Supporting Information
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.9b00022. Spectral data of selected intermediates and final compound (PDF)
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AUTHOR INFORMATION
Corresponding Author
*Fax: +91-20-39821445; E-mail: chinmoy.pramanik@emcure. co.in. ORCID
Chinmoy Pramanik: 0000-0002-0109-311X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors wish to thank Mr. Samit Mehta and our management and ARD group of Emcure Pharmaceuticals Ltd. for their willing support and constant encouragements.
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REFERENCES
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