An Efficient Synthesis of 4-Aminomethyl-1-(2- Phenylethyl)-Piperidin-4-ol: A Key Intermediate in Fenspiride HCl Synthesis

The article confers a scalable manufacturing process of Fenspiride HCl. 4-aminomethyl-1-(2phenylethyl)-piperidin-4-ol is the main building block in Fenspiride HCl synthesis. The reported reagents for 4-aminomethyl-1-(2-phenylethyl)-piperidin-4-ol synthesis are costly, explosive, highly toxic, produce hazardous waste, and also need to be handled with most care. The paper introduces aqueous ammonia as an alternate reagent in Fenspiride HCl and used in 4-aminomethyl-1-(2phenylethyl)-piperidin-4-ol synthesis. The new green chemistry aspect makes the process environment-friendly and cheaper. It also eliminates toxic, sensitive, and hazardous reagents and makes the process safe on uncomplicated on bulk scale production. The high pure Fenspiride HCl is obtained by following this process and meets the ICH limits with good yield.


Fenspiride
{8-(2-phenylethyl)-1-oxa-3, 8diazaspiro [4,5] decan-2-oneHCl} (1) is an oxazolidinone spiro compound and used for respiratory diseases treatment [1]. It has antitussives properties and is mainly used in the treatment of acute and chronic inflammatory diseases of ENT organs and respiratory, as well as it also widely in the maintenance treatment of asthma [2]. It is also been used for the treatment of allergy within otolaryngology system and respiratory tracts, respiratory manifestations of measles, flu, and symptomatic therapy of whooping cough [3,4] and has a potential benefit in endotoxemia treatment [5].
In the detailed literature survey for Fenspiride HCl (1), we found that limited literature available for the synthesis of Fenspiride HCl (1) which includes, use of several hazardous reagents and is difficult to handle on the bulk scale manufacturing.

Fig. 1. Structure of Fenspiride HCl
Although it is a very old drug, a detailed review of the literature revealed that there are very few processes available for the synthesis of Fenspiride hydrochloride (1).
Later, Ida Taccone reported the synthesis of Fenspiride [8], 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 transposition [9] with excess nitrous acid (Scheme 2, route I) to afford fenspiride.
Pramanik et.al [11] reported the synthesis (Scheme 4) starting from N-(2-phenylethyl)-4piperidone (2) which was undergoes for nitro aldol condensation with nitro methane in presence of potassium carbonate, followed by zinc reduction to get intermediate 4. Finally, BOC anhydride is used for cyclization to arrive at Fenspiride HCl (1).
It is reported that Nitroalkanes [12] have peculiar properties and to be handled with extreme care. Specifically while using nitro methane with strong base special care to taken to avoid the alkali metal salt formation, which is very shock-sensitive and may undergo the explosion in dry condition.
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 team [13] (Scheme 3). Piperidone 2 on Corey−Chaykovsky [14] 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 conditions 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 HCl which provided the target molecule fenspiride HCl with high HPLC purity (>99.7%) complying with 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 and produces high quality API, the process owns the risk/safety factor associated with the use of NaN3 along with the effluent treatment after reaction, the process could not be scaled up.

METHODOLOGY
All materials were purchased from commercial suppliers. Unless specified otherwise, all reagents and solvents were used as supplied by manufaturers. 1 HNMR spectra and 13 C NMR CDCl 3 and DMSO-d 6 and mass spectra were determined on an API-2000LCMS mass spectrometer from Biosystems.
After completion of the reaction, water was added to the stirred reaction mass, followed by the addition of toluene with continued stirring. Separation and concentration of the organic layer provided 4-tertiary-butoxy aminomethyl-1-(2phenylethyl)-piperidin-4-ol which was diluted with dichloromethane (500ml). The organic layer was separated and concentrated to give 4tert.butoxyaminomethyl-1-(2-phenylethyl)piperidin-4-ol of formula (14).

Example 3: Preparation of Fenspiride (1)
Sodium tertiary butoxide (47.3g) was gradually added to a mixture of toluene (800 ml) and compound (14)(145g), obtained in example 2, with stirring and the reaction mass heated between 95°C and 110°C, till completion of the reaction, as monitored by HPLC. The reaction mass was cooled and concentrated under reduced pressure, followed by the addition of water and filtration.
Ethyl acetate and water were then added to the solid obtained after filtration and heated between 35°C and 45°C. Organic layer separation followed by concentration gave a residue. Gradual addition of ethyl acetate to the residue separated out Fenspiride base, which was filtered after cooling. The wet cake was optionally washed with ethyl acetate and dried under a vacuum.

RESULTS AND DISCUSSION
The available literature on Fenspiride hydrochloride gives numerous methods of preparation that are full of hazardous reagents. As part of our ongoing efforts toward developing an efficient, commercially viable process of generic drugs, we decided to look for a better process involving simpler reagents/reaction conditions that result in hazard less manufacturing of Fenspiride. To meet our requirement, it is needed to enhance the batch size and exclude the hazardous reagent from the process Amino alcohol intermediate -(4) synthesis involves the hazardous reagents, hence we focused on the amino alcohol intermediate - (4) synthesis. Specifically, we decided to eliminate the use of reagents like LAH, NaN 3 , and Hydrazine from the synthesis. To make the hazard-free manufacturing of Fenspiride HCl, we came up with a strategy from pyridone -(2) via epoxide-(10) which could be easily converted to the critical/penultimate amino alcohol intermediate - (4) and subsequently Fenspiride HCl.  Starting with compound 2, on base promoted reaction with trimethyl sulphoxonium iodide provided epoxide derivative (10) with good quality and yield (Scheme 6). Using this route, we manufactured the epoxide derivative (10) on 150 kg scale The reaction mainly involves the epoxide ring opening by aqueous ammonia and which yields in the C-N bond formation. Pursuant, to our retrosynthetic strategy, epoxide ring opening of compound (10) with the aqueous ammonia was affected with the mild condition using aq ammonia as a base and reagent in methanol at room temperature to furnish the critical intermediate- (4) with excellent yield and purity ( scheme no 6).later we protected the amine -4 as its BOC derivative. The BOC-protection was attempted the cyclisation (isoxazolidone formation) of intermediate (14) under basic conditions, which would directly provide us the desired Fenspiride free base and subsequently HCl salt (1).

CONCLUSION
In conclusion, we developed a new process for the large scale manufacturing of Fenspiride hydrochloride involving simple process reagents/conditions. The article describes the synthesis of 4-aminomethyl-1-(2-phenylethyl)piperidin-4-ol using aq. ammonia as a new reagent in the synthesis. Which abolish the reagents, sodium azide, KCN, LAH nitromethane, hydrazine from the process and make the process simple and robust. The advanced process avoids the use of explosive reagents like nitromethane, and lethal reagents like palladium, zinc, which was used in the earlier synthetic routes of intermediate-4. The new synthesis makes the process cost-effective and commercially viable. Considering the operational simplicity on an industrial scale, all the chemicals and reagents which are used in the present route are very easy to handle on large-scale application.

DISCLAIMER
The products used for this research are commonly and predominantly use products in our area of research and country. There is absolutely no conflict of interest between the authors and producers of the products because we do not intend to use these products as an avenue for any litigation but for the advancement of knowledge. Also, the research was not funded by the producing company rather it was funded by personal efforts of the authors.

CONTENT
Spectral Copies of IR, ESI-MS, 1 H NMR, 13 C NMR and Elemental analysis of compound 4, 1. This material is available after references.

ETHICAL APPROVAL
It is not applicable.