FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13) TITLE OF THE INVENTION
"An Improved Process for Preparation of Fenspiride"
Emcure Pharmaceuticals Limited,
an Indian company, registered under the Indian Company's Act 1957
and having its registered office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to a simple, convenient process for the preparation of Fenspiride hydrochloride (la), conforming to regulatory specifications. More specifically, the invention relates to a novel method for synthesizing the oxazolidinone ring in Fenspiride (I) starting from 6-(2-phenylethyl)-l-oxa-6-azaspiro[2.5]octane of formula (III), which provides Fenspiride hydrochloride (la) of desired purity..
BACKGROUND OF THE INVENTION
Fenspiride of formula (I), chemically known as 8-(2-phenylethyl)-l-oxa-3,8-diazaspiro[4.5]decan-2-one and administered as its hydrochloride salt, is marketed under various brand names such as Decaspir, Fluiden, Espiran, Pneumorel, Respiride and Tegencia. The drug product exhibits anti-inflammatory, bronchodilatory activity and is indicated for diseases of upper and lower respiratory tract such as bronchial asthma, bronchitis, nasopharyngitis and laryngitis.

Various processes reported in the literature for preparation of Fenspiride focus on synthesis of the oxazolidinone ring, which is a characteristic feature in the structure of Fenspiride (I). US 3,399,192 discloses a process wherein the oxazolidinone ring is synthesized by cyanation of l-(2-phenylethyl)-4-piperidone followed by reduction of the corresponding cyanohydrin moiety with aluminium alanate and subsequent introduction of the carbonyl group in the resulting l-(2-phenylethyl)-4-aminomethyl-4-hydroxy piperidine using diethyl carbonate in presence of sodium methylate, to obtain the final product, Fenspiride (I).

The process involves use of highly toxic cyanide compounds as well as hazardous, moisture sensitive reagent such as aluminium alanate, which is highly flammable, and ignites on contact with moisture or in humid conditions. Therefore, the process has restrictions for its use on an industrial scale.
US 4,028,351 discloses a method, wherein the oxazolidinone moiety is introduced in the molecule by a sequence of reactions on the corresponding ketone, N-(2-phenylethyl)-4-piperidone. The method comprises reaction of N-(2-phenylethyl)-4-piperidone with ethyl bromoacetate in presence of activated zinc using a solvent mixture of benzene and ether to give ethyl-4-hydroxy-l-phenylethyl-4-piperidine acetate. The resultant ester on reaction with excess hydrazine hydrate in benzene gives 4-hydroxy-l-phenethyl-4-piperidineacetic acid hydrazide, which is further reacted with sodium nitrite in presence of hydrochloric acid to yield Fenspiride (I).
Although this process avoids use of hazardous cyanides, however, the use of highly carcinogenic and inflammable solvents like benzene and ether, use of zinc metal which requires elaborate separation method during work up for removal of zinc hydroxide sludge and specific disposal procedures during effluent treatment, restrains the use of this process on a commercial scale. Further, involvement of a rearrangement reaction in the sequence, and potentially hazardous intermediates such as acid hydrazides considerably reduces the yield of the desired product.
Synthetic Communication, 1994, 24(10), 1483-1487 discloses a process which involves reaction of 4-piperidone with trimethylsilyl cyanide, followed by reduction of the resulting product with lithium aluminium hydride and subsequent cyclization with triphosgene to give Fenspiride. The process utilizes hazardous reagents like trimethylsilyl cyanide, lithium aluminium hydride and triphosgene, which are extremely dangerous for utilization on a commercial scale. Trimethylsilyl cyanide is highly moisture sensitive and releases extremely toxic hydrogen cyanide gas on contact with water. Further, lithium aluminium hydride employed in the reduction step requires stringent anhydrous conditions as it is a very explosive hazard when it comes in contact with moisture.

Thus, there still exists a need for a convenient, easy-to-scale up process for synthesis of Fenspiride (I) which avoids hazardous reactions such as cyanation and reagents like lithium aluminium hydride but employs a simple and cost-effective synthetic approach for incorporating the key functionality; the oxazolidinone ring in the Fenspiride molecule.
The present inventors have developed a process for synthesis of Fenspiride (I) in which the oxazolidinone ring is introduced by reaction of alkali cyanate with the corresponding epoxide, 6-(2-phenylethyl)-l-oxa-6-azaspiro-[2.5] octane of formula (III).
OBJECT OF THE INVENTION
An objective of the present invention is to provide Fenspiride hydrochloride of formula (la) having desired purity by a convenient, and industrially viable process which does not involve use of toxic and hazardous reagents such as potassium cyanide.
Another object of the present invention is to provide an efficient and cost-effective process for preparation of Fenspiride hydrochloride (la) comprising reaction of alkali cyanate with 6-(2-phenylethyl)-l-oxa-6-azaspiro-[2.5] octane of formula (III) for introducing the oxazolidinone moiety in the Fenspiride molecule.
SUMMARY OF THE INVENTION
The present invention relates to a novel method for synthesis of 8-(2-phenylethyl)-l-oxa-3,8-diazaspiro[4.5]decan-2-one hydrochloride of formula (la) having desired purity.
An aspect of the invention relates to a novel and cost-effective process for preparation of 8-(2-phenylethyl)-l-oxa-3,8-diazaspiro[4.5]decan-2-one (I) by a process comprising reaction of 6-(2-phenylethyl)-l-oxa-6-azaspiro [2.5] octane of formula (III) with an alkali cyanate in a solvent or its mixture with water thereof at a temperature of 90-100°C and isolating Fenspiride (I), which on treatment with hydrogen chloride gave Fenspiride hydrochloride (la) in good yield and purity conforming to regulatory specifications.

Another aspect of the invention relates to a novel and cost-effective process for preparation of 8-(2-phenylethyl)-l-oxa-3,8-diazaspiro[4.5]decan-2-one (I) by a process comprising reaction of 6-(2-phenylethyl)-l-oxa-6-azaspiro [2.5] octane of formula (III) with potassium cyanate in a solvent or its mixture with water thereof at a temperature of 90-100°C and isolating Fenspiride (I), which on further treatment with hydrogen chloride gave Fenspiride hydrochloride (la) in good yield and purity conforming to regulatory specifications.
The objectives of the present invention will become more apparent from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
Various synthetic routes are reported in the literature for construction of oxazolidinone ring in active pharmaceutical ingredients or their intermediates. While pursuing the development of an industrially viable and economical process for Fenspiride, the present inventors have surprisingly found that oxazolidinone ring can be introduced in the Fenspiride molecule by reaction of an alkali cyanate such as sodium or potassium cyanate with the corresponding epoxide. This method not only avoids multiple synthetic steps for the synthesis of the oxazolidinone moiety but also circumvents problems such as higher proportion of associated impurities, longer reaction time and reactor occupancy but also provides Fenspiride (I) of desired purity and in good yield.

Scheme 1: Method embodied in the present invention for the preparation of Fenspiride hydrochloride (I)

In an embodiment, 6-(2-phenylethyl)-l-oxa-6-azaspiro [2.5] octane of formula (III), which is obtained by the method disclosed in Journal of Heterocyclic Chemistry, (1978), Vol.15, p.675-676, was treated with alkali cyanate such as potassium cyanate at 90 to 100°C, which upon completion of the reaction, as monitored by HPLC, yielded 8-(2-phenylethyi)-l-oxa-3,8-diazaspiro[4.5]decan-2-one of formula (I). The reaction was carried out in presence of a water miscible organic solvent or its mixture with water thereof.
The organic solvent was selected from the group comprising of N-methyl pyrrolidone, dimethyl sulfoxide and dimethyl formamide but preferably N-methyl pyrrolidone.
When the above mentioned reaction was carried out using aqueous solution of the organic solvent, the proportion of water was varied over a range of 10 to 50% with respect to the volume of solvent and it was observed that better yields were obtained when water to solvent proportion was around 25:75.
After completion of reaction based on HPLC monitoring, the reaction mass was extracted with a water-immiscible organic solvent like dichloromethane and the organic layer concentrated to give Fenspiride base (I). The free base was converted to Fenspiride hydrochloride (la) by treatment with hydrogen chloride in an organic solvent. The organic solvent was selected from a group comprising methanol, ethanol, acetone, methyl isobutyl ketone etc but preferably methyl isobutyl ketone. The salt formation was carried out in the temperature range of 5-15 °C.
Fenspiride hydrochloride salt which precipitated out was filtered and dried. The finished product which was obtained in good yield conformed to regulatory specifications.
It is pertinent to note that starting with the epoxide of formula (III), the present invention affords Fenspiride in a single step. This is in stark contrast to prior art methods wherein the oxazolidinone ring is introduced by subjecting the piperidone derivative to multiple synthetic steps such as
i) treatment of piperidone derivative with ethyl bromoacetate, followed by preparation of the acid hydrazide and rearrangement of hydrazide to oxazolidinone or

ii) by reaction of the piperidone derivative with trimethylsilyl cyanide, followed by reduction and subsequent reaction of the cyanohydrin intermediate with a carbonyl coupling agent like triphosgene. Thus, the synthetic method disclosed in the present invention affords Fenspiride in fewer synthetic steps as compared to methods in the prior art.
The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.
EXAMPLES Example 1
Preparation of 6-(2-phenylethyl)-l-oxa-6-azaspiro [2.5] octane (III)
A mixture of trimethyl sulfoxonium iodide (142gms) and dimethyl sulfoxide (300 ml) was stirred and cooled to 5-10°C. An aqueous solution of sodium hydroxide (40 gms in 300 ml water) was slowly added to the mixture, followed by gradual addition of l-(2-Phenylethyl)piperidin-4-one (II; 100 gms) at 5-10°C. The reaction temperature was raised to 25-30°C and the mixture was stirred till completion of the reaction, as monitored by TLC. The reaction mass was quenched with water and extracted with ethyl acetate at room temperature. The separated organic layer, upon concentration, gave 6-(2-phenylethyl)-l-oxa-6-azaspiro [2.5] octane (III) as a light brown colored liquid. Yield: 102gms; %Yield: 96% Purity: > 99%
Example 2
Preparation of Fenspiride hydrochloride (la)
Potassium cyanate (28 gms) was added to a solution of N-(2-phenylethyl)-2-oxo-6-azaspiro [2.5] octane (II; 25gms) in a 75:25 mixture of N-methyl pyrrolidone: water (100 ml) and heated to 90 -100 °C. After completion of the reaction, as monitored by HPLC, the reaction

mixture was cooled, quenched with water and extracted with dichloromethane. Separation of the organic layer, followed by concentration yielded Fenspiride base (I). Hydrogen chloride gas was purged in to a mixture of Fenspiride (25 gms) in methyl isobutyl ketone (75 ml) in the temperature range of 5-10°C. Precipitated hydrochloride salt was filtered and dried to give Fenspiride hydrochloride (la). Yield: 25.6 g Purity: 99.5%

We claim,
1. A process for preparation of Fenspiride hydrochloride of formula (la), comprising reaction of 6-(2-phenylethyl)-l-oxa-6-azaspiro[2.5]octane of formula (III) with alkali cyanate in an organic solvent or its mixture with water thereof at a temperature of 90-100°C and isolating Fenspiride (I), which on further treatment with hydrogen chloride in methyl isobutyl ketone as solvent gives Fenspiride hydrochloride (la).
2. A process according to claim 1, wherein the alkali cyanate is selected from sodium cyanate, potassium cyanate.
3. A process according to claim 1, wherein the organic solvent is selected from the group comprising of N-methyl pyrrolidone, dimethyl sulfoxide and dimethyl formarnide.
4. A process according to claims 1, wherein the organic solvent is preferably a mixture of N-methyl pyrrolidone and water.
5. A process according to claims 1 and 4, wherein the proportion of the organic solvent and water is between 9:1 and 1:1.
6. A process according to claims 1 and 5, wherein the proportion of the organic solvent and water is preferably 3:1.
7. A process according to claim 1, wherein Fenspiride (I) is isolated from the reaction mixture by cooling the mixture, quenching with water, extracting with a water-immiscible organic solvent and concentrating the organic layer to give Fenspiride (I).