DESC:FIELD OF THE INVENTION

The present invention relates to the process for the preparation of fenspiride having desired purity. Specifically, the invention relates to a process for fenspiride comprising amination of the epoxide 6-(2-phenylethyl)-1-oxa-6-azaspiro [2.5] octane (3), followed by reaction of resultant amino alcohol, 4-(aminomethyl)-1-(2-phenylethyl) piperidin-4-ol (4) with di-tertiarybutyl dicarbonate and cyclization of the resultant tertiarybutoxycarbonyl derivative (5) to provide fenspiride (1) having purity conforming to regulatory specifications.

BACKGROUND OF THE INVENTION

Fenspiride of formula (1), chemically known as 8-(2-phenylethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one is known to exhibit anti-inflammatory, bronchodilatory activity relating to upper and lower respiratory tract. The compound fenspiride, which is administered as its hydrochloride salt, is used in the treatment of diseases such as bronchial asthma, bronchitis, nasopharyngitis and laryngitis.

Fenspiride (1)
Fenspiride hydrochloride (1a)

Various processes reported in the literature for the preparation of fenspiride focus on synthesis of the oxazolidinone ring, which is a prominent feature in the fenspiride molecule. The process for preparation of fenspiride (1) was first disclosed in US 3,399,192 wherein the oxazolidinone ring was synthesized by cyanation of 1-(2-phenylethyl)-4-piperidone, followed by reduction of the corresponding cyanohydrin intermediate with aluminium alanate. Subsequent introduction of a carbonyl group in the resulting 1-(2-phenylethyl)-4-aminomethyl-4-hydroxy piperidine was carried out using diethyl carbonate in presence of sodium methylate. The method is suitable only for academic purpose, as it has serious industrial limitations due to the utilization of highly toxic cyanide compounds. The method also involves a hazardous, moisture sensitive reagent such as aluminium alanate, which is flammable and ignites on contact with moisture or in humid conditions, further adding to the disadvantages.

US 4,028,351 discloses a method wherein the oxazolidinone moiety in fenspiride is synthesized by 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-1-phenylethyl-4-piperidine acetate. The resultant ester, on reaction with excess hydrazine hydrate in benzene gives 4-hydroxy-1-phenethyl-4-piperidineacetic acid hydrazide, which is further reacted with sodium nitrite in presence of hydrochloric acid to yield fenspiride (1).

The said process, which does not involve hazardous cyanides, however, is quite lengthy in terms of reaction sequence, tedious isolation procedures and includes highly carcinogenic and inflammable solvents like benzene and ether. It further comprises use of zinc metal, which necessitates elaborate work up for removal of zinc hydroxide sludge and specific disposal procedures during effluent treatment. These factors seriously limit the implementation of the process on a commercial scale. Further, use of potentially hazardous intermediates such as acid hydrazides and involvement of a rearrangement reaction in the sequence considerably reduces the yield of the desired product, thus making it economically unviable.

Synthetic Communication, 1994, 24(10), 1483-1487 describes a process which involves reaction of N-(2-phenylethyl)-4-piperidone with trimethylsilyl cyanide, followed by reduction of the resulting cyanohydrin derivative 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 dangerous for use 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 due to its moisture sensitive nature and the possible hazard of explosion when it comes in contact with moisture.

ES 548648 discloses a process involving partial hydrogenation of 4-nitromethyl-1-(2-phenylethyl)piperidin-4-ol to give the corresponding hydroxyl (hydroxyl- aminomethyl) piperidine intermediate. Further reaction of the said intermediate with phosgene, followed by hydrogenation of the resulting hydroxamic acid derivative furnishes the oxazolidinone ring of fenspiride.

Based on the above discussion of prior art procedures, it would be evident that synthesis of the oxazolidinone ring in fenspiride involves different carbonylation reagents like phosgene, diethyl carbonate, carbonyl diimidazole etc. While hazardous, inflammable reagents like phosgene, diethyl carbonate create safety problems for the process, use of relatively safe carbonylating agents like carbonyl diimidazole involves a different procedural difficulty. The process includes removal of organic by-products like imidazole from the final product, which poses problems, requires additional unit operations in the manufacturing process leading to longer batch-cycle time and ultimately adding to the cost.
Further, keeping the industrial applicability in view, the synthetic processes for obtaining the precursors and intermediates for oxazolidinone derivative also needed to be short, convenient, high-yielding, free from use of hazardous reagents and most importantly, cost-effective.

Thus, there still exists a need for a convenient, easy-to-scale up process for synthesis of fenspiride (1) which avoids hazardous cyanation reactions, reagents like lithium aluminium hydride and uses a simple, convenient approach, involving minimum possible synthetic steps for incorporating the oxazolidinone ring in the desired molecule.

The present inventors have developed a process for synthesis of fenspiride (1) wherein facile synthesis of 4-aminomethyl-1-(2-phenylethyl)-piperidine-4-ol (4), followed by reaction with ditertiarybutyl dicarbonate and cyclization of the resulting intermediate, 4-tertiarybutoxyaminomethyl-1-(2-phenylethyl)-piperidin-4-ol (5) provides the desired compound. Intermediate (4) was prepared in two convenient, high-yielding steps starting with N-(2-phenylethyl)-4-piperidone of formula (2).

OBJECT OF THE INVENTION
An objective of the present invention is to provide fenspiride hydrochloride of formula (1a) having desired purity by a convenient and industrially viable process which does not involve use of toxic and hazardous reactions such as cyanation or reductions with moisture sensitive reagents like lithium aluminium hydride.

Another object of the present invention is to provide an efficient and cost-effective process for preparation of fenspiride (1) comprising synthesis and the subsequent facile cyclization of the key intermediate, 4-tertiarybutoxyaminomethyl-1-(2-phenylethyl)-piperidin-4-ol (5).
SUMMARY OF THE INVENTION
The present invention relates to a novel method for synthesis of 8-(2-phenylethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one hydrochloride of formula (1a) having desired purity.

An aspect of the invention relates to a process for preparation of fenspiride hydrochloride (1a) comprising treating 6-(2-phenylethyl)-1-oxa-6-azaspiro[2.5] octane (3) with aqueous ammonia in methanol to give 4-(amino methyl)-1-(2-phenylethyl) piperidin-4-ol (4), further reaction with ditertiarybutyl dicarbonate in presence of a base and a solvent to give 4-tertiarybutoxyaminomethyl-1-(2-phenylethyl)-piperidin-4-ol (5), reacting (5) with a base in an organic solvent to give fenspiride (1), followed by treatment with hydrochloric acid in isopropyl alcohol to yield fenspiride hydrochloride (1a).

The objectives of the present invention will become more apparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION
Construction of oxazolidinone ring in active pharmaceutical ingredients (APIs) or their intermediates has always been a challenging task for chemists and a wide range of synthetic methods have been reported in literature for the same. While pursuing the development of an industrially viable and economical process for synthesis of fenspiride, the present inventors surprisingly found out that oxazolidinone ring in the fenspiride molecule can be easily formed by preparation and subsequent cyclization of the key intermediate, 1-(2-phenylethyl)-4-tertiarybutoxyaminomethyl piperidin-4-ol of formula (5).

Based on the construction of oxazolidinone ring, which is an important aspect of structure of fenspiride, the inventors continued the process development related to synthesis of the tertiarybutoxy intermediate (5).
The intermediate (5) was prepared by epoxidation of 1-(2-phenylethyl)-4-piperidone (2) using trimethylsulfoxonium iodide, followed by ring-opening and amination in presence of ammonia to give 4-aminomethyl-1-(2-phenylethyl)-piperidine-4-ol (4).
A highly facile reaction with di-tertiarybutyl dicarbonate furnished the desired intermediate (5). Further cyclization of (5) in presence of base and organic solvent provided fenspiride (1), which on treatment with hydrochloric acid furnished the hydrochloride salt (1a).


Scheme 1: Method embodied in the present invention for the preparation of fenspiride hydrochloride (1a)
The present strategy avoided use of hazardous carbonylation reagents for construction of oxazolidine ring, and also eliminated additional purification steps for separating the side products in the carbonylation reaction. Tertiary butanol, which was the side product of this facile, high-yielding cyclization of 4-tertiarybutoxy aminomethyl-1-(2-phenylethyl)piperidin-4-ol (5), could be easily removed from the reaction during work up. As a result, no additional step was needed for removal of side product. Thus, by eliminating hazardous reagents and multiple synthetic steps for the synthesis of oxazolidinone moiety, problems such as higher amounts of associated impurities, longer reaction times were avoided, and fenspiride hydrochloride (1a) having desired purity was obtained in good yield.

Prior art methods disclose treatment of 1-(2-phenylethyl)-4-piperidone (2) with nitromethane to give the nitro derivative (2a), which, when subjected to hydrogenation/reduction provides the desired amino compound (4). The synthesis comprises use of hazardous nitromethane, which is an inflammable, explosive liquid with a low flash point of 360C. The synthesis also includes additional step of reducing the nitro group to desired amino functionality, which is done either by catalytic hydrogenation or under Clemmensen reduction conditions in presence of Zinc, hydrochloric acid. The present inventors observed that in addition to operational inconvenience involved in commercial use of reagents like nitromethane and zinc, synthesis of (4) employing these methods resulted in yield loss of almost 15% and consequent increase in project cost.

Scheme 2: Prior art method for synthesis of compound (4)

In an embodiment, 1-(2-phenylethyl)-4-piperidone of formula (2) was treated with trimethylsulfoxonium iodide at 0°C to 15°C in an organic solvent in presence of a base to provide 6-(2-phenylethyl)-1-oxa-6-azaspiro [2.5] octane of formula (3).

The organic solvent was selected from the group of polar aprotic solvents comprising dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N-methyl-2-pyrrolidone etc., preferably dimethyl sulfoxide. The base was selected from the group of inorganic bases comprising alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide etc. In the reaction, the base was preferably used as an aqueous solution.

After completion of reaction as monitored by TLC and HPLC, the reaction mixture was quenched with water and extracted with an organic solvent such as ethyl acetate. Separation and concentration of the organic layer provided the desired epoxide (3).

In another embodiment, compound (3) was dissolved in an organic solvent selected from the group of alcohols such as methanol, ethanol, n-propanol, isopropanol etc. and treated with aqueous ammonia at ambient temperature. After completion of the reaction as monitored by TLC and HPLC, the reaction mixture containing 4-aminomethyl-1-(2-phenylethyl)-piperidin-4-ol (4), was partially concentrated and used in-situ for further reaction.

Optionally, the reaction mixture or the concentrated residue was quenched with water and extracted with a water-immiscible solvent like dichloromethane. The organic layer was separated and concentrated to give the desired amino-alcohol (4).

In yet another embodiment, compound (4) or the reaction mass containing compound (4) was treated with di-tertiarybutyl dicarbonate, also known as Boc-anhydride, in an organic solvent, at 150C to 350C, in presence of a base. The solvent was selected from water as well as from the group of alcohols such as methanol, ethanol, n-propanol, isopropanol etc. and mixtures thereof.
The base was selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide etc.
After completion of the reaction as monitored by HPLC, the reaction mass was quenched with water and extracted with a hydrocarbon solvent selected from xylene, toluene, cyclohexane etc. Separation and concentration of the organic layer provided a residue which contained 4-tert-butoxyaminomethyl-1-(2-phenylethyl)-piperidin-4-ol (5). Optionally, the organic layer containing the desired compound (5) was subjected to cyclization in presence of a base to provide fenspiride (I).

In a further embodiment, compound (5), dissolved in an organic solvent was treated with a base. Alternatively, the organic layer containing compound (5) was directly subjected to reaction with the base. The reaction mixture was stirred at 90°C to 120°C.
The organic solvent was selected from the group comprising xylene(s), toluene, cyclohexane etc., preferably toluene.
The base was selected from alkali metal alkoxides derived from methanol, ethanol, tertiary butanol and alkali metals such as sodium and potassium. The base was preferably sodium tertiary butoxide.
After completion of reaction, the mixture was cooled, concentrated and quenched with water, followed by stirring and filtration.
Water and ethyl acetate were added to the filtered solid and the mixture was stirred at 35°C to 45°C. The organic layer was separated and after optional charcoal treatment, concentrated to give fenspiride which was then optionally treated with ethyl acetate.

Fenspiride (1) was converted to its hydrochloride salt by dissolving in a solvent such as isopropyl alcohol and treated with hydrogen chloride at 60-800C. The reaction mixture was stirred at 65-75°C till completion of the salt formation. After completion of reaction, the mass was cooled, stirred, and filtered to provide fenspiride hydrochloride (1a) having purity conforming to regulatory specifications. The hydrochloride salt so obtained was optionally treated with methyl isobutyl ketone.
Alternatively, fenspiride base was treated with gaseous hydrogen chloride using solvents such as methanol, ethanol, isobutanol, acetone, methyl isobutyl ketone, ethyl acetate etc.to provide the hydrochloride salt.
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)-1-oxa-6-azaspiro [2.5] octane (3)

Trimethylsulfoxonium iodide (140.3 g) was added to dimethyl sulfoxide (300 ml) and the mixture was cooled to 5°C to 10°C. Aqueous sodium hydroxide solution (40.0 g in 300 ml water) was slowly added to the mixture and stirred at the same temperature. 1-(2-phenylethyl)-4-piperidone (100.1 g) was then added to the stirred mixture at 50C to 100C, till completion of the reaction, as monitored by TLC and HPLC.
After completion, water was gradually added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was separated and concentrated to provide 6-(2-phenylethyl)-1-oxa-6-azaspiro [2.5] octane (3).
Yield: 101.12 g (95 %)
Purity: > 98 %

Example 2: Preparation of 4-aminomethyl-1-(2-phenylethyl)-piperidin-4-ol (4)

Aqueous ammonia solution (2000 ml) was placed in a round bottom flask and cooled to 150C to 250C. The solution of 6-(2-phenylethyl)-1-oxa-6-azaspiro [2.5] octane (3), obtained according to the procedure in Example 1, in methanol (500 ml) was gradually added to it with continued stirring. The reaction was continued at 15°C to 30°C, till completion, as monitored by TLC and HPLC.
After completion, the reaction mixture was partially concentrated to provide a residue containing 4-aminomethyl-1-(2-phenylethyl)-piperidin-4-ol (4), which was used for further reaction.
Yield: 98.05 g (90 %)
Purity: > 94 %

Example 3: Preparation of 4-tertiary-butoxy aminomethyl-1-(2-phenylethyl)-piperidin-4-ol (5)

Sodium hydroxide (59.0 g) was added to the partially concentrated mass containing compound (4) obtained in Example 2, and the mixture was cooled to 200C to 300C. Ditertiarybutyl dicarbonate (214.4 g) in methanol (300 ml) was then gradually added to it with continued stirring. The resulting mixture was stirred at 250C to 350C till completion of the reaction as monitored by HPLC.
After completion of the reaction, water was added to the stirred reaction mass, followed by addition of toluene with continued stirring. Separation and concentration of the organic layer provided 4-tertiary-butoxy aminomethyl-1-(2-phenylethyl)-piperidin-4-ol of formula (5).
Yield: 125.9 (90 %)
Purity: >96%
Example 4: Preparation of 4-tertiary-butoxy aminomethyl-1-(2-phenylethyl)-piperidin-4-ol (5)
Sodium hydroxide (11.8 g) was added to the solution of compound (4, 19.6 g) in isopropanol (25 ml), and the mixture was cooled to 200C to 300C. Di-tertiarybutyl dicarbonate (42.88 g) in isopropanol (75 ml) was then gradually added to it with continued stirring. The resulting mixture was stirred at 250C to 350C till completion of the reaction as monitored by HPLC.
After completion of the reaction, water was added to the stirred reaction mass, followed by addition of toluene with continued stirring. Separation and concentration of the organic layer provided 4-tertiary-butoxy aminomethyl-1-(2-phenylethyl)-piperidin-4-ol of formula (5).
Yield: 23.5 g (84%)
Purity: >93%

Example 5: Preparation of 4-tertiary-butoxy aminomethyl-1-(2-phenylethyl)-piperidin-4-ol (5)
Sodium hydroxide (17.7 g) was added to the solution of compound (4, 29.4 g) in ethanol (40 ml), and the mixture was cooled to 200C to 300C. Ditertiarybutyl dicarbonate (64.32 g) in n-propanol (110 ml) was then gradually added to it with continued stirring. The resulting mixture was stirred at 250C to 350C till completion of the reaction as monitored by HPLC.
After completion of the reaction, water was added to the stirred reaction mass, followed by addition of toluene with continued stirring. Separation and concentration of the organic layer provided 4-tertiary-butoxy aminomethyl-1-(2-phenylethyl)-piperidin-4-ol of formula (5).
Yield: 34.4 g (77%)
Purity: >94%

Example 6: Preparation of 4-tertiary-butoxy aminomethyl-1-(2-phenylethyl)-piperidin-4-ol (5)
Potassium hydroxide (16.5 g) was added to the solution of compound (4, 19.6 g) in isopropanol (25 ml), and the mixture was cooled to 200C to 300C. Ditertiarybutyl dicarbonate (44.50 g) in isopropanol (75 ml) was then gradually added to it with continued stirring. The resulting mixture was stirred at 250C to 350C till completion of the reaction as monitored by HPLC.
After completion of the reaction, water was added to the stirred reaction mass, followed by addition of toluene with continued stirring. Separation and concentration of the organic layer provided 4-tertiary-butoxy aminomethyl-1-(2-phenylethyl)-piperidin-4-ol of formula (5).
Yield: 24.1 g (86%)
Purity: >95%

Example 7: Preparation of 4-tertiary-butoxy aminomethyl-1-(2-phenylethyl)-piperidin-4-ol (5)
Lithium hydroxide (4.0 g) was added to the solution of compound (4, 9.8 g) in methanol water mixture (20 ml), and the solution was cooled to 200C to 300C. Ditertiarybutyl dicarbonate (21.44 g) in methanol (50 ml) was then gradually added to it with continued stirring. The resulting mixture was stirred at 250C to 350C till completion of the reaction as monitored by HPLC.
After completion of the reaction, water was added to the stirred reaction mass, followed by addition of toluene with continued stirring. Separation and concentration of the organic layer provided 4-tertiary-butoxy aminomethyl-1-(2-phenylethyl)-piperidin-4-ol of formula (5).
Yield: 11.2 g (80%)
Purity: >94%

Example 8: Preparation of Fenspiride (1)
Sodium tertiary butoxide (47.3g) was gradually added to the stirred mixture of toluene (800 ml) and compound (5) as obtained in Example 3, and the reaction mass was heated to 95°C to 110°C, till completion of reaction, as monitored by HPLC.
After completion of the reaction, the reaction mass was cooled and concentrated under reduced pressure, followed by addition of water and filtration.
Ethyl acetate and water were then added to the solid obtained after filtration and mixture was heated between 350C and 450C. Organic layer separation followed by concentration gave a residue. Gradual addition of ethyl acetate to the residue separated out fenspiride base (1), which was filtered after cooling. The wet cake was optionally washed with ethyl acetate before drying.
Yield: 78.5 g (80 %)
Purity: >99.90 %

Example 9: Preparation of Fenspiride (1)
Sodium ethoxide (3.9 g) was gradually added to the stirred mixture of ethanol (10ml), xylene (40 ml) and compound (5, 12.6 g) and the reaction mass was heated to 95°C to 110°C, till completion of reaction, as monitored by HPLC.
After completion of the reaction, the reaction mass was cooled and concentrated under reduced pressure, followed by addition of water and filtration.
Ethyl acetate and water were then added to the solid obtained after filtration and mixture was heated between 350C and 450C. Organic layer separation followed by concentration gave a residue. Gradual addition of ethyl acetate to the residue separated out fenspiride base (1), which was filtered after cooling. The wet cake was optionally washed with ethyl acetate before drying.
Yield: 7.3 g (74%)
Purity: >97 %
A similar procedure was followed using potassium methoxide as a base and a mixture of toluene and cyclohexane for cyclization step to obtain fenspiride having purity greater than 96% in78% yield.

Example 10: Preparation of Fenspiride hydrochloride (1a)
Concentrated hydrochloric acid (15 ml) was gradually added to the solution of fenspiride base (25.3 g) in isopropyl alcohol (150 ml) at around 65 to 750C and the reaction mixture was stirred at the same temperature till completion of salt formation as monitored by TLC and HPLC. The stirred mass was cooled gradually, and filtered to give fenspiride hydrochloride (1a). The solid thus obtained was optionally treated with methyl isobutyl ketone (MIBK) prior to drying.
Yield: 27.4 g (96 %)
Purity: >99.90 %

,CLAIMS:We claim:
1) A process for preparation of Fenspiride hydrochloride (1a) comprising,
(a) treating 6-(2-phenylethyl)-1-oxa-6-azaspiro[2.5] octane (3) with aqueous ammonia in methanol to give 4-aminomethyl-1-(2-phenylethyl)-piperidine-4-ol (4),
(b) reacting (4) with di-tertiarybutyl dicarbonate in presence of a base and a solvent to give 4-tertiarybutoxycarbonylaminomethyl-1-(2-phenylethyl)-piperidin-4-ol (5),
(c) treating (5) with a base in an organic solvent to give fenspiride (1),
(d) reacting (1) with hydrochloric acid in isopropyl alcohol to yield fenspiride hydrochloride (1a).

2) The process as claimed in claim 1(b), wherein the solvent is water, alcohol selected from methanol, ethanol, n-propanol, isopropanol and mixtures thereof.
3) The process as claimed in claim 1(b), wherein the base is an alkali metal hydroxide selected from sodium hydroxide, potassium hydroxide and lithium hydroxide.
4) The process as claimed in claim 1(c), wherein the organic solvent is selected from hydrocarbons consisting of xylene, toluene and cyclohexane.
5) The process as claimed in claim 1(c), wherein the base is an alkali metal alkoxide selected from sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertiary butoxide and potassium tertiary butoxide.
6) The process as claimed in claim 1(c), wherein the reaction is carried out between 90°C to 120°C.