Specification
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"
Emeure 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 PARTICULARLY DESCRIBES 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 the preparation of Fenspiride (I) starting from the key intermediate 6-(2-phenylethyl)-l-oxa-6-azaspiro[2.5] octane of formula (III).
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 the 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.
Fenspiride (I) Fenspiride hydrochloride (la)
US 3,399,192 discloses a process for preparation of Fenspiride (I) comprising cyanation of l-(2-phenylethyl)-4-piperidone, reduction of the corresponding cyanohydrin with aluminium alanate, followed by reaction of the resulting l-(2-phenylethyl)-4-aminomethyl-4-hydroxy piperidine with diethyl carbonate in presence of sodium methylate to give Fenspiride (I).
The process involves use of highly toxic cyanides 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, which comprises reaction of N-(2-phenylethyl)-4-piperidone with ethyl bromoacetate in presence of activated Zinc and 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 to yield Fenspiride.
The process has several disadvantages such as use of zinc metal which requires elaborate separation method during work up for removal of zinc hydroxide sludge and disposal procedures during effluent treatment, followed by use of carcinogenic and highly inflammable solvents like benzene and ether.
Synthetic Communications, 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, reduction with lithium aluminium hydride and employs a convenient, cost-effective synthetic method for incorporating the oxa-azaspiro function in the molecule.
The present inventors, after carrying out extensive experimentation for evolving a simple and convenient synthetic route, have been able to develop a novel methodology for preparing Fenspiride hydrochloride having the desired purity and conforming to regulatory specifications, starting from the oxa-azaspiro intermediate (III).
OBJECT OF THE INVENTION
An objective of the present invention is to provide Fenspiride hydrochloride (la) by a novel synthetic route, which avoids hazardous reactions.
Another objective of the invention is to provide Fenspiride hydrochloride (la) having desired purity and conforming to regulatory specifications.
SUMMARY OF THE INVENTION
The present invention relates to a novel synthetic method for preparation of Fenspiride hydrochloride (Ia), which overcomes the limitations faced in prior art.
An aspect of the present invention relates to a process for preparation of Fenspiride hydrochloride of formula (la) comprising conversion of 6-(2-phenylethyl)-l-oxa-6-azaspiro[2.5]octane of formula (III) to l-(2-phenylethyl)-4-aminomethyl-4-piperidinol of formula (VI), followed by reaction with a carbonyl group inserting agent and subsequent treatment with hydrogen chloride to give Fenspiride hydrochloride (la).
Another aspect of the invention relates to a process for preparation of l-(2-phenylethyl)-4-aminomethyl-4-piperidinol of formula (VI) comprising reaction of 6-(2-phenylethyl)-l-oxa-6-azaspiro[2.5]octane (III) with sodium azide in presence of ammonium chloride and a solvent followed by subsequent reduction of the resultant 4-(azidomethyl)-l-phenylethyl piperidine-4-ol of formula (IV) to provide l-(2-phenylethyl)-4-aminomethyl-4-piperidinol of formula (VI).
Yet another aspect of the invention comprises reaction of 6-(2-phenylethyl)-l-oxa-6-azaspiro [2.5] octane (III) with potassium phthalimide/phthalimide to give 2-((4-hydroxy-l-phenylethyl piperidine-4-yl) methyl) isoindoline-l,3-dione of formula (V), which on treatment with hydrazine hydrate in an alcohol provides 1 -(2-phenylethyl)-4-aminomethyl-4-piperidinol (VI).
The objectives of the present invention will become fully apparent from the detailed description.
DETAILED DESCRIPTION OF THE INVENTION
Extensive experimentation was carried out by the present inventors towards the study of alternative pathways for a convenient, environment friendly and economical synthesis of Fenspiride. During the study, it was surprisingly observed that the cyclic amide function could be easily introduced in Fenspiride (I) by starting from an oxa azaspiro intermediate (III).
The compound, 6-(2-phenylethyl)-l-oxa-6-azaspiro [2.5] octane (III) was prepared by the reaction of N-(2-phenyIethyl)-4-piperidone (II) with trimethyl sulfoxonium iodide in dimethyl sulfoxide as solvent and in presence of an aqueous solution of a base such as potassium carbonate or sodium hydroxide.
The piperidone derivative (II) was subjected to various reaction conditions employing different organic and inorganic bases such as triethyl amine, 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) or carbonates, bicarbonates and hydroxides of sodium and potassium etc. in varying molar quantities.
It was observed that excellent yield of the desired compound (III) was obtained when the molar ratio of [compound (II): trimethyl sulfoxonium iodide: base] was between (0.75:1.0:1.5) and (2.0:2.0:3.0). The reaction was carried out in the temperature range of 0- 20 C, preferably at 5-10°C and in presence of sodium hydroxide as the base.
The compound of formula (III) which may be carried forward without isolation is converted to the compound of formula (VI) by following the methods disclosed in the synthetic scheme.
Scheme 1: Method for preparation of Fenspiride (I) starting from 6-(2-phenylethyl)-l-oxa-6-azaspiro [2.5] octane of formula (III)
In an embodiment, the intermediate of formula (III) may be directly converted to 1-(2-phenylethyl)-4-aminomethyl-4-piperidinol (VI) by treatment with ammonia in an alcohol selected from group comprising methanol, ethanol and isopropanol, in the temperature range of 15 to 40 C. After completion of the reaction as monitored by HPLC, the reaction mixture was optionally quenched with water and extracted with a water-immiscible solvent like dichloromethane or ethyl acetate. The organic layer was concentrated to give l-(2-phenyIethyl)-4-aminomethyl-4-piperidinol of formula (VI).
In another embodiment, 6-(2-phenylethyl)-l-oxa-6-azaspiro[2.5]octane of formula (III), on reaction with sodium azide in presence of ammonium chloride and an organic solvent gave 4-(azidomethyl)-l-phenylethyl piperidine-4-ol of formula (IV). Subsequent hydrogenation of the azidomethyl intermediate (IV), using Pd/C in methanol or reduction with hydrazine hydrate in presence of Raney nickel gave l-(2-phenylethyl)-4-aminomethyl-4-piperidinol of formula (VI).
The compound of formula (III) or the residue containing the same compound was dissolved in an organic solvent selected from dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide etc. followed by addition of ammonium chloride and sodium azide. The reaction mixture was stirred at 20 to 30 C till completion of reaction as monitored by HPLC. The reaction mixture was quenched with water and the mixture was extracted with an organic solvent such as ethyl acetate. The organic layer was separated and concentrated to provide a residue containing 4-(azidomethyl)-l-phenylethyl piperidine-4-ol of formula (IV).
Hydrogenation of 4-(azidomethyl)-l-phenylethyl piperidine-4-ol (IV) was carried out at room temperature, with 3-5 Kg Hydrogen pressure in presence of Pd/C in a solvent such as methanol, ethyl acetate, dichloromethane etc. After completion of the reaction as monitored by HPLC, the reaction mixture was filtered and concentrated to provide l-(2-phenylethyl)-4-aminomethyl-4-piperidinol of formula (VI).
Alternatively, the azidomethyl derivative of formula (IV) was treated with hydrazine hydrate in presence of Raney nickel and methanol or isopropanol as solvent at ambient temperature till completion of the reaction as monitored by HPLC. After completion of the reaction, the reaction mass was filtered, quenched with water, and extracted with an organic solvent. The organic layer was concentrated to obtain a residue containing the compound of formula (VI). Alternatively, the filtered reaction mass was concentrated and the residue after treatment with 10% hydrochloric acid was concentrated to obtain compound of formula (VI).
In yet another embodiment, 6-(2-phenylethyl)-l-oxa-6-azaspiro [2.5] octane of formula (III) on reaction with potassium phthalimide/ phthalimide in an organic solvent such as dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide etc., preferably dimethyl formamide gave compound of formula (V). The reaction was carried out in the temperature range of 75 to 110°C After completion of the reaction, the reaction mass was quenched with water and extracted with dichloromethane. The organic layer was concentrated to yield 2-((4-hydroxy-l-phenethylpiperidine-4-yl)methyl)isoindoline-l,3-dione of formula (V).
Compound (V) was further treated with hydrazine hydrate at room temperature, using a solvent from the group comprising methanol, ethanol, isopropanol and n-propanol. .Upon completion of the reaction, concentration of the reaction mass, followed by addition of dichloromethane and concentration gave l-(2-phenylethyl)-4-aminomethyl-4-piperidinol of formula (VI).
The compound of formula (VI) on treatment with carbonyl diimidazole or triphosgene by conventional methods followed by treatment with hydrochloric acid led to Fenspiride hydrochloride, which was found to have purity and impurity level conforming to regulatory specifications.
Reaction of l-(2-phenylemyl)-4-aminomethyl-4-piperidinol (VI) with triphosgene was carried out at room temperature in presence of triethyl amine and solvent dichloromethane. After completion of the reaction, pH was adjusted between 8 and 9, followed by separation and concentration of the dichloromethane layer to give the Fenspiride base of formula (I).
Alternatively, compound (VI) was treated with carbonyl diimidazole using tetrahydrofuran as a solvent. The reaction was carried out at 0-5°C and upon completion of the reaction, Fenspiride base was isolated by distilling tetrahydrofuran, followed by treatment of the residue with water, extraction with dichloromethane and concentration of the organic layer.
A solution of Fenspiride base of formula (I) in an organic solvent was treated with
hydrogen chloride gas at room temperature. After separation of the hydrochloride
salt, the reaction mass was filtered to provide Fenspiride hydrochloride of formula
(la) having the desired purity.
The organic solvent was selected from a group comprising methanol, ethanol,
acetone, methyl isobutyl ketone, methyl ethyl ketone etc. The finished product,
Fenspiride hydrochloride (la) was obtained in good yield and also conformed to
regulatory specifications
The principles, preferred embodiments, and modes of operation of the present
invention have been described in the foregoing specification. The invention which is
intended to be protected herein, however, is not to be construed limited to the
particular forms disclosed, since these are to be regarded as illustrative rather than
restrictive. Variations and changes may be made by those skilled in the art, without
departing from the spirit of the invention.
The invention is further explained with the help of following illustrative examples,
however, in no way these examples should be construed as limiting the scope of the
invention.
Example 1
Preparation of 6-(2-phenylethyl)-l-oxa-6-azaspiro [2.5]octane (III)
A mixture of trimethyl sulfoxonium iodide (1420gms) and dimethyl sulfoxide (3000 ml) was stirred and cooled to 5-10°C. Aqueous solution of sodium hydroxide (400 g in 3000 ml water) was slowly added to the mixture, followed by gradual addition of l-(2-Phenylethyl)piperidin-4-one (II; 1000gms) at 5-10°C. The reaction temperature was raised to 25-30°C and reaction was continued 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: 1050 g Purity: > 99%
Example 2
Preparation of 4-(azidomethyI)-l-phenylethyl piperidine-4-ol (TV)
A mixture of dimethyl sulfoxide (2500 ml), 6-(2-phenylethyl)-l-oxa-6-azaspiro [2.5] octane (III) (1000gms) and ammonium chloride (740gms) was stirred at 10-15°C. Temperature of the reaction mass was raised to 20-25°C and sodium azide (837gms) was added gradually to it. The reaction mass was stirred at room temperature till completion of the reaction as monitored by HPLC.
The reaction mass was cooled to 0-5°C, quenched with water and extracted with ethyl acetate. The organic layer was separated and concentrated to yield 4-(azidomethyl)-l-phenylethyl piperidine-4-ol (IV). Yield: 1100 gms. Purity: >99%
Example 3
Preparation of l-(2-phenylethyl)-4-aminomethyl-4-piperidinol (VI)
Raney nickel (50gms; 5%w/w) was added to the mixture of 4-(azidomethyl)-l-
phenylethyl piperidine-4-ol (IV; l000gms) and isopropyl alcohol (6000 ml) and the
mass was stirred under nitrogen at 25-30°C. Hydrazine hydrate (950gms; 80-85%)
was gradually added to the mixture at 50-60°C. The reaction was continued at 25-
30°C and monitored by TLC for completion.
The reaction mass was filtered, neutralized with 10%HC1 and concentrated. The
compound of formula (VI), l-(2-phenylethyl)-4-aminomethyl-4-piperidinol was
isolated after adding ethyl acetate to the residue.
Yield: 750 gms
Purity: >98 %
Alternatively, solution of 4-(azidomethyl)-l-phenylethyl piperidine-4-ol (IV; 100 g)
in methanol (1000 ml) was prepared in an auto clave, and 5% Pd/C (5 g) was added to
it. The reaction was carried out under 3-5 kg hydrogen pressure at room temperature.
After completion of reaction, as monitored by TLC, filtration and concentration of the
filtrate yielded 30.0 g of compound (VI).
Example 4
Preparation of l-(2-phenylethyl)-4-aminomethyl-4-piperidinol (VI)
Potassium phthalimide (100.0 g) & phthalimide (150.0 g) were added to a stirred solution of 6-(2-phenylethyl)-l-oxa-6-azaspiro[2.5]octane (III;200gms) in dimethylformamide (1000 ml) at room temperature. The reaction mass was heated to 90-100 °C. After completion of the reaction, as monitored by TLC, the reaction mass was quenched with water and extracted with dichloromethane. The organic layer was concentrated to give 150 g of 2-((4-hydroxy-l-phenethylpiperidine-4-yl)methyl) isoindoline-l,3-dione (V).
Compound (V), (100.0 g) was reacted with hydrazine hydrate (26.0 g) in methanol (1000 ml) at room temperature. After completion of the reaction, as monitored by TLC, the mass was concentrated and (35gms) of compound (VI) was isolated by addition of dichloromethane. Yield: 35gms Purity: >99.5%.
Example 5
Preparation of l-(2-phenylethyl)-4-aminomethyl-4-piperidinol (VI)
Ammonia (25-30%, 200 ml) was added to a stirred solution of N-(2-phenyIethyl)-2-oxo-6-azaspiro [2.5] octane (HI) (100 g) in methanol (500 ml) at room temperature and the reaction mass was stirred at same temperature. After completion of reaction as monitored by HPLC, methanol was evaporated; the reaction mixture was extracted with dichloromethane and concentrated. Yield: 30 gms Purity: >99%.
Example 6
Preparation of Fenspiride (I)
A solution of triphosgene (126 g) in dichloromethane was added dropwise to the continuously stirred mixture of l-(2-phenylethyl)-4-aminomethyl-4-piperidinol (VI) (100.0 g), triethyl amine (65.0 g) and dichloromethane (850 ml) at room temperature. The reaction was continued till completion as monitored by TLC and upon completion, pH was between 8 and 9. Extraction of the reaction mass with dichloromethane and concentration gave Fenspiride (I). Yield: 40.0 g Purity: > 99 % Melting point: 143-145°C
Alternatively, carbonyl diimidazole (CDI) (830 g) was added lot wise to the cooled mixture of 1-(2-phenylethyl)-4-aminomethyl-4-piperidinol (VI) (lOOOgms) in tetrahydrofuran (5000 ml) at 0-5°C, the reaction mass was warmed to 25-30°C and stirred at the same temperature. After completion of reaction, as monitored by HPLC, the reaction mass was concentrated, mixed with water and extracted with dichloromethane. Upon concentration of the organic layer, Fenspiride (I) was isolated by adding ethyl acetate to the residue. Yield: 700 g Purity: > 99 % Melting point: 143-145°C
Example 7
Preparation of Fenspiride hydrochloride (Ia)
Hydrogen chloride gas was purged in to a solution of Fenspiride base (I), (250 gms) in methyl isobutyl ketone (750 ml) in the temperature range of 5 -10°C. The precipitated hydrochloride salt was filtered, and dried to give Fenspiride hydrochloride (la) Yield: 256gms Purity: >99.5%
CLAIMS
1. A process for preparation of Fenspiride hydrochloride of formula (la), comprising the steps of:
(a) conversion of 6-(2-phenylethyl)-l-oxa-6-azaspiro[2.5] octane of formula (III) to l-(2-phenylethyl)-4-aminomethyl-4-piperidinol of formula (VI),
(b) treatment of the compound of formula (VI) obtained in step (a) to give Fenspiride base of formula (I) and
(c) treatment of the compound of formula (I) obtained in step (b) with hydrogen chloride in an organic solvent to give Fenspiride hydrochloride (la).
2. A process according to claim 1, wherein the step (a) is carried out by reaction of 6-(2-phenyIethyl)-l-oxa-6-azaspiro [2.5] octane (III) with sodium azide and ammonium chloride, in an organic solvent, followed by reduction of the resultant 4-(azidomethyl)-l-phenylethyl piperidine-4-ol of formula (IV) to give l-(2-phenylethyl)-4-aminomethyI-4-piperidinoI(VI).
3. A process according to claim 2, wherein the organic solvent employed is dimethyl sulphoxide and the reducing agent is hydrogen with palladium on carbon or hydrazine hydrate along with Raney nickel.
4. A process according to claim 1, wherein the step (a) is carried out by reaction of 6-(2-phenylethyl)-l-oxa-6-azaspiro [2.5]octane (III) with potassium phthalimide and phthalimide in an organic solvent to give 2-((4-hydroxy-l-phenethylpiperidine-4-yl)methyl)isoindoline-l,3-dione of formula (V), which on treatment with hydrazine hydrate in a solvent gave 1 -(2-phenylethyl)-4-aminomethyl-4-piperidinoI (VI).
5. A process according to claim 4 wherein, the solvent employed for preparation of compound of formula (V) is dimethyl formamide and solvent for reaction of compound (V) to give compound of formula (VI) is an alcohol selected from the group comprising methanol, ethanol, isopropyl alcohol and n-propanol.
6. A process according to claim 1, wherein the step (a) is carried out by reaction of 6-(2-phenylethyl)-l-oxa-6-azaspiro [2.5] octane (III) with aqueous ammonia in an alcohol at 15-40°C and isolating by concentrating the reaction mixture, extracting the residue with a water-immiscible solvent like dichloromethane or ethyl acetate and concentrating the mixture.
7. A process according to claim 6, wherein, the alcohol is selected from the group comprising ethanol, methanol and isopropanol.
8. A process according to claim 1, wherein the step (b) is carried out by reacting l-(2-phenylethyl)-4-aminomethyl-4-piperidinol (VI) with carbonyl diimidazole.
9. A process according to claim 1 wherein, the organic solvent employed in step (c) for preparation of Fenspiride hydrochloride (la) is methyl isobutyl ketone.
