This application claims priority to this Indian patent application numbered 2275/CHE/2013 filed on May 24, 2013.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Fingolimod hydrochloride.

BACK GROUND OF THE INVENTION

Fingolimod hydrochloride became first oral drug approved to relapses and delay disability progression in patients with relapsing forms of multiple sclerosis. Before, the MS drugs on the markets were all delivered by frequent injections, either intravenously or intra-muscularly, varying from once-per-day to once-per-week depending on the drug. US5604229 patent describes a process for the preparation of fingolimod hydrochloride performed by a nine step sequence starting from 2-(4-octanoyl phenyl)ethyl acetate and the crucial reaction step includes the condensation of 2-(4-octylphenyl)ethyl iodide with diethyl acetamido malonate in the presence of sodium ethoxide base and ethanol, and a subsequent reduction with lithium aluminium hydride to obtain 2-acetamido-2-[2-(4-octylphenyl)ethyl]1,3-propanediol, which is acylated in the presence of acetic anhydride and pyridine to give 1 ,3-propanediyl-2-acetamido-2-[2-(4-octylphenyl)ethyl]ylidene diacetate, followed by hydrolysis using lithium hydroxide to obtain fingolimod. Further, it discloses the use of sodium hydroxide, sodium methoxide, potassium hydride, butyl lithium, triethylamine, diisopropylethylamine, and 1, 8-diazabicyclo [5.4.0] undeca-7-ene as bases in the condensation step. The entire process is as shown in scheme-l.

US6284915 patent discloses a process for the preparation of fingolimod hydrochloride which involves reacting 4'-(2-iodoethyl)octanophenone with diethyl acetamido malonate, in the presence of sodium hydride, to give diethyl acetamide-2-(4-octanoyl phenyl)ethyl malonate, which is further reacted with sodiumborohydride in methanol, followed by acetylation using acetic anhydride and pyridine, to obtain 1-(4-(3-acetamide-4-acetoxy-3-acetoxymethyl)butylphenyl)octyl acetate, which is further subjected to reduction in the presence of 5% Pd/carbon, which is hydrolyzed using 1N sodium hydroxide and methanol to give fingolimod followed by treatment with 1 N hydrochloric acid in ethanol to give fingolimod hydrochloride. The entire process is as shown in scheme-ll. US6605744 patent discloses a process for the preparation of fingoiimod hydrochloride which involves reacting diethyl acetamido-2-[4-octylphenyl)-2-oxomethylmalonate with sodiumborohydride in methanol followed by acetylation using acetic anhydride/pyridine to give 2-acetamido-4-acetoxy-2-acetoxymethyl-4-(4-octylphenyl)butyl acetate which is hydrolyzed to obtain 2-acetamido-2-[2-hydroxy-2-(4-octylphenyl)ethyl] propane-1 ,3-diol, which is further subjected to reduction in the presence of 5% Pd/carbon in ethanol, followed by treatment with 1 N hydrochloric acid in ethanol to give fingoiimod hydrochloride. The entire process is as shown in scheme-Ill.

WO2010055028A2 discloses crystalline forms of fingoiimod hydrochloride salt which are designated as Forms I, II, III, and IV. The publication also discloses a crystalline fingoiimod hydrochloride salt, wherein the salt is substantially in the form of a hydrate. WO2011009634A2 discloses pure polymorphic form B and a mixture of polymorphic forms A and B of fingoiimod hydrochloride, characterized by X-ray diffraction and differential scanning calorimetry. The publication also discloses processes for the preparation of polymorphic forms, wherein one of the processes for the preparation of polymorphic form B involves dissolving fingoiimod hydrochloride in water and subjecting the solution to freeze-drying. Despite the existence of various processes for the preparation of fingoiimod or its salts, there remains a need for improved processes for the preparation of fingoiimod and its salts, producing high yields and purity, and being well-suited for use on an industrial scale. The present process is simple, less time consuming, cost effective and commercially feasible process for the preparation of Fingoiimod hydrochloride.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide an improved process for the preparation of Fingoiimod hydrochloride of formula I comprising the steps of:

a) condensing the compound of formula VI with diethyl acetamido malonate to get the compound of formula V,

b) reducing the compound of formula V in the presence of a metal catalyst to get compound of formula IV,

c) reducing the compound of formula IV in the presence of a metal hydride to get the compound of formula III,

d) hydrolyzing the compound of formula III to get compound of formula II, and

e) converting the compound of formula II to hydrochloride salt of formula I. Entire process of the present invention is shown below scheme-IV.

DETAILED DESCRIPTION OF THE INVENTION

The present invention involves an improved process for the preparation of Fingolimod hydrochloride by condensing compound of formula VI with diethyl acetamido malonate in the presence of a base to get the compound of formula V. Reducing the carbonyl group in compound of formula V in the presence of a metal catalyst to get the compound of formula IV, which is reduced in the presence of a metal hydride to compound of formula III and hydrolyzing the compound of formula III to get free base of fingolimod, further converted to hydrochloride salt. In one embodiment the present invention relates to an improved process for the preparation of Fingolimod hydrochloride which comprising the steps of:

a) condensing the compound of formula VI with diethyl acetamido malonate to get the compound of formula V, o

b) reducing the compound of formula V in the presence of a metal catalyst to get compound of formula IV,

c) reducing the compound of formula IV with a metal hydride to get the compound of formula III,

d) hydrolyzing the compound of formula III to get fingolimod of formula II, and

e) converting the fingolimod base to finqolimod hydrochloride of formula I.

According to the present invention compound of formula VI is reacted with diethyl acetamido malonate in the presence of solvent and base to get compound of formula V, this compound reduced in the presence of a metal catalyst in a mixture of alcohol solvent and organic acid to get compound of formula IV. Compound of formula IV is further reduced with metal hydride in the presence of a dipotassium hydrogen phosphate in alcohol solvent to get compound of formula III, which is hydrolyzed to get fingolimod free base of formula II. Fingolimod free base is further converted to hydrochloride of formula I. According to the present embodiment, compound of formula VI is reacted with diethyl acetamido malonate in a solvent selected from toluene, dimethylformamide, ethyl acetate, ether or acetonitrile. The reaction is carried out at a temperature about 50-70°C for about 1-2hrs. After completion of the reaction, compound of formula V is extracted in an organic solvent selected from toluene, ethyl acetate, dichloromethane or ether solvent. Solvent is evaporated to get a residue of compound of formula V.

Hydrocarbon solvent selected from cyclohexane, n-hexane or n-heptane is added to the residue at about 45-50°C, followed by cooling to crystallize the compound. The obtained pure compound of formula V is filtered and washed with hydrocarbon solvent. According to the present embodiment, compound of formula V is reduced in the presence of a metal catalyst selected from palladium on carbon, Raney Ni or platinum oxide in a mixture of alcoholic solvent and organic acid. The alcoholic solvent selected from methanol, ethanol or isopropanol and the organic acid is acetic acid. This reduction is carried out at 10-15kg/cm2 pressure of hydrogen at 60-65°C for about 4-6hrs to get compound of formula IV. According to the present embodiment, compound of formula IV is reduced with a metal hydride selected from lithium aluminum hydride, sodium borohydride or vitride in the presence of alcoholic solvent selected from methanol, ethanol or isopropanol. The reaction is carried out in the presence of dipotassium hydrogen phosphate at ambient temperature for about 6-7hrs. The crude compound of formula III is purified with hydrocarbon solvent selected from cyclohexane, n-heptane or n-hexane.

Hydrolysis of compound of formula III is carried out in the presence of aqueous alkali solution such as aqueous sodium hydroxide or aqueous potassium hydroxide in the presence of alcohol solvent selected from methanol, ethanol, propanol or isopropanol. According to the present embodiment, fingolimod is converted to hydrochloride salt in the presence of alcoholic hydrocholic acid solution, such as methanolic HCI, ethanolic HCI or I PA HCI in the presence of alcohol solvent. The obtained product is purified with ethyl acetate solvent. The pure fingolimod hydrochloride is dried under nitrogen atmosphere at about 3-10°C for about 16-20 hrs to get pure fingolimod HCI polymorphic form-l.

ADVANTAGES OF THE PRESENT INVENTION

a) the present invention provides solvent purification to avoid the use of column chromatography,

b) the present invention does not required extreme conditions for the reaction and drying procedure,

c) the present invention provides high yield and high quality of Fingolimod hydrochloride Form-l. The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

EXAMPLES

Example 1: Preparing the compound of formula VII. 2-phenylethanol (100gm) was dissolved in mixture of solvents dimethylformamide (5mL) and methylene dichloride (300mL), thionyl chloride (116.7 gm) was dissolved at 40-45°C, and the reaction mass was maintained 12-15 hours. After completion of the reaction, cooled the reaction mass and water was added to quench the excess thionyl chloride at 20-22°C, after quenching the excess thionyl chloride raised the temperature to room temperature and separated the organic layer, concentrated the under vacuum at 39-55°C and obtained the residue.

Example 2: Preparing the compound of formula VI. Octanoic acid (100 gm) was taken in to dimethylformamide (1.5mL) below 35 °C. To this solution, thionyl chloride was added slowly at room temperature and continues stirring for 50-80 minutes. After forming octanoylchloride, dichloromethane (300mL) was added to the reaction mass and cooled to below 10°C, Aluminum chloride was added lot wise to the octanoyl chloride solution at 10-15°C and continue stirring the reaction mass at 10-25°C, slowly raised the temperature to 25-35 °C. To this reaction mixture compound of formula VII (76 gm) solution (diluted with DCM 130mL) was added slowly maintaining temperature below -10 °C for 60-90 minutes. Slowly raised the temperature 21-35°C and maintained reaction mass for 3 to 6 hours, after completion of reaction the above mass was added to the mixture of hydrochloric acid and water below 22 °C, stir the reaction mass at 20-33°C for 20-35 minutes and settle the reaction mass, separated the organic layer and aqueous layer was extracted with dichloromethane. Combine the organic layers and washed with sodium carbonate solution, distilled organic layer below 50°C and obtained compound of formula VI as a residue.

Example 3: Preparation of diethyl acetamido malonate. Diethyl malonate (100gm) was taken in acetic acid (115ml) at 21-35 °C, to this mixture water (165mL) was added at 21-35 °C and cooled to 0-5°C. To this reaction mixture sodium nitrite added lot wise slowly below 6°C for 90-120 minutes, slowly raised the reaction mass to 20-33°C for 40-60 minutes, continue stirring at same temperature for 10-12 hours, product was extracted with ethyl acetate. Acetic anhydride (178.2gm) was slowly added to the above ethyl acetate solution at 23-40 °C for 15-20 minutes, raised the temperature below 45CC. Zinc dust (157gm) was added to the reaction mixture lot wise at 45-55°C for 3-4 hours, reaction mass was maintained at 45-55°C for 3-6 hours by vigorous stirring, cooled the reaction mass to 21-35°C, filter the reaction mixture, washed with acetic acid (2X100mL) and combined the filtrates and distilled off, product obtained as a residue, this residue was dissolved in water at 40-60°C for 5-15 minutes and reaction mass was cooled to 10-15°C by vigorous stirring the product was crystalized out, further continue the stirring at below 5 °C for 1-2 hours, filtered the obtained solid and dried the product under atmospheric pressure till the diethyl acetamidomalonate content is NMT is 0.5%. If the water content is more than 0.5%, product was swapped with cyclohexane to get below 0.5% NMT of diethyl acetamidomalonate.

Example 4: Preparing the compound of formula V. Dimethyformamide (100mL) and sodium hydride (11.4gm) was taken below 35 °C, stir the reaction mass at 25-35°C for 10-15 minutes and cooled to below 5°C. To this reaction mass diethyl acetamidomalonate (100gm dissolved in 300mL DMF) solution was added at 0-15 °C for 60-90 minutes and maintained at same temperature for 10-15 minutes, reaction mass temperature was slowly raised to 25-35 °C for 40-60 minutes. To this compound of formula VI (102 gm dissolved in 150 mL DMF) was added at same temperature and maintained for 60-90 minutes and slowly raised the temperature to 60-70°C for 12-20 hours. After completion of the reaction, cooled the reaction mass to below 35°C, toluene (550 mL) and acetic acid (3gm) was added to the reaction mass and maintained at same temperature for 20-30 minutes. Slowly quench the reaction mixture with water and filter the reaction mass, separate the organic layer and washed with water ( 2X300mL) distilled off toluene below 60°C up to 160mL. This residue was cooled to below 35°C and added remaining toluene solution (775mL) and treated with carbon. Distilled off the toluene below 60GC, to this residue cyclohexane was added and stirred at below 30 GC for 1-2 hours and filter the product and washed with cyclohexane, dried at under atmospheric pressure for 6 to 10 hours at 40-50 °C.

Example 5: Preparing the compound of formula IV. Compound of formula V (100gm) was dissolved in mixture of solvents ethanol (250mL) and acetic acid (250mL) at 25-35 °C and given the carbon treatment through celite bed. Filterate was taken in hydrogenator and added 5% palladium carbon (20gm) with hydrogen pressure (15 to 16 kg/cm2) under nitrogen atmosphere at 21-35°C, raised the temperature under stirring at 60-65°C for 4-10 hours, cooled the reaction mass and remove the catalyst through celite bed, remove the solvent up to form viscous oil and cool the mass. pH adjusted with sodium bicarbonate up 7-8, continue stirring the product slurry to form precipitation at RT for one hour. Filtered the product and washed with water dried the product at 45°C to obtain compound of formula IV.

Example 6: Preparing the compound of formula III. Dipotassium hydrogen phosphate (200gm) was dissolved in water (260mL) and cooled the solution; pH of the above solution is 8.5-9.3. To this ethanolic solution of compound of formula IV (100 gm) was added, slowly aqueous sodiumborohydride solution (230mL) was added to the above reaction mixture at 10-18 °C for 2 hours, reaction mixture was maintained at same temperature for 3hours, slowly raised the temperature to RT and maintained 8-12 hours. After completion of reaction, water was added and separated the organic layer. pH of the reaction was adjusted with dilute hydrochloric acid up to 4-4.5, maintained at room temperature for one hour to decompose the boran complex. Once again pH was readjusted with sodium hydroxide solution up to 6.5 to 7.0, after adjusting pH removed the solvent through distillation and cooled the mass, ethyl acetate and water was added to the mass, separated the organic layer and removed the solvent through distillation to obtain a residue. This residue was further purified with cyclohexane precipitates product and filtered and dried.

Example 7: Preparing the compound of formula II. Compound of formula III (100gm) was dissolved in methanol (400mL) at 21 °C, added aqueous sodium hydroxide solution (75mL) and refluxed for 2 hours. After completion of reaction, water (150mL) was added to the reaction mass, stirred for 15-30minutes at same temperature, distilled out the methanol solvent up to the volume of 550mL, cooled the reaction mixture to room temperature and stirred for 1-2 hours. Filtered the obtained solid and washed with water, suck dried to obtain a compound of formula II.

Example 8: preparing the Fingolimod hydrochloride of formula I. Fingolimod free base (100gm) and ethanol was taken at room temperature to this ethanolic hydrochloride solution (87.5gm) was added at same temperature, reaction mass was heated to 38-40 °C and maintained for 30 minutes. Treated with carbon and distilled out the solvent to obtain a residue. To this residue ethyl acetate (900mL) was added and heated the reaction mass to 55 °C for 30 minutes, cooled the reaction mass to room temperature for 30 minutes and further cooled to 15-17 °C for 90 minutes. Filtered the product and washed with ethyl acetate, dried the product under reduced pressure for 16-20 hours at 3-6 °C to obtain a polymorphic form I fingolimod hydrochloride of formula I.

We claim:

1. An improved process for the preparation of Fingolimod hydrochloride which comprising the steps of:

a) condensing the compound of formula VI with diethyl acetamido malonate to get the compound of formula V,

b) reducing the compound of formula V in the presence of a metal catalyst to get compound of formula IV,V

c) reducing the compound of formula IV with a metal hydride to get the compound of formula III,

d) hydrolyzing the compound of formula III to get fingolimod of formula II, and

e) converting the fingolimod base to fingolimod hydrochloride of formula I.

2. The process according to claim 1, wherein step b) reduction is carried out with metal catalyst is selected from palladium on carbon, Raney Ni or platinum oxide.

3. The process according to claim 1, wherein step c) reduction is carried out with metal hydride is selected from lithium aluminum hydride, sodium borohydride or vitride.