DESC:RELATED PATENT APPLICATION(S)
This application claims the priority to and benefit of Indian Patent Application No. 201841002504 filed on February 06, 2018 and Indian Patent Application No. 201841017562 filed on May 09, 2018; the disclosures of which are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Fingolimod or its pharmaceutically acceptable salts and its intermediates thereof.
BACKGROUND OF THE INVENTION
Fingolimod hydrochloride is chemically known as 2-amino-2- [2- (4-octylphenyl) ethyl] -1,3-propanediol hydrochloride having the structure of formula I as mentioned below.
Formula I
Fingolimod hydrochloride is a sphingosine 1-phosphate receptor modulator used for the treatment of patients with relapsing forms of multiple sclerosis and marketed as Gilenya.
Fingolimod hydrochloride is first disclosed in the U.S. Patent No. 5,604,229 assigned to Yoshitomi Pharmaceutical. This Patent discloses the process for the preparation of Fingolimod as mentioned below.

The impurity formation during the preparation of the intermediates in the aforementioned process necessitates the use of column chromatographic procedures and other purification processes at every stage. These purification processes employed during the preparation of Fingolimod makes the process cumbersome in large scale.
The Publication Synlett 2001, No. 9, page 1411-1414, discloses a process for preparation of Fingolimod from the compound 1-(3-nitropropyl)-4-octylbenzene involving the steps of: reacting 1-(3-nitropropyl)-4-octylbenzene with formaldehyde to obtain 2-nitro-2-(4-octylphenethyl)propane-1,3-diol; and reducing the formed nitro compound to form Fingolimod as mentioned below.

The U.S. Patent No. 5,604,229 also discloses the reaction of 1-(3-nitropropyl)-4-octylbenzene with formalin in the presence of base to obtain a 2-nitro-2-(4-octylphenethyl)propane-1,3-diol and the reduction of the obtained nitro compound with a suitable reducing agent.
There are different procedures for preparing the 1-(3-nitropropyl)-4-octylbenzene.
The Indian Patent Application No. 1502/CHE/2011 assigned to Dr Reddy’s filed on April 29, 2011 discloses the process for preparation of 1-(3-nitropropyl)-4-octylbenzene from 3-nitro-1-(4-octylphenyl)propan-1-one, mentioned below.

The PCT Publication No. WO2011159870 assigned to Braco Imaging SPA discloses the process for the preparation of 1-(3-nitropropyl)-4-octylbenzene (filed on June 16, 2011 example-3) from the 1-bromo-3-phenylpropane as mentioned below:

The Indian Patent Application No. 1502/CHE/2011 filed on April 29, 2011 discloses the process for preparation of Fingolimod as mentioned below.

The Chinese Patent Application No. 1765872 filed on November 22, 2005 discloses the process for the preparation of Fingolimod hydrochloride as mentioned below.

The Indian Patent Application No. 4455/CHE/2011 filed on December 19, 2011 discloses the process for preparation of Fingolimod as mentioned below.

Besides the existence of various processes for the preparation of Fingolimod or its pharmaceutically acceptable salts, there remains a need for an improved processes for the preparation of Fingolimod or its pharmaceutically acceptable salts producing high yields and purity and being well-suited for use on an industrial scale.
OBJECT OF THE INVENTION
The object of the invention is to provide an improved process for the preparation of Fingolimod or its pharmaceutically acceptable salt thereof.
Another object of the invention is to provide an improved process for the preparation of Fingolimod Hydrochloride.
Yet another object of the invention is to provide a process for the preparation of compound of formula Va and the compound of formula III, an intermediate used in the process for the preparation of Fingolimod or its pharmaceutically acceptable salts thereof.
Still another object of the invention is to provide a process for the preparation of compound of Formula IV, an intermediate used in the process for the preparation of Fingolimod or its pharmaceutically acceptable salt thereof.
Yet another object of the invention is to provide a process for the purification of Fingolimod hydrochloride.
SUMMARY OF THE INVENTION
Accordingly, there is provided an improved process for the preparation of Fingolimod and its pharmaceutically acceptable salts thereof.
In one aspect of the invention, there is provided a process for preparing the Fingolimod hydrochloride of formula I,
Formula I
said process comprising steps of:
(a) reacting the octanoyl chloride compound of formula X
Formula X
with phenyl propyl acetate compound of formula XI
Formula XI
in presence of Lewis acid in suitable solvent to provide 4-octanoylphenethyl acetate compound of formula IX;
Formula IX
(b) reducing the compound of formula IX with suitable reducing agent in suitable solvent in presence of acid to provide 4-octylphenethyl acetate of formula VIII;
Formula VIII
(c) converting the compound of formula VIII in the presence of sodium alkoxide in suitable solvent to provide 2-(4-octylphenyl) ethanol compound of formula VII;
Formula VII
(d) reacting the alcoholic compound of formula VII with methane sulfonyl halide in the presence of suitable solvent to provide 4-octylphenylethyl methanesulfonate of formula VI;
Formula VI
(e) reacting the sulfonate compound of formula VI with alkali or alkali earth metal iodide in suitable solvent to provide 1-(2-iodopropyl)-4-octylbenzene of formula V;
Formula V
(f) reacting the compound of formula V with alkali or alkali earth metal nitrite in suitable solvent to provide 1-(2-nitropropyl)-4-octylbenzene of formula IV;
Formula IV
(g) reacting the compound of formula IV with formaldehyde or paraformaldehyde in the presence of suitable inorganic base to provide 2-nitro-2-(4-octylphenethyl)propan-1,3- diol of formula III;
Formula III
(h) reducing the compound of formula III in the presence of suitable reducing agent in suitable solvent to provide Fingolimod of formula II; and
Formula II
(i) reacting the compound of formula II with hydrochloric acid in suitable solvent to provide Fingolimod hydrochloride salt of formula I.
In some embodiment of the invention, the Lewis acid used in step (a) of the above described process for the preparation of Fingolimod hydrochloride is selected from the group comprising boron trifluoride, zinc chloride, zinc bromide, aluminium chloride or titanium tetrachloride.
In some embodiment of the invention, the reducing agent used in step (b) of the above described process for the preparation of Fingolimod hydrochloride is selected from triethylsilane, Pd/C, Sn/HCl or Raney Ni.
In some other embodiment of the invention, the sodium alkoxide used in step (c) of the above described process for the preparation of Fingolimod hydrochloride is selected from sodium methoxide or sodium ethoxide.
In another embodiment of the invention, the inorganic base used in the step (g) of the above described process for the preparation of Fingolimod hydrochloride is selected from sodium hydroxide, potassium hydroxide, ammonium hydroxide or sodium carbonate.
In some embodiments of the invention, the step (i) of the above described process for the preparation of Fingolimod hydrochloride of the formula I is carried in the presence of ether solvent, ester solvent, hydrocarbon solvent, alcoholic solvent or mixture thereof.
Formula I
In another aspect of the invention, there is provided a process for preparing the compound of formula IV, comprising the steps of:
(a) reacting the alcoholic compound of formula VII
Formula VII
with methane sulfonyl halide in the presence of suitable solvent to provide 4- octylphenylethylmethanesulfonate of formula VI;
Formula VI
(b) reacting the sulfonate compound of formula VI with alkali or alkali earth metal iodide in suitable solvent to provide 1-(2-iodopropyl)-4-octylbenzene of formula V; and
Formula V
(c) reacting the compound of formula V with alkali or alkali earth metal nitrite in suitable solvent to provide 1-(2-nitropropyl)-4-octylbenzene of formula IV.
Formula IV
In yet another aspect of the invention, there is provided a process for the preparation of formula IV by reacting the compound 1-(2-iodopropyl)-4-octylbenzene of formula V
Formula V
with alkali or alkali earth metal nitrite in suitable solvent to provide 1-(2-nitropropyl)-4-octylbenzene of formula IV.
Formula IV
In some embodiment, there is provided a process for preparing the compound of formula IV, wherein the said process comprises the steps of:
(a) reacting the alcoholic compound of formula VII with methane sulfonyl chloride in the presence of triethylamine and dichloromethane to provide 4-octylphenylethyl methanesulfonate of formula VI;
(b) reacting the sulfonate compound of formula VI with sodium iodide in 2-butanone to provide 1-(2-iodopropyl)-4-octylbenzene of formula V; and
(c) reacting the compound of formula V with sodium nitrite in dimethylformamide to provide 1-(2-nitropropyl)-4-octylbenzene of formula IV.
In another aspect of the invention, there is provided a process for preparation of Fingolimod of formula II and its pharmaceutically acceptable salts thereof, said process comprising the steps of:
Formula II
(a) reacting the compound of formula VIa
Formula VIa
with suitable reducing agent in suitable solvent selected from the group consisting of tetrahydrofuran, water or its mixture thereof to obtain the compound of formula Va;
Formula Va
(b) reacting the compound of formula Va with boron trifluoride and trialkylsilane to obtain the compound of formula IV;
Formula IV
(c) reacting the compound of formula IV with an aqueous formaldehyde in suitable base to obtain the compound of formula III; and
Formula III
(d) converting the compound of formula III to Fingolimod of formula II or its pharmaceutically acceptable salts.
In some embodiment of the invention, the reducing agent used in step (a) of the above described process for the preparation of Fingolimod of formula II or its pharmaceutically acceptable salts is selected from the group comprising sodium borohydride, potassium borohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminium hydride, vitride or borane-DMS.
In some embodiment of the invention, the step (b) of the above described process for the preparation of Fingolimod of formula II or its pharmaceutically acceptable salts is carried out in presence of chloro solvents, hydrocarbon solvents, ether solvents or mixture thereof.
In some embodiment of the invention, the base used in step (c) of the above described process for the preparation of Fingolimod of formula II or its pharmaceutically acceptable salts is selected from the group of organic bases comprising diisopropyl amine, diisobutyl amine, triethylamine, diethylamine, dicyclohexylamine, n-butylamine, diisopropyl ethylamine or pyridine or inorganic bases comprising sodium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate.
In some other aspect of the invention, there is provided a process for the preparation of compound of formula Va by reacting the compound of formula VIa
Formula VIa
with suitable reducing agent in suitable solvent selected from the group consisting of tetrahydrofuran, water and its mixtures thereof to obtain the compound of formula Va.
Formula Va
In yet another aspect of the present invention, there is provided a process for the preparation of compound of formula IV by reacting the compound of formula Va
Formula Va
with boron trifluoride and trialkylsilane to obtain the compound of formula IV.
Formula IV
In still another aspect of the invention, there is provided a process for the preparation of compound of formula III by reacting the compound of formula IV
Formula IV
with an aqueous formaldehyde in the presence of suitable base to obtain the compound of formula III.
Formula III
In some other aspect of the invention, there is provided a process for the purification of Fingolimod hydrochloride of formula I
Formula I
said process comprising the steps of:
(a) providing a solution of Fingolimod hydrochloride of the formula II in solvent selected from the group consisting of methanol, isopropanol, ethylacetate and water;
(b) optionally heating the reaction mixture obtained in step (a);
(c) facilitating crystallization of the reaction mixture obtained in step (a) or step (b); and
(d) isolating the crystalline Fingolimod hydrochloride obtained in in step (c).
In another aspect of the invention, there is provided a process for the purification of Fingolimod hydrochloride of formula I comprising the steps of:
(a) providing an aqueous solution of Fingolimod hydrochloride;
(b) optionally heating the reaction mixture obtained in step (a);
(c) adding anti-solvent to the reaction mixture obtained in step (a) or step (b);
(d) facilitating crystallization of the reaction mixture obtained in step (c); and
(e) isolating the crystalline Fingolimod hydrochloride obtained in step (d).
In yet another aspect of the invention, there is provided a process for the purification of Fingolimod hydrochloride of formula I comprising the steps of:
(a) providing an aqueous solution of Fingolimod hydrochloride;
(b) optionally heating the reaction mixture obtained in step (a);
(c) adding sodium chloride to the reaction mixture obtained in step (a) or step (b);
(d) facilitating crystallization of the reaction mixture obtained in step (c); and
(e) isolating the crystalline Fingolimod hydrochloride obtained in step (d).

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of hydrochloride or its pharmaceutically acceptable salts.
In one aspect of the invention, there is provided a process for preparation of Fingolimod hydrochloride of formula I, comprising the steps of:
(a) reacting the compound 1-(2-iodopropyl)-4-octylbenzene of formula V
Formula V
with alkali or alkali earth metal nitrite in suitable solvent to provide 1-(2- nitropropyl)-4-octylbenzene of formula IV,
Formula IV
(b) reacting the compound of formula IV with formaldehyde or paraformaldehyde in the presence of suitable inorganic base to provide 2-nitro-2-(4-octylphenethyl)propan-1,3-diol of formula III,
Formula III
(c) reducing the compound of formula III in the presence of suitable reducing agent in suitable solvent to provide Fingolimod of formula II; and
Formula II
(d) reacting the compound of formula II with hydrochloric acid in presence of suitable solvent to provide Fingolimod Hydrochloride salt of formula I.

Formula I
In step (a) the suitable solvent may be selected from the group comprising of polar aprotic solvents, ester solvents, hydrocarbon solvents preferably polar aprotic solvent or mixture thereof.
In step (b) the suitable inorganic base may be selected from the group comprising of sodium hydroxide, potassium hydroxide, ammonium hydroxide or sodium carbonate; and the suitable solvent may be selected from the group comprising of non-polar solvents, alcoholic solvent, ester solvent, ether solvent, hydrocarbon solvent or mixture thereof.
In step (c) the suitable reducing agent may be selected from the group comprising of Pd/C, Sn/HCl or Raney Ni; and the suitable solvent may be selected from the group comprising of polar protic solvents, alcoholic solvent, ether solvent, ester solvent, hydrocarbon solvent or mixture thereof.
In step (d) suitable solvent may be selected from the group comprising of ether solvent, ester solvent, hydrocarbon solvent, alcoholic solvent or mixture thereof.
In another aspect of the invention, there is provided a process for the preparation of Fingolimod hydrochloride compound of formula I,

Formula I

said process comprising the steps of:
(a) reacting the octanoyl chloride compound of formula X
Formula X
with phenyl propyl acetate compound of formula XI
Formula XI
in presence of Lewis acid in suitable solvent to provide 4-octanoylphenethyl acetate compound of formula IX;
Formula IX
(b) reducing the compound of formula IX with suitable reducing agent in suitable solvent in presence of acid to provide 4-octylphenethyl acetate of formula VIII;
Formula VIII
(c) converting the compound of formula VIIIin the presence of sodium alkoxide in suitable solvent to provide 2-(4-octylphenyl) ethanol compound of formula VII;

Formula VII
(d) reacting the alcoholic compound of formula VII with methane sulfonyl halide in the presence of suitable solvent to provide 4-octylphenylethyl methanesulfonate of formula VI;
Formula VI
(e) reacting the sulfonate compound of formula VI with alkali or alkali earth metal iodide in suitable solvent to provide 1-(2-iodopropyl)-4-octylbenzene of formula V;
Formula V
(f) reacting the compound of formula V with alkali or alkali earth metal nitrite in suitable solvent to provide 1-(2-nitropropyl)-4-octylbenzene of formula IV;
Formula IV
(g) reacting the compound of formula IV with formaldehyde or paraformaldehyde in the presence of suitable inorganic base to provide 2-nitro-2-(4-octylphenethyl)propan-1,3-diol of formula III;
Formula III
(h) reducing the compound of formula III in the presence of suitable reducing agent in suitable solvent to provide Fingolimod of formula II; and
Formula II
(i) reacting the compound of formula II with hydrochloric acid in suitable solvent to provide Fingolimod hydrochloride salt of formula I.
Formula I
In step (a) the suitable Lewis acid may be selected from the group comprising of boron trifluoride, zinc chloride, zinc bromide, aluminium chloride or titanium tetrachloride; and the suitable solvent may be selected from the group comprising of hydrocarbon solvent, ether solvent, chlorinated solvent, ester solvent or mixture thereof.
In step (b) the suitable reducing agent may be selected from the group comprising of triethylsilane, Pd/C, Sn/HCl , Raney Ni; and the suitable solvent may be selected from the group comprising of ester solvent, ether solvent, acetic acid, sulphuric acid, trifluoroacetic acid or mixture thereof.
In step (c) the sodium alkoxide may be selected from the group comprising of sodium methoxide, sodium ethoxide preferably sodium methoxide; and the suitable solvent may be selected from the group comprising of alcoholic solvent, ester solvent, hydrocarbon solvent, ester solvent or mixture thereof.
In step (d) the suitable solvent may be selected from the group comprising of chlorinated solvent, hydrocarbon solvent, ether solvent, hydrocarbon solvent, ester solvent or mixture thereof.
In step (e) the suitable solvent may be selected from the group comprising of non-polar solvent, ester solvent, hydrocarbon solvent, alcoholic solvent or mixture thereof.
In step (f) the suitable solvent may be selected from the group comprising of polar aprotic solvents, ester solvents, hydrocarbon solvents preferably polar aprotic solvent or mixture thereof.
In step (g) the suitable inorganic base may be selected from the group comprising of sodium hydroxide, potassium hydroxide, ammonium hydroxide or sodium carbonate; and the suitable solvent may be selected from the group comprising of non-polar solvents, alcoholic solvent, ester solvent, ether solvent, hydrocarbon solvent or mixture thereof.
In step (h) the suitable reducing agent may be selected from the group comprising of Pd/C, Sn/HCl or Raney Ni; and the suitable solvent may be selected from the group comprising of polar protic solvents, alcoholic solvent, ether solvent, ester solvent, hydrocarbon solvent or mixture thereof.
In step (i) suitable solvent may be selected from the group comprising of ether solvent, ester solvent, hydrocarbon solvent, alcoholic solvent or mixture thereof.
In another aspect of the present invention, there is provided a process for the preparation of Fingolimod compound of formula II,
Formula II
said process comprising the steps of:
(a) reacting the alcoholic compound of formula VII

Formula VII
with methane sulfonyl halide in the presence of suitable solvent to provide 4-octylphenyethyl methanesulfonate of formula VI;
Formula VI
(b) reacting the sulfonate compound of formula VI alkali or alkali earth metal iodide in suitable solvent to provide 1-(2-iodopropyl)-4-octylbenzene of formula V;
Formula V
(c) reacting the compound of formula V with alkali or alkali earth metal nitrite in suitable solvent to provide 1-(2-nitropropyl)-4-octylbenzene of formula IV;
Formula IV
(d) reacting the compound of formula IV with formaldehyde or paraformaldehyde in the presence of suitable inorganic base to provide 2-nitro-2-(4-octylphenethyl)propan-1,3-diol of formula III; and
Formula III
(e) reducing the compound of formula III in the presence of suitable reducing agent in suitable solvent to provide Fingolimod of formula II.
Formula II
In step (a) the suitable solvent may be selected from the group comprising of chlorinated solvent, hydrocarbon solvent, ether solvent, hydrocarbon solvent, ester solvent or mixture thereof.
In step (b) the suitable solvent may be selected from the group comprising of non-polar solvent, ester solvent, hydrocarbon solvent, alcoholic solvent or mixture thereof.
In step (c) the suitable solvent may be selected from the group comprising of polar aprotic solvents, ester solvents, hydrocarbon solvents preferably polar aprotic solvent or mixture thereof.
In step (d) the suitable inorganic base may be selected from the group comprising of sodium hydroxide, potassium hydroxide, ammonium hydroxide or sodium carbonate; and the suitable solvent may be selected from the group comprising of non-polar solvents, alcoholic solvent, ester solvent, ether solvent, hydrocarbon solvent or mixture thereof.
In step (e) the suitable reducing agent may be selected from the group comprising of Pd/C, Sn/HCl or Raney Ni; and the suitable solvent may be selected from the group comprising of polar protic solvents, alcoholic solvent, ether solvent, ester solvent, hydrocarbon solvent or mixture thereof.
In another aspect of the invention, there is provided a process for the preparation of 1-(2-nitropropyl)-4-octylbenzene of formula IV, comprising the steps of:
(a) reacting the alcoholic compound of formula VII

Formula VII

with methane sulfonyl halide in the presence of suitable solvent to provide 4-octylphenyethyl methanesulfonate of formula VI;
Formula VI
(b) reacting the sulfonate compound of formula VI alkali or alkali earth metal iodide in suitable solvent to provide 1-(2-iodopropyl)-4-octylbenzene of formula V;
Formula V
(c) reacting the compound of formula V with alkali or alkali earth metal nitrite in suitable solvent to provide 1-(2-nitropropyl)-4-octylbenzene of formula IV;
Formula IV
In step (a) the suitable solvent may be selected from the group comprising of chlorinated solvent, hydrocarbon solvent, ether solvent, hydrocarbon solvent, ester solvent or mixture thereof.
In step (b) the suitable solvent may be selected from the group comprising of non-polar solvent, ester solvent, hydrocarbon solvent, alcoholic solvent or mixture thereof.
In step (c) the suitable solvent may be selected from the group comprising of polar aprotic solvents, ester solvents, hydrocarbon solvents preferably polar aprotic solvent or mixture thereof.
In some embodiment, there is provided a process for preparing the compound of formula IV, wherein the said process comprises the steps of:
(a) reacting the alcoholic compound of formula VII with methane sulfonyl chloride in the presence of triethylamine and dichloromethane to provide 4-octylphenylethyl methanesulfonate of formula VI;
(b) reacting the sulfonate compound of formula VI with sodium iodide in 2-butanone to provide 1-(2-iodopropyl)-4-octylbenzene of formula V; and
(c) reacting the compound of formula V with sodium nitrite in dimethylformamide to provide 1-(2-nitropropyl)-4-octylbenzene of formula IV.

In another aspect of the invention, there is provided a process for preparing the compound of formula IV by reacting the compound 1-(2-iodopropyl)-4-octylbenzene of formula V
Formula V
with alkali or alkali earth metal nitrite in suitable solvent to provide 1-(2-nitropropyl)-4-octylbenzene of formula IV.
Formula IV
The said suitable solvent may be selected from the group comprising of polar aprotic solvents, ester solvents, hydrocarbon solvents or mixture thereof; preferably polar aprotic solvent.
In another aspect of the invention, there is provided a process for preparation of Fingolimod of formula II or its pharmaceutically acceptable salts,
Formula II

said process comprising the steps of:
(a) reacting the compound of formula VIa
Formula VIa
with suitable reducing agent in solvent selected from the group consisting of tetrahydrofuran, wateror its mixtures thereof to obtain the compound of formula Va;
Formula Va
(b) reacting the compound of formula Va with boron trifluoride and trialkylsilane to obtain the compound of formula IV;
Formula IV
(c) reacting the compound of formula IV with an aqueous formaldehyde in suitable base to obtain the compound of formula III; and
Formula III
(d) converting the compound of formula III to Fingolimod of formula II or its pharmaceutically acceptable salts.
In step (a), suitable reducing agent is selected from the group comprising of sodium borohydride, potassium borohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminium hydride, vitride or borane-DMS, preferably sodium borohydride.
In step (b), the solvent is selected from the group comprising of chloro solvents, hydrocarbon solvents, ether solvents and its mixtures thereof; preferably dichloromethane.
In step (c), suitable base is selected from organic bases including diisopropyl amine, diisobutyl amine, triethylamine, diethylamine, dicyclohexylamine, n-butylamine, diisopropyl ethylamine or pyridine or inorganic bases including sodium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and like.
In another aspect of the invention, there is provided a process for the preparation of compound of formula Va by reacting the compound of formula VIa
Formula VIa
with suitable reducing agent in solvent selected from the group consisting of tetrahydrofuran, water and its mixture thereof to obtain the compound of formula Va.
Formula Va
The said suitable reducing agent may be selected from the group comprising of sodium borohydride, potassium borohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminium hydride, vitride or borane-DMS; preferably sodium borohydride.
In another aspect of the invention, there is provided a process for the preparation of compound of formula IV by reacting the compound of formula Va
Formula Va
with boron trifluoride and trialkylsilane to obtain the compound of formula IV.
Formula IV
The said process may be carried out in a solvent selected from the group comprising of chloro solvents, hydrocarbon solvents, ether solvents or mixture thereof; preferably dichloromethane.
In another aspect of the present invention, there is provided a process for the preparation of compound of formula III by reacting the compound of formula IV
Formula IV
with an aqueous formaldehyde in suitable base to obtain the compound of formula III.
Formula III

The said suitable base may be selected from the group comprising of organic bases including diisopropyl amine, diisobutyl amine, triethylamine, diethylamine, dicyclohexylamine, n-butylamine, diisopropyl ethylamine or pyridine or inorganic bases including sodium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and like.
In another aspect of the invention, there is provided a process for the purification of Fingolimod hydrochloride of formula I
Formula I
said process comprising steps of:
(a) providing a solution of Fingolimod hydrochloride of the formula I in solvent selected from the group consisting of methanol, isopropanol, ethyl acetate and water;
(b) optionally heating the reaction mixture obtained in step (a);
(c) facilitating crystallization of the reaction mixture obtained in step (a) or step (b); and
(d) isolating the crystalline Fingolimod hydrochloride obtained in step (c).
In step (c), facilitating crystallization may be done by slow cooling, seeding, evaporation, precipitation, anti-solvent addition or reverse addition and like.
In step (d), isolation may be done by filtration, distillation, centrifugation or spray drying and like.
In another aspect of the invention, there is provided a process for the purification of Fingolimod hydrochloride of formula I comprising the steps of:
(a) providing an aqueous solution of Fingolimod hydrochloride;
(b) optionally heating the reaction mixture obtained in step (a);
(c) adding anti-solvent to the reaction mixture obtained in step (a) or step (b);
(d) facilitating crystallization of the reaction mixture obtained in step (c); and
(e) isolating the crystalline Fingolimod hydrochloride obtained in step (d).
The inventors of the present invention, surprisingly found that the process for the purification of Fingolimod hydrochloride is better by treating with an aqueous solution followed by anti-solvent addition.
In step (c), the anti-solvent may be selected from the group comprising of ethylacetate, tetrahydrofuran, dichloromethane, acetone, acetonitrile, dimethyl formamide, dimethyl sulfoxide, hexane, benzene, toluene, diethyl ether, dioxane, chloroform or mixture thereof; preferably acetone.
In step (d), facilitating crystallization may be done by slow cooling, seeding, evaporation, precipitation, anti-solvent addition or reverse addition and like.
In step (e), isolation may be done by filtration, distillation, centrifugation or spray drying and like.
In yet another aspect of the invention, there is provided a process for the purification of Fingolimod hydrochloride of formula I comprising the steps of:
(a) providing an aqueous solution of Fingolimod hydrochloride;
(b) optionally heating the reaction mixture obtained in step (a);
(c) adding sodium chloride to the reaction mixture obtained in step (a) or step (b);
(d) facilitating crystallization of the reaction mixture obtained in step (c); and
(e) isolating the crystalline Fingolimod hydrochloride obtained in step (d).
The inventors of the present invention, surprisingly found that the process for the purification of Fingolimod hydrochloride is better by treating with an aqueous solution followed by sodium chloride addition.
In step (d), facilitating crystallization may be done by slow cooling, seeding, evaporation, precipitation, anti-solvent addition or reverse addition and like.
In step (e) isolation may be done by filtration, distillation, centrifugation or spray drying and like.
The present invention is explained in detail with reference to the following examples described below, which are provided only for the purpose of illustration only and should not be construed as limiting the scope of the invention in any manner
EXAMPLES
Example-1: Preparation of 4-octanoylphenethyl acetate of formula IX:
To a mixture of aluminum chloride (4.75 g) and dichloromethane (25 ml), octanoyl chloride (6.84 g) was added dropwise and stirred for 60 minutes at room temperature. Phenyl propyl acetate (5.0 g) was added to the reaction mixture and stirred overnight. The reaction mass was then poured into chilled water (50 ml) and extracted with methyl tertiary butyl ether (50 ml). The extracted methyl tertiary butyl ether phase was washed with sodium carbonate solution (25 ml) followed by sodium chloride solution (25 ml) and dried over anhydrous sodium sulfate. The methyl tertiary butyl ether phase was concentrated to obtain compound of formula IX as a residue. Yield: 7.1 g.
Example-2: Preparation of 4-octylphenethyl acetate of formula VIII:
To a stirred solution of 4-octanoylphenethyl acetate of formula IX (as obtained in Example-1) (7.0 g) in trifluoroacetic acid (15.2 ml), triethylsilane (3.37 g) was added under ice-cooling and stirred for 16 hours at room temperature. The reaction mass was then poured into chilled water and extracted using ethyl acetate (70 ml). The extracted ethyl acetate phase was washed with sodium carbonate solution (35 ml) followed by sodium chloride solution (35 ml). The washed ethyl acetate phase was concentrated to obtain compound of formula VIII as a residue. Yield: 9.10 g.
Example-3: Preparation of 2-(4-octylphenyl) ethanol of formula VII:
To a solution of 4-octylphenethyl acetate of formula VIII (as obtained in Example-2) (9.1 g) in methanol (35 ml), sodium methoxide (2.1 g) was added and refluxed for 4 hours. The reaction mass was then concentrated to obtain a residue. Chilled water (90 ml) was poured into the obtained residue and extracted with ethyl acetate (90 ml). The extracted ethyl acetate phase was washed with 5% aqueous hydrochloric acid solution (45 ml) and concentrated to obtain compound of formula VII as a residue. The residue was purified by column chromatography. %Yield: 30%.
Example-4: Preparation of 4-octylphenylethanyl methane sulfonate of formula VI:
Triethylamine (1.3 ml) was added to a solution of 2-(4-octylphenyl) ethanol of formula VII (as obtained in Example-3) (1.4 g) in dichloromethane (35 ml) and cooled. Methane sulfonyl chloride (0.73 g) was added dropwise to the cooled reaction mixture and stirred for 2 hours at room temperature. The reaction mass was then poured into chilled water (7.0 ml) and extracted with dichloromethane (35 ml). The extracted dichloromethane phase was washed with a saturated sodium bicarbonate solution (7.0 ml) and 1% saturated aqueous hydrochloric acid solution (7.0 ml). The washed dichloromethane phase was concentrated to obtain compound of formula VI as an oily substance. % Yield: 70%.
Example-5: Preparation of 1-(2-iodopropyl)-4-octylbenzene of formula V:
To a solution of 4-octylphenylethanyl methane sulfonate of formula VI (as obtained in Example-4) (1.0g) in 2-butanone (15ml), sodium iodide (0.54g) was added and refluxed for 4 hours. The reaction mass was then concentrated and poured into chilled water (10 ml). The contents of the reaction mass were then extracted with ethyl acetate (150 ml). The extracted ethyl acetate phase was washed with sodium chloride solution (5 ml) and concentrated to obtain the compound of formula V as an oily residue. % Yield: 82%.
Example-6: Preparation of 1-(2-nitropropyl)-4-octylbenzene of formula IV:
To a cooled mixture of 1-(2-iodopropyl)-4-octylbenzene of formula V (as obtained in Example-5) (0.90 g) and dimethyl formamide (9 ml), sodium nitrite (1.73 g) was added at 10-15°C and stirred for 15 minutes at the same temperature. The temperature of the reaction mixture was raised to 25-30°C and stirred for 24 hrs. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 0-5°C. Chilled water (10 ml) was added to the cooled reaction mass and the contents were extracted with ethyl acetate (10 ml). The extracted ethyl acetate phase was washed with sodium chloride solution (5 ml) and concentrated to obtain the compound of formula IV as a residue. Yield: 0.5 g.
Example-7: Preparation of 3-chloro-1-(4-octylphenyl) propan-1-one:
To a mixture of octylbenzene (80 g) and dichloromethane (720 ml), aluminium chloride (61.65 g) was added at -15 to -10°C and maintained at the same temperature for 65 minutes. 3-Chloropropionoyl chloride (53.3 g) in dichloromethane (80 ml) was slowly added to the reaction mixture at -15 to -10°C and stirred for 1 hour. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was transferred into ice water (560 ml) and stirred for 25 minutes resulting into a biphasic mixture. Organic layer from the resulted biphasic mixture was separated, washed with ethylacetate (240 ml); bi carbonate solution (400 ml); 10% sodium chloride solution (400 ml); and concentrated to obtain a residue. The residue was mixed with heptane (160 ml), cooled to -10°C and stirred for 90 minutes at 0 to -10°C. The resultant solid was filtered, washed with pre chilled heptane (80 ml) and dried. Yield: 57.4 g.
Example-8: Preparation of 3-nitro-1-(4-octylphenyl) propan-1-one:
To a mixture of 3-chloro-1-(4-octylphenyl) propan-1-one (55 g) and dimethyl formamide (275 ml), sodium nitrite (134.7 g) was added at 28°C and stirred for 22 hours at 25-30°C. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 8°C. Water (550 ml) was added to the cooled reaction mass at 8-15°C and stirred for 50 minutes at the same temperature. The resultant solid was filtered, washed with water (110 ml) and suck dried. The wet solid was mixed with n-heptane (110 ml), then heated to 42°C and stirred for 15 minutes at the same temperature. The contents were then cooled to -3°C and maintained at 0°C to -5°C for 20 minutes. The resultant solid was filtered, washed with n-heptane (55 ml) and dried to obtain the titled compound. Yield: 55.5 g.
Example-9: Preparation of 3-nitro-1-(4-octylphenyl) propan-1-ol of formula Va:
To a mixture of 3-nitro-1-(4-octylphenyl) propan-1-one of formula VIa (200.0 g) and methyl tert-butyl ether (1000 ml), sodium borohydride (13.0 g) was added followed by the slow addition of methanol (150 ml) at 0-5°C then stirred for 1 hour at the same temperature. Progress of the reaction was monitored by TLC. After completion of the reaction, pH of the reaction mass was adjusted to 5-6 by the addition of 5% hydrochloric acid. Water (500 ml) was added to the reaction mass and stirred for 30 minutes at 25-30°C to form a biphasic mixture. Organic layer from the biphasic mixture was separated, washed with 20% sodium chloride solution (800 ml) and concentrated under reduced pressure to obtain the titled compound as a residue. Yield: 205.20 g
Example-10: Preparation of 3-nitro-1-(4-octylphenyl-propan-1-ol:
To a mixture of 3-nitro-1-(4-octylphenyl) propan-1-one of formula VIa (100 gm) and tetra hydro furan (500 ml), sodium borohydride (6.5 gm) was added at 5-10° C and maintained at the temperature for 1 hour at 2-10° C. Water (7 ml) was slowly added to the reaction mixture at 5-10° C. The reaction mass was heated to 25-30° C and stirred for 1 hour. Progress of the reaction was monitored by TLC. After completion of the reaction, the pH of the reaction mass was adjusted to 5-6 by the addition of hydrochloric acid (5%). The reaction mass was concentrated under reduced pressure to obtain a residue. Water (500 ml) and dichloromethane (500 ml) was added to the residue and stirred for 30 minutes at 25-30° C to form a biphasic mixture. The organic layer was separated from a biphasic mixture, washed with 10% sodium chloride solution (300 ml) and concentrated under reduced pressure to obtain a residue. Yield: 103.0 gm.
Example-11: Preparation of 3-nitro-1-(4-octylphenyl- propan-1-ol:
To a mixture of 3-nitro-1-(4-octylphenyl) propan-1-one (200 g) of formula VIa and methanol (1000 ml), Sodium borohydride (13 g) was added to the reaction mixture at 5-10°C and maintained at the temperature for 2 hours. The reaction mixture was heated to 25-30°C and maintained at the same temperature for 1 hour. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 5 C and the pH of the cooled reaction mass was adjusted to 3-4 by adding hydrochloric acid (5%). Concentrated the reaction mass under reduced pressure to obtain a residue. Dichloromethane (1000 ml) and water (1000 ml) was added to the residue at 25-30°C to form biphasic mixture. Organic layer was separated from the biphasic mixture, washed with sodium chloride solution (10%) and concentrated under reduced pressure to obtain a residue. Yield: 189.5 g.
Example-12: Preparation of 1-(3-nitropropyl)-4-octylbenzene of formula IV:
To a mixture of 3-nitro-1-(4-octylphenyl) propan-1-ol of formula Va (245 g) and trifluoro acetic acid (714.05 g), triethylsilane (116.52 g) was added at 0 to 5°C then heated to 25-30°C and maintained at the temperature for 4 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 5-10°C. Ethyl acetate (1225 ml) and water (1225 ml) was added to the cooled reaction mass and stirred for 30 minutes to form a biphasic mixture. Organic layer was separated from the biphasic mixture, washed with potassium carbonate solution (1960 ml), 10% sodium chloride solution (980 ml) and concentrated under reduced pressure to obtain the titled compound as a residue. Yield: 326.6 g.
Example-13: Preparation of 1-(3-nitropropyl)-4-octylbenzene of formula IV:
To a mixture of 3-nitro-1-(4-octylphenyl) propan-1-ol of formula Va (10 g) and dichloromethane, triethylsilane (4.76 g) was added at 0-5° C followed by the addition of boron trifluoride (14.5 g) then the reaction mixture was heated to 25-30°C and maintained at the same temperature for 4 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 10-15°C. 20% Potassium carbonate solution (50 ml) and ethyl acetate (60 ml) were added to the cooled reaction mass to form a biphasic mixture. Organic layer was separated from the biphasic mixture, washed with sodium chloride solution (20%) and concentrated to obtain the titled compound as a residue. Yield: 7.0 g.
Example-14: Preparation of 1-(3-nitropropyl)-4-octylbenzene of formula IV:
Step- A: To a mixture of 3-nitro-1-(4-octylphenyl) propan-1-one of formula VIa (25.0 g) and methanol (125 ml), sodium borohydride (1.62 g) was added at 0-5°C and maintained at the same temperature for 2 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, trifluoro acetic acid (4.86 g) was added to the reaction mass, then methanol was stripped off by distillation under reduced pressure.
Step-B: To the contents obtained from step-A, trifluoro acetic acid (72.9 g) was added at 28°C. Triethylsilane (11.88 g) was added to the reaction mixture at 5-10°C then heated to 25-30°C and maintained at the same temperature for 3 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 5-10°C. Water (125 ml) and ethyl acetate (125 ml) was added to the cooled reaction mass to obtain a biphasic mixture. Organic layer was separated from the biphasic mixture, washed with 20% potassium carbonate solution (375 ml), 10% sodium chloride solution (125 ml) and concentrated under reduced pressure to obtain the titled compound as a residue. Yield: 34.5 g.
Example-15: Preparation of 2-nitro-2-(4-octylphenyl) propan-1,3-diol of formula III:
To a mixture of 1-(3-nitropropyl)-4-octylbenzene of formula IV (100 g) and water, aqueous formaldehyde (87.7 g) was added followed by slow addition of triethylamine (36.47 g) at 25- 30°C and maintained at the same temperature for 2 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, ethyl acetate (500 ml) was added to form biphasic mixture. Organic layer was separated from the biphasic mixture, washed with sodium metabisulphite solution (600 ml), sodium chloride solution (300 ml) and concentrated under reduced pressure to obtain a residue. The residue was mixed with n-heptane (200 ml) at 25-30°C. Then the contents were cooled to 0-5°C and maintained at the same temperature for 2 hours. The resultant solid was filtered, washed with pre-chilled n-heptane (50 ml) and dried to obtain the titled compound. Yield: 69.0 g.
Example-16: Preparation of 2-nitro-2-(4-octylphenyl) propan-1,3-diol of formula III:
To a mixture of 1-(3-nitropropyl)-4-octylbenzene of formula IV (100 g) and methanol (500 ml), aqueous formaldehyde (261.9 g) was added followed by slow addition of triethylamine (109.44 g) at 25-30°C and maintained at the same temperature for 3 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, ethyl acetate (500 ml), water (500 ml) was added to the reaction mixture to form a biphasic mixture. Organic layer was separated from the biphasic mixture, washed with sodium metabisulphite solution (300 ml), sodium chloride solution (300 ml) and concentrated under reduced pressure to obtain a residue. The residue was mixed with n-heptane (150 ml) at 25-30°C. Then the contents were cooled to 0-5° C and maintained at the same temperature for 2 hours. The resultant solid was filtered, washed with pre-chilled n-heptane (50 ml) and dried to obtain the titled compound. Yield: 72.5 g.
Example-17: Preparation of 2-nitro-2-(4-octylphenyl) propan-1,3-diol of formula III:
To a mixture of 1-(3-nitropropyl)-4-octylbenzene of formula IV (10 g) and water (50 ml), aqueous formaldehyde (8.77 g) was added followed by slow addition of N-ethyl diisopropylamine (4.6 g) at 25-30°C and maintained at the same temperature for 2 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, ethyl acetate (50 ml) was added to the reaction mixture to form a biphasic mixture. Organic layer was separated from the biphasic mixture, washed with sodium metabisulphite solution (50 ml), sodium chloride solution (50 ml) and concentrated under reduced pressure to obtain a residue. The residue was mixed with n-heptane (20 ml) at 25-30°C. Then the contents were cooled to 0-5°C and maintained at the same temperature for 2 hours. The resultant solid was filtered, washed with pre-chilled n-heptane (5 ml) and dried. Yield: 6.0 g.
Example-18: Preparation of 2-nitro-2-(4-octylphenyl) propan-1,3-diol of formula III:
To a mixture of 1-(3-nitropropyl)-4-octylbenzene of formula IV (10 g) and water (50 ml), aqueous formaldehyde (8.77 g) was added followed by slow addition of tributylamine (6.68 g) at 25-30°C and maintained at the same temperature for 4 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, ethyl acetate (50 ml) was added to the reaction mixture to form a biphasic mixture. Organic layer was separated from the biphasic mixture, washed with sodium metabisulphite solution (50 ml), sodium chloride solution (50 ml) and concentrated under reduced pressure to obtain a residue. The residue was mixed with n-heptane (20 ml) at 25-30° C. Then the contents were cooled to 0-5°C and maintained at the same temperature for 2 hours. The resultant solid was filtered, washed with pre-chilled n-heptane (5 ml) and dried to obtain the titled compound. Yield: 5.2 g.
Example-19: Preparation of 2-nitro-2-(4-octylphenyl) propan-1,3-diol of formula III:
To a mixture of 1-(3-nitropropyl)-4-octylbenzene of formula IV (10 g) and water (100 ml), aqueous formaldehyde (8.77 g) was added followed by slow addition of sodium hydroxide (1.44 g) at 25-30°C and maintained at the same temperature for 1 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, ethyl acetate (50 ml) was added to the reaction mixture to form a biphasic mixture. Organic layer was separated from the biphasic mixture, was washed with sodium metabisulphite solution (50 ml), sodium chloride solution (50 ml) and concentrated under reduced pressure to obtain a residue. The residue was mixed with n-heptane (20 ml) at 25-30°C. Then the contents were cooled to 0-5°C and maintained at the same temperature for 2 hours. The resultant solid was filtered, washed with pre-chilled n-heptane (5 ml) and dried to obtain the titled compound. Yield: 4.95 g.
Example-20: Preparation of 2-nitro-2-(4-octylphenyl) propan-1,3-diol of formula III:
To a mixture of 1-(3-nitropropyl)-4-octylbenzene of formula IV (10 g) and water (50 ml), aqueous formaldehyde (8.77 g) was added followed by slow addition of lithium hydroxide monohydrate (1.51 g) at 25-30°C and maintained at the same temperature for 2 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, ethyl acetate (50 ml) was added into the reaction mixture to form a biphasic mixture. Organic layer was separated from the biphasic mixture, was washed with sodium metabisulphite solution (50 ml), sodium chloride solution (50 ml) and concentrated under reduced pressure to obtain a residue. The residue was mixed with n-heptane (20 ml) at 25-30°C. Then the contents were cooled to 0-5°C and maintained at the same temperature for 2 hours. The resultant solid was filtered, washed with pre-chilled n-heptane (5 ml) and dried to obtain the titled compound. Yield: 5.30 g.
Example-21: Preparation of 2-nitro-2-(4-octylphenyl) propan-1,3-diol of formula III:
To a mixture of 1-(3-nitropropyl)-4-octylbenzene of formula IV (10 g) and water (50 ml), aqueous formaldehyde (8.77 g) was added followed by slow addition of potassium carbonate (4.98 g) at 25-30°C and maintained at the same temperature for 4 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, ethyl acetate (50 ml) was added to the reaction mixture to form a biphasic mixture. Organic layer was separated from the biphasic mixture, washed with sodium metabisulphite solution (50 ml), sodium chloride solution (50 ml) and concentrated under reduced pressure to obtain a residue. The residue was mixed with n-heptane (20 ml) at 25-30°C. Then the contents were cooled to 0-5°C and maintained at the same temperature for 2 hours. The resultant solid was filtered, washed with pre-chilled n-heptane (5 ml) and dried to obtain the titled compound. Yield: 5.80 g.
Example-22: Preparation of 2-amino-2-(4-octylphenyl) propan-1,3-diol of formula II:
To a mixture of 2-nitro-2-(4-octylphenyl) propan-1,3-diol of formula III (68 g), methanol (680 ml) and palladium carbon 10% (13.6 g) in autoclave vessel at 25-30°C, hydrogen pressure (5 kg/cm2) was applied and maintained at the same temperature for 3 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, palladium carbon was filtered and washed with methanol (60 ml). The filtrate was concentrated under reduced pressure to form a residue. The residue was mixed with ethyl acetate (20 ml) and cooled to 0-5°C and maintained at the same temperature for 60 minutes. The resultant solid was filtered, washed with pre-chilled ethyl acetate (34 ml) and dried to obtain the titled compound. Yield: 48 g.
Example-23: Preparation of 2-amino-2-(4-octylphenyl) propan-1,3-diol of formula II:
To a mixture of 2-nitro-2-(4-octylphenyl) propan-1,3-diol of formula III (10 g), methanol (100 ml) and Raney nickel (2 ml) in autoclave vessel at 25-30°C, hydrogen pressure (5 kg/cm2) was applied and maintained at the same temperature for 3 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, Raney nickel was filtered, washed with methanol (20 ml). The filtrate was concentrated under reduced pressure to form a residue. The residue was mixed with ethyl acetate (20 ml) and cooled to 0-5°C and maintained at the same temperature for 60 minutes. The resultant solid was filtered, washed with pre-chilled ethyl acetate (5 ml) and dried to obtain the titled compound. Yield: 5.30 g.
Example-24: Preparation of 2-amino-2-(4-octylphenyl) propan-1,3-diol hydrochloride of formula I:
To a mixture of 2-amino-2-(4-octylphenyl) propan-1,3-diol of formula II (40 g) and ethyl acetate (240 ml), ethyl acetate hydrochloride (40 ml) was slowly added at 10-15°C. The contents of the reaction mixture were further cooled to 2°C and maintained at the same temperature for 1 hour. The resultant solid was filtered, washed with pre-chilled ethyl acetate (40 ml) and dried. Yield: 42 g.
Examaple-25: Purification of 2-amino-2-(4-octylphenyl) propan-1,3-diol hydrochloride of formula I:
A mixture of Fingolimod hydrochloride of formula I (35 g), methanol (35 ml) and ethyl acetate (350 ml) was heated to reflux for 30 minutes. The contents were then cooled to 0-5°C and maintained at the same temperature for 70 minutes. The resultant solid was filtered, washed with a pre-chilled mixture of methanol: ethyl acetate (3 ml: 32 ml) and dried to obtain the titled compound. Yield: 32.5 g.
Example-26: Purification of 2-amino-2-(4-octylphenyl) propan-1,3-diol hydrochloride of formula I:
A mixture of Fingolimod hydrochloride of formula I (5 g) and water (25 ml) was heated for 30 minutes at 40-45°C. The contents were further cooled to 25-30°C followed by the addition of acetone (75 ml) at 25-30°C. Then the contents were further cooled to 0-5°C and maintained at the same temperature for 1 hour. The resultant solid was filtered and dried to obtain the titled compound. Yield: 0.455 g.
Example-27: Purification of 2-amino-2-(4-octylphenyl) propan-1,3-diol hydrochloride of formula I:
A mixture of Fingolimod hydrochloride of formula I (10.0 g) and methanol (20 ml) was heated for 30 minutes at 38-40°C. The contents were then cooled to 0-5°C and maintained at the same temperature for 1 hour. The resultant solid was filtered and dried to obtain the titled compound. Yield: 2.6 g.
Example-28: Purification of 2-amino-2-(4-octylphenyl) propan-1,3-diol hydrochloride of formula I:
A mixture of Fingolimod hydrochloride of formula I (5 g) and isopropanol (25 ml) was heated for 30 minutes at 45-50°C. The contents were then cooled to 0-5°C and maintained at the same temperature for 60 minutes. The resultant solid was filtered and dried to obtain the purified 2-amino-2-(4-octylphenyl) propan-1,3-diol hydrochloride. Yield: 2.8 g.
Example-29: Purification of 2-amino-2-(4-octylphenyl) propan-1,3-diol hydrochloride of formula I:
A mixture of Fingolimod hydrochloride of formula I (5.0 g) and ethyl acetate (50 ml) was heated for 30 minutes at 73-78°C. The contents were then cooled to 0-5°C and maintained at the same temperature for 1 hour. The resultant solid was filtered, washed with pre-chilled ethyl acetate (10 ml) and dried to obtain the purified 2-amino-2-(4-octylphenyl) propan-1,3-diol hydrochloride. Yield: 4.9 g.
Example-30: Purification of 2-amino-2-(4-octylphenyl) propan-1,3-diol hydrochloride of formula I:
A mixture of Fingolimod hydrochloride of formula I (10 g) and water (50 ml) was heated for 30 minutes at 45-50°C. Sodium chloride (17.5 g) was added to the heated reaction mixture and maintained at the same temperature for 30 minutes. The contents were then cooled to 10°C and maintained at the temperature for 1 hour. The resultant solid was filtered and dried to obtain the purified 2-amino-2-(4-octylphenyl) propan-1,3-diol hydrochloride.
Yield: 9 g.
Example-31: Preparation of 2-nitro-2-(4-octylphenyl) propan-1,3-diol of formula III:
To a mixture of 1-(3-nitropropyl)-4-octylbenzene of formula IV (10 g) and toluene (50 ml), aqueous formaldehyde (8.77 g) was added followed by slow addition of triethylamine (3.64 g) at 25-30°C and maintained at the same temperature for 5 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, water (50 ml) was added to form a biphasic mixture. Organic layer was separated from the biphasic mixture, washed with sodium metabisulphite solution (50 ml), sodium chloride solution (50 ml) and concentrated under reduced pressure to obtain a residue. The residue was mixed with n-heptane (20 ml) at 25-30°C. The contents were then cooled to 0-5°C and maintained at the same temperature for 1 hour. The resultant solid was filtered, washed with pre-chilled n-heptane (5 ml) and dried to obtain the titled compound. Yield: 5.18 g.
Example-32: Preparation of 2-nitro-2-(4-octylphenyl) propan-1,3-diol of formula III:
To a mixture of 1-(3-nitropropyl)-4-octylbenzene of formula IV (10 gm) and ethylacetate (50 ml), aqueous formaldehyde (8.77 gm) was added followed by slow addition of triethylamine (0.73 gm) at 25-30° C and maintained at the same temperature for 3 hours. Progress of the reaction mixture was monitored by TLC. After completion of the reaction, water (50 ml) was added to the reaction mass to form a biphasic mixture. Organic layer was separated from the biphasic mixture, washed with sodium metabisulphite solution (50 ml, sodium chloride solution (50 ml) and concentrated under reduced pressure to obtain a residue. The residue was mixed with n-heptane (20 ml) at 25-30° C. Then the contents were then cooled to 0-5° C and maintained at the same temperature for 1 hours. The resultant solid was filtered, washed with pre-chilled n-heptane (5 ml) and dried. Yield: 5.04 gm.
Example-33: Preparation of 2-nitro-2-(4-octylphenyl) propan-1,3-diol of formula III:
Step-A: To a mixture of 3-nitro-1-(4-octylphenyl) propan-1-one of formula VIa (25.0 g) and methanol (125 ml), sodium borohydride (1.62 g) was added at 0-5°C and maintained at the same temperature for 2 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, reaction mass was allowed to proceed to next step.
Step-B: To the contents obtained from step-A, trifluoro acetic acid (4.86 g) was added and concentrated under reduced pressure. The resultant mixture was cooled to 5-10°C followed by the addition of trifluoro acetic acid (72.9 g) at 5-10°C. The reaction mixture was further cooled to 0-5°C followed by the addition of triethylsilane (11.88 g). Then the reaction mixture was heated to 25-30°C and maintained at the same temperature for 3 hours. Progress of the reaction monitored by TLC. After completion of the reaction, the contents were then cooled to 5-10°C. Water (125 ml), ethyl acetate (125 ml) was added to the cooled reaction mass to form a biphasic mixture. Organic layer was separated from the biphasic mixture, washed with potassium carbonate solution (20%), sodium chloride solution (10%) and concentrated under reduced pressure to obtain a residue.
Step-C: To a mixture of residue obtained from step-B, water (170 ml) and aqueous formaldehyde (29.7 g), triethylamine (12.3 g) was added at 25-30°C and maintained at 25-30°C for 2 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, ethyl acetate (170 ml) was added to form a biphasic mixture. Organic layer was separated from the biphasic mixture, washed with sodium metabisulphite solution (170 ml), sodium chloride solution (170 ml) and concentrated under reduced pressure to obtain residue. The residue was mixed with n-heptane (70 ml) at 25-30°C. Then the contents were cooled to 0-5°C and maintained at the same temperature for 1 hours. The resultant solid was filtered, washed with pre-chilled n-heptane (5 ml) and dried to obtain 2-nitro-2-(4-octylphenyl) propan-1,3-diol. Yield: 21.8 g.
,CLAIMS:1. A process for preparing the Fingolimod hydrochloride of formula I,

Formula I
said process comprising the steps of:
(a) reacting the octanoyl chloride compound of formula X
Formula X
with phenyl propyl acetate compound of formula XI
Formula XI
in presence of Lewis acid in suitable solvent to provide 4-octanoylphenethyl acetate compound of formula IX;
Formula IX
(b) reducing the compound of formula IX with suitable reducing agent in suitable solvent in presence of acid to provide 4-octylphenethyl acetate of formula VIII;
Formula VIII
(c) converting the compound of formula VIII in the presence of sodium alkoxide in suitable solvent to provide 2-(4-octylphenyl) ethanol compound of formula VII;
Formula VII
(d) reacting the alcoholic compound of formula VII with methane sulfonyl halide in the presence of suitable solvent to provide 4-octylphenylethyl methanesulfonate of formula VI;
Formula VI
(e) reacting the sulfonate compound of formula VI with alkali or alkali earth metal iodide in suitable solvent to provide 1-(2-iodopropyl)-4-octylbenzene of formula V;
Formula V
(f) reacting the compound of formula V with alkali or alkali earth metal nitrite in suitable solvent to provide 1-(2-nitropropyl)-4-octylbenzene of formula IV;
Formula IV
(g) reacting the compound of formula IV with formaldehyde or paraformaldehyde in the presence of suitable inorganic base to provide 2-nitro-2-(4-octylphenethyl)propan-1,3- diol of formula III;
Formula III
(h) reducing the compound of formula III in the presence of suitable reducing agent in suitable solvent to provide Fingolimod of formula II; and
Formula II
(i) reacting the compound of formula II with hydrochloric acid in suitable solvent to provide Fingolimod hydrochloride salt of formula I.

2. The process as claimed in claim 1, wherein the Lewis acid used in step (a) is selected from the group comprising boron trifluoride, zinc chloride, zinc bromide, aluminium chloride or titanium tetrachloride.

3. The process as claimed in claim 1, wherein the reducing agent used in step (b) is selected from triethylsilane, Pd/C, Sn/HCl or Raney Ni.

4. The process as claimed in claim 1, wherein the sodium alkoxide used in step (c) is selected from sodium methoxide or sodium ethoxide.

5. The process as claimed in claim 1, wherein the inorganic base used in the step (g) is selected from sodium hydroxide, potassium hydroxide, ammonium hydroxide or sodium carbonate.

6. The process as claimed in claim 1, wherein the step (i) is carried in presence of ether solvent, ester solvent, hydrocarbon solvent, alcoholic solvent or mixture thereof.

7. A process for preparing the compound of formula IV, comprising the steps of:
(a) reacting the alcoholic compound of formula VII
Formula VII

with methane sulfonyl halide in the presence of suitable solvent to provide 4- octylphenylethylmethanesulfonate of formula VI;
Formula VI
(b) reacting the sulfonate compound of formula VI with alkali or alkali earth metal iodide in suitable solvent to provide 1-(2-iodopropyl)-4-octylbenzene of formula V; and
Formula V
(c) reacting the compound of formula V with alkali or alkali earth metal nitrite in suitable solvent to provide 1-(2-nitropropyl)-4-octylbenzene of formula IV.
Formula IV

8. A process for preparing the compound of formula IV, by reacting the compound 1-(2-iodopropyl)-4-octylbenzene of formula V
Formula V
with alkali or alkali earth metal nitrite in suitable solvent to provide 1-(2-nitropropyl)- 4-octylbenzene of formula IV.
Formula IV

9. The process for preparing the compound of formula IV as claimed in claim 7, wherein the said process comprises the steps of:
(a) reacting the alcoholic compound of formula VII with methane sulfonyl chloride in the presence of triethylamine and dichloromethane to provide 4-octylphenylethyl methanesulfonate of formula VI;
(b) reacting the sulfonate compound of formula VI with sodium iodide in 2-butanone to provide 1-(2-iodopropyl)-4-octylbenzene of formula V; and
(c) reacting the compound of formula V with sodium nitrite in dimethylformamide to provide 1-(2-nitropropyl)-4-octylbenzene of formula IV.

10. A process for preparation of Fingolimod of formula II or its pharmaceutically acceptable salts thereof,
Formula II
said process comprising the steps of:
(a) reacting the compound of formula VIa
Formula VIa
with suitable reducing agent in solvent selected from the group consisting of tetrahydrofuran, water or its mixtures thereof to obtain the compound of formula Va;
Formula Va
(b) reacting the compound of formula Va with boron trifluoride and trialkylsilane to obtain the compound of formula IV;
Formula IV
(c) reacting the compound of formula IV with an aqueous formaldehyde in suitable base to obtain the compound of formula III; and
Formula III
(d) converting the compound of formula III to Fingolimod of formula II or its pharmaceutically acceptable salts thereof.

11. The process as claimed in claim 10, wherein the reducing agent used in step (a) is selected from the group comprising of sodium borohydride, potassium borohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminium hydride, vitride or borane-DMS; preferably sodium borohydride.

12. The process as claimed in claim 10, wherein the step (b) is carried out in presence of chloro solvents, hydrocarbon solvents, ether solvents or mixture thereof.

13. The process as claimed in claim 10, wherein the base used in step (c) is selected from organic bases comprising diisopropyl amine, diisobutyl amine, triethylamine, diethylamine, dicyclohexylamine, n-butylamine, diisopropyl ethylamine or pyridine; or inorganic bases comprising sodium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate.

14. A process for the preparation of compound of formula IV by reacting the compound of formula Va
Formula Va
with boron trifluoride and trialkylsilane to obtain the compound of formula IV.
Formula IV

15. The process as claimed in claim 14, wherein the said process is carried out in the presence of chloro solvents, hydrocarbon solvents, ether solvents or mixture thereof.

16. A process for the preparation of compound of formula III by reacting the compound of formula IV
Formula IV
with an aqueous formaldehyde in suitable base to obtain the compound of formula III.
Formula III

17. The process as claimed in claim 16, wherein the base is selected from organic bases comprising diisopropyl amine, diisobutyl amine, triethylamine, diethylamine, dicyclohexylamine, n-butylamine, diisopropyl ethylamine or pyridine or inorganic bases comprising sodium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate.

18. A process for the purification of Fingolimod hydrochloride of formula I comprising the steps of:
(a) providing a solution of Fingolimod hydrochloride of the formula I in solvent selected from the group consisting of methanol, isopropanol, ethyl acetate and water;
(b) optionally heating the reaction mixture obtained in step (a);
(c) facilitating crystallization of the reaction mixture obtained in step (a) or step (b); and
(d) isolating the crystalline Fingolimod hydrochloride obtained in step (c).

19. A process for the purification of Fingolimod hydrochloride of formula I comprising the steps of:
(a) providing an aqueous solution of Fingolimod hydrochloride;
(b) optionally heating the reaction mixture obtained in step (a);
(c) adding anti-solvent to the reaction mixture obtained in step (a) or step (b);
(d) facilitating crystallization of the reaction mixture obtained in step (c); and
(e) isolating the crystalline Fingolimod hydrochloride obtained in step (d).