Field of the invention:

The present invention relates to an improved and novel processes for the preparation of 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol hydrochloride represented by the structural formula-la.

Formula-la

Background of the invention:

2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol is a sphingosine 1-phosphate receptor modulator. US 5,604,229 patent disclosed 2-amino-l,3-propanediol derivatives, and their properties such as pharmacological activity. This patent disclosed a process for preparing 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol, which comprises of the reaction of phenethyl acetate with octanoyl chloride in presence of aluminium chloride followed by reducing the obtained 2-(4-octanoylphenyl)ethyl acetate with triethylsilane in trifluoro acetic acid to get 2-(4-octylphenyl)ethyl acetate. The obtained ester is treated with sodium methoxide in methanol to provide 2-(4-octylphenyl)ethyl alcohol, which is then treated with methane sulfonyl chloride in presence of triethylamine to provide 2-(4-octylphenyl)ethyl methane sulfonate. The mesylate compoimd is then treated with sodium iodide in 2-butanone to provide 2-(4-octylphenyl)ethyl iodide, which on condensation with diethyl acetamidomalonate in sodium ethoxide in ethanol provide diethyl 2-acetamido-2-(4-octylphenyl)ethyl malonate. The obtained compound upon reduction with lithium alxmiinium hydride followed by treatment with acetic anhydride in presence of pyridine provides 2-acetamido-2-[2-(4-octylphenyl)ethyl]propane-l,3-diyl acetate. The resulting compound upon treatment with lithium hydroxide in methanol followed by INHCl/ether in ethanol provides 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride sah.

However, the disclosed process has certain disadvantages that it involves many complicated steps, and it produces intermediates as oily substances or various isomeric mixtures. Hence it requires isolation and purification of intermediate products by methods such as silica gel chromatography, which is a complicated method and involves the usage of large quantity of organic solvents. Hence, it is difficult to remove undesired isomers, homologues and other impurities.

Thus, there is a need in the art to develop a process which makes it possible to prepare highly pure 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol hydrochloride in high yield, without involving any complicated steps in the process.

The present invention overcomes the problems associated with the prior-art by adopting a simple process, which provides Fingolimod hydrochloride with good yield and purity. The process of the present invention is simple, safer, economic and doesn't involve any complicated steps.

Advantages of the present invention:

• Provides a novel process for the preparation of l-(3-nitropropyl)-4-octylbenzene compound of formula-8, which is an intermediate of Fingolimod hydrochloride.

• Provides novel compounds of formulae-12 & 13, which are useful intermediates in the preparation of Fingolimod hydrochloride.

• Provides a novel process for the preparation of 2-nitro-2-(4-octylphenethyl)propane-l,3-diol compound of formula-9.

• Provides Fingolimod hydrochloride in high jdeld and purity.

• Provides a simple, safer and industrially feasible process for Fingolimod hydrochloride.
Brief description of the invention:

The first aspect of the present invention is to provide an improved process for the preparation of 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol hydrochloride compound of formula-la, comprising of;

a) Reacting the octanoyl chloride compound of formula-2 with benzene in presence of Lewis acid in a suitable solvent to provide 1-phenyloctan-l-one compound of formula-3,

b) reducing the compound of formula-3 with a suitable reducing agent in a suitable solvent in presence of an acid to provide octyl benzene compound of formula-4,

c) condensing the compound of formula-4 with 3-chloropropanoyl chloride in presence of Lewis acid in a suitable solvent to provide 3-chloro-l-(4-octylphenyl)propan-l-one compound of formula-5.

d) treating the compound of formula-5 with sodium nitrite in a suitable solvent to provide 3-nitro-l-(4-octylphenyl)propan-l-one compound of formula-6,

e) reducing the compound of formula-6 with a suitable reducing agent in a suitable solvent to provide 3-nitro-l-(4-octylphenyl)propan-l-ol compound of formula-7,

f) reducing the compound of formula-7 with a suitable reducing agent in a suitable solvent to provide l-(3-nitropropyl)-4-octylbenzene compound of formula-8,

g) reacting the compoimd of formula-8 with paraformaldehyde in presence of a suitable base in a suitable solvent to provide 2-nitro-2-(4-octylphenethyl)propane-l,3-diol compound of formula-9,

h) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent to
provide 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol compound of formula-1,

i) optionally purifying the compoimd of formula-1 from a suitable solvent,

j) treating the compoimd of formula-1 with a suitable HCl source in a suitable solvent to provide
2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol hydrochloride compound of formula-la.

The second aspect of the present invention is to provide a process for the preparation of octyl benzene compound of formula-4 by reducing the 1-phenyloctan-l-one compound of formula-3 with a suitable reducing agent in a suitable solvent in presence of an acid.

The third aspect of the present invention is to provide a novel process for the preparation of l-(3-nitropropyl)-4-octylbenzene compound of formula-8 by reducing the 3-nitro-l-(4-octylphenyl)propan-l-ol compound of formula-7 using a suitable reducing agent in a suitable solvent.

The fourth aspect of the present invention is to provide a process for the purification of 3-nitro-l-(4-octylphenyl)propan-l-one compound of formula-6, comprising of;

a) Dissolving the 3-nitro-l-(4-octylphenyl)propan-l-one compound of formula-6 in a suitable solvent by heating,

b) cooling the reaction mixture,

c) filtering the precipitated solid,

d) drying the compound to get pure compound of formula-6.

The fifth aspect of the present invention is to provide a novel process for the preparation of 4 2-nitro-2-(4-octylphenethyl)propane-l,3-diol compound of formula-9, comprising of;

a) Condensing the octyl benzene compound of formula-4 with chloro acetyl chloride in presence of Lewis acid in a suitable solvent to provide 2-chloro-l-(4-octylphenyl)ethanone compound of formula-11,

b) condensing the compound of formula-11 with diethyl 2-nitro malonate in presence of iodine source and a suitable base in a suitable solvent to provide diethyl 2-nitro-2-(2-(4-octylphenyl)-2-oxoethyl)malonate compound of formula-12,

c) reducing the compound of formula-12 with a suitable reducing agent in a suitable solvent to provide diethyl 2-nitro-2-(4-octylphenethyl)malonate compound of formula-13,

d) reducing the compound of formula-13 with a suitable reducing agent in a suitable solvent to provide 2-nitro-2-(4-octylphenethyl)propane-l,3-diol compound of formula-9.

The sixth aspect of the present invention is to provide novel intermediate compovmds for the preparation of 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol hydrochloride compound of formula-la.

The seventh aspect of the present invention is to provide a novel process for the preparation of diethyl 2-nitro-2-(2-(4-octylphenyl)-2-oxoethyl)malonate compoimd of formula-12, which comprising of condensing the 2-chloro-l-(4-octylphenyl)ethanone compound of formula-11 with diethyl 2-nitro malonate in presence of iodine source and a suitable base in a suitable solvent.

The eighth aspect of the present invention is to provide a novel process for the preparation of diethyl 2-nitro-2-(4-octylphenethyl)malonate compovmd of formula-13, which comprising of reducing the diethyl 2-mtro-2-(2-(4-octylphenyl)-2-oxoethyl)malonate compound of formula-12 with a suitable reducing agent in a suitable solvent.

The ninth aspect of the present invention is to provide a novel process for the preparation of 2-nitro-2-(4-octylphenethyl)propane-l,3-diol compound of formula-9, which comprising of reducing the diethyl 2-nitro-2-(4-octylphenethyl)malonate compound of formula-13 with a suitable reducing agent in a suitable solvent.

The tenth aspect of the present invention is to provide a process for the preparation of l-(3-nitropropyl)-4-octylbenzene compound of formula-8, comprising of reducing the 3-nitro-l-(4- octylphenyl)propan-l-one compound of formula-6 with a suitable reducing agent in a suitable solvent.

Brief Description of the drawings:

Figure 1: Illustrates the PXRD of 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol
hydrochloride compound of formula-la obtained as per the present invention.

Detailed description of the invention:

The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethylether, diethylether, methyl tert-butyl ether, tetrahydrofiiran and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulphoxide, dioxane, acetonitrile and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform and the like; "ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, isopropanol, n-butanol and the like; "polar solvents" such as water; and/or their mixtures thereof.

As used herein the present invention the term "suitable base" refers to "alkali metal carbonates" such as sodium carbonate, potassium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassixrai methoxide, potassium tert.butoxide and the like; and organic bases like diisopropyl amine, diisobutyl amine, triethylamine, pyridine and/or their mixtures thereof.

The first aspect of the present invention provides an improved process for the preparation of 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol hydrochloride compound of formula-la, comprising of the following steps; a) Reacting the octanoyl chloride compound of formula-2

Formula-2 with benzene in presence of Lewis acid in a suitable solvent to provide 1-phenyloctan-l-one compound of formula-3,

Formula-3 b) reducing the compoimd of formula-3 with a suitable reducing agent in a suitable solvent in presence of an acid to provide octyl benzene compound of formula-4,


Formula-4 c) condensing the compound of formula-4 with 3-chloropropanoyl chloride in presence of Lewis acid in a suitable solvent to provide 3-chloro-l-(4-octylphenyl)propan-l-one compound of formula-5,

Formula-S d) treating the compoimd of formula-5 with sodium nitrite in a suitable solvent to provide nitro-l-(4-octylphenyl)propan-l-one compound of formula-6,

Fonnula-6 e) reducing the compound of formula-6 with a suitable reducing agent in a suitable solvent to provide 3-nitro-l-(4-octylphenyl)propan-l-ol compound of formula-7,

Formula-7 f) reducing the compound of formula-7 with a suitable reducing agent in a suitable solvent to provide l-(3-nitropropyl)-4-octylbenzene compound of formula-8,

Formula-8 g) reacting the compound of formula-8 with paraformaldehyde in presence of a suitable base in a suitable solvent to provide 2-nitro-2-(4-octylphenethyl)propane-l,3-diol compound of formula-9,

Formula-9 h) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent to provide 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol compound of formula-1,

Formula-1 i) optionally purifying the compound of formula-1 from a suitable solvent, j) treating the compound of formula-1 with a suitable HCl source in a suitable solvent to provide 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol hydrochloride compound of formula-la.

Formula-la Wherein, in step-a) and step-c) the suitable Lewis acid is selected from aluminium chloride, boron trifluoride, zinc chloride, zinc bromide, tin-tetrachloride and titanium tetrachloride; preferably aluminium chloride; and the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents and ester solvents; preferably chloro solvents;

In step-b) the suitable reducing agent is selected from Pd/C, Pt/C, Zn-Hg/HCl, Sn/HCl, Raney Ni and triethylsilane, preferably Pd/C; and the suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents, acetic acid, oxalic acid and propionic acid; and the suitable acid is selected from sulfuric acid and hydrochloric acid; preferably sulfuric acid;
In step-d) the suitable solvent is selected from polar-aprotic solvents, alcoholic solvents and hydrocarbon solvents; preferably polar-aprotic solvents;

In step-e) the suitable reducing agent is selected form sodium borohydride, potassium borohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminium hydride, vitride and borane-DMS, preferably sodium borohydride; and the suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents, chloro solvents and water, preferably alcoholic solvents;

In step-f) the suitable reducing agent is preferably triethylsilane; and the suitable solvent is selected from trifluoro acetic acid, alcoholic solvents, chloro solvents, hydrocarbon solvents, ether solvents and water; preferably trifluoro acetic acid;

In step-g) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and alkali metal bicarbonates and organic bases like diisopropyl amine, diisobutyl amine, triethylamine and pyridine, preferably triethylamine; and the suitable solvent is selected from alcoholic solvents, chloro solvents and ether solvents; preferably alcoholic solvents;

In step-h) the suitable reducing agent is selected from Pd/C, Pt/C, Zn-Hg/HCl, Sn-HCl, Raney Ni, sodium borohydride, lithium borohydride, lithivmi aluminium hydride and the like, preferably Pd/C; and the suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents and chloro solvents; preferably alcoholic solvents;

In step-i) the suitable solvent is selected from ester solvents and alcoholic solvents; preferably ethyl acetate;

In step-j) the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents and/or their mixtures; and the suitable HCl source is selected from hydrochloric acid, dry HCl gas, ethyl acetate-HCl, isopropyl alcohol-HCl and the like; preferably ethyl acetate-HCl.

A preferred embodiment of the present invention is to provide an improved process for the preparation of 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol hydrochloride compound of formula-la, comprising of the following steps;

a) Reacting the octanoyl chloride compound of formula-2 with benzene in presence of aluminium chloride in methylene chloride to provide 1-phenyloctan-l-one compound of formula-3,

b) reducing the compound of formula-3 with Pd/C in acetic acid in presence of sulfuric acid to provide octyl benzene compound of formula-4,

c) condensing the compound of formula-4 with 3-chloropropanoyl chloride in presence of aluminium chloride in methylene chloride to provide 3-chloro-l-(4-octylphenyl)propan-l-one compound of formula-5,

d) reacting the compound of formula-5 with sodium nitrite in dimethyl formamide to provide 3-nitro-l-(4-octylphenyl)propan-l-one compound of formula-6,

e) reducing the compound of formula-6 with sodium borohydride in methanol to provide 3-nitro-l-(4-octylphenyl)propan-l-ol compound of formula-7,

f) reducing the compound of formula-7 with triethylsilane in trifluoro acetic acid to provide l-(3-nitropropyl)-4-octylbenzene compound of formula-8,

g) reacting the compound of formula-8 with paraformaldehyde in methanol in presence of triethylamine to provide 2-nitro-2-(4-octylphenethyl)propane-l,3-diol compound of formula-9,

h) reducing the compoxmd of formula-9 with Pd/C in methanol to provide 2-amino-2-[2-(4- octylphenyl)ethyl]propan-l,3-diol compound of formula-1,

i) optionally purifying the compound of formula-1 from ethyl acetate,

j) treating the compoimd of formula-1 with ethyl acetate-HCl in ethyl acetate to provide 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol hydrochloride compoimd of formula-la.

Fingolimod hydrochloride as produced by the process of the present invention is a crystalline solid having X-Ray powder diffraction pattern as depicted in Fig-1.

Fingolimod hydrochloride obtained by the process of the present invention is substantially free of the 2-(N,N-dimethylamino)-2-[2-(4-octylphenyl)ethyl]-l,3-propanediol, which is hereinafter referred to as N,N-dimethyl impurity represented by the following structural formula-10.

Formula-10 The second aspect of the present invention provides a process for the preparation of octyl benzene compound of formula-4 by reducing the 1-phenyloctan-l-one compound of formula-3 with a suitable reducing agent in a suitable solvent in presence of an acid.

Wherein, the suitable reducing agent is selected from Pd/C, Pt/C, Zn-Hg/HCl, Sn/HCl, Raney-Ni, triethylsilane, preferably Pd/C; and the suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents, acetic acid and oxalic acid; preferably acetic acid; and the suitable acid is selected from sulfuric acid and hydrochloric acid; preferably sulfuric acid.
The preferred embodiment of the present invention provides a process for the preparation of octyl benzene compound of formula-4 by reducing the 1-phenyloctan-l-one compound of formula-3 with Pd/C in acetic acid in presence of sulfuric acid.

The third aspect of the present invention provides a novel process for the preparation of 1-(3-nitropropyl)-4-octylbenzene compound of formula-8 by reducing the 3-nitro-l-(4-octylphenyl)propan-l-ol compound of formula-7 using a suitable reducing agent in a suitable solvent.

Wherein, the suitable reducing agent is triethylsilane; and the suitable solvent is selected from trifluoro acetic acid, alcoholic solvents, chloro solvents, hydrocarbon solvents, ether solvents and water; preferably trifluoro acetic acid.

The preferred embodiment of the present invention provides a novel process for the preparation of l-(3-nitropropyl)-4-octylbenzene compoimd of formula-8 by reducing the 3-nitro-l-(4-octylphenyl)propan-l-ol compoimd of formula-7 with triethylsilane in trifluoro acetic acid.

The fourth aspect of the present invention provides a process for the purification of 3-nitro-l-(4-octylphenyl)propan-l-one compoimd of formula-6, comprising of;

a) Dissolving the 3-nitro-l-(4-octylphenyl)propan-l-one compound of formula-6 in a suitable solvent by heating,

b) cooling the reaction mixture,

c) filtering the precipitated solid,

d) drying the compound to get pure compound of formula-6.

Wherein, in step-a) the suitable solvent is selected from hydrocarbon solvents, ether solvents, alcoholic solvents and/or their mixtures;

In step-b) the reaction mixture is cooled to 15-40°C preferably to 25-30°C and then further cooled to -5-10°C, more preferably to 0-5°C;

The preferred embodiment of the present invention provides a process for the purification of 3-nitro-l-(4-octylphenyl)propan-l-one compound of formula-6, comprising of;

a) Dissolving the 3-nitro-l-(4-octylphenyl)propan-l-one compound of formula-6 in pet ether by heating the reaction mixture to reflux temperature,

b) cooling the reaction mixture,

c) filtering the compound,

d) drying the compound to get pure compound of formula-6.

The fifth aspect of the present invention provides a novel process for the preparation of 2-nitro-2-(4-octylphenethyl)propane-l,3-diol compound of fonnula-9, comprising of; a) Condensing the octyl benzene compoimd of formula-4 with chloro acetyl chloride in presence of Lewis acid in a suitable solvent to provide 2-chloro-l-(4-octylphenyl)ethanone compound of formula-11,

Formula-11 b) condensing the compound of formula-ll with diethyl 2-nitro malonate in presence or absence of suitable iodine source and a suitable base in a suitable solvent to provide diethyl 2-nitro-2-(2-(4- octylphenyl)-2-oxoethyl)malonate compound of formula-12,

Formula-12 c) reducing the compound of formula-12 with a suitable reducing agent in a suitable solvent to provide diethyl 2-nitro-2-(4-octylphenethyl)malonate compound of formula-13, COOEt
NO2 COOEt Formula-13 12 d) reducing the compound of formula-13 with a suitable reducing agent in a suitable solvent to provide 2-nitro-2-(4-octylphenethyl)propane-l,3-diol compound of formula-9.

Wherein, in step-a) the suitable Lewis acid is selected from aluminium chloride, boron trifluoride, zinc chloride, zinc bromide, tin-tetrachloride and titanium tetrachloride; preferably aluminium chloride; and the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents and ester solvents;

In step-b) the suitable base is preferably selected from alkali metal hydroxides and alkali metal alkoxides; and the suitable solvent is selected from alcoholic solvents, polar-aprotic solvents, ether solvents and hydrocarbon solvents; and the suitable iodine source is preferably potassium iodide;

In step-c) the suitable reducing agent is preferably triethylsilane; and the suitable solvent is selected from trifluoro acetic acid, alcoholic solvents, chloro solvents, hydrocarbon solvents, ether solvents and water; preferably trifluoro acetic acid;

In step-d) the suitable reducing agent is selected from sodium borohydride, Raney Ni, Pd/C, Pd-acetic acid and the like, preferably sodium borohydride; and the suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents and chloro solvents; preferably alcoholic solvents.

A preferred embodiment of the present invention provides a novel process for the preparation of 2-nitro-2-(4-octylphenethyl)propane-l,3-diol compound of fonnula-9, comprising of;

a) Condensing the octyl benzene compound of formula-4 with chloro acetyl chloride in presence of alimiinium chloride in dichloromethane to provide 2-chloro-l-(4-octylphenyl)ethanone compoimd of formula-11,

b) condensing the compound of formula-11 with diethyl 2-nitro malonate in presence of potassium iodide and sodium hydroxide in ethanol to provide diethyl 2-nitro-2-(2-(4-octylphenyl)-2-oxoethyl)malonate compound of formula-12,

c) reducing the compound of formula-12 with triethylsilane in trifluoro acetic acid to provide diethyl 2-nitro-2-(4-octylphenethyl)malonate compound of formula-13,

d) reducing the compound of formula-13 with sodium borohydride in methanol to provide 2-nitro-2-(4-octylphenethyl)propane-l,3-diol compound of formula-9.
13

The sixth aspect of the present invention provides novel compounds of formulae-12 & 13, which are useful intermediates in the preparation of 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol hydrochloride compound of formula-la.

a) Diethyl 2-nitro-2-(2-(4-octylphenyl)-2-oxoethyl)malonate COOEt N02 COOEt Formula-12

b) Diethyl 2-nitro-2-(4-octylphenethyl)malonate COOEt NO2 COOEt Formula-13

The seventh aspect of the present invention provides a novel process for the preparation of diethyl 2-nitro-2-(2-(4-octylphenyl)-2-oxoethyl)malonate compound of formula-12, which comprising of condensing the 2-chloro-l-(4-octylphenyl)ethanone compound of formula-11 with diethyl 2-nitro malonate in presence of a suitable iodine source and a suitable base in a suitable solvent.

Wherein, the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides and alkali metal carbonates; and the suitable solvent is selected from alcoholic solvents, polar-aprotic solvents, ether solvents and hydrocarbon solvents; preferably alcoholic solvents; and the suitable iodine source is potassium iodide.

A preferred embodiment of the present invention provides a novel process for the preparation of diethyl 2-nitro-2-(2-(4-octylphenyl)-2-oxoethyl)malonate compound of formula-12, which comprising of condensing the 2-chloro-l-(4-octylphenyl)ethanone compound of formula-11 with diethyl 2-nitro malonate in presence of potassium iodide and sodium hydroxide in ethanol.

The eighth aspect of the present invention provides a novel process for the preparation of diethyl 2-nitro-2-(4-octylphenethyl)malonate compound of formula-13, which comprising of reducing the diethyl 2-nitro-2-(2-(4-octylphenyl)-2-oxoethyl)malonate compound of formula-12 with a suitable reducing agent in a suitable solvent.

Wherein, the suitable reducing agent is preferably triethylsilane; and the suitable solvent is selected from trifluoro acetic acid, alcoholic solvents, chloro solvents, hydrocarbon solvents, ether solvents and water; preferably trifluoro acetic acid.

A preferred embodiment of the present invention provides a novel process for the preparation of diethyl 2-nitro-2-(4-octylphenethyl)malonate compound of formula-13, which comprising of reducing the diethyl 2-nitro-2-(2-(4-octylphenyI)-2-oxoethyI)malonate compound of formula-12 with triethylsilane in trifluoro acetic acid.

The ninth aspect of the present invention provides a novel process for the preparation of 2-nitro-2-(4-octylphenethyl)propane-l,3-diol compound of formula-9, which comprising of reducing the diethyl 2-nitro-2-(4-octylphenethyl)malonate compound of formula-13 with a suitable reducing agent in a suitable solvent.

Wherein, the suitable reducing agent is selected from sodixmi borohydride, Raney Ni, Pd/C, Pd(0Ac)2 and the like, preferably sodium borohydride; and the suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents and chloro solvents; preferably alcoholic solvents.

A preferred embodiment of the present invention provides a novel process for the preparation of 2-nitro-2-(4-octylphenethyl)propane-l,3-diol compound of formula-9, which comprising of reducing the diethyl 2-nitro-2-(4-octylphenethyl)malonate compound of formula-13 with sodiimi borohydride in methanol.

The tenth aspect of the present invention provides a process for the preparation of l-(3-nitropropyl)-4-octylbenzene compound of formula-8, comprising of reducing the 3-nitro-l-(4-octylphenyl)propan-l-one compound of formula-6 with a suitable reducing agent preferably triethylsilane in a suitable solvent selected from trifluoro acetic acid, alcoholic solvents, chloro solvents, hydrocarbon solvents, ether solvents and water; preferably trifluoro acetic acid.

Fingolimod hydrochloride obtained by the process of the present invention is analyzed by HPLC under the following conditions;

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector and integrator; Column: Xterra RP18, 250x4.6, 5 |xm; Flow rate: 1.0 mL/minute; Wavelength: 220 run; Column temperature: 45°C; Injection volume: 10 |j,L; Run time: 52 minutes; Mobile phase-A: A solution of 3 mL of 85% orthophosphoric acid in 1000 ml of miUi-Q water with pH adjusted to 7.2 using dilute KOH solution; Diluent (Mobile phase-B): Acetonitrile: water (90:10 v/v); Elution: Gradient.

PXRD analysis of 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol hydrochloride was carried out using BRUKER/AXS X-Ray diflfractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.037min.

Fingolimod HCl produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball mills, roller and hammer mills and jet mills. Milling or micronization may be performed before drying or after the completion of drying of the product.
The present invention is schematically represented as follows. Scheme-1:

Formula-9

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention. Examples: Example-1: Preparation of 1-phenyloctan-l-one.

Benzene (250 gm) and methylene chloride (2500 ml) were charged into a clean and dry RBF under nitrogen atmosphere at 25-30°C and the reaction mixture was cooled to 0-5°C. Aluminium chloride (640 gm) was added to the reaction mixture at 0-5°C and stirred for 1 hr at the same temperature. Octanoyl chloride (520 gm) was added to the reaction mixture at 0-5°C and stirred for 2 hrs at the same temperature. The reaction mixture was quenched with chilled water at 0-5°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with methylene chloride. Both the organic layers were combined and washed with 10% sodium bicarbonate solution followed by 10% sodium chloride solution at 25-30°C. Distilled off the solvent completely under reduced pressure at 40-50°C and the obtained residue is subjected to high vacuum distillation to get the title compound as colorless liquid. Yield: 425.0 gm; B.P: 285-290°C.

Example-2: Preparation of octyl benzene 1-phenyloctan-l-one (250 gm), acetic acid (1250 ml) and 5% Pd/C (50 gm) were charged into the autoclave at 25-30°C under nitrogen atmosphere. To this reaction mixture, conc.H2S04 (25 ml) was added at 25-30°C and the temperature of the reaction mixture was raised to 70-75°C. 6-8 Kg/Cm^ hydrogen gas pressure was applied to the reaction mixture for 8 hrs at 70-75°C. After completion of the reaction, the reaction mixture was cooled to 25-30°C. Filtered the Pd/C through celite bed and washed with acetic acid. 70% of acetic acid was distilled off from the resulting reaction mixture under vacuum at 50-60°C. Both the layers were separated, water (250 ml) and methylene chloride (750 ml) were added to the acetic acid layer. Both the organic and aqueous layers were separated and the aqueous layer was extracted with methylene chloride. Combined the total organic layer and cooled to 10-15°C. The pH of the reaction mixture was adjusted to 7.5 using 10% sodium carbonate solution at 10-15 °C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with 10% sodivmi chloride solution. The resulting organic layer was dried over sodium sulfate and the solvent was completely distilled off under vacuum to get the title compound. Yield: 198.0 gm; B.P: 261-263°C.

Example-3: Preparation of 3-chloro-l-(4-octylphenyl)propan-l-one Octyl benzene (200 gm) and methylene chloride (1800 ml) were charged into a clean and dry RBF under nitrogen atmosphere at 25-30°C and cooled the reaction mixture to -10 to 0°C. Aluminium chloride (185 gm) was added to the reaction mixture at -10 to 0°C and stirred for 1 hr at the same temperature. 3-Chloro propanoyl chloride (80 ml) and methylene chloride (200 ml) were added to the reaction mixture at -10 to -5°C and stirred for 1 hr at the same temperature. After completion of the reaction, the reaction mixture was quenched with chilled water at 0-10°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with methylene chloride. Both the organic layers were combined and ethyl acetate (600 ml) was added at 25-30°C. The organic layer was washed with 10% sodium bicarbonate solution followed by 10% sodium chloride solution. The obtained organic layer was dried over sodium sulfate and the solvent was completely distilled off from the reaction mixture under vacuum at 40-50°C. Pet ether (100 ml) was added to the obtained crude compound and distilled off the solvent completely under reduced pressure at 35-40°C. Cooled the residue to 25-30°C and pet ether (200 ml) was added to it.

The obtained reaction mixture was cooled to -10°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid and washed with pre-cooled pet ether at -10°C and then dried to get the title compound. Yield: 200.0 gm; M.R: 52-54°C.

Example-4: Preparation of 3-nitro-l-(4-octylphenyl)propan-l-one 3-Chloro-l-(4-octylphenyl)propan-l-one (100 gm) and dimethyl formamide (500 ml) were charged into a clean and dry RBF under nitrogen atmosphere at 25-30°C and the reaction mixture was cooled to 10-15°C. Sodium nitrite (245 gm) was added to the resulting mixture 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 at the same temperature. After completion of the reaction, the reaction mixture was cooled to 0-5°C and chilled water (1000 ml) was added to it at the same temperature. The resulting mixture was stirred for 2 hrs at 0-5°C. The precipitate was filtered, washed with chilled water and then dried under vacuum to get the title compound. Yield: 100.0 gm.

Example-5: Purification of 3-nitro-l-(4-octyIphenyl)propan-l-one 3-Nitro-l-(4-octylphenyl)propan-l-one (100 gm) and pet ether (500 ml) were charged in a clean and dry RBF at 25-30°C. The resulting mixture was heated to reflux and stirred for 30 min at the same temperature. The temperature of the reaction mixture was reduced to 25-30°C and then further cooled to 0-5°C. The resulting mixture was stirred for 1 hr at 0-5°C. The precipitated solid was filtered, washed with chilled pet ether and then dried under reduced pressure to get the pure title compound. Yield: 75.0 gm; M.R: 51-52°C; Purity by HPLC: 99.7%.

Example-6: Preparation of 3-nitro-l-(4-octyIphenyl)propan-l-ol 3-Nitro-l-(4-octylphenyl)propan-l-one (73 gm) and methanol (730 ml) were charged into a clean and dry RBF imder nitrogen atmosphere at 25-30°C. The reaction mixture was cooled to 0-5 °C and sodium borohydride (29 gm) was added to it under nitrogen atmosphere at the same temperature. The resulting mixture was stirred for 1 hr at 0-5 °C. After completion of the reaction, the solvent was completely distilled off from the reaction mixture under reduced pressure at 40-50°C. The obtained residue was cooled to 25-30°C and water (365 ml) was added to it at the same temperature. The resulting mixture was cooled to 5-10°C and adjusted the pH to 7.5 using 20% acetic acid solution. The obtained mixture was stirred for 30 min at 25-30°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with methylene chloride.

Both the organic layers were combined and washed with 10% sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 70.0 gm. Exampie-7: Preparation of l-(3-nitropropyl)-4-octylbenzene 3-Nitro-l-(4-octylphenyl)propan-l-ol (69 gm) and trifluoro acetic acid (110 ml) were charged into a clean and dry RBF under nitrogen atmosphere at 10-15°C. The reaction mixture was cooled to 0-5°C and triethylsilane (75 ml) was added to it and stirred for 60 min at the same temperature. The temperature of the reaction mixture was raised to 25-30°C and stirred for 10 hrs at the same temperature. After completion of the reaction, the reaction mixture was cooled to 10-15°C and water (345 ml) followed by ethyl acetate (345 ml) were added to it and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Both the organic layers were combined and washed with water, 10% sodium carbonate solution followed by 10% sodium chloride solution. The resulting organic layer was dried over sodium sulfate and the solvent was completely distilled off under reduced pressure to get the title compound. Yield: 59.0 gm.

Example-8: Preparation of l-(3-nitropropyl)-4-octylbenzene 3-nitro-l-(4-octylphenyl)propan-l-one (20 gm) and trifluoroacetic acid (50 ml) were charged into a clean and dry RBF under nitrogen atmosphere at 10-15°C. The reaction mixture was cooled to 0-5°C and triethylsilane (66 ml) was added to it and stirred for 1 hr at the same temperature. The temperature of the reaction mixture was raised to 25-30°C and stirred for 10 hrs at the same temperature. After completion of the reaction, the reaction mixture was cooled to 10-15°C and water (100 ml) followed by ethyl acetate (100 ml) were added to it and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Both the organic layers were combined and washed with water, 10% sodium carbonate solution followed by 10% sodium chloride solution. The resulting organic layer was dried over sodium sulfate and the solvent was completely distilled off under reduced pressure to get the title compound. Yield: 16.0 gm.

Example-9: Preparation of 2-nitro-2-(4-octyIphenethyl)propan-l,3-diol l-(3-Nitropropyl)-4-octylbenzene (65 gm) and methanol (650 ml) were charged into a clean and dry RBF at 25-30°C. To the resulting solution, paraformaldehyde (63 gm) and triethylamine (98 ml) were added. The reaction mixture was heated to 60-70°C and stirred for 3 hrs at the same temperature. After completion of the reaction, the temperature of the reaction mixture was reduced to 45-50°C and the solvent was completely distilled off from the reaction mixture under reduced pressure at the same temperature. The obtained residue was cooled to 35-40°C and ethyl acetate (325 ml) followed by water (325 ml) were added to it at the same temperature. The temperature of the reaction mixture was reduced to 25-3 0°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Both the organic layers were combined and washed twice with 5% sodium metabisulphite solution. The resulting organic layer and water (195 ml) were charged into a clean and dry RBF at 25-30°C. The reaction mixture was heated to 35-40°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with sodium chloride solution. The resulting organic layer was dried over sodium sulfate and the solvent was completely distilled off under reduced pressure. Pet ether (65 ml) was added to the obtained crude material and the solvent was completely distilled off under reduced pressure. The temperature of the resulting mixture was reduced to 25-30°C and pet ether (130 ml) was added to it. The obtained mixture was cooled to -10 to -5°C and stirred for 60 min at the same temperature. The precipitated solid was filtered, washed with chilled pet ether and then dried at 40-45°C to get the title compound as crystalline solid. Yield: 56.0 gm; M.R: 97-99°C.

Example-10: Preparation of 2-chloro-l-(4-octylphenyl)ethanone Octyl benzene (200 gm) and methylene chloride (1800 ml) were charged into a clean and dry RBF under nitrogen atmosphere at 25-30°C and cooled the reaction mixture to -10 to 0°C. Aluminium chloride (185 gm) was added to the obtained mixture at -10 to 0°C and stirred for 1 hr at the same temperature. Chloroacetyl chloride (80 ml) and methylene chloride (200 ml) were added to the reaction mixture at -10 to -5°C and stirred for 1 hr at the same temperature. After completion of the reaction, the reaction mixture was quenched with chilled water at 0-10°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with methylene chloride. Both the organic layers were combined and ethyl acetate (600 ml) was added at 25-30°C. The organic layer was washed with 10% sodium bicarbonate solution followed by 10% sodium chloride solution. The obtained organic layer was dried over sodiimi sulfate and the solvent was completely distilled off from the reaction mixture under reduced pressure at 40-50°C. Pet ether (100 ml) was added to the obtained crude compound and distilled off the solvent completely under reduced pressure. Cooled the residue to 25-30°C and pet ether (200 ml) was added to it. The obtained reaction mixture was cooled to -10°C and stirred for 1 hr at the same temperature. The precipitated solid was filtered, washed with pre-cooled pet ether at -10°C and dried to get the title compound. Yield: 200.0 gm.

Example-11: Preparation of diethyl 2-nitro-2-(2-(4-octylphenyI)-2-oxoethyl)malonate Diethyl 2-nitro malonate (25 g) was taken in a clean and dry RBF at 25-30°C. To this, a solution (80 ml) of sodium hydroxide (5.0 g) in absolute ethanol was drop wise added at 65°C under nitrogen atmosphere and the reaction mixture was stirred for 30 minutes at the same temperature. A solution of 2-chloro-l-(4-octylphenyl)ethanone (13.8 g) in anhydrous tetrahydrofuran and potassium iodide(9 gm) were added to the reaction mixture at 65°C and stirred for 30 minutes at the same temperature. The resulting mixture was concentrated and poured into ice-water and then extracted with ethyl acetate. The organic layer was washed with saturated sodiimi chloride solution and dried over anhydrous magnesiimi sulfate. Distilled off the solvent completely fi-om the organic layer to get the title compound. Yield: 11.0 gm.

Example-12: Preparation of diethyl 2-nitro-2-(4-octylphenethyl)malonate Triethylsilane (45 ml) was added to a solution of diethyl 2-nitro-2-(2-(4-octylphenyl)-2-oxoethyl)malonate (20 g) in trifluoro acetic acid (32 ml) under ice-cooling and the reaction mixture was stirred at room temperature for 2 hrs. Distilled off the solvent under reduced pressure and ice-water (100 ml) was added. A cooled and saturated aqueous solution of sodium hydrogen carbonate was added to the obtained mixture and was extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and the solvent was distilled off completely to get the title compound. Yield: 16 gms.

Example-13: Preparation of 2-nitro-2-(4-octylphenethyl)propan-l,3-diol Diethyl 2-nitro-2-(4-octylphenethyl)malonate (10 g) and methanol (100 ml) were charged into a clean and dry RBF under nitrogen atmosphere at 25-30°C. The reaction mixture was cooled to 0-5°C and sodium borohydride (3.5 g) was added to it under nitrogen atmosphere at the same temperature. The resulting mixture was stirred for 1 hr at 0-5°C. After completion of the reaction, the solvent was completely distilled off from the reaction mixture under reduced pressure. Water (50 ml) was added to the obtained compound. The resulting mixture was cooled to 5-10°C and adjusted the pH of the reaction mixture to 7.5 using 20% acetic acid solution. The resulting mixture was stirred for 30 min at 25-30°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with methylene chloride. Both the organic layers were combined and washed with 10% sodium chloride solution. The solvent was completely distilled off from the organic layer under reduced pressure to get the title compound. Yield: 7.0 gm.

Example-14: Preparation of 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-dioI 2-Nitro-2-(4-octylphenethyl)propan-l,3-diol (60 gm) and methanol (600 ml) were charged into par hydrogenator at 25-30°C. 5% Pd/C (30 gm) was added to the reaction mixture under nitrogen atmosphere at 25-30°C. 3-4 Kg/Cm^ hydrogen gas pressure was applied to the reaction mixture at 25-3 0°C and stirred for 6 hrs at the same temperature. After the completion of the reaction, filtered the Pd/C through hyflow bed and washed with methanol. The solvent was completely distilled off from the filtrate imder reduced pressure. Ethyl acetate (60 ml) was added to the obtained crude material and the solvent was completely distilled off imder reduced pressure. The obtamed crude was cooled to 25-30°C and ethyl acetate (120 ml) was added to it. The resulting mixture was further cooled to 0-5 °C and stirred for 1 hr at the same temperature. The precipitated solid was filtered, washed with chilled ethyl acetate and then dried at 35-40°C to get the title compound as a crystalline solid. Yield: 43.0 gm.

Example-15: Purification of 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol 2-Amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol (18 gm) and ethyl acetate (180 ml) were taken in a clean and dry RBF at 25-30°C. The reaction mixture was heated to reflux and stirred for 30 min at the same temperature. Cooled the reaction mixture to 25-30°C and then farther cooled to 0-5°C. The precipitated solid was filtered, washed with chilled ethyl acetate and then dried to get the title compound as a crystalline flaky solid. Yield: 16.0 gm; M.R: 120-122°C.

ExampIe-16: Preparation of Fingolimod hydrochloride

2-Amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol (64 gm) and ethyl acetate (450 ml) were charged in a clean and dry RBF at 25-30°C. The resulting mixture was cooled to 10-15°C and 23 ethyl acetate-HCl solution (130 ml) was added to it until pH reaches to 1.0 at the same temperature. The resulting mixture was cooled to 0-5°C and stirred for 1 hr at the same temperature. The precipitated solid was filtered, washed with chilled ethyl acetate and then dried at 40-50°C to get the title compound as a crystalline solid. Yield: 70.0 gm. The PXRD of the obtained compound is similar to figure-I.

Example-17: Preparation of Fingolimod hydrochloride 2-Amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol (4 gm) and ethanol (48 ml) were charged in a clean and dry RBF at 25-30°C and the reaction mixture was cooled to 0-5°C. Dry HCl gas was passed into the reaction mixture until pH of the reaction mixture reaches to 2.0. The solvent was completely distilled off from the reaction mixture under reduced pressure. Methyl tert.butyl ether (12 ml) was added to the resulting mixture and cooled to 0-5°C. The precipitated solid was filtered, washed with chilled methyl tert.butyl ether and then dried to get the title compoimd as crystalline flaky solid. Yield: 3.0 gm. The PXRD of the obtained compound is similar to figure-I.

£xample-18: Preparation of Fingolimod hydrochloride 2-Amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol (2.0 gm) and isopropyl alcohol (20 ml) were charged in a clean and dry RBF at 25-30°C. Isopropyl alcohol-HCl solution (10 ml) was added to the obtained reaction mixture until pH of the reaction mixture reaches to 2.0 and stirred the reaction mixture for 30 min at 25-30°C. The precipitated solid was filtered, washed with isopropyl alcohol and then dried to get the title compound as a crystalline flaky solid. Yield: 1.6 gm. The PXRD of the obtained compound is similar to figure-I.

Example-19: Purification of Fingolimod hydrochloride Fingolimod hydrochloride (70 gm), ethyl acetate (630 ml) and methanol (70 ml) were charged into a clean and dry RBF at 25-30°C. The resulting mixture was heated to reflux temperature and stirred for 30 min at the same temperature. Cooled the reaction mixture to 25-3 0°C and then fiuther cooled to 0-5 °C and stirred for 1 hr at the same temperature. The precipitated solid was filtered, washed with chilled ethyl acetate followed by methanol and dried to get pure Fingolimod hydrochloride as a crystalline flaky solid. Yield: 65.0 gm; M.R: 108°C; Purity by HPLC: 99.95%; The PXRD of the obtained compound is similar to figure-I.

We Claim:

1. A process for the preparation of 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol hydrochloride compound of formula-la, comprising of the following steps; a) Reacting the octanoyl chloride compound of formula-2

Formula-2 with benzene in presence of Lewis acid in a suitable solvent to provide 1-phenyloctan-l-one compound of formula-3,

Formula-3 b) reducing the compound of formula-3 with a suitable reducing agent in a suitable solvent in presence of an acid to provide octyl benzene compound of formula-4,

Formula-4 c) condensing the compound of formula-4 with 3-chloropropanoyl chloride in presence of Lewis acid in a suitable solvent to provide 3-chloro-l-(4-octylphenyl)propan-l-one compoimd of formula-5,

Formula-5 d) reacting the compound of formula-5 with sodium nitrite in a suitable solvent to provide 3-nitro-I-(4-octylphenyl)propan-l-one compound of formula-6,

Formula-6 e) reducing the compound of formula-6 with a suitable reducing agent in a suitable solvent to provide 3-nitro-l-(4-octylphenyl)propan-l-ol compound of formula-7,

Formula-7 f) reducing the compound of formula-? with a suitable reducing agent in a suitable solvent to provide l-(3-nitropropyl)-4-octylbenzene compound of formula-8,
"NO2


Formula-8 g) reacting the compound of formula-8 with paraformaldehyde in presence of a suitable base in a suitable solvent to provide 2-nitro-2-(4-octylphenethyl)propane-l,3-diol compound of formula-9,,0H ,0H Formula-9 h) reducing the compoimd of formula-9 with a suitable reducing agent in a suitable solvent to provide 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol compound of formula-1,


Formula-1 i) optionally purifying the compound of formula-1 from a suitable solvent, j) treating the compound of formula-1 with a suitable HCl source in a suitable solvent to provide 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol hydrochloride compound of formula-la.

2. A process according to claim 1, wherein,

in step-a) & step-c) the suitable Lewis acid is selected from aluminium chloride, boron trifluoride, zinc chloride, zinc bromide, tin tetrachloride and titanium tetrachloride; preferably aluminium chloride; and the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents and ester solvents; preferably chloro solvents;

in step-b) the suitable reducing agent is selected from Pd/C, Pt/C, Zn-Hg/HCl, Sn/HCl, Raney Ni, triethylsilane; preferably Pd/C; and the suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents, acetic acid, oxalic acid and propionic acid; and the suitable acid is selected from sulfuric acid, hydrochloric acid; preferably sulfuric acid; in step-d) the suitable solvent is selected from polar-aprotic solvents, alcoholic solvents and hydrocarbon solvents; preferably polar-aprotic solvents;

in step-e) the suitable reducing agent is selected from sodium borohydride, potassium borohydride, lithium borohydride, lithium alxuninium hydride, vitride, borane-DMS; preferably sodium borohydride; and the suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents, chloro solvents and water; preferably alcoholic solvents; in step-f) the suitable reducing agent is preferably triethylsilane; and the suitable solvent is selected from trifluoro acetic acid, alcoholic solvents, chloro solvents, hydrocarbon solvents, ether solvents and water; preferably trifluoro acetic acid;

in step-g) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and alkali metal bicarbonates and organic bases like diisopropyl amine, diisobutyl amine, triethylamine, pyridine; preferably triethylamine; and the suitable solvent is selected from alcoholic solvents, chloro solvents and ether solvents; preferably alcoholic solvents;

in step-h) the suitable reducing agent is selected from Pd/C, Pt/C, Zn-Hg/HCl, Sn-HCl, Raney Ni, lithium borohydride, lithium aluminium hydride and the like; preferably Pd/C; and the suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents and chloro solvents; preferably alcoholic solvents;

in step-i) the suitable solvent is selected from ester solvents and alcoholic solvents; preferably ethyl acetate; in step-j) the suitable solvent is selected from alcoholic solvents, ether solvents, ester solvents

and/or their mixtures; and the suitable HCl source is selected from hydrochloric acid, dry HCl gas, ethyl acetate-HCl, isopropyl alcohol-HCl and the like; preferably ethyl acetate-HCl.

3. Aprocess for the preparation of 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol hydrochloride compound of formula-la, comprising of the following steps;

a) Reacting the octanoyl chloride compound of formula-2 with benzene in presence of aluminium chloride in methylene chloride to provide 1-phenyloctan-l-one compound of formula-3,

b) reducing the compound of formula-3 with Pd/C in acetic acid in presence of sulfuric acid to provide octyl benzene compound of formula-4,

c) condensing the compound of fonnula-4 with 3-chloropropanoyl chloride in presence of aluminium chloride in methylene chloride to provide 3-chloro-l-(4-octylphenyl)propan-l-one compound of formula-5,

d) reacting the compovmd of formula-5 with sodium nitrite in dimethyl formamide to provide 3-nitro-l-(4-octylphenyl)propan-l-one compound of formula-6,

e) reducing the compoimd of formula-6 with sodium borohydride in methanol to provide 3-nitro-l-(4-octylphenyl)propan-l-ol compound of formula-7,

f) reducing the compound of formula-7 with triethylsilane in trifluoro acetic acid to provide l-(3-nitropropyl)-4-octylbenzene compound of formula-8,

g) reacting the compound of formula-8 with paraformaldehyde in methanol in presence of triethylamine to provide 2-nitro-2-(4-octylphenethyl)propane-l,3-diol compound of formula-9,

h) reducing the compound of fonnula-9 with Pd/C in methanol to provide 2-amino-2-[2-(4- octylphenyl)ethyl]propan-l,3-dioI compound of formula-1,

i) optionally purifying the compound of formula-1 from ethyl acetate,

j) treating the compound of formula-1 with ethyl acetate-HCl in ethyl acetate to provide 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l,3-diol hydrochloride compound of formula-la.

4. A novel process for the preparation of 2-nitro-2-(4-octylphenethyl)propane-1,3-diol compound of formula-9, comprising of;

a) Condensing the octyl benzene compound of formula-4 with chloro acetyl chloride in presence of a Lewis acid selected from aluminium chloride, boron trifluoride,

zinc chloride, zinc bromide, tin-tetrachloride and titanium tetrachloride in a suitable solvent selected from chloro solvents, hydrocarbon solvents, ether solvents and ester solvents to provide 2-chloro-l-(4-octylphenyl)ethanone compound of formula-11, Formula-11

b) condensing the compound of formula-11 with diethyl 2-nitro malonate in presence or absence of a suitable iodine source and a suitable base selected from alkali metal hydroxides and alkali metal alkoxides in a suitable solvent selected from alcoholic solvents, polar- aprotic solvents, ether solvents and hydrocarbon solvents to provide diethyl 2-nitro-2-(2-(4- octylphenyI)-2-oxoethyl)malonate compound of formula-12,

c) reducing the compoxmd of formula-12 with a suitable reducing agent preferably triethylsilane in a suitable solvent selected from trifluoro acetic acid, alcoholic solvents, chloro solvents, hydrocarbon solvents, ether solvents, water to provide diethyl 2-nitro-2-(4- octylphenethyl)malonate compound of formula-13,

Formula-13 d) reducing the compound of formula-13 with a suitable reducing agent preferably sodium borohydride in a suitable solvent selected from alcoholic solvents, chloro solvents, hydrocarbon solvents, ether solvents and ester solvents to provide 2-nitro-2-(4-octylphenethyl)propane-l,3-diol compound of formula-9.

5. A process for the preparation of octyl benzene compound of formula-4 comprising of reducing the 1-phenyIoctan-l-one compound of formula-3 with a suitable reducing agent selected from Pd/C, Pt/C, Zn-Hg/HCl, Sn/HCl, Raney Ni and triethylsilane, preferably Pd/C; in a suitable solvent selected from alcoholic solvents, ester solvents, hydrocarbon solvents, acetic acid and oxalic acid, preferably acetic acid in presence of sulfixric acid.

6. A novel process for the preparation of l-(3-nitropropyl)-4-octylbenzene compound of formula-8,

comprising of reducing the 3-nitro-l-(4-octylphenyl)propan-l-ol compound of formula-7 with a suitable reducing agent preferably triethylsilane, in a suitable solvent selected from trifluoro acetic acid, alcoholic solvents, chloro solvents, hydrocarbon solvents, ether solvents and water; preferably trifluoroacetic acid.

7. A process for the purification of 3-nitro-l-(4-octylphenyl)propan-l-one compound of formula-6,

comprising of;

a) Dissolving the 3-nitro-l-(4-octylphenyl)propan-l-one compound of fonnula-6 in a suitable solvent selected from hydrocarbon solvents, ether solvents, alcoholic solvents and/or their mixtures by heating,

b) cooling the reaction mixture,

c) filtering the precipitated solid,

d) drying the compound to get pure compoimd of formula-6.

8. A process for the purification of 3-nitro-l-(4-octylphenyl)propan-l-one compoimd of fonnula-6,

comprising of;

a) Dissolving the 3-nitro-l-(4-octylphenyl)propan-l-one compound of formula-6 in pet ether by heating the reaction mixture to reflux temperature,

b) cooling the reaction mixture,

c) filtering the precipitated solid,

d) drying the compound to get pure compoimd of fonnula-6.

9. A novel process for the preparation of diethyl 2-nitro-2-(2-(4-octylphenyl)-2-oxoethyl)malonate compound of formula-12 comprising of condensing the 2-chloro-l-(4-octylphenyl)ethanone 30 ompound of formula-11 with diethyl 2-nitro malonate in presence of potassium iodide and a suitable base selected from alkali metal hydroxides and alkali metal alkoxides, in a suitable solvent selected from alcoholic solvents, polar-aprotic solvents, ether solvents and hydrocarbon solvents; preferably ethanol.

10. A process for the preparation of l-(3-nitropropyl)-4-octylbenzene compound of formula-8, comprising of reducing the 3-nitro-l-(4-octylphenyl)propan-l-one compound of formula-6 with triethylsilane in presence of trifluoro acetic acid to provide l-(3-nitropropyl)-4-octylbenzene compound of formula-8.

11. Compounds having the following structural formulae;