DESC:FIELD OF THE INVENTION
The present invention provides an improved process for the preparation of 1-phenyloctane of formula (I) and its use in preparation of Fingolimod or its pharmaceutically acceptable salt.

BACKGROUND OF THE INVENTION
“Fingolimod hydrochloride” has chemical names 2-amino-2-[2-(4-octylphenyl)ethyl]propan-1,3-diol hydrochloride; or 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propandiol hydrochloride. It has following structure:

Fingolimod hydrochloride is a sphingosine 1-phosphate receptor modulator and is the active ingredient in a product sold by Novartis as GILENYA® in the form of hard gelatin capsules for oral use, for the treatment of patients with relapsing forms of multiple sclerosis.
1-Phenyloctane used in the synthesis of Fingolimod hydrochloride, is a key starting material for the preparation of Fingolimod hydrochloride.
IN 2013CH00278 (only in India) discloses preparation of 1-phenyloctane by hydrogenation of octanophenone using Pd/C in methanol.

Chem, 6(3), 675-688; 2020 discloses preparation of 1-phenyloctane by reacting phenylethylbromide and 1-hexene in presence of alkylzirconocene and ZrCp2HCl and further purification using flash column chromatography.

J. Am. Chem. Soc. 1951, 73, 7, 3524–3526 discloses preparation of 1-phenyl octane by reacting benzyl chloride with n-heptyl magnesium bromide. However major product is by benzyl compound instead of 1-phenyl octane.

Tetrahedron Letters 55 (2014) 5774–5777 discloses preparation of 1-phenyl octane by reacting phenpropylbromide with pentyl magnesiumbromide.

Most of the process known in the art utilizes 1-phenyloctane of formula (I) for the preparation of Fingolimod. However, preparation of this intermediate by the method known in the art results in a compound having high content of the impurities such as pentyl bromide, hexyl bromide, heptyl bromide, 1-pentyl benzene, 1-hexyl benzene, 1-phenyl heptane, 1-phenyl nonane 2-phenylethylbromide, hexanol and 1,1'-butane-1,4-diyldibenzene (5-8%) which causes low yield and affects the purity of 1-phenyloctane as well as final product i.e. Fingolimod.
Despite the existence of various processes for the preparation of 1-phenyloctane, there remains a need for improved process with high yield and purity, and being well-suited for use on an industrial scale. Present inventors have focused on the problems associated with the prior art process and has developed an improved process for the preparation of the compound of Formula (I) in high yield and good purity.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of 1-phenyloctane which comprises reacting compound of formula (II) with hexyl magnesium halide of formula (III) in the presence of copper catalyst and suitable solvent(s).

In another aspect 1-phenyloctane of formula (I) as obtained by the process of present invention is further converted to Fingolimod or its pharmaceutically acceptable salt by conventional process or as exemplified in the specifiction.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, in one embodiment present invention provides a process for preparation of 1-phenyloctane and its use in the preparation of Fingolimod Hydrochloride.

In another embodiment, preparation of 1-phenyloctane involves reaction of compound of formula (II) with hexyl magnesium halide of formula (III) in presence of copper catalyst and suitable solvent(s) to provide 1-phenyloctane of formula (I).

In yet another embodiment, the present invention more particularly provides a process for the preparation of 1-phenyloctane, comprising of following step:

The copper catalyst as used herein includes but not limited to copper(I) oxide (Cu2O), copper(I) chloride (CuCl), copper(I) iodide (CuI), copper(I) bromide (CuBr), copper(II) chloride (CuCl2), copper(II) chloride dihydrate (CuCl2. 2H2O), Copper(II) oxide (CuO), copper(II) bromide (CuBr2), copper triflate and like.
The suitable solvent(s) used herein includes such as tetrahydrofuran (THF), 2-methyl THF, cyclopentyl methyl ether and the like.

In another embodiment reaction of compound of formula (II) with hexyl magnesium halide of formula (III) is carried out within the temperature range of -15oC to 30oC and more preferably within the temperature range of 20oC to 25oC.
After completion of the reaction aqueous solution comprising acids is added to the reaction mixture, the preferred acids are hydrochloric acid, sulphuric acid or nitric acid. If required solvents like methyl tert-butyl ether (MTBE), diethyl ether, dimethyl ether, cyclopentyl methyl ether, diisopropyl ether, di-tertbutyl ether, tetrahydropyran is added such that the reaction mixture forms an aqueous phase and an organic phase. The organic phase comprising the product is separated from the aqueous phase. The solvents is preferably distilled off under vacuum, the distillation is preferably performed at a temperature below or equal about 60 °C. The obtained 1-phenyloctane is further subjected to fractional distillation.
In another embodiment, fractional distillation of 1-phenyloctane is carried out at a vapor temperature of about 80°C to 105 °C. The fraction of 1-phenyloctane obtained at vapor temperature of about 98°C to 103 °C is having purity greater than 99% by GC method.
1-phenyl octane as obtained by the process of present invention is having any individual impurities such as 2-phenethylbromide, hexanol, 1,1’-butane-1,4-diyldibenzene, 1-phenyl heptane, 1-phenyl nonane, n-Octane, 1-pentylbenzene, n-Octanoic acid, 1-Hexylbenzene and 1-Phenyldecane is not more than 0.15% by GC method.
The suitable hexyl magnesium halide solution used in above process step can be obtained either commercially or can be synthesized using appropriate hexyl halide and magnesium in suitable solvent(s) according to the process known in prior art.
In another embodiment, the sequence of addition of phenyl ethyl derivative compound of formula (II), hexyl magnesium halide solution and copper catalyst or mixture thereof can be in any order and well known to the person skilled in the art.
It is to be understood that the invention is not limited in its application to the details set forth in the following description or exemplified by the examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.
The purity of 1-phenyloctane were measured by GC (gas chromatography) method. Analytical instrument: Gas chromatograph with flame ionization detector and an auto sampler (Make: Agilent 7890B); DB-1 (60 m X 0.32 mm X 5.0 µ) use Agilent part no. 123-1065 column. Chromatographic conditions: Initial column temperature 60 ° C, held for 3 min, at a temperature increase rate of 7.5 ° C / min to 240 ° C, held for 33 min; vaporization chamber temperature 220 ° C, split ratio of 35:1; Carrier gas flow:4.0 mL/min.
EXAMPLES
The following examples are provided here to enable one skilled in the art to practice the invention and merely illustrate the process of this invention. However, it do not intended in any way to limit the scope of the present invention.
Example-1: Preparation of 1-phenyloctane:
Cupric chloride dihydrate (0.093 g) was added to a stirred solution of hexyl magnesium chloride (338 ml; 2M in THF) at 20-25 oC. 2-phenethylbromide solution (100 g in 180 ml THF) was added to the reaction mixture under nitrogen atmosphere. The reaction mixture was further stirred for 2 hours at 20-25 oC. After completion of the reaction, reaction mixture was cooled to below 10oC and quenched with hydrochloride solution followed by addition of MTBE (200 ml) with stirring. The organic layer was separated and solvent was distilled out under vacuum. The residual mass was further subjected to fractional distillation to obtained desired product as oil (40 g). Purity 99.35 % and any individual impurity not more than 0.15 % by GC.
Example-2: Preparation of 1-phenyloctane:
Solution of cupric chloride dihydrate (0.093 g in 100 mL of THF) was added to a stirred solution of hexyl magnesium chloride (338 ml; 2M in THF) and 2-phenethylbromide solution (100 g) in 180 ml of THF under nitrogen atmosphere at 18-22 oC. The reaction mixture was stirred for further 2 hours at same temperature. The reaction mixture was cooled below 10oC and quenched with hydrochloride solution followed by addition of MTBE (200 ml) with stirring. The organic layer was separated and solvent was distilled out under vacuum. The residual mass was further subjected to fractional distillation to obtained desired product as oil (36 g). Purity 99.30 % and any individual impurity not more than 0.15 % by GC.
Example-3: Preparation of 1-phenyloctane:
To a stirred solution of hexyl magnesium chloride (676 ml; 2M in THF), cupric bromide (0.12 g) was added followed by addition of 2-phenethylbromide solution (100 g in 180 ml THF) under nitrogen atmosphere with stirring at 22-28 oC. The reaction mixture was cooled between 0-5oC and quenched with hydrochloride solution followed by addition of MTBE (200 ml) with stirring. The organic layer was separated and solvent was distilled out under vacuum. The residual mass was further subjected to fractional distillation to obtained desired product as oil (37 g). Purity 99.31 % and any individual impurity not more than 0.15 % by GC.
Example 4: Preparation of fingolimod HCl
Stage I: Preparation of Diethyl 2-acetamido-2-(4-octylphenyl)ethyl Malonate.
1-Phenyloctane was reacted with chloroacetyl chloride in presence of aluminium chloride in dichloromethane to obtain 2-chloro-1-(4-octylphenyl) ethanone. The obtained 2-Chloro-1-(4-octylphenyl) ethanone was reacted with diethyl acetamidomalonate in the presence of sodium hydride and sodium iodide in toluene to obtain 2-(Acetylamino)-2-[2-(4-octylphenyl)-2-oxo ethyl] propanedioic acid diethyl ester, which was further reacted with titanium tetrachloride and triethylsilane in dichloromethane to obtain diethyl 2-acetamido-2-(4-octylphenyl)ethyl malonate.

Stage II: Preparation of 1, 3-propanediyl-2-acetamido-2-[2-(4-octylphenyl) ethyl] ylidenediacetate.

2-Acetylamino-2-[2-(4-octylphenyl)ethyl]propane-1,3-dioate was reacted with sodium borohydride in methanol to obtain 2-acetyl amino-2-[2- 4-octylphenyl) ethyl]1, 3-propanediol. The obtain product was further reacted with acetic anhydride in presence of triethylamine and catalytic DMAP in dichloromethane to obtain 1,3-propanediyl-2-acetamido-2-[2-(4-octylphenyl) ethyl] ylidenediacetate.
Stage III: Preparation of 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol.

1,3-propanediyl-2-acetamido-2-[2-(4-octylphenyl)ethyl]ylidenediacetate was reacted with lithium hydroxide monohydrate in aqueous methanol obtain 2-amino-2-[2-(4-octylphenyl)-ethyl]-1,3-propanediol.
Stage IV: Preparation of 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride.

2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol was treated with isopropyl alcohol hydrochloride in isopropyl alcohol to obtain 2-amino-2-[2-(4-octylphenyl) ethyl]-1,3-propanediol hydrochloride.
,CLAIMS:We Claim:
1. A process for the preparation of 1-phenyloctane of formula (I) comprising reacting compound of formula (II) with hexyl magnesium halide of formula (III) in presence of copper catalyst and suitable solvent(s) at temperature of from 15 °C to 30 °C.

wherein X represents halogen selected from fluorine, chloride, bromine and iodine.
2. The process as claimed in claim 1, wherein compound of formula (II) is selected from 2-phenethylbromide, 2-phenethylfluoride, 2-phenethyiodide and 2-phenethylchloride.
3. The process as claimed in claim 1, wherein hexyl magnesium halide of formula (III) is selected from hexyl magnesium chloride, hexyl magnesium bromide and hexyl magnesium iodide.
4. The process as claimed in claim 1, wherein copper catalyst is selected from copper(I) oxide (Cu2O), copper(I) chloride (CuCl), copper(I) iodide (CuI), copper(I) bromide (CuBr), copper(II) chloride (CuCl2), copper(II) chloride dihydrate (CuCl2. 2H2O), Copper(II) oxide (CuO), copper(II) bromide (CuBr2) and copper triflate.
5. The process as claimed in claim 1, wherein solvent is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether.
6. The process as claimed in claim 1, further comprising isolation of compound of formula (I) by using fractional distillation method.
7. The process as claimed in claim 6, wherein fraction distillation is carried out at about 80°C to 105 °C vapor temperature.
8. The process as claimed in claim 7, wherein the fraction of 1-phenyloctane obtained at about 98°C to 103 °C vapor temperature.
9. The process as claimed in claim 1, further comprising converting the 1-phenyloctane of formula (I) into Fingolimod or its pharmaceutically acceptable salt.