Formula X Formula XI
wherein, Ri and R2 is selected from aryl, alkyl, O-alky, O-aryl, heteroaryl, alkyl-aryl,
substituted alkyl-aryl, alicyclic, substituted heteroaryl, and biphenylphosphine, compounds
such as biarylphosphines, bialkylphosphines, bialkylphosphines; and
cl) isolating compound of Formula XI or its salt to give voclosporin or its
pharmaceutically acceptable salt provided that P is hydrogen; or
c2) deprotecting compound of Formula XI in presence of suitable solvent to give
voclosporin or its pharmaceutically acceptable salt provided that Pisa protecting group.

In another aspect, the present invention provides a process for the preparation of solid form of voclosporin or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of voclosporin or pharmaceutically acceptable salt thereof; in one or more suitable solvent; and
b) isolating the solid form of voclosporin or pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a process for the preparation of amorphous form of voclosporin or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of voclosporin or pharmaceutically acceptable salt thereof; in one or more suitable solvent; and
b) isolating the amorphous form of voclosporin or pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a process for the preparation of solid dispersion of voclosporin or its pharmaceutically acceptable salt, wherein said process comprising the steps of:
a) providing a solution of voclosporin its pharmaceutically acceptable salt in suitable solvent and one or more pharmaceutically acceptable carrier; and
c) isolating the solid dispersion of voclosporin or its pharmaceutically acceptable salt.
Another aspect of the present invention is to provide a pharmaceutical composition comprising voclosporin or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.
DETAILED DESCRIPTION
Definitions:
The terms "pharmaceutically acceptable salt or salt" as used in the context of the present invention includes organic or inorganic acid addition salts. Inorganic acids selected from but are not limited to hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt, carbonate salts; organic acids selected from but are not limited to succinic acid, formic acids, acetic acid, diphenyl acetic acid, palmoic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid,

fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, /?-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, l-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-l,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid and the like. The inorganic salts may further includes alkali metal and alkaline earth metal salts such as sodium, potassium, barium, lithium, calcium, magnesium, rhodium, zinc, cesium, selenium, and the like or, benethamine, benzathine, diethanolamine, ethanolamine, 4-(2-hydroxyethyl)morpholine, 1-(2-hydroxyethyl)pyrrolidine, N-methyl glucamine, piperazine, triethanol amine or tromethamine and the like.
The term "suitable solvent" as used in the context of the present invention comprises of polar and non-polar solvent selected from, but not limited to, the group comprising of alcohols such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, polyethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole; ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; esters solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate; hydrocarbon such as toluene, xylene, hexane, n-heptane, n-pentane, anisole, ethyl benzene, cyclohexane and the like; nitriles such as acetonitrile, propionitrile, butanenitrile; sulfoxides such as dimethyl sulfoxide; formamides such as N-methyl formamamide; carbonates; water; and mixtures thereof.

The term "suitable oxidizing agent" as used in the context of the present invention is selected from, but not limited to ozone, potassium permanganate, osmium tetroxide, sodium periodate, ruthenium based oxidizing agent such as ruthenium tetroxide, ruthenium chloride hydrate, chromium trioxide, chromic acid, chromate salts such as potassium dichromate, sodium dichromate, sodium chromate and potassium chromate; ammonium permanganate, sodium perchlorate, ammonium perchlorate, calcium chlorate, potassium chlorate, ferric chlorate, hydrogen peroxide and mixture thereof.
The term "suitable metal catalyst" as used in the context of the present invention refers to organometallic reagents, having inorganic elements such as boron, silicon, titanium, lithium, sulfur, zirconium, rhodium or other suitable inorganic element from group 4,5,6 or group 13 of periodic table that may include Cp2Zr(H)Cl or Cp2Zr(D)Cl, [3-(diphenylphosphino)allylltitanium, lithiated allyldiphenylphosphine, allylborane compounds such as 2-[(E)-4-(Trimethylsilyl)methyl]-3,5-hexadienyl]cyclohexanone) and organo titanium catalysts having isopropoxy, phenoxy, diethylamino ligands, such as chlorotriisopropoxytitanium chlorotriphenoxytitanium, chlorotris(diethylamino)titanium, and organo rhodium catalysts such as rhodium carbonyl chloride and other suitable organometallic compounds or mixture thereof suitable for stereoselective synthesis of terminal 1-3-diene system with desired stereoselectivity.

We Claim:

1. A process for the preparation of voclosporin (ISATX247) or its pharmaceutically acceptable salt, comprising the steps of:
a) oxidizing compound of Formula IX or its salt with suitable oxidizing agent in presence of suitable solvent to give compound of Formula X or its salt;


Formula IX

Formula X

wherein, P is selected from hydrogen or protecting group
b) reacting compound of Formula X or its salt with suitable metal catalyst in presence of
suitable solvent to give compound of Formula XI or its salt;

X V vr

-N-An

Formula X

Formula XI

and

cl) isolating compound of Formula XI or its salt to give voclosporin or its pharmaceutically acceptable salt provided that P is hydrogen; or
c2) deprotecting compound of Formula XI in presence of suitable solvent to give voclosporin or its pharmaceutically acceptable salt provided that Pisa protecting group.
2. The process as claimed in claim 1, wherein said step b) comprising of:

i) reacting compound of Formula X or its salt with compound of Formula XIII or its salt in presence of suitable solvent to give compound of Formula XI or its salt; o
o
YYr YA
Y Y 'Y o ^ Y'"AH ' Y o
>-' y° HN OP Formula XIII o'"\^° HN "
MY °^YY " "V °^
«YoV" ° .Ar- Y-
^yvy XY°\V

Formula X Formula XI
wherein, P is selected from hydrogen or protecting group and, Ri and R2 is selected from aryl, alkyl, O-alky, O-aryl, heteroaryl, alkyl-aryl, substituted alkyl-aryl, alicyclic, substituted heteroaryl, and biphenylphosphine, compounds such as biarylphosphines, bialkylphosphines, bialkylphosphines.
3. The process as claimed in claim 1, wherein said step b) comprising of:
reacting compound of Formula X or its salt with compound of Formula XII or its salt in presence of suitable solvent to give protected diene compound of Formula XI;
0
YVV Y»V
J-
R YTN^ Y° °
O QT NH "N-A /
Formula XII O-'^NJ*0 HN OP
*" HN. ,,»

Formula X Formula XI
wherein, R is selected from aryl, heteroaryl, alkyl-aryl, substituted alkyl-aryl, alicyclic, substituted heteroaryl.
4. The process as claimed in claim 1, wherein said oxidizing agent is selected from the group comprising of ozone, potassium permanganate, osmium tetroxide, sodium periodate,

ruthenium tetroxide, ruthenium chloride hydrate, chromium trioxide, chromic acid, potassium dichromate, sodium dichromate, sodium chromate, potassium chromate, ammonium permanganate, sodium perchlorate, ammonium perchlorate, calcium chlorate, potassium chlorate, ferric chlorate, hydrogen peroxide and mixture thereof.
5. The process as claimed in claim 1, wherein said protecting group is selected from benzyl, t-butoxy carbonyl, tetrahydropyranyl, acetic acid, pivalic acid, and benzoic acid.
6. The process as claimed in claim 1, wherein said voclosporin is further comprising the steps of:

a) reacting with suitable metal catalyst to form an intermediate metal complex; and
b) treating with acid to give trans isomer of voclosporin.

7. The process as claimed in claim 1, wherein said Z isomer of voclosporin or its pharmaceutically acceptable salt is less than 20% as measured by HPLC.
8. A process for the preparation of amorphous form of voclosporin or pharmaceutically acceptable salt thereof, comprising the steps of: