DESC:FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Lifitegrast and its intermediates.

BACKGROUND OF THE INVENTION
Lifitegrast is chemically (S)-2-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6­carboxamido)-3-(3-(methylsulfonyl) phenyl)propanoic acid a compound of formula I as shown below.

- Formula I
Lifitegrast is a lymphocyte function-associated antigen-1 (LFA-1) antagonist indicated for the treatment of the signs and symptoms of dry eye disease is approved in USA and marketed under the trade name XIIDRA by Shire Development.

US 7,314,938 B2 discloses Lifitegrast generically and process for the preparation of analogous compounds.

US 8,084,047 disclose specifically Lifitegrast and is silent about the preparation of Lifitegrast.

US 8,080,562 B2 (US ‘562) discloses a process for preparation of Lifitegrast. US ‘562 discloses the following scheme for the preparation of Lifitegrast.

Further US ‘562 discloses the following route for the preparation of Lifitegrast

US 9,725,413 B2 discloses the preparation of Lifitegrast intermediate by two-step carboxylation reaction of an aryl group using continuous flow reaction conditions which is depicted as follows:

US 7,314,938 describes a process for preparation of Lifitegrast intermediate by following the
route as below:

The processes disclosed in the prior art involves more number of steps which include ester hydrolysis for the preparation of Lifitegrast intermediate. Further the prior art processes involves the use of acid addition salt of compound of formula 10 which leads to the formation of Lifitegrast dimer impurity and Lifitegrast enantiomer impurity.

However the present inventors have found a process for the preparation of Lifitegrast which is industrially feasible and commercially viable.

OBJECTIVES OF THE INVENTION
The objective of the present invention is to provide a process for the preparation of Lifitegrast intermediate which is industrially feasible.
Another objective of the invention is to provide process for the preparation of (S)-2-(2-(Benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6­carboxamido)-3-(3-(methylsulfonyl) phenyl)propanoic acid with high yields and purity.

SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of Lifitegrast compound of formula I, which comprises:

- Formula I
a. deprotecting the compound of formula II

- Formula II
to obtain compound of formula III or salt thereof;

- Formula III
b. condensing the compound of formula III or salt thereof with a compound of formula IV

- Formula IV
to obtain a compound of formula V;

- Formula V
c. condensing the compound of formula V with a compound of formula VI or salt thereof

- Formula VI
to obtain a compound of formula VII;

- Formula VII

d. hydrolysis of compound of formula VII to obtain the compound of formula I; wherein steps a and b are optionally in-situ reactions.

In another embodiment, the present invention relates to a process for the preparation of compound of formula III which comprises: deprotecting the compound of formula II to obtain compound of formula III in the presence of deprotecting agent selected from acids or acid chlorides.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of Lifitegrast compound of formula I, which comprises: deprotecting the compound of formula II with a deprotecting agent selected from group comprising of acid or acid chloride to obtain compound of formula III or salt thereof; optionally in-situ condensing the compound of formula III or salt thereof with a compound of formula IV in the presence of coupling agent and base to obtain a compound of formula V; condensing the compound of formula V with a compound of formula VI or salt thereof in the presence of coupling agent and base to obtain compound of formula VII; hydrolysis of compound of formula VII in the presence of acid selected from hydrogen chloride, sulfuric acid, and phosphoric acid, trifluoroacetic acid or base selected from group comprising of ammonium hydroxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, calcium oxide, Ca(OH)2, sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, potassium phosphate and ammonium phosphate to obtain the compound of formula I

In another aspect of the present invention, deprotection of compound of formula II is carried out in the presence of acid or acid halide selected from group comprising of methanolic HCl, ethanolic HCl, thionyl chloride, oxalyl chloride, phosphoryl chloride, and phosphorus pentachloride, hydrogen chloride, sulfuric acid, phosphoric acid, sulfonic acid and trifluoroacetic acid.

In another aspect of the present invention, coupling agent is selected from the group comprising of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI. HCl), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), TBTU (O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate).

In another aspect of the present invention the base used in the condensation of formula III with formula IV and formula V with formula VI is organic base selected from group comprising of triethylamine, , isopropylamine, tri n-butylamine, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, methyl amine, diethylamine, tetramethylammonium hydroxide and tetrabutylammonium hydroxide.

In another aspect of the present invention, deprotection of compound of formula II is carried out in the presence of solvent selected from the group comprising protic solvent selected from water, alcohols, acetic acid, formic acid; aprotic or non-polar solvents selected from the group comprising of ketones, esters, ethers, nitriles, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethyl formamide, hydrocarbons, halogenated hydrocarbons.

In another aspect of the present invention, prior to the condensation of formula V with formula VI, desaltification of salt of formula VI is carried out using base selected from group comprising of ammonium hydroxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, calcium oxide, Ca(OH)2, sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, potassium phosphate and ammonium phosphate.

In another aspect of the present invention, condensation of formula III with formula IV and formula V with formula VI is carried out in the presence of aprotic or non-polar solvents selected from the group comprising of ketones, esters, ethers, nitriles, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethyl formamide, hydrocarbons, halogenated hydrocarbons.

In another aspect of the present invention ketones used throughout the invention are aliphatic ketones selected from the group comprising acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone, cyclobutanone, cyclopentanone, cyclohexanone or mixtures thereof; esters used throughout the invention are aliphatic esters or aromatic esters wherein aliphatic esters are selected from ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate or mixtures thereof; nitriles used throughout the invention are selected from the group comprising of aliphatic nitriles such as C2-C8 nitrile; alcohols used throughout the invention are selected from aliphatic alcohols selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, pentanol, isobutanol, tertiary butanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol or mixtures thereof, aromatic alcohols used throughout the invention are selected from the group comprising of phenols, benzylalcohol or mixtures thereof; ethers used throughout the invention are selected from the group comprising of symmetrical or asymmetrical ethers or cyclic ethers selected from diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran or mixtures thereof; halogenated hydrocarbons are selected from methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride or mixtures thereof; hydrocarbons selected from the group comprising aliphatic hydrocarbons comprising alkanes from C1-7 alkanes, aromatic hydrocarbons selected from toluene, xylene or mixtures thereof and cycloalkanes selected from cyclohexane, cylcopentane or mixtures thereof, C1-7 alkanes are selected from hexane, heptane or mixtures thereof.

EXAMPLES
Reference Example:
Preparation of Lifitegrast:
Compound 5 was treated with triethylamine (TEA, 5 equivalents) and 2-(7-Aza-lH-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 1.25 equivalents) for 10 minutes in dimethylformamide (DMF), and then compound 10 was added to the solution. After stirring at room temperature for 18 hours, the product, compound 11 was isolated in 70% yield. Removal of the trityl protecting group was accomplished by treating compound 1, with HCL in dioxane (4N, excess) at room temperature for 2 hours, diethyl ether added, and the solid product, compound 12, was isolated by filtration in 95% yield.

The benzofuran carboxylic acid 18 was treated with oxalyl chloride (1.2 equivalents) and a catalytic amount of DMF, stirring for 5.5 hours until a clear solution was obtained. The solvent was removed under reduced pressure and the acid chloride of compound 18 was stored under argon until use, on the next day. The acid chloride, in methylene chloride was added slowly to a methylene chloride solution of the compound of Formula I and diisopropylethylamine (DIPEA) which was cooled to 0-50C. The reaction was not permitted to rise above 5°C, and after completion of addition, was stirred at 5°C for a further 0.5 hour. Upon aqueous workup and extraction with methylene chloride, the product, compound 19, was isolated in quantitative yield. The benzyl ester of compound 19 was removed by transfer hydrogenolysis using 10% palladium on carbon, using formic acid and triethylamine in a 5:1 mixture of methanol:THF, to produce the compound of Formula I in 95% yield. A final step of slurrying in methyl ethylketone (MEK) produced Form A of the compound of Formula I. The product was washed with water to remove residual MEK. Alternatively, the product of the hydrogenolysis step was slurried in acetonitrile yielded Form A of the compound of Formula I.

Example 1.
Charged compound of formula II (100 gm), methanolic hydrochloride (12-16%; 300 ml), stirred for about 4 hours to 5 hours at 25 – 35°C. The solid thus obtained was filtered, washed with acetone. The wet solid obtained was taken in acetone, stirred for 2 hours at 25 – 35°C, filtered the solid and dried to give 80 g of compound of formula III(Purity: ~99 %).

Example 2.
Charged compound of formula IV(49 gm), dimethylformamide, EDCI.HCl and HOBt.H2O at 25 – 35°C. cooled the reaction mass to 20 – 30°C. To the reaction mass was added diisopropylethylamine drop wise and stirred for 20 – 30 minutes. Compound of formula III (80 gm) was added and stirred the reaction mixture for 4 hours to 6 hours at 25-35°C. The reaction mixture was added water and ethylacetete, stirred for 10 minutes and separated the layers. The pH of the aqueous layer was adjusted with 2N HCl at 25 – 35°C. Stirred the reaction mass for 1 – 2 hours, filtered the solid separated and washed with water. Charged acetone in to the wet solid and stirred for 1 hour at 25 – 35°C. Filtered the solid, washed with acetone and dried to give 85 gm of compound of formula V(Purity: NLT 96 %).

Example 3.
Charged compound of hydrochloride salt of formula VI (84 gm), sodium carbonate, water, methylene dichloride at 25-35°C and stirred. Separated the layers and the aqueous layer was extracted with methylenedichloride. Total organic layer was concentrated to get residue. To the residue added dimethylformamide, compound of formula V (80 gm), HATU at 25 – 35°C. Cooled the reaction temperature to 20 – 30°C and added triethylamine and stirred the reaction mass for 4 hours to 6 hours at 25 – 35°C. To the reaction mixture was added water and stirred for 15 minutes to 30 minutes at 25 – 35°C. Filtered the solid and added methylene dichloride. Concentrated the organic layer and co-distilled with acetone. Added acetone, stirred the reaction mixture for 8 hours to 10 hours at 0 – 10°C and filtered the solid thus obtained and dried to give 90 gm of compound of formula VII.

Example 4.
Charged compound of formula VII (75 gm), tetrahydrofuran at 25 -30°C and cooled to 0-10°C. Added lithium hydroxide solution for about 30 to 45 minutes at 0-10°C, stirred for 1 hour to 1 hour 30 minutes and adjusted the pH to 2.0 – 3.5 with aq HCl solution. The reaction mixture was added methylene dichloride and separated the organic layer. Combined organic layers were concentrated and codistilled with acetone. Added acetone, stirred for 1 hour at 25 – 35°C. Cooled the reaction mass to -5 to 5°C, stirred for 4 hours to 6 hours and the solid obtained was filtered, washed with acetone and dried to yield 60gm of compound of formula I .
,CLAIMS:We claim:
1. A process for the preparation of Lifitegrast compound of formula I, which comprises:

- Formula I
a. deprotecting the compound of formula II

- Formula II
to obtain compound of formula III or salt thereof;

- Formula III
b. condensing the compound of formula III or salt thereof with a compound of formula IV

- Formula IV
to obtain a compound of formula V;

- Formula V
c. condensing the compound of formula V with a compound of formula VI or salt thereof;

- Formula VI
to obtain a compound of formula VII;

- Formula VII

d. hydrolysis of compound of formula VII to obtain the compound of formula I; wherein steps a and b are optionally in-situ reactions.

2. A process for the preparation of formula III or salt thereof,

- Formula III
which comprises:
deprotecting the compound of formula II

- Formula II
with a deprotecting agent selected from group comprising acid or acid halide.

3. The process according to claim 2, wherein acid or acid halide are selected from group comprising of methanolic HCl, ethanolic HCl, thionyl chloride, oxalyl chloride, phosphoryl chloride, and phosphorus pentachloride, hydrogen chloride, sulfuric acid, phosphoric acid, sulfonic acid and trifluoroacetic acid.

4. The process according to claim 1and 2, wherein deprotection of compound of formula II is carried out in the presence of solvent selected from the group comprising protic solvent selected from water, alcohols, acetic acid, formic acid; aprotic or non-polar solvents selected from the group comprising of ketones, esters, ethers, nitriles, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethyl formamide, hydrocarbons, halogenated hydrocarbons.

5. The process according to claim 1, wherein steps b and c are carried out in the presence of condensing agent selected from the group comprising of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI. HCl), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), TBTU (O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate).

6. The process according to claim 1, wherein steps b and c are carried out in the presence of a organic base selected from the group comprising of triethylamine, , isopropylamine, tri n-butylamine, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, methyl amine, diethylamine, tetramethylammonium hydroxide and tetrabutylammonium hydroxide.

7. The process according to claim 1, wherein step d is carried out in the presence of acid selected from group comprising of hydrogen chloride, sulfuric acid, and phosphoric acid, trifluoroacetic acid or base selected from group comprising of ammonium hydroxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, calcium oxide, Ca(OH)2, sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, potassium phosphate and ammonium phosphate.

8. The process according to claim 1, wherein steps b and c are carried out in the presence of aprotic or non-polar solvents selected from the group comprising of ketones, esters, ethers, nitriles, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethyl formamide, hydrocarbons, halogenated hydrocarbons.

9. The process according to claim 1, wherein prior to the condensation of formula V with formula VI, desaltification of salt of formula VI is carried out using base selected from group comprising of ammonium hydroxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, calcium oxide, Ca(OH)2, sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, potassium phosphate and ammonium phosphate.