FORM 2
THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
An improved process for the preparation of Lifitegrast
2. APPLICANT (S)
(a) NAME: Enaltec Labs Pvt. Ltd.
(b) NATIONALITY: An Indian Company incorporated under the Indian
Companies ACT 1956
(c) ADDRESS:
Enaltec Labs Pvt. Ltd., 17th Floor, Kesar Solitaire, Plot No. 5, Sector 19, Sanpada, Navi Mumbai- 400705, Maharashtra, India.

FIELD OF THE INVENTION:
The present invention relates to an improved process for preparation of Lifitegrast; the compound of structural formula (I)

BACKGROUND OF THE INVENTION:
Lifitegrast is chemically defined as (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-l,2,3,4-tetrahydroisoquinoline-6carboxamido)-3-(3(methylsulfonyl)phenyl)propanoic acid and is represented by formula (I)

Lifitegrast is approved in USA used for the treatment of keratoconjunctivitis sicca (dry eye syndrome) and drug available in market under the trade name XIIDRA by Shire Development.

Lifitegrast was first disclosed in U.S Patent No.7,314,938 and 8,084,047 wherein Lifitegrast synthesis was provided analogously.
U.S Patent No. 8,871,935 discloses a process for preparation of Lifitegrast wherein the process involves condensation of the compound of formula (XII) with the compound of formula (XI) to get the compound of formula (X), followed by deprotecting the compound of formula (X) and reacting the resultant compound of formula (IX) with compound of formula (IV) to get the compound of formula (VIII). The compound of formula (VIII) is then subjected to debenzylation to yield the compound of formula (I). Finally, the crude compound of formula (I) is subjected to crystallization. The process can be shown in Scheme I


The process disclosed in the prior art involves the use of expensive starting material, the compound of formula (XI). The inventors of present invention provides an industrially feasible, economic and environment friendly process for the preparation of Lifitegrast using novel intermediate.
OBJECT OF PRESENT INVENTION
1. An object of the present invention is to provide an improved process for the preparation of Lifitegrast; the compound of structural formula (I).
2. Another object of present invention is to provide an improved process for preparation of Lifitegrast; the compound of structural formula (I) using novel intermediate; the compound of formula (III) or its acid addition salts.
3. Yet another object of the present invention to provide simple, economic and industrially scalable process for the preparation of Lifitegrast; the compound of structural formula (I).
SUMMARY OF THE INVENTION
*
In accordance with an aspect of the present invention, there is to provided an improved process for the preparation of Lifitegrast; the compound of structural formula (I)


comprising the steps of,
a) reacting the compound of formula (VII) with the compound of formula (VI) or its salt, in the presence of a coupling reagent and a base in suitable solvent to obtain the compound of formula (V),

b) deprotecting the compound of formula (V) to obtain the compound of formula (HI),

c) optionally, converting the compound of formula (III) to its acid addition salt,
d) coupling the compound of formula (III) or its acid addition salt, with the compound of formula (IV) in presence of a coupling reagent using base in suitable solvent to get the compound of formula (II)

e) hydrolyzing the compound of formula (II) in presence of alkali metal hydroxide in a suitable solvent to get compound of formula (I).

f) optionally, purifying the compound of formula (I) obtained in step (e).
The route of synthesis of Lifitegrast; the compound of formula (I) according to present invention can be illustrated as below in Scheme II


DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to simple, economic and industrially scalable process for the preparation of Lifitegrast; the compound of structural formula I using novel intermediate; the compound of structural formula III or acid addition salt thereof.
According to present invention, there is provided an improved process for the preparation of Lifitegrast; the compound of structural formula (I)

comprising the steps of,
a) reacting the compound of formula (VII),

with the compound of formula (VI) or its salt,

in the presence of a coupling reagent and a base in an organic solvent at a temperature in the range of 0°C to 50°C to obtain the compound of formula (V),

b) deprotecting the compound of formula (V) to obtain a compound of formula (HI),

c) optionally, converting the compound of formula (III) to its acid addition salt;
d) coupling the compound of formula (III) or its acid addition salt, with compound of formula (IV),

in presence of a coupling reagent and a base in an organic solvent to obtain the compound of formula (II)

e) hydrolyzing the compound of formula (II) in the presence of alkali metal hydroxide in an organic solvent to obtain the compound of formula (I).


f) optionally purifying the compound of formula (I) obtained in step (e).
In an embodiment of the present invention, the coupling reagent used in step (a) is selected from group consisting of HATU [l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexa fluorophosphate], HOBt (Hydroxybenzotriazole), HOAt (l-Hydroxy-7-azabenzotriazole), HBTU (2-(1H-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate) and TBTU (O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate).
In accordance with an embodiment of the present invention, the base used in step (a) is organic base selected from group consisting of triethylamine, diisoproylethylamine, pyridine and methyl amine.
In accordance with an embodiment of the present invention, the base used in step (a) is inorganic base selected from group consisting of potassium carbonate and sodium carbonate.
In accordance with an embodiment of the present invention, the organic solvent used in step (a) is selected from group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, dipropyl ketone, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, methylene chloride, ethylene dichloride, carbon tetrachloride, chloroform, diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, diisopropyl ether, methyl acetate, ethyl

acetate, propyl acetate, butyl acetate, isobutyl acetate, acetonitrile, dimethyl formamide, dimethyl sulfoxide or the mixture(s) thereof.
In accordance with an embodiment of the present invention, the compound of formula (VII) is reacted with the compound of formula (VI) or its salt at temperature in the range of 0°C to 50°C for a period of 2-8 hours to obtain the compound of formula (V).
In accordance with an embodiment of the present invention, the compound of formula (V) can be isolated by the combination of steps comprising of distillation, filtration and drying.
In specific embodiment of the present invention, the compound of formula (V) can be isolated by removal of solvent in reaction mass by distillation, addition of second solvent followed by addition of antisolvent; filtration and drying of obtained product at 40-80°C.
In another embodiment of the present invention, in the step (b), the deprotection of compound of formula (V) is carry out using acidic reagent dissolved in organic solvent to get compound of formula (ITT).
In accordance with another embodiment of the present invention the acidic reagent used in step (b) is selected from hydrochloric acid and trifluoroacetic acid.
In accordance with another embodiment of the present invention organic solvent used in step (b) is selected from group consisting of methanol, ethanol, isopropyl alcohol, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate, dioxane and mixture thereof.
In accordance with another embodiment of the present invention, in the step (b), deprotection of the compound of formula (V) is carry out at a temperature in the

range of -10°C to 10°C for a period of 2 hours to 10 hours to get the compound of formula (III).
In accordance with an embodiment of the present invention, the compound of formula (III) can be isolated by extraction of product, washing of aqueous layer, addition of base to adjust PH 8-9 and again extraction in organic solvent followed by distillation, addition of second solvent and filtration.
In another embodiment of the present invention, in the step (c), the compound of formula (III) is optionally converted to its acid addition salt with HX, wherein X is CI or Br, by treating compound of formula (III) with solution of HX in organic solvent.
In accordance with another embodiment of the present invention, in the step (c), the organic solvent are selected from methanol, ethanol, isopropyl alcohol, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate or mixture(s) thereof.
In accordance with another embodiment of the present invention, in the step (c), the compound of formula (III) can be isolated by the combination of steps comprising of filtration, centrifugation and drying.
In another embodiment of the present invention the coupling reagent used in the step (d) is but not limited to thionyl chloride.
In another embodiment of the present invention the base used in the step (d) is potassium carbonate and sodium carbonate.
In accordance with another embodiment of the present invention, in the step (d), the coupling is carry out at a temperature in the range of 0°C to 40°C for a period of 2-10 hours to get compound of formula (II).

In accordance with another embodiment of the present invention, the organic solvent used in the step (d) is selected from methylene chloride, ethylene dichloride, carbon tetrachloride, chloroform, dioxane, acetonitrile, dimethyl formamide, dimethyl sulfoxide, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate or mixture(s) thereof.
In accordance with another embodiment of the present invention, in the step (d), the compound of formula (II) can be isolated by the combination of steps comprising of distillation, filtration and drying.
In the specific embodiment of the present invention, in the step (d), the compound of formula (II) can be isolated by removal of first solvent in reaction mass by distillation, addition of second solvent to concentrated reaction mass followed by addition of antisolvent; filtration and drying.
In accordance with another embodiment of the present invention, the compound of formula (II) can be further purified by using organic solvent selected from acetone, methyl isobutyl ketone and methyl ethyl ketone.
In accordance with another embodiment of the present invention the alkali metal hydroxide used in the step (e) is selected from group consisting of sodium hydroxide, potassium hydroxide and lithium hydroxide.
In accordance with another embodiment of the present invention the organic solvent used in the step (e) is selected from group consisting of methanol, ethanol, isopropyl alcohol, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate, diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, diisopropyl ether or mixture(s) thereof.

In accordance with another embodiment of the present invention, in the step (e), the compound of formula (II) can be hydrolyzed at a temperature in the range of 0°C to 40°C for a period of 2 hours to 10 hours to get compound of formula (I).
In accordance with another embodiment of the present invention, in the step (e), the compound of formula (I) can be isolated by the combination of steps comprising of filtration, centrifugation and drying.
In another embodiment of the present invention, the compound of formula (I) can be optionally purified by using solvents selected from group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, dipropyl ketone, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, diisopropyl ether, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate or mixture(s) thereof.
In the following example, the preferred aspects of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Examples:
Example 1: Preparation of Lifitegrast
Step-1: Preparation of (S)-tert-butyl 5,7-dichloro-6-((l-methoxy-3-(3-(methylsulfonyl)phenyl)-l-oxopropan-2-yI)carbamoyl)-3,4-dihydroisoquinoline-2(lH)-carboxylate [Formula (V)]
In a round bottom flask, a solution of 2-(Tert-butoxycarbonyl)-5,7-dichloro-l,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (the compound of formula VII) (64.9g),

HATU (107.08 g), Triethyl amine (102.5 g) and MDC (800 ml) was charged and reaction mass was stirred for 50-60 minutes. To the reaction mass, (S)-Methyl 2-amino-3-(3-methylsulfonyl)phenyl) propanoate.HCl (the compound of formula VI) (50 g) was charged and resulting reaction mixture stirred at 25°C to 30°C for 4 hours. After consumption of starting material, water was added and reaction mass was stirred for 30 min. Layers were separated and MDC layer distilled under vacuum. The oily mass was further dissolved in DMF (260 ml) and poured in water (1040 ml) to precipitate out the white compound of formula (V). The filtered compound of formula (V) was dried in oven at 50-55°C. (Wt-99 g)
Step-2: Preparation of (S)-methyl 2-(5,7-dichloro-l,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate hydrochloride [Formula (III)]
To a solution of (S)-Tert-butyl 5,7-dichloro-6-((l-methoxy-3-(3-(methylsulfonyl) phenyl)-l-oxopropan-2-yl)carbamoyl)-3,4-dihydroisoquinoline-2(lH)-carboxylate (Formula V)(80 g) in dichloromethane (800 ml) , 4M HC1 in dioxane was added at 0°C to 5°C and reaction mass was stirred for 5-6 hrs at 25°C to 30°C. After consumption of the compound of formula (V), 800 ml water was added and stirred for 30 minutes. Layers were separated and aqueous layers washed with 400 ml ethyl acetate and then treated with sodium bicarbonate solution to make pH 8-9 and extracted with dichloromethane (240 ml). The dichloromethane layer was distilled and to the obtained reaction mass ethyl acetate.HCl solution was added. The slurry was filtered and the filter cake was washed with ethyl acetate (100 mL) to obtain solid material. The solid material was air-dried for 45-60 minutes and further dried in vacuum at 30°C. (Wt- 64 g).
Step-3: Preparation of (S)-methyl 2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-l,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate [Formula (II)]

To a solution of benzofuran-6-carboxylic acid (31.06g) in dichloromethane (300 ml),
. thionyl chloride (34.12 g) and catalytic DMF (2.0 ml) were charged 25°C to 30°C and
reaction mixture was stirred at 40°C to 45°C for 4 hours. After consumption of
starting material, solvents were distilled under vacuum. The obtained oil was
dissolved in dichloromethane and solution was added slowly to a solution of (S)-
methyl 2-(5,7-dichloro-l,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-
(methylsulfonyl) phenyl)propanoate hydrochloride (formula III) (50.0 g) and potassium carbonate (90.34 g) in dichloromethane (300 ml) at 10°C to 15°C and reaction mass was stirred for 3-4 hours. After consumption of the compound of formula III, water was added and reaction mass was stirred for 20-25 minutes. Layers were separated and dichloromethane layer was washed with water. The dichloromethane layer was distilled under vacuum to obtained oil. The oil was dissolved in DMF (150 ml) and to the solution water (1500 ml) was added to obtain white solid. The white solid was filtered and dried under vacuum at 45°C of compound of formula II. (Wt-54 g).
To the compound of formula II (50 g), methyl isobutyl ketone was added and reaction mass was heated to 80°C for 30 minutes. Reaction mass was cooled to 25°C, stirred for 1 hour, filtered and dried under vacuum at 45°C to get the compound of formula II. (48 g).
Step-4: Preparation of (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid [Formula (I)]
To a solution of (S)-methyl 2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-l,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoate (25 g) in methanol (125 ml), lithium hydroxide solution (1.9 g) in water (50 ml) was added at 10°C to 15°C and reaction mass was stirred for 2 hours. After consumption of the compound of formula II, 500 ml water was added and reaction mass was stirred

for 10 minutes. To the reaction mass, dilute HC1 (10%, 10 ml) was added slowly to make pH 1-2 and reaction mass was stirred at 10°C to 15°C for 2 hours to precipitate solid. The precipitated solid was filtered and washed with 250 ml water. The obtained wet solid dried in oven at 50°C to 55°C for 12 hours to obtain the compound of formula 1 (Lifitegrast). (Wt-21.5 g).
Step-5: Purification of (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-l,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid (Lifitegrast).
To a crude Lifitegrast, (Formula I)(13 g), Methyl ethyl ketone (39 ml) was added and reaction mass was stirred for 24 hours. The obtained solid was filtered and washed with Methyl ethyl ketone (130 ml). The wet solid was dried in vacuum at 45°C to 50°C, to get Lifitegrast. (Wt-11g).

We claim:
1. A process for the preparation of Lifitegrast; the compound of structural formula (I)

comprising,
a) reacting the compound of formula (VII),

with the compound of formula (VI) or its salt,

in the presence of a coupling reagent and a base in an organic solvent at a temperature in the range of 0°C to 50°C to obtain the compound of formula (V)


b) deprotecting the compound of formula (V) to obtain the compound of formula (HI),

c) optionally, converting the compound of formula (III) to its acid addition salt;
d) coupling the compound of formula (III) or its acid addition salt, with the compound of formula (IV),

in the presence of a coupling reagent and a base in an organic solvent to obtain the compound of formula (II)

e) hydrolyzing the compound of formula (II) in presence of alkali metal hydroxide in an organic solvent to obtain the compound of formula (I).


i) optionally purifying the compound of formula (I) obtained in step (e).
2. The process as claimed in claim 1, wherein the coupling reagent used in the step (a) is selected from group consisting of HATU [1-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexa fluorophosphate], HOBt (Hydroxybenzotriazole), HOAt (l-Hydroxy-7-azabenzotriazole), HBTU (2-( lH-benzotriazol-1 -yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) and TBTU (0-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate).
3. The process as claimed in claim 1, wherein base used in the step (a), is organic base selected from the group consisting of triethylamine, diisoproylethylamine, pyridine, methyl amine.
4. The process as claimed in claim 1, wherein base used in the step (a), is inorganic base selected from the group consisting of potassium carbonate and sodium carbonate.
5. The process as claimed in claim 1, wherein deprotection is carried out in step (b) by using hydrochloric acid or trifluoroacetic acid; dissolved in organic solvents selected from the group consisting of methanol, ethanol, isopropyl alcohol, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate, dioxane or mixture(s) thereof.
6. The process as claimed in claim 1, wherein the step (c), the compound of formula (III) is optionally converted into its acid addition salt.
7. The process as claimed in claim 1, wherein coupling reagent used in step (d) is thionyl chloride.

8. The process as claimed in claim 1, wherein base used in step (d) is selected from the group consisting of potassium carbonate and sodium carbonate.
9. The process as claimed in claim 1, wherein organic solvent used in the step (a), step (d) and in step (e) is selected from the group consisting of methylene chloride, ethylene dichloride, carbon tetrachloride, chloroform, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, dipropyl ketone, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, diisopropyl ether, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate, acetonitrile, dimethyl formamide, dimethyl sulfoxide or mixture(s) thereof.
10. The process as claimed in claim 1, wherein alkali metal hydroxide used in the step (e) is selected from the group consisting of sodium hydroxide, potassium hydroxide and lithium hydroxide.