DESC:THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
COMPLETE SPECIFICATION

“PROCESS FOR PREPARATION OF LIFITEGRAST”

Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO – Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala,
Andheri (East), Mumbai – 400 099

The following specification particularly describes the invention and the manner in which it is to be performed.

Field Of The Invention
The present invention relates to process for the preparation of lifitegrast.
Background of The Invention
Lifitegrast, which is chemically known as (S)-2-(2-(benzofuran-6-carbonyl)-5, 7-dichloro-1, 2, 3, 4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl) phenyl)propanoic acid is represented by compound of Formula I.

I
Xiidra™ Shire’s lifitegrast opthalimic solution 5% for topical ophthalmic use is a lymphocyte function-associated antigen-1 (LFA-1)antagonist indicated for the treatment of signs and symptoms of dry eye disease.
Summary of the Invention
In one embodiment, the present invention provides a process for the preparation of lifitegrast, a compound of formula I comprising:

I
a) reacting a compound of formula VI with a compound of formula VII
VI VII
to obtain a compound of formula VIII,

VIII
wherein R1 and R2 is independently selected from the group consisting of H, alkyl and aryl, wherein the alkyl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of nitro, cyano, amino, halogen, alkyl and aryl; or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic group, optionally containing N, O or S and optionally substituted with one or more substituents selected from the group consisting of N, O and S; and
b) deprotecting the compound of formula VIII to obtain lifitegrast a compound of formula I.
Detailed Description of the Invention
The term "alkyl" as used herein refers to an aliphatic-hydrocarbon group which may be straight or branched having C1-C20 carbon atoms in the chain. Preferred alkyl groups have C1-C12 carbon atoms, more preferably have C1-C6 carbon atoms in the chain. Branched means that one or lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. The alkyl groups include but are not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, octyl, nonyl, decyl. The alkyl groups may be optionally substituted with aryl, halogen, nitro, amino and cyano.
The term "aryl" as used herein refers to an aromatic hydrocarbyl group having a single ring or multiple aromatic rings fused together, optionally containing hetero atoms. The hetero atoms may be selected from the group consisting of N, O and S. These aryl groups may be optionally substituted with a halogen, nitro, cyano, amino or C1-C6 alkyl. Preferred aryl groups have C6-C18 carbon atoms, more preferably have C6-C10 carbon atoms.
The aryl groups include but are not limited to phenyl, naphthyl or tetrahydronaphthyl, each of which may optionally be substituted by 1-4 substituents, such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy.
The term "cycloalkyl" refers to saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon groups of C3-C12 carbon atoms. Cycloalkyl refers to cyclic hydrocarbon groups having between C3 and C9 ring carbon atoms or between C3 and C7 ring carbon atoms.
The term ‘halogen’ refers to iodo, bromo, chloro or fluoro.
The term “alkoxy” refers to methoxy, ethoxy or isopropoxy groups.
In one embodiment, the present invention provides a process for the preparation of lifitegrast, a compound of formula I comprising:

I
a) reacting a compound of formula VI with a compound of formula VII

VI VII
to obtain a compound of formula VIII,

VIII
wherein R1 and R2 is independently selected from the group consisting of H, alkyl and aryl, wherein the alkyl or aryl group are optionally substituted with nitro, cyano, amino, halogen, alkyl and aryl; or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic group, optionally containing N, O or S and optionally substituted with one or more substituents selected from the group consisting of N, O and S; and
b) deprotecting the compound of formula VIII to obtain lifitegrast a compound of formula I.
In one embodiment, R1 and R2 is independently H or C1-C6 alkyl wherein C1-C6 alkyl is optionally substituted with C6-C10 aryl.
In one embodiment, R1 and R2 is independently H or C6-C10 aryl wherein C6-C10 aryl is optionally substituted with C1-C6 alkyl.
In one embodiment, R1 and R2 together with the nitrogen atom to which they are attached form a cyclic group wherein the cyclic group may be a 5-10 membered monocyclic or bicyclic group.
In one embodiment, R1 and R2 is independently selected from the group consisting of H, C1-C6 alkyl and C6-C18 aryl, wherein the C1-C6 alkyl or C6-C18 aryl group are optionally substituted with chloro, nitro, cyano, amino; or R1 and R2 together with the nitrogen atom to which they are attached form cyclic group which may be a 5-10 member monocyclic or bicyclic ring group, optionally containing N, O or S and the cyclic group may be optionally substituted with heteroatoms selected from the group consisting of N, O and S.
In one embodiment, R1 and R2 is independently selected from the group consisting of H, C1-C4 alkyl and C6-C10 aryl, wherein the C1-C4 alkyl or C6-C10 aryl group are optionally substituted with chloro, nitro, amino; or R1 and R2 together with the nitrogen atom to which they are attached form cyclic group wherein the monocyclic ring is having not more than 6 carbon atoms optionally containing N, O or S and the cyclic group may be optionally substituted with heteroatoms selected from the group consisting of N, O and S;or R1 and R2 together with the nitrogen atom to which they are attached form cyclic group wherein the bicyclic ring is not having more than 10 carbon atom optionally containing N, O or S and the cyclic group may be optionally substituted with heteroatoms selected from the group consisting of N, O and S.
In one embodiment, R1 and R2 is C1-C4 alkyl selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl.
In one embodiment, R1 and R2 is methyl.
In one embodiment, R1 and R2 is independently H or C1-C4 alkyl wherein C1-C4 alkyl is optionally substituted with C6-C10 aryl selected from the group consisting of phenyl, methoxyphenyl, nitrophenyl and chlorobenzene.
In one embodiment, R1 and R2 is H or C1-C4 alkyl optionally substituted with C6-C10 aryl such as phenyl.
In one embodiment, R1 and R2 is independently H or C6-C10 aryl wherein C6-C10 aryl is optionally substituted with C1-C6 alkyl, halogen, nitro, cyano or amino. In one embodiment, R1 and R2 is independently H or C6-C10 aryl, optionally substituted with methyl, chloro, nitro or amino.
In one embodiment, R1 and R2 is independently H or C6-C10 aryl selected from the group consisting of phenyl, toluoyl, chlorobenzene, nitrobenzene and aminobenzene.
In one embodiment, R1 and R2 together with the nitrogen atom to which they are attached form a cyclic group wherein the monocyclic ring is selected from the group consisting of pyridyl, thiazolyl, oxazolyl, pyrimidinyl, and imidazolyl and the like.
In one embodiment, R1 and R2 together with the nitrogen atom to which they are attached form a cyclic group wherein the bicyclic ring is selected from the group consisting of phthalimide, benzofuryl, benzisoxazolyl, indolyl and the like.
In one embodiment, R1 and R2 together with the nitrogen atom to which they are attached form a cyclic group selected from the group consisting of morpholidinyl, piperidinyl, phthalimide.
In one embodiment, step (a) of the above process the compound of formula VI is reacted with a compound of formula VII in the presence of a coupling agent.
In one embodiment, the compound of formula VI is reacted with the compound of formula VII in the presence of a coupling agent and a solvent to obtain a compound of formula VIII.
In one embodiment, the coupling agent may be selected from the group consisting of EDC.HCl [N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, HATU[(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate], T3P®[1-Propanephosphonic anhydride] and CDI(1,1'-carbonyldiimidazole).
In one embodiment, the compound of formula VI is reacted with the compound of formula VII in the presence of a coupling agent, a solvent and optionally a catalyst to obtain a compound of formula VIII.
In one embodiment, the catalyst may be selected from the group consisting of HOBT [1-hydroxybenzotriazole], DMAP[4-(N,N-dimethylamino)pyridine], DIEA [N,N-Diisopropylethylamine] and HOPO[2-hydroxypyridine-N-oxide].
In one embodiment, the compound of formula VI is reacted with the compound of formula VII in presence of an agent which promotes carboxamide formation from carboxylic acids such as but not limited to thionyl chloride, sulfuryl chloride, phosphorous pentachloride, an anhydride or a mixed anhydride such as pivalic anhydride, acetic anhydride to obtain a compound of formula VIII.
In one embodiment, the solvent is selected from the group consisting of ether such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, methyl-tetrahydrofuran and the like; esters such as ethyl acetate, isopropyl acetate and the like; amides such as dimethyl formamide, dimethyl acetamide and the like; ketones such as, N-methyl pyrrolidinone, acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, cyclohexane and the like; halogenated hydrocarbons such as methylene dichloride, ethylene dichloride, chloroform and the like; nitrile such as acetonitrile; dimethyl sulfoxide, sulfolane, water or mixture thereof.
In one embodiment, salt of compound of formula VI is reacted with the compound of formula VII to obtain a salt of compound of formula VIII, optionally the salt may be basified to obtain compound of formula VIII.
In one embodiment, in step a) when R1 and R2 are methyl the process comprises reacting a compound of formula VI with a compound of formula VII (a)

VI VII (a)
to obtain a compound of formula VIII (a)

VIII (a).
In one embodiment, the present invention provides (2S)-2-[[2-(1-benzofuran-6-carbonyl)-5,7-dichloro-3,4-dihydro-1H-isoquinoline-6-carbonyl]amino]-3-(3-methylsulfonylphenyl)-N,N-dimethylpropanamide the compound of formula VIII (a).
In one embodiment, in step a) when R1 is H and R2 is benzyl the process comprises reacting a compound of formula VI with a compound of formula VII (b)

VI VII (b)
to obtain a compound of formula VIII (b)

VIII (b).
In one embodiment, in step a) when R1 is H and R2 is phenyl the process comprises reacting a compound of formula VI with a compound of formula VII (c) to obtain a compound of formula VIII (c)

VI VII (c)

VIII (c).
In one embodiment, in step a) R1 and R2 together with the nitrogen atom to which they are attached form a phthalimide group, the process comprising reacting a compound of formula VI with a compound of formula VII (d) to obtain a compound of formula VIII (d).

VI VII (d)

VIII (d)
In one embodiment, step b) of the above process involves deprotecting the compound of formula VIII to obtain lifitegrast a compound of formula I.
In one embodiment, the deprotection of the compound of formula VIII may be carried out using suitable reagents.
Suitable reagents may be selected from the group consisting of acid like hydrochloric acid, trifluoroacetic acid, hydrobromic acid, sulphuric acid, hydrobromic acid, p-toluene sulfonic acid, boron tribromide, formic acid; reducing agents such as using palladium/carbon, palladium acetate or palladium hydroxide; base such as piperidine, ammonia, methylamine, cyclohexyl amine; hydrides such as sodium hydride, hydroxides such as sodium hydroxide, potassium hydroxide and the like; alkoxides such as potassium tertiary butoxide, sodium methoxide and the like.
The deprotection reaction may be carried out in presence of a solvent. The solvent may be selected from the group consisting of water, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, tertiary-butanol; ketones such as acetone, methyl ethyl ketone; nitriles such as acetonitrile, propionitrile; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran, tetrahydropyran; esters such as ethyl formate, ethyl acetate, propyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform, methylene dichloride; hydrocarbons such as n-hexane, cyclohexane, benzene, toluene and methyl cyclohexane; nitrile such as acetonitrile, sulfoxides such as dimethyl sulfoxide; polar solvents such as sulfolane, hexamethylphosphorylamide and mixtures thereof.
In one embodiment, in step b) when R1 and R2 are methyl, the compound of formula VIII (a), the deprotection is carried out by acid hydrolysis or base hydrolysis.
Suitable acid may be selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid.
In one embodiment, in step b) when R1 and R2 are methyl the compound of formula VIII (a), the deprotection is carried out with hydrochloric acid.
In one embodiment, in step b) when R1 is H and R2 is benzyl, the compound of formula VIII (b) may be deprotected by acid hydrolysis or base hydrolysis.
In one embodiment, in step b) when R1 is H and R2 is phenyl, the compound of formula VIII (c) may be deprotected by acid hydrolysis or base hydrolysis.
In one embodiment, in step b) when R1 and R2 together with the nitrogen atom to which they are attached form a phthalimide group, the compound of formula VIII (d) may be deprotected by acid hydrolysis or base hydrolysis.
In one embodiment, the present invention provides a process for the preparation of lifitegrast comprising hydrolysing a compound of formula IX to obtain a compound of formula I, wherein R is alkyl or aryl.

IX

I
In one embodiment, the present invention provides a process for the preparation of lifitegrast, a compound of formula I, comprising condensing a compound of formula VI with a compound of formula X to obtain a compound formula I.

VI X
In one embodiment, the present invention provides a process for the preparation of lifitegrast, a compound of formula I, comprising deprotecting a compound of formula XI, wherein R3 is selected from the group consisting of tertiary butyl thiophene, 1-oxy-2,5-pyrrolidinone, tert-butyloxy and benzyloxy group.

XI
In one embodiment, the present invention provides lifitegrast Form A.
In one embodiment, the present invention provides a process for the preparation of crystalline lifitegrast, the process comprising:
(a) dissolving lifitegrast, or salt or solvate thereof, in a suitable solvent to form a solution;
(b) optionally adding an anti-solvent to the solution of step (a); and
(c) isolating the crystalline lifitegrast.
In (a) of the above process of the preparation of crystalline lifitegrast, lifitegrast or salt or solvate thereof, is dissolved in a suitable solvent to form a solution.
In one embodiment, lifitegrast is dissolved in a suitable solvent to form a solution.
In one embodiment, salt of lifitegrast is dissolved in a suitable solvent to form a solution.
In one embodiment, solvate of lifitegrast is dissolved in a suitable solvent to form a solution.
The salt of lifitegrast includes salt with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid.
The solvate of lifitegrast includes solvate with water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, acetonitrile, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, chloroform, dichloromethane, hexane, n-heptane, toluene, N-methyl pyrrolidone, dimethyl formamide or dimethyl sulfoxide.
The solvent used for dissolution includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water; or mixtures thereof.
Suitable temperature for dissolution may range from about 25°C to about the reflux temperature of the solvent. Stirring may be continued for any desired time period to achieve a complete dissolution of the compound. The stirring time may range from about 30 minutes to about 1 hour, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.
In step (b) the process involves adding an anti-solvent to the solution of step (a).
In one embodiment, the crystalline lifitegrast is obtained by adding an anti-solvent to the solution obtained in (a) to form a mixture and optionally, cooling and stirring the obtained mixture. The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about 0°C to reflux temperature of the solvent.
The anti-solvent is selected such that lifitegrast is precipitated out from the solution.
The anti-solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
In one embodiment, step (c ) of the above process involves isolating the crystalline lifitegrast.
In one embodiment, isolation involves removing the solvent from the solution obtained in step (a) or step (b). Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg.
In (c) of the process for the preparation of crystalline lifitegrast, the lifitegrast is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
In one embodiment, the present invention provides lifitegrast in a purity of about 99.9% w/w, as determined by HPLC (high performance liquid chromatography).
The present invention provides lifitegrast in stable form.
In one embodiment, stable crystalline form of lifitergrast has no detectable quantity of any other crystalline or amorphous form at room temperature or under accelerated stability conditions for extended period of time.
In one embodiment, the present invention provides pure lifitegrast in stable form.
In one preferred embodiment, the present invention provides pure lifitegrast in stable form with a purity of about 99.9% w/w, as determined by HPLC.
The present invention provides lifitegrast in amorphous form.
The present invention provides a process for the preparation of solvates of lifitegrast, the process comprising:
(a) dissolving lifitegrast in a suitable solvent to form a solution;
(b) obtaining solvate of lifitegrast from the solution of step (a); and
(c) isolating the solvate of lifitegrast.
The solvate of lifitegrast includes solvate with water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, methyl isobutyl ketone, dioxane, chloroform, dichloromethane, xylene, hexane, n-heptane, toluene, N-methyl pyrrolidone, dimethyl formamide, acetonitrile or dimethyl sulfoxide.
The suitable solvent includes water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, methyl isobutyl ketone, dioxane, chloroform, dichloromethane, xylene, hexane, n-heptane, toluene, N-methyl pyrrolidone, dimethyl formamide, acetonitrile or dimethyl sulfoxide.
In (b) of the process for the preparation of solvate of lifitegrast, the solvate of lifitegrast is obtained from the solution of step (a), the process comprising:
(i) cooling and stirring the solution obtained in (a); or
(ii) removing the solvent from the solution obtained in (a); or
(iii) treating the solution of step (a) with an anti-solvent to form a mixture and optionally, cooling and stirring the obtained mixture.
The anti-solvent is selected such that the solvate of lifitegrast is precipitated out from the solution.
The anti-solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
The present invention provides a process for the preparation of salt of lifitegrast, the process comprising:
(a) dissolving lifitegrast in a suitable solvent to form a solution;
(b) adding an acid to the above solution of step (a) to obtain an acid addition salt of lifitegrast;
(c) isolating the salt of lifitegrast.
The salt of lifitegrast includes salt with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, lactic acid, mandelic acid, salicylic acid, citric acid, malonic acid, malic acid.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.

Examples:
Example 1: Synthesis of (2S)-2-[[2-(1-benzofuran-6-carbonyl)-5,7-dichloro-3,4-dihydro-1H-isoquinoline-6-carbonyl]amino]-3-(3-methylsulfonylphenyl)-N,N-dimethylpropanamide [VIII (a) when R1, R2=methyl].
A mixture of Compound VI (10g) and N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride[EDC.HCl] (5.0g) was stirred in dimethyl formamide (100 ml) for 30 mins to obtain a reaction mass. To this reaction mass diisopropylethyl amine (DIPEA) (10g), 1-hydroxybenzotriazole (0.1g) and (2S)-2-amino-N,N-dimethyl-3-[3-(methylsulfonyl)phenyl]-propanamide (7.0g) were added. The reaction mass was stirred at 25-30°C for 12 to about 18 hours. The reaction mass diluted with water to afford title compound as solid (13.0g).
Example 2: Synthesis of (2S)-2-[[2-(1-benzofuran-6-carbonyl)-5,7-dichloro-3,4-dihydro-1H-isoquinoline-6-carbonyl]amino]-3-(3-methylsulfonylphenyl)-N,N-dimethylpropanamide [VIII (a) when R1, R2=methyl].
A mixture of compound VI (10g), (2S)-2-amino-N,N-dimethyl-3-[3-(methylsulfonyl)phenyl] propanamide (7.0g), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate [HATU] (7.0g) and triethylamine (13.0g) in dimethyl formamide (50ml) were stirred at room temperature for 15 hrs to obtain a reaction mass. The solvent from the reaction mass was removed under reduced pressure to give title compound. The title product was purified by a) column chromatography using 30-40% ethyl acetate in hexane to give compound VIII (5.1g) b) crystallised from a mixture of ethyl acetate and hexane.
Example 3: Synthesis of (2S)-2-[[2-(1-benzofuran-6-carbonyl)-5,7-dichloro-3,4-dihydro-1H-isoquinoline-6-carbonyl]amino]-3-(3-methylsulfonylphenyl)-N,N-dimethylpropanamide [VIII (a) when R1, R2=methyl].
To a solution of compound VI (10.0g) in methylene dichloride(100ml) was added oxalyl chloride (10ml) and stirred for 2 hrs to obtain a reaction mass. To the reaction mass was added triethylamine (12.0g) followed by (2S)-2-amino-N,N-dimethyl-3-[3-(methylsulfonyl)phenyl] propanamide (7.0g). The reaction mass was stirred for 5 hrs at 25-30°C. The reaction mass was distilled under vacuum and diluted with water to give title compound as solid (12.0g).
Example 4: Synthesis of (2S)-2-[[2-(1-benzofuran-6-carbonyl)-5,7-dichloro-3,4-dihydro-1H-isoquinoline-6-carbonyl]amino]-3-(3-methylsulfonylphenyl)-N,N-dimethylpropanamide [VIII (a) when R1, R2=methyl].
A solution of Compound VI (10.0g), and diisopropylethyl amine [DIPEA] (15 ml) in tetrahydrofuran(100 ml) was cooled to -78°C to obtain a reaction mixture. The reaction mixture stirred for 30 mins. A solution of (2S)-2-amino-N,N-dimethyl-3-[3-(methylsulfonyl)phenyl] propanamide (7.0g) in tetrahydrofuran (5ml) was added to the reaction mass. The reaction mixture was maintained for 2 hrs at -78°C. The temperature was raised to 25-30°C and stirred for 2 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. Organic layer was distilled under vacuum to afford title product.
Preparation of lifitegrast, the Compound I:

Example 5: (2S)-2-[[2-(1-benzofuran-6-carbonyl)-5,7-dichloro-3,4-dihydro-1H-isoquinoline-6-carbonyl]amino]-3-(3-methylsulfonylphenyl)-N,N-dimethylpropanamide, the compound of formula VIII (a), (5.0g) was refluxed in conc.hydrochloric acid (50 ml) for about 15 to 18 hrs. The reaction mixture was cooled to 25-30°C and diluted with water. The reaction mass was extracted with ethyl acetate. Organic layer washed with saturated sodium bicarbonate and evaporated under reduced pressure to afford lifitegrast (2.5g).
Example 6: (2S)-2-[[2-(1-benzofuran-6-carbonyl)-5,7-dichloro-3,4-dihydro-1H-isoquinoline-6-carbonyl]amino]-3-(3-methylsulfonylphenyl)-N,N-dimethylpropanamide, the compound of formula VIII (a), (5.0g) was dissolved in methanol (50 ml) to this was added sodium hydroxide solution to obtain a reaction mixture . The reaction mixture was refluxed for 12 to about 18 hour. The reaction mixture was cooled to 25-30°C and pH was adjusted using hydrochloride acid. The aqueous layer was extracted using ethyl acetate. The ethyl acetate layer was washed with saturated sodium bicarbonate solution and distilled to give lifitegrast (2.4g).
,CLAIMS:We claim:
1] A process for the preparation of lifitegrast, a compound of formula I comprising:

I
a) reacting a compound of formula VI with a compound of formula VII

VI VII
to obtain a compound of formula VIII,

VIII
wherein R1 and R2 is independently selected from the group consisting of H, alkyl and aryl, wherein the alkyl or aryl groups are optionally substituted with one or more substituents selected from the group consisting of nitro, cyano, amino, halogen, alkyl and aryl; or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic group, optionally containing N, O or S and optionally substituted with one or more substituents selected from the group consisting of N, O and S; and
b) hydrolysing the compound of formula VIII to obtain lifitegrast a compound of formula I.
2] The process as claimed in claim 1, wherein R1 and R2 is independently H or C1-C6 alkyl, wherein C1-C6 alkyl is optionally substituted with C6-C10 aryl.
3] The process as claimed in claim 1, wherein R1 and R2 is independently H or C6-C10 aryl, wherein C6-C10 aryl is optionally substituted with C1-C6 alkyl.
4] The process as claimed in claim 1, wherein R1 and R2 together with the nitrogen atom to which they are attached form a cyclic group wherein the cyclic group is 5-10 membered monocyclic or bicyclic group.
5] The process as claimed in claim 2, wherein R1 and R2 is C1-C4 alkyl selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl.
6] The process as claimed in claim 5, wherein R1 and R2 is methyl.
7] The process as claimed in claim 1, wherein the compound of formula VI is reacted with a compound of formula VII in the presence of a coupling agent.
8] The process as claimed in claim 6, wherein the deprotection is carried out by acid hydrolysis.
9] The process as claimed in claim 8, wherein the deprotection is carried out with hydrochloric acid.

Dated this 8th Day of December, 2017
(Signed)____________________
Dr. Madhavi Karnik
Senior General Manager-IPM
Glenmark Pharmaceuticals Limited