DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“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 ophthalmic 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.
The present invention provides a process for lifitegrast, a compound of formula I, in a chiral purity of at least 99% and wherein the level of R isomer of lifitegrast is less than 1% as determined by HPLC, via a novel organic amine salt of lifitegrast.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of lifitegrast, a compound of formula I, the process comprising:

I III
(a) deprotecting a compound of formula III, wherein R is selected from C1-C6 alkyl optionally substituted with C6-C18 aryl, and wherein the aryl group may be optionally substituted with one or more substituents selected from the group consisting of nitro, cyano, amino, halogen, hydroxyl, C1-C6 alkoxy and C1-C6 alkyl;
wherein the deprotection is carried out by subjecting the compound of formula III to treatment with a Lewis acid selected from the group consisting of lithium iodide, magnesium iodide, trimethylsilyl iodide, aluminium triiodide, and mixtures thereof, to obtain lifitegrast; and
(b) optionally, reacting the lifitegrast obtained in step (a) with an organic amine OA to form an organic amine salt thereof, a compound of formula II,
II.
In another embodiment, the present invention provides lifitegrast benzylamine salt, a compound of formula IIA,
IIA.
In another embodiment, the present invention provides a process for the preparation of lifitegrast benzylamine salt, a compound of formula IIA, the process comprising:
(a) reacting lifitegrast with benzylamine in presence of a solvent to form a reaction mixture;
(b) obtaining lifitegrast benzylamine salt from the reaction mixture of step (a); and
(c) isolating the lifitegrast benzylamine salt, the compound of formula IIA.
In another embodiment, the present invention provides a process for the preparation of lifitegrast, a compound of formula I comprising:
(a) reacting crude lifitegrast, with an organic amine OA, to form an organic amine salt thereof, a compound of formula II; and
(b) treating the compound of formula II with an acid to form lifitegrast, a compound of formula I, in a chiral purity of at least 99% and wherein the level of R isomer of lifitegrast is less than 1% as determined by HPLC.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is 1H NMR of compound IIA according to example 1.
Figure 2 is a characteristic XRPD of crystalline compound IIA according to example 1.
Figure 3 is XRD of amorphous lifitegrast according to example 3.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of lifitegrast, a compound of formula I, the process comprising:
(a) deprotecting a compound of formula III, wherein R is as defined above;
wherein the deprotection is carried out by subjecting the compound of formula III to treatment with a Lewis acid selected from the group consisting of lithium iodide, magnesium iodide, trimethylsilyl iodide, aluminium triiodide, and mixtures thereof, to obtain lifitegrast; and
(b) optionally, reacting the lifitegrast obtained in step (a) with an organic amine OA to form an organic amine salt thereof, a compound of formula II.
In the present application, the term “room temperature” means a temperature of about 25°C to about 30°C. The term "C1-C6 alkyl" as used herein refers to an aliphatic hydrocarbon group which may be straight or branched having 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, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl. The term “C6-C18 aryl" as used herein refers to an aromatic hydrocarbon group having a single ring or multiple aromatic rings fused together. 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. The term “halogen” refers to iodo, bromo, chloro or fluoro. The term "C1-C6 alkoxy" as used herein refers to C1-C6 alkyl group, wherein alkyl is as defined herein, that is linked to the rest of the molecule or to another group through an oxygen atom. The alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy.
In (a) of the above process for the preparation of lifitegrast, the compound of formula III is deprotected to obtain lifitegrast, wherein the deprotection is carried out by subjecting the compound of formula III to treatment with a Lewis acid selected from the group consisting of lithium iodide, magnesium iodide, trimethylsilyl iodide, aluminium triiodide, and mixtures thereof.
In one embodiment, in compound of formula III, when R is C1-C6 alkyl optionally substituted with C6 aryl, and wherein the aryl group may be optionally substituted with one or more substituents selected from the group consisting of nitro, cyano, amino, halogen, hydroxyl, C1-C6 alkoxy and C1-C6 alkyl, the deprotection is carried out by subjecting the compound of formula III to treatment with a Lewis acid selected from the group consisting of lithium iodide, magnesium iodide, trimethylsilyl iodide, aluminium triiodide, and mixtures thereof.
In another embodiment, in compound of formula III, when R is C1-C6 alkyl optionally substituted with C6 aryl, the deprotection is carried out by subjecting the compound of formula III to treatment with a Lewis acid selected from the group consisting of lithium iodide, magnesium iodide, trimethylsilyl iodide, aluminium triiodide, and mixtures thereof.
In one embodiment, in compound of formula III, when R is C1 alkyl substituted with C6 aryl, the compound of formula III is lifitegrast benzyl ester represented by compound of formula IIIA,
IIIA.
In one embodiment, the compound of formula IIIA is deprotected to obtain lifitegrast, wherein the deprotection is carried out by subjecting the compound of formula IIIA to treatment with a Lewis acid selected from the group consisting of lithium iodide, magnesium iodide, trimethylsilyl iodide, aluminium triiodide, and mixtures thereof.
In one embodiment, the deprotection is carried out by subjecting the compound of formula III to non-hydrolytic treatment with a Lewis acid.
In one embodiment, in compound of formula III, when R is C1-C6 alkyl optionally substituted with C6-C18 aryl, the deprotection is carried out by non-hydrolytic cleavage using a Lewis acid.
In one embodiment, the term “non-hydrolytic” means subjecting the compound of formula III with a Lewis acid in the absence of water.
In one embodiment, the term “non-hydrolytic cleavage” means the ester cleavage of the O-R bond in the compound of formula III, carried out in the absence of water.
In one embodiment, the term “non-hydrolytic cleavage” means the ester cleavage of the O-R bond in the compound of formula III being facilitated due to the coordination of the ester carbonyl in the compound of formula III with the electrophilic metal ion of the Lewis acid (MX).
In one embodiment, the term “non-hydrolytic cleavage” means the ester cleavage of the O-R bond in the compound of formula III being facilitated by the nucleophile X of the Lewis acid (MX).
In one embodiment, the term “non-hydrolytic cleavage” excludes the ester cleavage in the compound of formula III is not by water nucleophile or hydroxide nucleophile.
The deprotection reaction may be carried out in the presence of an aprotic solvent.
In one embodiment, the aprotic solvent includes, but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, dimethoxy ethane, 2-methyltetrahydrofuran and the like; nitriles such as acetonitrile and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane; sulfur compounds such as carbon disulfide; tertiary amines such as pyridine; amides such as dimethylformamide; or mixtures thereof.
In one embodiment, the deprotection is carried out at about room temperature to about the reflux temperature of the solvent.
In one embodiment, the lifitegrast obtained in step (a) is in-situ and carried forward to step (b).
The term “in-situ” means the intermediates formed in the steps referred to are not isolated. The term “not isolated” means the intermediates referred to are not separated as a solid.
In one embodiment, the term “in-situ” means the process of the invention is carried out without isolation of lifitegrast in the form of a solid compound.
In one embodiment, the lifitegrast obtained in step (a) may be present in the filtrate and used for reaction with organic amine, without isolating it from the filtrate.
In one embodiment, the lifitegrast obtained in (a) and present in the filtrate, may be isolated in a solid form or as a residue by removal of the solvent by evaporation or distillation and then reacted with the organic amine.
In one embodiment, the lifitegrast obtained in (a) has a chemical purity of 50-99.5% as determined by HPLC.
In (b) of the above process for the preparation of lifitegrast, the lifitegrast obtained in step (a) is reacted with an organic amine OA to form an organic amine salt thereof, a compound of formula II.
An organic amine, OA is an organic compound which acts as a base. They usually contain nitrogen atoms, which can easily be protonated.
In one embodiment, OA is an organic amine of formula NR1R2R3, wherein R1, R2, R3 may be independently selected from the group consisting of H or C1-C6 alkyl optionally substituted with C6-C18 aryl; wherein the aryl group may be optionally substituted with one or more substituents selected from the group consisting of nitro, cyano, amino, halogen, hydroxyl, C1-C6 alkoxy and C1-C6 alkyl.
In one embodiment, OA is an organic amine of formula NR1R2R3, wherein R1 is H, R2 is H, R3 is C1-C6 alkyl group substituted with a C6 aryl group.
In one embodiment, OA is an organic amine of formula NR1R2R3, selected from the group consisting of benzylamine, methylamine, dimethylamine, trimethylamine, tert-butyl amine, ethylamine, diethylamine, triethylamine, diisopropylethylamine.
In one embodiment, the organic amine is benzylamine.
In one embodiment, OA organic amine is a cyclic amine like pyridine, piperidine, piperazine and the like.
In one embodiment, OA is an organic amine selected from the group consisting of meglumine, tromethamine, choline, ethanolamine, dibenzylethylenediamine.
In one embodiment, compound of formula II is lifitegrast benzylamine salt, a compound of formula IIA.
In one embodiment, the reaction of lifitegrast with organic amine is carried out in an organic solvent.
In one embodiment, the organic amine salt, a compound of formula II is separated from the reaction mass by filtration and if required subjected to purification by recrystallization.
The recrystallization may be carried out in a solvent selected from the group consisting of alcohol such as methanol, ethanol, isopropanol and the like; ketone such as acetone, methyl isobutyl ketone, ethyl methyl ketone and the like; nitrile such as acetonitrile, propionitrile and the like; water; and mixtures thereof.
In one embodiment, the present invention provides a process for the preparation of lifitegrast, a compound of formula I, the process comprising:
(a) deprotecting a compound of formula III, wherein R is as defined above;
wherein the deprotection is carried out by subjecting the compound of formula III to treatment with a Lewis acid selected from the group consisting of lithium iodide, magnesium iodide, trimethylsilyl iodide, aluminium triiodide, and mixtures thereof, to obtain lifitegrast; and
(b) reacting the lifitegrast obtained in step (a) with an organic amine OA to form an organic amine salt thereof, a compound of formula II.
In one embodiment, the organic amine salt of lifitegrast, the compound of formula II, is treated with an acid to form lifitegrast, the compound of formula I.
In one embodiment, the acid may be an inorganic acid or an organic acid.
In one embodiment, the inorganic acid may be selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the like.
In one embodiment, the organic acid may be selected from the group consisting of acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
In one embodiment, the present invention provides a process for lifitegrast, a compound of formula I, in a chiral purity of at least 99% and wherein the level of R isomer of lifitegrast is less than 1% as determined by HPLC.
In one embodiment, the present invention provides a process for lifitegrast, a compound of formula I, in a chiral purity of at least 99% and wherein corresponding R isomer of lifitegrast is not detected, as determined by HPLC.
In one embodiment, the present invention provides a process wherein lifitegrast, a compound of formula I, is obtained in a chemical purity of at least 99% and wherein the level of one or more compounds of formula A, B, C, D or E is less than 0.15% w/w relative to the amount of lifitegrast as determined by HPLC,
A B
C D
E.
In another embodiment, the present invention provides a process wherein lifitegrast, a compound of formula I, is obtained in a chemical purity of at least 99% and wherein the level of one or more compounds of formula F, G, IIIA or VIII is less than 0.15% w/w relative to the amount of lifitegrast as determined by HPLC,
F G

IIIA VIII.
In one embodiment, the present invention provides compound of formula A, B, C, D and E and a process for preparation thereof.
The present invention provides lifitigrast obtained by above process, as analyzed by chemical purity using high performance liquid chromatography (HPLC) with the conditions described below: Reagents and Solvents: O-Phosphoric acid (AR grade, Merck), Acetonitrile (Gradient grade, Rankem), Methanol (HPLC grade, Rankem), Water (Milli Q or equivalent); Chromatographic Conditions: Apparatus: A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software; Column: Inertsil ODS 3V, 250 x 4.6mm, 5µ; Column temperature: 50°C; Sample Cooler temperature: 25°C; Mobile Phase A: Buffer; Mobile Phase B: Acetonitrile; Buffer: 0.1% O-Phosphoric acid in water
Time (min.) % Mobile Phase A % Mobile Phase B
0.01 85 15
15 70 30
60 55 45
70 25 75
85 25 75
88 85 15
95 85 15
Diluent: Water : Methanol (80:20, v/v); Flow Rate: 1.0mL/minute; Detection: UV 210nm; Injection Volume: 50µL; Run time: 95minutes; Needle wash: Water: Methanol (20:80 v/v)
The retention time of lifitegrast is about 41.0 minutes under these conditions. Relative retention time for compound of formula A is about 0.82, compound of formula D is about 1.54, compound of formula E is about 1.34, compound of formula F is about 0.13, compound of formula G is about 0.45, compound of formula IIIA is about 1.72 and compound of formula V is about 0.53 with respect to lifitegrast.
In one embodiment, the present invention provides a process for the preparation of lifitegrast comprising:
(a) providing a solution of lifitegrast, prepared by the process as defined above, in a solvent; and
(b) isolating lifitegrast by (i) removing the solvent from the solution obtained in (a); or (ii) combining the solution obtained in (a) with an antisolvent followed by optional cooling; or (iii) slurring the compound obtained from (b)(i); or (iv) cooling the solution obtained in (a); wherein the lifitegrast obtained is in amorphous form.
In one embodiment, providing a solution of lifitegrast in a solvent in (a) comprises a solution obtained from reaction mixture in the final stage of process for preparation of lifitegrast.
In one embodiment, providing a solution of lifitegrast in a solvent in (a) comprises a solution obtained after dissolving lifitegrast in a solvent.
Solvent used in (a) includes, but is not limited to esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, tert-butyl acetate and the like; haloalkanes such as methylene dichloride, ethylene dichloride, chloroform and the like; acyclic ethers such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tert-butyl ether, and the like; cyclic ethers such as tetrahydrofuran, dioxane; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; aliphatic hydrocarbons such as hexane, heptane, cyclohexane and the like; aromatic hydrocarbons such as toluene, xylene, chlorobenzene and the like; nitriles such as acetonitrile, propanenitrile and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water; or mixtures thereof.
In one embodiment, the solvent may be selected from the group consisting of esters, haloalkanes, alcohols, ketones, cyclic ethers, nitriles, dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; and mixtures thereof. Preferably the solvent selected is ethyl acetate.
Removal of solvent in (b)(i) may be carried out by solvent distillation, concentration, spray drying, fluid bed drying, lyophilization, flash drying, spin flash drying, or thin-film drying.
In one embodiment, removal of solvent in (b)(i) may be carried out by solvent distillation, preferably under vacuum.
In one embodiment, removal of solvent in (b)(i) may be carried out by spray drying.
In one embodiment, the spray drying is performed at a temperature of about 50-75°C.
Antisolvent used in (b)(ii) is a solvent which on addition to a solution of lifitegrast in (a) causes precipitation of lifitegrast owing to insolubility of lifitegrast in the solvent system generated.
In one embodiment, the antisolvent used in b(ii) may include an acyclic ether such as diethyl ether, dimethyl ether, ethyl methyl ether, diisopropyl ether, methyl tert-butyl ether, and the like; an aliphatic hydrocarbon such as hexane, heptane, cyclohexane and the like; water; or mixtures thereof.
In one embodiment, the antisolvent used in b(ii) may be diisopropyl ether.
In one embodiment, the antisolvent used in b(ii) may be n-hexane, n-heptane or cyclohexane.
In one embodiment, the antisolvent used in b(ii) may be water.
In one embodiment, the present invention provides a process for the preparation of amorphous form of lifitegrast comprising:
(a) providing a solution of lifitegrast, prepared by the process as defined above, in a solvent; and
(b) isolating the amorphous form of lifitegrast by combining the solution obtained in (a) with an antisolvent followed by optional cooling.
In one embodiment, the present invention provides a process for preparation of amorphous lifitegrast wherein the solvent used in (a) is ethyl acetate and the antisolvent used in (b) is cyclohexane.
After the addition of the antisolvent as in b(ii), optional cooling may be performed to obtain the precipitate.
In one embodiment, the amorphous lifitegrast obtained in (b) may, optionally, be filtered and dried. Drying may be performed at a temperature of about 55°C to about 110°C. Drying may be performed preferably in the presence of vacuum.
In one embodiment, the amorphous lifitegrast is obtained in a chiral purity of at least 99% and wherein corresponding R isomer of lifitegrast is less than 1%, as determined by HPLC.
In one embodiment, the amorphous lifitegrast is obtained in a chemical purity of at least 99% and wherein the level of one or more compounds of formula A, B, C, D or E is less than 0.15% w/w relative to the amount of lifitegrast as determined by HPLC.
In one embodiment, the present invention provides lifitegrast benzylamine salt, a compound of formula IIA.
In one embodiment, the present invention provides compound of formula IIA characterized by a proton NMR spectrum having peaks at d 8.11-8.12, 8.04-8.06, 7.71-7.83, 7.62-7.64, 7.43-7.52, 7.3-7.39,7.05, 4.74, 4.41-4.46, 3.95, 3.62, 3.26-3.30, 3.08-3.16, 2.77-2.80.
In one embodiment, the present invention provides compound of formula IIA in crystalline form.
In one embodiment, the present invention provides compound of formula IIA in crystalline form characterized by 2? peaks at 15.0, 19.1, 19.8, 20.6 and 21.1 ± 0.2°.
In one embodiment, the present invention provides a process for the preparation of lifitegrast benzylamine salt, a compound of formula IIA, the process comprising:
(a) reacting lifitegrast with benzylamine in presence of a solvent to form a reaction mixture;
(b) obtaining lifitegrast benzylamine salt from the reaction mixture of step (a); and
(c) isolating the lifitegrast benzylamine salt, the compound of formula IIA.
In (a) of the above process for preparation of lifitegrast benzylamine salt, lifitegrast is reacted with benzylamine in presence of a solvent to form a reaction mixture.
The 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, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
The reaction may be carried out at a temperature of about 25°C to about 100°C. The stirring time may range from about 30 minutes to about 10 hours, or longer.
In (b) of the above process for preparation of lifitegrast benzylamine salt, lifitegrast benzylamine salt is obtained from the reaction mixture of step (a), the process comprising:
(i) cooling and stirring the mixture obtained in (a); or
(ii) removing the solvent from the mixture obtained in (a); or
(iii) treating the mixture of step (a) with an anti-solvent optionally, cooling and stirring the obtained mixture.
In one embodiment, the lifitegrast benzylamine salt is obtained by cooling and stirring the solution of step (a). The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about -20°C to about 30°C.
In one embodiment, the lifitegrast benzylamine salt is obtained by removing the solvent from the solution obtained in (a). 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 one embodiment, the lifitegrast benzylamine salt 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 -10°C to about 120°C.
The anti-solvent is selected such that the lifitegrast benzylamine salt is precipitated out from the solution.
In (c) of the process for the preparation of lifitegrast benzylamine salt, the lifitegrast benzylamine salt 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.
The isolated lifitegrast benzylamine salt may be further dried. The drying may be carried out at temperature from about room temperature to about 100°C with or without vacuum. The drying may be carried out for any desired time until the required product quality is achieved. The drying time may vary from about 1 hour to about 25 hours, or longer.
In one embodiment, the present invention provides a process for the preparation of lifitegrast, a compound of formula I comprising:
(a) reacting crude lifitegrast, with an organic amine OA, to form an organic amine salt thereof, a compound of formula II; and
(b) treating the compound of formula II with an acid to form lifitegrast, a compound of formula I, in a chiral purity of at least 99% and wherein the level of R isomer of lifitegrast is less than 1% as determined by HPLC.
The organic amine, OA is as described supra.
In various embodiment, OA is as defined above.
In one embodiment, the organic amine is benzylamine.
In one embodiment the “crude lifitegrast” means lifitegrast having a chemical purity of 50-99.5% as determined by HPLC.
In one embodiment the “crude lifitegrast” means lifitegrast having a chemical purity of 80-95% as determined by HPLC.
In one embodiment, the crude lifitegrast obtained from an earlier reaction may be present in the filtrate and used for reaction with organic amine, without isolating it from the filtrate.
In one embodiment, the crude lifitegrast obtained from an earlier reaction and present in the filtrate, may be isolated in a solid form or as a residue by removal of the solvent by evaporation or distillation and then reacted with the organic amine.
In one embodiment, the reaction of crude lifitegrast with organic amine is carried out in an organic solvent.
In one embodiment, the organic amine salt, a compound of formula II is separated from the reaction mass by filtration and if required subjected to purification by recrystallization.
The recrystallization may be carried out as discussed supra.
In one embodiment, the organic amine salt compound of formula II is treated with an acid selected from an inorganic acid or an organic acid, to form lifitegrast.
The inorganic acid and organic acid may be selected as discussed supra.
In one embodiment, the present invention provides a process for lifitegrast, a compound of formula I, in a chiral purity of at least 99% and wherein the level of R isomer of lifitegrast is less than 1% as determined by HPLC.
In one embodiment, the present invention provides a process for lifitegrast, a compound of formula I, in a chiral purity of at least 99% and wherein corresponding R isomer of lifitegrast is not detected, as determined by HPLC.
In one embodiment, the present invention provides a process for the preparation of lifitegrast, a compound of formula I comprising:
(a) reacting crude lifitegrast, with an organic amine OA, of formula NR1R2R3, wherein R1 is H, R2 is H, R3 is C1-C6 alkyl group substituted with a phenyl group to form an organic amine salt thereof, a compound of formula II; and
(b) treating the compound of formula II with an acid to form lifitegrast, a compound of formula I, in a chiral purity of at least 99% and wherein the level of R isomer of lifitegrast is less than 1% as determined by HPLC.
In one embodiment, the present invention provides a process for lifitegrast, wherein the compound of formula II is lifitegrast benzylamine salt, a compound of formula IIA.
In one embodiment, the present invention provides a process for the preparation of crude lifitegrast, comprising deprotecting a compound of formula III, wherein R is selected from C1-C6 alkyl optionally substituted with C6-C18 aryl and wherein the aryl group may be optionally substituted with one or more substituents selected from the group consisting of nitro, cyano, amino, halogen, hydroxyl, C1-C6 alkoxy and C1-C6 alkyl.
In one embodiment, in compound of formula III, when R is C1-C6 alkyl group, the deprotection is carried out by acid or base hydrolysis.
In one embodiment, the acid hydrolysis may be carried out by using hydrochloric acid, sulfuric acid and the like.
In one embodiment, the base hydrolysis may be carried out using sodium hydroxide, potassium hydroxide and lithium hydroxide or by using carbonates or bicarbonates of alkali metal or alkaline earth metals.
In one embodiment, in compound of formula III, when R is C1-C6 alkyl group substituted with C6-C18 aryl, the deprotection is carried out by acid or base hydrolysis or by hydrogenolysis.
The hydrogenolysis of compound of formula III may be carried out using metal catalysts such as platinum, palladium, nickel, rhodium or ruthenium supported on solid supports like calcium carbonate, alumina, barium sulfate, silica or activated charcoal carbon.
In one embodiment, the hydrogenolysis catalyst may be palladium/carbon.
The hydrogenolysis of compound of formula III may be carried out in the presence of hydrogen or hydrogen transfer reagents selected from formic acid, salts of formic acid, phosphonic acid, triethylsilane, hydrazine, where hydrogen is preferred.
In one embodiment, formic acid and triethylamine are used in the hydrogenolysis step.
In one embodiment, in compound of formula III, when R is C1-C6 alkyl, or C1-C6 alkyl group substituted with C6-C18 aryl, the deprotection is carried out by subjecting the compound of formula III to treatment with a Lewis acid.
In one embodiment, when R is C1-C6 alkyl optionally substituted with C6-C18 aryl, the deprotection is carried out by subjecting the compound of formula III to non-hydrolytic treatment with a Lewis acid.
The term “non-hydrolytic cleavage” is as defined supra.
In one embodiment, the Lewis acid may be selected from the group as discussed supra.
The deprotection reaction may be carried out in the presence of an aprotic solvent. The aprotic solvent is as discussed supra.
In one embodiment, the deprotection is carried out at room temperature to the reflux temperature of the solvent.
In one embodiment, the present invention provides a process for the preparation of lifitegrast comprising:
(a) providing a solution of lifitegrast, prepared by the process as defined above, in a solvent; and
(b) isolating lifitegrast by (i) removing the solvent from the solution obtained in (a); or (ii) combining the solution obtained in (a) with an antisolvent followed by optional cooling; or (iii) slurring the compound obtained from (b)(i); or (iv) cooling the solution obtained in (a); wherein the lifitegrast obtained is in amorphous form.
The steps (a) and (b) are as discussed supra.
In one embodiment, the present invention provides a process for preparation of amorphous lifitegrast wherein the solvent used in (a) is ethyl acetate and the antisolvent used in (b) is cyclohexane.
In one embodiment, the present invention provides use of lifitegrast benzylamine salt, compound of formula IIA, in the preparation of lifitegrast.
In another embodiment, the present invention provides use of lifitegrast benzylamine salt, compound of formula IIA, in the preparation of amorphous lifitegrast.
In one embodiment, the present invention provides a process for lifitegrast, wherein lifitegrast obtained has reduced levels of chemical catalyst as an impurity compared to lifitegrast made using palladium, platinum, or nickel as a catalyst to remove an ester group to yield the carboxylic acid. In another embodiment, the present invention provides a process for lifitegrast, wherein the level of chemical catalyst such as palladium, platinum, or nickel is less than 100 ppm, preferably less than 50 ppm, more preferably less than 1 ppm. In another embodiment, the present invention provides a process for lifitegrast, wherein the lifitegrast obtained is essentially free of chemical catalyst such as palladium, platinum, or nickel.
In one embodiment, the present invention provides a process for the preparation of compound of formula IIIA, by condensing a compound of formula IV or acid addition salt thereof with 1-benzofuran-6-carboxylic acid, a compound of formula VIII or an activated derivative thereof,
IV VIII.
In one embodiment, the compound of formula IV is reacted with 1-benzofuran-6-carboxylic acid in the presence of a coupling agent, a solvent and optionally a catalyst to obtain a compound of formula IIIA.
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 catalyst may be selected from the group consisting of HOBT [1-hydroxybenzotriazole], HOAt [1-hydroxyazatriazole], DMAP [4-(N,N-dimethylamino)pyridine], DIPEA [N,N-Diisopropylethylamine] and HOPO [2-hydroxypyridine-N-oxide].
In one embodiment, the compound of formula IV is obtained by deprotecting a compound of formula V
V
In one embodiment, the compound of formula V may be obtained by coupling a compound of formula VI or acid addition salt thereof with a compound of formula VII.
VI VII
The coupling reaction may be carried out as discussed supra.
HPLC method
High performance liquid chromatography (HPLC) was performed with the conditions described below for detecting stereochemical purity:
Column: Chiralpak AD-H, 250 X 4.6mm, 5µ, Make: Daicel, Column temperature: 35°C, Sample cooler temperature: 15ºC, Mobile phase: n-Hexane: Isopropyl alcohol (500: 500 v/v) add 1.0ml Trifluoroacetic acid and mix well, Diluent: Ethanol: Isopropyl alcohol (100: 900 v/v) add 1.0ml Trifluoroacetic acid and mix well; Flow Rate: 1.0 mL/minute, Detection wavelength: UV 220nm, Injection volume: 20 µL.
Instrumental Settings
A. Proton NMR spectra were recorded in CDCl3 and DMSO-d6 using NMR instrument- Varian 300 MHZ.
B. XRPD: The measurements were performed on Philips X-Ray Diffractometer model XPERT-PRO (PANalytical) Detector: X’celerator [1] using Cu lamp with type and wavelength of the X-ray radiation: K-a1 1.54060[Å], K-a2 1.5444[Å]
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 as defined in the features and advantages.
EXAMPLES
Example 1: Preparation of Lifitegrast benzyl amine salt compound of formula IIA
A solution of lithium hydroxide monohydrate (6.2g) in 240mL of water was added slowly to an acetone solution of compound IIIA (80g) at about 0 to -5°C. The reaction mass was maintained at 0 to -5°C for 1h. The reaction mass was diluted with water and ethyl acetate, stirred and layers were separated. The aqueous layer was extracted with ethyl acetate. Ethyl acetate was added to the aqueous layer, acidified with dilute hydrochloric acid to a pH of about 2 and layers were separated. The aqueous layer was further extracted with ethyl acetate. The combined organic layer was washed with water and concentrated under vacuum to give the foamy solid (62g). The solid was dissolved in ethyl acetate and isopropanol, and heated to 70-75°C and benzyl amine (10.8g) was added and stirred at 70-75°C for 1h. The reaction mass was then cooled to room temperature, stirred for 5-6 hours and the precipitated solid was filtered. The solid was dried in an air oven to obtain crude benzyl amine salt of lifitegrast (62g), which was crystallized from aqueous ethanol to obtain pure compound of Formula IIA. Yield: 45g; HPLC purity: 98.5%; chiral purity: 100%
XRD peaks of Lifitegrast benzyl amine salt
Pos. [o2?] Rel. Int. [%] Pos. [o2?] Rel. Int. [%] Pos. [o2?] Rel. Int. [%] Pos. [o2?] Rel. Int. [%]
2.25 l.61 17.44 29.27 24.36 34.58 36.35 8.94
8.78 29.38 19.10 100.00 25.26 46.10 38.80 6.12
9.99 29.71 19.80 91.05 26.64 16.65 41.10 3.41
11.03 6.41 20.60 64.03 28.76 23.98 43.35 6.20
14.31 13.44 21.10 79.82 30.51 31.20 44.25 4.41
15.00 56.53 21.97 30.57 32.08 8.93 45.51 4.99
15.63 27.78 22.33 37.12 33.60 19.15 48.59 4.26
16.51 5.58 23.70 93.74 35.55 7.14

Example 2: Preparation of amorphous Lifitegrast
The pure benzyl amine salt of lifitegrast was added to ethyl acetate and water. The reaction mass acidified with dilute hydrochloric acid to a pH of about 2 and stirred for 30 minutes. The layers were separated and aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and concentrated under vacuum to give a foamy solid which was dissolved in ethyl acetate. The solution was slowly added to cyclohexane at room temperature and stirred for 2-3 hours. The reaction mass was filtered and solid was dried in air oven at about 40-45°C. Yield: 45 gm; HPLC Purity: 99.7%; Chiral purity: 100%, (R-isomer Not Detected).
Example 3: Preparation of amorphous lifitegrast from benzyl amine salt of (2S)-2-[[2-(1-benzofuran-6-carbonyl)-5,7-dichloro-3,4-dihydro-1H-isoquinoline-6-carbonyl]amino]-3-(3-methylsulfonylphenyl)propanoic acid
The pure benzyl amine salt of lifitegrast (55 gm) was added to ethyl acetate and water under stirring. The reaction mass was acidified with dilute hydrochloric acid to a pH of about 2 and stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and concentrated under vacuum to give a foamy solid which was dissolved in ethyl acetate. The ethyl acetate solution was slowly added to cyclohexane at room temperature, stirred for 2-3 hours and filtered. The solid was dried in an air oven at about 40-45°C to give amorphous lifitegrast. Yield: 45 gm; HPLC purity: 99.7 %; Chiral purity: 100% (R-isomer Not Detected).
Comparative Example 1: Preparation of amorphous Lifitegrast
The aq solution of lithium hydroxide monohydrate (6.2gm) was added slowly to acetone solution of compound IIIA (80gm) at about 0 to -5° C. The reaction mass was maintained at 0 to -5°C for 1 hour. After completion of reaction, reaction mass was diluted with water and ethyl acetate, stirred and layers were separated. The aq. layer was extracted with ethyl acetate. Fresh ethyl acetate was added to the aq layer and acidified with dilute hydrochloric acid to a pH of about 2 and stirred. The layers were separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layers was washed with water and concentrated under vacuum to give the foamy solid (62gm). The foamy solid was taken in a mixture of ethyl acetate and cyclohexane, stirred and filtered. The solid was dried in an air oven at about 40-45°C. Yield: 62 gm (89%); HPLC Purity: 96.0%; Chiral purity: 98.5% (R-isomer around 1.5%).
Comparative Example 2: Preparation of amorphous Lifitegrast
To a solution of compound IIIA (80gm) in ethyl acetate, 10 % palladium on carbon (8 gm) was added and stirred for 1 hour. The reaction mass was kept in hydrogenator at 1-2 kg/cm pressure at about 25-30°C for 1 hour. After completion of reaction, reaction mass was filtered through hyflow bed to remove the catalyst. The organic layer was concentrated under vacuum to afford a foamy solid (62gm). The solid was added to a mixture of ethyl acetate and cyclohexane, stirred and filtered. The solid was dried in an air oven at about 40-45°C. Yield: 62 gm (64%); HPLC Purity: 94.0%; Compound of formula A: 1.0%; Chiral purity; 96.5% (R-isomer around 3.5%).
Example 4: Preparation of benzyl amine salt of lifitegrast
To a solution of benzyl-(2S)-N-[(5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl)carbonyl]-3-(methylsulfonyl)-L-phenylalaninate hydrochloride (100g) and 1-benzofuran-6-carboxylic acid (28.5g) in dichloromethane (2000mL) was added EDC.HCl (48.1g), HOBT (34g) followed by triethylamine (50.8g) under stirring and the reaction mixture was stirred at about room temperature for about 12h. Water was added to the reaction mixture which was stirred for about 30min. The two layers were separated and the organic layer was concentrated under vacuum to give compound of formula IIIA as foamy solid. To the obtained solid, ethyl acetate (2000mL) and lithium iodide (100g) was added. The reaction mixture was stirred for about 24h at about reflux temperature. Water was added to the reaction mixture and the two layers were separated. The organic layer was concentrated under vacuum to give a foamy solid which was dissolved in ethyl acetate and isopropanol. The reaction mixture was heated to about 70°C to about 75°C and benzyl amine (10.8g) was added to it. The reaction mixture was stirred at about the same temperature for about 1h. The reaction mixture was cooled to about room temperature and was stirred for about 6h. The precipitated solid was filtered and dried to give crude benzyl amine salt of lifitegrast (62g). The crude benzyl amine salt of Lifitegrast was crystallized from 5% aqueous ethanol to give pure benzyl amine salt of lifitegrast (45g). HPLC purity: 99.88%; Compound of formula A: Not detected; Chiral purity: 100% (R-isomer not detected)
Example 5: Preparation of amorphous lifitegrast from benzyl amine salt of lifitegrast
A mixture of pure benzyl amine salt of lifitegrast (100g) in ethyl acetate (675mL) and water (450mL) was acidified with dilute hydrochloric acid to a pH of about 2 and was stirred for about 30min. The two layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and concentrated under vacuum to give a foamy solid which was stirred in cyclohexane containing 30% ethyl acetate. The solid obtained was filtered and dried at about 40°C to about 45°C to give amorphous lifitegrast (90g) which was milled in jet mill at about 4-5kg pressure under nitrogen to afford ICH quality amorphous lifitegrast. HPLC purity: 99.8%; Compound of formula A: Not detected; Chiral purity: 100% (R-isomer Not Detected)
Example 6: Preparation of benzyl amine salt of lifitegrast
To a solution of benzyl-(2S)-N-[(5,7-dichloro-1,2,3,4-tetrahydroisoquinolin-6-yl)carbonyl]-3-(methylsulfonyl)-L-phenylalaninate hydrochloride (100g) and 1-benzofuran-6-carboxylic acid (28.5g) in dichloromethane (1000mL) was added EDC.HCl (48.1g), HOBT (34g) followed by triethylamine (50.8g) under stirring and the reaction mixture was stirred at room temperature for about 4h. The reaction mas was diluted with dichloromethane, and water was added to the reaction mixture. The reaction mass was stirred for about 15min and the two layers were separated. The organic layer was washed with of 2% aqueous potassium carbonate and then washed with water. The layers were separated and the organic layer was washed with 1% aqueous hydrochloric acid followed by washing with water. The organic layer was treated with charcoal and filtered through hyflow bed. The organic layer was concentrated under vacuum to give compound of formula IIIA as foamy solid (yield: 118g, 100%). 1000 ml ethyl acetate and 110g lithium iodide was added to the concentrated mass. The reaction mixture was stirred for about 24h at about reflux temperature. The reaction mass was cooled to about room temperature and water was added to the reaction mass. The reaction mass was stirred for 15min to get a clear solution. The layers were separated and the aqueous layer was washed with ethyl acetate. Ethyl acetate and tetrahydrofuran were added to the aqueous layer and acidified with 15% hydrochloric acid. The layers were separated and the aqueous layer was extracted with a mixture of ethyl acetate and tetrahydrofuran followed by extraction with ethyl acetate. The combined organic layer was washed with 4% aqueous sodium metabisulphite solution followed by washing with water. The organic layer was filtered through hyflow bed and concentrated under vacuum to give a foamy solid (yield: 100g, 97%; HPLC purity: 99.0%; R-isomer: 1.2%). The solid was dissolved in ethyl acetate and isopropyl alcohol and benzylamine (21.5g) was added to the reaction mass. The reaction mixture was stirred at ambient temperature for about 8h. The precipitated solid was filtered and dried to give benzylamine salt of lifitegrast (90g). The benzyl amine salt of Lifitegrast was crystallized from aqueous ethanol to give benzylamine salt of lifitegrast (80g). HPLC purity: 99.88%; Chiral purity: 100% (R-isomer not detected); Compound of formula A: Not detected; Compound of formula B: < 0.05%; Compound of formula C: < 0.01%; Compound of formula D: < 0.03%; Compound of formula D: < 0.03%
Example 7: Preparation of amorphous lifitegrast from benzyl amine salt of lifitegrast
A mixture of pure benzyl amine salt of lifitegrast (100g) in dichloromethane (1500mL) and water (1000mL) was acidified with dilute hydrochloric acid to a pH of about 2 and was stirred for about 30min. The two layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water and concentrated under vacuum to give a foamy solid which was stirred in cyclohexane containing ethyl acetate. The solid obtained was filtered and dried at about 40°C to about 45°C to give amorphous lifitegrast (90g) which was milled in jet mill at about 4-5 kg pressure under nitrogen to afford ICH quality amorphous lifitegrast. HPLC purity: 99.8%; Chiral purity: 100% (R-isomer Not Detected); Compound of formula A: Not detected; Compound of formula B: < 0.05%; Compound of formula C: < 0.01%; Compound of formula D: < 0.03%; Compound of formula D: < 0.03%
,CLAIMS:WE CLAIM
1. A process for the preparation of lifitegrast, a compound of formula I, the process comprising:

I III
(a) deprotecting a compound of formula III, wherein R is selected from C1-C6 alkyl optionally substituted with C6-C18 aryl, and wherein the aryl group may be optionally substituted with one or more substituents selected from the group consisting of nitro, cyano, amino, halogen, hydroxyl, C1-C6 alkoxy and C1-C6 alkyl;
wherein the deprotection is carried out by subjecting the compound of formula III to treatment with a Lewis acid selected from the group consisting of lithium iodide, magnesium iodide, trimethylsilyl iodide, aluminium triiodide, and mixtures thereof, to obtain lifitegrast; and
(b) optionally, reacting the lifitegrast obtained in step (a) with an organic amine OA to form an organic amine salt thereof, a compound of formula II,
II.
2. The process as claimed in claim 1, wherein the lifitegrast obtained in step (a) is in-situ and carried forward to step (b).
3. The process as claimed in claim 1, further comprising reacting the organic amine salt of lifitegrast, the compound of formula II, with an acid to form lifitegrast, the compound of formula I.
4. The process as claimed in claim 3, wherein the lifitegrast is obtained in a chiral purity of at least 99% and the level of R isomer of lifitegrast is less than 1% as determined by HPLC; and wherein the lifitegrast is obtained in a chemical purity of at least 99% and the level of one or more compounds of formula A, B, C, D or E is less than 0.15% w/w, relative to the amount of lifitegrast as determined by HPLC,
A B
C D
E.
5. The process for the preparation of lifitegrast comprising:
(a) providing a solution of lifitegrast, prepared by the process as claimed in claim 10, in a solvent; and
(b) isolating lifitegrast by (i) removing the solvent from the solution obtained in (a); or (ii) combining the solution obtained in (a) with an antisolvent followed by optional cooling; or (iii) slurring the compound obtained from (b)(i); or (iv) cooling the solution obtained in (a); wherein the lifitegrast obtained is in amorphous form.
6. Lifitegrast benzylamine salt, a compound of formula IIA,
IIA.
7. A process for the preparation of lifitegrast benzylamine salt, a compound of formula IIA, the process comprising:
(a) reacting lifitegrast with benzylamine in presence of a solvent to form a reaction mixture;
(b) obtaining lifitegrast benzylamine salt from the reaction mixture of step (a); and
(c) isolating the lifitegrast benzylamine salt, the compound of formula IIA.
8. A process for the preparation of lifitegrast, a compound of formula I comprising:
(a) reacting crude lifitegrast, with an organic amine OA, to form an organic amine salt thereof, a compound of formula II; and
(b) treating the compound of formula II with an acid to form lifitegrast, a compound of formula I, in a chiral purity of at least 99% and wherein the level of R isomer of lifitegrast is less than 1% as determined by HPLC.
9. The process as claimed in claim 8, wherein the crude lifitegrast is prepared by a process comprising deprotecting a compound of formula III, wherein R is selected from C1-C6 alkyl optionally substituted with C6-C18 aryl, and wherein the aryl group may be optionally substituted with one or more substituents selected from the group consisting of nitro, cyano, amino, halogen, hydroxyl, C1-C6 alkoxy and C1-C6 alkyl,
III
wherein the deprotection is carried out by acid hydrolysis or by base hydrolysis or by hydrogenolysis or by subjecting the compound of formula III to treatment with a Lewis acid.
10. The process for the preparation of lifitegrast comprising:
(a) providing a solution of lifitegrast, prepared by the process as claimed in claim 8, in a solvent; and
(b) isolating lifitegrast by (i) removing the solvent from the solution obtained in (a); or (ii) combining the solution obtained in (a) with an antisolvent followed by optional cooling; or (iii) slurring the compound obtained from (b)(i); or (iv) cooling the solution obtained in (a); wherein the lifitegrast obtained is in amorphous form.
Dated this 12th day of September, 2018
(Signed)
Dr. Madhavi Karnik
Senior General Manager-IPM
Glenmark Pharmaceuticals Limited