DESC:FIELD OF THE INVENTION

The present invention relates to a novel process for preparation of Lifitegrast (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-methylsulfonyl) phenyl) propanoic acid of formula I.

BACKGROUND OF THE INVENTION

Lifitegrast 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. Lifitegrast has been found to be an effective inhibitor of Lymphocyte Function-Associated Antigen-1 (LFA-1) interactions with the family of Intercellular Adhesion Molecules (ICAM), and has desirable pharmacokinetic properties, including rapid systemic clearance.

The present invention is directed to provide novel process for the preparation of (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3-methylsulfonyl) phenyl)propanoic acid of formula I which includes mild reaction conditions, simple operation, less expensive cost effective process.

SUMMARY OF THE INVENTION

A primary object of the present invention is to provide an novel process for the preparation of (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3-methylsulfonyl) phenyl)propanoic acid of formula I (Lifitegrast) and pharmaceutically acceptable salts thereof.

An object of the present invention is to provide novel process for the preparation of (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3-methylsulfonyl) phenyl)propanoic acid of formula I comprising steps of:

a) reaction of (S)-2-amino-3-[3-( methylsulfonyl)phenyl]propan-1-ol of formula (VII) with 2-(1-benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid of formula (III) to obtain (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3- methylsulfonyl) phenyl) propanol compound of formula (VI);

b) oxidation of compound of formula (VI) to obtain (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3-methylsulfonyl) phenyl) propanoic acid of formula I;

An object of the present invention is to provide novel process for the preparation of (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3-methylsulfonyl) phenyl)propanoic acid of formula I comprising steps of:
a) reaction of (S)-2-amino-3-[3-(methylsulfanyl)phenyl]propan-1-ol of formula (II) with 2-(1-benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid of formula (III) to obtain (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3- methylsulfanyl) phenyl) propanol compound of formula (IV);

b) oxidation of compound of formula (IV) to obtain (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3-methylsulfonyl) phenyl) propanoic acid of formula I (either in a single step or in a series of steps);

An object of the present invention is to provide novel compound (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3- methylsulfanyl) phenyl) propanol compound of formula (IV) for the preparation of Lifitegrast

An object of the present invention is to provide novel compound (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3- methylsulfanyl) phenyl) propanoic acid compound of formula (V) for the preparation of Lifitegrast

An object of the present invention is to provide novel compound (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3-methylsulfonyl) phenyl) propanol compound of formula (VI) for the preparation of Lifitegrast

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an novel process for the preparation of (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3-methylsulfonyl) phenyl)propanoic acid of formula I (Lifitegrast) and pharmaceutically acceptable salts thereof.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are suitable for pharmaceutical use, preferably for use in the tissues of humans and lower animals without undue irritation, allergic response and the like. Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. For example, S. M. Berge, et al., describe pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below. For example, a free base function can be reacted with a suitable acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e. g. sodium or potassium salts; and alkaline earth metal salts, e. g. calcium or magnesium salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed by direct reaction with the drug carboxylic acid or by using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, sulfonate and aryl sulfonate.

In one embodiment the present invention provides a novel process for the preparation of (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3-methylsulfonyl) phenyl)propanoic acid of formula I comprising steps of:
a) reaction of (S)-2-amino-3-[3-(methylsulfanyl)phenyl]propan-1-ol of formula (II) with 2-(1-benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid of formula (III) to obtain (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3- methylsulfanyl) phenyl) propanol compound of formula (IV);

b) oxidation of compound of formula (IV) to obtain (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3-methylsulfonyl) phenyl) propanoic acid of formula I;

In a preferred process according to the invention, (S)-2-amino-3-[3-(methylsulfanyl)phenyl]propan-1-ol of formula (II) with 2-(1-benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid of formula (III) wherein approaches to amide bond formation with a suitable amide coupling reagents. The suitable amide coupling reagents are selected from the Carbodiimides such as dicyclohexylcarbodiimide (DCC); however, these reagents need to be used in conjunction with additives such as 1-hydroxy-1H-benzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt).

In a preferred process according to the invention, the oxidation process reaction may include first oxidation of alcohol group with oxidizing agent to obtain compound of formula V and further oxidation of sulfide group with oxidizing agent to obtain compound of formula I or first oxidation of sulfide group with oxidizing agent to obtain compound of formula VI and further oxidation of alcohol group with oxidizing agent to obtain compound of formula I, the process is represented by Scheme I

The above process is represented stepwise as shown below:
Scheme II

In another embodiment the present invention provides a novel process for the preparation of (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3-methylsulfonyl) phenyl)propanoic acid of formula I comprising steps of:
a) reaction of (S)-2-amino-3-[3-( methylsulfonyl)phenyl]propan-1-ol of formula (VII) with 2-(1-benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid of formula (III) to obtain (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3- methylsulfonyl) phenyl) propanol compound of formula (VI);

b) oxidation of compound of formula (VI) to obtain (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3-methylsulfonyl) phenyl) propanoic acid of formula I;

In various embodiments, the solvent is an aprotic solvent, a protic solvent, a polar solvent, a non-polar solvent, an ionic solvent. Suitable solvent is selected from but not limited to dioxane, tetrahydrofuran, acetone, hexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, n-butanol, isopropanol, n-propanol, ethanol, methanol, water, water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof. Polar aprotic solvents such as acetone, Dimethylformamide (DMF), acetonitrile, Dimethyl sulfoxide (DMSO), sulfolane; alcohols such as methanol, ethanol, propanol, butanol; chloro solvents like methylene chloride, Methylene dichloride (MDC), chloroform, monochlorobenzene, Ethylene Dichloride (EDC), ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane, and combinations thereof.

In a preferred process according to the invention, (S)-2-amino-3-[3-( methylsulfonyl)phenyl]propan-1-ol of formula (VII) with 2-(1-benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid of formula (III) to obtain (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3- methylsulfonyl) phenyl) propanol compound of formula (VI) wherein approaches to amide bond formation with a suitable amide coupling reagents. The suitable amide coupling reagents are selected from the Carbodiimides such as dicyclohexylcarbodiimide (DCC) are; however, these reagents need to be used in conjunction with additives such as 1-hydroxy-1H-benzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt).

In a preferred process according to the invention, the oxidation process reaction may include oxidation of alcohol group with oxidizing agent to obtain compound of formula I.

The above process is represented stepwise as shown below:
Scheme III

The process of the invention is illustrated with reference to the following Examples and is not intended to limit the scope of the invention. Any permutations and modifications in the process are possible keeping in mind the scope of the invention.

Example 1:
Preparation of 2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline -6-carboxylic acid:

N,N-Dicyclohexyl carbodiimide (14.0 g, 67.84 mmol) was added slowly to a solution of benzofuran-6-carboxylic acid (10.0 g, 61.67 mmol) and N-Hydroxy succinamide (7.8 g, 67.84 mmol) in N,N-Dimethyl formamide (80.0 mL) at room temperature. Reaction mixture was stirred at this temperature for 6 hours. A solution of 5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (14.42 g, 58.59 mmol) in N,N-Dimethyl formamide (20.0 mL) was added followed by DIPEA (1.1 mL, 6.16 mmol) and stirring continued for 15 hours. After completion of reaction (monitored by TLC), saturated sodium bicarbonate solution (400 ml) was added to reaction mixture and the product was extracted with ethyl acetate (2x 200 mL). The combined organic layers were washed with water (3 x 200 mL), brine (200 mL) and dried over anhydrous sodium sulphate, filtered and solvent removed under reduced pressure at 45°C. The resulting crude was purified by column chromatography over silica gel, using CH2Cl2:MeOH (95:5), yielding 2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid as pale yellow semisolid (12.0 g, 50% yield). Purity by HPLC: 90 %.

Example 2:
Preparation of (S)-2-(benzofuran-6-carbonyl)-5,7-dichloro-N-(1-hydroxy-3 -(3-(methylthio)phenyl)propan-2-yl)-1,2,3,4-tetrahydroisoquinoline -6-carboxamide:
N,N-Diisopropylethyl amine (13.4 mL, 76.88 mmol) was added to a solution of 2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (10.0 g, 25.62 mmol) and HBTU (14.58 g, 38.44 mmol) in tetrahydrofuran (80.0 mL) at room temperature. After stirring the reaction mixture for 1 hour, a solution of (S)-2-amino-3-(3-(methylthio)phenyl)propan-1-ol (5.05 g, 25.62 mmol) in tetrahydrofuran (20.0 mL) was added and stirring continued for 6 hours. After completion of reaction (monitored by TLC), saturated sodium bicarbonate solution (100 mL) was added to reaction mixture and product was extracted with ethyl acetate (100 mL). The resulting organic layer washed with water (50 mL), Brine (50 mL) and dried over sodium sulphate, filtered and solvent removed under reduced pressure at 45°C. The resulting crude product was purified by column chromatography over silica gel, using CH2Cl2:MeOH (95:5), furnishing pure (S)-2-(benzofuran-6-carbonyl)-5,7-dichloro-N-(1-hydroxy -3- (3- (methylthio) phenyl)propan-2-yl) -1,2,3,4-tetrahydroisoquinoline -6-carboxamide as a pale yellow oil (7.5 g, 51% yield). Purity by HPLC: 90 %.

Example 3:
Preparation of (S)-2-(benzofuran-6-carbonyl)-5,7-dichloro-N-(1-hydroxy-3-(3-(methylsulfonyl)phenyl)propan-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide:

Oxone (1.78 g, 5.79 mmol) was added slowly to a solution of 2-(benzofuran -6-carbonyl)-5,7-dichloro-N-(1-hydroxy-3-(3-(methylthio) phenyl) propan-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (1.2 g, 2.11 mmol) in methanol (24 mL) and water (2.4 mL) at room temperature. Stirring was continued at this temperature for 15 hours. After completion of reaction (monitored by TLC), water (100 mL) was added to reaction mixture and the product was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine (75 mL), dried over sodium sulphate, filtered and solvent removed under reduced pressure, yielding (S)-2-(benzofuran-6-carbonyl) -5,7-dichloro-N-(1-hydroxy-3-(3-(methylsulfonyl) phenyl) propan-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide as off White solid (1.0 g, 78% yield). Purity by HPLC: 82 %.

Example 4:
Preparation of (S)-2-(2-(benzofuran-6-carbonyl) -5,7-dichloro-1,2,3,4-tetrahydro isoquinoline -6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoic acid:

Freshly prepared Jones reagent (2.5 mL) was added slowly to a solution of (S)-2-(benzofuran-6-carbonyl) -5,7-dichloro-N- (1-hydroxy-3-(3-(methylsulfonyl) phenyl) propan-2-yl) -1,2,3,4-tetrahydroisoquinoline-6-carboxamide (1.0 g, 1.66 mmol) in acetone (10.0 mL) at room temperature. After completion of reaction (monitored by TLC), methanol (1.0 mL) was added to reaction mixture and stirred for 30 minutes. Solvent was removed under reduced pressure. The resulting residue was diluted with water (20 mL) and product extracted with ethyl acetate (2 x 40 mL). The combined organic layer dried over sodium sulphate, filtered and solvent removed under reduced pressure. The resulting crude was purified by column chromatography over silica gel, using CH2Cl2:MeOH (95:5), yielding (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline -6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoic acid as a white solid (0.5 g, 50% yield). Purity by HPLC: 95 %.

The above process is represented stepwise as shown below:
Reaction Scheme IV:
,CLAIMS:CLAIMS:

We Claim,

[CLAIM 1]. A novel process for the preparation of Lifitegrast ((S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3-methylsulfonyl) phenyl)propanoic acid) of formula I comprising steps of:
a) reaction of (S)-2-amino-3-[3-( methylsulfonyl)phenyl]propan-1-ol of formula (VII) with 2-(1-benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid of formula (III) in presences of amide coupling reagents to obtain (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3- methylsulfonyl) phenyl) propanol compound of formula (VI);

b) oxidation of compound of formula (VI) to obtain (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3-methylsulfonyl) phenyl) propanoic acid of formula I;

[CLAIM 2]. A novel process for the preparation of Lifitegrast ((S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3-methylsulfonyl) phenyl)propanoic acid) of formula I comprising steps of:
a) reaction of (S)-2-amino-3-[3-(methylsulfanyl)phenyl]propan-1-ol of formula (II) with 2-(1-benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid of formula (III) in presences of amide coupling reagents to obtain (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3- methylsulfanyl) phenyl) propanol compound of formula (IV);

b) oxidation of compound of formula (IV) to obtain (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3-methylsulfonyl) phenyl) propanoic acid of formula I;

[CLAIM 3]. The novel process for the preparation of Lifitegrast as claimed in claim 1 and 2 wherein amide coupling reagents are selected Carbodiimides, dicyclohexylcarbodiimide (DCC), N,N-Diisopropylethyl amine (DIPEA), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 1-hydroxy-1H-benzotriazole (HOBt) and 1-hydroxy-7-azabenzotriazole (HOAt).

[CLAIM 4]. The novel process for the preparation of Lifitegrast as claimed in claim 1 and 2 wherein solvent are selected from dioxane, tetrahydrofuran, acetone, hexane, benzene, toluene, xylene, heptane, cyclohexane, 1,4-dioxane, chloroform, diethyl ether, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, n-butanol, isopropanol, n-propanol, ethanol, methanol, water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, acetone, Dimethylformamide, acetonitrile, Dimethyl sulfoxide, sulfolane methylene chloride, Methylene dichloride, chloroform, monochlorobenzene, ethylene chloride, Ethylene Dichloride; and combinations thereof

[CLAIM 5]. A novel compound (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3- methylsulfanyl) phenyl) propanol compound of formula (IV) for the preparation of Lifitegrast

[CLAIM 6]. A novel compound (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3- methylsulfanyl) phenyl) propanoic acid compound of formula (V) for the preparation of Lifitegrast

[CLAIM 7]. A novel compound (S)-2-(2 -(benzofuran-6-carbonyl) -5,7-dichloro- 1,2,3,4 -tetrahydro isoquinoline -6-carboxamido)-3-(3-methylsulfonyl) phenyl) propanol compound of formula (VI) for the preparation of Lifitegrast

Dated this 26th Day of Dec 2018