WO2025186758A1

WO2025186758A1 - Process for preparing lifitegrast

Info

Publication number: WO2025186758A1
Application number: PCT/IB2025/052432
Authority: WO
Inventors: Mattia STUCCHI; Giacomo Bruno; Davide VITALI
Original assignee: Olon SpA
Current assignee: Olon SpA
Priority date: 2024-03-08
Filing date: 2025-03-06
Publication date: 2025-09-12
Anticipated expiration: 2026-09-08
Also published as: WO2025186758A8

Abstract

Process for preparing lifitegrast comprising : a) reacting the compound of Formula V with a chlorinating agent, in a water-immiscible organic solvent and in the presence of a base to obtain a solution of the compound of Formula V-A; b) reacting the compound of Formula IV with the solution of the compound of Formula V-A obtained in step a) in a biphasic mixture comprising an organic phase and an aqueous phase, in the presence of a base, to obtain a solution of the compound of Formula VI, wherein the compound of Formula VI is dissolved in the organic phase; c) separating the organic phase containing the compound of Formula VI from the aqueous phase of the biphasic mixture obtained in step b); d) distilling the solvent of the organic phase containing the compound of Formula VI obtained in step c) and adding a water-miscible solvent to prepare a solution of the compound of Formula VI; e ) reacting the solution of the compound of Formula VI obtained in step d) with an alkali metal hydroxide in aqueous solution to obtain the compound of Formula I-A; f ) adding an acid to the solution of the compound of Formula I-A obtained in step e ) to obtain the lifitegrast.

Description

PROCESS FOR PREPARING LIFITEGRAST

FIELD OF THE INVENTION

The present invention concerns a process for preparing lifitegrast of Formula I:

PRIOR ART

Lifitegrast is the international non-proprietary name for the compound N-[[2- (6-Benzofuranylcarbonyl)- 5,7-dichloro-l,2,3,4-tetrahydro- 6- isoquinolinyl]carbonyl]-3- (methylsulfonyl)-L- phenylalanine, having Formula I:

Lifitegrast is used for the treatment of keratoconjunctivitis sicca syndrome (KGS) or for the treatment of dry eye disease (DED).

In the international patent application WO2009139817A2 a process for preparing lifitegrast is described according to the following synthesis scheme (Scheme A):

In the first step of this process the activation of the carboxyl necessary for the preparation of the amide is carried out using hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) in the presence of triethylamine (TEA). In the third step, instead, the activation of the carboxyl is carried out using oxalyl chloride in the presence of N,N- diisopropylethylamine (DIPEA). Both HATU and oxalyl chloride are chlorinating agents that require special precautions for use in industrial plants because they are sensitive to moisture and in case of hydrolysis impurities can be formed that are difficult to eliminate and the conversion of the reaction decreases resulting in a lower yield. In addition, in order to use these chlorinating agents it is necessary to add a base such as TEA or DIPEA which functions as an acceptor of the acidity that develops from the condensation reaction. Within the reaction mass there are therefore several by- products that must be eliminated to obtain intermediates with a high degree of purity. In the last step of the process described in WO2009139817A2, the release of the carboxylic acid protecting group of lifitegrast is carried out by palladium-on-carbon (Pd/C) catalysed formic acid hydrogenation in the presence of triethylamine. The use of these reagents results in several impurities being present in the reaction end mass that are difficult to eliminate, such as unreacted formic acid, Pd/C and triethylamine hydrochloride. In the international patent application

WO2014018748A1 several synthesis routes for lifitegrast are reported, including the one reported in the following synthesis scheme (Scheme B):

In the same patent application WO2014018748A1, the compound of Formula IV can also be obtained according to the following synthesis scheme (Scheme C): The synthesis route according to WO2014018748A1 shows numerous problems. In particular, it should be highlighted that the presence of water in the reaction between the acyl chloride of the compound of Formula II and the compound of Formula III (according to step a of Scheme B or according to step a of Scheme C) causes the partial degradation of the chloride itself, leading to a worsening of the purity profile and to a yield loss.

Furthermore, the compound of Formula VI, obtained in step b), is not easily isolatable under the described conditions, filtration is slow and difficult, therefore not manageable on an industrial scale. Difficulties in isolation lead to an ineffective purging of the impurities and the compound of Formula VI has a low purity. This affects the subsequent hydrolysis step (step c) from which a lifitegrast of unsuitable purity for pharmacological use is obtained. The raw product thus obtained must be recrystallised (step d) thus making the process inefficient in terms of time and costs.

The Applicant has posed the problem of finding a process for producing lifitegrast at an industrial level that allows to overcome the problems of the prior art, in particular with regard to the yield and purity of the final product.

SUMMARY OF THE INVENTION

The Applicant has solved the above problem, and others as better illustrated in the following, by means of a simplified process as defined in claim 1, which allows to obtain lifitegrast of high purity, with high process yields and reduced preparation times, such as to make it suitable for an industrial scale implementation.

The present invention therefore concerns a process for preparing lifitegrast of Formula I said process comprising: a) reacting the compound of Formula V with a chlorinating agent, in a water-immiscible organic solvent and in the presence of a base to obtain a solution of the compound of Formula V-A b) reacting the compound of Formula IV with the solution of the compound of Formula V-A obtained in step a) in a biphasic mixture comprising an organic phase and an aqueous phase, in the presence of a base, to obtain a solution of the compound of Formula VI wherein the compound of Formula VI is dissolved in the organic phase; c) separating the organic phase containing the compound of Formula VI from the aqueous phase of the biphasic mixture obtained in step b); d) distilling the solvent of the organic phase containing the compound of Formula VI obtained in step c) and adding a water-miscible solvent to prepare a solution of the compound of Formula VI; e) reacting the solution of the compound of Formula VI obtained in step d) with an alkali metal hydroxide in aqueous solution to obtain a solution of the compound of Formula I-A where M+ is an alkali metal cation; f) adding an acid to the solution of the compound of Formula I-A obtained in step e) to obtain the compound of Formula I.

Advantageously, the organic phase obtained in step c) is previously subjected to washing with an acid solution and subsequently with a basic solution, and then directly subjected to step d) without isolating the product of Formula VI from the organic phase.

The compound of Formula I obtained from the solution of the compound of Formula VI meets the purity characteristics necessary for use in the pharmacological field, without the need for further purifications. Therefore, the process of the present invention represents a simplification with respect to the known processes, so as to make it suitable for an industrial implementation with obvious advantages in terms of time and costs. Further features and advantages of the present invention will be apparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention, in the following description and claims the definitions of numerical ranges comprise the individual values within the range itself and the corresponding extremes, unless otherwise specified.

For the purposes of the present invention, in the following description and claims, the term "comprise" further includes the terms "consisting of" or

"consisting essentially of".

Below is a summary scheme (Scheme 1) of the lifitegrast according to a particular embodiment of the process according to the invention:

With reference to step a) of the process according to the invention, this step refers to the chlorination of the compound of Formula V to obtain the compound of Formula V-A.

According to a preferred aspect, in step a) the chlorinating agent is selected from: thionyl chloride (SOC1₂), phosphorus trichloride (PCI₃), phosphorus pentachloride (PCI₅), oxalyl chloride, more preferably the chlorinating agent is thionyl chloride.

According to another preferred aspect, in step a) the molar ratio between chlorinating agent and the compound of Formula V is between 1.05 and 1.50, more preferably between 1.10 and 1.30.

Preferably, in step a) the water-immiscible organic solvent is selected from: water-immiscible esters, preferably isopropyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate; water- immiscible ketones, preferably methyl ethyl ketone; chlorinated solvents, preferably methylene chloride, chloroform, carbon tetrachloride; water-immiscible ethers, for example t-butyl methyl ether; water- immiscible aromatic hydrocarbons, preferably toluene, xylene, benzene, more preferably toluene; or mixtures thereof.

Preferably, in step a) the ratio (calculated in weight/weight) between the organic solvent and the compound of Formula V is between 1.1 and 4.0, preferably between 1.8 and 4.0.

According to a preferred aspect, in step a) the temperature is between 0°C and 30°C, more preferably between 5°C and 25°C.

According to another preferred aspect of the invention, in step a) the base is selected from: pyridine, N-ethyl-diisopropylamine (DIPEA), hexamethylenediamine (HMDA) and N-methylmorpholine (NMM), or mixtures thereof; preferably the base is NMM.

Preferably, in step a) the molar ratio between the base and the compound of Formula V is between 0.90 and 1.30, more preferably between 0.95 and 1.10.

Preferably, in step a) the reaction time is between 0.5 hours and 5 hours, more preferably between 0.5 and 3 hours.

With reference to step b) of the process according to the invention, said step refers to the condensation between the compound of Formula V-A and the compound of Formula IV.

According to a preferred aspect of the invention, in step b) the molar ratio between the compound of Formula V and the compound of Formula IV is between 1.0 and 1.30, more preferably between 1.0 and 1.15.

According to a preferred aspect of the invention, in step b) the compound of Formula IV is dissolved in a biphasic mixture comprising an aqueous phase and an organic phase obtained with a water-immiscible solvent, in the presence of a base.

Preferably, in step b) the organic phase is obtained using a water-immiscible organic solvent selected from: water-immiscible esters, preferably isopropyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate; water-immiscible ketones, preferably methyl ethyl ketone; chlorinated solvents, preferably methylene chloride, chloroform, carbon tetrachloride; water- immiscible ethers, for example t-butyl methyl ether; water-immiscible aromatic hydrocarbons, preferably toluene, xylene, benzene, more preferably toluene; or mixtures thereof.

Preferably, in step b) the ratio (calculated in weight/weight) between the organic solvent used to prepare the organic phase and the compound of Formula IV is between 1.1 and 5.0, preferably between 1.5 and 5.0.

Preferably, in step b) the ratio (calculated in weight/weight) between the water used to prepare the aqueous phase and the compound of Formula IV is between 0.5 and 3.0, preferably between 0.6 and 2.0.

Preferably, in step b) the base is selected from: pyridine, N-ethyl-diisopropylamine (DIPEA), hexamethylenediamine (HMDA) and N-methylmorpholine (NMM), or mixtures thereof; more preferably the base is NMM.

Preferably, in step b) the molar ratio between the base and the compound of Formula IV is between 1.9 and 3.0, more preferably between 2.0 and 2.8.

Preferably, in step b) the temperature is between 0°C and 30°C, more preferably between 5°C and 25°C.

According to a preferred aspect of the invention, in step b) the organic solution of the compound of Formula V-A prepared in step a) is added to the biphasic mixture containing the compound of Formula IV at a temperature between 0°C and 30°C, preferably between 5°C and 25°C.

Preferably, in step b) the reaction is carried out by stirring for a time between 4 and 10 hours, preferably between 5 and 9 hours, at a temperature between 15°C and 30°C, preferably between 20°C and 25°C.

According to a preferred aspect of the invention, in step b) at the end of the reaction, decolorizing activated carbon, which has the function of clarifying the mixture, and celite, which has the function of assisting the filtration of the activated carbon, are added to the biphasic mixture.

Preferably, the ratio (calculated in weight/weight) between the activated carbon and the compound of Formula IV is between 0.02 w/w and 0.10 w/w, more preferably between 0.03 w/w and 0.08 w/w. Preferably, the ratio (calculated in weight/weight) between the celite and the compound of Formula IV is between 0.02 w/w and 0.10 w/w, more preferably between 0.03 w/w and 0.08 w/w. Preferably, the stirring is maintained in the presence of activated carbon and celite for a time interval between 1 and 5 hours, then the suspended solid is filtered.

With reference to step c) of the process according to the invention, this step refers to the separation of the organic phase containing the compound of Formula VI from the aqueous phase of the biphasic mixture obtained in step b).

According to a preferred aspect of the invention, in step c), after filtration of the biphasic mixture obtained in step b) in order to separate it from the added adsorbent solid, the aqueous phase is separated from the organic phase and sent to disposal.

Preferably, in step c) the organic phase separated from the biphasic mixture obtained in step b) is washed with an acid solution, wherein the acid used is preferably selected from hydrochloric acid, acetic acid, citric acid, or mixtures thereof; more preferably the acid is hydrochloric acid.

Preferably, in step c) the organic phase, after acid washing, is washed with a basic solution, wherein the base used is selected from: alkali metal carbonates, alkali metal hydrogen carbonates, or mixtures thereof; preferably the base is potassium hydrogen carbonate.

Advantageously, the organic phase obtained in step c), previously subjected to washing with an acid solution and subsequently with a basic solution, is used directly in step d) without the need for purification of the product, since the above washings allow to obtain a purity that already meets the quality specifications required for the compound of Formula VI. The process is therefore more efficient in terms of production times and costs.

With reference to step d) of the process according to the invention, said step refers to the distillation of the solvent of step c) and to the preparation of a solution of the compound of Formula VI in a water- miscible solvent.

According to a preferred aspect of the invention, in step d) the organic phase is concentrated under vacuum until reaching a volume in the range between 1.5 v/w and 2.5 v/w, preferably between 1.8 and 2.2 v/w, expressed as a ratio between the volume of the organic phase and the weight of the compound of Formula IV.

Preferably, in step d) the organic phase is concentrated under vacuum maintaining a temperature between 30°C and 60°C, more preferably between 35°C and 50°C.

According to a preferred aspect of the invention, in step d) the water-miscible solvent is selected from: water-miscible ketones, preferably acetone; water- miscible alcohols; water-miscible ethers; water-miscible nitriles, preferably acetonitrile.

In step d), a water-miscible solvent is added to the concentrated organic phase obtained following distillation. The ratio (calculated in weight/weight) between the added solvent and the compound of Formula IV is preferably between 3.0 w/w and 7.0 w/w, more preferably between 4.0 w/w and 6.0 w/w.

Preferably, in step d) the solution thus obtained is again concentrated under vacuum until reaching a volume in the range between 1.5 v/w and 2.5 v/w, more preferably between 1.8 and 2.2 v/w, expressed as a ratio between the volume of the organic phase and the weight of the compound of Formula IV.

Preferably, a temperature between 30°C and 60°C, more preferably between 35°C and 50°C, is maintained during distillation. This further distillation serves to eliminate the last traces of the solvents used in steps a), b) and c).

Preferably, in step d) the ratio (calculated in weight/weight) between the charged water-miscible solvent and the compound of Formula IV is between 1.5 w/w and 6.0 w/w, preferably between 1.8 w/w and 4.0 w/w.

With reference to step e) of the process according to the invention, this step refers to the hydrolysis of the compound of Formula VI to obtain the compound of Formula I-A.

According to a preferred aspect of the invention, in step e) water is added to the solution of the compound of Formula VI obtained in step d). Preferably, the ratio (calculated in weight/weight) between the added water and the compound of Formula IV is between 0.5 w/w and 3.0 w/w, more preferably between 1.0 w/w and 2.0 w/w. Preferably, a phase-transfer catalyst, preferably a quaternary ammonium salt, more preferably tetrabutylammonium hydroxide (TBAH), is added to the solution thus obtained. Preferably, the ratio (calculated in weight/weight) between the phase-transfer catalyst and the compound of Formula IV is between 0.010 w/w and 0.024 w/w, more preferably between 0.014 w/w and 0.020 w/w.

In step e) the base in aqueous solution is an alkali metal hydroxide, preferably it is sodium hydroxide (NaOH).

Preferably, in step e) the ratio (calculated in weight/weight) between the base and the compound of Formula IV is between 0.200 w/w and 0.334 w/w, preferably between 0.240 w/w and 0.300 w/w. According to a preferred aspect of the invention, in step e) the reaction is carried out by stirring for a time between 0.5 hours and 5 hours, preferably between 1 and 4 hours, at a temperature between 15°C and 30°C, preferably between 20°C and 25°C.

With reference to step f) of the process according to the invention, this step refers to the acidification of the compound of Formula I-A to obtain the compound of Formula I.

Preferably, in step f) the acid is selected from halogenidric acids, preferably hydrochloric acid. According to a preferred aspect of the invention, in step f) the pH obtained after acidification is between 1.4 and 2.6, preferably between 1.6 and 2.4. According to a preferred aspect of the invention, in step f), after the addition of the acid, water is added to precipitate the compound of Formula I. Preferably, in step f) the ratio (calculated in weight/weight) between the water added for precipitation and the compound of Formula IV is between 1.50 w/w and 7.5 w/w, preferably between 2.0 w/w and 4.0 w/w.

According to a preferred aspect of the invention, in step f) the water used for the precipitation of the compound of Formula I is added gradually, more preferably in two or more aliquots.

Preferably, in step f) the compound of Formula I is isolated by filtration.

Preferably, in step f) the compound of Formula I, after filtration, is dried at a temperature lower than 80°C, more preferably lower than 70°C.

According to a preferred aspect of the invention, step f) may be followed by a step f’) for purifying the compound of Formula I.

Preferably, in step f’) the compound of Formula I is dissolved in a mixture of water and acetone, in the presence of sodium hydroxide at a temperature lower than 30°C. This temperature allows to prevent thermal degradation of the compound of Formula I. The solution is decolorized with activated carbon and filtered. Hydrochloric acid is added to the clear solution up to a pH between 1.6 and 2.4. The product is precipitated from this solution by addition of water. The compound of Formula I is filtered and dried at a temperature lower than 70°C.

According to a preferred aspect of the invention, the compound of Formula IV can be prepared according to the following synthetic scheme (Scheme 2):

Preferably, the compound of Formula II is reacted with the thionyl chloride in isopropylacetate and in the presence of N-methylmorpholine to obtain the compound of

Formula II-A. Preferably, the compound of Formula II-A is reacted with the compound of Formula III in isopropylacetate and in the presence of N- methylmorpholine to obtain a solution of the compound of Formula IV-A. Preferably, the compound of Formula IV-A is reacted with HC1 in 1,4-dioxane to obtain the compound of Formula IV. Preferably, the compound of Formula IV is isolated by filtration and dried.

The following examples of implementation are provided merely to illustrate the present invention and should not be construed in a sense that would limit the scope of protection defined by the enclosed claims.

LIST OF ABBREVIATIONS

Eq.: equivalents w/w: weight/weight

IPAc: isopropyl acetate

NMM: N-methylmorpholine

MEK: methyl ethyl ketone

HC1: hydrochloric acid

KHCO3: potassium bicarbonate

TBAH: tetrabutylammonium hydroxide

NaOH: sodium hydroxyde

Example 1. Preparation of the compound of Formula I.

The equivalents of the reagents reported in Example 1 were parameterized with respect to the compound of Formula IV, according to the following general formula: Relative ratio of the equivalents of the compound A = (equivalents of the compound A / equivalents of the compound of Formula IV)

By way of example, therefore, the calculation for the compound of Formula V is reported:

- Charged equivalents of the compound of Formula V: 10.5 eq.

- Charged equivalents of the compound of Formula IV: 10.0 eq.

- Relative ratio of the equivalents of the compound of Formula V = (10.5 / 10.0) = 1.05 eq.

The amounts by weight of the solvents reported in Example 1 were parameterized with respect to the compound of Formula IV, according to the following general formula :

Relative ratio by weight of the solvent B = (weight of the solvent B / weight of the compound of Formula IV)

By way of example, therefore, the calculation for a generic solvent B is reported:

- weight of the charged solvent B: 3.5 kg

- weight of the charged compound of Formula IV: 2.0 kg

- Relative ratio by weight of the solvent B = (3.5 / 2.0) = 1.75 w/w.

The end-of-distillation volume reported in Example 1 was parameterized with respect to the compound of Formula IV, according to the following general formula: End-of-distillation volume = (volume of the solution in the reactor / weight of the compound of Formula IV) An example of calculation is reported:

- volume of the solution contained in the reactor: 5.0 It

- weight of the charged compound of Formula IV: 2.0 kg

- End-of-distillation volume = (5.0 / 2.0) = 2.5 v/w. Example 1-A: preparation of the compound of Formula V- A.

The compound of Formula V (1.05 eq., 0.29 w/w) and IPAc (1.50 w/w) was charged into the reactor 1. While maintaining the temperature of about 15°C, 1.26 eq., 0.25 w/w of thionyl chloride were dripped. At the end of the thionyl chloride addition, maintaining the temperature of about 15°C, 1.26 eq., 0.21 w/w of NMM were dripped. Stirring was maintained for at least 30 minutes. End-of-reaction control was performed (compound of Formula V < 0.5%).

Example 1-B: preparation of the solution of the compound of Formula VI.

1.00 eq., 1.00 w/w of the compound of Formula IV, 0.75 w/w of water and 1.85 w/w of MEK were charged into the reactor 2. While maintaining the temperature of 15°C, 2.1 eq., 0.36 w/w of NMM were dripped. While maintaining the temperature of 15°C, the slurry contained in the reactor 1 was transferred into the reactor 2. 0.42 w/w of IPAc was charged into the reactor 1, stirring was started and was transferred into the reactor 2 to wash the transfer lines. Stirring of the reactor 2 was maintained at the temperature of 20°-25 °C for at least 6 hours. End-of-reaction control was performed (compound of Formula IV < 0.5%).

0.04 w/w of Anticromos™ activated carbon and 0.04 w/w of celite were charged into the reactor 2, stirring was maintained for at least 1 hour. The suspended solids were then filtered and the clear biphasic solution was sent to the reactor 3. Stirring was stopped and the lower aqueous phase was separated and sent to disposal. The upper organic phase was washed with 1.5 w/w of 5% aqueous HC1 solution and the lower aqueous phase was separated and sent to disposal. Subsequently, the upper organic phase was washed for 2 times with an aqueous solution of 20% KHCO3 (1.5 w/w for each wash). Purity control of the compound VI in solution (purity of the compound of Formula VI > 95.5%) was performed. If the control had been negative, a further wash would have been performed with 1.5 w/w of a 20% aqueous solution of KHCO3. Example 1-C: preparation of the compound of Formula I.

The washed organic phase was concentrated under vacuum at a temperature of 40°-45 °C until reaching 2 v/w. 5.0 w/w of acetone were charged and the organic phase was again distilled under vacuum at a temperature of 40°-45 °C until reaching 2 v/w. 2.35 w/w of acetone were charged into the reactor and the temperature of the solution was brought to 20°-25 °C. 1.6 w/w of water and 0.017 w/w of 40% aqueous TBAH solution were then charged. Subsequently 0.267 w/w of a 30% aqueous NaOH solution was charged and stirring was maintained for at least 2 hours. End-of-reaction control was performed (compound of Formula VI < 0.15%). A positive analytical control was charged with 33% HC1 until a pH=l.6-2.4, about 0.21 w/w. Precipitation of the product can be triggered with 0.005 w/w of the compound of Formula I. Stirring was maintained for at least 12 hours.

1.25 w/w of water were charged into the reactor and stirring was maintained for at least 6 hours. At the end of the stirring hours a further 1.25 w/w of water was charged and stirring was maintained for at least 6 hours. The suspended solid was filtered and the panel was washed with a mixture of 0.39 w/w of acetone and 0.5 w/w of water and subsequently the panel was washed with 2.0 w/w of water. The solid obtained was dried under vacuum while maintaining the temperature lower than 65 °C. The end- of-drying control was then performed.

A weight yield of 93%, calculated on the weight of the compound of Formula IV, was obtained.

Example 1-C': crystallization of the compound of Formula I.

1.0 w/w of the compound of Formula I (calculated as dry weight), 1.0 w/w of water and 3.2 w/w of acetone were charged into the reactor 1. While maintaining the internal temperature lower than 25 °C, 0.2 w/w of 30% NaOH were charged and the resulting solution was treated with activated carbon. Subsequently, the suspended activated carbon was filtered on a 1.2 micron filter and then on a 0.2 micron filter. The filtered clear solution was sent to the reactor 2 and the lines were washed with 0.5 w/w of a 4:1 w/w acetone-water mixture. While maintaining the temperature of 20°-25 °C, 0.17 w/w of 33% HC1 were charged. The pH control, which must be between 1.6 and 2.4, has been performed. In case of negative control, the pH can be adjusted using NaOH solution or HC1 solution. While maintaining the stirring, the temperature was brought to about 22 °C. Optionally the precipitation can be triggered with 0.005 w/w of the compound of Formula I. Stirring was maintained for at least 12 hours at the temperature of about 20 °C. At the end of the 12 hours, 1.2 v/w of water were charged and stirring was maintained for another 6 hours. At the end of the 6 hours a further 1.2 v/w of water was charged and stirring was maintained for a further 6 hours. The solid was then filtered and the panel was washed with 1.0 v/w of acetone-water 1-1 v/v of mixture. The panel was then washed 3 times with 3 v/w of water. The solid obtained was dried under vacuum while maintaining the temperature lower than 65 °C. The end-of-drying control was then performed. A crystallization weight yield of 88% was obtained.

Example 2. Preparation of the compound of Formula IV.

The equivalents of the reagents reported in Example 2 were parameterized with respect to the compound of Formula III, according to the following general formula: Relative ratio of the equivalents of the compound A = (equivalents of the compound A / equivalents of the compound of Formula III)

By way of example, therefore, the calculation for the compound of Formula II is reported:

- Charged equivalents of the compound of Formula II: 10.25 eq.

- Charged equivalents of the compound of Formula III: 10.00 eq.

- Relative ratio of the equivalents of the compound of Formula II = (10.25 / 10.00) = 1.025 eq.

The amounts by weight of the solvents reported in Example 2 were parameterized with respect to the compound of Formula III, according to the following general formula:

Relative ratio by weight of the solvent B = (weight of the solvent B / weight of the compound of Formula III)

- weight of the charged solvent B: 3.5 kg

- weight of the charged compound of Formula III: 2.0 kg

- Relative ratio by weight of the solvent B = (3.5 / 2.0) = 1.75 w/w

The end-of-distillation volume reported in Example 1 was parameterized with respect to the compound of Formula III, according to the following general formula: end-of-distillation volume = (volume of the solution in the reactor / weight of the compound of Formula III)

An example of calculation is reported:

- volume of the solution contained in the reactor: 5.0 It weight of the charged compound of Formula III: 2.0 kg

- End-of-distillation volume = (5.0 / 2.0) = 2.5 v/w. Example 2-1. Preparation of HC1 solution in 1,4-dioxane.

3.36 w/w of 1,4-dioxane were charged into the reactor 3 and while maintaining the temperature of about 20 °C, HC1 gas was blown into the reactor up to a weight gain of 0.54 w/w (5.6 eq., 14% w/w). Process control was performed for HC1 concentration (HC1 concentration > 13% w/w). In case of negative analytical control the load of HC1 was continued up to the desired value.

Example 2-L: preparation of the compound of Formula II- A.

The compound of Formula II (1.025 eq., 0.96 w/w) and IPAc 5.3 w/w were charged into the reactor 1. While maintaining the temperature of about 15 °C, 1.18 eq., 0.379 w/w of thionyl chloride were dripped. At the end of the thionyl chloride addition, by maintaining the temperature of about 20 °C, 3.38 eq., 0.925 w/w of NMM were dripped. Stirring was maintained for at least 30 minutes. End-of-reaction control was performed (compound of Formula II < 1.0%).

Example 2-M: preparation of the solution of the compound of Formula IV-A.

1.0 eq., 1.0 w/w of the compound of Formula III and 3.1 w/w of IPAc were charged into the reactor 2. While maintaining the temperature of about 15 °C, 2.26 eq., 0.617 of w/w of NMM were dripped. Stirring was maintained until complete dissolution. While maintaining the temperature of about 15 °C, the slurry contained in the reactor 1 was transferred into the reactor 2. Stirring of the reactor 2 was maintained at a temperature of 20 °C for at least 1 hour. End-of-reaction control was performed (compound of Formula III < 0.25%).

3.46 w/w of water were charged into the reactor 2, stirring was maintained for 1 hour. Stirring was stopped and the lower aqueous phase was separated and sent to disposal. The washed organic phase was concentrated under vacuum at a temperature of 40°-45 °C until reaching 5 v/w. Water content control was performed (KF < 0.03% w/w). In case of negative analytical control, 4.35 w/w of IPAc were charged into the reactor and the solvent was distilled under vacuum at a temperature of 40°-45 °C until reaching 5 v/w. With positive analytical control, the concentration phase continued by distilling under vacuum at a temperature of 40°-45 °C until reaching 3 v/w.

Example 2-N. Preparation of the compound of Formula IV.

The temperature of reactor 2 was stabilized at about 20 °C and 6.8 w/w of 1,4-dioxane were charged. While maintaining the temperature of about 20 °C, the solution of HC1 in 1,4-dioxane prepared in Example 2-1 was transferred into the reactor 2 containing the solution of the compound of Formula IV-A prepared in Example 2-M and stirring was maintained for at least 12 hours. During the reaction time, precipitation of the compound of Formula IV was observed. End-of-reaction control was performed (compound of Formula IV-A < 1.5%). With positive analytical control, the suspended solid was filtered and the panel was washed with 3.8 w/w of 1,4- dioxane and 2.4 w/w of IPAc. The solid thus obtained was then dried under vacuum at a maximum temperature of 70 °C. The end-of-drying control was performed (weight loss < 30% w/w). A process weight yield of 140% was obtained.

Claims

1. Process for preparing lifitegrast of Formula I said process comprising: a) reacting the compound of Formula V with a chlorinating agent, in a water-immiscible organic solvent and in the presence of a base to obtain a solution of the compound of Formula V-A, b) reacting the compound of Formula IV with the solution of the compound of Formula V-A obtained in step a) in a biphasic mixture comprising an organic phase and an aqueous phase, in the presence of a base, to obtain a solution of the compound of Formula VI wherein the compound of Formula VI is dissolved in the organic phase; c) separating the organic phase containing the compound of Formula VI from the aqueous phase of the biphasic mixture obtained in step b); d) distilling the solvent of the organic phase containing the compound of Formula VI obtained in step c) and adding a water-miscible solvent to prepare a solution of the compound of Formula VI; e) reacting the solution of the compound of Formula VI obtained in step d) with an alkali metal hydroxide in aqueous solution to obtain a solution of the compound of Formula I-A where M+ is an alkali metal cation; f) adding an acid to the solution of the compound of Formula I-A obtained in step e) to obtain the compound of Formula I.

2. Process according to claim 1, wherein in step a) the chlorinating agent is selected from: thionyl chloride (SOC1₂), phosphorus trichloride (PCI₃), phosphorus pentachloride (PCI₅), oxalyl chloride, preferably the chlorinating agent is thionyl chloride.

3. Process according to any one of the previous claims, wherein in step a) the water-immiscible organic solvent is selected from: water-immiscible esters, preferably isopropyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate; water- immiscible ketones, preferably methyl ethyl ketone; chlorinated solvents, preferably methylene chloride, chloroform, carbon tetrachloride; water-immiscible ethers, for example t-butyl methyl ether; water- immiscible aromatic hydrocarbons, preferably toluene, xylene, benzene, more preferably toluene; or mixtures thereof.

4. Process according to any one of the previous claims, wherein in step b) the molar ratio between the compound of Formula V and the compound of Formula IV is between 1.0 and 1.30, preferably between 1.0 and 1.15.

5. Process according to any one of the previous claims, wherein in step b) the organic phase is obtained using a water-immiscible organic solvent selected from: water-immiscible esters, preferably isopropyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate; water-immiscible ketones, preferably methyl ethyl ketone; chlorinated solvents, preferably methylene chloride, chloroform, carbon tetrachloride; water- immiscible ethers, for example t-butyl methyl ether; water-immiscible aromatic hydrocarbons, preferably toluene, xylene, benzene, more preferably toluene; or mixtures thereof.

6. Process according to any one of the previous claims, wherein in step b) the ratio (calculated in weight/weight) between the organic solvent used to prepare the organic phase and the compound of Formula IV is between 1.1 and 5.0, preferably between 1.5 and 5.0.

7. Process according to any one of the previous claims, wherein the organic phase obtained in step c) is previously subjected to washing with an acid solution and subsequently with a basic solution, and then directly subjected to step d) without isolating the product of Formula VI from the organic phase.

8. Process according to any one of the previous claims, wherein in step d) the organic phase is concentrated under vacuum while maintaining a temperature of from 30°C to 60°C, preferably from 35°C to 50°C.

9. Process according to any one of the previous claims, wherein in step d) the water-miscible solvent is selected from: water-miscible ketones, preferably acetone; water-miscible alcohols; water-miscible ethers; water-miscible nitriles, preferably acetonitrile.

10. Process according to any one of the previous claims, wherein in step e) water is added to the solution of the compound of Formula VI obtained in step d), preferably with a ratio (calculated in weight/weight) between the added water and the compound of Formula IV between 0.5 w/w and 3.0 w/w, more preferably between 1.0 w/w and 2.0 w/w.

11. Process according to any one of the previous claims, wherein in step f) the acid is added in such an amount as to obtain a pH between 1.4 and 2.6, preferably between 1.6 and 2.4.

12. Process according to any one of the previous claims, wherein in step f), after the addition of the acid, water is added to precipitate the compound of

Formula I.