ES3038762A1 - Process for the synthesis of 5-methoxy-2-(2H-1,2,3-triazol-2yl)benzoic acid, sodium salt of said acid as a synthesis intermediate and use of the acid or its salt in the preparation of daridorexant and certain intermediates in the synthesis thereof - Google Patents

Abstract

The invention relates to a process for the synthesis of 5-methoxy-2-(2H-1,2,3-triazol-2yl)benzoic acid, the sodium salt of said acid as a synthesis intermediate, and the use of the acid or its salt in the preparation of daridorexant and certain intermediates in the synthesis thereof . (Machine-translation by Google Translate, not legally binding)

Description

DESCRIPTION

Process for the synthesis of 5-methoxy-2-(2H-1,2,3-triazol-2yl)benzoic acid, sodium salt of said acid as a synthesis intermediate and use of the acid or its salt in the preparation of daridorexant and certain intermediates in the synthesis thereof

Field of invention

Process for the synthesis of 5-methoxy-2-(2H-1,2,3-triazol-2yl)benzoic acid, sodium salt of said acid as a synthesis intermediate and use of the acid or its salt in the preparation of daridorexant and certain intermediates in the synthesis thereof.

Background of the invention

Daridorexant is a dual orexin receptor antagonist, acting on both orexin 1 and orexin 2 receptors. The neuropeptides orexin A and orexin B act on orexin receptors, promoting wakefulness. Daridorexant antagonizes the activation of orexin receptors by these neuropeptides and, consequently, reduces wakefulness, facilitating sleep without disrupting sleep structure. Therefore, daridorexant (Quviviq®) is indicated for the treatment of insomnia.

As a medicine, daridorexant is marketed in the form of its hydrochloride salt and in the form of tablets for oral administration.

Daridorexant is the compound [(2S)-2-(5-chloro-4-methyl-1H-benzimidazol-2-yl)-2-methylpyrrolidin-1-yl]-[5-methoxy-2-(triazol-2-yl)phenyl]methanone and has the following chemical structure:

International patent application WO 2013/182972 A1 (see page 91) describing daridorexant (page 56, line 1) also provides a general route for its synthesis (see page 91) using an acid of formula Ar1-COOH as one of the starting products for the synthesis.

In the case of daridorexant, the acid with the formula Ar1-COOH is 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid, whose synthesis is described in example A.2 on page 99 of international patent application WO 2013/182972 A1.

This procedure starts with 2-iodo-5-methoxybenzoic acid and reacts it with 1H-1,2,3-triazole in the presence of Cu and Cs<2>CO<3> in DMF at 80°C. The reaction product is a salt that is neutralized with 1M aqueous HCl and extracted with ethyl acetate.

As described in the example, starting with 1.798 mmol of (I) yields 313 mg (1.428 mmol) of (III-H), which represents a yield of 79.4%.

The procedure for obtaining 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid is also described in patent application WO 2015/083070 A1 (reference example 1) which reports a yield of only 60.01%.

Furthermore, the application describes (see reference example 1) that the reaction is not regiospecific since 1H-1,2,3-triazole reacts partially through the central nitrogen atom (nitrogen 2) to give the desired product (5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid) but also reacts through the side nitrogen atoms (nitrogens 1 or 3) to give the undesired regioisomer, 5-methoxy-2-(1H-1,2,3-triazol-1-yl)benzoic acid (IV-H):

As described in reference example 1, the unwanted regioisomer (IV-H) represents 6% of the product obtained.

Furthermore, due to the high structural similarity of compounds (III-H) and (IV-H), the separation of both is complex.

Therefore, there is a need for more optimized procedures for obtaining 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid, particularly with higher yield and lower content of the regioisomer (IV-H) for the synthesis of this product on an industrial scale.

Summary of the invention

The inventors have developed, after multiple trials, an alternative procedure that, starting also from the compound of formula (I), allows obtaining the product of formula (III-H) or its pharmaceutically acceptable salts with better yields and greater purity.

Surprisingly, the inventors have discovered that it is possible to obtain and isolate the sodium salt of 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid with high yields and high purity, particularly with unwanted regioisomer (III-H) contents of less than 1%.

Therefore, in a first aspect, the present invention relates to a process for obtaining 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid of formula (III-H):

which includes:

a) react 2-iodo-5-methoxybenzoic acid (I) with 1H-1,2,3-triazole (II) in the presence of CU<2>O and a sodium salt, preferably Na<2>CO<3> to obtain the sodium salt of 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (III-Na)

b) reacting the sodium salt of 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (III-Na) with an acid of pKa less than 4 to obtain 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (III-H)

in an organic solvent solution.

In a second aspect, the present invention relates to the sodium salt of 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (III-Na) which is an intermediate in the process according to the first aspect of the invention.

In a third aspect, the present invention relates to a process for obtaining methyl (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2-carboxylate (VII):

which includes:

a) the preparation of the compound of formula (III-H) as described in the first aspect of the invention

b) the reaction of the compound of formula (III-H) with a carboxylic acid chloride forming agent to obtain the compound of formula (V):

c) the reaction of the compound of formula (V) with methyl (VI)-2-methylpyrrolidine-2-carboxylate or a salt thereof, preferably the hydrochloride:

in the presence of an organic amine to obtain the compound of formula (VII):

In a fourth aspect, the present invention relates to a process for obtaining (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2-carboxylic acid (VIII):

which includes:

a) the preparation of the compound of formula (VII) as described in the third aspect of the invention

b) the reaction of the compound of formula (VII) with an inorganic base to obtain the compound of formula (VIII).

In a fifth aspect, the present invention relates to a process for obtaining daridorexant:

which includes:

a) the preparation of the compound of formula (VIII) as described in the fourth aspect of the invention;

b) the reaction of the compound of formula (VIII) with a carboxylic acid chloride forming agent to obtain the compound of formula (IX):

c) the reaction of the compound of formula (IX) with 4-chloro-3-methylbenzen-1,2-diamine (X):

in the presence of an organic amine to obtain the compound of formula (XI):

d) the reaction of the compound of formula (XI) with an acid to obtain a daridorexant salt with the anion of said acid;

(e) optionally reacting the daridorexant salt obtained in step (d) with a base to obtain daridorexant; and

f) if step e) has been carried out, optionally react the daridorexant obtained in step e) with an acid to obtain a salt of daridorexant with the anion of said acid.

In a sixth aspect, the invention relates to the use of the compound of formula (III-Na) or of the crystalline forms of said compound in the preparation of daridorexant or of its pharmaceutically acceptable salts.

DESCRIPTION OF THE FIGURES

Figure 1 shows the X-ray diffractogram (XRPD) of the product from Example 1.

DETAILED DESCRIPTION OF THE INVENTION

Procedure for preparing the compound of formula (III-H)

In a first aspect, the present invention relates to a process for obtaining 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid of formula (III-H):

which includes:

a) react 2-iodo-5-methoxybenzoic acid (I) with 1H-1,2,3-triazole (II) in the presence of CU<2>O and a sodium salt, preferably Na<2>CO<3> to obtain the sodium salt of 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (III-Na)

b) reacting the sodium salt of 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (III-Na) with an acid of pKa less than 4 to obtain 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (III-H)

in an organic solvent solution.

In an embodiment of the first aspect of the invention, step a) is carried out in a polar aprotic solvent.

The term "polar aprotic solvent" refers to a solvent that lacks an acidic proton and is polar, such as ethyl acetate, acetone, acetonitrile, dichloromethane, dimethylacetamide, dimethylformamide, dimethylpropyleneurea, dimethyl sulfoxide, hexamethylphosphoramide, N-methylpyrrolidone-2-one, pyridine, sulfolane, and tetrahydrofuran. Acetonitrile is a polar aprotic solvent of particular interest.

In an embodiment of the first aspect of the invention, step a) is carried out at a temperature between 80 and 90 °C, preferably between 85 and 90 °C.

In an embodiment of the first aspect of the invention, step b) is carried out in a solvent mixture comprising water and a water-immiscible solvent that allows the compound of formula (III-H), such as dichloromethane or methyl tert-butyl ether, to be kept in solution.

In an embodiment of the first aspect of the invention, step b) is carried out using an acid with pKa less than 4 selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, perchloric acid, p-toluenesulfonic acid, phosphoric acid, and oxalic acid.

Process for obtaining (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methyldirrolidin-2-carboxylate (VII)

In a third aspect, the present invention relates to a process for obtaining methyl (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2-carboxylate (VII):

which includes:

a) the preparation of the compound of formula (III-H) as described in the first aspect of the invention

b) the reaction of the compound of formula (III-H) with a carboxylic acid chloride forming agent to obtain the compound of formula (V):

c) the reaction of the compound of formula (V) with methyl (VI)-2-methylpyrrolidine-2-carboxylate or a salt thereof, preferably the hydrochloride:

in the presence of an organic amine to obtain the compound of formula (VII):

In an embodiment of the third aspect, the carboxylic acid chloride forming agent employed in step b) is selected from the group consisting of oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, and trichloroisocyanuric acid, preferably oxalyl chloride.

In an embodiment of the third aspect of the invention, the compound of formula (V) is used in the form of a salt thereof selected from the group consisting of oxalate, hydrobromide and hydrochloride salts, preferably hydrochloride.

In an embodiment of the third aspect of the invention, the organic amine used in step c) is selected from the group consisting of C rC<4>-trialkylamines, preferably triethylamine, trimethylamine and diisopropylethylamine, preferably triethylamine.

Process for obtaining (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methyldirrolidin-2-carboxylic acid (VIII)

In a fourth aspect, the present invention relates to a process for obtaining (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2-carboxylic acid (VIII):

which includes:

a) the preparation of the compound of formula (VII) as described in the third aspect of the invention

b) the reaction of the compound of formula (VII) with an inorganic base to obtain the compound of formula (VIII).

In an embodiment of the fourth aspect of the invention, the inorganic base is selected from the group consisting of lithium hydroxide, sodium hydroxide, or potassium hydroxide, preferably sodium hydroxide.

Procedure for obtaining Daridorexant (VIII)

In a fifth aspect, the present invention relates to a process for obtaining daridorexant:

which includes:

a) the preparation of the compound of formula (VIII) as described in the fourth aspect of the invention;

b) the reaction of the compound of formula (VIII) with a carboxylic acid chloride forming agent to obtain the compound of formula (IX):

c) the reaction of the compound of formula (IX) with 4-doro-3-methylbenzen-1,2-diamine (X):

in the presence of an organic amine to obtain the compound of formula (XI):

d) the reaction of the compound of formula (XI) with an acid to obtain a daridorexant salt with the anion of said acid;

(e) optionally reacting the daridorexant salt obtained in step (d) with a base to obtain daridorexant; and

f) if step e) has been carried out, optionally react the daridorexant obtained in step e) with an acid to obtain a salt of daridorexant with the anion of said acid.

In an embodiment of the fifth aspect, the carboxylic acid chloride forming agent employed in step b) is selected from the group consisting of oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, and trichloroisocyanuric acid, preferably oxalyl chloride.

In an embodiment of the fifth aspect of the invention, the organic amine used in step c) is selected from the group consisting of Ci-C<4>-trialkylamines, preferably triethylamine, trimethylamine and diisopropylethylamine, preferably triethylamine.

In one embodiment of the fifth aspect of the invention, step d) is carried out using an organic or inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, preferably hydrochloric acid, to give the corresponding daridorexant salt, and steps e) and f) are omitted.

In another embodiment of the fifth aspect of the invention, step d) is carried out using a first organic or inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, and steps e) and f) are carried out using in the latter a second organic or inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid.

The term "salt" should be understood to mean any form of the defined compounds that assumes an ionic form, or is charged and coupled with a counterion (a cation or anion), or is in solution. For example, salts of compounds of formula (I) may be addition salts of acids and can be synthesized from the parent compound containing a basic moiety by conventional chemical methods. Generally, such salts are prepared, for example, by reacting the free base forms of these compounds with a stoichiometric amount of an appropriate acid in water or an organic solvent, or a mixture of the two. Non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred. Examples of acid addition salts include mineral acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate.

Use of the compound with formula (III-Na)

The compound with formula (III-Na), as well as its crystalline forms, described herein is a novel intermediate in the synthesis procedure of daridorexant and its pharmaceutically acceptable salts.

Therefore, in another aspect, the invention relates to the use of the compound of formula (III-Na) or of the crystalline forms of said compound in the preparation of noradrenaline and its pharmaceutically acceptable salts.

In the context of the present invention, X-ray diffractograms can be recorded using a powder diffraction system with a copper anode that emits CuKa radiation with a wavelength of 1.54 Å, in particular, following the method described in the examples.

In the context of the present invention, differential scanning calorimetry diagrams can be obtained as described in the examples.

In the context of the present invention, the threshold temperature or “T onset” refers to the temperature resulting from extrapolating the baseline before the start of the transition and the baseline during energy absorption (tangent of the curve). It can be calculated as defined in DIN ISO 11357-1:2016(E).

In the context of the present invention, the terms “approximate”, “approximate” and “approximately” refer to the value that characterizes ±5% of said value.

In the context of the present invention, the term “base” refers to a substance capable of accepting a proton (from an acid).

To facilitate understanding of the preceding ideas, some examples of experimental procedures and embodiments of the present invention are described below. These examples are for illustrative purposes only.

Examples

Materials and methods

A) The purity of all products obtained, with the exception of the final product, daridorexant hydrochloride salt, was analyzed using Ultra-High Performance Liquid Chromatography (ULP) on a Waters Acquity instrument equipped with a photodiode detector, mass spectrometer, and thermostatically controlled oven for the column. A BEH C18 column (100 x 2.1 mm; 1.7 µm) and the mobile phases A (200 mM ammonium formate, pH 4.8), B (acetonitrile), and C (water) were used under the following analytical conditions:

Flow rate: 0.5 mL/min

Column temperature: 45 °C

Wavelength: 210 nm

Injection volume: 1 L

Thinner: Acetonitrile/Water (1:1)

Gradient:

B) The purity of the final product, daridorexant hydrochloride salt, was analyzed using Ultra-High Performance Liquid Chromatography (ULPC) on a Waters Acquity instrument equipped with a photodiode detector, mass spectrometer, and thermostatically controlled oven for the column. A BEH C18 column (100 x 2.1 mm; 1.7 µm) and the mobile phases A (200 mM ammonium formate, pH 4.8), B (acetonitrile), and C (water) were used under the following analytical conditions:

Flow rate: 0.5 mL/min

Column temperature: 45 °C

Wavelength: 210 nm

Injection volume: 1 L

Thinner: Acetonitrile/Water (1:1)

Gradient:

Differential Scanning Calorimetry (DSC)

The DSC analysis for the sodium salt compound of 5-methoxy-2-(triazol-2-yl)benzoic acid was performed on a Mettler Toledo 822e instrument with STARe SW15 software, using the following parameters: heating range of 30 to 500 °C with a ramp of 8 °C/min and N<2> flow of 60 ml/min. The measurement is performed with a perforated closed capsule.

The DSC analysis for the remaining compounds for which the result is indicated was performed on a Mettler Toledo 822e instrument with STARe SW15 software, using the following parameters: heating range of 30 to 300 °C with a ramp of 10 °C/min and N<2> flow of 50 ml/min. The measurement is performed with a perforated closed capsule.

X-ray crystallography (XRPD)

XRPD analysis was performed using a BRUKER D2 PHASER X-ray powder diffractometer equipped with a copper anode. The radiation used was CuKa with a wavelength of 1.54 Å. The following scanning parameters were used: 3-50 degrees, 20, continuous scanning, rate: 5.6 degrees/minute.

Example 1. Synthesis of the sodium salt of 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (111-Na)

75 g (0.270 mol) of 2-iodo-5-methoxybenzoic acid (I) was dissolved in 1500 mL of acetonitrile at approximately 20 °C. 39 mL of 1H-1,2,3-triazole (II) (0.673 mol) was added, maintaining the specified temperature. The resulting mixture was stirred for 5 minutes to obtain a solution, to which 71.48 g (0.674 mol) of sodium carbonate was added. The resulting suspension was heated to approximately 40 °C, and 11.58 g (0.081 mol) of copper(I) oxide was added, maintaining the specified temperature. The reaction mixture was heated to the reflux temperature (between 85 and 90 °C) and stirred for 20 hours under the specified conditions.

After maintenance was completed, the reaction mass was controlled by HPLC analysis to observe a regioisomer-N-2 ratio to the regioisomer-N-1 ratio of 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid of 92.5:7.5. The reaction mass was cooled to approximately 70 °C and 48.6 mL of water was added. The resulting mixture was slowly cooled to approximately 30 °C and kept under stirring for 2 hours. The resulting solid was filtered and washed successively with three 50 mL fractions of acetonitrile. Finally, it was dried in a vacuum oven at a temperature of 50 °C to obtain 62.4 g of a yellowish solid corresponding to the sodium salt of 5-methoxy-2-(1,2,3-triazol-2-yl)benzoic acid (purity of 99.24% and N-2 (III-H) and N-1 (IV-H) regiosiomer ratio 99.5:0.5 by HPLC).

The X-ray diffractogram (XRPD) of the product from Example 1 exhibits the following peaks (°20): 6.7°20, 7.2°20, 8.720, 11.7°20, 12.2°20, 13.4°20, 14.5°20, 17.5°20, 22.8°20, 24.5°20, 24.8°20, 25.0°20, 28.3°20, and 30.1°20, all with a margin of error of ±0.2°20. The powder X-ray diffractogram of the compound is shown in Figure 1.

The differential scanning calorimetry (DSC) spectrum of the product of example 1 comprises two exothermic peaks having a threshold temperature of approximately 284.5 °C and followed by an exothermic peak having a threshold temperature of approximately 303.0 °C.

Example 2. Synthesis of 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (III-H)

The solid obtained following the methodology in Example 1 was mixed with 600 mL of water. Approximately 30 mL of solvent were distilled under vacuum at a temperature between 55 and 65 °C. 30 mL of water were added, and approximately 30 mL more solvent was distilled under vacuum. Another 30 mL of water was added, and the resulting suspension was filtered at approximately 50 °C to remove insolubles. The filtrate was washed with three 50 mL portions of water, each previously heated to approximately 50 °C. Approximately 400 mL of water were distilled under vacuum, and the resulting solution was cooled to approximately 20 °C. 300 mL of dichloromethane were added, and the pH was adjusted to between 4 and 6 by adding a 36% aqueous HCl solution, and subsequently to between 3 and 4 by adding a saturated citric acid solution. The resulting mixture was stirred at 30–35 °C for 1 hour, after which the aqueous phase was separated from the organic phase. The aqueous phase was washed successively with two 75 mL fractions of dichloromethane. The organic phases thus obtained were combined, the solution was treated with anhydrous Na<2>SO<4> to remove the remaining water, and a final solution comprising 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (III-H) (46.2 g (0.211 mol) of product according to HPLC analysis of the solution content) was obtained, which was used in the next synthesis stage.

Example 3. Synthesis of methyl (VII) (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2-carboxylate

Approximately 200 mL of dichloromethane were removed from the solution obtained by vacuum distillation, following the methodology described in Example 2 above. Nine mL of DMF were added to the resulting solution, followed by 23.5 mL (0.274 mol) of oxalyl chloride, slowly adding it while maintaining a temperature between 18 and 22 °C. The resulting solution was kept under stirring at approximately 20 °C for 1 hour.

A suspension of 38.8 g (0.216 mol) of methyl(VI-HCl) (S)-2-methylpyrrolidine-2-carboxylate hydrochloride was prepared in 270 mL of dichloromethane. The reaction mixture was stirred at approximately 20 °C until a solution was obtained. The resulting solution was cooled to between 0 and 10 °C, and 118 mL (0.847 mol) of triethylamine was slowly added. The reaction mixture was stirred for 10 minutes at the specified temperature, and the solution obtained in the first step of this example was slowly added, maintaining the temperature between 0 and 5 °C. The reaction mixture was stirred for 3 hours at approximately 10 °C and for a further 2 hours at approximately 20 °C.

After holding, the reaction mass was cooled to between 0 and 10 °C, and 190 mL of water were slowly added, followed by 60 mL of a 5% aqueous Na₂CO₃ solution. The mixture was allowed to reach approximately 20 °C and was stirred for 30 minutes. The aqueous phase was separated from the organic phase and washed successively with two 35 mL fractions of dichloromethane. The resulting organic phases were combined, and the organic phase was washed with a 110 mL fraction of water. The solvent was removed from the resulting solution by vacuum distillation to obtain a light brown solid (approximately 73 g (0.211 mol)), which was used in the next step of the synthesis.

Example 4. Synthesis of (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2-carboxylic acid (VIII)

The solid obtained following the methodology described in Example 3 was dissolved in 365 mL of methanol at approximately 20 °C. 141 mL (0.637 mol) of a 16 wt% aqueous NaOH solution was slowly added while maintaining the specified temperature, and the resulting solution was heated to approximately 80 °C after the addition was complete. The solution was kept under stirring at the specified temperature for 2 hours.

After maintenance was completed, the solvent was removed by vacuum distillation. 25 mL of water were added to the resulting residue, and the solvent was again removed by vacuum distillation. Another 25 mL of water was added to the resulting residue, and the solvent was again removed by vacuum distillation. 220 mL of water were added, and the pH of the solution was adjusted to approximately 5 by adding a 36% aqueous HCl solution, and then to approximately 3 by adding a saturated aqueous citric acid solution. 245 mL of dichloromethane was added to the resulting mixture to obtain a solution. The aqueous phase was separated from the organic phase and washed with two 35 mL fractions of dichloromethane. The resulting organic phases were combined, and the organic phase was washed with a 90 mL fraction of water. 1.9 g of activated carbon were added, and the resulting mixture was stirred at 30–35 °C for 30 minutes. The mixture was filtered through diatomaceous earth at the specified temperature, and the filtrate was washed with three 15 mL fractions of dichloromethane. The solvent was removed by vacuum distillation, and 45 mL of dichloromethane and 220 mL of toluene were added. Approximately 35 mL of solvent was distilled under vacuum, and 35 mL of toluene was added. The resulting mixture was held at approximately 70 °C for 30 minutes. The mixture was then slowly cooled to approximately 20 °C and stirred for one hour at that temperature. The resulting solid was filtered and successively washed with three 15 mL fractions of toluene. Finally, it was dried in a vacuum oven at a temperature of 50 °C to obtain 57.5 g of a cream-colored solid corresponding to (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2-carboxylic acid (VIII) (yield of 64.5% from compound (VII), purity of 95.34% by HPLC).

The differential scanning calorimetry (DSC) spectrum of the compound of formula (VIII) comprises an endothermic peak exhibiting a threshold temperature of approximately 173.5 °C.

Example 5. Synthesis of (S)-N-(2-amino-4-chloro-3-methylphenyl)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2-carboxamide (XI)

93 g (0.281 mol) of (2S)-1-[5-methoxy-2-(triazol-2-yl)benzoyl]-2-methylpyrrolidine-2-carboxylic acid (VIII) were mixed with 500 ml of dichloromethane and 4.5 ml of DMF at a temperature of approximately 20 °C. 27.8 ml (323.8 mol) of oxalyl chloride were slowly added to the mixture while maintaining the temperature below 20 °C. The resulting solution was kept under stirring at a temperature of approximately 20 °C for 1 hour.

44.1 g (0.281 mol) of 4-chloro-3-methylbenzene-1,2-diamine (X) was dissolved in 465 mL of dichloromethane at approximately 20 °C. Subsequently, 118 mL of triethylamine was slowly added at a temperature between 5 and 10 °C. The reaction mixture was stirred for 10 minutes at the specified temperature, and the solution obtained in the first step of this example was slowly added, maintaining the temperature between 5 and 10 °C. After the addition was complete, the reaction mixture was allowed to reach a temperature of approximately 20 °C and was kept stirred for 3 hours at the specified temperature.

After maintenance, the reaction mass was cooled to between 5 and 10 °C, and 250 mL of water were slowly added, followed by 100 mL of a 5% aqueous Na₂CO₃ solution. The mixture was allowed to reach approximately 20 °C and was stirred for 30 minutes. The aqueous phase was separated from the organic phase and washed successively with two 80 mL fractions of dichloromethane. The resulting organic phases were combined, and the organic phase was washed with a 100 mL fraction of water. The solvent was removed from the resulting solution by vacuum distillation to obtain a solid, to which 180 mL of isopropyl acetate was added. Approximately 40 mL of solvent were distilled under vacuum, and 450 mL of methyl tert-butyl ether were added while maintaining a temperature between 50 and 55 °C. The resulting suspension was stirred for 1 hour at this temperature. It was then cooled to approximately 20 °C and stirred for 2 hours at this temperature. The solid was filtered and washed successively with three 60 mL fractions of methyl tert-butyl ether. Finally, it was dried in a vacuum oven at a temperature of 50 °C to obtain 111.5 g of a cream-colored solid corresponding to (S)-N-(2-amino-4-chloro-3-methylphenyl)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2-carboxamide (XI) (yield of 84.5%, purity of 98.61%).

The differential scanning calorimetry (DSC) spectrum of the compound of formula (XI) comprises an endothermic peak exhibiting a threshold temperature of approximately 179.7 °C.

Example 6. Synthesis of the hydrochloride salt of (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl) (5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (daridorexant hydrochloride)

100.5 g (0.214 mol) of (S)-N-(2-amino-4-chloro-3-methylphenyl)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2-carboxamide (XI) were mixed with 400 mL of methanol at approximately 30 °C. 21.5 mL of a 32% aqueous HCl solution were slowly added while maintaining the temperature between 30 and 35 °C. 5 g of activated carbon were added, and the mixture was stirred for 30 minutes at the specified temperature. The mixture was filtered through diatomaceous earth at approximately 35 °C, and the filtrate was washed with three 35 mL fractions of methanol. To the resulting colorless solution, 31.6 ml of a 32% aqueous HCl solution were slowly added, and the resulting solution was heated to approximately 65 °C. The reaction mixture was kept under stirring for 5 hours at the indicated temperature.

After maintenance, the solvent was removed by vacuum distillation, and 50 mL of isopropanol was added. The solvent was again removed by vacuum distillation, and 1040 mL of isopropanol was added to the resulting residue, maintaining a temperature of approximately 50 °C. The resulting suspension was stirred for one hour at a temperature between 50 and 55 °C and then cooled to approximately 20 °C over three hours. The mixture was stirred at the specified temperature for two hours, and the resulting solid was filtered and washed successively with three 40 mL fractions of isopropanol. Finally, it was dried in a vacuum oven at 50 °C to obtain 98.3 g of a white solid corresponding to the hydrochloride salt of (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (daridorexant hydrochloride) (yield of 94.1%, purity of 99.95%). The X-ray powder diffraction (XRPD) obtained for the product matched that disclosed in European patent EP 3077390 B1 (Figure 1 of said document).

Claims (1)

CLAIMS 1. Process for obtaining 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid of formula (III-H): comprising: a) reacting 2-iodo-5-methoxybenzoic acid (I) with 1H-1,2,3-triazole (II) in the presence of Cu<2>O and a sodium salt, preferably Na<2>CO<3>, to obtain the sodium salt of 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (III-Na) b) reacting the sodium salt of 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (III-Na) with an acid of pKa less than 4 to obtain 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (III-H) in an organic solvent solution. 2. A process according to claim 1, characterized in that step a) is carried out in a polar aprotic solvent, preferably acetonitrile. 3. A process according to any of claims 1 to 2, characterized in that step a) is carried out at a temperature between 80 and 90 °C, preferably between 85 and 90 °C. 4. A process according to any of claims 1 to 3, characterized in that step b) is carried out in a solvent mixture comprising water and a water-immiscible solvent, preferably dichloromethane or methyl tert-butyl ether. 5. A process according to any one of claims 1 to 4, characterized in that the acid with a pKa less than 4 is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, nitric acid, perchloric acid, p-toluenesulfonic acid, phosphoric acid, and oxalic acid, preferably hydrochloric acid. 6. Sodium salt of 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid of formula (III-Na): 7. Crystalline form of the sodium salt of 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid of formula (III-Na) characterized in that it has an X-ray diffractogram (XRPD) measured with CuKa radiation with a wavelength of 1.54 Å comprising the following peaks (° 26): 6.7° 20, 7.2° 20, 8.7° 20, 11.7° 20, 12.2° 20, 13.4° 20, 14.5° 20, 17.5° 20, 22.8° 20, 24.5° 20, 24.8° 20, 25.0° 20, 28.3° 20 and 30.1° 20 all with a margin of error of ± 0.2° 20. 8.- Procedure for obtaining methyl (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2-carboxylate (VII): comprising: a) preparing the compound of formula (III-H) according to any one of claims 1 to 5; b) reacting the compound of formula (III-H) with a carboxylic acid chloride forming agent to obtain the compound of formula (V); and c) reacting the compound of formula (V) with methyl (VI)-2-methylpyrrolidine-2-carboxylate or a salt thereof, preferably the hydrochloride: in the presence of an organic amine to obtain the compound of formula (VII): 9. A process according to claim 8, characterized in that the carboxylic acid chloride forming agent is oxalyl chloride. 10. A process according to any one of claims 8 to 9, characterized in that the compound of formula (V) is used in the form of its hydrochloride salt. 11. A process according to any one of claims 8 to 10, characterized in that the organic amine used in step (c) is triethylamine. 12. A process for obtaining (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidine-2-carboxylic acid (VIII): comprising: a) preparing the compound of formula (VII) according to any one of claims 8 to 11; and b) reacting the compound of formula (VII) with an inorganic base to obtain the compound of formula (VIII). 13. A process according to claim 12, characterized in that the inorganic base is sodium hydroxide. 14. A process for obtaining daridorexant: comprising: a) preparing the compound of formula (VIII) according to any one of claims 12 to 13; b) reacting the compound of formula (VIII) with a carboxylic acid chloride forming agent to obtain the compound of formula (IX): c) the reaction of the compound of formula (IX) with 4-doro-3-methylbenzen-1,2-diamine (X): in the presence of an organic amine to obtain the compound of formula (XI): d) reacting the compound of formula (XI) with an acid to obtain a daridorexant salt containing the anion of said acid; e) optionally reacting the daridorexant salt obtained in step d) with a base to obtain daridorexant; and f) if step e) has been carried out, optionally reacting the daridorexant obtained in step e) with an acid to obtain a daridorexant salt containing the anion of said acid. 15. A process according to claim 14, characterized in that step d) is carried out using hydrochloric acid to give the daridorexant hydrochloride salt, and steps e) and f) are omitted. 16. Use of the compound of formula (III-Na) or of the crystalline forms of said compound in the preparation of daridorexant or of pharmaceutically acceptable salts thereof.