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WO2025215225A1 - Method for the synthesis of 5-methoxy-2-(2h-1,2,3-triazol-2-yl)benzoic acid, a sodium salt of said acid as a synthetic intermediate, and use of the acid or the salt thereof in the preparation of daridorexant and certain intermediates in the synthesis thereof - Google Patents

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

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Publication number
WO2025215225A1
WO2025215225A1 PCT/EP2025/060068 EP2025060068W WO2025215225A1 WO 2025215225 A1 WO2025215225 A1 WO 2025215225A1 EP 2025060068 W EP2025060068 W EP 2025060068W WO 2025215225 A1 WO2025215225 A1 WO 2025215225A1
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Prior art keywords
acid
formula
compound
daridorexant
methoxy
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French (fr)
Inventor
Abdeslam AKHATOU
Roberto BALLETTE
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Moehs Iberica SL
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Moehs Iberica SL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • Daridorexant is a dual orexin receptor antagonist that acts on orexin 1 and orexin 2 receptors.
  • the neuropeptides orexin A and orexin B act on orexin receptors by promoting wakefulness.
  • Daridorexant antagonizes orexin receptor activation by said neuropeptides and, as a result, reduces wakefulness activation, making it easier to fall asleep without altering sleep structure. Consequently, daridorexant (Quviviq®) is indicated for the treatment of insomnia.
  • 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-1 H-benzimidazol-2-yl)-2- methylpyrrolidin-1-yl]-[5-methoxy-2-(triazol-2-yl)phenyl]methanone and has the following chemical structure:
  • Daridorexant International patent application WO 2013/182972 A1 (see page 91), which describes daridorexant (page 56, line 1), also provides a general pathway for the synthesis of daridorexant (see page 91) using an acid of formula Ar 1 -COOH as one of the starting products for the synthesis.
  • the acid of formula Ar 1 -COOH is 5-methoxy-2-(2/7-1 ,2,3-triazol-2- yl)benzoic acid, the synthesis of which is described in example A.2 on page 99 of international patent application WO 2013/182972 A1.
  • Said method starts from 2-yodo-5-methoxybenzoic acid which is reacted with 1/7-1 ,2,3-triazole in the presence of Cui and CS2CO3 in DMF at 80°C.
  • the reaction product is a salt that is neutralized with 1M aqueous HCI and extracted with ethyl acetate.
  • said application describes (see reference example 1) that the reaction is not regiospecific because 1/7-1 ,2,3-triazole reacts partially through the central nitrogen atom (nitrogen 2) to yield the desired product (5-methoxy-2-(2/7-1 ,2,3-triazol-2-yl)benzoic acid), however, it also reacts through the lateral nitrogen atoms (nitrogen atoms 1 or 3) to yield the unwanted regioisomer, 5-methoxy-2-(1/7-1 ,2,3-triazol-1-yl)benzoic acid (IV-H):
  • the unwanted regioisomer (IV-H) represents 6% of the obtained product.
  • the present invention relates to a method for obtaining 5-methoxy- 2-(2/7-1 ,2,3-triazol-2-yl)benzoic acid of formula (lll-H):
  • (lll-H) which comprises: a) reacting 2-yodo-5-methoxybenzoic acid (I) with 1 /7-1 ,2,3-triazole (II) in the presence of C112O and a sodium salt, preferably Na2COs, to obtain the sodium salt of 5-methoxy-2- (2/7-1 ,2,3-triazol-2-yl)benzoic acid (lll-Na) b) reacting the sodium salt of 5-methoxy-2-(2/7-1 ,2,3-triazol-2-yl)benzoic acid (lll-Na) with an acid having a pKa below 4 to obtain 5-methoxy-2-(2/7-1 ,2,3-triazol-2-yl)benzoic acid (lll-H)
  • the present invention relates to the sodium salt of 5-methoxy-2-(2H-1 ,2,3- triazol-2-yl)benzoic acid (lll-Na) which is an intermediate in the method according to the first aspect of the invention.
  • the present invention relates to a method for obtaining methyl (S)-1-(5- methoxy-2-(2/7-1 ,2,3-tnazol-2-yl)benzoyl)-2-methylpyrrohdin-2-carboxylate (VII): which comprises: a) preparing the compound of formula (lll-H) as described in the first aspect of the invention b) reacting the compound of formula (lll-H) with a carboxylic acid chloride forming agent to obtain the compound of formula (V): c) reacting the compound of formula (V) with methyl (S)-2-methylpyrrolidin-2-carboxylate
  • the present invention relates to a method for obtaining (S)-1-(5-methoxy-2- (2/7-1 ,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidin-2-carboxylic acid (VIII):
  • the present invention relates to a method for obtaining daridorexant or a salt thereof: Daridorexant which comprises: a) preparing the compound of formula (VIII) as described in the fourth aspect of the invention; b) reacting the compound of formula (VIII) with a carboxylic acid chloride forming agent to obtain the compound of formula (IX): c) reacting the compound of formula (IX) with 4-chloro-3-methylbenzene-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 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 reacting the daridorexant obtained in step e) with an acid to obtain a daridorexant;
  • the invention relates to the use of the compound of formula (lll-Na) or the crystalline forms of said compound in the preparation of daridorexant or the pharmaceutically acceptable salts thereof.
  • Figure 1 shows the X-ray diffractogram (XRPD) of the product of Example 1 .
  • the present invention relates to a method for obtaining 5-methoxy-2-(2/7-1 ,2,3- triazol-2-yl)benzoic acid of formula (lll-H):
  • (lll-H) which comprises: a) reacting 2-yodo-5-methoxybenzoic acid (I) with 1 /7-1 ,2,3-triazole (II) in the presence of C112O and a sodium salt, preferably Na2COs, to obtain the sodium salt of 5-methoxy-2- (2/7-1 ,2,3-triazol-2-yl)benzoic acid (lll-Na)
  • step a) is carried out in an aprotic polar solvent.
  • aprotic polar solvent refers to a solvent that lacks an acidic proton and is polar such as ethyl acetate, acetone, acetonitrile, dichloromethane, dimethylacetamide, dimethylformamide, dimethyl propylene urea, dimethylsulfoxide, hexamethylphosphoramide, N-methylpyrrolidin-2-one, pyridine, sulfolane, and tetrahydrofuran.
  • An aprotic polar solvent of particular interest is acetonitrile.
  • step a) is carried out at a temperature comprised between 80 and 90°C, preferably between 85 and 90°C.
  • step b) is carried out in a mixture of solvents comprising water and a solvent not miscible in water which allows maintaining the compound of formula (lll-H) in solution, such as dichloromethane or methyl-tert-butyl ether.
  • step b) is carried out using an acid having a pKa below 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.
  • an acid having a pKa below 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.
  • the present invention relates to a method for obtaining methyl (S)-1-(5- methoxy-2-(2/7-1 ,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidin-2-carboxylate (VII): which comprises: a) preparing the compound of formula (lll-H) as described in the first aspect of the invention b) reacting the compound of formula (lll-H) with a carboxylic acid chloride forming agent to obtain the compound of formula (V): c) reacting the compound of formula (V) with methyl (S)-2-methylpyrrolidin-2-carboxylate
  • the carboxylic acid chloride forming agent used 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.
  • the compound of formula (V) is used in the form of a salt thereof which is selected from the group consisting of oxalate, hydrobromide, and hydrochloride salts, preferably hydrochloride salts.
  • the organic amine used in step c) is selected from the group consisting of Ci-C4-trialkylamines, preferably triethylamine, trimethylamine, and diisopropylethylamine, preferably triethylamine.
  • the present invention relates to a method for obtaining (S)-1-(5-methoxy-2- (2/7-1 ,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidin-2-carboxylic acid (VIII): which comprises: a) preparing the compound of formula (VII) as described in the third aspect of the invention b) reacting the compound of formula (VII) with an inorganic base to obtain the compound of formula (VIII).
  • the inorganic base is selected from the group consisting of lithium hydroxide, sodium hydroxide, or potassium hydroxide, preferably sodium hydroxide.
  • the present invention relates to a method for obtaining daridorexant or a salt thereof:
  • Daridorexant which comprises: a) preparing the compound of formula (VIII) as described in the fourth aspect of the invention; b) reacting the compound of formula (VIII) with a carboxylic acid chloride forming agent to obtain the compound of formula (IX): c) reacting the compound of formula (IX) with 4-chloro-3-methylbenzene-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 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 reacting the daridorexant obtained in step e) with an acid to obtain a daridorexant salt with the anion of said acid.
  • the carboxylic acid chloride forming agent used in the 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.
  • the organic amine used in step c) is selected from the group consisting of Ci-C4-trialkylamines, preferably triethylamine, trimethylamine, and diisopropylethylamine, preferably triethylamine.
  • step d) is performed 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 yield the corresponding daridorexant salt, and steps e) and f) are omitted.
  • 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 yield the corresponding daridorexant salt, and steps e) and f) are omitted.
  • step d) is performed 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 performed, using in said steps 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.
  • a first organic or inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, fumaric acid, citric
  • salts of the compounds of formula (I) can be acid addition salts and can be synthesized from the original compound containing a basic residue by means of conventional chemical methods.
  • such salts are prepared, for example, by reacting the free base forms of those compounds with a stoichiometric amount of a suitable acid in water or in an organic solvent or in a mixture thereof.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate.
  • mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate
  • organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate.
  • the compound of formula (lll-Na), as well as its crystalline forms, described herein is a novel intermediate used in the method for the synthesis of daridorexant and the pharmaceutically acceptable salts thereof.
  • the invention relates to the use of the compound of formula (III- Na) or the crystalline forms of said compound in the preparation of daridorexant and the pharmaceutically acceptable salts thereof.
  • the X-ray diffractograms can be recorded using a powder diffraction system with a copper anode that emits CuK a radiation with a wavelength of 1.54 A, particularly following the method described in the examples.
  • differential scanning calorimetry diagrams can be obtained as described in the examples.
  • the threshold temperature or “T onset” refers to the temperature resulting from extrapolating the baseline before the start of transition and the baseline during energy absorption (tangent of the curve). It can be calculated as defined in DIN ISO 11357-1 :2016(E) standard.
  • the terms “approximate” and “about” when referring to a value are used to indicate any value comprised in the range defined by a lower limit of -5% of said value and an upper limit of +5% of said value.
  • base refers to a substance capable of accepting a proton (from an acid).
  • DSC analysis for the compound, sodium salt of 5-methoxy-2-(triazol-2-yl)benzoic acid was performed in a Mettler Toledo 822e apparatus with STARe SW15 software using the following parameters: heating interval of 30 to 500°C with a ramp of 8°C/min and an N2 flow of 60 mL/min. The measurement is taken with a closed perforated capsule.
  • DSC analysis for the rest of the compounds in which the result is indicated was performed in a Mettler Toledo 822e apparatus with STARe SW15 software using the following parameters: heating interval of 30 to 300°C with a ramp of 10°C/min and an N2 flow of 50 mL/min. The measurement is taken with a closed perforated capsule.
  • XRPD analysis was performed using a BRUKER D2 PHASER X-ray powder diffractometer equipped with a copper anode.
  • the radiation used is CuKa with a wavelength of 1.54 A.
  • the following scan parameters were used: 3-50 degrees 20, continuous scan, ratio: 5.6 degrees/minute.
  • reaction mass was controlled by means of UHPLC analysis to observe a ratio between the N-2 regioisomer and the N-1 regioisomer of 5-methoxy-2-(2/7-1 ,2,3-triazol-2- yl)benzoic acid of 92.5:7.5.
  • the reaction mass was cooled at the temperature of about 70°C and 48.6 mL of water were added.
  • the resulting mixture was slowly cooled to the temperature of about 30°C and kept under stirring for 2 hours.
  • the resulting solid in the mixture was filtered and washed successively with three fractions of 50 mL of acetonitrile each.
  • the X-ray diffractogram (XRPD) of the product of Example 1 has the following peaks (° 20): 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 of them with a margin of error of ⁇ 0.2° 20.
  • the X-ray powder 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 about 284.5°C and of about 303.0°C.
  • Example 2 The solid obtained following the methodology of Example 1 was mixed with 600 mL of water. About 30 mL of solvent were vacuum distilled at the temperature of between 55 and 65°C. 30 mL of water were added and about 30 mL more of solvent were vacuum distilled again. 30 mL of water were added and the obtained suspension was filtered at the temperature of about 50°C to remove insoluble components. The filtrate was washed with 3 fractions of water of 50 mL each previously heated to the temperature of about 50°C. About 400 mL of water were vacuum distilled and the obtained solution was cooled at the temperature of about 20°C.
  • a suspension of 38.8 g (0.216 mol) of the hydrochloride of methyl (S)-2-methylpyrrolidin-2- carboxylate (VI HCI) in 270 mL of dichloromethane was prepared.
  • the reaction mass was kept under stirring at a temperature of about 20°C until obtaining a solution.
  • the obtained solution was cooled to the temperature of between 0 and 10°C and 118 mL (0.847 mol) of triethylamine were slowly added.
  • the reaction mixture was kept under stirring for 10 minutes at the indicated temperature and the solution obtained in the first point of the current example was slowly added thereto, maintaining the temperature between 0 and 5°C.
  • the reaction mixture was kept under stirring for 3 hours at the temperature of about 10°C and for 2 more hours at the temperature of about 20°C.
  • reaction mass was cooled to the temperature of between 0 and 10°C and 190 mL of water were slowly added followed by 60 mL of a 5% aqueous Na2COs solution.
  • the temperature of the mixture was left to reach about 20°C and was then kept under stirring for 30 minutes.
  • the aqueous phase was separated from the organic phase and washed successively with two fractions of 35 mL of dichloromethane each.
  • the organic phases thus obtained were combined and the resulting organic phase was washed with a fraction of 110 mL of water.
  • the solvent was removed from the solution thus obtained by means of vacuum distillation to obtain a light brown solid (about 73 g (0.211 mol)) which was used in the next step of synthesis.
  • Example 3 The solid obtained following the methodology described in Example 3 was dissolved in 365 mL of methanol at the temperature of about 20°C. 141 mL (0.637 mol) of a 16 wt% aqueous NaOH solution were slowly added, maintaining the indicated temperature, and once the addition has ended the resulting solution was heated to the temperature of about 80°C. The solution was kept under stirring at the indicated temperature for 2 hours.
  • the differential scanning calorimetry (DSC) spectrum of the compound of formula (VIII) comprises an endothermic peak having a threshold temperature of about 173.5°C.
  • reaction mass was cooled to the temperature of between 5 and 10°C and 250 mL of water were slowly added followed by 100 mL of a 5% aqueous Na2COs solution.
  • the temperature of the mixture was left to reach about 20°C and it was kept under stirring for 30 minutes.
  • the aqueous phase was separated from the organic phase and washed successively with two fractions of 80 mL of dichloromethane each.
  • the organic phases thus obtained were combined and the resulting organic phase was washed with a fraction of 100 mL of water.
  • the solvent was removed from the solution thus obtained by means of vacuum distillation to obtain a solid to which 180 mL of isopropyl acetate were added.
  • the differential scanning calorimetry (DSC) spectrum of the compound of formula (XI) comprises an endothermic peak having a threshold temperature of about 179.7°C.
  • the mixture was filtered through diatomaceous earth at the temperature of about 35°C, the filtrate was washed with three fractions of 35 mL of methanol each. 31.6 mL of a 32% aqueous HCI solution were slowly added to the colorless solution obtained and the obtained solution was heated at the temperature of about 65°C. The reaction mixture was kept under stirring for 5 hours at the indicated temperature.

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Abstract

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

Description

DESCRIPTION
METHOD FOR THE SYNTHESIS OF 5-METHOXY-2-(2H-1,2,3-TRIAZOL-2-YL)BENZOIC ACID, A SODIUM SALT OF SAID ACID AS A SYNTHETIC INTERMEDIATE, AND USE OF THE ACID OR THE SALT THEREOF IN THE PREPARATION OF DARIDOREXANT AND CERTAIN INTERMEDIATES IN THE SYNTHESIS THEREOF.
Field of the Invention
Method for the synthesis of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid, a sodium salt of said acid as a synthetic intermediate, and use of the acid or the salt thereof in the preparation of daridorexant and certain intermediates in the synthesis thereof.
Background of the Invention
Daridorexant is a dual orexin receptor antagonist that acts on orexin 1 and orexin 2 receptors. The neuropeptides orexin A and orexin B act on orexin receptors by promoting wakefulness. Daridorexant antagonizes orexin receptor activation by said neuropeptides and, as a result, reduces wakefulness activation, making it easier to fall asleep without altering sleep structure. Consequently, daridorexant (Quviviq®) is indicated for the treatment of insomnia.
As a medicinal product, 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-1 H-benzimidazol-2-yl)-2- methylpyrrolidin-1-yl]-[5-methoxy-2-(triazol-2-yl)phenyl]methanone and has the following chemical structure:
Daridorexant International patent application WO 2013/182972 A1 (see page 91), which describes daridorexant (page 56, line 1), also provides a general pathway for the synthesis of daridorexant (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 of formula Ar1-COOH is 5-methoxy-2-(2/7-1 ,2,3-triazol-2- yl)benzoic acid, the synthesis of which is described in example A.2 on page 99 of international patent application WO 2013/182972 A1.
Said method starts from 2-yodo-5-methoxybenzoic acid which is reacted with 1/7-1 ,2,3-triazole in the presence of Cui and CS2CO3 in DMF at 80°C. The reaction product is a salt that is neutralized with 1M aqueous HCI and extracted with ethyl acetate.
As described in said example, 313 mg (1.428 mmol) of (lll-H) are obtained from 1.798 mmol of (I), with this representing a yield of 79.4%.
The method for obtaining 5-methoxy-2-(2/7-1 ,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, said application describes (see reference example 1) that the reaction is not regiospecific because 1/7-1 ,2,3-triazole reacts partially through the central nitrogen atom (nitrogen 2) to yield the desired product (5-methoxy-2-(2/7-1 ,2,3-triazol-2-yl)benzoic acid), however, it also reacts through the lateral nitrogen atoms (nitrogen atoms 1 or 3) to yield the unwanted regioisomer, 5-methoxy-2-(1/7-1 ,2,3-triazol-1-yl)benzoic acid (IV-H):
As described in reference example 1 , the unwanted regioisomer (IV-H) represents 6% of the obtained product.
Furthermore due to the high structural similarity of compounds (lll-H) and (IV-H), their separation is complex.
There is therefore a need to provide more optimized methods for obtaining 5-methoxy-2-(2/7- 1 ,2,3-triazol-2-yl)benzoic acid, particularly with a higher yield and lower regioisomer (IV-H) content for the synthesis of said product on an industrial scale.
Summary of the Invention
After several tests, the inventors have developed an alternative method which, likewise starting from the compound of formula (I), allows obtaining the product of formula (lll-H) or its pharmaceutically acceptable salts with better yields and higher 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 purity, particularly with unwanted regioisomer (lll-H) contents below 1 %.
Therefore, in a first aspect, the present invention relates to a method for obtaining 5-methoxy- 2-(2/7-1 ,2,3-triazol-2-yl)benzoic acid of formula (lll-H):
(lll-H) which comprises: a) reacting 2-yodo-5-methoxybenzoic acid (I) with 1 /7-1 ,2,3-triazole (II) in the presence of C112O and a sodium salt, preferably Na2COs, to obtain the sodium salt of 5-methoxy-2- (2/7-1 ,2,3-triazol-2-yl)benzoic acid (lll-Na) b) reacting the sodium salt of 5-methoxy-2-(2/7-1 ,2,3-triazol-2-yl)benzoic acid (lll-Na) with an acid having a pKa below 4 to obtain 5-methoxy-2-(2/7-1 ,2,3-triazol-2-yl)benzoic acid (lll-H)
(lll-H) in a solution of organic solvent.
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 (lll-Na) which is an intermediate in the method according to the first aspect of the invention.
In a third aspect, the present invention relates to a method for obtaining methyl (S)-1-(5- methoxy-2-(2/7-1 ,2,3-tnazol-2-yl)benzoyl)-2-methylpyrrohdin-2-carboxylate (VII): which comprises: a) preparing the compound of formula (lll-H) as described in the first aspect of the invention b) reacting the compound of formula (lll-H) with a carboxylic acid chloride forming agent to obtain the compound of formula (V): c) reacting the compound of formula (V) with methyl (S)-2-methylpyrrolidin-2-carboxylate
(VI) 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 method for obtaining (S)-1-(5-methoxy-2- (2/7-1 ,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidin-2-carboxylic acid (VIII):
which comprises: a) preparing the compound of formula (VII) as described in the third aspect of the invention b) reacting 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 method for obtaining daridorexant or a salt thereof: Daridorexant which comprises: a) preparing the compound of formula (VIII) as described in the fourth aspect of the invention; b) reacting the compound of formula (VIII) with a carboxylic acid chloride forming agent to obtain the compound of formula (IX): c) reacting the compound of formula (IX) with 4-chloro-3-methylbenzene-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 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 reacting the daridorexant obtained in step e) with an acid to obtain a daridorexant salt with the anion of said acid.
In a sixth aspect, the invention relates to the use of the compound of formula (lll-Na) or the crystalline forms of said compound in the preparation of daridorexant or the pharmaceutically acceptable salts thereof.
Description of the Figures
Figure 1 shows the X-ray diffractogram (XRPD) of the product of Example 1 .
Detailed Description of the Invention
Method for preparing the compound of formula (lll-H)
In a first aspect, the present invention relates to a method for obtaining 5-methoxy-2-(2/7-1 ,2,3- triazol-2-yl)benzoic acid of formula (lll-H):
(lll-H) which comprises: a) reacting 2-yodo-5-methoxybenzoic acid (I) with 1 /7-1 ,2,3-triazole (II) in the presence of C112O and a sodium salt, preferably Na2COs, to obtain the sodium salt of 5-methoxy-2- (2/7-1 ,2,3-triazol-2-yl)benzoic acid (lll-Na)
(lll-Na) b) reacting the sodium salt of 5-methoxy-2-(2/7-1 ,2,3-triazol-2-yl)benzoic acid (lll-Na) with an acid having a pKa below 4 to obtain 5-methoxy-2-(2/7-1 ,2,3-triazol-2-yl)benzoic acid (lll-H)
(lll-H) in a solution of organic solvent.
In an embodiment of the first aspect of the invention, step a) is carried out in an aprotic polar solvent.
The term “aprotic polar solvent” refers to a solvent that lacks an acidic proton and is polar such as ethyl acetate, acetone, acetonitrile, dichloromethane, dimethylacetamide, dimethylformamide, dimethyl propylene urea, dimethylsulfoxide, hexamethylphosphoramide, N-methylpyrrolidin-2-one, pyridine, sulfolane, and tetrahydrofuran. An aprotic polar solvent of particular interest is acetonitrile.
In an embodiment of the first aspect of the invention, step a) is carried out at a temperature comprised 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 mixture of solvents comprising water and a solvent not miscible in water which allows maintaining the compound of formula (lll-H) in solution, such as dichloromethane or methyl-tert-butyl ether.
In an embodiment of the first aspect of the invention, step b) is carried out using an acid having a pKa below 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.
Method for obtaining methyl (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2- methyloyrrolidin-2-carboxylate (VII)
In a third aspect, the present invention relates to a method for obtaining methyl (S)-1-(5- methoxy-2-(2/7-1 ,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidin-2-carboxylate (VII): which comprises: a) preparing the compound of formula (lll-H) as described in the first aspect of the invention b) reacting the compound of formula (lll-H) with a carboxylic acid chloride forming agent to obtain the compound of formula (V): c) reacting the compound of formula (V) with methyl (S)-2-methylpyrrolidin-2-carboxylate
(VI) 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 used 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 which is selected from the group consisting of oxalate, hydrobromide, and hydrochloride salts, preferably hydrochloride salts.
In an embodiment of the third aspect of the invention, the organic amine used in step c) is selected from the group consisting of Ci-C4-trialkylamines, preferably triethylamine, trimethylamine, and diisopropylethylamine, preferably triethylamine.
Method for obtaining (S)-1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidin-2- carboxylic acid (VIII)
In a fourth aspect, the present invention relates to a method for obtaining (S)-1-(5-methoxy-2- (2/7-1 ,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidin-2-carboxylic acid (VIII): which comprises: a) preparing the compound of formula (VII) as described in the third aspect of the invention b) reacting 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.
Method for obtaining daridorexant (VIII)
In a fifth aspect, the present invention relates to a method for obtaining daridorexant or a salt thereof:
Daridorexant which comprises: a) preparing the compound of formula (VIII) as described in the fourth aspect of the invention; b) reacting the compound of formula (VIII) with a carboxylic acid chloride forming agent to obtain the compound of formula (IX): c) reacting the compound of formula (IX) with 4-chloro-3-methylbenzene-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 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 reacting the daridorexant obtained in step e) with an acid to obtain a daridorexant salt with the anion of said acid.
In an embodiment of the fifth aspect, the carboxylic acid chloride forming agent used in the 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-C4-trialkylamines, preferably triethylamine, trimethylamine, and diisopropylethylamine, preferably triethylamine. In an embodiment of the fifth aspect of the invention, step d) is performed 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 yield the corresponding daridorexant salt, and steps e) and f) are omitted.
In another embodiment of the fifth aspect of the invention, step d) is performed 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 performed, using in said steps 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 take an ionic form or are charged and coupled with a counterion (a cation or anion) or are in solution. For example, salts of the compounds of formula (I) can be acid addition salts and can be synthesized from the original compound containing a basic residue by means of conventional chemical methods. Generally, such salts are prepared, for example, by reacting the free base forms of those compounds with a stoichiometric amount of a suitable acid in water or in an organic solvent or in a mixture thereof. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Examples of acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate.
Use of the compound of formula (lll-Na)
The compound of formula (lll-Na), as well as its crystalline forms, described herein is a novel intermediate used in the method for the synthesis of daridorexant and the pharmaceutically acceptable salts thereof. To that end, in another aspect, the invention relates to the use of the compound of formula (III- Na) or the crystalline forms of said compound in the preparation of daridorexant and the pharmaceutically acceptable salts thereof.
In the context of the present invention, the 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 A, particularly 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 transition and the baseline during energy absorption (tangent of the curve). It can be calculated as defined in DIN ISO 11357-1 :2016(E) standard.
In the context of the present invention, the terms “approximate” and “about” when referring to a value are used to indicate any value comprised in the range defined by a lower limit of -5% of said value and an upper limit of +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 the understanding of the preceding ideas, some examples of the experimental methods and embodiments of the present invention are described below. Said examples are merely illustrative.
Examples
Materials and methods
A) The purity of all the obtained products, with the exception of the end product, i.e., the daridorexant hydrochloride salt, was analyzed by means of the ultra-high resolution liquid chromatography technique in a Waters Acquity model apparatus provided with a photodiode detector, a mass detector, and a thermostatted oven for the column. A BEH C18 column (100 x 2.1 mm; 1.7 pm) and mobile phases A (200 mM of ammonium formate, pH 4.8), B (acetonitrile), and C (water) were used with the following analysis conditions:
Flow rate: 0.5 mL/min
Column temperature: 45°C
Wavelength: 210 nm
Injection volume: 1 pL
Diluent: acetonitrile/water (1 :1)
Gradient:
B) The purity of the end product, i.e., daridorexant hydrochloride salt, was analyzed by means of the ultra-high resolution liquid chromatography technique in a Waters Acquity model apparatus provided with a photodiode detector, a mass detector, and a thermostatted oven for the column. A BEH C18 column (100 x 2.1 mm; 1.7 pm) and mobile phases A (200 mM of ammonium formate, pH 4.8), B (acetonitrile), and C (water) were used with the following analysis conditions:
Flow rate: 0.5 mL/min
Column temperature: 45°C
Wavelength: 210 nm
Injection volume: 1 pL
Diluent: acetonitrile/water (1 :1)
Gradient: Differential scanning calorimetry (DSC)
DSC analysis for the compound, sodium salt of 5-methoxy-2-(triazol-2-yl)benzoic acid, was performed in a Mettler Toledo 822e apparatus with STARe SW15 software using the following parameters: heating interval of 30 to 500°C with a ramp of 8°C/min and an N2 flow of 60 mL/min. The measurement is taken with a closed perforated capsule.
DSC analysis for the rest of the compounds in which the result is indicated was performed in a Mettler Toledo 822e apparatus with STARe SW15 software using the following parameters: heating interval of 30 to 300°C with a ramp of 10°C/min and an N2 flow of 50 mL/min. The measurement is taken with a closed perforated 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 is CuKa with a wavelength of 1.54 A. The following scan parameters were used: 3-50 degrees 20, continuous scan, ratio: 5.6 degrees/minute.
Example 1. Synthesis of the sodium salt of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (lll-Na)
75 g (0.270 mol) of 2-yodo-5-methoxybenzoic acid (I) were dissolved in 1500 mL of acetonitrile at the temperature of about 20°C. 39 mL of 1/7-1 ,2,3-triazole (II) (0.673 mol) were added, maintaining the indicated temperature. The mixture obtained was kept under stirring for 5 minutes to obtain a solution to which 71.48 g (0.674 mol) of sodium carbonate were added. The suspension obtained was heated to the temperature of about 40°C and 11.58 g (0.081 mol) of copper oxide (I) were added, maintaining the indicated temperature. The reaction mass was heated to the reflux temperature (temperature of between 85 and 90°C) and kept under stirring for 20 hours in the indicated conditions.
Thereafter, the reaction mass was controlled by means of UHPLC analysis to observe a ratio between the N-2 regioisomer and the N-1 regioisomer of 5-methoxy-2-(2/7-1 ,2,3-triazol-2- yl)benzoic acid of 92.5:7.5. The reaction mass was cooled at the temperature of about 70°C and 48.6 mL of water were added. The resulting mixture was slowly cooled to the temperature of about 30°C and kept under stirring for 2 hours. The resulting solid in the mixture was filtered and washed successively with three fractions of 50 mL of acetonitrile each. Finally, it was dried in a vacuum oven at the 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 (99.24% purity and regioisomers N-2 (lll-H) and N-1 (IV-H) ratio of 99.5:0.5 by means of UHPLC).
The X-ray diffractogram (XRPD) of the product of Example 1 has the following peaks (° 20): 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 of them with a margin of error of ± 0.2° 20. The X-ray powder 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 about 284.5°C and of about 303.0°C.
Example. 2. Synthesis of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (lll-H)
(lll-Na) (lll-H)
The solid obtained following the methodology of Example 1 was mixed with 600 mL of water. About 30 mL of solvent were vacuum distilled at the temperature of between 55 and 65°C. 30 mL of water were added and about 30 mL more of solvent were vacuum distilled again. 30 mL of water were added and the obtained suspension was filtered at the temperature of about 50°C to remove insoluble components. The filtrate was washed with 3 fractions of water of 50 mL each previously heated to the temperature of about 50°C. About 400 mL of water were vacuum distilled and the obtained solution was cooled at the temperature of about 20°C. 300 mL of dichloromethane were added and the pH was adjusted to a value of between 4 and 6 by means of adding a 36% aqueous HCI solution and then to a value of between 3 and 4 by means of adding a saturated citric acid solution. The resulting mixture was kept under stirring at the temperature between 30 and 35°C for 1 hour and the aqueous phase was then separated from the organic phase. The aqueous phase was washed successively with two fractions of 75 mL of dichloromethane each. The organic phases thus obtained were combined, the solution was treated with Na2SC>4 anhydrous to remove remaining water and a final solution comprising 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (lll-H) was obtained (46.2 g (0.211 mol) of product according to the UHPLC analysis of the contents of the solution), which was used in the subsequent step of synthesis.
Example 3. Synthesis of methyl (S)-1-(5-methoxy-2-(2/7-1 ,2,3-triazol-2-yl)benzoyl)-2- methylpyrrolidin-2-carboxylate (VII)
About 200 mL of dichloromethane were removed from the solution obtained following the methodology described in Example 2 above by means of vacuum distillation. 9 mL of DMF were added to the resulting solution and 23.5 mL (0.274 mol) of oxalyl chloride were then slowly added, maintaining the temperature between 18 and 22°C. The resulting solution was kept under stirring at the temperature of about 20°C for 1 hour.
A suspension of 38.8 g (0.216 mol) of the hydrochloride of methyl (S)-2-methylpyrrolidin-2- carboxylate (VI HCI) in 270 mL of dichloromethane was prepared. The reaction mass was kept under stirring at a temperature of about 20°C until obtaining a solution. The obtained solution was cooled to the temperature of between 0 and 10°C and 118 mL (0.847 mol) of triethylamine were slowly added. The reaction mixture was kept under stirring for 10 minutes at the indicated temperature and the solution obtained in the first point of the current example was slowly added thereto, maintaining the temperature between 0 and 5°C. The reaction mixture was kept under stirring for 3 hours at the temperature of about 10°C and for 2 more hours at the temperature of about 20°C.
Thereafter, the reaction mass was cooled to the temperature of between 0 and 10°C and 190 mL of water were slowly added followed by 60 mL of a 5% aqueous Na2COs solution. The temperature of the mixture was left to reach about 20°C and was then kept under stirring for 30 minutes. The aqueous phase was separated from the organic phase and washed successively with two fractions of 35 mL of dichloromethane each. The organic phases thus obtained were combined and the resulting organic phase was washed with a fraction of 110 mL of water. The solvent was removed from the solution thus obtained by means of vacuum distillation to obtain a light brown solid (about 73 g (0.211 mol)) which was used in the next step of synthesis.
Example 4. Synthesis of (S)-1-(5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoyl)-2- methylpyrrolidin-2-carboxylic acid (VIII)
The solid obtained following the methodology described in Example 3 was dissolved in 365 mL of methanol at the temperature of about 20°C. 141 mL (0.637 mol) of a 16 wt% aqueous NaOH solution were slowly added, maintaining the indicated temperature, and once the addition has ended the resulting solution was heated to the temperature of about 80°C. The solution was kept under stirring at the indicated temperature for 2 hours.
Thereafter, the solvent was removed by means of vacuum distillation. 25 mL of water were added to the residue obtained and the solvent was again removed by means of vacuum distillation. 25 mL of water were added again to the residue obtained and the solvent was again removed by means of vacuum distillation. 220 mL of water were added and the pH of the solution was adjusted to a value of about 5 with the addition of a 36% aqueous HCI solution and then to a value of about 3 with the addition of a saturated aqueous citric acid solution. 245 mL of dichloromethane were added to the obtained mixture to obtain a solution. The aqueous phase was separated from the organic phase and washed with two fractions of 35 mL of dichloromethane each. The organic phases thus obtained were combined and the resulting organic phase was washed with a fraction of 90 mL of water. 1 .9 g of active carbon were added and the resulting mixture was kept under stirring at the temperature of between 30 and 35°C for 30 minutes. The mixture was filtered through diatomaceous earth at the indicated temperature and the filtrate was washed with 3 fractions of 15 mL of dichloromethane each. The solvent was removed by means of vacuum distillation and 45 mL of dichloromethane and 220 mL of toluene were added. About 35 mL of solvent were vacuum distilled and 35 mL of toluene were added, maintaining the obtained mixture at the temperature of about 70°C for 30 minutes. The mixture was slowly cooled to the temperature of about 20°C and kept under stirring for one hour at said temperature. The resulting solid in the mixture was filtered and washed successively with three fractions of 15 mL of toluene each. Finally, it was dried in a vacuum oven at the 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-methylpyrrolidin-2- carboxylic acid (VIII) (64.5% yield from compound (VII), 95.34% purity by means of UHPLC).
The differential scanning calorimetry (DSC) spectrum of the compound of formula (VIII) comprises an endothermic peak having a threshold temperature of about 173.5°C.
Example 5. Synthesis of (S)-N-(2-amino-4-chloro-3-methylphenyl)-1-(5-methoxy-2-(2/7-1 ,2,3- triazol-2-yl)benzoyl)-2-methylpyrrolidin-2-carboxamide (XI)
93 g (0,281 mol) of (2S)-1-[5-methoxy-2-(triazol-2-yl)benzoyl]-2-methyl-pyrrolidin-2-carboxylic acid (VIII) were mixed with 500 mL of dichloromethane and 4.5 mL of DMF at the temperature of about 20°C. 27.8 mL (323.8 mol) of oxalyl chloride were slowly added to the preceding mixture, maintaining the temperature below 20°C. The resulting solution was kept under stirring at the temperature of about 20°C for 1 hour. 44.1 g (0.281 mol) of 4-chloro-3-methylbenzene-1 ,2-diamine (X) were dissolved with 465 mL of dichloromethane at the temperature of about 20°C. 118 mL of triethylamine were then slowly added at the temperature of between 5 and 10°C. The reaction mixture was kept under stirring for 10 minutes at the indicated temperature and the solution obtained in the first point of the current example was slowly added thereto, maintaining the temperature between 5 and 10°C. After the addition, the reaction mass was allowed to reach the temperature of about 20°C and kept under stirring for 3 hours at the indicated temperature.
Thereafter, the reaction mass was cooled to the temperature of between 5 and 10°C and 250 mL of water were slowly added followed by 100 mL of a 5% aqueous Na2COs solution. The temperature of the mixture was left to reach about 20°C and it was kept under stirring for 30 minutes. The aqueous phase was separated from the organic phase and washed successively with two fractions of 80 mL of dichloromethane each. The organic phases thus obtained were combined and the resulting organic phase was washed with a fraction of 100 mL of water. The solvent was removed from the solution thus obtained by means of vacuum distillation to obtain a solid to which 180 mL of isopropyl acetate were added. About 40 mL of solvent were vacuum distilled and 450 mL of methyl-tert-butyl ether were added, maintaining the temperature between 50 and 55°C, and the obtained suspension was kept under stirring for 1 hour at the indicated temperature. It was then cooled to the temperature of about 20°C and kept under stirring at said temperature for 2 hours. The resulting solid in the mixture was filtered and washed successively with three fractions of 60 mL of methyl-tert-butyl ether each. Finally, it was dried in a vacuum oven at the temperature of 50°C to obtain 111.5 g of a creamcolored solid corresponding to (S)-N-(2-amino-4-chloro-3-methylphenyl)-1-(5-methoxy-2-(2/7- 1 ,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidin-2-carboxamide (XI) (84.5% yield, 98.61 % purity).
The differential scanning calorimetry (DSC) spectrum of the compound of formula (XI) comprises an endothermic peak having a threshold temperature of about 179.7°C.
Example 6. Synthesis of the hydrochloride salt of (S)-(2-(5-chloro-4-methyl-1 H- benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2/7-1 ,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-(2/7-1 ,2,3- triazol-2-yl)benzoyl)-2-methylpyrrolidin-2-carboxamide (XI) were mixed with 400 mL of methanol at the temperature of about 30°C. 21.5 mL of a 32% aqueous HCI solution were slowly added, maintaining the temperature between 30 and 35°C. 5 g of active carbon were added and the mixture was kept under stirring for 30 minutes at the indicated temperature. The mixture was filtered through diatomaceous earth at the temperature of about 35°C, the filtrate was washed with three fractions of 35 mL of methanol each. 31.6 mL of a 32% aqueous HCI solution were slowly added to the colorless solution obtained and the obtained solution was heated at the temperature of about 65°C. The reaction mixture was kept under stirring for 5 hours at the indicated temperature.
Thereafter, the solvent was removed by means of vacuum distillation and 50 mL of isopropanol, were added. The solvent was again removed by means of vacuum distillation and 1040 mL of isopropanol were added to the obtained residue, maintaining the temperature of about 50°C. The obtained suspension was kept under stirring for one hour at the temperature of between 50 and 55°C and then cooled to the temperature of about 20°C within three hours. The resulting mixture was kept under stirring at the indicated temperature for 2 hours and the resulting solid in the mixture was filtered and washed successively with three fractions of 40 mL of isopropanol each. Finally, it was dried in a vacuum oven at the temperature of 50°C to obtain 98.3 g of a white solid corresponding to the hydrochloride salt of (S)-(2-(5-chloro-4- methyl-1 H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1 -yl)(5-methoxy-2-(2H-1 ,2,3-triazol-2- yl)phenyl)methanone (daridorexant hydrochloride) (94.1 % yield, 99.95% purity). The X-ray powder diffractogram (XRPD) obtained for the product matched the one disclosed in European patent EP 3 077 390 B1 (Figure 1 of said document).

Claims

1 . A method for obtaining 5-methoxy-2-(2/7-1 ,2,3-triazol-2-yl)benzoic acid of formula (lll-H):
(lll-H) which comprises: a) reacting 2-yodo-5-methoxybenzoic acid (I) with 1 /7-1 ,2,3-triazole (II) in the presence of CU2O and a sodium salt, preferably Na2COs, to obtain the sodium salt of 5-methoxy-2- (2/7-1 ,2,3-triazol-2-yl)benzoic acid (lll-Na)
(lll-Na) ; and b) reacting the sodium salt of 5-methoxy-2-(2/7-1 ,2,3-triazol-2-yl)benzoic acid (lll-Na) with an acid having a pKa below 4 to obtain 5-methoxy-2-(2/7-1 ,2,3-triazol-2-yl)benzoic acid (lll-H) in a solution of organic solvent.
2. The method according to claim 1 , characterized in that step a) is carried out in an aprotic polar solvent, preferably acetonitrile.
3. The method according to any of claims 1 to 2, characterized in that step a) is carried out at a temperature comprised between 80 and 90°C, preferably between 85 and 90°C.
4. The method according to any of claims 1 to 3, characterized in that step b) is carried out in a mixture of solvents comprising water and a solvent not miscible in water, preferably dichloromethane or methyl-tert-butyl ether.
5. The method according to any of claims 1 to 4, characterized in that the acid having a pKa below 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. A sodium salt of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid of formula (I Il-Na) :
(lll-Na)
7. A crystalline form of the sodium salt of 5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid of formula (lll-Na), characterized in that it has an X-ray diffractogram (XRPD) measured with CuKa radiation with a wavelength of 1.54 A comprising 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 of them with a margin of error of ± 0.2° 20.
8. A method for obtaining methyl (S)-1-(5-methoxy-2-(2/7-1 ,2,3-triazol-2-yl)benzoyl)-2- methylpyrrolidin-2-carboxylate (VII): which comprises: a) preparing the compound of formula (III -H) according to any of claims 1 to 5; b) reacting the compound of formula (lll-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 (S)-2-methylpyrrolidin-2-carboxylate
(VI) or a salt thereof, preferably the hydrochloride: in the presence of an organic amine to obtain the compound of formula (VII):
9. The method according to claim 8, characterized in that the carboxylic acid chloride forming agent is oxalyl chloride.
10. The method according to any of claims 8 to 9, characterized in that the compound of formula (V) is used in the form of its hydrochloride salt.
11. The method according to any of claims 8 to 10, characterized in that the organic amine used in step c) is triethylamine.
12. A method for obtaining (S)-1-(5-methoxy-2-(2/7-1,2,3-triazol-2-yl)benzoyl)-2- methylpyrrolidin-2-carboxylic acid (VIII):
which comprises: a) preparing the compound of formula (VII) according to any 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. The method according to claim 12, characterized in that the inorganic base is sodium hydroxide.
14. A method for obtaining daridorexant or a salt thereof:
Daridorexant which comprises: a) preparing the compound of formula (VIII) according to any 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) reacting the compound of formula (IX) with 4-chloro-3-methylbenzene-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 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 reacting the daridorexant obtained in step e) with an acid to obtain a daridorexant salt with the anion of said acid.
15. The method according to claim 14, characterized in that step d) is performed using hydrochloric acid to yield daridorexant hydrochloride salt and steps e) and f) are omitted.
16. Use of the compound of formula (lll-Na) or the crystalline forms of said compound in the preparation of daridorexant or the pharmaceutically acceptable salts thereof.
PCT/EP2025/060068 2024-04-12 2025-04-11 Method for the synthesis of 5-methoxy-2-(2h-1,2,3-triazol-2-yl)benzoic acid, a sodium salt of said acid as a synthetic intermediate, and use of the acid or the salt thereof in the preparation of daridorexant and certain intermediates in the synthesis thereof Pending WO2025215225A1 (en)

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Citations (5)

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WO2013182972A1 (en) 2012-06-04 2013-12-12 Actelion Pharmaceuticals Ltd Benzimidazole-proline derivatives
US20140275065A1 (en) * 2013-03-13 2014-09-18 Janssen Pharmaceutica Nv Substituted 7-azabicyles and their use as orexin receptor modulators
WO2015083070A1 (en) 2013-12-03 2015-06-11 Actelion Pharmaceuticals Ltd Crystalline form of (s)-(2-(6-chloro-7-methyl-1h-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1 -yl)(5-methoxy-2-(2h-1,2,3-triazol-2-yl)phenyl)methanone and its use as orexin receptor antagonists
EP3077390B1 (en) 2013-12-03 2017-09-13 Idorsia Pharmaceuticals Ltd Crystalline salt form of (s)-(2-(6-chloro-7-methyl-1h-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2h-1,2,3-triazol-2-yl)phenyl)methanone as orexin receptor antagonist
WO2018202689A1 (en) * 2017-05-03 2018-11-08 Idorsia Pharmaceuticals Ltd Preparation of 2-([1,2,3]triazol-2-yl)-benzoic acid derivatives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013182972A1 (en) 2012-06-04 2013-12-12 Actelion Pharmaceuticals Ltd Benzimidazole-proline derivatives
US20140275065A1 (en) * 2013-03-13 2014-09-18 Janssen Pharmaceutica Nv Substituted 7-azabicyles and their use as orexin receptor modulators
WO2015083070A1 (en) 2013-12-03 2015-06-11 Actelion Pharmaceuticals Ltd Crystalline form of (s)-(2-(6-chloro-7-methyl-1h-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1 -yl)(5-methoxy-2-(2h-1,2,3-triazol-2-yl)phenyl)methanone and its use as orexin receptor antagonists
EP3077390B1 (en) 2013-12-03 2017-09-13 Idorsia Pharmaceuticals Ltd Crystalline salt form of (s)-(2-(6-chloro-7-methyl-1h-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2h-1,2,3-triazol-2-yl)phenyl)methanone as orexin receptor antagonist
WO2018202689A1 (en) * 2017-05-03 2018-11-08 Idorsia Pharmaceuticals Ltd Preparation of 2-([1,2,3]triazol-2-yl)-benzoic acid derivatives

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