Method for the synthesis of 2,4-dimethylpyrimidin-5-ol, novel intermediates therein, and use of the product in the synthesis of lemborexant

Abstract

To provide a novel method for synthesizing 2,4-dimethylpyrimidine-5-ol, a novel intermediate for the method, and use of a product in the synthesis of lemborexant.SOLUTION: The present invention provides a novel method for synthesizing 2,4-dimethylpyrimidine-5-ol, which is an important intermediate in synthesis of lemborexant, a novel intermediate for the method, and use of a product in the synthesis of lemborexant.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a novel method for the synthesis of 2,4-dimethylpyrimidin-5-ol, a useful intermediate in the synthesis of lemborexant, novel intermediates in that method, and the use of the product in the synthesis of lemborexant. [Background technology]

[0002] Lemborexant is a medication for the treatment of insomnia, which is characterized by difficulty falling asleep or staying asleep.

[0003] Lemborexant, or (1S,2R)-2-[(2,4-dimethylpyrimidin-5-yl)oxymethyl]-2-(3-fluorophenyl)-N-(5-fluoro-2-pyridinyl)cyclopropanecarboxamide, has the following chemical structure: [ka]

[0004] European Patent EP3178814B1 describes a method for obtaining lemborexant, which comprises the following steps: [ka]

[0005] As can be seen in the synthesis scheme above, the compound with the structure shown below, 2,4-dimethylpyrimidin-5-ol [ka] is a key intermediate for the production of lemborexant.

[0006] EP 3178814B1 refers to documents WO 2012 / 039371 and WO 2013 / 123240, which describe methods for obtaining the compound 2,4-dimethylpyrimidin-5-ol. Furthermore, EP 3178814B1 itself describes other methods for obtaining said intermediate.

[0007] The method described in document WO2012 / 039371 comprises the following steps: [ka]

[0008] The method described in document WO2013 / 123240 comprises the following steps: [ka]

[0009] The methods described in documents WO2012 / 039371 and WO2013 / 123240 are not suitable for the industrial production of 2,4-dimethylpyrimidin-5-ol because they use the expensive product 2,4-dichloro-5-methoxypyrimidine as a starting material, and contain the volatile intermediate 2,4-dimethyl-5-methoxypyrimidine or its hydrochloride salt, a hygroscopic product, as well as corrosive and irritating reagents (such as trimethylaluminum or boron tribromide) that require careful handling.

[0010] Therefore, European Patent EP3178814B1 has developed a method for synthesizing the industrially applicable intermediate 2,4-dimethylpyrimidin-5-ol, which solves the above problems.

[0011] The synthesis described in document EP 3178814 B1 comprises the following steps: [ka]

[0012] In this synthesis, the readily available compound 4-nitrophenol is used as the starting material, and N,N-dimethylformamide dimethyl acetal is used in step 2 of this method. Additionally, the 4-nitrophenyl group aids in the regioselective condensation in step 3 and also functions as a protecting group that can be separated under relatively mild conditions in hydrolysis step 4. Summary of the Invention

[0013] Although improvements to obtain the industrially important intermediate 2,4-dimethylpyrimidin-5-ol are described in EP 3178814 B1, there is a need to provide further optimized processes for the synthesis of said intermediate to the product lemborexant on an industrial scale, particularly in higher yields.

[0014] The inventors unexpectedly discovered that using N,N-dimethylformamide diethyl acetal instead of N,N-dimethylformamide dimethyl acetal in Step 2 of the preparation of 2,4-dimethylpyrimidin-5-ol (a key intermediate in the synthesis of lemborexant) described in EP 3178814B1 unexpectedly increased the yield. While the yield for this step described in EP 3178814B1 ranges from 41% to 55%, in the present invention, a yield of approximately 65% ​​is achieved by using N,N-dimethylformamide diethyl acetal. Furthermore, by replacing p-nitrophenol in EP 3178814B1 with o-nitrophenol, the yield is further improved, reaching approximately 85%. Furthermore, both the key intermediate 2,4-dimethylpyrimidin-5-ol and the synthetic process intermediate are obtained with high levels of purity.

[0015] Thus, in a first aspect, the present invention provides a compound of formula (I): [ka] or a stereoisomer or salt thereof, comprising reacting a compound of formula (II) [ka] reacting the compound with N,N-dimethylformamide diethyl acetal The present invention relates to a method comprising:

[0016] In a second aspect, the present invention provides a compound of formula (III): [ka] or a salt thereof, comprising: By carrying out the method as defined in the first aspect, a compound of formula (I): [ka] or a stereoisomer or salt thereof; and converting the compound of formula (I) or a stereoisomer or salt thereof into a compound of formula (III) or a salt thereof. The present invention relates to a method comprising:

[0017] Specifically, the method defined in the above aspect comprises: a) carrying out the method defined in the first aspect to obtain a compound of formula (I): [ka] or a stereoisomer or salt thereof; b) reacting the compound of formula (I) or a stereoisomer or salt thereof with a compound of formula (IV) or a salt thereof in the presence of a base to produce a compound of formula (V) or a salt thereof. [ka] ; and c) hydrolyzing the compound of formula (V) or a salt thereof to produce the compound of formula (III) or a salt thereof. Includes.

[0018] In a third aspect, the present invention provides a method for preparing lemborexant, comprising: a) carrying out the method defined in the second aspect to obtain a compound of formula (III): [ka] or a salt thereof; b) reacting the compound of formula (III) or a salt thereof with a compound of formula (VIII) in the presence of a base to produce a compound of formula (IX). [ka] c) hydrolyzing the compound of formula (IX) in the presence of a base to obtain a compound of formula (X): [ka] to produce a compound of; d) treating the compound of formula (X) with an oxidizing agent to obtain a compound of formula (XI): [ka] producing a compound of the formula: e) reacting the compound of formula (XI) with the compound of formula (XII) [ka] in the presence of a base and a coupling agent to produce lemborexant. The present invention relates to a method comprising:

[0019] In a fourth aspect, the present invention provides a compound of formula (IIa): [ka] The present invention relates to a crystalline form of the compound of formula (I).

[0020] In a fifth aspect, the present invention provides a compound of formula (Ia): [ka] or a stereoisomer or salt thereof.

[0021] In a sixth aspect, the present invention provides a compound of formula (Va): [ka] The present invention relates to the compound

[0022] In another aspect, the present invention relates to the use of the compound of formula (IIa), the compound of formula (Ia) or a stereoisomer or salt thereof, the compound of formula (Va), and / or a crystalline form of said compound in the preparation of the compound of formula (III) or a salt thereof.

[0023] In another aspect, the present invention relates to the use of the compound of formula (IIa), the compound of formula (Ia) or a stereoisomer thereof, the compound of formula (Va), and / or a crystalline form of the compound in the preparation of lemborexant.

[0024] In another aspect, the present invention relates to a crystalline form of the compound of formula (III), characterized in that the powder X-ray diffraction spectrum measured using CuKα radiation contains peaks at 12.8, 15.5, 16.6, 17.9, 21.8, 22.1, 23.6, 25.0, 25.7, 27.1, and 30.1°2θ±0.2°2θ. [Brief explanation of the drawings]

[0025] [Figure 1] FIG. 1 shows the powder X-ray diffraction diagram (XRPD) of the compound of formula (IIa) corresponding to 1-(2-nitrophenoxy)propan-2-one. [Figure 2] FIG. 2 shows the powder X-ray diffraction diagram (XRPD) of the compound of formula (Ia) corresponding to (Z)-4-(dimethylamino)-3-(2-nitrophenoxy)but-3-en-2-one. [Figure 3]FIG. 3 shows the powder X-ray diffraction diagram (XRPD) of the compound of formula (Va) corresponding to 2,4-dimethyl-5-(2-nitrophenoxy)pyrimidine. [Figure 4] FIG. 4 shows the powder X-ray diffraction diagram (XRPD) of the compound of formula (III) corresponding to 2,4-dimethylpyrimidin-5-ol. DETAILED DESCRIPTION OF THE INVENTION

[0026] Process for preparing compounds of formula (I) The first aspect of the present invention is a compound of formula (I) [ka] or a stereoisomer or salt thereof, comprising reacting a compound of formula (II): [ka] reacting the compound with N,N-dimethylformamide diethyl acetal The present invention relates to a method comprising:

[0027] The method is similar to that described in EP 3178814B1, but uses N,N-dimethylformamide diethyl acetal instead of N,N-dimethylformamide dimethyl acetal. Surprisingly, this reagent substitution provides a method with higher reaction yields. While the yields for this step described in EP 3178814B1 range from 41% to 55%, in the present invention, by using N,N-dimethylformamide diethyl acetal, yields of at least about 65% are achieved.

[0028] The -NO2 group (nitro group) in the compound of formula (I) may be in the ortho, meta, or para position (relative to the other phenyl ring substituents), preferably in the ortho or para position, more preferably in the ortho position.

[0029] When the -NO2 group of the compound of formula (I) is in the ortho position, the -NO2 group of the compound of formula (II) is also in the ortho position. When the -NO2 group of the compound of formula (I) is in the para position, the -NO2 group of the compound of formula (II) is also in the para position. When the -NO2 group of the compound of formula (I) is in the meta position, the -NO2 group of the compound of formula (II) is also in the meta position.

[0030] Compounds of formula (I) and (II) in which the -NO2 group is in the para position are described in EP3178814B1.

[0031] The inventors have found that the reaction yield is higher when the -NO2 group is in the ortho position. Therefore, in a preferred embodiment, the -NO2 group is in the ortho position.

[0032] In a preferred embodiment, the ratio of N,N-dimethylformamide diethyl acetal to the compound of formula (II) is 1 to 2 moles, more preferably 1.05 to 2 moles, and more preferably 1.05 to 1.3 moles, of N,N-dimethylformamide diethyl acetal per mole of the compound of formula (II).

[0033] The reaction can be carried out both in the presence and in the absence of a solvent.

[0034] In one embodiment, the reaction is carried out in the presence of a solvent. When the reaction is carried out in the presence of a solvent, the solvent is preferably an aromatic hydrocarbon, such as toluene or xylene, more preferably toluene.

[0035] In another embodiment, the reaction is carried out in the absence of a solvent.

[0036] The method can be carried out at a temperature of preferably 35°C to 90°C, more preferably 35°C to 60°C, even more preferably 35°C to 50°C, and even more preferably 45°C to 50°C.

[0037] The reaction is preferably carried out for at least 3 hours, preferably at least 4 hours, more preferably up to 24 hours. In one particular embodiment, the reaction is carried out for 3 to 6 hours.

[0038] The reaction is carried out while stirring the reaction mixture.

[0039] In a preferred embodiment, the reaction is followed by the next step of adding a protic or aprotic polar solvent, such as a C1-C4 alkanol solvent or a C1-C4 dialkyl ether, to the resulting reaction mixture. Examples of these solvents include isopropanol, tert-butanol, methyl tert-butyl ether, or diisopropyl ether. Preferably, 2 to 6 mL of solvent is added per gram of the compound of Formula (II), and preferably 3 to 5 mL of solvent is added per gram of the compound of Formula (II). The solvent used is preferably diisopropyl ether. Specifically, this process involves adding diisopropyl ether to the resulting reaction mixture. Preferably, after the solvent addition, the resulting mixture is cooled at a temperature of 20 to 25°C, preferably with stirring, more preferably for 10 to 15 hours. Preferably, after this time has elapsed, the mixture is cooled at a temperature of 0 to 5°C, preferably with stirring. This process produces a suspension, and the resulting solid (the compound of Formula (I)) can be separated by conventional means, such as filtration. Treatment with diisopropyl ether has the advantage of purifying the compound of formula (I).

[0040] Stereoisomers of the compounds of formula (I) refer to the position of the substituents relative to the double bond, which may be in the cis (Z) or trans (E) position.

[0041] The compounds of formula (I) refer to both the cis and trans isomers and any mixtures thereof, preferably the cis isomer.

[0042] The term "salt" should be understood to mean any form of the defined compound, whether in ionic form or carrying a charge, associated with a counterion (cation or anion), or in a dissolved state. For example, salts of compounds of formula (I) can be acid addition salts, which can be synthesized by conventional chemical methods from the parent compound containing a basic moiety. Generally, such salts are prepared, for example, by reacting the free base form of the compound with a stoichiometric amount of a suitable acid in water or an organic solvent, or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Examples of acid addition salts include inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate, and organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate.

[0043] Process for preparing compounds of formula (III) In a second aspect, the present invention provides a compound of formula (III), which is a key intermediate in the synthesis of lemborexant: [ka] or a salt thereof, comprising: By carrying out the method as defined in the first aspect, a compound of formula (I): [ka] or a stereoisomer or salt thereof; and converting the compound of formula (I) or a stereoisomer or salt thereof into a compound of formula (III) or a salt thereof. The present invention relates to a method comprising:

[0044] The conversion of a compound of formula (I) or a stereoisomer or salt thereof to a compound of formula (III) or a salt thereof can be carried out using any synthetic method known to those skilled in the art.

[0045] Preferably, the method comprises: a) carrying out the method defined in the first aspect to obtain a compound of formula (I): [ka] or a stereoisomer or salt thereof; b) reacting the compound of formula (I) or a stereoisomer or salt thereof with a compound of formula (IV) or a salt thereof in the presence of a base to produce a compound of formula (V) or a salt thereof. [ka] c) hydrolyzing the compound of formula (V) or a salt thereof to produce the compound of formula (III) or a salt thereof. Includes.

[0046] The first step of the method of the second aspect is to carry out the method of the first aspect of the invention, as described in detail above.

[0047] The -NO2 group (nitro group) in the compound of formula (I) may be in the ortho, meta, or para position (relative to the other phenyl ring substituents), preferably in the ortho or para position, more preferably in the ortho position.

[0048] When the -NO2 group of the compound of formula (I) is in the ortho position, the -NO2 group of the compound of formula (V) is also in the ortho position. When the -NO2 group of the compound of formula (I) is in the para position, the -NO2 group of the compound of formula (V) is also in the para position. When the -NO2 group of the compound of formula (I) is in the meta position, the -NO2 group of the compound of formula (V) is also in the meta position.

[0049] Compounds of formula (I) and (V) in which the -NO2 group is in the para position are described in EP3178814B1.

[0050] The inventors have found that the reaction yield is higher when the -NO2 group is in the ortho position. Therefore, in a preferred embodiment, the -NO2 group is in the ortho position.

[0051] Step b) of the method of the second aspect comprises reacting the compound of formula (I) or a stereoisomer or salt thereof with a compound of formula (IV) or a salt thereof in the presence of a base to produce a compound of formula (V) or a salt thereof. [ka] Includes.

[0052] The term "salt" should be understood to mean any form of the defined compound, whether in ionic form or carrying a charge, associated with a counterion (cation or anion), or in solution. For example, salts of the compounds of formula (I), formula (IV), and formula (V) can be acid addition salts and can be synthesized by conventional chemical methods from the original compound containing a basic moiety. Generally, such salts are prepared, for example, by reacting the free base form of the compound with a stoichiometric amount of a suitable acid in water or an organic solvent, or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Examples of acid addition salts include inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate, and organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate.

[0053] In one particular embodiment, the compound of formula (IV) is in the form of the hydrochloride salt.

[0054] Step b) of the process is carried out in the presence of a base. In the context of the present invention, the term "base" refers to a substance capable of accepting an (acidic) proton. Examples of bases suitable for step b) are alkali metal C1-C4 alkoxides, preferably sodium C1-C4 alkoxides, more preferably sodium ethoxide or sodium methoxide, and even more preferably sodium ethoxide.

[0055] The expression "alkali metal" refers to a metal selected from sodium, potassium, lithium, rubidium, cesium, and francium, preferably sodium or potassium, more preferably sodium.

[0056] The term "alkoxide" refers to an alkyl-O - "alkyl" refers to a straight or branched chain hydrocarbon radical, consisting of carbon and hydrogen atoms, free of unsaturation, having the indicated number of carbon atoms (e.g., 1 to 4, preferably 1 to 3, more preferably 1 or 2 carbon atoms, and connected by a single bond to O - Examples of alkoxides are methoxide, ethoxide, n-propoxide, isopropoxide, tert-butoxide, n-butoxide, preferably methoxide or ethoxide, more preferably ethoxide.

[0057] Specifically, in step b), the base is used in an amount of 1 to 4 moles, preferably 2 to 3 moles, more preferably 2.4 to 2.6 moles per mole of the compound of formula (IV) or a salt thereof.

[0058] Step b) is preferably carried out in the presence of a solvent selected from the group consisting of a C1-C4 alkanol, preferably ethanol, methanol, or mixtures thereof, even more preferably ethanol.

[0059] The term "alkanol" refers to an alkyl-OH group, where alkyl is as defined above. Examples of C1-C4 alkanols are methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, sec-butanol, iso-butanol, preferably methanol and ethanol.

[0060] Preferably, in step b), the alkyl groups of the alkanol and the alkoxide are the same. More preferably, step b) is carried out using sodium ethoxide as the base and ethanol as the solvent, or sodium methoxide as the base and methanol as the solvent, and even more preferably, step b) is carried out using sodium ethoxide as the base and ethanol as the solvent.

[0061] In one particular embodiment, in step b), the compound of formula (IV) or a salt thereof is used in an amount of 1 to 3 moles, preferably 1 to 4 moles, more preferably 2 to 3 moles, and even more preferably 2.2 to 2.6 moles, relative to 1 mole of the compound of formula (I) or a stereoisomer or salt thereof.

[0062] Specifically, step b) is carried out at a temperature of 50° C. to 80° C., preferably 65° C. to 80° C. Step b) is preferably carried out for 3 to 10 hours, preferably with stirring.

[0063] The compound of formula (V) in step b) is preferably not in the form of a salt, ie in the form of the free base.

[0064] The next step in the process of the second aspect is step c) of hydrolyzing the compound of formula (V) or a salt thereof to produce a compound of formula (III) or a salt thereof.

[0065] As explained above, the term "salt" should be understood to mean any form of the defined compound, whether it is in ionic form or has a charge, is associated with a counterion (cation or anion), or is in a dissolved state. For example, salts of the compound of formula (III) can be base addition salts, which can be synthesized by conventional chemical methods from the original compound containing an acidic moiety. Generally, such salts are prepared, for example, by reacting the free acid form of the compound with a stoichiometric amount of a suitable base in water or an organic solvent, or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Examples of base addition salts include inorganic salts such as ammonium, and organic alkali salts such as ethylenediamine, ethanolamine, N,N-dialkyleneethanolamine, triethanolamine, glucamine, and basic amino acid salts. Examples of metal salts include sodium, potassium, calcium, magnesium, aluminum, and lithium salts.

[0066] In a preferred embodiment, step c) is carried out in the presence of a base selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, and alkaline earth metal carbonates. Examples of bases are sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate, and magnesium carbonate.

[0067] The expression "alkaline earth metal" refers to metals selected from the group consisting of beryllium, magnesium, calcium, strontium, barium, and radium, preferably magnesium and calcium.

[0068] In a preferred embodiment, the base in step c) is an alkali metal hydroxide, preferably sodium hydroxide or potassium carbonate, more preferably sodium hydroxide.

[0069] Specifically, in step c), the base is used in an amount of 1 to 5 moles, preferably 2 to 4 moles, more preferably 2.5 to 3.5 moles per mole of the compound of formula (V) or a salt thereof.

[0070] In a preferred embodiment, step c) is carried out in the presence of an aqueous solvent, preferably a mixture of water and a C1-C4 alkanol, preferably a mixture of water and ethanol or a mixture of water and methanol, even more preferably a mixture of water and ethanol.

[0071] Specifically, step c) is carried out at a temperature of 50° C. to 80° C., preferably 60° C. to 70° C. Step c) is preferably carried out for 15 to 24 hours, preferably with stirring.

[0072] The compound of formula (III) obtained in step c) can be isolated from the reaction medium by conventional techniques.

[0073] In certain embodiments of the methods of the first and second aspects of the present invention, the compound of formula (II) is a compound of formula (VI) and a compound of formula (VII) [ka] where X is chlorine or bromine, preferably chlorine.

[0074] The -NO2 group (nitro group) in the compound of formula (VI) can be in the ortho, meta, or para position (relative to the other phenyl ring substituents), preferably in the ortho or para position, more preferably in the ortho position.

[0075] When the -NO2 group of the compound of formula (VI) is in the ortho position, the -NO2 group of the compound of formula (II) is also in the ortho position. When the -NO2 group of the compound of formula (VI) is in the para position, the -NO2 group of the compound of formula (II) is also in the para position. When the -NO2 group of the compound of formula (VI) is in the meta position, the -NO2 group of the compound of formula (II) is also in the meta position.

[0076] The inventors have found that the reaction yield is higher when the -NO2 group is in the ortho position. Therefore, in a preferred embodiment, the -NO2 group is in the ortho position.

[0077] In one particular embodiment, the compound of formula (VI) is used in an amount of 1 to 2 moles, preferably 1 to 1.5 moles, more preferably 1 to 1.1 moles, per mole of the compound of formula (VII).

[0078] In a preferred embodiment, the reaction of the compound of formula (VI) with the compound of formula (VII) is carried out in the presence of a base and a phase transfer catalyst.

[0079] The base is preferably an alkali metal or alkaline earth metal carbonate. Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate, and magnesium carbonate, preferably potassium carbonate. In one specific embodiment, the base is used in an amount of 1 to 2 moles, preferably 1 to 1.5 moles, more preferably 1 to 1.1 moles, per mole of the compound of formula (VI).

[0080] Examples of the phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium iodide and tetramethylammonium iodide. The phase transfer catalyst is preferably tetrabutylammonium iodide (TBAI). In one specific embodiment, the phase transfer catalyst is used in an amount of 0.001 to 0.1 g, preferably 0.001 to 0.01 g, per gram of the compound of formula (VI).

[0081] In a preferred embodiment, the base is an alkali metal or alkaline earth metal carbonate, preferably potassium carbonate, and / or the phase transfer catalyst is tetrabutylammonium iodide.

[0082] The reaction is preferably carried out in the presence of an organic solvent such as, for example, a C1-C4 dialkyl ketone (such as methyl ethyl ketone, acetone, or methyl isopropyl ketone), preferably methyl ethyl ketone.

[0083] Specifically, this reaction is carried out preferably for 3 to 6 hours at a temperature of 50 to 80° C., preferably 55 to 65° C. It is preferably carried out with stirring.

[0084] The resulting compound of formula (II) can be isolated from the reaction medium by conventional techniques.5

[0085] Method for preparing lemborexant In a third aspect, the present invention provides a method for preparing lemborexant, comprising: a) carrying out the method defined in the second aspect to obtain a compound of formula (III): [ka] or a salt thereof; b) reacting the compound of formula (III) or a salt thereof with a compound of formula (VIII) in the presence of a base to produce a compound of formula (IX). [ka] c) hydrolyzing the compound of formula (IX) in the presence of a base to obtain a compound of formula (X): [ka] to produce a compound of; d) treating the compound of formula (X) with an oxidizing agent to obtain a compound of formula (XI): [ka] producing a compound of the formula: e) reacting the compound of formula (XI) with a compound of formula (XII): [ka] in the presence of a base and a coupling agent to produce lemborexant. The present invention relates to a method comprising:

[0086] The first step of the method of the third aspect is to carry out the method of the second aspect of the invention, as described in detail above.

[0087] Step b) of the method of the third aspect comprises reacting the compound of formula (III) or a salt thereof with a compound of formula (VIII) in the presence of a base to produce a compound of formula (IX). [ka] Includes.

[0088] The compound of formula (VIII) can be obtained according to the synthesis method described in Example D of document EP 2814798 B1.

[0089] A suitable base for the reaction of step b) is an alkali metal carbonate, preferably cesium carbonate. Specifically, the base can be used in an amount of 1 to 2 moles, preferably 1.5 to 2 moles, per mole of the compound of formula (VIII). This reaction can be carried out in the presence of an organic solvent such as acetonitrile, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, ethyl acetate, and mixtures thereof, preferably acetonitrile. This reaction can be carried out at a temperature of 50°C to 80°C, preferably 65°C to 75°C. Specifically, step b) is carried out with stirring.

[0090] Compounds of formula (IX) can be obtained using the specific conditions described in Example D of document EP 2814798 B1, which is incorporated herein by reference.

[0091] Step c) of the method of the third aspect comprises hydrolyzing the compound of formula (IX) in the presence of a base to obtain a compound of formula (X): [ka] The method includes producing a compound of the formula:

[0092] A suitable base for the hydrolysis is an alkali metal hydroxide, preferably sodium hydroxide. Specifically, step c) is carried out in the presence of water. Specifically, step c) is carried out at a temperature of 20°C to 25°C. Preferably, step c) is carried out with stirring.

[0093] Compounds of formula (X) can be obtained using the specific conditions described in Example D of document EP 2814798 B1, which is incorporated herein by reference.

[0094] Step d) of the method of the third aspect comprises treating the compound of formula (X) with an oxidizing agent to produce a compound of formula (XI): [ka] To produce a compound of Includes.

[0095] The oxidizing agent in step d) is preferably NaClO or NaClO2. Oxidation with NaClO oxidizes the alcohol group to an aldehyde, and oxidation with NaClO2 oxidizes the aldehyde to an acid group, thereby producing a compound of formula (XI). Specifically, the oxidation is carried out in two steps: first, using NaClO, and then, in the second step, oxidizing the aldehyde with NaClO2 without isolating the formed aldehyde intermediate. Specifically, 1 to 1.5 moles of the oxidizing agent are used per mole of the compound of formula (X). Preferably, 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) is further used as a catalyst. Specifically, this reaction is carried out in the presence of an aromatic hydrocarbon, preferably toluene. Specifically, this reaction is carried out at a temperature of -5°C to 5°C. Preferably, the addition of the oxidizing agent / agent is carried out at a temperature of -5°C to 5°C, and the reaction mixture is maintained at 15°C to 25°C. Specifically, 1 to 1.5 moles of NaClO are used per mole of the compound of formula (X), and specifically, 1 to 1.2 moles of NaClO2 are used per mole of the compound of formula (X). Step d) is preferably carried out with stirring.

[0096] Compounds of formula (XI) can be obtained using the specific conditions described in Example F of document EP 2814798 B1, which is incorporated herein by reference.

[0097] Step e) of the method of the third aspect comprises reacting the compound of formula (XI) with a compound of formula (XII): [ka] in the presence of a base and a coupling agent to produce lemborexant. Includes.

[0098] A suitable base for carrying out step e) is an organic amine, preferably an N(C1-C4 alkyl)3 type amine, where each alkyl group is preferably independently selected from methyl, ethyl, and isopropyl. The organic amine is preferably N,N-diisopropylethylamine. Specifically, the base is used in an amount of 1 to 3 moles, preferably 1.8 to 2.2 moles, per mole of the compound of formula (XI).

[0099] An example of a coupling agent suitable for step e) is propylphosphonic anhydride (T3P). Specifically, the coupling agent is used in an amount of 1 to 2 moles, preferably 1.2 to 1.6 moles, per mole of the compound of formula (XI).

[0100] Specifically, step e) is carried out in the presence of an organic solvent, such as, for example, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, acetone, toluene, acetonitrile, dichloromethane, and mixtures thereof, preferably ethyl acetate. Step e) is preferably carried out with stirring.

[0101] Lemborexant can be obtained using specific conditions described in Example G of document EP2814798B1, which is incorporated herein by reference.

[0102] Compound of formula (IIa) In a fourth aspect, the present invention provides a compound of formula (IIa): [ka] The present invention relates to a crystalline form of the compound of formula (I).

[0103] In another embodiment, the crystalline form of the compound of formula (IIa) is characterized by a powder X-ray diffraction spectrum measured using CuKα radiation essentially similar to that shown in FIG.

[0104] In another embodiment, the crystalline form of the compound of Formula (IIa) is characterized by exhibiting a differential scanning calorimetry (DSC) diagram comprising an endothermic peak with a threshold temperature of about 57.6°C ± 2°C and an exothermic peak with a threshold temperature of about 208.0°C ± 2°C.

[0105] Compounds of formula (Ia) In a fifth aspect, the present invention provides a compound of formula (Ia): [ka] or a stereoisomer thereof.

[0106] In a preferred embodiment, the compound of formula (Ia) is characterized in that it is a crystalline solid having a powder X-ray diffraction spectrum measured using CuKα radiation, the X-ray diffraction spectrum containing peaks at 11.6, 16.6, 18.7, 21.5, 22.9, 23.4, 23.7, and 26.4°2θ±0.2°2θ.

[0107] In another embodiment, the compound of formula (Ia) is characterized as a crystalline solid having a powder X-ray diffraction spectrum, measured using CuKα radiation, essentially similar to that shown in FIG. 2.

[0108] In another embodiment, the compound of formula (Ia) is a crystalline solid as defined above, further characterized by exhibiting a differential scanning calorimetry (DSC) diagram comprising an endothermic peak with a threshold temperature of about 149.9°C ± 2°C and an exothermic peak with a threshold temperature of about 230.4°C ± 2°C.

[0109] Stereoisomers of the compounds of formula (Ia) refer to the position of the substituents relative to the double bond, which may be in the cis (Z) or trans (E) position.

[0110] The compounds of formula (Ia) refer to both the cis and trans isomers and any mixtures thereof, preferably the cis isomer.

[0111] Compound of formula (Va) In a sixth aspect, the present invention provides a compound of formula (Va): [ka] The present invention relates to the compound

[0112] In a preferred embodiment, the compound of formula (Va) is characterized in that it is a crystalline solid having a powder X-ray diffraction spectrum measured using CuKα radiation, the X-ray diffraction spectrum containing peaks at 12.5, 14.6, 17.6, 23.6, and 25.1°2θ±0.2°2θ.

[0113] In another embodiment, the compound of formula (Va) is characterized as a crystalline solid having a powder X-ray diffraction spectrum measured using CuKα radiation essentially similar to that shown in Figure 3.

[0114] In another embodiment, the compound of formula (Va) is a crystalline solid as defined above, further characterized by exhibiting a differential scanning calorimetry (DSC) diagram comprising an endothermic peak with a threshold temperature of about 104.9°C ± 2°C.

[0115] Uses of Compounds of Formula (IIa), Formula (Ia), and Formula (Va) The compounds of Formula (IIa), Formula (Ia), and Formula (Va), and their crystalline forms, described herein are novel intermediates in the synthesis of the compound of Formula (III) or a salt thereof and lemborexant.

[0116] Therefore, in another aspect, the present invention relates to the use of a compound of formula (IIa), a compound of formula (Ia) or a stereoisomer or salt thereof, a compound of formula (Va), or a crystalline form of said compound, as defined in the present invention, in the preparation of said compound of formula (III) or a salt thereof.

[0117] The compound of formula (III) or a salt thereof may be prepared using the intermediates as described in detail in the first and second aspects of the present invention.

[0118] In another aspect, the present invention relates to the use of a compound of formula (IIa), a compound of formula (Ia) or a stereoisomer or salt thereof, a compound of formula (Va), and / or a crystalline form of said compound, as defined herein, in the preparation of lemborexant.

[0119] Lemborexant can be prepared from the key intermediate of formula (III) using the synthetic methods described in EP 3178814 B1 and EP 2814798 B1 and the method defined in the third aspect of the present invention, which comprises the following steps: [ka]

[0120] Polymorphism of the compound of formula (III) In another aspect, the present invention relates to a crystalline form of the compound of formula (III), characterized in that the powder X-ray diffraction spectrum measured using CuKα radiation contains peaks at 12.8, 15.5, 16.6, 17.9, 21.8, 22.1, 23.6, 25.0, 25.7, 27.1, 30.1°2θ±0.2°2θ.

[0121] In another embodiment, the crystalline form of the compound of formula (III) is characterized by a powder X-ray diffraction spectrum measured using CuKα radiation essentially similar to that shown in Figure 4.

[0122] In another embodiment, the crystalline form of the compound of formula (III) is characterized by exhibiting a differential scanning calorimetry (DSC) diagram comprising an endothermic peak with a threshold temperature of about 137.1°C ± 2°C and an endothermic peak with a threshold temperature of about 267.9°C ± 2°C.

[0123] In the context of the present invention, X-ray diffraction patterns can be recorded in particular using a powder diffraction system equipped with a copper anode emitting CuKα radiation with a wavelength of 1.54 Å, according to the method described in the examples.

[0124] In the context of the present invention, differential scanning calorimetry diagrams can be obtained as described in the examples.

[0125] In the context of the present invention, the threshold temperature or "T onset" refers to the temperature obtained from the extrapolation (tangent to the curve) of the baseline before the onset of the transition and the baseline during energy absorption. It can be calculated as defined in the standard DIN ISO 11357-1:2016(E).

[0126] In the context of the present invention, the terms "approximately" and "about" refer to values ​​that are worthy of characterization within ±5% of the value stated.

[0127] In the context of the present invention, the term "base" refers to a substance that can accept a (acidic) proton.

[0128] To facilitate understanding of the above concepts, several examples of experimental methods and embodiments of the present invention will be described below, which are merely illustrative. [Example]

[0129] Example 1: Obtaining (Z)-4-(dimethylamino)-3-(4-nitrophenoxy)but-3-en-2-one 41.87 g (204.95 mmol) of 96.4% pure 1-(4-nitrophenoxy)propan-2-one was mixed with 120 mL of toluene and 40.7 mL of N,N-dimethylformamide diethyl acetal (225.44 mmol). The resulting mixture was heated to 80° C. to obtain a solution, which was then stirred at the indicated temperature for 21 hours.

[0130] After stirring at the temperature, 80 mL of toluene was added and the reaction mixture was cooled to a temperature of about 20°C. The reaction mass was then cooled to a temperature of 0-5°C and stirred for 1.5 hours. The resulting solid was filtered and dried in an oven at 25-30°C, finally obtaining 33.4 g of (Z)-4-(dimethylamino)-3-(4-nitrophenoxy)but-3-en-2-one (yield 65.1%). The purity was 99.9% by gas chromatography.

[0131] Example A1: Obtaining 1-(2-nitrophenoxy)propan-2-one 156.5 g (1.132 mol) of potassium carbonate was suspended in 900 mL of methyl ethyl ketone at approximately 20°C under a nitrogen atmosphere. While maintaining the temperature, 150.0 g (1.078 mol) of ortho-nitrophenol and 1 g of tetrabutylammonium iodide were slowly added. The resulting suspension was gradually heated to 60-65°C, and a previously prepared solution of 94.14 mL (1.132 mol) of chloroacetone in 100 mL of methyl ethyl ketone was slowly added at the same temperature interval. The reaction mixture was stirred for 4 hours at 60-65°C.

[0132] After stirring was continued at the temperature, the reaction mixture was cooled to a temperature of about 20° C., and the salt obtained from the reaction was filtered off. The solvent was distilled under vacuum to obtain 208.3 g of a solid corresponding to 1-(2-nitrophenoxy)propan-2-one (purity was 99.5% by gas chromatography).

[0133] The resulting product exhibits a differential scanning calorimetry (DSC) diagram containing an endothermic peak with a threshold temperature of about 57.6°C ± 2°C and an exothermic peak with a threshold temperature of about 208.0°C ± 2°C. 1 H-NMR (d6-DMSO, 400 MHz) δ (ppm): 7.92 (1H, dd), 7.63 (1H, t), 7.25 (1H, d), 7.16 (1H, t), 5.07 (2H, s), 2.21 (3H, s). 13 C-NMR (d6-DMSO, 400 MHz) δ (ppm): 203.94, 151.41, 140.34, 135.05, 125.85, 121.84, 116.08, 73.71, 27.04.

[0134] Figure 1 shows the X-ray powder diffraction diagram (XRPD, X-ray powder diffraction) obtained for 1-(2-nitrophenoxy)propan-2-one of Example A1, which has a crystalline form exhibiting peaks at the following angles (2θ) ±0.2: 9.9, 12.2, 16.2, 18.7, 20.0, 24.5, 27.0.

[0135] Example A2: Obtaining (Z)-4-(dimethylamino)-3-(2-nitrophenoxy)but-3-en-2-one 30.16 g (153.76 mmol) of 1-(2-nitrophenoxy)propan-2-one obtained in Example A1 was mixed with 32.3 mL of N,N-dimethylformamide diethyl acetal (184.46 mmol), and the resulting mixture was heated at a temperature of 45-50°C to obtain a solution, which was then stirred at the indicated temperature for 4 hours.

[0136] After continuing stirring at the same temperature, 120 mL of diisopropyl ether was slowly added, and the mixture temperature was maintained at 45-50°C. The resulting suspension was cooled to 20°C and stirred for 12 hours. Next, the mixture was cooled to 0-5°C, and the resulting solid was filtered and dried in an oven at 25-30°C. Finally, 33.3 g of (Z)-4-(dimethylamino)-3-(2-nitrophenoxy)but-3-en-2-one (85.2% yield from ortho-nitrophenol) was obtained. The purity was 99.6% by gas chromatography.

[0137] The resulting product exhibits a differential scanning calorimetry (DSC) diagram containing an endothermic peak with a threshold temperature of about 149.9°C ± 2°C and an exothermic peak with a threshold temperature of about 230.4°C ± 2°C. 1 H-NMR (d6-DMSO, 400 MHz) δ (ppm): 7.94 (d, 1H), 7.61 (d, 1H), 7.53 (s, 1H), 7.14 (t, 1H), 7.04 (s, 1H), 3.06 (s, 6H), 2.14 (s, 3H). 13 C-NMR (d6-DMSO, 400 MHz) δ (ppm): 197.6, 152.52, 144.64, 139.69, 135.30, 134.20, 125.99, 125.41, 121.81, 117.04, 25.00.

[0138] Figure 2 shows the X-ray powder diffraction diagram (XRPD, X-ray powder diffraction) obtained for (Z)-4-(dimethylamino)-3-(2-nitrophenoxy)but-3-en-2-one of Example A2, which has a crystalline form exhibiting peaks at the following angles (2θ) ±0.2: 11.6, 16.6, 18.7, 21.5, 22.9, 23.4, 23.7, 26.4.

[0139] Example A3: Obtaining 2,4-dimethyl-5-(2-nitrophenoxy)pyrimidine 49.3 g (695.6 mmol) of 96% EtONa was slowly added to 362 mL of ethanol while maintaining the temperature at 15-20°C. 67.1 g (695.6 mmol) of 98% acetamidine hydrochloride was slowly added to the resulting solution at 25-30°C. While maintaining the temperature, 72.5 g (289.7 mmol) of (Z)-4-(dimethylamino)-3-(2-nitrophenoxy)but-3-en-2-one was slowly added. The reaction mixture was heated to 75-80°C and stirred at this temperature for 4 hours.

[0140] After stirring was continued at the same temperature, the reaction mixture was cooled to 18-20°C and stirred at the same temperature for 1 hour, and the resulting solid was filtered. The solvent was removed from the resulting solution by vacuum distillation to obtain a solid corresponding to 2,4-dimethyl-5-(2-nitrophenoxy)pyrimidine.

[0141] The resulting product exhibits a differential scanning calorimetry (DSC) diagram containing an endothermic peak with a threshold temperature of about 104.9°C ± 2°C. 1 H-NMR (d6-DMSO, 400 MHz) δ (ppm): 8.40 (s, 1H), 8.14 (dd, 1H), 7.71 (m, 1H), 7.42 (m, 1H), 7.16 (dd, 1H), 2.64 (s, 3H), 2.40 (s, 3H). 13 C-NMR (d6-DMSO, 400 MHz) δ (ppm): 164.12, 159.43, 149.70, 148.30, 147.40, 141.16, 136.15, 126.80, 125.24, 119.99, 25.79, 19.32.

[0142] Figure 3 shows the powder X-ray diffractogram (XRPD, X-ray powder diffraction) obtained for 2,4-dimethyl-5-(2-nitrophenoxy)pyrimidine of Example A3, which has a crystalline form exhibiting peaks at the following angles (2θ) ±0.2: 12.5, 14.6, 17.6, 23.6, 25.1.

[0143] Example A4: Obtaining 2,4-dimethylpyrimidin-5-ol The solid obtained in the step of Example A3 was dissolved in 350 mL of methanol at a temperature of about 20° C. 72.4 g (869.1 mmol) of a previously prepared 48% by weight aqueous sodium hydroxide solution was slowly added while maintaining the temperature at 35-40° C. The reaction mixture was heated to a temperature of about 65° C. and kept stirring at said temperature for 20 hours.

[0144] After stirring at the temperature, the reaction mixture was cooled to 30-35°C, and approximately 150 mL of solvent was distilled off under vacuum. 325 mL of water and 70 mL of toluene were added, and the resulting mixture was stirred at 30-35°C for 1 hour. The resulting organic phase was separated, and 60 mL of toluene was added to the aqueous phase while maintaining the temperature. The new organic phase was separated, and the resulting aqueous phase was cooled to approximately 20°C. 36% aqueous HCl was slowly added until the pH reached approximately 3.5. The resulting aqueous solution was washed twice with 60 mL of toluene, and then the pH was adjusted to approximately 5.5 with 30% aqueous NaOH. 2 g of carbon and 2 g of diatomaceous earth were added, and the resulting mixture was stirred at 35-40°C for 30 minutes. The solid was separated by filtration, washed three times with 20 mL of water, and pooled with the previously obtained aqueous solution. The pH was adjusted to 6-7 with 30% aqueous NaOH, and 150 mL of ethyl acetate was added. The organic phase was separated, and the aqueous phase was washed twice with 150 mL of ethyl acetate. The solvent was removed from the pooled organic phases by vacuum distillation, yielding 32.0 g (257.8 mmol) of a solid equivalent to 2,4-dimethylpyrimidin-5-ol (88.9% yield from (Z)-4-(dimethylamino)-3-(2-nitrophenoxy)but-3-en-2-one). The purity was 99.6% by gas chromatography or 99.78% by UHPLC.

[0145] The resulting product exhibits a differential scanning calorimetry (DSC) diagram containing two endothermic peaks with threshold temperatures of about 137.1°C ± 2°C and 267.9°C ± 2°C.

[0146] Figure 4 shows the X-ray powder diffractogram (XRPD, X-ray powder diffraction) obtained for 2,4-dimethylpyrimidin-5-ol of Example A4, which has a crystalline form exhibiting peaks at the following angles (2θ) ±0.2: 12.8, 15.5, 16.6, 17.9, 21.8, 22.1, 23.6, 25.0, 25.7, 27.1, 30.1.

[0147] Example B1: Obtaining 1-(4-nitrophenoxy)propan-2-one 52.16 g (377.4 mmol) of potassium carbonate was suspended in 175 mL of methyl ethyl ketone at approximately 20°C under a nitrogen atmosphere. While maintaining the temperature, 50.0 g (359.4 mmol) of para-nitrophenol and 0.25 g of tetrabutylammonium iodide were slowly added. The resulting suspension was gradually heated to 55-60°C, and 31.4 mL of chloroacetone was slowly added at the same temperature interval. The reaction mixture was heated to 65-70°C and stirred at the same temperature for 4 hours.

[0148] After stirring was continued at the temperature, the reaction mixture was cooled to a temperature of about 20° C., and the salt obtained from the reaction was filtered. The solvent was distilled under vacuum to obtain 73.5 g of a solid corresponding to 1-(4-nitrophenoxy)propan-2-one.

[0149] Example B2: Obtaining (Z)-4-(dimethylamino)-3-(4-nitrophenoxy)but-3-en-2-one 31.4 g (153.7 mmol) of 1-(4-nitrophenoxy)propan-2-one obtained in Example B1 was mixed with 33.3 mL of N,N-dimethylformamide diethyl acetal (184.45 mmol), and the resulting mixture was heated at a temperature of 45-50°C to obtain a solution, which was then stirred at the indicated temperature for 4 hours.

[0150] After continuing stirring at the same temperature, 120 mL of diisopropyl ether was slowly added, and the mixture temperature was maintained at 45-50°C. The resulting suspension was cooled to 20°C and stirred for 12 hours. Next, the mixture was cooled to 0-5°C and stirred for 1 hour. The resulting solid was filtered and dried in an oven at 25-30°C, finally obtaining 26.36 g of (Z)-4-(dimethylamino)-3-(4-nitrophenoxy)but-3-en-2-one (68.6% yield from para-nitrophenol). The purity was 99.5% by gas chromatography.

[0151] Example B3: Obtaining 2,4-dimethyl-5-(4-nitrophenoxy)pyrimidine 24.4 g (252.8 mmol) of 98% acetamidine hydrochloride was mixed with 260 mL of methanol. While maintaining the temperature at 20-30°C, 45.5 g of a previously prepared 30% by weight solution of sodium methoxide in methanol was slowly added, followed by 26.36 g (105.3 mmol) of (Z)-4-(dimethylamino)-3-(4-nitrophenoxy)but-3-en-2-one. The reaction mixture was heated to a temperature of 65-70°C and stirred at this temperature for 6 hours.

[0152] After stirring was continued at the same temperature, the reaction mixture was cooled to 18-20°C and stirred at the same temperature for 1 hour, and the resulting solid was filtered. The solvent was removed from the resulting solution by vacuum distillation to obtain a solid corresponding to 2,4-dimethyl-5-(4-nitrophenoxy)pyrimidine.

[0153] Example B4: Obtaining 2,4-dimethylpyrimidin-5-ol The solid obtained in the step of Example B3 was dissolved in 130 mL of methanol at a temperature of about 20° C. 26.4 g (316.0 mmol) of a previously prepared 48% by weight aqueous sodium hydroxide solution was slowly added while maintaining the temperature at 35-40° C. The reaction mixture was heated to a temperature of about 65° C. and continued to stir at the temperature for 12 hours.

[0154] After stirring at the temperature, the reaction mixture was cooled to 30-35°C, and approximately 65 mL of solvent was distilled under vacuum. 130 mL of water and 40 mL of toluene were added, and the resulting mixture was stirred at 30-35°C for 1 hour. The resulting organic phase was separated, and 40 mL of toluene was added to the aqueous phase while maintaining the temperature. The new organic phase was separated, and the resulting aqueous phase was cooled to approximately 20°C. 36% aqueous HCl was slowly added until a pH value of approximately 3.5 was reached. The resulting aqueous solution was washed twice with 40 mL of toluene, and then the pH was adjusted to approximately 5.5 with 30% aqueous NaOH. 1.5 g of carbon and 1.5 g of diatomaceous earth were added, and the resulting mixture was stirred at 20-25°C for 30 minutes. The solid was separated by filtration, washed three times with 10 mL of water, and pooled with the previously obtained aqueous solution. The pH was adjusted to 6-7 with 30% aqueous NaOH, and 100 mL of ethyl acetate was added. The organic phase was separated, and the aqueous phase was washed twice with 80 mL of ethyl acetate. The solvent was removed from the pooled organic phases by vacuum distillation, yielding 10.43 g of a solid corresponding to 2,4-dimethylpyrimidin-5-ol (79.7% yield from (Z)-4-(dimethylamino)-3-(4-nitrophenoxy)but-3-en-2-one). The purity was 99.7% by gas chromatography or 99.81% by UHPLC.

[0155] material and method Chromatography When the purity of the obtained product was analyzed by gas chromatography, the following experimental conditions were followed: Non-polar CP Sil 5CB column (open tubular fused silica column with dimensions of 10 m x 0.53 mm) Injector temperature: 220℃ Detector temperature: 260℃ Column temperature: 50-250°C, 10°C / min gradient, maintained at 250°C for 10 minutes Sensitivity: 10 -10 Attenuation: 4 Carrier gas: N2 Injector: Split (split sample injection)

[0156] The purity of the obtained product was analyzed by ultra-high performance liquid chromatography (UHPLC) using a Waters system equipped with a variable wavelength detector and a column thermostat. A CSH C18 column (1.7 μm × 50 mm and 3 mm) and mobile phases A (ammonium acetate 10 mM, pH 4.8) and B (acetonitrile) were used under the following analytical conditions: ·Flow rate: (mL / min): 0.5 Column temperature (℃): 40 ·Wavelength (nm): 225 ·Injection volume (μL): 1 Acquisition time (min): 10 Diluent: acetonitrile / water (1:1) ·gradient:

[0157] [Table 1]

[0158] Differential scanning calorimetry (DSC) DSC analysis was performed on a Mettler Toledo 822e instrument equipped with STARe SW15 software. Parameters: heating range 30-300 °C (10 °C / min ramp) and N2 flow 50 mL / min. Measurements were performed using a closed perforated capsule.

[0159] Nuclear magnetic resonance Proton nuclear magnetic resonance analysis ( 1 H-NMR) and 13 C-NMR was performed on a 400 MHz Brucker Avance III spectrometer. Chemical shifts are relative to the DMSO-d6 signal (2.54 ppm for proton and 40.5 ppm for carbon).

[0160] 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 CuKα with a wavelength of 1.54060 Å. Scan parameters: 3–50 2θ degrees, continuous scan, rate: 5.6 degrees / min.

[0161] As described hereinabove, the present invention encompasses the following aspects and embodiments:

[0162] Aspect 1. Formula (I): [ka] or a stereoisomer or salt thereof, comprising reacting a compound of formula (II) [ka] with N,N-dimethylformamide diethyl acetal.

[0163] Aspect 2. The method of Aspect 1, wherein the -NO2 group of the compounds of Formula (I) and Formula (II) is in the ortho or para position, preferably the ortho position.

[0164] Aspect 3. The method according to any one of Aspects 1 to 2, wherein the ratio of N,N-dimethylformamide diethyl acetal to the compound of Formula (II) is 1 to 2 moles of N,N-dimethylformamide diethyl acetal per 1 mole of the compound of Formula (II).

[0165] Aspect 4. The method of any one of Aspects 1 to 3, carried out in the presence of toluene.

[0166] Embodiment 5. The method of any one of embodiments 1 to 3, carried out in the absence of a solvent.

[0167] Embodiment 6. The method of any one of embodiments 1 to 5, carried out at a temperature of 45 to 50°C.

[0168] Embodiment 7. The method of any one of embodiments 1 to 6, comprising a subsequent step of treating with diisopropyl ether, preferably 3 to 5 mL of diisopropyl ether per gram of compound of formula (II).

[0169] Aspect 8. The method of aspect 7, wherein the treatment with diisopropyl ether is carried out at a temperature of 20 to 25°C.

[0170] Aspect 9. Formula (III): [ka] or a salt thereof, comprising: The method of any one of aspects 1 to 8 is carried out to obtain a compound of formula (I): [ka] or a stereoisomer or salt thereof; and converting the compound of formula (I) or a stereoisomer or salt thereof into a compound of formula (III) or a salt thereof. A method comprising:

[0171] Aspect 10. a) performing the method of any one of embodiments 1 to 9 to obtain a compound of formula (I): [ka] or a stereoisomer or salt thereof; b) reacting the compound of formula (I) or a stereoisomer or salt thereof with a compound of formula (IV) or a salt thereof in the presence of a base to produce a compound of formula (V) or a salt thereof. [ka] and c) hydrolyzing the compound of formula (V) or a salt thereof to produce the compound of formula (III) or a salt thereof. 10. The method of embodiment 9, comprising:

[0172] Aspect 11. The method of Aspect 9 or 10, wherein the —NO 2 group of the compound of Formula (I) and the compound of Formula (V) is in the ortho or para position, preferably the ortho position.

[0173] Embodiment 12. The method of embodiment 10 or 11, wherein the base in step b) is an alkali metal C1-C4 alkoxide, preferably a sodium C1-C4 alkoxide, more preferably sodium ethoxide or sodium methoxide, even more preferably sodium ethoxide.

[0174] Embodiment 13. The method of any one of embodiments 10 to 12, wherein step b) is carried out in the presence of a solvent selected from the group consisting of C1-C4 alkanols, preferably ethanol, methanol, or a mixture thereof, even more preferably ethanol.

[0175] Embodiment 14. The method of any one of embodiments 10 to 13, wherein step c) is carried out in the presence of a base selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, and alkaline earth metal carbonates.

[0176] Aspect 15. The method of aspect 14, wherein the base is selected from the group consisting of sodium hydroxide and potassium carbonate, preferably sodium hydroxide.

[0177] Embodiment 16. The method of any one of embodiments 10 to 15, wherein step c) is carried out in the presence of an aqueous solvent, preferably a mixture of water and a C1-C4 alkanol, preferably a mixture of water and ethanol or a mixture of water and methanol, even more preferably a mixture of water and ethanol.

[0178] Aspect 17. The compound of formula (II) is a compound of formula (VI) and a compound of formula (VII) [ka] 17. The method according to any one of aspects 1 to 16, wherein X is chlorine or bromine, preferably chlorine, and the compound is obtained by reacting:

[0179] Aspect 18. The method of Aspect 17, wherein the —NO 2 group of the compound of formula (VI) is in the ortho or para position, preferably the ortho position.

[0180] Embodiment 19. The method of embodiment 17 or 18, wherein the reaction is carried out in the presence of a base and a phase transfer catalyst.

[0181] Aspect 20. The method of aspect 19, wherein the base is an alkali metal or alkaline earth metal carbonate, preferably potassium carbonate, and / or the phase transfer catalyst is tetrabutylammonium iodide.

[0182] Embodiment 21. A method for preparing lemborexant, comprising: a) performing the method of any one of aspects 9 to 20 to obtain a compound of formula (III): [ka] or a salt thereof; b) reacting the compound of formula (III) or a salt thereof with a compound of formula (VIII) in the presence of a base to produce a compound of formula (IX). [ka] c) hydrolyzing the compound of formula (IX) in the presence of a base to obtain a compound of formula (X): [ka] to produce a compound of; d) treating the compound of formula (X) with an oxidizing agent to obtain a compound of formula (XI): [ka] producing a compound of the formula: e) reacting the compound of formula (XI) with a compound of formula (XII): [ka] in the presence of a base and a coupling agent to produce lemborexant. A method comprising:

[0183] Aspect 22. The method of aspect 21, wherein the base in step b) is an alkali metal carbonate, preferably cesium carbonate.

[0184] Embodiment 23. The method of any one of embodiments 21 or 22, wherein the base in step c) is sodium hydroxide.

[0185] Embodiment 24. The method of any one of embodiments 21 to 23, wherein the oxidizing agent in step d) is NaClO and NaClO2.

[0186] Embodiment 25. The method of any one of embodiments 21 to 24, wherein the base in step e) is an organic amine, preferably N,N-diisopropylethylamine, and / or the coupling agent in step e) is propylphosphonic anhydride.

[0187] Aspect 26. A compound of formula (IIa): wherein the powder X-ray diffraction spectrum measured using CuKα radiation includes peaks at 9.9, 12.2, 16.2, 18.7, 20.0, 24.5, and 27.0° 2θ ± 0.2° 2θ. [ka] The crystalline form of the compound.

[0188] Embodiment 27. A crystalline form of the compound of formula (IIa) according to embodiment 26, characterized in that it exhibits a differential scanning calorimetry (DSC) diagram comprising an endothermic peak with a threshold temperature of about 57.6°C ± 2°C and an exothermic peak with a threshold temperature of about 208.0°C ± 2°C.

[0189] Embodiment 28. Formula (Ia): [ka] or a stereoisomer or salt thereof.

[0190] Aspect 29. The compound of formula (Ia) according to aspect 28, characterized in that it is a crystalline solid, having a powder X-ray diffraction spectrum measured using CuKα radiation, comprising peaks at 11.6, 16.6, 18.7, 21.5, 22.9, 23.4, 23.7, 26.4°2θ±0.2°2θ.

[0191] Embodiment 30. The compound of formula (Ia) according to embodiment 29, characterized in that it exhibits a differential scanning calorimetry (DSC) diagram comprising an endothermic peak having a threshold temperature of about 149.9°C ± 2°C and an exothermic peak having a threshold temperature of about 230.4°C ± 2°C.

[0192] Aspect 31. Formula (Va): [ka] Compound.

[0193] Aspect 32. The compound of formula (Va) according to aspect 31, characterized in that it is a crystalline solid, having a powder X-ray diffraction spectrum measured using CuKα radiation, comprising peaks at 12.5, 14.6, 17.6, 23.6, and 25.1°2θ±0.2°2θ.

[0194] Embodiment 33. A compound of formula (Va) according to embodiment 32, characterized in that it exhibits a differential scanning calorimetry (DSC) diagram comprising an endothermic peak with a threshold temperature of about 104.9°C ± 2°C.

[0195] Aspect 34. Use of a compound of Formula (IIa), a crystalline form of a compound of Formula (IIa) according to any one of Aspects 26 or 27, a compound of Formula (Ia) or a stereoisomer thereof according to any one of Aspects 28 to 30, and / or a compound of Formula (Va) according to any one of Aspects 31 to 33, in the preparation of a compound of Formula (III) or a salt thereof.

[0196] Aspect 35. Use of a compound of Formula (IIa), a crystalline form of a compound of Formula (IIa) according to any one of Aspects 26 or 27, a compound of Formula (Ia) or a stereoisomer thereof according to any one of Aspects 28-30, and / or a compound of Formula (Va) according to any one of Aspects 31-33 in the preparation of lemborexant.

[0197] Aspect 36. A crystalline form of the compound of formula (III), characterized in that the powder X-ray diffraction spectrum measured using CuKα radiation contains peaks at 12.8, 15.5, 16.6, 17.9, 21.8, 22.1, 23.6, 25.0, 25.7, 27.1, and 30.1°2θ±0.2°2θ.

[0198] Embodiment 37. The crystalline form of embodiment 36, characterized in that it exhibits a differential scanning calorimetry (DSC) diagram comprising an endothermic peak with a threshold temperature of about 137.1°C ± 2°C and an endothermic peak with a threshold temperature of about 267.9°C ± 2°C.

Claims

1. Formula (I): 【Chemistry 1】 or a stereoisomer or salt thereof, comprising a compound of formula (II): 【Chemistry 2】 with N,N-dimethylformamide diethyl acetal.

2. The —NO group of the compounds of formula (I) and formula (II) ２ 2. The method of claim 1, wherein the group is in the ortho or para position.

3. The method according to claim 1, wherein the —NO 2 group of the compounds of formula (I) and formula (II) is in the ortho position.

4. 2. The method according to claim 1, wherein the ratio of N,N-dimethylformamide diethyl acetal to the compound of formula (II) is 1 to 2 moles of N,N-dimethylformamide diethyl acetal per 1 mole of the compound of formula (II).

5. The process according to any one of claims 1 to 3, carried out in the absence of a solvent.

6. Formula (III): 【Transformation 3】 or a salt thereof, comprising: The method of any one of claims 1 to 3 is carried out to obtain a compound of formula (I): 【Chemistry 4】 or a stereoisomer or salt thereof; and converting the compound of formula (I) or a stereoisomer or salt thereof into a compound of formula (III) or a salt thereof A method comprising:

7. a) carrying out the method of claim 1 to obtain a compound of formula (I): 【Transformation 5】 or a stereoisomer or salt thereof; b) reacting the compound of formula (I) or a stereoisomer or salt thereof with a compound of formula (IV) or a salt thereof in the presence of a base to produce a compound of formula (V) or a salt thereof. 【Transformation 6】 and c) hydrolyzing the compound of formula (V) or a salt thereof to produce the compound of formula (III) or a salt thereof. The method of claim 6, comprising:

8. The compound of formula (I) and the compound of formula (V) ２ 7. The method of claim 6, wherein the group is in the ortho or para position.

9. The method according to claim 8, wherein the —NO 2 groups of the compound of formula (I) and the compound of formula (V) are in the ortho position.

10. The base in step b) is an alkali metal C １ -C ４ The method of claim 7, wherein the compound is an alkoxide.

11. 8. The method of claim 7, wherein step c) is carried out in the presence of an aqueous solvent.

12. The method of claim 11, wherein step c) is carried out in the presence of a mixture of water and a C 1 -C 4 alkanol.

13. The compound of formula (II) is a compound of formula (VI) and a compound of formula (VII) 【Transformation 7】 2. The method of claim 1, wherein X is chlorine or bromine.

14. The —NO group of the compound of formula (VI) ２ 14. The method of claim 13, wherein the group is in the ortho or para position.

15. The method of claim 14, wherein the —NO 2 group of the compound of formula (VI) is in the ortho position.

16. 1. A process for preparing lemborexant, comprising: a) carrying out the method of claim 6 to obtain a compound of formula (III): 【Transformation 8】 or a salt thereof; b) reacting the compound of formula (III) or a salt thereof with a compound of formula (VIII) in the presence of a base to produce a compound of formula (IX). 【Chemistry 9】 c) hydrolyzing the compound of formula (IX) in the presence of a base to obtain a compound of formula (X): 【Chemistry 10】 producing a compound of formula (I); d) treating the compound of formula (X) with an oxidizing agent to obtain a compound of formula (XI): 【Chemistry 11】 producing a compound of formula (I); and e) reacting the compound of formula (XI) with a compound of formula (XII): 【Chemistry 12】 in the presence of a base and a coupling agent to produce lemborexant. A method comprising:

17. 17. The method of claim 16, wherein the base in step b) is an alkali metal carbonate.

18. 17. The method of claim 16, wherein the base in step c) is sodium hydroxide.

19. The oxidizing agent in step d) is NaClO and NaClO ２ 17. The method of claim 16, wherein:

20. 17. The method of claim 16, wherein the base in step e) is an organic amine and / or the coupling agent in step e) is propylphosphonic anhydride.

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