Method for the preparation of 4-(3,5-difluorophenyl)-N-[3-(6-methylpyrimidine-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine-2-amine

Abstract

The present invention relates to compound (I) TIFF2023553941000066.tif49165 or a pharmaceutically acceptable salt thereof, Compound (I) is useful as a key intermediate for synthesizing compounds for the prevention and treatment of diseases associated with the deposition of β-amyloid in the brain, particularly Alzheimer's disease, as well as other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica, and Down's syndrome.

Description

[Technical Field]

[0001] The present invention relates to compound (I) [ka] With regard to a method for preparing a pharmaceutically acceptable salt thereof, compound (I) is a γ-secretase modulator and may be useful as an important intermediate for synthesizing compounds for the prevention and treatment of diseases associated with β-amyloid deposition in the brain, particularly Alzheimer's disease, as well as other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with Dutch amyloidosis (HCHWA-D), polyinfarct dementia, Boxer dementia, and Down syndrome. [Background technology]

[0002] The synthetic approach for compound (I) is disclosed in International Publication Nos. 2018060300 and 2018065340. However, the current process has the following problems: (a) For example, [ka] Regarding the manufacture of 19.8% and [ka] Regarding the production, there are seven linear synthesis steps with a very low yield of 62%. (b) Intermediate [ka] Column purification involving cumbersome post-processing steps for all intermediates and final products, (c) Safety concerns regarding the toxic reagent of hydrazine, (d) The use of high-filling, expensive catalyst Pd (20%), which can result in higher costs for large-scale API manufacturing and complex processes for removing the catalyst. (e) High cost due to HPLC separation, (f) Concerns about the safety, reproducibility, and scalability of newly formed triazole rings during large-scale production make it not suitable for large-scale production.

Summary of the Invention

[0003] Based on the above problems, one object of the present invention is to find an efficient synthesis method that can solve some or all of the above problems and can be applied on a technical scale.

[0004] One aspect of the present invention relates to a method for preparing a compound of formula (I)

Chemical Formula

[0005] Another aspect of the present invention relates to a novel method for preparing compound (III)

Chemical Formula

Chemical Formula

[0006] (a) A completely new process with few steps; (b) Safe and robust for scale-up, without a triazole ring formation step; (c) Performing a post-treatment process and without column purification but are not limited thereto.

[0007] In another embodiment, a pharmaceutical composition comprising compound (I) and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or combination thereof is provided herein.

[0008]

[0008] In another embodiment, compounds (I) are provided herein for the treatment or prevention of diseases associated with the deposition of β-amyloid in the brain, particularly Alzheimer's disease, or diseases selected from cerebral amyloid angiopathy, hereditary cerebral hemorrhage with Dutch amyloidosis (HCHWA-D), polyinfarct dementia, Boxer dementia, and Down syndrome.

[0009] In another embodiment, the use of compound (I) for the treatment or prevention of diseases associated with the deposition of β-amyloid in the brain, particularly Alzheimer's disease, or diseases selected from cerebral amyloid angiopathy, hereditary cerebral hemorrhage with Dutch amyloidosis (HCHWA-D), polyinfarct dementia, Boxer dementia, and Down syndrome is provided herein.

[0010] In another embodiment, the use of compound (I) or a pharmaceutical composition for producing a pharmaceutical for the treatment or prevention of diseases associated with the deposition of β-amyloid in the brain, particularly Alzheimer's disease, or a disease selected from cerebral amyloid angiopathy, hereditary cerebral hemorrhage with Dutch amyloidosis (HCHWA-D), polyinfarct dementia, Boxer dementia, and Down syndrome is provided herein.

[0011] In another embodiment, the present invention provides a method for treating or preventing a disease associated with the deposition of β-amyloid in the brain, particularly Alzheimer's disease, or a disease selected from cerebral amyloid angiopathy, hereditary cerebral hemorrhage with Dutch amyloidosis (HCHWA-D), polyinfarct dementia, Boxer dementia, and Down syndrome, the method comprising administering a therapeutically effective amount of compound (I) or a pharmaceutical composition disclosed herein. [Modes for carrying out the invention]

[0012] definition The term "pharmaceutically acceptable salt" refers to a typical acid or base addition salt formed from a suitable non-toxic organic or inorganic acid or organic or inorganic base, which retains the biological efficacy and properties of the compound of formula I. Acid addition salts include, for example, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, and fumaric acid. Base addition salts include those derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides, such as tetramethylammonium hydroxide. Chemical modification of pharmaceutical compounds into salts is a well-known technique among pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, fluidity, and solubility of the compound. This is described, for example, in Bastin RJ, et al., Organic Process Research & Development 2000, 4, 427-435; or Ansel, H., et al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457.

[0013] Abbreviation API (Active Ingredients in Pharmaceuticals) (Boc)2O Di-tert-butyl dicarbonate DCM Dichloromethane DEAD Diethylazodicarboxylate DIPEA N,N-diisopropylethylamine DMF Dimethylformamide DMSO (Dimethyl Sulfoxide) Eq.Equivalent HCl or EA (ethyl acetate) EtOH Ethanol IPA Isopropanol Isopropyl acetate (IPAc) K2CO3 potassium carbonate KOAc Potassium Acetate KOH (Potassium Hydroxide) Pd2(dba)3 Tris(dibenzylideneacetone) Dipalladium(0) Pd(OAc)2 Palladium(II) acetate LiHMDS (Lithium Bis(Trimethylsilyl)amide) 2-MeTHF 2-methyltetrahydrofuran MeOH methanol MOM Methoxymethyl MgSO4 Magnesium Sulfate MTBE methyl tert-butyl ether NaH (sodium hydride) NaHMDS (Sodium Bis(Trimethylsilyl)amide) NaOAc sodium acetate NaOtBu sodium tert-butanol NH4Cl (Ammonium Chloride) NMP N-methyl-2-pyrrolidone PPh3 Triphenylphosphine SEM 2-(trimethylsilyl)ethoxymethyl tBuOH tert-butanol TEA (Triethylamine) THF (Tetrahydrofuran) TFA (Trifluoroacetic Acid) v / v volume ratio wt.% (weight percentage)

[0014] The present invention provides an innovative process as outlined in Schemes 1-3. [ka]

[0015] The synthesis process is as follows: Step a) Compound (III) [ka] Compound (II) [ka] Formation via reaction with MOM chloride; Step b) Compound (IV) [ka] Formation via the alkylation reaction of compound (III) and 3,5-difluoroaniline; Step c) Compound (VI) [ka] Compounds (IV) and (V) [ka] Formation via reaction with; Step d) Compound (VII) [ka] Formation of compound (VI) via deprotection reaction; Step e) Compound (VIII) [ka] Formation of compound (VII) via internal Mitsunobu cyclization reaction Includes.

[0016] Detailed explanations of steps a) to e) are as follows.

[0017] Step a) Compound (III) [ka] Compound (II) [ka] Formation via reaction with MOM chloride.

[0018] Compound (III) is synthesized in the presence of a suitable solvent and a suitable base.

[0019] A suitable solvent is selected from DCM and THF. Preferably, the solvent is THF.

[0020] A suitable base is selected from KOAc, NaOAc, and NaH. Preferably, the preferred base is NaH.

[0021] Step b) Compound (IV) [ka] Formation via the alkylation reaction of compound (III) with 3,5-difluoroaniline.

[0022] Compound (IV) is synthesized in a suitable solvent containing a suitable base.

[0023] Suitable solvents are selected from 2-MeTHF, DCM, and THF. Preferably, the solvent is THF.

[0024] Suitable bases are selected from NaHMDS, K2CO3, KOH, NaOH, NaH, and LiHMDS. Preferably, the base is LiHMDS.

[0025] The appropriate equivalent amount of a suitable base is 1.0 to 2.5 equivalents. Preferably, the equivalent amount is selected from about 1.0 equivalent, about 1.2 equivalents, about 1.5 equivalents, about 2.0 equivalents, and about 2.5 equivalents. More preferably, the equivalent amount is about 2.0 equivalents.

[0026] The equivalent amount of 3,5-difluoroaniline is 1.0 to 2.5 equivalents. Preferably, the equivalent amount is selected from about 1.0 equivalent, about 1.2 equivalents, about 1.5 equivalents, about 2.0 equivalents, and about 2.5 equivalents. More preferably, the equivalent amount is about 2.5 equivalents.

[0027] The reaction is carried out at -20 to 70°C, 10 to 70°C, preferably 25 to 30°C.

[0028] The temperature system designed in this invention provides high yield and a good purging effect against impurities.

[0029] Step c) Compound (VI) [ka] Compounds (IV) and (V) [ka] Formation via reaction with [the specified substance].

[0030] Compound (VI) is synthesized in the presence of compound (V) along with an appropriate amount of base.

[0031] The appropriate amount of compound (V) is 1.7 equivalents to about 2.26 equivalents. Preferably, the amount is about 1.7 equivalents.

[0032] Suitable bases are selected from NaOH, Na2CO3, Cs2CO3, and potassium carbonate. Preferably, the base is potassium carbonate.

[0033] The appropriate amount of base is 2.0 to 3.0 equivalents, preferably about 2.06 equivalents.

[0034] Step d) Compound (VII) [ka] Formation of compound (VI) via a deprotection reaction.

[0035] Compound (VII) in this process is synthesized via a deprotection reaction in the presence of an appropriate volume of acid.

[0036] A suitable acid is selected from HBr, TFA, and HCl. Preferably, the acid is HCl. More preferably, the acid is HCl in water (36.5% by weight).

[0037] The appropriate volume of acid used in the deprotection reaction is 1V to 2V. Preferably, the volume is approximately 2V.

[0038] Step e) Compound (VIII) [ka] Formation of compound (VII) via the internal Mitsunobu cyclization reaction.

[0039] Compound (VIII) is cyclized in the presence of DEAD and PPh3 using an appropriate volume of solvent.

[0040] A suitable solvent is selected from DMSO, NMP, and DMF. Preferably, the solvent is DMF.

[0041] The appropriate volume of solvent is 5V to 10V. Preferably, the volume is approximately 5V. [ka]

[0042] The synthesis process is as follows: Step f) Compound (IX) [ka] Compound (II) [ka] and 1-chloro-3-iodopropane Formation via reaction with; Step g) Compound (VIII) [ka] Formation via telescopic alkylation reaction from compound (IX) and 3,5-difluoroaniline Includes.

[0043] Detailed explanations of steps f) to g) are as follows.

[0044] Step f) Compound (IX) [ka] Compound (II) [ka] and 1-chloro-3-iodopropane [ka] Formation via reaction with [the specified substance].

[0045] The compound of formula (IX) is synthesized using a suitable base in the presence of a suitable solvent.

[0046] A suitable solvent is selected from MeTHF and THF. Preferably, the solvent is THF.

[0047] A suitable base is selected from KOAc, NaOAc, NaOH, KOH, K2CO3, and Na2CO3. Preferably, the preferred base is K2CO3.

[0048] The reaction is carried out at 0°C to 70°C, preferably 20°C to 30°C, and more preferably 20°C to 25°C.

[0049] Dimers form while using dibolomopropane or dichloropropane as an alkylating reagent. [ka] Although these were detected, their low selectivity makes them unsuitable for large-scale production. In this invention, compound (IX) is provided using 1-chloro-3-iodopropane, which can be well controlled to avoid dimeric impurities in large-scale production.

[0050] Step g) Compound (VIII) [ka] Formation via telescopic alkylation reaction from compound (IX) and 3,5-difluoroaniline.

[0051] Compound (VIII) is synthesized in a suitable solvent containing a suitable base.

[0052] A suitable solvent is selected from 2-MeTHF, DCM, and THF. Preferably, the solvent is 2-MeTHF.

[0053] Suitable bases are selected from NaHMDS, K2CO3, KOH, NaOH, NaH, and LiHMDS. Preferably, the base is LiHMDS.

[0054] The appropriate equivalent amount of base is 1.0 to 3.75 equivalents. Preferably, the equivalent amount is 1.0, 1.2, 1.5, or 3.75 equivalents. More preferably, the equivalent amount is 3.75 equivalents.

[0055] The appropriate equivalent amount of 3,5-difluoroaniline is 1.0 to 1.5 equivalents, preferably selected from 1.0, 1.2, and 1.5 equivalents. Preferably, the equivalent amount is 1.2 equivalents.

[0056] The reaction is carried out at -20°C to 70°C, preferably 0°C to 25°C, more preferably first at 0°C to 5°C and then at 20°C to 25°C.

[0057] Temperature is important for the entire process with respect to cyclization. In this invention, step g) can be carried out in two stages, which are telescopic without solid isolation. The temperature of step g) in this invention provides high yield and a good purging effect against impurities. [ka]

[0058] Step h) Compound (I) [ka] Formation of compound (VIII) and compound (X) (prepared according to the method described in International Publication No. 2019141832) via a Buchwald cross-coupling reaction.

[0059] A detailed explanation of step h) is as follows:

[0060] Compound (I) in this process is synthesized via a Buchwald cross-coupling reaction in a suitable solvent, in the presence of a suitable catalyst, base, and ligand. Compound (I) is purified by recrystallization in a suitable solvent.

[0061] Suitable catalysts for cross-coupling reactions are selected from Pd2(dba3)·CHCl3 and Pd(OAc)2. Preferably, the catalyst is Pd2(dba3)·CHCl3.

[0062] Suitable bases for cross-coupling reactions are selected from Na2CO3, K2CO3, NaHCO3, KHCO3, NaOH, KOH, and NaOtBu. Preferably, the base is NaOtBu.

[0063] Suitable solvents for the cross-coupling reaction are selected from IPAc, siRNA, MTBE, toluene, THF, and 2-MeTHF. Preferably, the solvent is 2-MeTHF.

[0064] The cross-coupling reaction is carried out in a suitable solvent at a temperature of 20°C to 80°C, preferably 70°C to 75°C.

[0065] The ligand is selected from BrettPhos, AdCyBrettPhos, tBuBrettPhos, AdBrettPhos, RocPhos, tBuXphos, BippyPhos, Me4tBuXphos, and Me3MeOtBuXphos, and preferably the ligand is tBuXphos.

[0066] Recrystallization is carried out in a suitable solvent at a temperature of 20°C to 80°C, preferably 70°C to 75°C. Suitable solvents are selected from heptane, hexane, and petroleum ether. Preferably, the solvent is heptane. More preferably, the solvent is n-heptane.

[0067] For recrystallization, the pH of the solution was adjusted to 3-8. Preferably, the pH of the solution was first adjusted to 3-4 to obtain a clear solution, and then adjusted to 7-8.

[0068] The recrystallization conditions in this invention can produce a high-yield product with a good purging effect against impurities and excess residual solvent. [Examples]

[0069] Examples The present invention will be better understood by referring to the following embodiments. However, these should not be construed as limiting the scope of the invention.

[0070] Example 1 3,5-Dibromo-1H-1,2,4-triazole (compound (III)) [ka]

[0071] To a 3.5L solution of NaH (125g, 3.11mol, 1.1 equivalents) in THF (3.5L) in a 10L glass-lined reactor, 3,5-dibromo-1H-1,2,4-triazole (641g, 2.83mol) was slowly added in small portions at 0-5°C. After stirring at 0-5°C for 1 hour, MOM chloride (275g, 3.40mol) was added dropwise to the mixture at 0°C. The mixture was stirred at 20-25°C for 16 hours. The reaction mixture was quenched at 0-5°C by adding ice water (6.5kg, 10V) dropwise, and then extracted three times with EA (6.5L). The combined organic layer was washed with water (6.5kg) and 20% by weight NaCl aqueous solution (6.5kg), and then concentrated to obtain compound (III) (613kg, yield 80%, purity 99.4%). Compound (III): 1 H NMR(400MHz,CDCl3)δ=5.44(s,2H),3.47(s,3H). [M+H] + =269.8

[0072] Example 2 5-Bromo-N-(3,5-difluorophenyl)-2-(methoxymethyl)-1,2,4-triazole-3-amine (compound (IV)) [ka]

[0073] To a solution of compound (III) (613 g, 2.3 mol) in anhydrous THF (3 L) in a 10 L glass-lined reactor, 3,5-difluoroaniline (741 g, 5.75 mol, 2.5 equivalents) was added at 20-25°C. After stirring for 30 minutes and cooling to 0-5°C, LiHMDS (1 M in THF, 4.6 L, 4.6 mol, 2.0 equivalents) was added dropwise at 0-5°C. The reaction mixture was further heated to 25-30°C with stirring for 16 hours. Saturated NH4Cl aqueous solution (6.1 kg, 10 V) was added dropwise to the reaction mixture to quench the reaction at 0-5°C, and then extracted three times with EA (6.5 L). The combined organic layers were washed with water (6.5 kg) and 20 wt% NaCl aqueous solution (6.5 kg), and then concentrated under vacuum. Petroleum (3.2 kg) was added to the reaction mixture and then slurryed at 20-25°C for 1 hour. The solid was separated by filtration and washed with petroleum (1 kg). The filtrate was dried in a vacuum oven (30 mmHg, 40°C) for 32 hours to obtain compound (IV) (541 g, yield 75%, purity 98.8%). Compound (IV): 1 H NMR(400MHz,DMSO-d6)δ=7.14-7.11(t,1H),6.94(s,1H),5.40(s,2H),3.46(s,1H). [M+H] + =320.8

[0074] A series of studies conducted to demonstrate the effect of reaction temperature showed that 25–30°C is the optimal condition for the alkylation reaction. Furthermore, 2.0 equivalents of LiHMDS and 2.5 equivalents of 3,5-difluoroaniline yield even better results. [Table 1]

[0075] Example 3 5-Bromo-N-(3,5-difluorophenyl)-2-(methoxymethyl)-N-(3-tetrahydropyran-2-yloxypropyl)-1,2,4-triazole-3-amine (compound (VI)) [ka]

[0076] To a solution of compound (IV) (843 g, 2.64 mol) in DMF (4000 mL) in a 10 L glass-lined reactor, K2CO3 (750 g, 5.43 mol, 2.06 equivalents) and 2-(3-bromopropoxy)tetrahydropyran (1000 g, 4.48 mol, 1.7 equivalents) were added at 20-25°C and stirred for 16 hours. The resulting reaction mixture was cooled to 0-5°C. Water (3 kg) was added to the reaction mixture and then extracted three times with EA (6.5 L). The combined organic layers were washed with water (6.5 kg) and 20 wt% NaCl aqueous solution (6.5 kg), then concentrated to obtain compound (VI) as a brown oil (1.51 kg, yield 100%, purity 94.0%), which was used in the next step without further purification. Compound (VI): 1 H NMR(400MHz,DMSO-d6)δ=6.54-6.47(dd,2H),5.02(s,1H),4.60-4.58(d,2 H),3.97-3.81(m,5H),3.64-3.45(m,3H),3.36(s,3H),1.99-1.56(m,13H).

[0077] Example 4 3-(N-(3-bromo-1H-1,2,4-triazole-5-yl)-3,5-difluoroanilino)propan-1-carbamate (compound (VII)) [ka]

[0078] Compound (VI) (1510 g), methanol (6000 mL), hydrochloric acid (2.4 L), and water (2.4 L) were added to a 20 L glass-lined reactor at 20-25°C. The mixture was then heated to 70-75°C and stirred for 5 hours. The resulting reaction mixture was cooled to 20-25°C, concentrated to remove methanol, and the residue was adjusted to pH 8-9 with 4N NaOH aqueous solution (6.9 L). The resulting reaction mixture was extracted twice with EA (15 L). The combined organic layers were washed with brine and 20 L of 20 wt% NaCl aqueous solution, dried over Mg2SO4, concentrated to remove the solvent. EA (2 L) was added to the resulting reaction mixture, then heated to 50-55°C. Heptane (6 L) was then added dropwise to the reaction mixture, and the mixture was cooled to 20-25°C over 6 hours, followed by stirring for another hour. The solid was separated by filtration, washed with EA / heptane (1 / 3, 500 mL), and dried in a vacuum (30 mmHg, 40°C) for 16 hours to obtain compound (VII) as a white solid (621 g, yield 70%, purity 99.0%). Compound (VII): 1 H NMR:(400MHz,CDCl3)δ ppm:12.17-10.22(s,1H),6.90-6.88(dd,2H),6.66-6.60(t,1H),4.03-3.99(t,2H),3.71-3.68(d,2H),1.88-1.85(t,2H).

[0079] Example 5 2-Bromo-4-(3,5-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine (compound (I)) [ka]

[0080] Compound (VII) (621 g, 1.86 mol), DMF (4 L), and PPh3 (800 g, 3.05 mol, 1.64 equivalents) were added to a 10 L glass-lined reactor at 20-25°C. The resulting mixture was cooled to -20-10°C, and then DEAD (500 g, 2.87 mol) was added dropwise to the mixture at -20-10°C and stirred for 3 hours. Water (6.21 kg, 10 L) was added dropwise to the reaction mixture to quench the reaction at 0-5°C, and then extracted three times with EA (6.5 L). The combined organic layers were washed with 20 wt% NaCl aqueous solution (10 L), dried over Mg2SO4, concentrated, and the solvent was removed. The resulting residue was diluted with MeOH (6.2 L, 10V) at 20-25°C and stirred for 1 hour. The solid was then separated by filtration and rinsed with MeOH (600 mL). The resulting residue was diluted with EA (6.2 L, 10V) at 20-25°C and then heated to 70-75°C and stirred for 1 hour. The resulting mixture was cooled to 20-25°C, the solid was then separated by filtration and rinsed with EA (600 mL). The resulting cake was dried in a vacuum oven (30 mmHg, 40°C) for 16 hours to obtain compound (I) as a white solid (287 g, yield 48.0%, purity 98.0%). Compound (VIII): 1 H NMR(400MHz,DMSO-d6)δ=7.39-7.34(m,2H),6.97-6.92(m,1H),4.11-4.08(m,2H),3.85-3.83(m,2H),2.26-2.20(m,2H).

[0081] Example 6 3,5-Dibromo-1H-1,2,4-Triazole (Compound IX) [ka]

[0082] In a 250 mL reactor, 3,5-dibromo-1H-1,2,4-triazole (10 g, 44.1 mmol, equivalent: 1), THF (88 g, 100 ml), potassium carbonate (12.2 g, 88.2 mmol, equivalent: 2.0), and 1-chloro-3-iodopropane (11 g, 53.8 mmol, equivalent: 1.22) were added. The mixture was stirred at 20°C to 25°C for 16 hours. Water (100 mL) was added to the reaction mixture, and then extracted with EA (100 mL). The combined organic layers were washed with 20 wt% NaCl aqueous solution (50 mL), dried over Mg2SO4, and then concentrated to remove the solvent and obtain compound (IX). The crude product was used in the next step without further purification.

[0083] Example 7 3,5-Dibromo-1H-1,2,4-Triazole (Compound IX) [ka]

[0084] In a 250 mL reactor, 3,5-dibromo-1H-1,2,4-triazole (35 g, 154 mmol, equivalent: 1), THF (88 g, 350 ml; potassium carbonate (42.6 g, 309 mmol, equivalent: 2.0)), and 1-chloro-3-iodopropane (31.5 g, 154 mmol, equivalent: 1) were added and stirred at 20°C to 25°C for 48 hours. Water (300 mL) was added to the reaction mixture, and then extracted with 2-MeTHF (150 mL). The combined organic layers were washed with 20 wt% NaCl aqueous solution (150 mL), dried over Mg2SO4, and then concentrated to remove the solvent to obtain compound (IX) (54.5 g, purity 78.94% GC-MS, yield 91.9%). The crude product was used in the next step without further purification.

[0085] Example 8 3,5-Dibromo-1H-1,2,4-Triazole (Compound IX) [ka]

[0086] In a 2 L reactor, 3,5-dibromo-1H-1,2,4-triazole (110 g, 475 mmol, equivalent: 1), THF (880 g, 1 L), potassium carbonate (134 g, 950 mmol, equivalent: 2.0), and 1-chloro-3-iodopropane (129 g, 618 mmol, equivalent: 1.3) were added and stirred at 20°C to 25°C for 48 hours. Water (550 mL) was added to the reaction mixture, then separated, and the organic layer was washed with 20 wt% NaCl aqueous solution (225 mL), dried over Mg2SO4, and then concentrated to remove the solvent to obtain compound (IX) (165 g, purity 81% (GC-MS), yield 92.7%). The crude product was used in the next step without further purification.

[0087] Example 9 2-Bromo-4-(3,5-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine (compound (VIII)) [ka]

[0088] 3,5-difluoroaniline (5.79 g, 44.9 mmol, 1.2 equivalents), compound (IX) (14 g, 37.4 mmol, 1.0 equivalent), and 2-MeTHF (140 mL) were added to a 500 mL glass-lined reactor at 20°C to 25°C. After stirring for 30 minutes and cooling to 0 to 5°C, LiHMDS (1 M in THF, 140 mL, 140 mmol, 3.75 equivalents) was added dropwise at 0°C to 5°C. The reaction mixture was further heated to 20°C to 25°C while stirring for 1 hour. Saturated NH4Cl aqueous solution (200 mL, 10V) was added dropwise to the reaction mixture to quench the reaction at 20 to 25°C, and then 20% by weight NaCl aqueous solution (100 mL) was added to the reactants at 20 to 25°C and stirred for 1 hour. The resulting mixture was extracted with EA (200 mL). The combined organic layers were washed with 20 wt% NaCl aqueous solution (100 mL), dried over Mg2SO4, and then concentrated to remove the solvent. EA (50 mL) was added to the resulting reaction mixture, then heated to 50°C-55°C, then heptane (150 mL) was added dropwise to the reaction mixture, and the mixture was cooled to 20°C-25°C over 6 hours, followed by stirring for 1 hour. The solid was separated by filtration, washed with EA / heptane (1 / 3, 10 mL), and dried in a vacuum oven (30 mmHg, 40°C) for 32 hours to obtain compound (IV) as a gray solid (8 g, yield 67.2%, purity 99.0%). Compound (VIII): 1 H NMR(400MHz,DMSO-d6)δ=7.39-7.34(m,2H),6.97-6.92(m,1H),4.11-4.08(m,2H),3.85-3.83(m,2H),2.26-2.20(m,2H).

[0089] A series of studies were conducted to demonstrate the effects of reaction temperature and the equivalent amount of the aniline compound (IXa), and it was shown that 0°C to 25°C and 1.2 equivalents of compound (IXa) are the optimal conditions for this cyclization reaction. [ka] [Table 2]

[0090] Example 10 2-Bromo-4-(3,5-difluorophenyl)-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine (Compound (VIII)

Chemical formula

[0091] In a 3 L glass-lined reactor, 3,5-difluoroaniline (69.6 g, 529 mmol, 1.2 equivalents), Compound (IX) (165 g, 441 mmol, 1.0 equivalent), and 2-MeTHF (825 mL) were charged at 20°C to 25°C. After stirring for 30 minutes and cooling to 0°C to 5°C, LiHMDS (1.9 M in THF, 835 mL, 1.59 mol, 3.6 equivalents) was added dropwise at 0°C to 5°C. The reaction mixture was warmed to 20°C to 25°C while stirring for an additional 1 hour. Saturated aqueous NH4Cl solution (2 L, 10 v) was added dropwise to the reaction mixture to quench the reaction at 20 to 25°C, and then 20 wt% aqueous NaCl solution (1 L) was added to the reaction mixture at 20 to 25°C and stirred for 1 hour. The resulting mixture was extracted with EA (2000 mL). The combined organic layers were washed with 20 wt% aqueous NaCl solution (1 L), dried over Mg2SO4, and then concentrated to remove the solvent. EA (500 mL) was added to the resulting reaction mixture, then heated to 50°C to 55°C, then heptane (1.5 L) was added dropwise to the reaction mixture, then cooled to 20°C to 25°C over 6 hours, and further stirred for 1 hour. The solid was separated by filtration, washed with EA / heptane (1 / 1, 100 mL), and dried in a vacuum oven (30 mmHg, 40°C) for 32 hours to obtain Compound (IV) as a gray solid (94 g, yield 67.7%, purity 98.8%). Compound (VIII): 1 H NMR (400 MHz, DMSO-d6) δ = 7.39 - 7.34 (m, 2H), 6.97 - 6.92 (m, 1H), 4.11 - 4.08 (m, 2H), 3.85 - 3.83 (m, 2H), 2.26 - 2.20 (m, 2H).

[0092] Example 11 4-(3,5-difluorophenyl)-N-[3-(6-methylpyrimidine-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine-2-amine (compound (I)) [ka]

[0093] In a 50 mL one-necked flask, NaOtBu (1.2 g, 12.4 mmol, equivalent: 4), 2-MeTHF (10.2 g, 120 ml, 10V), and (1R,5S,8S)-3-(6-methylpyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-amine dihydrochloride (1.06 mg, 3.42 mmol, equivalent: 1.1) were added all at once under N2 conditions at 20°C to 25°C. Then, compound (VIII) (1 g, 3.11 mmol, equivalent: 1), Pd2dba3·CHCl3 (32.2 mg, 31 μmol, equivalent: 0.01), and tBuXphos (26.4 mg, 62.2 μmol, equivalent: 0.02) were added to the resulting mixture at 20°C to 25°C. The resulting mixture was heated to approximately 75°C and stirred for 2 hours. The mixture was cooled to 20°C-25°C, water (10 mL) and MeOH (10 mL) were added, and then extracted twice with 2-MeTHF (25 mL). The combined organic layers were filtered through an MCC pad and then concentrated to remove the solvent. 2-MeTHF (5 mL) was added to the residue, and the reaction mixture was heated to 20°C-25°C. Hpetane (15 mL) was added dropwise to the reaction mixture, and then cooled to 20°C-25°C and stirred for a further 10 hours. The product was collected by filtration, washed with heptane (2 mL), and dried in a vacuum oven (30 mmHg, 40°C) for 16 hours to obtain compound (IV) (1.1 g, yield 77.5%, purity 98.8%).

[0094] Compound (VI): 1H NMR(400MHz,DMSO-d6)δ ppm 8.35(s,1H),7.45(dd,J=10.6,2.0Hz,2H),6.78-6.86(m,1H),6.63(s,1H),5.84(d,J=4.1Hz,1 H),3.96-4.41(m,2H),3.93(t,J=6.0Hz,2H),3.75-3.81(m,2H),3.54(d,J=4.1Hz,1H),2.96(br d,J=12.1Hz,2H),2.44(br s,2H),2.25(s,3H),2.19(quin,J=5.8Hz,2H),1.83-1.88(m,2H),1.27-1.33(m,2H). 13 C NMR(101MHz,DMSO-d6)δ ppm 21.85(s,1C),24.20(s,1C),25.74(s,2C),38.73(s,2C),43.86(s,1C),45.64(s, 1C),50.63(s,2C),62.08(s,1C),97.20(t,J=26.41Hz,1C),101.92(s,1C),102.8 1(d,J=29.34Hz,2C),145.80(t,J=13.94Hz,1C),149.51(s,1C),157.61(s,1C),1 60.39(s,1C),162.79(dd,J=242.09,16.14Hz,2C),163.20(s,1C),164.75(s,1C) 19 F NMR(376MHz,DMSO-d6)δ=-110.00-1110.13(m,2F) [α]D 25 =0.199 o HRMS: Calculated value 453.225 [C 23 H 26 F2N8+H] + , measured value 453.2354 [M+H] +

[0095] Example 12 4-(3,5-difluorophenyl)-N-[3-(6-methylpyrimidine-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine-2-amine (compound (I)) [ka]

[0096] In a 250 mL single-necked flask, NaOtBu (12 g, 124 mmol, equivalent: 4), 2-MeTHF (102 g, 120 ml, 10V), and (1R,5S,8S)-3-(6-methylpyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-amine dihydrochloride (10.7 g, 34.2 mmol, equivalent: 1.1) were added all at once under N2 conditions at 20°C to 25°C. Then, compound (VIII) (10 g, 31.1 mmol, equivalent: 1), Pd2dba3·CHCl3 (322 mg, 311 μmol, equivalent: 0.01), and tBuXphos (264 mg, 622 μmol, equivalent: 0.02) were added to the resulting mixture at 20°C to 25°C. The resulting mixture was heated to 75°C and stirred for 2 hours. The mixture was cooled to 20°C-25°C, water (100 mL) and MeOH (100 mL) were added, and then extracted twice with 2-MeTHF (250 mL). The combined organic layer was filtered through an MCC (microcrystalline cellulose) pad and then concentrated to remove the solvent. 2-MeTHF (50 mL) was added to the residue, and then the reaction mixture was heated to 20°C-25°C. Heptane (150 mL) was added dropwise to the reaction mixture, and then cooled to 20°C-25°C and stirred for a further 10 hours. The product was collected by filtration, washed with heptane (20), and dried in a vacuum oven (30 mmHg, 40°C) for 16 hours to obtain compound (I) (12 g, yield 85%, purity 98.1%).

[0097] Compound (I): 1H NMR(400MHz,DMSO-d6)δ ppm 8.35(s,1H),7.45(dd,J=10.6,2.0Hz,2H),6.78-6.86(m,1H),6.63(s,1H),5.84(d,J=4.1Hz,1 H),3.96-4.41(m,2H),3.93(t,J=6.0Hz,2H),3.75-3.81(m,2H),3.54(d,J=4.1Hz,1H),2.96(br d,J=12.1Hz,2H),2.44(br s,2H),2.25(s,3H),2.19(quin,J=5.8Hz,2H),1.83-1.88(m,2H),1.27-1.33(m,2H). 13 C NMR(101MHz,DMSO-d6)δ ppm 21.85(s,1C),24.20(s,1C),25.74(s,2C),38.73(s,2C),43.86(s,1C),45.64(s, 1C),50.63(s,2C),62.08(s,1C),97.20(t,J=26.41Hz,1C),101.92(s,1C),102.8 1(d,J=29.34Hz,2C),145.80(t,J=13.94Hz,1C),149.51(s,1C),157.61(s,1C),1 60.39(s,1C),162.79(dd,J=242.09,16.14Hz,2C),163.20(s,1C),164.75(s,1C) 19 F NMR(376MHz,DMSO-d6)δ=-110.00-1110.13(m,2F) [α]D 25 =0.199 o HRMS: calculated value 453.225[C 23 H 26 F2N8+H] + , measured value 453.2354 [M+H] +

[0098] Example 13 4-(3,5-difluorophenyl)-N-[3-(6-methylpyrimidine-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrimidine-2-amine (compound (I)) [ka]

[0099] In a 5L three-necked flask, NaOtBu (191g, 1.99mol, equivalent: 4), 2-MeTHF (1.6L, 10V), and (1R,5S,8S)-3-(6-methylpyrimidine-4-yl)-3-azabicyclo[3.2.1]octane-8-amine dihydrochloride (171g, 547mmol, equivalent: 1.1) were added all at once under N2 conditions at 20°C to 25°C. Then, compound (VIII) (160g, 498mmol, equivalent: 1), Pd2(dba3)·CHCl3 (4.56g, 4.98mmol, equivalent: 0.01), and tBuXphos (4.23g, 9.95mmol, equivalent: 0.02) were added to the resulting mixture at 20°C to 25°C. The resulting mixture was heated to 70°C-75°C and stirred for 2 hours. Heptane (1.6 L) was added to the mixture, and then it was cooled to 20°C-25°C. The crude solid was collected by filtration and rinsed with Hep / 2-MeTHF (1:1, 150 mL). The resulting cake was slurryed with water and stirred at 20°C-25°C for 2 hours. The crude solid was collected by filtration and rinsed with water (200 mL). The resulting cake was diluted in a 2 L reactor with MeOH (400 mL) and DCM (1 L). Charcoal (20 g) was added to the suspension and heated to 60°C-65°C with stirring for 2 hours, and then cooled to 20°C-25°C. The suspension was filtered through Celite and rinsed with MeOH / DCM (4:10, 100 mL). The filtrate was concentrated, the residue was diluted with 2-MeTHF (500 mL), heated to 60°C-65°C, and stirred for 30 minutes. To the resulting mixture, heptane (1500 mL) was added dropwise at 60°C-65°C, then cooled to 60°C-65°C and stirred for 10 hours. The crude product was collected by filtration, rinsed with heptane (200 mL), then the cake was diluted with water (160 mL), and the pH was adjusted to 3-4 with HCl (36.5% by weight, 129 mL). NaOH (1 M, 568 mL) was added to the resulting reaction mixture, the pH was adjusted to 7-8, and the resulting mixture was stirred at 20°C-25°C for 1 hour. The product was collected by filtration, washed with heptane (20), and dried in a vacuum oven (30 mmHg, 40°C) for 16 hours to obtain compound (I) (200 g, yield 87.9%, purity 98.98%).

[0100] Compound (I):1 1H NMR (400 MHz, DMSO-d6) δ ppm 8.35 (s, 1H), 7.45 (dd, J = 10.6, 2.0 Hz, 2H), 6.78 - 6.86 (m, 1H), 6.63 (s, 1H), 5.84 (d, J = 4.1 Hz, 1H), 3.96 - 4.41 (m, 2H), 3.93 (t, J = 6.0 Hz, 2H), 3.75 - 3.81 (m, 2H), 3.54 (d, J = 4.1 Hz, 1H), 2.96 (br d, J = 12.1 Hz, 2H), 2.44 (br s, 2H), 2.25 (s, 3H), 2.19 (quin, J = 5.8 Hz, 2H), 1.83 - 1.88 (m, 2H), 1.27 - 1.33 (m, 2H). 13 13C NMR (101 MHz, DMSO-d6) δ ppm 21.85 (s, 1C), 24.20 (s, 1C), 25.74 (s, 2C), 38.73 (s, 2C), 43.86 (s, 1C), 45.64 (s, 1C), 50.63 (s, 2C), 62.08 (s, 1C), 97.20 (t, J = 26.41 Hz, 1C), 101.92 (s, 1C), 102.81 (d, J = 29.34 Hz, 2C), 145.80 (t, J = 13.94 Hz, 1C), 149.51 (s, 1C), 157.61 (s, 1C), 160.39 (s, 1C), 162.79 (dd, J = 242.09, 16.14 Hz, 2C), 163.20 (s, 1C), 164.75 (s, 1C) 19 19F NMR (376 MHz, DMSO-d6) δ = -110.00 - 1,110.13 (m, 2F) [α]D 25 = 0.199 o HRMS: Calculated value 453.225 [C 23 H 26 F2N8 + H] + , Measured value 453.2354 [M + H] +

Claims

1. Compound (VIII) 【Chemistry 48】 Or a method for preparing a pharmaceutically acceptable salt thereof, comprising the following steps: Step a) Compound (III) 【Chemistry 49】 Compound (II) [Transformation 50] Formation via reaction with MOM chloride; Step b) Compound (IV) 【Chemistry 51】 Formation via the alkylation reaction of compound (III) with 3,5-difluoroaniline; Step c) Compound (VI) 【Chemistry 52】 Compound (IV) and Compound (V) 【Chemistry 53】 Formation via reaction with; Step d) Compound (VII) 【Chemistry 54】 Formation of compound (VI) via deprotection reaction; Step e) Compound (VIII) 【Transformation 55】 Formation of compound (VII) via internal Mitsunobu cyclization reaction Methods that include...

2. The method according to claim 1, characterized in that the formation of compound (III) in step a) is carried out in the presence of a solvent, the solvent being selected from DCM and THF.

3. The method according to claim 1 or 2, characterized in that the formation of compound (III) in step a) is carried out in the presence of a base, the base is selected from KOAc, NaOAc and NaH.

4. The method according to any one of claims 1 to 3, characterized in that the formation of compound (IV) in step b) is carried out in the presence of a solvent, the solvent being selected from 2-MeTHF, DCM, and THF.

5. The formation of compound (IV) in step b) is carried out in the presence of a base, wherein the base is NaHMDS, K ２ CO ３ The method according to any one of claims 1 to 4, characterized in that it is selected from KOH, NaOH, NaH and LiHMDS.

6. The method according to claim 5, characterized in that the equivalent amount of the base is 1.0 equivalent to 2.5 equivalents.

7. The method according to any one of claims 1 to 6, characterized in that the equivalent amount of 3,5-difluoroaniline is 1.0 equivalent to 2.5 equivalents.

8. The method according to any one of claims 1 to 7, characterized in that the formation of compound (IV) in step b) is carried out at -20 to 70°C.

9. The formation of compound (VI) in step c) is carried out in the presence of a base, wherein the base is NaOH, Na ２ CO ３ , Cs ２ CO ３ The method according to any one of claims 1 to 8, characterized in that it is selected from potassium carbonate.

10. The method according to claim 9, characterized in that the amount of base is 2.0 equivalents to 3.0 equivalents.

11. The method according to any one of claims 1 to 10, characterized in that the equivalent amount of compound (V) is 1.7 equivalents to 2.26 equivalents.

12. The method according to any one of claims 1 to 11, characterized in that the formation of compound (VII) in step d) is carried out in the presence of an acid, the acid being selected from HBr, TFA and HCl.

13. The method according to claim 12, characterized in that the volume of the acid is 1V to 2V.

14. The formation of compound (VIII) in step e) is performed using a solvent DEAD, PPH ３ The method according to any one of claims 1 to 13, characterized in that it is carried out in the presence of and the solvent is selected from DMSO, NMP, and DMF.

15. The method according to claim 14, characterized in that the volume of the solvent is 5V to 10V.

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