Method for the preparation of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)piperidine-4-sulfonamide

Abstract

The present invention relates to a method for preparing compound (6). Compound (6) is an important precursor for forming 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)piperidine-4-sulfonamide (compound (I), formula (I)) or a pharmaceutically acceptable salt thereof, which is useful as an NLRP3 inhibitor. TIFF2026529642000024.tif30161

Description

[Technical Field]

[0001] The present invention relates to a method for preparing compound (6). [ka]

[0002] Compound (6) is an important precursor for forming 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)piperidine-4-sulfonamide (compound (I)) or a pharmaceutically acceptable salt thereof, which is useful as an NLRP3 inhibitor. [ka] [Background technology]

[0003] 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)piperidine-4-sulfonamide is disclosed in International Publication No. 2019 / 008025 as an NLRP3 inhibitor (see Example 6). However, there is a need to provide an improved method for preparing 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)piperidine-4-sulfonamide and its salts. In particular, there is a need to provide an efficient method suitable for large-scale synthesis, for example, that avoids multiple complex and partially low-yield chemical steps and the overall inefficient synthesis of atoms.

[0004] WO 2022 / 268935 discloses a method for producing 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide, which comprises contacting compound (6) with compound (Y) in the presence of a solvent and a base to obtain compound (I), which is 1-ethyl-N-((1,2,3,5,6,7-hexahyd ro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide, or a salt thereof.

化

[0005] There is also a need to provide 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide and salts thereof in higher yields, particularly at large scale, compared to prior art methods. Furthermore, for large-scale industrialization, more environmentally friendly synthetic routes, reduced solvent waste, and improved safety are also concerns. The present invention solves the aforementioned problems by providing an improved route to the formation of compound (6).

[0006] The novel method disclosed herein enables a reduction in process steps and an increase in the overall yield of compound (6) from 11% to 52% when compared to that disclosed in WO 2022 / 268935. Furthermore, the present invention can be carried out in either batch or continuous processes, allowing the use of fewer reagents and solvents leading to less waste.

Summary of the Invention

[0007] The present invention provides a method for preparing compound (6), the method comprising Scheme A shown below.

化

[0008] The term "pharmaceutically acceptable salt" refers to conventional acid addition salts or base addition salts that retain the biological activity and properties of the compound of Formula I and are formed from appropriate non-toxic organic or inorganic acids, or organic or inorganic bases. Examples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and 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. Examples of base addition salts include those derived from ammonium, potassium, sodium and quaternary ammonium hydroxides, such as tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound into a salt thereof is a technique well known to pharmaceutical chemists for improving the physical and chemical stability, hygroscopicity, flowability and solubility of the compound. This is described, for example, in Bastin R.J., et al., Organic Process Research & Development 2000, 4, 427-435, or Ansel, H., et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457.

[0009] Abbreviation Aq. Aqueous solution AKX AQUAMICRON (登録商標) AKX ACN Acetonitrile AL Aqueous layer DCM Dichloromethane GC Gas chromatography HPLC High performance liquid chromatography HOSA Hydroxylamine-O-sulfonic acid IT Internal temperature LC / MS Liquid chromatography-mass spectrometry MeCN Acetonitrile OL Organic layer Pd / C Palladium on carbon r.t Room temperature THF (Tetrahydrofuran) V Volume relative to the starting material w / w% weight percentage concentration %aa (Under-peak area of ​​compound (a) / Sum of under-peak areas of compound (a) and all other components) × 100

[0010] The present invention provides a method for preparing compound (6) outlined in Scheme A and a method for preparing compound (I) outlined in the subsequent Scheme B. [ka] [ka]

[0011] The synthesis of compound (6) includes one or more of the following steps: Steps (a) and (b): (2) is obtained by the first ethylation reaction of (1), and subsequently this is reacted with thionyl chloride in toluene to form (3), forming compound (3). [ka] Steps (c), (d), and (e): Compound (3) is reacted via Grignard formation to obtain compound (4), then sulfonate compound (5) is formed, and this is then oxidized to obtain compound (6). [ka]

[0012] Reaction step (a) typically involves dissolving compound (1) in a mixture of methanol and acetonitrile and hydrogenating it in the presence of a Pd / C catalyst.

[0013] Suitable conditions for hydrogenation in step (a) include 10-20 bar H2 at 80°C to achieve complete conversion without side reactions within 1-3 hours.

[0014] Suitable catalyst loads for reaction step (a) are 3.3 wt% to 10 wt% catalyst, containing 10 wt% Pd / C.

[0015] In reaction step (b), compound (2) in toluene is heated to 60°C, and while maintaining the internal temperature at 60-75°C, the thionyl chloride reagent in toluene is added over at least 1 hour.

[0016] Alternatively, 48% HBr (aqueous solution) produces a bromo intermediate instead of the chloro intermediate shown, which also works.

[0017] Other solvents that can be used as alternatives to toluene include ACN (acetonitrile), DCM (dichloromethane), and mixtures of toluene and TBAC (tetrabutylammonium chloride) as additives.

[0018] Further alternative reagents include PBr3, SOBr2, Br2 / PPh3, and CBr4 / PPh3 (for forming bromo intermediates), as well as thionyl chloride, CCl4 / PPh3, POCl3, and PCl3 (for forming chloro intermediates).

[0019] Reaction step (c) typically involves adding compound (3), diluted with THF, to magnesium that has been activated at 40°C by the addition of 1,2-dibromoethane, and then heating to 60°C for the reaction. Activation may be carried out using iodine in diethyl ether solvent.

[0020] Reaction step (d) typically involves reacting compound (4) with sulfur dioxide in a cooled mixture at 0°C. The sulfur dioxide may be in the form of a gas or as a solution in THF.

[0021] The subsequent workup in reaction step (d) typically involves adding the reaction mixture to a pre-cooled solution of dehydrated trisodium citrate in water and separating the product compound (5) from the organic phase. Alternative salts may be potassium carbonate, monosodium diphosphate, sodium bisulfate, and disodium citrate, and alternative acids may be acetic acid, citric acid, hydrochloric acid, and water.

[0022] Reaction step (e) typically involves adding HOSA (hydroxylamine-O-sulfonic acid) to an aqueous solution of compound (5) at a temperature of 20–25°C.

[0023] Unless otherwise specified, any reference to an element should be considered a reference to all isotopes of that element. Therefore, for example, unless otherwise specified, any reference to hydrogen should be considered to include all isotopes of hydrogen, including deuterium and tritium.

[0024] Unless otherwise specified, any reference to a compound or group should be considered a reference to all tautomers of that compound or group.

[0025] A further embodiment of the present invention includes reacting compound (6) obtained by the above method with compound (13) to obtain compound (I). [ka]

[0026] Further embodiments of the present invention relate to compound (I) obtained using compound (6) produced by the method described above.

[0027] The compounds used in and provided by the present invention may be used in both their free base form and their acid addition salt form. For the purposes of the present invention, the “salt” of the compounds of the present invention includes an acid addition salt. The acid addition salt is preferably an inorganic acid, for example a hydrohalic acid (e.g., hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid) or another inorganic acid (e.g., nitric acid, perchloric acid, sulfuric acid or phosphoric acid); or an organic acid, for example an organic carboxylic acid (e.g., propionic acid, butyric acid, glycolic acid, lactic acid, mandelic acid, citric acid, acetic acid, benzoic acid, salicylic acid, succinic acid, malic acid or hydroxysuccinic acid, tartaric acid, fumaric acid, maleic acid, hydroxymaleic acid, mucinic acid or galacidic acid). A pharmaceutically acceptable, non-toxic addition salt with a suitable acid, including but not limited to taric acid, gluconic acid, pantothenic acid, or pamoic acid, organic sulfonic acid (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluene-p-sulfonic acid, naphthalene-2-sulfonic acid, or camphorsulfonic acid) or amino acid (e.g., ornithine, glutamic acid, or aspartic acid). The acid addition salt may be mono, di, tri, or polyacid addition salt. Preferred salts are hydrohalide acid addition salts, sulfuric acid addition salts, phosphate addition salts, or organic acid addition salts. A preferred salt is hydrochloric acid addition salt.

[0028] When the compound of the present invention contains a quaternary ammonium group, the compound is typically used in salt form. The counterion for the quaternary ammonium group may be any pharmaceutically acceptable non-toxic counterion. Examples of suitable counterions include the conjugate bases of protic acids mentioned above with respect to acid addition salts.

[0029] The compounds used in the present invention and provided by the present invention can be used in both their free acid forms and their salt forms. For the purposes of the present invention, "salts" of the compounds of the present invention include those formed between a protonic acid functional group (such as a carboxylic acid group or a urea group) of the compound of the present invention and a suitable cation. Suitable cations include, but are not limited to, lithium, sodium, potassium, magnesium, calcium and ammonium. The salt may be a mono-, di-, tri- or poly-salt. Preferably, the salt is a mono- or di-lithium, sodium, potassium, magnesium, calcium or ammonium salt. More preferably, the salt is a mono- or di-sodium salt or a mono- or di-potassium salt.

[0030] Preferably, any salt is a pharmaceutically acceptable non-toxic salt. However, in addition to pharmaceutically acceptable salts, other salts are included in the present invention because they have the potential to act as intermediates in the purification or preparation of pharmaceutically acceptable salts, or are useful for the identification, characterization or purification of free acids or free bases.

[0031] The compounds and / or salts used in the present invention and provided by the present invention may be anhydrous, or may be in the form of hydrates (for example, hemihydrate, monohydrate, dihydrate or trihydrate) or other solvates. Such other solvates may be formed using common organic solvents including, but not limited to, alcoholic solvents such as methanol, ethanol or isopropanol.

[0032] The compounds, salts and solvates used in the present invention and provided by the present invention are 12 C, 13 C, 1 H, 2 H(D), 14 N, 15 N, 16 O, 17 O, 18 O, 19 F and 127Any stable isotopes, including but not limited to I, and 11 C, 14 C, 3 H(T), 13 N, 15 O, 18 F, 123 I, 124 I, 125 I and 131 It may contain any radioactive isotope, including but not limited to I.

[0033] Unless otherwise specified, the compounds, salts, and solvates used in and provided by the present invention may be in any polymorph or amorphous form.

[0034] Conventional procedures for the selection and preparation of appropriate pharmaceutical formulations are, for example, "Aulton's Pharmaceutics - The Design and Manufacture of Medicines," MEAulton and KMG Taylor, Churchill Livingstone Elsevier, 4 th This is described in Ed., 2013. The pharmaceutically acceptable excipients, including adjuvants, diluents, or carriers that can be used in the pharmaceutical compositions of the present invention are those that have been conventionally used in the field of pharmaceutical formulations.

[0035] Further aspects of the present invention provide compound (I) or a salt thereof obtained using compound (6) produced by the above method, for use in medicine and / or for use in the treatment or prevention of disease, disorder or symptom.

[0036] Further aspects of the present invention provide pharmaceutical compositions comprising compound (I) or a salt thereof obtained using compound (6) produced by the above method, for use in medicine and / or for use in the treatment or prevention of disease, disorder or symptoms.

[0037] Typically, treatment or prevention of a disease, disorder, or symptom involves administering compound (I) or a salt thereof obtained using compound (6) prepared using the method described above. [Examples]

[0038] Unless otherwise specified, all solvents, reagents, and compounds were purchased and used without further purification.

[0039] Experimental method NMR method: NMR spectra were obtained using a Bruker AV 400MHz spectrometer (model: Advance IIID) operated at room temperature (25°C).

[0040] GC method: GC analysis was performed using one of the following instruments: Agilent 7890, 6890, or Agilent 6890N equipped with an ALS injector.

[0041] HPLC method: The HPLC in steps (a) to (d) of reaction scheme 2 was performed using a Waters Alliance e2695 HPLC system equipped with a PDA detector, with 10 mm ammonium bicarbonate in water as mobile phase A and acetonitrile as mobile phase B.

[0042] The HPLC for reaction scheme 3 was performed using an Agilent 1290 HPLC system equipped with a DAD detector (column: Waters CORTECS UPLC T3) and mobile phase A: 5 mM K2HPO4 (pH 6.2) in water and mobile phase B: acetonitrile.

[0043] Where used herein, unless otherwise specified, all references to HPLC purity are measured as % a / a.

[0044] KF method: Coulometric KF (Karl Fischer) titration was performed using AKX reagent with a Mitsubishi CA-20 or Predicta OM1000.

[0045] Example of synthesis 1-Ethylpiperidine-4-sulfonamide (6) 1-Ethyl-4-piperidinesulfonamide (6) was prepared according to the reaction sequence shown in reaction scheme 1. [ka]

[0046] Scheme 1. Synthesis of 1-ethyl-4-piperidinesulfonamide (6) Reaction scheme 1 - Steps (a) and (b) [ka] Piperidine-4-ol(1) (340.0 g, 3.36 mol, 1.0 equivalent) was dissolved in a mixture of acetonitrile (207.0 g, 5.04 mol, 1.5 equivalents) and methanol (1020 ml, 3.0 V). Dissolution was endothermic. The resulting solution was transferred to a 2.0 L autoclave. After purging with nitrogen, 11.0 g of Pd / C 10% was added. The autoclave was purged with hydrogen and the hydrogen pressure was set to 10-15 bar. Subsequently, hydrogenation was carried out at 75-85°C and 10-15 bar hydrogen until hydrogen uptake stopped. After complete conversion (GC), the reaction mixture was cooled to 20-30°C and the pressure was carefully released. The reaction mixture was discharged and the catalyst was filtered off. The reactor and filter were rinsed with methanol. The resulting solution was concentrated first at atmospheric pressure and then under reduced pressure to obtain crude 1-ethylpiperidine-4-ol (2) as a colorless liquid with a purity of 99.7% a / a (GC). The crude product was diluted with toluene (510 ml, 1.5V) and concentrated to approximately 600 ml under reduced pressure. The solution was used directly in the chlorination step.

[0047] To a 10 L glass reactor, toluene (800 ml, 1 V) and thionyl chloride (1,473 g, 12.5 mol, 2.0 equivalents) were added, and the mixture was heated to 60°C. Subsequently, a solution of 1-ethylpiperidine-4-ol(2) (800 g, 6.2 mol, 1.0 equivalent) and toluene (400 ml, 0.5 V) was added over at least 1 hour at 60-75°C. The reaction was strongly exothermic, accompanied by vigorous gas generation (SO2, HCl). After the addition, the reaction mixture was stirred under reflux (73°C) for at least 1 hour. Then, the reaction mixture was cooled to 20-25°C and quenched with water (4,000 ml, 5 V) at below 30°C. The quench was strongly exothermic, accompanied by gas generation (SO2). The pH of the quench mixture was set to 11.0 or higher with a 30% w / w NaOH aqueous solution (4,600 g) while maintaining the temperature below 30°C. The aqueous layer was separated, and the organic layer was washed with water (800 ml, 1 V). The organic layer was distilled under reduced pressure (100 to 20 mbar) at 60-90°C using a 30 cm Vigreux column to obtain 4-chloro-1-ethylpiperidine (3) (655 g, 71.6%) as a colorless liquid.

[0048] Final product: 4-chloro-1-ethylpiperidine(3) Yield: 72% HPLC purity: 99.5%

[0049] Reaction scheme 1 - Steps (c), (d), and (e) [ka] Magnesium (10.07 g, 415 mmol, 1.02 equivalents) was added to THF (300 ml, 5V) heated to 40°C and activated by adding 1,2-dibromoethane (1.75 ml, 20 mmol, 0.05 equivalents). The mixture was heated to 60°C and 4-chloro-1-ethylpiperidine(3) (60 g, 406 mmol, 1.00 equivalent) diluted with THF (60 ml, 1V) was added over at least 1 hour. After the addition was complete, the mixture was stirred under reflux for at least 3 hours (GC 4-chloro-1-ethylpiperidine(3) <3%-a / a).

[0050] During Grignard formation, the following two byproducts are generated: elimination product (A) (2.5%-a / a) and Wurtz coupling product (B) (2.0%-a / a). Both were detected by LC-MS. [ka]

[0051] The mixture was cooled to 0°C, and sulfur dioxide (13% w / w in THF, 210 g, 427 mmol, 1.05 equivalents) was added while maintaining the reaction temperature at 0-10°C. After the addition was complete, the mixture was stirred at 0°C for at least 20 minutes. The reaction mixture was then added under adiabatic conditions to a pre-cooled (0-10°C) solution of trisodium citrate dihydrate (155 g, 528 mmol, 1.30 equivalents) in water (360 ml, 6V). The resulting two-phase mixture (IT = 14-22°C) was heated to room temperature, and the phases were separated. The organic phase was discarded.

[0052] HOSA (50.6 g, 447 mmol, 1.10 equivalents) was added in 10 portions to an aqueous solution containing 1-ethylpiperidine-4-sulfinic acid (5) while maintaining the temperature at 20-25°C. After the addition was complete, the mixture was stirred at 20°C for at least 20 minutes. Then, sodium sulfite (10.3 g, 81 mmol, 0.20 equivalents) was added, and the mixture was stirred at 20°C for at least 20 minutes. The pH of the mixture was adjusted to pH=8.90-9.10 by adding ammonia (25% w / w in water, typically 67 ml, 813 mmol, 2.00 equivalents) over at 20-25°C for at least 1 hour. This generally resulted in precipitation of the product at pH=8.2-8.5. After aging the suspension at 20°C for at least 1 hour, the precipitate was filtered and washed with water (60 ml, 1V). The solid was dried in a vacuum cabinet at 50°C to obtain 1-ethyl-4-piperidinesulfonamide (6) (56.5 g, 72%) as a white solid.

[0053] Final product: 1-ethylpiperidine-4-sulfonamide (6) Yield: 72% HPLC purity:98.3w / w%

[0054] 1,2,3,5,6,7-Hexahydro-s-indacene-4-amine(12) 1,2,3,5,6,7-Hexahydro-s-indacene-4-amine (12) was prepared according to the reaction sequence shown in reaction scheme 2. [ka]

[0055] Reaction scheme 2 - Step (a) [ka] DCM (385 L) and AlCl3 (99.86 kg) were added to a clean, dry glass-lined reactor under a nitrogen atmosphere at 25-30°C. The reaction mixture was cooled to -10°C.

[0056] 3-Chloropropanoyl chloride (90.99 kg) was slowly added under a nitrogen atmosphere at -10 to -5°C. The reaction mixture was maintained under a nitrogen atmosphere at 10°C for 30 minutes. Then, 2,3-dihydro-1H-indene(8) (77.00 kg) was slowly added to the reaction mixture under a nitrogen atmosphere at -10 to -5°C.

[0057] The reaction mixture was maintained at 10-15°C for 2 hours.

[0058] After the reaction was complete, the reaction mixture was slowly added to a 6N hydrochloric acid solution (prepared from water (308 L) and concentrated hydrochloric acid (308 L)) at 0-10°C. DCM (231 L) was added, and the temperature of the reaction mixture was raised to 30-35°C. The reaction mixture was stirred at 30-35°C for 30 minutes and then allowed to stand at 30-35°C for 30 minutes. The layers were separated, and the organic layer (OL-1) was set aside. DCM (231 L) was added to the aqueous layer at 25-30°C. The reaction mixture was stirred at 25-30°C for 30 minutes and then allowed to stand at 25-30°C for 30 minutes. The layers were separated (aqueous layer (AL-1) and organic layer (OL-2)), and AL-1 was set aside. OL-1 and OL-2 were combined at 25-30°C. Demineralized water (385 L) was added to the combined organic layer. The reaction mixture was stirred at 25-30°C for 30 minutes, and then allowed to stand at 25-30°C for 30 minutes. The layers were separated (aqueous layer (AL-2) and organic layer (OL-3)), and AL-2 was set aside.

[0059] A 10% saturated sodium bicarbonate solution (prepared from desalted water (385 L) and sodium bicarbonate (38.5 kg)) was added to OL-3 at 25-30°C. The reaction mixture was stirred at 25-30°C for 30 minutes and then allowed to stand at 25-30°C for 30 minutes. The layers were separated (aqueous layer (AL-3) and organic layer (OL-4)), and AL-3 was set aside. OL-4 was dried with anhydrous Na2SO4 (38.5 kg), and the anhydrous Na2SO4 was washed with DCM (150 L) at 25-30°C.

[0060] The solvent was distilled under vacuum at a temperature of 35-40°C until 5% remained.

[0061] 308 L of n-hexane was added to the reaction mixture at 35-40°C, and the solvent was completely distilled at 35-40°C until no more condensation droplets formed. 150 L of n-hexane was added to the reaction mixture at 35-40°C, and the reaction mixture was cooled to 5-10°C and maintained at 5-10°C for 30 minutes.

[0062] The solid product was filtered, washed with cooled hexane (77 L), and dried in a hot air oven at 40-45°C for 6 hours to obtain the final product.

[0063] Final product: 3-Chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one(9) Yield: 120.5Kg Yield: 88.6% HPLC purity: 99.3% Moisture content: 0.09% 1 H NMR:(500MHz,CDCl3):δ 7.81(S,1H),7.76(d,1H),7.31(d,1H),3.93(t,2H),3.45(t,2H),2.97(t,4H),2.15(q,2H)

[0064] Reaction scheme 2 - Steps (b) and (c) [ka] 300.0 L of sulfuric acid was added to a 2.0 KL clean, dry glass-lined reactor at 25-30°C. 60.0 kg of 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one(9) was added in batches at 25-30°C, and the reaction mixture was maintained at 25-30°C for 30 minutes. The reaction mixture was slowly heated to 65-70°C and maintained at 65-70°C for 24 hours. The absence of 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)-propan-1-one(9) was confirmed by HPLC (limit: ≤1.0%).

[0065] Next, the reaction mixture was cooled to 0-5°C. *1 The mixture was slowly added at 0-5°C, and the reaction mixture was maintained at 0-5°C for 1 hour.

[0066] Demineralized water (900.0 L) was added to a clean, dry, glass-lined reactor at 25-30°C in a 2.0 KL vessel. The water was cooled to 0-5°C. The reaction mixture was slowly added to the reactor at 0-5°C. Toluene (480.0 L) was added, and the temperature was raised to 30-35°C. The reaction mixture was maintained at 30-35°C for 30 minutes, and then allowed to stand at 30-35°C for 30 minutes. The reaction mixture was then placed in a Celite container. (登録商標)Bed (Celite) (登録商標) (Prepared using 6.0 kg of toluene and 30.0 L of Celite) was passed through a filter. (登録商標) The bed was cleaned with toluene (60.0 L). The solid was filtered and vacuum-dried for 30 minutes.

[0067] The reaction mixture was placed in a 2.0 KL clean, dry, glass-lined reactor. The reaction mixture was allowed to stand at 30-35°C for 30 minutes. The layers were separated (aqueous layer (AL-1) and organic layer (OL-1)), and OL-1 was set aside. Toluene (60.0 L) was added to AL-1. The reaction mixture was stirred at 35-40°C for 30 minutes, and then allowed to stand at 35-40°C for 30 minutes. The layers were separated (aqueous layer (AL-2) and organic layer (OL-2)), and OL-2 was set aside. OL-1 and OL-2 were combined to form OL-3.

[0068] A 5% saturated sodium bicarbonate solution (prepared from desalted water (300.0 L) and sodium bicarbonate (15.0 kg)) was slowly added to OL-3 at 30-35°C. The reaction mixture was stirred at 35-40°C for 30 minutes, and then allowed to stand at 35-40°C for 30 minutes. The reaction mixture was then processed using Celite. (登録商標) Bed (Celite) (登録商標) (Prepared using 6.0 kg of celine and 60.0 L of desalinated water) was passed through a filter. (登録商標) The bed was cleaned with toluene (60.0L).

[0069] The reaction mixture was placed in a 3.0 KL clean, dry, glass-lined reactor. The reaction mixture was allowed to stand at 30-35°C for 30 minutes. The layers were separated (aqueous layer (AL-3) and organic layer (OL-4)), and OL-4 was set aside.

[0070] Toluene (60.0 L) was added to AL-3. The layers were separated (aqueous layer (AL-4) and organic layer (OL-5)), and OL-5 was set aside. OL-4 and OL-5 were combined to form OL-6. A brine solution (prepared from desalted water (300.0 L) and sodium chloride (12.0 kg)) was prepared at 25-30°C. The reaction mixture was stirred at 30-35°C for 30 minutes and then allowed to stand at 30-35°C for 30 minutes. The layers were separated (aqueous layer (AL-5) and organic layer (OL-7)), and OL-7 was set aside. OL-7 was dried with anhydrous Na2SO4 (9.0 kg), and the anhydrous Na2SO4 was washed with toluene (30.0 L) at 25-30°C. The solvent was distilled under vacuum at 40-45°C until 5% remained. Methanol (60.0 L) was added to the reaction mixture at 40-45°C, reducing the reaction mass to 60 L.

[0071] Methanol (120.0 L) was added to the reaction mixture at 40-45°C, and the reaction mixture was cooled to 5-10°C and maintained at 5-10°C for 30 minutes. The solid product was filtered, washed with cooled methanol (30.0 L), and dried in a hot air oven at 40-45°C for 6 hours to obtain the product.

[0072] *1: To prepare the nitration mixture, sulfuric acid (27.0 L) was added to a 160 L clean, dry glass-lined reactor at 25-30°C. The reaction mixture was cooled to 0-5°C. Nitric acid (27.0 L) at 0-5°C was slowly added, and the reaction mixture was maintained at 0-5°C for 30 minutes to obtain the nitration mixture.

[0073] Final products: 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (11a) and 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (11b) Combined yield (11a+11b): 38.87Kg Combined yield (11a + 11b): 62.24% Weight ratio (11a:11b):9:1 HPLC purity: 95.9% Moisture content: 0.19% 1H NMR:(500MHz,CDCl3):δ7.44(S,1H),2.21(m,2H),2.78(t,2H),3.02(m,4H),3.13(t,2H)

[0074] Reaction scheme 2 - Step (d) [ka] A mixture of 8-nitro-1,2,3,5,6,7-hexahydro-s-indacene-1-one (11a) and 4-nitro-1,2,3,5,6,7-hexahydro-s-indacene-1-one (11b) (9:1 ratio; 27.0 kg) was placed in a 600 L clean, dry-pressure reactor at 25-30°C.

[0075] Methanol (270 L) was added at 25-30°C. Methanesulfonic acid (14.3 kg) was slowly added at 25-30°C, and the reaction mixture was maintained for 30 minutes. 15% Pd(OH)2 slurry (60% wet) *2 Added.

[0076] The reaction mixture was degassed under vacuum and refilled three times with an argon atmosphere (0.5 kg). The reaction mixture was then degassed under vacuum and refilled three times with a hydrogen atmosphere (0.5 kg). Subsequently, the reaction mixture was stirred under hydrogen pressure (100 Psi) at room temperature for 32 hours.

[0077] After the reaction was complete, the reaction mixture was cooled to 25-30°C. The reaction mixture was degassed under vacuum and packed three times with a nitrogen atmosphere (0.5 kg).

[0078] The reaction mixture was passed through a candy filter to remove Pd(OH)2, then through a microfilter, and the bed was washed with methanol (54 L). 95% of the solvent was removed by distillation under vacuum at less than 45°C to 50°C. Demineralized water (135 L) was added to the reaction mixture at 25-30°C and maintained for 30 minutes. The reaction mixture was cooled to 5-10°C. The pH was adjusted to approximately 9-10 with 2N NaOH aqueous solution (prepared from NaOH (6.48 kg) and demineralized water (81 L)), and the reaction mixture was stirred for 30 minutes. Next, toluene (135 L) was added to the reaction mixture, and the reaction mixture was stirred for 30 minutes. The reaction mixture was stirred for another 30 minutes while raising the temperature to 25-30°C. The reaction mixture was allowed to stand for 30 minutes while maintaining the temperature at 25-30°C.

[0079] Reaction light Celite (登録商標) Bed (Celite) (登録商標) (Prepared using 5.4 kg of toluene and 13.5 L of Celite) was passed through a filter. (登録商標) The bed was cleaned with toluene (54L).

[0080] The layers were separated (aqueous layer (AL-1) and organic layer (OL-1)), and OL-1 was set aside. Toluene (54 L) was added to AL-1 at 25-30°C. The reaction mixture was stirred at 25-30°C for 30 minutes and then allowed to stand at 25-30°C for 30 minutes. The layers were separated (aqueous layer (AL-2) and organic layer (OL-2)), and AL-2 was set aside. Toluene (54 L) was added to AL-1 at 25-30°C. Brine solution (prepared using desalted water (135 L) and sodium chloride (54 kg)) was added to the combined organic layers (OL-1 and OL-2) at 25-30°C. The reaction mixture was stirred at 25-30°C for 30 minutes and then allowed to stand at 25-30°C for 30 minutes.

[0081] The layers were separated (aqueous layer (AL-3) and organic layer (OL-3)), and AL-3 was set aside. 1.3 kg of charcoal was added to OL-3, the temperature was raised to 35-40°C, and maintained at 35-40°C for 30 minutes. The reaction mixture was then heated to 35-40°C in Celite. (登録商標) Bed (Celite) (登録商標)(Prepared using 5.4 kg of toluene and 54 L of Celite) was passed through the filter. (登録商標) The bed was washed with toluene (54 L). The organic layer was dried with anhydrous sodium 2SO4 (13.5 kg). The sodium 2SO4 was washed with toluene (27 L).

[0082] The solvent was distilled under vacuum at 35-40°C until 5% remained. Methanol (40.5 L) was added to the reaction mixture at 35-40°C and distilled until 5% remained. Methanol (97.2 L) and water (10.8 L) were added to the reaction mixture at 35-40°C. The reaction mixture was heated to 50-55°C, stirred at 50-55°C for 1 hour, slowly cooled to 0-5°C, and maintained at 0-5°C for 30 minutes.

[0083] The solid product was filtered, washed with cold methanol (13.5 L), and dried in a hot air oven at 40-45°C for 6 hours to obtain the final product.

[0084] *2: To prepare a 15% Pd(OH)2 slurry, 20% carbon-supported Pd(OH)2 (60% wet, 4.05 kg) was added to methanol (27 L).

[0085] Final product: 1,2,3,5,6,7-Hexahydro-s-indacene-4-amine(12) Yield: 11.3Kg Yield: 41.85% HPLC purity: 98.1% Moisture content: 0.10 1 H NMR:(400MHz,DMSO-d6):δ 6.38(S,1H),4.45(S,2H),2.75(t,4H),2.58(t,4H),1.98(t,4H).

[0086] Purification of 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (12) (A) 1,2,3,5,6,7-Hexahydro-s-indacene-4-amine (12) (54.5 kg) was added to a clean, dry reactor in a 250 L container at 25-30°C. Toluene (27.2 L) was added at 25-30°C, and the reaction mixture was stirred at 25-30°C for 30 minutes. Methanol (163 L) was added to the reaction mixture at 25-30°C. The reaction mixture was stirred at 25-30°C for 30 minutes, cooled to -5-0°C, and stirred at -5-0°C for 30 minutes. The solid product was filtered, washed with cold methanol (54.5 L), and dried at 40-45°C for 6 hours.

[0087] Final product: 1,2,3,5,6,7-Hexahydro-s-indacene-4-amine(12) Yield: 40.5Kg Yield: 74.31% HPLC purity: 99.5% Moisture content: 0.3% 1 H NMR:(400MHz,DMSO-d6):δ 6.33(s,1H),4.53(s,2H),2.72(t,4H),2.57(t,4H),1.98(t,4H).

[0088] 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacene-4-yl)carbamoyl)piperidine-4-sulfonamide (potassium salt)(I) [ka]

[0089] Batch-mode preparation of 1,2,3,5,6,7-hexahydro-s-indacene-4-amine-isocyanate (13): 1,2,3,5,6,7-Hexahydro-s-indacene-4-amine (12) (1.00 g, 1.00 equivalent) was dissolved in toluene (9.60 g) in a 50 mL reactor at 10-20°C. N,N-diisopropylethylamine (2.25 g, 3.00 equivalent) was added, followed by the addition of 20% by weight phosgene solution (4.28 g, 1.50 equivalent) over 3 minutes. The resulting suspension was further stirred at 10-20°C for 30 minutes. The reaction mixture was washed with saturated NaHCO3 solution (5.0 mL) and water (5.0 mL). The layers were separated to obtain 1,2,3,5,6,7-hexahydro-s-indacene-4-amine isocyanate in toluene (OL-1, about 20 mL, containing 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (12) (5.77 mmol)). The obtained solution OL-1 was used in the next step (coupling of indacenamine isocyanate (12) with 1-ethyl-4-piperidinesulfonamide (7)) to obtain (14) in an overall yield of about 80%.

[0090] Preparation of 1,2,3,5,6,7-hexahydro-s-indacene-4-amine-isocyanate (13) in flow mode: Preparation of the supply solution: Supply solution A: 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (12) (43.31 g) was dissolved in toluene (206.69 g) to obtain a 0.90 M solution. Supply solution B: Potassium carbonate (103.5g) was dissolved in water (950g) to obtain a 0.75M solution.

[0091] Feed A (0.70 mL / min, 1.10 equivalents), 20% w / w phosgene solution toluene (0.45 mL / min, 1.50 equivalents), and feed B solution (2.35 mL / min, 3.10 equivalents) were simultaneously added to reactor 1 (approximately 25 mL) at 0-10°C (internal temperature). The residence time in reactor 1 was 5-10 minutes. The two-phase solution was continuously discharged from reactor 1, and the layers were continuously separated to obtain an organic layer (OL-1) containing 1,2,3,5,6,7-hexahydro-s-indacene-4-amine isocyanate (13) and an aqueous layer (AL-1) directed towards waste. The organic layer OL-1 was recovered under steady state over 81 minutes to obtain approximately 90 mL of 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (12) (51 mmol). The resulting solution OL-1 is used in the next step.

[0092] Coupling of indacenamine-isocyanate (12) and 1-ethyl-4-piperidinesulfonamide (7): 1-Ethyl-4-piperidinesulfonamide (7) (8.88 g, 46 mmol, 1.0 equivalent) was added to the container. Tetrahydrofuran (62.52 g) was added to the container and the mixture was adjusted to 20-25°C. The mixture was stirred at 20-25°C for at least 20 minutes until the aggregates disappeared and a homogeneous suspension was formed. Potassium tert-butoxide (1.05 M, 43.98 mL, 46 mmol) was added to the container over 90-120 minutes, the temperature was maintained at 20-25°C, and the mixture was stirred at 20-25°C for 2-4 hours to obtain a thick white suspension.

[0093] Organic layer OL-1 containing 1,2,3,5,6,7-hexahydro-s-indacene-4-amine isocyanate (13) (51 mmol of 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (12), approximately 90 mL), prepared in batch or flow mode, was added to the resulting white suspension in toluene over 2 hours while maintained at 20-25°C. The reaction mixture rapidly became a well-stirred suspension, and a slightly cloudy brown solution was obtained at the end of the addition. The reaction mixture was stirred for a further 1-2 hours at 20-25°C. The water content was analyzed by KF, and the conversion of 1,2,3,5,6,7-hexahydro-s-indacene-4-amine was confirmed by LC / MS or HPLC analysis (typically >95%). Optionally, clear filtration was performed through a Celite layer (G3 filter). Water (4.44 g, 0.5V) was added dropwise to the reaction mixture over 2 hours at 25-40°C. The solid began to crystallize at a water content of approximately 0.5-1% by weight. A suspension was formed at the end of the addition. The reaction mixture was cooled to 0-5°C (IT) over 1 hour and stirred for a further 16 hours at 0-5°C. The solid was filtered through a G3 filter and washed with a toluene / THF (1 / 1 volume, 44.4 mL) mixture.

[0094] The solid was dried under a nitrogen stream at a maximum temperature of 50°C and 10–20 mbar for 12 hours. The dry weight of the crude solid was measured and identified. 1 Analysis was performed using 1H NMR spectroscopy and HPLC.

[0095] Final product: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)-carbamoyl)piperidine-4-sulfonamide (potassium salt) (1) Yield: approx. 16.0g Yield: Approximately 80% NMR purity:>97% HPLC purity:>99%

[0096] Recrystallization of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)-carbamoyl)piperidine-4-sulfonamide (potassium salt) (1) Crude 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)carbamoyl)piperidine-4-sulfonamide (potassium salt) (14) (15.00 g) was added to the reaction vessel. Methanol (33.55 g) and then acetonitrile (33.55 g) were added to the vessel, and the mixture was stirred for 10-20 minutes (until a homogeneous, turbid solution free of solid lumps was formed), adjusting the temperature as needed to 15-25°C. The solution was filtered through a 1 μm filter at 15-25°C. The filter was washed with a methanol / acetonitrile mixture (7.59 g) at 15-25°C, and then acetonitrile (64.0 g) was added, followed by the addition of a seed crystal of (14) (0.138 g) in acetonitrile (approximately 1 g). A suspension was formed.

[0097] The solution was concentrated to approximately 122 mL at 25-35°C. Acetonitrile (54.32 g) was added to the mixture, and the solution was concentrated to approximately 122 L at 25-35°C. Acetonitrile (52.53 g) was added to the mixture, and the mixture was diluted to approximately 122 mL at a temperature below 35°C. The mixture was analyzed for residual methanol content. Acceptance criterion: ≤0.3% w / w methanol. Acetonitrile (53.45 g) was added to a container, and the temperature was adjusted to 15-25°C. The slurry was aged at 15-25°C for at least 1 hour (target 1-2 hours), and then filtered through a 20 μm cloth at 15-25°C. The filter cake was washed twice with acetonitrile (43.39 g) at 15-25°C. The solid was dried under a nitrogen stream at a maximum of 50°C to obtain 13.75 g (92%) of white solid.

[0098] Final product: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indasen-4-yl)-carbamoyl)piperidine-4-sulfonamide (potassium salt) (1) Yield: 13.75g Yield: 92% HPLC purity: 99.7%

Claims

1. (a) A step to obtain (2) by the first ethylation reaction of (1), thereafter, (b) Next, the process of reacting (2) with thionyl chloride in toluene to form (3). 【Chemistry 1】 after that, (c) A step of reacting compound (3) via Grignard formation to form compound (4), and then, (d) A step of forming a sulfonate compound (5), and then this (e) A step of oxidation to obtain compound (6) 【Chemistry 2】 A method for preparing compound (6) or a salt thereof, which includes the above.

2. The method according to claim 1, wherein reaction step (a) comprises dissolving compound (1) in a mixture of methanol and acetonitrile, and hydrogenating it in the presence of a Pd / C catalyst.

3. Hydrogenation in step (a) is performed at 80°C, 10-20 bar H ２ The method according to claim 1 or 2, which is carried out within 1 to 3 hours.

4. The method according to claim 2 or 3, wherein the loading amount in reaction step (a) is 10% by weight of Pd / C, which is the catalyst loading amount of 3.3% by weight of catalyst to 10% by weight of catalyst.

5. The method according to any one of claims 1 to 4, wherein in reaction step (b), compound (2) in toluene is heated to 60°C, and while maintaining the internal temperature at 60 to 75°C, thionyl chloride reagent in toluene is added over at least 1 hour.

6. The method according to any one of claims 1 to 5, wherein reaction step (c) typically includes adding THF, heating to 40°C, and adding compound (3) diluted in THF to magnesium activated by the addition of 1,2-dibromoethane.

7. The method according to any one of claims 1 to 6, wherein reaction step (d) comprises reacting compound (4) with sulfur dioxide in a mixture cooled to 0°C.

8. The method according to any one of claims 1 to 8, wherein the subsequent post-treatment in reaction step (d) includes adding the reaction mixture to a pre-cooled solution of trisodium citrate dehydrated in water, and separating the product compound (5) from the organic phase.

9. The method according to any one of claims 1 to 8, wherein reaction step (e) typically includes adding HOSA (hydroxylamine-O-sulfonic acid) to an aqueous solution of compound (5) at a temperature of 20 to 25°C.

10. A method for obtaining a compound of formula (I) by reacting a compound (6) obtained by any of the methods described in claims 1 to 9 with a compound (13). 【Transformation 3】

11. A pharmaceutical composition comprising compound (I) or a salt thereof obtained by the method of claim 10, and a pharmaceutically acceptable excipient.

12. A compound of formula (6), comprising a compound of formula (A) and / or (B). 【Chemistry 4】

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