Process for the preparation of preparing 1-ethyl-n-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) piperidine-4-sulfonamide

Abstract

The invention relates to a method for preparing a compound (6). Compound (6) is a key precursor for the formation of 1-ethyl-N-((1, 2, 3, 5, 6, 7-hexahydro-s-dicyclopentadienobenzo-4-yl) carbamoyl) piperidine-4-sulfonamide (compound (I)) or a pharmaceutically acceptable salt thereof, which is useful as an NLRP3 inhibitor. (I).

Description

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) ™ (19) World Intellectual Property ~S Organization ; LNA AMA ACA TA International Bureau —— (10) International Publication Number (43) International Publication Date ——a WO 2025 / 036914 Al 20 February 2025 (20.02.2025) WIPOIPCT (51) International Patent Classification: RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, C07D 211 / 64 (2006.01) CO7D 401 / 04 (2006.01) TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, CO7D 211 / 72 (2006.01) ZA, ZM, ZW. (21) International Application Number: (84) Designated States (unless otherwise indicated, for every PCT / EP2024 / 072842 kind of regional protection available): ARIPO (BW, CV, 22) Int tional Filing Date: GH, GM, KE, LR, LS, MW, MZ, NA, RW, SC, SD, SL, ST, (22) International Filing Date: 14 Anoust 2024 (14.08.2024 SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, ugus (14.08.2024) RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, (25) Filing Language: EnglishDE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, 26) Publication L . Enelish LU, LV, MC, ME, MK, MT, NL, NO, PL, PT, RO, RS, SE, (26) Publication Language: nglis SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CL, CM, GA, GN, (30) Priority Data: GQ, GW, KM, ML, MR, NE, SN, TD, TG). 23191567.9 16 August 2023 (16.08.2023) EP (71) Applicant (for all designated States except US): F. HOFF Published: on ~ — with international h t (Art. 21(3 MANN-LA ROCHE AG [CH / CH]; Grenzacherstrasse with international search report (Ar OY 124, 4070 Basel (CH). (71) Applicant (for US only): HOFFMANN-LA ROCHE INC. [US / US]; Overlook at Great Notch, 150 Clove Road, 8th Floor, Suite 8 - Legal Department, Little Falls, New Jer- — sey 07424 (US). ==—= (72) Inventors: BERGNER, Eike Johannes; c / o F. Hoff- — mann-La Roche AG, Grenzacherstrasse 124, 4070 Basel — (CH). CINQUALBRE, Joséphine Eliette Frangoise; c / o — F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 — Basel (CH). KALDRE, Dainis; c / o F. Hoffmann-La Roche= AG, Grenzacherstrasse 124, 4070 Basel (CH). m= (74) Agent: JOCHNOWITZ, Evan; c / o F. Hoffmann-La — Roche AG, Patent Department, Grenzacherstrasse 124, = 4070 Basel (CH). ms (81) Designated States (unless otherwise indicated, for every >= kind of national protection available); AE, AG, AL, AM, — AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, — CA, CH, CL, CN, CO, CR, CU, CV, CZ, DE, DJ, DK, DM, _—— DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, >= HN, HR, HU, ID, IL, IN, IQ, IR, IS, IT, JM, JO, JP, KE, KG, — KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, — MA, MD, MG, MK, MN, MU, MW, MX, MY, MZ, NA, = NG, NL, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, == (54) Title: PROCESS FOR THE PREPARATION OF PREPARING 1-ETHYL-N-((1,2,3,5,6,7-HEXAH YDRO-S-INDACEN-4- meee = YL)CARBAMOYL)PIPERIDINE-4-SULFONAMIDE = < QP sy 9 x cy“ 3 °F 0 \o SN © w (57) Abstract: The present invention relates to a process for the preparation of compound (6), (6). Compound (6) is akey precursor for q)the formation of 1-ethyl-N-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoy1)piperidine-4-sulfonamide (compound (I), Formula (I) 4 or a pharmaceutically acceptable salt thereof, which is useful as an NLRP3 inhibitor. WO 2025 / 036914 PCT / EP2024 / 072842 Process for the preparation of preparing 1-ethyl-N-(G,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide The present invention relates to a process for the preparation of compound (6), QO SUN (6) Compound (6) is a key precursor for the formation of 1-ethyl-N-((1,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (compound (1)) ora pharmaceutically acceptable salt thereof, which is useful as an NLRP3 inhibitor. O, o oO N H H Ny (1). Background 1-Ethyl-N-(,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide is disclosed in WO 2019 / 008025 as an NLRP3 inhibitor (see Example 6). However, there is a need to provide improved processes for preparing 1-ethyl-N-((4,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide and salts thereof. In particular, there is a need to provide efficient processes that are suitable for large scale synthesis and which, for example, avoid multiple, complex and partially low yielding chemical steps and overall atom inefficient synthesis. W02022 / 268935 demonstrates processes to make 1-Ethyl-N-((1,2,3,5,6,7-hexahydro- s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide involving contacting compound (6) with compound (Y) in the presence of a solvent and base to obtain compound (J), which is 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4- sulfonamide, or a salt thereof. WO 2025 / 036914 PCT / EP2024 / 072842 -9- 0 Bey H2 + i: yx ——_» oP L “e (6) (Y) (I) wherein X is a leaving group. There is also a need to provide 1-ethyl-N-((,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)piperidine-4-sulfonamide and salts thereof at a higher yield compared to prior art processes, especially on a large scale.Further, for large-scale industrialization, greener synthesis routes, reduced solvent waste, and improved safety are also of concern. The present invention solves the aforementioned problems by providing an improved route to the formation of compound (6). The new process disclosed herein permits a reduction of steps and an increase in overall yield to obtain compound (6) from 11% to 52% when compared to that disclosed in WO 2022 / 268935 Furthermore, the present invention can be implemented in both batch or continuous methods and allows the use of less reagents and solvents leading to less waste. Summary of the Invention The invention provides a process of preparing compound (6), the process comprising the scheme A shown below. Scheme A OH OH cl MgCl O.,ONa onb5 N N N N N " - A NL LL L (1) (2) (3) (4) (5) (6) The term “pharmaceutically acceptable salt” refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of thecompounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid-addition salts include for example those WO 2025 / 036914 PCT / EP2024 / 072842 -3- 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, fumaric acid, and the like. Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide. The chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in BastinR.J., et al., Organic Process Research & Development 2000, 4, 427-435; or in Ansel, H., et al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 5 1456-1457. Abbreviations Aq. aqueous AKX AQUAMICRON® 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 charcoal rt Room temperature THF tetrahydrofuran Vv volume relative to the starting material w / w% Weight in weight %a-a (area under peak of compound (a) / combined area under peaks of compound (a) and all other components) x 100 The invention provides the process for preparing the compound (6) as outlined in Scheme A and the subsequent preparation of compound (J) as outlined in Scheme B. WO 2025 / 036914 PCT / EP2024 / 072842 - 4 - Scheme A OH OH Cl MgCl O.ONa onteg Cy (a) Cy (b)Cy (c) C) (d) A (e) Cy N N N N N N L L L < r (1) (2) (3) (4) (5) (6) Scheme B NH2 we CCD CED (12) (13) QO, fe) fe) lor H H NUN 0, 2 0 Say 2 NN (6) The synthesis of compound (6) comprises one or more of the following steps: Steps (a) and (b): The formation of compound (3) via a first ethylation reaction of (4) to yield (2), which is then subsequently reacted with thionyl chloride in toluene to form (3) OH OH Cl oleae N N N " ~ L (1) (2) (3) , WO 2025 / 036914 PCT / EP2024 / 072842 - 5 - steps (c) (d) and (e): Reacting compound (3) to compound (4) via a Grignard formation, followed by formation of the sulfonate compound (5) which is then oxidized to yield compound (6) NH oO ONa 2 Cl MgCl Ser | 9 S O=S=O (c) = (d) - (e) = N N . 7 tC t (3) (4) (5) (6) The reaction step (a) typically involves dissolving compound (1) in a methanol and acetonitrile mixture and performing a hydrogenation in the presence of a Pd / C catalyst. Suitable conditions for performing the hydrogenation in step (a) include10-20 bar H2 at 80°C to achieve complete conversation without any side reaction within 1 to 3h. Suitable catalyst loadings for reaction step (a) include 10%-wt Pd / C with catalyst loadings between 3.3%-wt catalyst to 10%-wt catalyst. In reaction step (b) compound (2) in toluene is heated to 60°C and thionyl chloride reagent in toluene is dosed over at least 1 hour while maintaining internal temperature at 60-75°C. Alternatively, 48% HBr (aq.) would yield a bromo intermediate instead of the represented chloro one, which functions also. Other solvents as alternative to toluene are ACN (acetonitrile), DCM (dichloromethane), and a mixture of toluene and TBAC (tetrabutylammonium chloride) as additive. Further alternative reagents include PBr3, SOBr2, Brz / PPh3, CBr4 / PPhg (to form a bromo intermediate), as well as thionyl chloride, CCl4 / PPhs, POCI;, PCl3 to form a chloro intermediate. WO 2025 / 036914 PCT / EP2024 / 072842 -6- The reaction step (c) typically involves adding compound (3) diluted inTHF to Magnesium that is charged with THF, heated to 40°C and activated by addition of 1,2- dibromoethane at 40°C and then heated to 60°C for the reaction. Activation may also be performed with iodine in diethyl ether solvent. The reaction step (d) typically involves reacting compound (4) with sulphur dioxide in a cooled mixture at 0°C. The sulphur dioxide may be as a gas or in solution in THF. Subsequent work-up in reaction step (d) typically involves adding the reaction mixture to a precooled solution of trisodium citrate dehydrate in water and separating out the product compound (5) from the organic phase. Alternative salts may be potassium carbonate, mono sodium biphosphate, sodium bisulphate, disodium citrate, while alternative acids are acetic acid, citric acid, hydrochloric acid and water. The reaction step (e) typically involves adding HOSA (hydroxylamine-O-sulfonic acid ) to an aqueous solution of compound (5) at temperatures between 20 and 25°C. Unless stated otherwise, anyreference to an element is to be considered a reference to all isotopes of that element. Thus, for example, unless stated otherwise any reference to hydrogen is considered to encompass all isotopes of hydrogen including deuterium and tritium. Unless stated otherwise, any reference to a compound or group is to be considered a reference to all tautomers of that compound or group. A further embodiment of the invention includes reacting compound (6) obtained by the processes mentioned above with compound (13) to yield compound (1). WO 2025 / 036914 PCT / EP2024 / 072842 -7- NH2 wen CCD —| ado (12) (13) 09 9 pel > Sy Ay 0, 9 ()) or SNH NN (6) . A further embodiment of the invention relates to compound (I) obtained using compound (6) that was produced using the processes described above. The compounds used in and provided by the present invention can be used both, in their free base form and their acid addition salt form. For the purposes of this invention, a “salt” of a compound of the inventionincludes an acid addition salt. Acid addition salts are preferably pharmaceutically acceptable, non-toxic addition salts with suitable acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (for example, nitric, perchloric, sulfuric or phosphoric acid); or organic acids such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic sulfonic acids (for example, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, toluene-p-sulfonic, naphthalene-2-sulfonic or camphorsulfonic acid) or amino acids (for example, ornithinic, glutamic or aspartic acid). The acid addition salt may be a mono-, di-, tri- ormulti-acid addition salt. A preferred salt is a hydrohalogenic, sulfuric, phosphoric or organic acid addition salt. A preferred salt is a hydrochloric acid addition salt. Where a compound of the invention includes a quaternary ammonium group, typically the compound is used in its salt form. The counter ion to the quaternary ammonium group may be any pharmaceutically acceptable, non-toxic counter ion. Examples of suitable counter ions include the conjugate bases of the protic acids discussed above in relation to acid addition salts. WO 2025 / 036914 PCT / EP2024 / 072842 -8- The compounds used in and provided by the present invention can also be used both, in their free acid form and their salt form. For the purposes of this invention, a “salt” of a compound of the present invention includes one formed between a protic acid functionality (such as a carboxylic acid group or a urea group) of a compound of the present invention and a suitable cation. Suitable cations include, but are not limitedto lithium, sodium, potassium, magnesium, calcium and ammonium. The salt may be a mono-, di-, tri- or multi-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. 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, since they have potential to serve as intermediates in the purification or preparation of other, for example, pharmaceutically acceptable salts, or are useful for identification, characterisation or purification of the free acid or base. The compounds and / or salts used in and provided by the present invention may be anhydrous or in the form of a hydrate (e.g. a hemihydrate, monohydrate, dihydrate or trihydrate) or other solvate. Such other solvates may be formed with common organic solvents, including but notlimited to, alcoholic solvents e.g. methanol, ethanol or isopropanol. The compounds, salts and solvates used in and provided by the present invention may contain any stable isotope including, but not limited to 12C, 3C, 1H, 2H (D), #4N, *5N, 1°O, 170, 180, 19F and #271, and any radioisotope including, but not limited to "C, 4C, 3H (T), 13N, 150, '8F, 223], 241, 125T and 33°I. Unless stated otherwise, the compounds, salts and solvates used in and provided by the present invention may be in any polymorphic or amorphous form. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Aulton’s Pharmaceutics - The Design and Manufacture of Medicines”, M. E. Aulton and K. M. G. Taylor, Churchill Livingstone Elsevier, 4'* Ed., 2013. Pharmaceutically acceptable excipients including adjuvants, diluents or carriers that may be used in the pharmaceutical compositions of the WO 2025 / 036914 PCT / EP2024 / 072842 - 9 - invention, arethose conventionally employed in the field of pharmaceutical formulation. An additional aspect of the present invention provides compound (I) or the salt thereof, as obtained using compound (6) that was produced using the processes described above, for use in medicine, and / or for use in the treatment or prevention of a disease, disorder or condition. An additional aspect of the present invention provides a pharmaceutical composition comprising compound (J) or the salt thereof, as obtained using compound (6) that was produced using the processes described above, for use in medicine, and / or for use in the treatment or prevention of a disease, disorder or condition. Typically, the treatment or prevention of the disease, disorder or condition comprises the administration of the compound (J) or the salt thereof, as obtained using compound (6) that was produced using the processes described above. Examples All solvents, reagents and compounds were purchased and used without furtherpurification unless stated otherwise. Experimental Methods NMR Methods: NMR spectra were obtained on Bruker AV 400MHz spectrometer (model: Advance IIID) operated at room temperature (25°C). GC Methods: GC analysis was conducted on one of the following machines: Agilent 7890, 6890, or Agilent 6890N with ALS injector. HPLC Methods: HPLC in reaction scheme 2, steps (a)-(d) was run on Waters Alliance e2695 HPLC with PDA detector using 10Mm ammonium bicarbonate in water as mobile phase-A and acetonitrile as mobile phase-B. WO 2025 / 036914 PCT / EP2024 / 072842 - 10 - HPLC in the reaction scheme 3, was run on Agilent 1290 HPLC with DAD detector (Column: Waters CORTECS UPLC T3) using 5 mM K2HPO4 in water (pH 6.2) as mobile phase-A and acetonitrile as mobile phase-B. As used herein, unless stated otherwise all references to HPLC purity are measured as the % a / a. KF Methods: Coulometric KF (Karl Fischer) titration was run using AKX reagent on Mitsubishi CA- 20 or Predicta OM1000. Synthesis Examples1-ethylpiperidine-4-sulfonamide (6) 1-ethyl-4-piperidinesulfonamide (6) was prepared according to the reaction sequence illustrated in reaction scheme 1. OH OH Cl MgCl Ox-ONa onsen Cy (a) Cy (b) Cy (c) So (d) Cy (e) Cy N N N N N N t t t t i (1) (2) (3) (4) (5) (6) Scheme 1. 1-ethyl-4-piperidinesulfonamide (6) synthesis Reaction scheme 1 — step (a) and (b) OH OH Cl ope & N N N H L L (1) (2) (3) WO 2025 / 036914 PCT / EP2024 / 072842 -- Piperidin-4-ol (4) (340.0 g, 3.36 mol, 1.0 eq.) was dissolved in a mixture of acetonitrile (207.0 g, 5.04 mol, 1.5 eq.) and methanol (1'020 ml, 3.0 V). The dissolution was endothermic. The resulting solution was transferred to a 2.0 L autoclave. After purging with nitrogen, 11.0 g Pd / C 10% were added. The autoclave was purged with hydrogen and the hydrogen pressure was set to 10-15 bar. Subsequently, hydrogenation was performed at 75-85°C and 10-15 bar hydrogen until the hydrogen uptake had ceased. After complete conversion (GC), the reaction mixture was cooledto 20-30°C and the pressure carefully released. The reaction mixture was drained, and the catalyst filtered off. The reactor and the filter were rinsed with methanol. The resulting solution was first concentrated at normal pressure and then at reduced pressure to give crude 1- ethylpiperidin-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, 1.5 V) and concentrated to about 600 ml under reduced pressure. The solution was directly used for the chlorination step. 10 L glass reactor was charged with toluene (800 ml, 1 V) and thionyl chloride (1'473 g, 12.5 mol, 2.0 eq.) and the mixture heated to 60°C. Subsequently, a solution of 1- ethylpiperidin-4-ol (2) (800 g, 6.2 mol, 1.0 eq.) and toluene (400 ml, 0.5 V) was dosed over at least 1 h at 60-75°C. The reaction was strongly exothermic and went along with vigorous gassing (SOz, HCl). After the addition, the reaction mixture was stirred at reflux (73°C) for at least 1h. Then,the reaction mixture was cooled to 20-25°C and quenched at < 30°C on water (4'000 ml, 5 V). The quench was strongly exothermic and went along with gassing (SO.). The pH of the quench mixture was set to = 11.0 with 30%-w / w NaOH aq. (4'600 g), keeping the temperature at < 30°C. The aqueous layer was separated, and the organic layer washed with water (800 ml, 1 V). The organic layer was distilled under reduced pressure (100 to 20 mbar) at 60 to 90°C over a 30 cm Vigreux column to yield 4-chloro-1-etylpiperidine (3) (655 g, 71.6%) as a colourless liquid. Final Product: 4-Chloro-1-ethylpiperidine (3) Yield: 72% HPLC purity: 99.5% Reaction scheme 1 — step (c), (d) and (e) WO 2025 / 036914 PCT / EP2024 / 072842 - 12 - NH oO ONa 2 Cl MgCl yer | 9 S O=S=0 (c) = (d) - (e) = N N re oe ns (3) (4) (5) (6) Magnesium (10.07 g, 415 mmol, 1.02 eq.) was charged to THF (300 ml, 5 V) heated to 40°C and activated by addition of 1,2-dibromoethane (1.75 ml, 20 mmol, 0.05 eq.). The mixture was heated to 60°C and4-chloro-1-ethylpiperidine (3) (60 g, 406 mmol, 1.00 eq.) diluted with THF (60 ml, 1 V) was added over at least 1h. After complete addition the mixture was stirred for at least 3 h at reflux (GC 4-chloro-1-ethylpiperidine (3) <3%-a / a). Two side products are generated during the Grignard formation: the elimination product (A) (2.5%-a / a) and Wurtz coupling product (B) (2.0%-a / a)). They were both detected by LCMS. N @ LC C (A) (B) The mixture was cooled to 0°C and sulphur dioxide (13%-w / w in THF, 210 g, 427 mmol, 1.05 eq.) was added under maintenance of the reaction temperature between O- 10°C. After complete addition the mixture was stirred for at least 20 min at 0°C. Afterwards, the reaction mixture was added under adiabatic conditions to a precooled (0-10°C) solution of trisodium citrate dihydrate (155 g, 528 mmol, 1.30 eq.) in water (360 ml, 6 V). The resulting biphasic mixture (IT = 14-22°C) was warmed to r.t. and the phases were separated. The organic phase was discarded. WO2025 / 036914 PCT / EP2024 / 072842 - 13 - HOSA (50.6 g, 447 mmol, 1.10 eq.) was added in 10 portions to the aqueous solution, containing 1-ethylpiperidine-4-sulfinic acid (5), keeping the temperature between 20- 25°C. After complete addition, the mixture was stirred for at least 20 min at 20°C. Then sodium sulphite (10.3 g, 81 mmol, 0.20 eq.) was added and the mixture was stirred for at least 20 min at 20°C. The pH of the mixture was adjusted to pH = 8.90-9.10 by addition of ammonia (25%-w / w in water, typically 67 ml, 813 mmol, 2.00 eq.) over at least 1h at 20-25°C. Thereby, product precipitation occurred in general at pH = 8.2- 8.5. The suspension was aged for at least 1 h at 20°C before the precipitate was filtered and washed with water (60 ml, 1 V). The solid was dried in the vacuum cabinet at 50°C to give 1-ethyl-4-piperidinesulfonamide (6) (56,5 g, 72%) as a white solid. Final Product: 1-ethylpiperidine-4-sulfonamide (6) Yield: 72% HPLC purity: 98.3 w / w%1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) was prepared according to the reaction sequence illustrated in Reaction Scheme 2. 0 + 0 —__» Cl CD ac —_—+ (8) (9) + OCD) — ooo" aso ce NO, (10) (11a) (11b) (12) Scheme 2. Synthesis of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) Reaction scheme 2 - step (a) O 0 + ———» Cl CD ae (8) (9) WO 2025 / 036914 PCT / EP2024 / 072842 -14- DCM (385 L) and AICI, (99.86 Kg) were charged at 25 to 30°C under a nitrogen atmosphere into a reactor clean and dry glass-lined reactor. The reaction mixture was cooled to -10°C. 3-chloropropanoyl chloride (90.99 Kg) was added slowly at -10 to -5°C under a nitrogen atmosphere. The reaction mixture was maintained for 30 minutes at 10°C under a nitrogen atmosphere. 2,3-dihydro-1H-indene (8) (77.00 Kg was then added slowly to the reaction mixture at -10 to -5°C under nitrogen atmosphere. The reaction mixture was maintained for 2 hours at 10 to 15°C. After completion of thereaction, the reaction mixture was added slowly to a 6 N hydrochloric acid solution (prepared from water (308 L) and conc. hydrochloric acid (308 L)) at 0 to 10°C. DCM (231 L) was added and the reaction mixture temperature was raised to 30 to 35°C. The reaction mixture was stirred at 30 to 35°C for 30 minutes and allowed to settle at 30 to 35°C for 30 minutes. The layers were separated and the organic layer (OL-1) was kept aside. DCM (231 L) was charged to the aqueous layer at 25 to 30°C. The reaction mixture was stirred at 25 to 30°C for 30 minutes and allowed to settle at 25 to 30°C for 30 minutes. The layers were separated (aqueous layer (AL-1) and organic layer (OL-2)) and AL-1 was kept aside. OL-1 and OL-2 were combined at 25 to 30°C. Demineralised water (385 L) was added to the combined organic layers. The reaction mixture was stirred at 25 to 30°C for 30 minutes and allowed to settle at 25 to 30°C for 30 minutes. The layers were separated (aqueous layer (AL-2) and organic layer(OL-3)) and AL-2 was kept aside. 10 % Saturated sodium bicarbonate solution (prepared from demineralised water (385 L) and sodium bicarbonate (38.5 Kg)) was charged to OL-3 at 25 to 30°C. The reaction mixture was stirred at 25 to 30°C for 30 minutes and allowed to settle at 25 to 30°C for 30 minutes. The layers were separated (aqueous layer (AL-3) and organic layer (OL-4)) and AL-3 was kept aside. OL-4 was dried over anhydrous Na.SO, (38.5 Kg) and the anhydrous Na.SO, was washed with DCM (150 L) at 25 to 30°C. The solvent was distilled under vacuum at below 35 to 40°C until 5 % remained. n-hexane (308 L) was charged to the reaction mixture at 35 to 40°C and the solvent was distilled completely at 35 to 40°C until no condensate drops were formed. N-hexane WO 2025 / 036914 PCT / EP2024 / 072842 - 15 - (150 L) was charged to the reaction mixture at 35 to 40°C and the reaction mixture was cooled to 5 to 10°C and maintained at 5 to 10°C for 30 minutes. The solid product was filtered, washed withcooled hexane (77 L), and dried in a hot air oven at 40 to 45°C for 6 hours to afford the product. Final Product: 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (9) Output: 120.5 Kg Yield: 88.6 % HPLC purity: 99.3 % Moisture content: 0.09 % 1H NMR: (500 MHz, CDCl3): 6 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) Reaction scheme 2 — step (b) and step (c) ° fe) o = NO» fo) -~CD—| GSD}—acD- GSD + NO, (9) (10) (11a) (11b) Sulfuric acid (300.0 L) was charged at 25 to 30°C into a 2.0 KL clean and dry glass- lined reactor. 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (9) (60.0 Kg) was charged lot wise at 25 to 30°C and the reaction mixture was maintained for 30 minutes at 25 to 30°C. The reaction mixture was slowly heated to 65 to 70°C and maintained at 65 to 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 %). Then the reaction mixture was cooled to 0 to5°C. A nitration mixture” was added slowly at 0 to 5°C and the reaction mixture was maintained at 0 to 5°C for 1 hour. The reaction mixture was maintained at 0 to 5°C. Demineralised water (900.0 L) was charged at 25 to 30°C into a 2.0 KL clean and dry glass-lined reactor. The water was cooled to 0 to 5°C. The reaction mixture was added slowly added to the reactor at 0 to 5°C. Toluene (480.0 L) was added and the WO 2025 / 036914 PCT / EP2024 / 072842 - 16 - temperature was raised to 30 to 35°C. The reaction mixture was maintained at 30 to 35°C for 30 minutes and allowed to settle at 30 to 35°C for 30 minutes. The reaction mixture was filtered through a Celite® bed (prepared with Celite® (6.0 Kg) and toluene (30.0 L)). The Celite® bed was washed with toluene (60.0 L). The solid was filtered and sucked dry for 30 min. The reaction mixture was charged to a 2.0 KL clean and dry glass-lined reactor. The reaction mixture was allowed to settle at 30 to 35°C for 30 minutes. The layers were separated(aqueous layer (AL-1) and organic layer (OL-1)) and OL-1 was kept aside. Toluene (60.0 L) was charged to AL-1. The reaction mixture was stirred at 35 to 40°C for 30 minutes and allowed to settle at 35 to 40°C for 30 minutes. The layers were separated (aqueous layer (AL-2) and organic layer (OL-2)) and OL-2 was kept aside. OL-1 and OL-2 were combined to form OL-3. A5 % saturated sodium bicarbonate solution (prepared from demineralised water (300.0 L) and sodium bicarbonate (15.0 Kg)) was slowly charged to OL-3 at 30 to 35°C. The reaction mixture was stirred at 35 to 40°C for 30 minutes and allowed to settle at 35 to 40°C for 30 minutes. The reaction mixture was filtered through a Celite® bed (prepared with Celite® (6.0 Kg) and demineralised water (60.0 L)). The Celite® bed was washed with toluene (60.0 L). The reaction mixture was charged to a 3.0 KL clean and dry glass-lined reactor. The reaction mixture was allowed to settle at 30 to 35°C for 30 minutes. The layers were separated(aqueous layer (AL-3) and organic layer (OL-4)) and OL-4 was kept aside. Toluene (60.0 L) was charged to AL-3. The layers were separated (aqueous layer (AL-4) and organic layer (OL-5)) and OL-5 was kept aside. OL-4 and OL-5 were combined to form OL-6. Brine solution (prepared from demineralised water (300.0 L) and sodium chloride (12.0 Kg) at 25 to 30°C. The reaction mixture was stirred at 30 to 35°C for 30 minutes and allowed to settle at 30 to 35°C for 30 minutes. The layers were separated (aqueous layer (AL-5) and organic layer (OL-7)) and OL-7 was kept aside. OL-7 was dried over anhydrous Na.SO, (9.0 Kg) and the anhydrous Na.SO, was washed with toluene (30.0 L) at 25 to 30°C. The solvent was distilled under vacuum at below 40 to 45°C until 5 % remained. Methanol (60.0 L) was charged to the reaction mixture at 40 to 45°C and down to 60 L of reaction mass. WO 2025 / 036914 PCT / EP2024 / 072842 - 17 - Methanol (120.0 L) was charged to the reaction mixture at 40 to 45°C and the reactionmixture was cooled to 5 to 10°C and maintained at 5 to 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 to 45°C for 6 hours to afford the product. *1: To prepare the nitration mixture, sulfuric acid (27.0 L) was charged at 25 to 30°C into a 160 L clean and dry glass-lined reactor. The reaction mixture was cooled to 0 to 5°C. Nitric acid (27.0 L) at 0 to 5°C was added slowly and the reaction mixture was maintained for 30 minutes at 0 to 5°C to afford the nitration mixture. Final Product: 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 Output (11a+11b): 38.87 Kg Combined Yield (11a+11b): 62.24 % Weight ratio (11a:11b): 9:1 HPLC purity: 95.9% Moisture content: 0.19% 1H NMR: (500 MHz, CDCl,):57.44(S, 1H), 2.21(m, 2H), 2.78 (t, 2H), 3.02 (m, 4H), 3.13 (t, 2H) Reaction scheme 2 — step (d) + SOO OCD —-OCD NO, (11a) (11b) (12) A mixture of8-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) (9:1 ratio; 27.0 Kg) at 25 to 30°C was charged into a 600 L clean and dry pressure reactor. Methanol (270 L) was charged at 25 to 30°C. Methane sulfonic acid (14.3 Kg) was slowly charged at 25 to 30°C and the reaction mixture was maintained for 30 minutes. 15 % Pd(OH): slurry (60 % wet)? was added. WO 2025 / 036914 PCT / EP2024 / 072842 -18 - The reaction mixture was degassed under vacuum and filled with an argon atmosphere (0.5 Kg) three times. The reaction mixture was degassed under vacuum and filled with a hydrogen atmosphere (0.5 Kg) three times. Then the reaction mixture was stirred under hydrogen pressure (100 Psi) at room temperature for 32 hours. After completion of the reaction, the reaction mixture was cooled to 25 to 30°C. The reaction mixture was degassed under vacuum and filled with nitrogen atmosphere (0.5 Kg) three times. The reaction mixture was filtered through acandy filter to remove Pd(OH)s, followed by a micro filter and the bed was washed with methanol (54 L). 95 % of the solvent was distilled off under vacuum at below 45 to 50°C. Demineralised water (135 L) was charged into the reaction mixture at 25 to 30°C and maintained for 30 minutes. The reaction mixture was cooled to 5-10°C. The pH was adjusted to about 9-10 with 2 N aqueous NaOH solution (prepared from NaOH (6.48 Kg) and demineralised water (81 L)) and the reaction mixture was stirred for 30 minutes. Then toluene (135 L) was charged to the reaction mixture and the reaction mixture was stirred for 30 minutes. The reaction mixture was stirred for a further 30 minutes, whilst bringing the temperature up to 25 to 30°C. The reaction mixture was allowed to settle for 30 minutes, whilst the temperature was maintained at 25 to 30°C. The reaction mixture was filtered through a Celite® bed (prepared with Celite® (5.4 Kg) and toluene (13.5 L). The Celite® bed was washed with toluene (54 L).The layers were separated (aqueous layer (AL-1) and organic layer (OL-1)) and OL-1 was kept aside. Toluene (54 L) was added to AL-1 at 25 to 30°C. The reaction mixture was stirred at 25 to 30°C for 30 minutes and allowed to settle at 25 to 30°C for 30 minutes. The layers were separated (aqueous layer (AL-2) and organic layer (OL-2)) and AL-2 was kept aside. Toluene (54 L) was added to AL-1 at 25 to 30°C. A brine solution (prepared with demineralised water (435 L) and sodium chloride (54 Kg)) was charged to the combined organic layers (OL-1 and OL-2) at 25 to 30°C. The reaction mixture was stirred at 25 to 30°C for 30 minutes and allowed to settle at 25 to 30°C for 30 minutes. The layers were separated (aqueous layer (AL-3) and organic layer (OL-3)) and AL-3 was kept aside. Charcoal (1.3 Kg) was added to OL-3 and the temperature was raised to WO 2025 / 036914 PCT / EP2024 / 072842 -19 - 35-40°C and maintained at 35 to 40°C for 30 minutes. The reaction mixture was filtered through a Celite®bed (prepared with Celite® (5.4 Kg) and toluene (54 L)) at 35 to 40°C. The Celite® bed was washed with toluene (54 L). The organic layer was dried over anhydrous Na.SO, (43.5 Kg). The Na2SO, was washed with toluene (27 L). The solvent was distilled under vacuum at below 35 to 40°C until 5 % remained. Methanol (40.5 L) was charged to the reaction mixture at 35 to 40°C and distilled until 5 % remained. Methanol (97.2 L) and water (10.8 L) were charged to the reaction mixture at 35 to 40°C. The reaction mixture was heated to 50 to 55°C, stirred for 1 hour at 50 to 55°C, slowly cooled to 0 to 5°C and maintained at 0 to 5°C for 30 minutes. The solid product was filtered and washed with cold methanol (43.5 L), and dried ina hot air oven at 40 to 45°C for 6 hours to afford the product. *2: To prepare the 15 % Pd(OH)>» slurry, 20 % Pd(OH)z on carbon (60 % wet; 4.05 Kg) was added to methanol (27 L). Final product: 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) Output: 11.3 Kg Yield: 41.85 % HPLCpurity: 98.1 % Moisture content: 0.10 1H NMR: (400 MHz, DMSO-d): 6 6.38 (S, 1H), 4.45 (S, 2H), 2.75 (t, 4H), 2.58 (t, 4H), 1.98 (t, 4H). Purification (A) of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) 1,2,3,5,6,7-Hexahydro-s-indacen-4-amine (12) (54.5 Kg) was charged at 25 to 30°C into a 250 Lclean and dry reactor. Toluene (27.2 L) was charged at 25 to 30°C and the reaction mixture was stirred at 25 to 30°C for 30 minutes. Methanol (163 L) was charged to the reaction mixture at 25 to 30°C. The reaction mixture was stirred at 25 to 30°C for 30 minutes, cooled to -5 to o°C, and stirred at -5 to o°C for 30 minutes. The solid product was filtered, washed with cold methanol (54.5 L), and dried at 40 to 45°C for 6 hours. Final Product: 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) WO 2025 / 036914 PCT / EP2024 / 072842 -20 - Output: 40.5 Kg Yield: 74.31 % HPLC purity: 99.5 % Moisture content: 0.3 % 1H NMR: (400 MHz, DMSO-d): 6 6.33 (s, 1H), 4.53 (Ss, 2H), 2.72 (t, 4H), 2.57 (t, 4H), 1.98 (t, 4H).1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoy])piperidine-4- sulfonamide (potassium salt) (1) NH2 ca cco—| ato (12) (13) 09 9 sel —_> S.y AY wer H H 0, 9 ()) or SNH NN (6) Reaction scheme 3. Synthesis of (1) 1,2,3,5,6,7-hexahydro-s-indacen-4-amine-isocyanate (13) preparation in a batch mode: 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) (1.00 g, 1.00 equiv) was dissolved in toluene (9.60 g) in a 50 mL reactor at 10 — 20 °C. N,N-diisopropylethylamine (2.25 g, 3.00 equiv) was added followed by the 20wt% phosgene solution (4.28 g, 1.50 equiv) over 3 minutes and the formed suspension was further stirred for 30 minutes at 10 — 20 °C. The reaction mixture was washed with saturated NaHCO, solution (5.0 mL) and water (5.0 mL). The layers were separated to give 1,2,3,5,6,7-hexahydro-s-indacen-4-amine- isocyanate in toluene (OL-1, ca. 20 mL, contains 1,2,3,5,6,7-hexahydro-s-indacen-4- amine (12) (5.77 mmol). The obtained solution OL-1 is used in the next step (Coupling ofindacenamine-isocyanate (12) with 1-ethyl-4-piperidinesulfonamide (7)) to yield (44) in ca. 80% overall yield. WO 2025 / 036914 PCT / EP2024 / 072842 -21- 1,2,3,5,6,7-hexahydro-s-indacen-4-amine-isocyanate (13) preparation in a flow mode: Feed solutions preparation: Feed solution A: 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (42) (43.31 g) was dissolved in toluene (206.69 g) to give a 0.90 M solution. Feed solution B: Potassium carbonate (103.5 g) was dissolved in water (950 g) to give a 0.75 M solution. Feed A (0.70 mL / min, 1.10 equiv), 20 % w / w phosgene solution toluene (0.45 mL / min, 1.50 equiv) and Feed B solution (2.35 mL / min, 3.10 equiv) was dosed simultaneously at O to 10 °C (Internal temperature) in a reactor 1 (ca. 25 mL). Residence time in reactor 1 is 5 — 10 minutes. The biphasic solution from reactor 1 is continuously pumped out and layers are separated continuously to give organic layer (OL-1) with 1,2,3,5,6,7- hexahydro-s-indacen-4-amine isocyanate (13) and aqueous layer (AL-1)that is directed to the waste. Organic layer OL-1 is collected over 81 minutes at steady state to afford ca. 90 mL of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) (51 mmol). The obtained solution OL-1 is used in the next step. Coupling of indacenamine-isocyanate (12) with 1-ethyl-4- piperidinesulfonamide (7): 1-ethyl-4-piperidinesulfonamide (7) (8.88 g, 46 mmol, 1.0 equiv) was charged to a vessel. Tetrahydrofuran (62.52 g) was charged to the vessel and the mixture was adjusted to 20 to 25°C. The mixture was stirred for at least 20 minutes at 20 to 25°C until clumps disappeared and homogenous suspension was formed. Potassium tert-butoxide (1.05 M, 43.98 mL, 46 mmol) was charged to the vessel over 90 to 120 minutes, maintaining the temperature at 20 to 25°C and the mixture stirred for 2 to 4 hours at 20 to 25°C to give a thick, white suspension. The organic layer OL-1 containing 1,2,3,5,6,7-hexahydro-s-indacen-4-amine -isocyanate (13) (51 mmol of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine(42) , ca. 90 mL) prepared in a batch or a flow mode was added to the formed white suspension in toluene over 2 hours by keeping 20 — 25 °C. The reaction mixture quickly became a well stirrable suspension and at the end of addition a slightly turbid brown solution. The reaction mixture was stirred further 1 — 2 h at 20 to 25°C. The water content was analysed by KF and conversion of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine confirmed by LC / MS or HPLC WO 2025 / 036914 PCT / EP2024 / 072842 -909- analysis (typically > 95%). Optionally a clear filtration via Celite layer (G3 filter) is performed. Water (4.44 g, 0.5 V) was added to the reaction mixture at 25 to 40 °C dropwise over 2 hours. Solids started to crystallize at about 0.5 — 1 wt% water content. At the end of dosing a suspension was formed. The reaction mixture was cooled to 0 to 5 °C CIT) over 1h and stirred further for 16 h at 0 to 5 °C. Solids were filtered through a G3 filter and washed with toluene / THF (1 / 1 by volume, 44.4 mL)mixture. The solid was dried at up to 50°C, 10 — 20 mbar under a flow of nitrogen over 12 h. The dried weight of the crude solid was measured, identified and analysed using 'H NMR spectroscopy and HPLC. Final Product: 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)- carbamoy]l)piperidine-4-sulfonamide (potassium salt) (4) Output: ca. 16.0 g Yield: ca. 80 % NMR purity: >97% HPLC purity: >99% Recrystallization of 1-ethyl-N-((4,2,3,5,.6,7-hexahydro-s-indacen-4-yl)- carbamoy])piperidine-4-sulfonamide (potassium salt) (1) Crude 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4- sulfonamide (potassium salt) (14) (45.00 g) was charged to a reaction vessel. Methanol (33.55 g) was charged to the vessel followed by acetonitrile (33.55 g) and the temperature was adjusted to 15 to 25°C as required with stirring for 10 to 20 minutes (until a homogeneous cloudy solution with no lumps of solid present was formed). The solution was filtered through a 1 um filter at 15 to 25°C.The filter was washed with methanol / acetonitrile mixture (7.59 g) at 15 to 25°C and further acetonitrile (64.0 g) was added followed by seed crystals (0.138 g) of (14) in acetonitrile (ca. 1g). Suspension was formed. The solution was concentrated to ca. 122 mL at 25 to 35°C. Acetonitrile (54.32 g) was charged to the mixture and the solution was concentrated to ca. 122 L at 25 to 35°C. Acetonitrile (52.53 g) was charged to the mixture and the mixture was concentrated to ca. 122 mL at < 35°C. The mixture was analysed for residual methanol content. Pass criterion < 0.3% w / w methanol. Acetonitrile (53.45 g) was charged to the vessel and the WO 2025 / 036914 PCT / EP2024 / 072842 - 23 - temperature was adjusted to 15 to 25°C. The slurry was aged for at least 1 hour (target 1 to 2 hours) at 15 to 25°C and then filtered over 20 um cloth at 15 to 25°C. The filter cake was twice washed with acetonitrile (43.39 g) at 15 to 25°C. The solid was dried at up to 50°C under a flow of nitrogen to yield13.75 g (92%) of the white solid. Final Product: 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)- carbamoy]l)piperidine-4-sulfonamide (potassium salt) (4) Output: 13.75 g Yield: 92 % HPLC purity: 99.7 % WO 2025 / 036914 PCT / EP2024 / 072842 - 24 - Claims 1. A process of preparing compound (6) or a salt thereof, comprising the step of: (a) a first ethylation reaction of (1) to yield (2), followed by (b) subsequently reacting (2) with thionyl chloride in toluene to form (3) OH OH Cl oes N N N " N L (1) (2) (3). followed by (c) reacting compound (3) to compound (4) via a Grignard formation, followed by (d) formation of the sulfonate compound (5) which is then (e) oxidized to yield compound (6) NH 16) ONa 2 Cl MgCl Ser | 9 § O=S=O (c) = (d) 7 (e) = N N 7 7 a t (3) (4) (5) (6) 2. The process of claim 1, wherein reaction step (a) involves dissolving compound (41) in a methanol and acetonitrile mixture and performing a hydrogenation in the presence of a Pd / C catalyst. 3. The process of claims 1or 2, wherein the hydrogenation in step (a) is conducted at 10-20 bar H2 at 80°C within 1 to 3 hours. 4. The process of claim 2 or 3, wherein the loading for reaction step (a) is 10%-wt Pd / C with catalyst loadings between 3.3%-wt catalyst to 10%-wt catalyst. WO 2025 / 036914 PCT / EP2024 / 072842 - 25 - 5. The process of any of claims 1 to 4, wherein for reaction step (b) compound (2) is in toluene is heated to 60°C and thionyl chloride reagent in toluene is dosed over at least 1 hour while maintaining internal temperature at 60-75°C. 6. The process of any of claims 1 to 5, wherein reaction step (c) typically involves adding compound (3) diluted in THF to Magnesium that is charged with THF, heated to 40°C and activated by addition of 1,2-dibromoethane. 7. The process of any of claims 1 to 6, wherein reaction step (d) involves reacting compound (4) with sulphur dioxide in a cooled mixture at 0°C. 8. The process of any of claims 1 to 8, wherein the subsequent work-up in reaction step (d)involves adding the reaction mixture to a precooled solution of trisodium citrate dehydrate in water and separating out the product compound (5) from the organic phase. 9. The process of any of claims 1 to 8, wherein reaction step (e) typically involves adding HOSA (hydroxylamine-O-sulfonic acid) to an aqueous solution of compound (5) at temperatures between 20 and 25°C. 10. The process of reacting compound (6) obtained by any of the process of claims 1 to 9, with compound (13) to yield compound of formula (I). NH2 wen COD CCD (12) (13) Q.9 0 vous H H NN 0.9 ()) ~_N 6) WO 2025 / 036914 PCT / EP2024 / 072842 -26- 11. A pharmaceutical composition comprising compound (1) or a salt thereof, as obtained from the process of claim 10, and a pharmaceutically acceptable excipient. 12. Acompound of formula (6) comprising a compound of formula (A) and / or (B) N eS iC ie (A) (B) INTERNATIONAL SEARCH REPORT ; International application No PCT / EP2024 / 072842 A. CLASSIFICATION OF SUBJECT MATTER INV.©C07D211 / 64 C07D211 / 72 C07D401 / 04 ADD. According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) cO7D Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) EPO-Internal, CHEM ABS Data C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* | Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. Xx WO 2022 / 268935 A2 (HOFFMANN LA ROCHE [CH]; 11,12 HOFFMANN LA ROCHE [US] ) 29 December 2022 (2022-12-29) A page 10, compound (47); 1-10 claims 16-30, 32 A ARTHUR P. PHILLIPS ET AL: "Synthetic 12 Hypotensive Agents. III. Some 4,4'-Bipiperidines", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 77, no. 23, 1December 1955 (1955-12-01), pages 6393-6395, XP055187758, ISSN: 0002-7863, DOI: 10.1021 / ja01628a109 figure 1 [| Further documents are listed in the continuation of Box C. See patent family annex. * Special categories of cited documents : . . . 7 — "T" later document published after the international filing date or priority wan a we . date and not in conflict with the application but cited to understand A" document defining the general state of the art which is not considered on ; Af ‘ to be of particular relevance the principle or theory underlying the invention "E" earlier application or patent but published on or after the international "X" document of particular relevance:; the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive ‘ document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other "Y" document of : . : : : : heaparticular relevance;; the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is "O" document referring to an oral disclosure, use, exhibition or other combined with one or more other such documents, such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 7 November 2024 14 / 11 / 2024 Name and mailing address of the ISA / Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL - 2280 HV Rijswijk Tel. (+31-70) 340-2040, . . . 2 Fax: (+31-70) 340-3016 Kleidernigg, Oliver Form PCT / ISA / 210 (second sheet) (April 2005) INTERNATIONAL SEARCH REPORT ; a International application No Information on patent family members cited in search report date member(sdate WO 2022268935 A2 29-12-2022 AR 126215 Al 27-09-2023 AU 2022300325 Al 02-11-2023 CA 3219597 Al 29-12-2022 CN 118019727 A 10-05-2024 EP 4359385 A2 01-05-2024 IL 308071 A 01-12-2023 JP 2024524215 A 05-07-2024 KR 20240024842 A 26-02-2024 TW 202317514 A 01-05-2023 US 2024150291 Al 09-05-2024 wo 2022268935 A2 29-12-2022 Form PCT / ISA / 210 (patent family annex) (April 2005) (19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480051425.7 (22) Application Date 2024.08.14 (30) Priority Data 23191567.9 2023.08.16 EP (85) PCT International Application Entering National Phase Date 2026.02.05 (86) Application Data of PCT International Application PCT / EP2024 / 072842 2024.08.14 (87) Publication data of PCT international application WO2025 / 036914 EN 2025.02.20 (71) Applicant Hofmeister Roche Ltd. Address Switzerland (72) Inventors E.J. Bergner J.E.F. Chinquarebrough D. Calderley (74) Patent Agency Beijing Zhongzi Law Firm 11247 Patent Attorney An Peidong Huang Gesheng (51) Int.Cl. C07D 211 / 64 (2006.01) C07D 211 / 72 (2006.01) C07D 401 / 04 (2006.01) (54) Invention title Preparation of 1-ethyl-N-((1 Preparation Method of 2,3,5,6,7-Hexahydro-S-dicyclopentadienzobenzo-4-yl)carbamoyl)piperidine-4-sulfonamide (57) Abstract This invention relates to a method for preparing compound (6). Compound (6) is used to form 1-ethyl-N-((1,2,3,5,6,7-hexahydro-S-dicyclopentadienzobenzo-4-yl)carbamoyl)piperidine-4-sulfonamide (compound (I)) or pharmaceutically acceptable thereof, which can be used as an NLRP3 inhibitor.Key precursors of acceptable salts. (I). Claims 2 pages Description 16 pages CN 121666381 A 2026.03.13 CN 1 21 66 63 81 A 1. A method for preparing compound (6) or a salt thereof, the method comprising the steps of: (a) firstly, ethylating (1) to obtain (2), then (b) subsequently reacting (2) with thionyl chloride in toluene to form (3); then (c) reacting compound (3) to compound (4) via Grignard formation, then (d) forming a sulfonate compound (5), and then (e) oxidizing said sulfonate compound to obtain compound (6). 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. The method according to claim 1 or 2, wherein the hydrogenation in step (a) is carried out at 80°C and 10 to 20 bar H2 for 1 to 3 hours. 4. The method according to claim 2 or 3, wherein the loading for reaction step (a) is 10%-wt Pd / C, and the catalyst loading is between 3.3%-wt catalyst and 10%-wt catalyst. 5. The method according to any one of claims 1 to 4, wherein for reaction step (b), compound (2) in toluene is heated to 60°C and subjected to incorporation of a thionyl chloride reagent in toluene for at least 1 hour, while maintaining the internal temperature at 60°C to 75°C. 6. The method according to any one of claims 1 to 5, wherein reaction step (c) generally comprises adding compound (3) diluted in THF to magnesium that has been charged together with THF, heated to 40°C, and 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 cooled mixture at 0°C. 8. The method according to any one of claims 1 to 8, wherein a subsequent treatment in reaction step (d) comprises 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. 9. The method according to any one of claims 1 to 8, wherein reaction step (e) generally comprises adding HOSA (hydroxylamine-O-sulfonic acid) to an aqueous solution of compound (5) at a temperature between 20°C and 25°C.10. A method for reacting compound (6) obtained by any one of claims 1 to 9 with compound (13) to obtain compound (I). 11. A pharmaceutical composition comprising: compound (I) obtained by the method according to claim 10 or a salt thereof; and a pharmaceutically acceptable excipient. 12. A compound of formula (6) comprising compounds of formula (A) and / or (B). Claims 2 / 2 Page 3 CN 121666381 A Method for preparing 1-ethyl-N-((1,2,3,5,6,7-hexahydro-S-dicyclopentadienylbenzo-4-yl)carbamoyl)piperidine-4-sulfonamide

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

[0002] .

[0003] Compound (6) is a key precursor for forming 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzo-4-yl)carbamoyl)piperidine-4-sulfonamide (compound (I)) or a pharmaceutically acceptable salt thereof, which can be used as an NLRP3 inhibitor.

[0004]

[0005] (I). Background Art

[0006] 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-s-dicyclopentadienylbenzo-4-yl)carbamoyl)piperidine-4-sulfonamide is disclosed as an NLRP3 inhibitor in WO 2019 / 008025 (see Example 6). However, there is a need for improved methods for the preparation of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzo-4-yl)carbamoyl)piperidine-4-sulfonamides and their salts. Specifically, there is a need for efficient methods suitable for large-scale synthesis that, for example, avoid multiple complex and partially low-yield chemical steps and overall atom-inefficient synthesis.

[0007] WO2022 / 268935 discloses a method for preparing 1-ethyl-N-((1,2,3,5,6,7-hexahydro-S-dicyclopentadienylbenzo-4-yl)carbamoyl)piperidine-4-sulfonamide, comprising 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-hexahydro-S-dicyclopentadienylbenzo-4-yl)carbamoyl)piperidine-4-sulfonamide or a salt thereof.

[0008]

[0009] Wherein X is a leaving group.

[0010] There is also a need to provide 1-ethyl-N-((1,2,3,5,6,7-hexahydro-S-dicyclopentadienylbenzo-4-yl)carbamoyl)piperidine-4-sulfonamide and its salts at higher yields compared to existing methods, especially on a large scale. Furthermore, the specification...Page 1 / 16 4 CN 121666381 A For large-scale industrialization, greener synthetic routes, reduced solvent waste and improved safety are also of concern. The present invention addresses the above problems by providing an improved route for forming compound (6).

[0011] Compared with the method disclosed in WO 2022 / 268935, the new method disclosed herein allows for fewer steps and increases the overall yield of compound (6) from 11% to 52%. Furthermore, the present invention can be carried out in batch or continuous methods and allows for the use of fewer reagents and solvents, thereby reducing waste. Summary of the Invention

[0012] The present invention provides a method for preparing compound (6) comprising scheme A as shown below.

[0013] Scheme A

[0014]

[0015] The term “pharmaceuticalally acceptable salt” refers to a conventional acid addition salt or base addition salt formed from a suitable non-toxic organic or inorganic acid or organic or inorganic base that retains the biological efficacy and properties of a compound of formula I. Acid addition salts include, for example, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, and nitric acid; and salts derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc. Base addition salts include those derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides such as tetramethylammonium hydroxide. The chemical modification of pharmaceutical compounds into salts to obtain improved physical and chemical stability, hygroscopicity, flowability, and solubility is a well-known technique among medicinal chemists. Examples are described in, for instance, Bastin RJ 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 5, 1456-1457.

[0016] Abbreviation Specification 2 / 16 Page 5 CN 121666381 A

[0017]

[0018] The present invention provides a method for preparing compound (6) as outlined in Scheme A and a subsequent preparation of compound (I) as outlined in Scheme B.

[0019] Scheme A

[0020]

[0021] Scheme B

[0022] Specification 3 / 16 Page 6 CN 121666381 A

[0023] The synthesis of compound (6) includes one or more of the following steps:

[0024] Steps (a) and (b): forming the compound via the following manner(3): First, (1) is ethylated to obtain (2), and then it is reacted with thionyl chloride in toluene to form (3)

[0025] ;

[0026] Steps (c), (d) and (e): Compound (3) is reacted to compound (4) via Grignard formation, followed by the formation of sulfonate compound (5), which is then oxidized to obtain compound (6)

[0027] .

[0028] Reaction step (a) generally involves dissolving compound (1) in a mixture of methanol and acetonitrile and hydrogenating it in the presence of a Pd / C catalyst.

[0029] Suitable conditions for hydrogenation in step (a) include 10 to 20 bar H2 at 80°C to achieve complete conversion within 1 to 3 h without any side reactions.

[0030] Suitable catalyst loading for reaction step (a) includes 10%-wt Pd / C, wherein the catalyst loading is between 3.3%-wt catalyst and 10%-wt catalyst.

[0031] In reaction step (b), the compound (2) in toluene is heated to 60°C and subjected to incorporation of a thionyl chloride reagent in toluene for at least 1 hour, while the internal temperature is maintained at 60°C to 75°C.

[0032] Alternatively, 48% HBr (aqueous solution) will produce a bromine intermediate instead of the chlorine intermediate, which also functions.

[0033] Other solvents as substitutes for toluene are ACN (acetonitrile), DCM (dichloromethane), and mixtures of toluene and TBAC (tetrabutylammonium chloride) (as additives).

[0034] Other alternative reagents include PBr3, SOBr2, Br2 / PPh3, CBr4 / PPh3 (forming a bromine intermediate), and thionyl chloride, CCl4 / PPh3, POCl3, PCl3 (forming a chlorine intermediate).

[0035] Reaction step (c) typically involves adding compound (3) diluted in THF to magnesium, which is charged together with THF, heated to 40°C and activated by the addition of 1,2-dibromoethane, and then heated to 60°C to carry out the reaction. Activation can also be performed with iodine in an ether solvent.

[0036] Reaction step (d) typically involves reacting compound (4) with sulfur dioxide in a cooled mixture at 0°C. Sulfur dioxide can be a gas or a solution in THF. Instructions 4 / 16, page 7, CN 121666381 A

[0037] The subsequent treatment of 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, dihydrogen phosphate, etc.Sodium, sodium bisulfate, disodium citrate, and alternative acids are acetic acid, citric acid, hydrochloric acid, and water.

[0038] Reaction step (e) typically involves adding HOSA (hydroxylamine-O-sulfonic acid) to an aqueous solution of compound (5) at a temperature between 20°C and 25°C.

[0039] Unless otherwise stated, any reference to an element is considered to be a reference to all isotopes of that element. Thus, for example, unless otherwise stated, any reference to hydrogen is considered to cover all isotopes of hydrogen, including deuterium and tritium.

[0040] Unless otherwise stated, any reference to a compound or group is considered to be a reference to all tautomers of that compound or group.

[0041] Another embodiment of the invention involves reacting compound (6) obtained by the above method with compound (13) to obtain compound (I).

[0042] .

[0043] Another embodiment of the invention relates to compound (I) obtained using compound (6) produced by the above method.

[0044] The compounds used and provided in this invention can be used both as free bases and as acid addition salts. For the purposes of this invention, the term "salt" in the compounds of this invention includes acid addition salts. Acid addition salts are preferably pharmaceutically acceptable and non-toxic addition salts of suitable acids, including but not limited to: inorganic acids such as hydrohalic acids (e.g., hydrofluoric acid, hydrochloric acid, hydrobromic acid, or hydroiodic acid) or other inorganic acids (e.g., nitric acid, perchloric acid, sulfuric acid, or phosphoric acid); or organic acids such as organic carboxylic acids (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, viscous acid or galactopyric acid, gluconic acid, pantothenic acid, or dihydroxynaphthyl acid), organic sulfonic acids (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 2-naphthalenesulfonic acid, or camphorsulfonic acid) or amino acids (e.g., ornithine, glutamic acid, or aspartic acid). Acid addition salts can be monoacid addition salts, diacid addition salts, triacid addition salts, or polyacid addition salts. Preferred salts are hydrochloric acid addition salts, sulfuric acid addition salts, phosphoric acid addition salts, or organic acid addition salts. Preferred salts are hydrochloric acid addition salts.

[0045] When the compounds of the present invention contain a quaternary ammonium group, the compound is typically used in its salt form. The counterion of the quaternary ammonium group can be any pharmaceutically acceptable, non-toxic counterion. Examples of suitable counterions include the conjugate base of the protonic acid discussed above with respect to acid addition salts. Specification 5 / 16 pages 8 CN 121666381 A

[0046] The compounds used and provided in the present invention can also be used in their free acid form and salt form. For the purposes of the present invention, the term "salt" of the compounds of the present invention includes the protonic acid functional group (such as a formic acid group orA salt formed between a urea group and a suitable cation. Suitable cations include, but are not limited to, lithium, sodium, potassium, magnesium, calcium, and ammonium. The salt can be a monosalt, disalt, trisalt, or multisalt. Preferably, the salt is a monolithium or dilithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, or ammonium salt. More preferably, the salt is a monosodium or disodium salt, or a monopotassium or dipotassium salt.

[0047] Preferably, any salt is a pharmaceutically acceptable, non-toxic salt. However, other salts besides pharmaceutically acceptable salts are also included in this invention because they have the potential to serve as intermediates for purifying or preparing other, such as pharmaceutically acceptable salts, or for identifying, characterizing, or purifying free acids or bases.

[0048] The compounds and / or salts used and provided in this invention can be in the form of anhydrous or hydrated (e.g., hemihydrate, monohydrate, dihydrate, or trihydrate) or other solvates. Such other solvates can be formed using common organic solvents, including but not limited to alcohol solvents such as methanol, ethanol, or isopropanol.

[0049] The compounds, salts, and solvates used and provided in this invention may contain any stable isotopes, including but not limited to 12C, 13C, 1H, 2H (D), 14N, 15N, 16O, 17O, 18O, 19F, and 127I; and any radioactive isotopes, including but not limited to 11C, 14C, 3H (T), 13N, 15O, 18F, 123I, 124I, 125I, and 131I.

[0050] Unless otherwise stated, the compounds, salts, and solvates used and provided in this invention may be in any polymorphic or amorphous form.

[0051] Conventional procedures for selecting and preparing suitable pharmaceutical formulations are described, for example, in “Aulton's Pharmaceutics – The Design and Manufacture of Medicines”, ME Aulton and KMG Taylor, Churchill Livingstone Elsevier, 4th edition, 2013. Pharmaceutical excipients that can be used in the pharmaceutical compositions of the present invention include adjuvants, diluents, or carriers, those conventionally used in the field of pharmaceutical formulations.

[0052] Another aspect of the present invention provides a compound (I) or a salt thereof obtained using the compound (6) produced by the above-described method, for medical and / or treatment or prevention of diseases, symptoms, or conditions.

[0053] Another aspect of the present invention provides a pharmaceutical composition comprising a compound (I) or a salt thereof obtained using the compound (6) produced by the above-described method, for medical and / or treatment or prevention of diseases, symptoms, or conditions.

[0054] Generally, treatment or prevention of diseases, symptoms, or conditions includes administration of the compound (6) produced by the above-described method.The obtained compound (I) or its salt.

[0055] Examples

[0056] Unless otherwise stated, all solvents, reagents and compounds were purchased and used without further purification.

[0057] Experimental Methods

[0058] NMR Method:

[0059] NMR spectra were obtained on a Bruker AV 400MHz spectrometer (model: Advance IIID) operating at room temperature (25°C).

[0060] GC Method:

[0061] GC analysis was performed on one of the following machines: an Agilent 7890, 6890 or Agilent 6890N equipped with an ALS injector.

[0062] HPLC Methods:

[0063] In reaction scheme 2, the HPLC in steps (a) to (d) was run on a Waters Alliance e2695 HPLC with a PDA detector, using a solution of 10 mM ammonium bicarbonate in water as mobile phase A and acetonitrile as mobile phase B.

[0064] In reaction scheme 3, the HPLC was run on an Agilent 1290 HPLC (column: Waters CORTECS UPLC T3) with a DAD detector, using a solution of 5 mM K2HPO4 in water (pH 6.2) as mobile phase A and acetonitrile as mobile phase B.

[0065] As used herein, unless otherwise stated, all references to HPLC purity are measured as % a / a.

[0066] KF Method:

[0067] Coulometric KF titration was performed using AKX reagent on a Mitsubishi CA-20 or Predicta OM1000.

[0068] Synthetic Examples

[0069] 1-Ethylpiperidine-4-sulfonamide (6)

[0070] 1-Ethyl-4-piperidinesulfonamide (6) was prepared according to the reaction sequence shown in reaction scheme 1.

[0071]

[0072] Scheme 1. Synthesis of 1-ethyl-4-piperidinesulfonamide (6)

[0073] Reaction Scheme 1 – Steps (a) and (b)

[0074]

[0075] Piperidine-4-ol (1) (340.0 g, 3.36 mol, 1.0 eq.) was dissolved in a mixture of acetonitrile (207.0 g, 5.04 mol, 1.5 eq.) and methanol (1.020 ml, 3.0 V). The dissolution was endothermic. The resulting solution was transferred to 2.0 LIn an 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 to 15 bar. Hydrogenation was then carried out at 75°C to 85°C and 10 to 15 bar of hydrogen until hydrogen absorption ceased. After complete conversion (GC), the reaction mixture was cooled to 20°C to 30°C and the pressure was carefully released. The reaction mixture was drained and the catalyst was filtered off. The reactor and filter were rinsed with methanol. The resulting solution was first concentrated at atmospheric pressure and then concentrated under reduced pressure to give 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, 1.5 V) and concentrated under reduced pressure to about 600 ml. This solution was used directly in the chlorination step.

[0076] A 10 L glass reactor was loaded with toluene (800 ml, 1 V) and thionyl chloride (1,473 g, 12.5 mol, 2.0 eq.), and the mixture was heated to 60 °C. Subsequently, a solution of 1-ethylpiperidin-4-ol (2) (800 g, 6.2 mol, 1.0 eq.) and toluene (400 ml, 0.5 V) was incorporated at 60 °C to 75 °C for at least 1 h. The reaction was strongly exothermic and accompanied by vigorous outgassing (SO2, HCl). After the addition, the reaction mixture was stirred under reflux (73 °C) for at least 1 h. The reaction mixture was then cooled to 20 °C to 25 °C and quenched at <30 °C in water (4,000 ml, 5 V). Quenching is strongly exothermic and accompanied by exhalation (SO2). The pH of the quenching mixture was set to ≥ 11.0 with 30% w / w NaOH aqueous solution (4,600 g) while maintaining the temperature <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 °C to 90 °C via a 30 cm Vigreux column to give 4-chloro-1-ethylpiperidine (3) (655 g, 71.6%) as a colorless liquid.

[0077] Final product: 4-chloro-1-ethylpiperidine (3)

[0078] Yield: 72%

[0079] HPLC purity: 99.5%

[0080] Reaction scheme 1 – Steps (c), (d) and (e)

[0081]

[0082] Magnesium (10.07 g, 415 mmol, 1.02 eq.) was loaded into THFThe mixture was heated to 40°C in 300 ml, 5 V and activated by the addition of 1,2-dibromoethane (1.75 ml, 20 mmol, 0.05 eq.). The mixture was heated to 60°C and 4-chloro-1-ethylpiperidine (3) diluted with THF (60 ml, 1 V) (60 g, 406 mmol, 1.00 eq.) was added over at least 1 hour. After complete addition, the mixture was stirred under reflux for at least 3 hours (GC 4-chloro-1-ethylpiperidine (3) <3%-a / a).

[0083] Two byproducts were generated during Grignard formation: elimination product (A) (2.5%-a / a) and Wurtz coupling product (B) (2.0%-a / a). Both were detected by LCMS.

[0084]

[0085] The mixture was cooled to 0°C, and sulfur dioxide (13% w / w, in THF, 210 g, 427 mmol, 1.05 eq.) was added while maintaining the reaction temperature between 0 and 10°C. After complete addition, the mixture was stirred at 0°C for at least 20 min. Subsequently, the reaction mixture was added adiabatic to a pre-cooled (0°C–10°C) solution of trisodium citrate dihydrate (155 g, 528 mmol, 1.30 eq.) in water (360 ml, 6°C). The resulting biphase mixture (IT = 14°C–22°C) was warmed to room temperature and the phases were separated. The organic phase was discarded.

[0086] HOSA (50.6 g, 447 mmol, 1.10 eq.) was added in 10 parts to an aqueous solution containing 1-ethylpiperidine-4-sulfinic acid (5), and the temperature was maintained between 20°C and 25°C. After complete addition, the mixture was stirred at 20°C for at least 20 min. Sodium sulfite (10.3 g, 81 mmol, 0.20 eq.) was then added and the mixture was stirred at 20°C for at least 20 min. The pH of the mixture was adjusted to pH = 8.90–9.10 by adding ammonia (25% w / w, typically 67 ml, 813 mmol, 2.00 eq. in water) at 20°C to 25°C for at least 1 h. Therefore, product precipitation usually occurs at pH = 8.2–8.5. The suspension was aged at 20°C for at least 1 h, then the precipitate was filtered and washed with water (60 ml, 1 V). The solid was dried in a vacuum chamber at 50°C to give 1-ethyl-4-piperidinesulfonamide (6) as a white solid.(56.5 g, 72%).

[0087] Final product: 1-ethylpiperidine-4-sulfonamide (6)

[0088] Yield: 72%

[0089] HPLC purity: 98.3 w / w%

[0090] 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-amine (12)

[0091] 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-amine (12) was prepared according to the reaction sequence shown in reaction scheme 2.

[0092]

[0093] Scheme 2. Synthesis of 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzene-4-amine (12)

[0094] Reaction Scheme 2 - Step (a)

[0095]

[0096] DCM (385 L) and AlCl3 (99.86 Kg) were charged into a reactor, i.e., a clean and dry glass-lined reactor, at 25 to 30 °C under a nitrogen atmosphere. The reaction mixture was cooled to -10 °C.

[0097] 3-chloropropionyl chloride (90.99 Kg) was slowly added at -10 to -5 °C under a nitrogen atmosphere. The reaction mixture was maintained at 10 °C under a nitrogen atmosphere 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.

[0098] The reaction mixture was maintained at 10 to 15 °C for 2 hours.

[0099] After the reaction was complete, the reaction mixture was slowly added to a 6 N hydrochloric acid solution (prepared from water (308 L) and concentrated hydrochloric acid (308 L)) at 0 to 10 °C. DCM (231 L) was added and the temperature of the reaction mixture was raised to 30 to 35 °C. The reaction mixture was stirred at 30 to 35 °C for 30 minutes and allowed to stand at 30 to 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 to 30 °C. Stir the reaction mixture at 25 to 30°C for 30 minutes and let it stand at 25 to 30°C for 30 minutes. Separate the layers (aqueous layer (AL-1) and organic layer (OL-2)) and place AL-1 on the side of the instruction manual (page 9 / 16, CN 121666381 A). Mix OL-1 and OL-2 at 25 to 30°C. Add softened water (385 L) to the combined organic layer. Stir the reaction mixture at 25 to 30°C for 30 minutes and let it stand at 25 to 30°C for 30 minutes. Separate the layers.The layers (aqueous layer (AL-2) and organic layer (OL-3)) were separated, and AL-2 was set aside.

[0100] A 10% saturated sodium bicarbonate solution (prepared from softened water (385 L) and sodium bicarbonate (38.5 Kg)) was added to OL-3 at 25 to 30°C. The reaction mixture was stirred at 25 to 30°C for 30 minutes and allowed to stand at 25 to 30°C for 30 minutes. The layers (aqueous layer (AL-3) and organic layer (OL-4)) were separated, and AL-3 was set aside. OL-4 was dried with anhydrous Na2SO4 (38.5 Kg) and washed with DCM (150 L) at 25 to 30°C.

[0101] The solvent was distilled under vacuum at a temperature below 35 to 40°C until 5% remained.

[0102] Hexane (308 L) was charged into the reaction mixture at 35 to 40 °C, and the solvent was completely distilled at 35 to 40 °C until no condensation droplets formed. N-Hexane (150 L) was charged into the reaction mixture at 35 to 40 °C, and the reaction mixture was cooled to 5 to 10 °C and maintained at 5 to 10 °C for 30 minutes.

[0103] The solid product was filtered, washed with cooled hexane (77 L), and dried in a hot air oven at 40 to 45 °C for 6 hours to obtain the product.

[0104] Final product: 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)prop-1-one (9)

[0105] Output: 120.5 Kg

[0106] Yield: 88.6%

[0107] HPLC purity: 99.3%

[0108] Moisture content: 0.09%

[0109] 1H NMR: (500 MHz, 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)

[0110] Reaction scheme 2 – Step (b) Step (c)

[0111]

[0112] Sulfuric acid (300.0 L) was charged into a 2.0 KL clean and dry glass-lined reactor at 25 to 30 °C. 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)prop-1-one (9) (60.0 Kg) was added in batches at 25 to 30 °C and the reaction mixture was maintained at 25 to 30 °C for 30 minutes. The reaction mixture was then slowly heated to 65 to 70 °C.The reaction mixture was maintained at 65 to 70°C for 24 hours. HPLC confirmed the absence of 3-chloro-1-(2,3-dihydro-1H-indene-5-yl)prop-1-one (9) (limit: ≤ 1.0%).

[0113] The reaction mixture was then cooled to 0 to 5°C. Nitration mixture*1 was slowly added at 0 to 5°C, and the reaction mixture was maintained at 0 to 5°C for 1 hour. The reaction mixture was maintained at 0 to 5°C.

[0114] Softened water (900.0 L) was charged into a 2.0 KL clean and dry glass-lined reactor at 25 to 30°C. The water was cooled to 0 to 5°C. The reaction mixture was slowly added to the reactor at 0 to 5°C. Toluene (480.0 L) was added, and the temperature was raised to 30 to 35°C. The reaction mixture was maintained at 30 to 35°C for 30 minutes and allowed to stand at 30 to 35°C for 30 minutes. The reaction mixture was filtered through a diatomaceous earth® bed (prepared with diatomaceous earth® (6.0 kg) and toluene (30.0 L)). The diatomaceous earth® bed was washed with toluene (60.0 L). The solids were filtered off and blotted dry for 30 minutes.

[0115] The reaction mixture was loaded into a 2.0 kg clean and dry glass-lined reactor. The reaction mixture was stirred at 30 to 35°C for 30 minutes. The layers (aqueous layer (AL-1) and organic layer (OL-1)) were separated and OL-1 was set aside. Toluene (60.0 L) was loaded into AL-1. The reaction mixture was stirred at 35 to 40°C for 30 minutes and allowed to stand at 35 to 40°C for 30 minutes. Separate the layers (aqueous layer (AL-2) and organic layer (OL-2)) and set OL-2 aside. OL-1 and OL-2 are combined to form OL-3.

[0116] A 5% saturated sodium bicarbonate solution (prepared from softened water (300.0 L) and sodium bicarbonate (15.0 Kg)) is slowly added to OL-3 at 30 to 35°C. The reaction mixture is stirred at 35 to 40°C for 30 minutes and then allowed to stand at 35 to 40°C for 30 minutes. The reaction mixture is filtered through a diatomaceous earth® bed (prepared from diatomaceous earth® (6.0 Kg) and softened water (60.0 L)). The diatomaceous earth® bed is washed with toluene (60.0 L).

[0117] The reaction mixture is loaded into a 3.0 KL clean and dry glass-lined reactor. The reaction mixture is heated at 30 to 35°C.Stir for 30 minutes. Separate the layers (aqueous layer (AL-3) and organic layer (OL-4)) and set OL-4 aside.

[0118] Add toluene (60.0 L) to AL-3. Separate the layers (aqueous layer (AL-4) and organic layer (OL-5)) and set OL-5 aside. Combine OL-4 and OL-5 to form OL-6. A brine solution (prepared from softened water (300.0 L) and sodium chloride (12.0 Kg) at 25 to 30 °C) was used. The reaction mixture was stirred at 30 to 35 °C for 30 minutes and allowed to stand at 30 to 35 °C for 30 minutes. The layers (aqueous layer (AL-5) and organic layer (OL-7)) were separated and OL-7 was set aside. OL-7 was dried with anhydrous Na2SO4 (9.0 Kg) and washed with toluene (30.0 L) at 25 to 30 °C. The solvent was distilled under vacuum at a temperature below 40 to 45 °C until 5% remained. Methanol (60.0 L) was added to the reaction mixture at 40 to 45 °C and the volume of reactants was reduced to 60 L.

[0119] Methanol (120.0 L) was added to the reaction mixture at 40 to 45 °C and the reaction mixture was cooled to 5 °C. The mixture was heated to 10°C and maintained at 5 to 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 to 45°C for 6 hours to obtain the product.

[0120] *1: To prepare the nitration mixture, sulfuric acid (27.0 L) was charged into a clean and dry glass-lined reactor at 25 to 30°C to 160 L. The reaction mixture was cooled to 0 to 5°C. Nitric acid (27.0 L) was slowly added at 0 to 5°C and the reaction mixture was maintained at 0 to 5°C for 30 minutes to provide the nitration mixture.

[0121] Final product: 8-nitro-1,2,3,5,6,7-hexahydro-S-dicyclopentadienylbenzene-1-one (11a) And 4-nitro-1,2,3,5,6,7-hexahydro-S-dicyclopentadienylbenzo-1-one (11b)

[0122] Combined output (11a+11b): 38.87 Kg

[0123] Combined gain (11a+11b): 62.24%

[0124] Weight ratio (11a:11b): 9:1

[0125] HPLC purity: 95.9%

[0126] Moisture content: 0.19%

[0127] 1H NMR: (500 MHz, CDCl3): δ7.44 (S, 1H), 2.21(m, 2H) , 2.78 (t, 2H) , 3.02 (m, 4H) , 3.13 (t, 2H)

[0128] Reaction Scheme 2 – Step (d) Specification 11 / 16 pages 14 CN 121666381 A

[0129]

[0130] A mixture of 8-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzo-1-one (11a) and 4-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzo-1-one (11b) (9:1 ratio; 27.0 Kg) was loaded into a 600 L clean and dry pressure reactor at 25 to 30 °C.

[0131] Methanol (270 L) was charged at 25 to 30°C. Methanesulfonic acid (14.3 Kg) was slowly charged at 25 to 30°C and the reaction mixture was maintained for 30 minutes. 15% Pd(OH)2 slurry (60% wet) *2 was added.

[0132] The reaction mixture was degassed under vacuum and purged with an argon atmosphere (0.5 Kg) three times. The reaction mixture was then degassed under vacuum and purged with a hydrogen atmosphere (0.5 Kg) three times. Then, the reaction mixture was stirred at room temperature under a hydrogen atmosphere (100 Psi) for 32 hours.

[0133] After the reaction was complete, the reaction mixture was cooled to 25 to 30°C. The reaction mixture was degassed under vacuum and purged with a nitrogen atmosphere (0.5 Kg) three times.

[0134] The reaction mixture was filtered through a candy filter to remove Pd(OH)2, then filtered through a microfilter and the bed was washed with methanol (54 L). Distill off 95% of the solvent under vacuum at a temperature below 45 to 50°C. Add softened water (135 L) to the reaction mixture at 25 to 30°C and maintain for 30 minutes. Cool the reaction mixture to 5–10°C. Adjust the pH to approximately 9–10 with a 2 N NaOH aqueous solution (prepared from NaOH (6.48 Kg) and softened water (81 L)) and stir the reaction mixture for 30 minutes. Then add toluene (135 L) to the reaction mixture and stir for 30 minutes. Stir the reaction mixture for another 30 minutes while maintaining the temperature at 25 to 30°C. Let the reaction mixture stand for 30 minutes while maintaining the temperature at 25 to 30°C.

[0135] Filter the reaction mixture through a diatomaceous earth® bed (prepared from diatomaceous earth® (5.4 Kg) and toluene (13.5 L)). Wash the diatomaceous earth® bed with toluene (54 L).

[0136] Separate the layers (water layer (AL-1))Add toluene (54 L) to AL-1 at 25 to 30 °C. Stir the reaction mixture at 25 to 30 °C for 30 minutes and let it stand at 25 to 30 °C for 30 minutes. Separate the layers (aqueous layer (AL-2) and organic layer (AL-2)) and set AL-2 aside. Add toluene (54 L) to AL-1 at 25 to 30 °C. Add a brine solution (prepared with softened water (135 L) and sodium chloride (54 kg)) to the combined organic layers (AL-1 and AL-2) at 25 to 30 °C. Stir the reaction mixture at 25 to 30 °C for 30 minutes and let it stand at 25 to 30 °C for 30 minutes.

[0137] Separate the layers (aqueous layer (AL-3) and organic layer (OL-3)) and set AL-3 aside. Add charcoal (1.3 kg) to OL-3 and raise the temperature to 35 to 40°C and maintain it at 35 to 40°C for 30 minutes. Filter the reaction mixture at 35 to 40°C through a diatomaceous earth® bed (prepared with diatomaceous earth® (5.4 kg) and toluene (54 L)). Wash the diatomaceous earth® bed with toluene (54 L). Dry the organic layer with anhydrous Na2SO4 (13.5 kg). Wash the Na2SO4 with toluene (27 L).

[0138] Distill the solvent under vacuum at a temperature below 35 to 40°C until 5% remains. Add methanol (40.5 L) to the reaction mixture at 35 to 40°C and distill until 5% remains. Methanol (97.2, page 12 / 16, CN 121666381 AL) and water (10.8 L) were added to the reaction mixture at 35 to 40°C. The reaction mixture was heated to 50 to 55°C and stirred at 50 to 55°C for 1 hour, then slowly cooled to 0 to 5°C and maintained at 0 to 5°C for 30 minutes.

[0139] The solid product was filtered and washed with cold methanol (13.5 L) and dried in a hot air oven at 40 to 45°C for 6 hours to obtain the product.

[0140] *2: To prepare a 15% Pd(OH)2 slurry, carbon-supported 20% Pd(OH)2 (60% wet; 4.05 Kg) was added to methanol (27 L).

[0141] Final product: 1,2,3,5,6,7-hexahydro-S-dicyclopentadienylphenyl-4-amine (12)

[0142] Output: 11.3 Kg

[0143] Yield: 41.85%

[0144] HPLC purity: 98.1%

[0145] Moisture content: 0.10

[0146] 1H NMR: (400 MHz, DMSO-d6): δ 6.38 (S, 1H), 4.45 (S, 2H), 2.75 (t, 4H), 2.58 (t, 4H), 1.98 (t, 4H).

[0147] Purification of 1,2,3,5,6,7-hexahydro-S-dicyclopentadienzylphenyl-4-amine (12) (A)

[0148] 54.5 kg of 1,2,3,5,6,7-hexahydro-S-dicyclopentadienzylphenyl-4-amine (12) was charged into a 250 L clean and dry reactor at 25 to 30 °C. 27.2 L of toluene was added at 25 to 30 °C and the reaction mixture was stirred at 25 to 30 °C for 30 min. 163 L of methanol was added to the reaction mixture at 25 to 30 °C. The reaction mixture was stirred at 25 to 30 °C for 30 min, cooled to -5 to 0 °C, and stirred at -5 to 0 °C for 30 min. The solid product was filtered, washed with cold methanol (54.5 L), and dried at 40 to 45 °C for 6 hours.

[0149] Final product: 1,2,3,5,6,7-hexahydro-S-dicyclopentadienylphenyl-4-amine (12)

[0150] Output: 40.5 Kg

[0151] Yield: 74.31%

[0152] HPLC purity: 99.5%

[0153] Moisture content: 0.3%

[0154] 1H NMR: (400 MHz, DMSO-d6): δ 6.33 (s, 1H), 4.53 (s, 2H), 2.72 (t, 4H), 2.57 (t, 4H), 1.98 (t, 4H).

[0155] 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienzophenyl-4-yl)carbamoyl)piperidine-4-sulfonamide (potassium salt) (I) Specification 13 / 16 pages 16 CN 121666381 A

[0156]

[0157] Synthesis of reaction scheme 3. (I)

[0158] 1,2,3,5,6,7-hexahydro-s-dicyclopentadienzophenyl-4-amine isocyanate (13) prepared in batches:

[0159] 1,2,3,5,6,7-hexahydro-s-dicyclopentadienzophenyl-4-amine (12) (1.00 g, 1.00 equivalent) was placed in a 50 mL reactor at 10–20 °C.Dissolved in toluene (9.60 g) at ℃. Add N,N-diisopropylethylamine (2.25 g, 3.00 equivalent), followed by 20 wt% phosgene solution (4.28 g, 1.50 equivalent) over 3 minutes, and further stir the resulting suspension at 10–20 ℃ for 30 minutes. Wash the reaction mixture with saturated NaHCO3 solution (5.0 mL) and water (5.0 mL). Separate the layers to give a toluene solution of 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-amine isocyanate (OL-1, about 20 mL, containing 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-amine (12) (5.77 mmol)). The obtained solution OL-1 was used in the next step (coupling of dicyclopentadienylaniline-isocyanate (12) with 1-ethyl-4-piperidinesulfonamide (7)) to produce (14) in approximately 80% of the total yield.

[0160] Preparation of 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylaniline-4-amine-isocyanate (13) by flow-through:

[0161] Preparation of feed solutions:

[0162] Feed solution A: 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylaniline-4-amine (12) (43.31 g) was dissolved in toluene (206.69 g) to obtain a 0.90 M solution.

[0163] Feed solution B: Potassium carbonate (103.5 g) was dissolved in water (950 g) to obtain a 0.75 M solution.

[0164] Feed A (0.70 mL / min, 1.10 equivalent), 20% w / w phosgene toluene solution (0.45 mL / min, 1.50 equivalent), and feed B solution (2.35 mL / min, 3.10 equivalent) were simultaneously fed into reactor 1 (approximately 25 mL) at 0 to 10 °C (internal temperature). The residence time in reactor 1 was 5–10 minutes. The two-phase solution from reactor 1 was continuously pumped out and the layers were continuously separated to obtain an organic layer (OL-1) containing 1,2,3,5,6,7-hexahydro-S-dicyclopentadiene-phenyl-4-amine isocyanate (13) and an aqueous layer (AL-1) directed to the waste. The organic layer OL-1 was collected over 81 minutes at steady state to give approximately 90 mL of 1,2,3,5,6,7-hexahydro-s-dicyclopentadienzylphenyl-4-amine (12) (51 mmol). The obtained solution OL-1 was used for the next step.

[0165] Coupling of dicyclopentadienzylphenyl-isocyanate (12) with 1-ethyl-4-piperidinesulfonamide (7):

[0166] 1-Ethyl-4-piperidinesulfonamide (7) (8.88 g, 46 mmol, 1.0 equivalent) was added to a container. Tetrahydrofuran (62.52 g) was added to the container and the mixture was brought to 20 to 25°C. The mixture was stirred at 20 to 25°C for at least 20 minutes until lumps disappeared and a homogeneous suspension was formed. Potassium tert-butoxide (1.05 M, 43.98 mL, CN 121666381 A 46 mmol) was added to the container over 90 to 120 minutes, the temperature was maintained at 20 to 25°C, and the mixture was stirred at 20 to 25°C for 2 to 4 hours to obtain a thick white suspension.

[0167] An organic layer OL-1 containing 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-amine isocyanate (13) (51 mmol of 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-amine (12), about 90 mL) prepared in a batch or flow manner was added to the resulting white toluene suspension over 2 hours while maintaining at 20–25 °C. The reaction mixture quickly became a well-stirred suspension and, at the end of the addition, became a slightly turbid brown solution. The reaction mixture was further stirred at 20–25 °C for 1–2 h. The water content was analyzed by KF, and the conversion of 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-amine (typically >95%) was confirmed by LC / MS or HPLC. Optionally, the mixture was clarified by filtration through a diatomaceous earth layer (G3 filter). Water (4.44 g, 0.5 V) was added dropwise to the reaction mixture over 2 hours at 25–40 °C. The solid began to crystallize at a water content of about 0.5–1 wt%. A suspension was formed at the end of the feeding. The reaction mixture was cooled to 0–5 °C (IT) over 1 h and further stirred at 0–5 °C for 16 h. The solid was filtered through a G3 filter and washed with a toluene / THF mixture (1 / 1, 44.4 mL by volume).

[0168] The solid was dried over a nitrogen flow of 10–20 mbar at up to 50 °C for 12 h. The dry weight of the crude solid was measured, identified, and analyzed using 1H NMR spectroscopy and HPLC.

[0169] Final product: 1-ethyl-N-((1,2,3,5,6,7-hexahydro-S-dicyclopentadienylbenzo-4-yl)-carbamoyl)piperidine-4-sulfonamide (potassium salt) (1)

[0170] Output: Approximately 16.0 g

[0171] Yield: Approximately 80%

[0172] NMR purity: >97%

[0173] HPLC purity: >99%

[0174] Recrystallization of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-S-dicyclopentadienylbenzo-4-yl)-carbamoyl)piperidine-4-sulfonamide (potassium salt) (1)

[0175] Crude 1-ethyl-N-((1,2,3,5,6,7-hexahydro-S-dicyclopentadienylbenzo-4-yl)carbamoyl)piperidine-4-sulfonamide (potassium salt) (14) (15.00 g) was loaded into a reaction vessel. Methanol (33.55 g) followed by acetonitrile (33.55 g) was added to the vessel, and the temperature was adjusted to 15 to 25°C as needed, while stirring for 10 to 20 minutes (until a homogeneous turbid solution without solid lumps was formed). The solution was filtered through a 1 μm filter at 15 to 25 °C. The filter was washed with a methanol / acetonitrile mixture (7.59 g) at 15 to 25 °C, and acetonitrile (64.0 g) was added, followed by seed crystals (0.138 g) of (14) in acetonitrile (about 1 g). A suspension was formed.

[0176] The solution was concentrated to about 122 mL at 25 to 35 °C. Acetonitrile (54.32 g) was added to the mixture and the solution was concentrated to about 122 L at 25 to 35 °C. Acetonitrile (52.53 g) was added to the mixture and the mixture was concentrated to about 122 mL at ≤ 35 °C. The residual methanol content of the mixture was analyzed. It was determined to be ≤ 0.3% w / w methanol by standard. Acetonitrile (53.45 g) was added to a container and the temperature was adjusted to 15 to 25 °C. The slurry was aged at 15 to 25°C for at least 1 hour (target 1 to 2 hours), and then filtered through a 20 µm cloth at 15 to 25°C. The filter cake was washed twice with acetonitrile (43.39 g) at 15 to 25°C. The solids were dried under a nitrogen stream at up to 50°C, yielding 13.75 g (92%) of white solids.

[0177] Final product: 1-ethyl-N-((1,2,3,5,6,7-hexahydro-S-dicyclopentadienzobenzo-4-yl)-carbamoyl)piperidine-4-sulfonamide (potassium salt) (1)

[0178] Output: 13.75 g Instructions for Use, pages 15 / 16, 18 CN 121666381 A

[0179] Yield: 92%

[0180] HPLC purity: 99.7% Instructions for Use, pages 16 / 16, 19 CN 121666381 A PH 250413 Title: PROCESS FOR THE PREPARATION OF PREPARING1-ETHYL-N-((1,2,3,5,6,7-HEXAHYDRO-S-INDACEN-4-YL) CARBAMOYL) PIPERIDINE-4-SULFONAMIDE Title of Invention: Preparation Method of 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide The present invention relates to a process for the preparation of compound (6). Compound (6) is a key precursor for the formation of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (compound (I)) or a pharmaceutically acceptable salt thereof, which is useful as an NLRP3 inhibitor. Compound (6) is a key precursor for the formation of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzo-4-yl)carbamoyl)piperidine-4-sulfonamide (compound (I)) or a pharmaceutically acceptable salt thereof, which can be used as an NLRP3 inhibitor. Abstract

Claims

1. A method for preparing compound (6) or a salt thereof, the method comprising the following steps: (a) First, the ethylation reaction of (1) is carried out to obtain (2), followed by... (b) Then react (2) with thionyl chloride in toluene to form (3). ； Next is (c) Compound (3) reacts to compound (4) via Grignard formation, followed by (d) Formation of sulfonate compound (5), then (e) Oxidize the sulfonate compound to obtain compound (6). 。 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. The method according to claim 1 or 2, wherein the hydrogenation in step (a) is carried out at 80°C and 10 to 20 bar H2 for 1 to 3 hours.

4. The method according to claim 2 or 3, wherein the loading for reaction step (a) is 10%-wt Pd / C, and wherein the catalyst loading is between 3.3%-wt catalyst and 10%-wt catalyst.

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

6. The method according to any one of claims 1 to 5, wherein reaction step (c) generally comprises adding compound (3) diluted in THF to magnesium that has been charged together with THF, heated to 40°C and 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 cooled mixture at 0°C.

8. The method according to any one of claims 1 to 8, wherein the subsequent treatment in reaction step (d) comprises 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.

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

10. A method for reacting compound (6) obtained by the method according to any one of claims 1 to 9 with compound (13) to obtain compound (I). 。 11. A pharmaceutical composition comprising: a compound (I) obtained by the method according to claim 10, or a salt thereof; and a pharmaceutically acceptable excipient.

12. A compound of formula (6) comprising compounds of formula (A) and / or (B). 。