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 present invention relates to a process for the preparation of compound (6), (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), Formula (I)) or a pharmaceutically acceptable salt thereof, which is useful as an NLRP3 inhibitor.

Description

[0001] Process for the preparation of preparing i-ethyl-N-((i,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide

[0002] The present invention relates to a process for the preparation of compound (6),

[0003] Compound (6) is a key precursor for the formation of i-ethyl-N-((i,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.

[0004] Background i-Ethyl- -((i,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 i-ethyl- -((i,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.

[0005] WO2O22 / 268935 demonstrates processes to make i-Ethyl-N-((i,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 (I), which is i-Ethyl-N-((i,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4- sulfonamide, or a salt thereof. wherein X is a leaving group.

[0006] There is also a need to provide i-ethyl-N-((i,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).

[0007] 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.

[0008] Summary of the Invention

[0009] The invention provides a process of preparing compound (6), the process comprising the scheme A shown below.

[0010] The term “pharmaceutically acceptable salt” refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds 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 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 Bastin R.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.

[0011] Abbreviations

[0012] Aq. aqueous

[0013] AKX AQUAMICRON® AKX

[0014] ACN acetonitrile

[0015] AL aqueous layer

[0016] DCM dichloromethane

[0017] GC gas chromatography

[0018] HPLC high performance liquid chromatography

[0019] HOSA hydroxylamine-O-sulfonic acid

[0020] IT Internal temperature

[0021] LC / MS Liquid chromatography-mass spectrometry

[0022] MeCN Acetonitrile

[0023] OL organic layer

[0024] Pd / C Palladium on charcoal r.t Room temperature

[0025] THF tetrahydrofuran

[0026] V volume relative to the starting material w / w% Weight in weight

[0027] %a-a (area under peak of compound (a) / combined area under peaks of compound (a) and all other components) x 100

[0028] The invention provides the process for preparing the compound (6) as outlined in Scheme A and the subsequent preparation of compound (I) as outlined in Scheme B. Scheme A

[0029] The synthesis of compound (6) comprises one or more of the following steps:

[0030] Steps (a) and (b): The formation of compound (3) via a first ethylation reaction of (1) to yield (2), which is then subsequently reacted with thionyl chloride in toluene to form (3) 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)

[0031] 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.

[0032] Suitable conditions for performing the hydrogenation in step (a) include 10-20 bar H2at 8o°C to achieve complete conversation without any side reaction within 1 to 3I1.

[0033] Suitable catalyst loadings for reaction step (a) include 10%-wt Pd / C with catalyst loadings between 3.3%-wt catalyst to 10%-wt catalyst.

[0034] In reaction step (b) compound (2) in toluene is heated to 6o°C and thionyl chloride reagent in toluene is dosed over at least 1 hour while maintaining internal temperature at 60-75°C.

[0035] Alternatively, 48% HBr (aq.) would yield a bromo intermediate instead of the represented chloro one, which functions also.

[0036] Other solvents as alternative to toluene are ACN (acetonitrile), DCM (dichloromethane), and a mixture of toluene and TBAC (tetrabutylammonium chloride) as additive.

[0037] Further alternative reagents include PBr3, S0Br2, Br2 / PPh3, CBr4 / PPh3(to form a bromo intermediate), as well as thionyl chloride, CCl4 / PPh3, POCl3, PCl3to form a chloro intermediate. The reaction step (c) typically involves adding compound (3) diluted in THF to Magnesium that is charged with THF, heated to 4O°C and activated by addition of 1,2- dibromoethane at 4O°C and then heated to 6o°C for the reaction. Activation may also be performed with iodine in diethyl ether solvent.

[0038] The reaction step (d) typically involves reacting compound (4) with sulphur dioxide in a cooled mixture at o°C. The sulphur dioxide may be as a gas or in solution in THF.

[0039] 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 maybe potassium carbonate, mono sodium biphosphate, sodium bisulphate, disodium citrate, while alternative acids are acetic acid, citric acid, hydrochloric acid and water.

[0040] 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.

[0041] Unless stated otherwise, any reference 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.

[0042] Unless stated otherwise, any reference to a compound or group is to be considered a reference to all tautomers of that compound or group.

[0043] A further embodiment of the invention includes reacting compound (6) obtained by the processes mentioned above with compound (13) to yield compound (I).

[0044]

[0045] A further embodiment of the invention relates to compound (I) obtained using compound (6) that was produced using the processes described above.

[0046] 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 invention includes 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- or multi-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.

[0047] 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 maybe 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. 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 limited to 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.

[0048] 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.

[0049] The compounds and / or salts used in and provided by the present invention maybe 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 not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.

[0050] The compounds, salts and solvates used in and provided by the present invention may contain any stable isotope including, but not limited to12C,13C,1H,2H (D),14N,15N,16O,170,180,19F and127I, and any radioisotope including, but not limited to “C,14C,3H (T),13N,130,18F,123I,124I,125I and131I.

[0051] Unless stated otherwise, the compounds, salts and solvates used in and provided by the present invention maybe in any polymorphic or amorphous form.

[0052] 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, 4thEd., 2013. Pharmaceutically acceptable excipients including adjuvants, diluents or carriers that maybe used in the pharmaceutical compositions of the invention, are those conventionally employed in the field of pharmaceutical formulation.

[0053] 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.

[0054] An additional aspect of the present invention provides a pharmaceutical composition comprising 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.

[0055] Typically, the treatment or prevention of the disease, disorder or condition comprises the administration of the compound (I) or the salt thereof, as obtained using compound (6) that was produced using the processes described above.

[0056] Examples

[0057] All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

[0058] Experimental Methods

[0059] NMR Methods:

[0060] NMR spectra were obtained on Bruker AV 400MHz spectrometer (model: Advance HID) operated at room temperature (25°C).

[0061] GC Methods:

[0062] GC analysis was conducted on one of the following machines: Agilent 7890, 6890, or Agilent 6890N with ALS injector.

[0063] HPLC Methods:

[0064] HPLC in reaction scheme 2, steps (a)-(d) was run on Waters Alliance e2695 HPLC with PDA detector using 10 Mm ammonium bicarbonate in water as mobile phase-A and acetonitrile as mobile phase-B. 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.

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

[0066] KF Methods:

[0067] Coulometric KF (Karl Fischer) titration was run using AKX reagent on Mitsubishi CA- 20 or Predicta OMiooo.

[0068] Synthesis Examples i-ethylpiperidine-4-sulfonamide (6) i-ethyl-4-piperidinesulfonamide (6) was prepared according to the reaction sequence illustrated in reaction scheme 1.

[0069] Scheme 1. i-ethyl-4-piperidinesulfonamide (6) synthesis

[0070] Reaction scheme 1 - step (a) and (b) Piperidin-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 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 cooled to 2O-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.

[0071] 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 6o°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 6o-75°C. The reaction was strongly exothermic and went along with vigorous gassing (S02, HC1). After the addition, the reaction mixture was stirred at reflux (73°C) for at least 1 h. Then, the reaction mixture was cooled to 2O-25°C and quenched at < 30°C on water (4'000 ml, 5 V). The quench was strongly exothermic and went along with gassing (S02). The pH of the quench mixture was set to > 11.0 with 30%-w / wNaOH 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 9O°C over a 30 cm Vigreux column to yield 4-chloro-i-etylpiperidine (3) (655 g, 71.6%) as a colourless liquid.

[0072] Final Product: 4-Chloro-i-ethylpiperidine (3)

[0073] Yield: 72%

[0074] HPLC purity: 99.5%

[0075] Reaction scheme 1 - step (c), (d) and (e)

[0076]

[0077] Magnesium (10.07 g, 415 mmol, 1.02 eq.) was charged to THF (300 ml, 5 V) heated to 4O°C and activated by addition of 1,2-dibromoethane (1.75 ml, 20 mmol, 0.05 eq.). The mixture was heated to 6o°C and 4-chloro-i-ethylpiperidine (3) (60 g, 406 mmol, 1.00 eq.) diluted with THF (60 ml, 1 V) was added over at least 1 h. After complete addition the mixture was stirred for at least 3 h at reflux (GC 4-chloro-i-ethylpiperidine (3) <3%-a / a).

[0078] 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.

[0079] The mixture was cooled to o°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- io°C. After complete addition the mixture was stirred for at least 20 min at o°C. Afterwards, the reaction mixture was added under adiabatic conditions to a precooled (o-io°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. HOSA (50.6 g, 447 mmol, 1.10 eq.) was added in 10 portions to the aqueous solution, containing i-ethylpiperidine-4-sulfmic 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 1 h at 2O-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 5O°C to give i-ethyl-4-piperidinesulfonamide (6) (56,5 g, 72%) as a white solid.

[0080] Final Product: i-ethylpiperidine-4-sulfonamide (6)

[0081] Yield: 72%

[0082] HPLC purity: 98.3 w / w%

[0083] 1,2,2,5,6,7-hexahvdro-s-indacen-4.-amine (12)

[0084] 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) was prepared according to the reaction sequence illustrated in Reaction Scheme 2.

[0085] Scheme 2. Synthesis of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12)

[0086] Reaction scheme 2 - step (a) DCM (385 L) and A1Cl3(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 -io°C.

[0087] 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 io°C under a nitrogen atmosphere. 2,3-dihydro-iW-indene (8) (77.00 Kg was then added slowly to the reaction mixture at -10 to -5°C under nitrogen atmosphere.

[0088] The reaction mixture was maintained for 2 hours at 10 to 15°C.

[0089] After completion of the reaction, the reaction mixture was added slowly to a 6 N hydrochloric acid solution (prepared from water (308 L) and cone, hydrochloric acid (308 L)) at o to io°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-i) 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-i) and organic layer (OL-2)) and AL-i was kept aside. OL-i 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.

[0090] 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 Na2SO4(38.5 Kg) and the anhydrous Na2SO4was washed with DCM (150 L) at 25 to 30°C.

[0091] The solvent was distilled under vacuum at below 35 to 4O°C until 5 % remained, n-hexane (308 L) was charged to the reaction mixture at 35 to 4O°C and the solvent was distilled completely at 35 to 4O°C until no condensate drops were formed. N-hexane (150 L) was charged to the reaction mixture at 35 to 40°C and the reaction mixture was cooled to 5 to io°C and maintained at 5 to io°C for 30 minutes.

[0092] 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 afford the product.

[0093] Final Product: 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-i-one (9)

[0094] Output: 120.5 Kg

[0095] Yield: 88.6 %

[0096] HPLC purity: 99.3 %

[0097] Moisture content: 0.09 %

[0098] 1H NMR: (500 MHz, CDCI3): 8 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)

[0099] Reaction scheme 2 - step (b) and step (c)

[0100] 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-i-(2,3-dihydro-1H-inden-5-yl)propan-i-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-i-(2,3-dihydro-1H-inden-5-yl)propan- i-one (9) was confirmed by HPLC (Limit: < 1.0 %).

[0101] Then the reaction mixture was cooled to o to 5°C. A nitration mixture*1was added slowly at o to 5°C and the reaction mixture was maintained at o to 5°C for 1 hour. The reaction mixture was maintained at o to 5°C.

[0102] 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 o to 5°C. The reaction mixture was added slowly added to the reactor at o 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 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.

[0103] 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-i) and organic layer (OL-i)) and OL-i was kept aside. Toluene (60.0 L) was charged to AL-i. The reaction mixture was stirred at 35 to 4O°C for 30 minutes and allowed to settle at 35 to 4O°C for 30 minutes. The layers were separated (aqueous layer (AL-2) and organic layer (OL-2)) and OL-2 was kept aside. OL-i and OL-2 were combined to form OL-3.

[0104] A 5 % 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 4O°C for 30 minutes and allowed to settle at 35 to 4O°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).

[0105] 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.

[0106] 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 Na2SO4(9.0 Kg) and the anhydrous Na2SO4was 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. Methanol (120.0 L) was charged to the reaction mixture at 40 to 45°C and the reaction mixture was cooled to 5 to io°C and maintained at 5 to io°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.

[0107] *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 o to 5°C. Nitric acid (27.0 L) at o to 5°C was added slowly and the reaction mixture was maintained for 30 minutes at o to 5°C to afford the nitration mixture.

[0108] Final Product: 8-nitro-i,2,3,5,6,7-hexahydro-s-indacen-i-one (11a) and 4- nitro-i,2,3,5,6,7-hexahydro-s-indacen-i-one (11b)

[0109] Combined Output (11a+11b): 38.87 Kg

[0110] Combined Yield (11a+nb): 62.24 %

[0111] Weight ratio (na:11b): 9:1

[0112] HPLC purity: 95.9%

[0113] Moisture content: 0.19%1H NMR: (500 MHz, CDCl3):δ7.44(S, 1H), 2.2i(m, 2H), 2.78 (t, 2H), 3.02 (m, 4H), 3.13 (t, 2H)

[0114] Reaction scheme 2 - step (d)

[0115] A mixture of 8-nitro-i,2,3,5,6,7-hexahydro-s-indacen-i-one (11a) and 4-nitro- 1,2,3,5,6,7-hexahydro-s-indacen-i-one (11b) (9:1 ratio; 27.0 Kg) at 25 to 30°C was charged into a 600 L clean and dry pressure reactor.

[0116] 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(0H)2slurry (60 % wet)*2was added. 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 (too Psi) at room temperature for 32 hours.

[0117] 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.

[0118] The reaction mixture was filtered through a candy filter to remove Pd(0H)2, 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 5O°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-io°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.

[0119] 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).

[0120] The layers were separated (aqueous layer (AL-i) and organic layer (OL-i)) and OL-i was kept aside. Toluene (54 L) was added to AL-i 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-i at 25 to 30°C. A brine solution (prepared with demineralised water (135 L) and sodium chloride (54 Kg)) was charged to the combined organic layers (OL-i 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.

[0121] 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 35-40°C and maintained at 35 to 4O°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 4O°C. The Celite® bed was washed with toluene (54 L). The organic layer was dried over anhydrous Na2SO4(13.5 Kg). The Na2SO4was washed with toluene (27 L).

[0122] The solvent was distilled under vacuum at below 35 to 4O°C until 5 % remained. Methanol (40.5 L) was charged to the reaction mixture at 35 to 4O°C and distilled until 5 % remained. Methanol (97.2 L) and water (10.8 L) were charged to the reaction mixture at 35 to 4O°C. The reaction mixture was heated to 50 to 55°C, stirred for 1 hour at 50 to 55°C, slowly cooled to o to 5°C and maintained at o to 5°C for 30 minutes.

[0123] 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 afford the product.

[0124] *2: To prepare the 15 % Pd(0H)2slurry, 20 % Pd(0H)2on carbon (60 % wet; 4.05 Kg) was added to methanol (27 L).

[0125] Final product: i,2,3,5,6,7-hexahydro-s-indacen-4-amine (12)

[0126] Output: 11.3 Kg

[0127] Yield: 41.85 %

[0128] HPLC purity: 98.1 %

[0129] Moisture content: 0.101H 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).

[0130] Purification (A) of i,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) i,2,3,5,6,7-Hexahydro-s-indacen-4-amine (12) (54.5 Kg) was charged at 25 to 30°C into a 250 L clean 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.

[0131] Final Product: 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) Output: 40.5 Kg

[0132] Yield: 74.31 %

[0133] HPLC purity: 99.5 %

[0134] Moisture content: 0.3 %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). i-EthyldV-(( 1,2,3,5,6,7-hexahydro-s-indacen-4.-yl)carbamoyl)piperidine-4.- sulfonamide (potassium salt) (I)

[0135] Reaction scheme 3. Synthesis of (I)

[0136] 1.2.3.5.6.7-hexahydro-s-indacen-4-amine-isocyanate (13) preparation in a batch mode:

[0137] 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 NaHCO3solution (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 of indacenamine-isocyanate (12) with 1-ethyl-4-piperidinesulfonamide (7)) to yield (14) in ca. 80% overall yield. i,2,3,5,6,7-hexahydro-s-indacen-4-amine-isocyanate (13) preparation in a flow mode:

[0138] Feed solutions preparation:

[0139] Feed solution A: i,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) (43.31 g) was dissolved in toluene (206.69 g) to give a 0.90 M solution.

[0140] Feed solution B: Potassium carbonate (103.5 g) was dissolved in water (950 g) to give a 0.75 M solution.

[0141] 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-i) that is directed to the waste. Organic layer OL-i is collected over 81 minutes at steady state to afford ca. 90 mL of i,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) (51 mmol). The obtained solution OL-i is used in the next step.

[0142] Coupling of indacenamine-isocyanate (12) with i-ethyl-4- piperidinesulfonamide (7): i-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.

[0143] The organic layer OL-i containing i,2,3,5,6,7-hexahydro-s-indacen-4-amine -isocyanate (13) (51 mmol of i,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) , 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 i,2,3,5,6,7-hexahydro-s-indacen-4-amine confirmed by LC / MS or HPLC 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 o to 5 °C (IT) over 1 h and stirred further for 16 h at o to 5 °C. Solids were filtered through a G3 filter and washed with toluene / THF (1 / 1 by volume, 44.4 mL) mixture.

[0144] The solid was dried at up to 5O°C, 10 - 20 mbar under a flow of nitrogen over 12 h. The dried weight of the crude solid was measured, identified and analysed using1H NMR spectroscopy and HPLC.

[0145] Final Product: i-ethyl-IV-((i,2,3,5,6,7-hexahydro-s-indacen-4-yl)- carbamoyl)piperidine-4-sulfonamide (potassium salt) (1)

[0146] Output: ca. 16.0 g

[0147] Yield: ca. 80 %

[0148] NMR purity: >97%

[0149] HPLC purity: >99%

[0150] Recrystallization of i-ethyl-IV-(( 1,2,3,5,6,7-hexahydro-s-indacen-4.-yl)- carbamoyl)piperidine-4-sulfonamide (potassium salt) (1)

[0151] Crude i-ethyl-N-((i,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4- sulfonamide (potassium salt) (14) (15.00 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 pm filter at 15 to 25°C. The filter was washed with methanol / aceto nitrile 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. 1 g). Suspension was formed.

[0152] 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 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 pm 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 5O°C under a flow of nitrogen to yield 13.75 g (92%) of the white solid.

[0153] Final Product: i-ethyl-iV-((i,2,3,5,6,7-hexahydro-s-indacen-4-yl)- carbamoyl)piperidine-4-sulfonamide (potassium salt) (1)

[0154] Output: 13.75 g

[0155] Yield: 92 %

[0156] HPLC purity: 99.7 %

Claims

Claims1. A process of preparing compound (6) or a salt thereof, comprising the step of:(a) a first ethylation reaction of (i) to yield (2), followed by(b) subsequently reacting (2) with thionyl chloride in toluene to form (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)2. The process of claim 1, wherein reaction step (a) involves dissolving compound (1) in a methanol and acetonitrile mixture and performing a hydrogenation in the presence of a Pd / C catalyst.

3. The process of claims 1 or 2, wherein the hydrogenation in step (a) is conducted at 10-20 bar H2at 8o°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.

5. The process of any of claims 1 to 4, wherein for reaction step (b) compound (2) is in toluene is heated to 6o°C and thionyl chloride reagent in toluene is dosed over at least 1 hour while maintaining internal temperature at 6o-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 4O°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 o°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).

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

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

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