Novel approach

Abstract

The present invention relates to methods for preparing N-((1,2,3,4,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide and its salts. The present invention further relates to pharmaceutical compositions comprising such compounds and the use of such compounds to treat and prevent medical conditions and diseases, most particularly through NLRP3 inhibition.

Description

Technical Field

[0001] The present invention relates to methods for preparing N-((1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide and its salts. The present invention further relates to pharmaceutical compositions comprising such compounds and the use of such compounds to treat and prevent medical conditions and diseases, most particularly through NLRP3 inhibition. Background Art

[0002] N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienol-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide has been disclosed as an NLRP3 inhibitor in WO 2016 / 131098 A1. However, there is still a need to provide an improved method for preparing N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienol-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide and its salts, which provides N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienol-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide and its salts on a larger scale and / or in higher yield and / or in higher purity compared to the prior art methods. Summary of the invention

[0003] A first aspect of the present invention provides a method for preparing N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienolbenzo-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide or a salt thereof, the method comprising the steps of contacting 1-isopropyl-3-(alkoxycarbonylamino-sulfonyl)-1H-pyrazole with 1,2,3,5,6,7-hexahydro-s-dicyclopentadienolbenzo-4-amine in the presence of a solvent to obtain N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienolbenzo-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide:

[0004]

[0005] Where R is C 1-6 alkyl.

[0006] In one embodiment, R is selected from methyl, ethyl and propyl. Typically, R is methyl. When R is methyl, a method for preparing N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienol-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide or a salt thereof is provided, the method comprising contacting 1-isopropyl-3-(methoxycarbonylaminosulfonyl)-1H-pyrazole with 1,2,3,5,6,7-hexahydro-s-dicyclopentadienol-4-amine in the presence of a solvent to obtain N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienol-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide:

[0007]

[0008] In one embodiment of the first aspect of the present invention, the solvent comprises dimethyl carbonate, methyl ethyl ketone, acetone, tert-butyl acetate, ethyl acetate, toluene or a mixture thereof. Typically, the solvent comprises dimethyl carbonate.

[0009] In one embodiment of the first aspect of the invention, the reaction is carried out at a temperature of 40° C. to 95° C. Typically, the reaction is carried out at a temperature of 50° C. to 95° C. Typically, the reaction mixture is heated at a temperature of 70° C. to 95° C. for 10 to 40 hours.

[0010] Compared to similar prior art processes, the process of the first aspect of the invention has reproducible high yields, is carried out using mild reaction conditions, provides products with excellent HPLC purity, and is therefore suitable for large-scale clinical manufacturing.

[0011] In one embodiment of the first aspect of the present invention, the 1-isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole is prepared by the method according to the second aspect of the present invention.

[0012] In one embodiment of the first aspect of the present invention, 1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-4-amine is prepared by the method according to the third aspect of the present invention.

[0013] The second aspect of the present invention provides a method for preparing 1-isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole:

[0014]

[0015] Where R is C 1-6 Alkyl, the method comprising one or more steps selected from the following:

[0016] (a) contacting 3-nitro-1H-pyrazole with iPr-X to obtain 1-isopropyl-3-nitro-1H-pyrazole, wherein X is a leaving group:

[0017]

[0018] (b) Reducing 1-isopropyl-3-nitro-1H-pyrazole to obtain 1-isopropyl-3-amino-1H-pyrazole:

[0019]

[0020] (c) Converting 1-isopropyl-3-amino-1H-pyrazole into 1-isopropyl-3-iodo-1H-pyrazole:

[0021]

[0022] (d) Converting 1-isopropyl-3-iodo-1H-pyrazole to 1-isopropyl-1H-pyrazole-3-sulfonamide:

[0023] as well as

[0024] (e) Converting 1-isopropyl-1H-pyrazole-3-sulfonamide into 1-isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole:

[0025]

[0026] In one embodiment, R is selected from methyl, ethyl and propyl. Typically, R is methyl. When R is methyl, a method for preparing 1-isopropyl-3-(methoxy-carbonylaminosulfonyl)-1H-pyrazole is provided.

[0027] In one embodiment, the method comprises one, two, three, four or all five of steps (a) to (e). Typically, the method comprises steps (d) and (e). The method may comprise steps (c), (d) and (e). The method may comprise steps (b), (c), (d) and (e). The method may comprise steps (a), (b), (c), (d) and (e).

[0028] When the process comprises steps (d) and (e), 1-isopropyl-3-iodo-1H-pyrazole required for step (d) may be obtained by steps (a), (b) and (c) or by any other process.

[0029] Compared to similar prior art methods, the methods of steps (a), (b), (c), (d) and (e) have reproducible high yields, are carried out using mild, non-toxic reagents and mild reaction conditions, provide products with excellent HPLC purity, and are therefore suitable for large-scale clinical manufacturing.

[0030] Therefore, the second aspect of the present invention also provides 1-isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole:

[0031]

[0032] Where R is C 1-6 alkyl.

[0033] Typically, the 1-isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole has an HPLC purity of 98% or more, or 98.5% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more.

[0034] In one embodiment, R is selected from methyl, ethyl and propyl. Typically, R is methyl. When R is methyl, the second aspect of the present invention provides 1-isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole.

[0035] In one embodiment, in step (a), the leaving group X is selected from fluorine, chlorine, bromine, iodine, toluenesulfonyl, mesyl and trifluoromethanesulfonyl. Typically, X is a leaving group selected from chlorine, bromine and iodine. Typically, X is a leaving group selected from bromine and iodine. More typically, X is iodine.

[0036] In one embodiment, in step (a), 3-nitro-1H-pyrazole is contacted with iPr-X in the presence of a base. Typically, the base is an inorganic base. Typically, the base comprises potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, or a mixture thereof. More typically, the base comprises potassium carbonate.

[0037] Step (a) can be carried out in the presence of a solvent. Typically, the solvent is an aprotic solvent. Typically, the solvent is a polar solvent. Typically, the solvent is a polar aprotic solvent. Typically, the solvent comprises acetonitrile, THF, DMF, HMPA, DMSO, N-methylpyrrolidone, methyl ethyl ketone, tert-butyl acetate, ethyl acetate, acetone, propylene carbonate or a mixture thereof. Typically, the solvent comprises acetonitrile.

[0038] In one embodiment, the reaction of step (a) is carried out at a temperature of 10°C to 80°C. Typically, the reaction of step (a) is carried out at a temperature of 30°C to 70°C.

[0039] In one embodiment, the reduction of step (b) is carried out using a catalyst and hydrogen. Typically, the catalyst is a metal catalyst comprising platinum, palladium, rhodium, ruthenium or nickel. Typically, the catalyst is Pd / C, Pd(OH)2, Pt / C, PtO2, platinum black or Raney nickel. More typically, the catalyst is Pd / C or Pd(OH)2. Typically, hydrogen is used at a pressure of 80-120Psi, typically about 100Psi. The catalyst and hydrogen can be used in the presence of an acid such as sulfuric acid or methanesulfonic acid.

[0040] Alternatively, the reduction in step (b) is carried out using a metal and a hydrogen source. Typically, the metal is Zn powder or iron. Typically, the hydrogen source is sulfuric acid, acetic acid, formic acid, ammonium formate or ammonium chloride.

[0041] In one embodiment, the reduction of step (b) is carried out in the presence of a solvent. Typically, the solvent is a polar solvent. Typically, the solvent comprises methanol, ethanol, isopropanol, n-butanol, THF, water, ethyl acetate, acetic acid or a mixture thereof. Typically, the solvent comprises methanol, ethanol, THF, water or a mixture thereof.

[0042] In one embodiment, the reduction of step (b) is carried out at a temperature of 10°C to 80°C. Typically, the reduction of step (b) is carried out at a temperature of 20°C to 60°C.

[0043] In one embodiment, in step (c), 1-isopropyl-3-amino-1H-pyrazole is converted into a diazo intermediate, which is then converted into 1-isopropyl-3-iodo-1H-pyrazole. Typically, 1-isopropyl-3-amino-1H-pyrazole is converted into a diazo intermediate using sodium nitrite and an acid such as sulfuric acid, hydrochloric acid or HBF4. More typically, 1-isopropyl-3-amino-1H-pyrazole is converted into a diazo intermediate using an aqueous solution of sulfuric acid and sodium nitrite. Typically, diazo intermediates are converted into 1-isopropyl-3-iodo-1H-pyrazole using potassium iodide or sodium iodide. More typically, diazo intermediates are converted into 1-isopropyl-3-iodo-1H-pyrazole using potassium iodide.

[0044] Step (c) can be carried out in the presence of a solvent. In one embodiment, the solvent is a polar solvent. In one embodiment, the solvent is a polar aprotic solvent, such as acetonitrile, THF, DMF, HMPA, DMSO, N-methyl pyrrolidone, methyl ethyl ketone, tert-butyl acetate, ethyl acetate, acetone, propylene carbonate or a mixture thereof. Typically, a polar aprotic solvent comprises acetonitrile. In one embodiment, the solvent is a polar protic solvent, such as methanol, ethanol, isopropanol, n-butanol, water or a mixture thereof. Typically, a polar protic solvent comprises water. In one embodiment, the solvent is a mixture of a polar protic solvent and a polar aprotic solvent, such as a mixture of water and acetonitrile.

[0045] In one embodiment, the reaction of step (c) is carried out at a temperature of -20°C to 20°C. Typically, the reaction of step (c) is carried out at a temperature of -10°C to 10°C.

[0046] In one embodiment, in step (d), 1-isopropyl-3-iodo-1H-pyrazole is converted to 1-isopropyl-1H-pyrazole-3-sulfonamide by treatment with a Grignard reagent or an organolithium reagent, followed by treatment with sulfur dioxide gas, followed by treatment with hydroxylamine-O-sulfonic acid.

[0047] Typically, the Grignard reagent is isopropylmagnesium chloride or isopropylmagnesium chloride lithium chloride complex. More typically, the Grignard reagent is isopropylmagnesium chloride. Typically, the organolithium reagent is isopropyllithium. Typically, the hydroxylamine-O-sulfonic acid is provided in the form of aqueous hydroxylamine-O-sulfonic acid in the presence of trisodium citrate.

[0048] Step (d) can be carried out in the presence of a solvent. In one embodiment, the solvent is an aprotic solvent. In one embodiment, the solvent is an aprotic polar solvent, such as 2-methyltetrahydrofuran, acetonitrile, THF, DMF, HMPA, DMSO, N-methyl pyrrolidone, methyl ethyl ketone, tert-butyl acetate, ethyl acetate, acetone, propylene carbonate or a mixture thereof. Typically, an aprotic polar solvent comprises 2-methyltetrahydrofuran. In one embodiment, the solvent is an aprotic hydrocarbon solvent, such as n-pentane, n-hexane, n-heptane, toluene or a mixture thereof. Typically, an aprotic hydrocarbon solvent comprises n-heptane. In one embodiment, the solvent is a mixture of an aprotic polar solvent and an aprotic hydrocarbon solvent, such as a mixture of 2-methyltetrahydrofuran and n-heptane.

[0049] In one embodiment, the reaction of step (d) is carried out at a temperature of 5°C to 40°C. Typically, the reaction of step (d) is carried out at a temperature of 5°C to 25°C.

[0050] In one embodiment, in step (e), 1-isopropyl-1H-pyrazole-3-sulfonamide is converted to 1-isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole by treatment with carbonate in the presence of a base.

[0051] In one embodiment, in step (e), the carbonate is selected from dimethyl carbonate, diethyl carbonate, dimethyl pyrocarbonate and diethyl pyrocarbonate. Typically, the carbonate is dimethyl carbonate or dimethyl pyrocarbonate. More typically, the carbonate is dimethyl carbonate.

[0052] In one embodiment, in step (e), the base is an inorganic base. Typically, the base comprises sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, or a mixture thereof. More typically, the base comprises sodium methoxide.

[0053] Step (e) can be carried out in the presence of a solvent. Typically, the solvent is an alcohol solvent. Typically, the solvent comprises methanol, ethanol, isopropanol, n-butanol or a mixture thereof. Typically, the solvent comprises methanol.

[0054] In one embodiment, the reaction of step (e) is carried out at a temperature of 10°C to 80°C. Typically, the reaction of step (e) is carried out at a temperature of 30°C to 65°C.

[0055] In a specific embodiment of the second aspect of the present invention, a method for preparing 1-isopropyl-3-(methoxycarbonylaminosulfonyl)-1H-pyrazole is provided:

[0056]

[0057] The method comprises the following steps:

[0058] (d) 1-isopropyl-3-iodo-1H-pyrazole is converted to 1-isopropyl-1H-pyrazole-3-sulfonamide by treatment with a Grignard reagent or an organolithium reagent, followed by treatment with sulfur dioxide gas, followed by treatment with hydroxylamine-O-sulfonic acid:

[0059] as well as

[0060] (e) Conversion of 1-isopropyl-1H-pyrazole-3-sulfonamide to 1-isopropyl-3-(methoxycarbonylaminosulfonyl)-1H-pyrazole by treatment with dimethyl carbonate or dimethyl pyrocarbonate in the presence of a base:

[0061]

[0062] In another specific embodiment of the second aspect of the present invention, a method for preparing 1-isopropyl-3-(methoxycarbonylaminosulfonyl)-1H-pyrazole is provided:

[0063]

[0064] The method comprises the following steps:

[0065] (a) Contacting 3-nitro-1H-pyrazole with 2-iodo-propane in the presence of a base to obtain 1-isopropyl-3-nitro-1H-pyrazole:

[0066]

[0067] (b) Reducing 1-isopropyl-3-nitro-1H-pyrazole to obtain 1-isopropyl-3-amino-1H-pyrazole:

[0068]

[0069] (c) Conversion of 1-isopropyl-3-amino-1H-pyrazole to 1-isopropyl-3-iodo-1H-pyrazole by treatment with an aqueous solution of sulfuric acid and sodium nitrite followed by potassium iodide:

[0070]

[0071] (d) 1-isopropyl-3-iodo-1H-pyrazole is converted to 1-isopropyl-1H-pyrazole-3-sulfonamide by treatment with a Grignard reagent or an organolithium reagent, followed by treatment with sulfur dioxide gas, followed by treatment with hydroxylamine-O-sulfonic acid:

[0072] as well as

[0073] (e) Conversion of 1-isopropyl-1H-pyrazole-3-sulfonamide to 1-isopropyl-3-(methoxycarbonylaminosulfonyl)-1H-pyrazole by treatment with dimethyl carbonate or dimethyl pyrocarbonate in the presence of a base:

[0074]

[0075] The third aspect of the present invention provides a method for preparing 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone-4-amine:

[0076]

[0077] The method comprises one or more steps selected from the following:

[0078] (i) contacting 2,3-dihydro-1H-indene with YCH2CH2COZ to obtain substituted 1-(2,3-dihydro-1H-inden-5-yl)propan-1-one, wherein Y and Z are leaving groups:

[0079]

[0080] (ii) contacting the substituted 1-(2,3-dihydro-1H-inden-5-yl)propan-1-one with an acid to obtain 1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-1-one:

[0081]

[0082] (iii) converting 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone to 4-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone and / or 8-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone:

[0083] as well as

[0084] (iv) reducing 4-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienacene-1-one and / or 8-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienacene-1-one to obtain 1,2,3,5,6,7-hexahydro-s-dicyclopentadienacene-4-amine:

[0085]

[0086] In one embodiment, the method comprises one, two, three or all four of steps (i) to (iv).

[0087] Compared to similar prior art methods, the methods of steps (i), (ii), (iii) and (iv) have reproducible high yields, are carried out using mild, non-toxic reagents and mild reaction conditions, provide products with excellent HPLC purity, and are therefore suitable for large-scale clinical manufacturing.

[0088] In one embodiment, in step (i), leaving groups Y and Z are independently selected from fluorine, chlorine, bromine, iodine, tosyl, mesyl and trifluoromethanesulfonyl. Typically, Y and Z are independently selected from chlorine, bromine and iodine. Typically, both Y and Z are chlorine. When both Y and Z are chlorine, in step (i), 2,3-dihydro-1H-indene is contacted with 3-chloropropionyl chloride to obtain 3-chloro-1-(2,3-dihydro-1H-indene-5-yl)propan-1-one.

[0089] In one embodiment, the reaction of step (i) is carried out in the presence of a catalyst such as a Lewis acid, such as aluminum chloride.

[0090] Step (i) can be carried out in the presence of a solvent. In one embodiment, the solvent is a non-polar solvent, such as dichloromethane, chloroform, diethyl ether, n-pentane, n-hexane, n-heptane, toluene or a mixture thereof. Typically, the solvent is dichloromethane.

[0091] In one embodiment, the reaction of step (i) is carried out at a temperature of -20°C to 50°C. Typically, the reaction of step (i) is carried out at a temperature of -10°C to 40°C.

[0092] In one embodiment, in step (ii), the acid is sulfuric acid, hydrochloric acid or a mixture thereof. Typically, the acid is sulfuric acid. Typically, no additional solvent is used.

[0093] In one embodiment, the reaction of step (ii) is carried out at a temperature of 10°C to 90°C. Typically, the reaction of step (ii) is carried out at a temperature of 30°C to 80°C.

[0094] In one embodiment, in step (iii), 1,2,3,5,6,7-hexahydro-s-dicyclopentaphenone-1-one is converted into 4-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentaphenone-1-one or 8-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentaphenone-1-one or a mixture thereof by treatment with sulfuric acid and nitric acid. Typically, no additional solvent is used.

[0095] In one embodiment, the reaction of step (iii) is carried out at a temperature of 0°C to 20°C. Typically, the reaction of step (iii) is carried out at a temperature of 0°C to 10°C.

[0096] The reactions of steps (ii) and (iii) are carried out without isolating 1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-1-one.

[0097] In one embodiment, the reduction of step (iv) is carried out using a catalyst and hydrogen. Typically, the catalyst is a metal catalyst comprising platinum, palladium, rhodium, ruthenium or nickel. Typically, the catalyst is Pd / C, Pd(OH)2, Pt / C, PtO2, platinum black or Raney nickel. More typically, the catalyst is Pd / C or Pd(OH)2. Typically, hydrogen is used at a pressure of 80-120Psi, typically about 100Psi. The catalyst and hydrogen can be used in the presence of an acid such as sulfuric acid or methanesulfonic acid.

[0098] Alternatively, the reduction in step (iv) is carried out using a metal and a hydrogen source. Typically, the metal is Zn powder or iron. Typically, the hydrogen source is sulfuric acid, acetic acid, formic acid, ammonium formate or ammonium chloride.

[0099] In one embodiment, the reduction of step (iv) is carried out in the presence of a solvent. Typically, the solvent is a polar solvent. Typically, the solvent comprises methanol, ethanol, isopropanol, n-butanol, THF, water, ethyl acetate, acetic acid or a mixture thereof. Typically, the solvent comprises methanol, ethanol, THF, water or a mixture thereof.

[0100] In one embodiment, the reduction of step (iv) is carried out at a temperature of 10°C to 80°C. Typically, the reduction of step (iv) is carried out at a temperature of 20°C to 60°C.

[0101] In a specific embodiment of the third aspect of the present invention, a method for preparing 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone-4-amine is provided:

[0102]

[0103] The method comprises the following steps:

[0104] (i) Contacting 2,3-dihydro-1H-indene with 3-chloropropionyl chloride in the presence of a Lewis acid to obtain 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one:

[0105]

[0106] (ii) contacting 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one with an acid to obtain 1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-1-one:

[0107]

[0108] (iii) converting 1,2,3,5,6,7-hexahydro-s-dicyclopentaphenone-1-one into 4-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentaphenone-1-one and / or 8-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentaphenone-1-one by treatment with sulfuric acid and nitric acid:

[0109] as well as

[0110] (iv) reducing 4-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienacene-1-one and / or 8-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienacene-1-one to obtain 1,2,3,5,6,7-hexahydro-s-dicyclopentadienacene-4-amine:

[0111]

[0112] The fourth aspect of the present invention provides N-((1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide or a salt thereof obtainable by or through the process of the first, second or third aspect of the present invention.

[0113] Typically, N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide or a salt thereof has an HPLC purity of 98% or more, or 98.5% or more, or 98.6% or more, or 98.7% or more, or 98.8% or more, or 98.9% or more, or 99% or more, or 99.1% or more, or 99.2% or more, or 99.3% or more.

[0114] N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide can be used in the free acid form and in the form of its salt. The salt can be formed with suitable cations including, but not limited to, lithium, sodium, potassium, magnesium, calcium and ammonium. The salt can be a monosalt or a disalt. The salt is preferably a mono- or di-lithium, sodium, potassium, magnesium, calcium or ammonium salt. The salt is preferably a monosodium salt or a disodium salt or a monopotassium salt or a dipotassium salt. The salt is more preferably a monosodium monohydrate salt.

[0115] Preferably, any salt is a pharmaceutically acceptable non-toxic salt. However, in addition to pharmaceutically acceptable salts, other salts are also included in the present invention because they may serve as intermediates in the purification or preparation of other, for example, pharmaceutically acceptable salts, or can be used to identify, characterize or purify free acids.

[0116] N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide and its salts may be anhydrous or in the form of a hydrate (e.g., a hemihydrate, a monohydrate, a dihydrate or a trihydrate) or other solvate. Such other solvates may be formed with common organic solvents, including but not limited to alcohol solvents such as methanol, ethanol or isopropanol.

[0117] N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide and salts thereof may contain any stable isotope, including but not limited to 12 C. 13 C. 1 H. 2 H(D), 14 N. 15 N. 16 O. 17 O and 18 O and any radioactive isotopes, including but not limited to 11 C. 14 C. 3 H(T), 13 N and 15 O.

[0118] N-((1,2,3,5,6,7-Hexahydro-s-dicyclopentaphen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide and its salts may be in any polymorphic or amorphous form.

[0119] The fifth aspect of the present invention provides a pharmaceutical composition comprising N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzo-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide or a salt thereof and a pharmaceutically acceptable excipient.

[0120] 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. Pharmaceutically acceptable excipients include adjuvants, diluents or carriers that can be used in the pharmaceutical composition of the present invention, which are those conventionally used in the art of pharmaceutical formulation.

[0121] A sixth aspect of the invention provides a compound of the fourth aspect of the invention, or a pharmaceutical composition of the fifth aspect of the invention, for use in medicine and / or for use in the treatment or prevention of a disease, disorder or condition.

[0122] Co-pending and co-owned patent applications PCT / EP2018 / 072111, PCT / EP2018 / 072115, PCT / EP2018 / 072119, PCT / EP2018 / 072123, PCT / EP2018 / 072125, PCT / EP2018 / 072133 and PCT / EP2018 / 072134 (all of which are incorporated herein by reference) disclose the use of sulfonylureas, such as the compounds of the fourth aspect of the invention, most particularly through NLRP3 inhibition to treat and prevent diseases, disorders and conditions. The diseases, disorders and conditions mentioned in these co-pending and co-owned patent applications are incorporated herein by reference.

[0123] In one embodiment, the disease, disorder or condition to be treated or prevented is selected from:

[0124] (i) Inflammation;

[0125] (ii) Autoimmune diseases;

[0126] (iii) cancer;

[0127] (iv) infection;

[0128] (v) central nervous system diseases;

[0129] (vi) metabolic diseases;

[0130] (vii) cardiovascular disease;

[0131] (viii) respiratory diseases;

[0132] (ix) liver disease;

[0133] (x) Kidney disease;

[0134] (xi) eye diseases;

[0135] (xii) Skin diseases;

[0136] (xiii) lymphatic diseases;

[0137] (xiv) psychological disorders;

[0138] (xv) graft-versus-host disease;

[0139] (xvi) allodynia;

[0140] (xvii) conditions related to diabetes; and

[0141] (xviii) any disease in which the individual has been identified as harboring a germline or somatic non-silent mutation in NLRP3.

[0142] In another embodiment, the disease, disorder or condition to be treated or prevented is selected from:

[0143] (i) cryopyrin-associated periodic syndrome (CAPS);

[0144] (ii) Muckle-Well syndrome (MWS);

[0145] (iii) familial cold autoinflammatory syndrome (FCAS);

[0146] (iv) neonatal-onset multisystem inflammatory disease (NOMID);

[0147] (v) Familial Mediterranean fever (FMF);

[0148] (vi) septic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA);

[0149] (vii) Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS);

[0150] (viii) tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS);

[0151] (ix) systemic juvenile idiopathic arthritis;

[0152] (x) Adult-onset Still's disease (AOSD);

[0153] (xi) relapsing polychondritis;

[0154] (xii) Schnitzler syndrome;

[0155] (xiii) Sweet's syndrome;

[0156] (xiv) Behcet's disease;

[0157] (xv) antisynthetase syndrome;

[0158] (xvi) deficiency of interleukin-1 receptor antagonist (DIRA); and

[0159] (xvii) A20 haploinsufficiency (HA20).

[0160] Typically, the treatment and prevention of diseases, disorders and conditions comprises administering to a subject a compound of the fourth aspect of the invention, or a pharmaceutical composition of the fifth aspect of the invention.

[0161] Any of the pharmaceutical compositions used in the present invention may be administered by oral, parenteral (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural), airway (aerosol), rectal, vaginal, ocular, or topical (including transdermal, buccal, mucosal, sublingual and topical ocular) administration.

[0162] Generally, the mode of administration is chosen to be that which is most appropriate for the condition, disease or disorder to be treated or prevented.

[0163] The dosage of the compound of the fourth aspect of the present invention certainly varies with the condition, disease or illness to be treated or prevented. Generally speaking, suitable dosage is in the range of 0.01 to 500 mg per kg of recipient body weight per day. The desired dose can be provided at appropriate intervals, such as once every other day, once a day, twice a day, three times a day or four times a day. The desired dose can be administered in unit dosage form, for example, each unit dosage form contains 1 mg to 50 g of active ingredient.

[0164] The seventh aspect of the present invention provides a method for inhibiting NLRP3, the method comprising using the compound of the fourth aspect of the present invention or the pharmaceutical composition of the fifth aspect of the present invention to inhibit NLRP3.

[0165] For the avoidance of doubt, any embodiment of a given aspect of the present invention may be combined with any other embodiment of the same aspect of the present invention, as long as it is practicable. In addition, it should be understood that any preferred, typical or optional embodiment of any aspect of the present invention should also be regarded as a preferred, typical or optional embodiment of any other aspect of the present invention, as long as it is practicable. Example

[0166] All solvents, reagents, and compounds were purchased and used without further purification unless otherwise stated.

[0167] abbreviation

[0168] DCM Dichloromethane

[0169] DMF N,N-Dimethylformamide

[0170] DMSO Dimethyl sulfoxide

[0171] eq equivalent

[0172] HMPA Hexamethylphosphoramide

[0173] iPr Isopropyl

[0174] MTBE Methyl tert-butyl ether

[0175] Pd / C Palladium on Carbon

[0176] 10% Pd / C 10% Pd w / w adsorbed on carbon

[0177] 5%Pd / C 5%Pd w / w adsorbed on carbon

[0178] prep-HPLC Preparative High Performance Liquid Chromatography

[0179] THF Tetrahydrofuran

[0180] vol volume

[0181] Experimental methods

[0182] NMR Method:

[0183] NMR spectra were run at 293-298 K using VNMRJ on one of the following spectrometers: Agilent 500 MHz, 400 MHz, or 300 MHz spectrometer, Bruker BioSpin AG 400 MHz spectrometer, Bruker 500 MHz spectrometer, or Varian 400 MHz spectrometer.

[0184] LC-MS method:

[0185] Reaction Scheme 1 (steps ac) and Reaction Scheme 2 (steps i-iv (Method A)): A Waters-Acquity UPLC system with a PDA detector and a SQD mass detector was used.

[0186] Reaction Scheme 1 (step de) and Reaction Scheme 3: Agilent 1260 Infinity II (liquid chromatography) 6125B MSD Single Quadrupol (mass spectrometry) with API electrospray source was used.

[0187] Reaction Scheme 2 (Steps i-iv (Methods B and C)): UPLC-Waters, Quatropremier XE-Waters was used. Mobile phase A: 0.1% formic acid in water. Mobile phase B: 0.1% formic acid in acetonitrile.

[0188] HPLC Method:

[0189] Reaction Scheme 1 (steps ac) and Reaction Scheme 2 (steps i-iv (Method A)): Reverse phase chromatography was performed using a Waters Alliance HPLC system with a PDA detector.

[0190] Reaction Scheme 1 (step de) and Reaction Scheme 3: Agilent 1260 Infinity II was used.

[0191] Reaction Scheme 2 (Steps i-iv (Methods B and C)): Reverse phase chromatography was performed using a Waters e-2695 series with a 2998 PDA detector. Mobile phase A: 0.01 M ammonium acetate in water; Mobile phase B: acetonitrile; Column: X-Bridge C18 (150 mm×4.6 mm, 3.5 microns).

[0192] Synthesis Example

[0193] 1-Isopropyl-3-(methoxycarbonylaminosulfonyl)-1H-pyrazole (6)

[0194] 1-Isopropyl-3-(methoxycarbonylaminosulfonyl)-1H-pyrazole (6) is prepared according to the reaction sequence illustrated in Reaction Scheme 1.

[0195]

[0196] Reaction Scheme 1

[0197] Reaction Scheme 1-Step a

[0198]

[0199] A 1.0 kiloliter clean and dry reactor was charged with acetonitrile (155 L) and 3-nitro-1H-pyrazole (1) (15.50 Kg) at 25°C-30°C. Potassium carbonate (37.88 Kg) and 2-iodo-propane (24.46 Kg) were added to the reaction mixture at 25°C-30°C. The temperature was then raised to 40°C-45°C and maintained at 40°C-45°C for 24 hours. 2-iodo-propane (2.33 Kg) was then further added to the reaction mixture at 40°C-45°C and the reaction mixture was maintained at 40°C-45°C for 96 hours. 2-iodo-propane (3.49 Kg) and potassium carbonate (3.78 Kg) were then further added to the reaction mixture at 40°C-45°C. The temperature was then raised to 60°C-65°C and maintained at 60°C-65°C for 16 hours.

[0200] The absence of 3-nitro-1H-pyrazole (1) was confirmed by HPLC (limit: NMT 1.0%). If the reaction mixture did not meet the HPLC limit for a given run, it was maintained at 60-65°C with stirring until the desired HPLC purity was obtained.

[0201] After the reaction is completed, 80%-90% solvent is distilled out under vacuum at less than 45°C. A mixture of acetonitrile (31L) and MTBE (124L) (2:8) is loaded into the reaction mixture and the reaction mixture is stirred at 25°C-30°C for 30 minutes. The resulting salt is filtered and washed with a mixture of acetonitrile (15.5L) and MTBE (62L) (2:8) at 25°C-30°C. The filtrate is completely distilled out at 45°C. The resulting crude product is co-distilled with MTBE (15.5L) at 45°C and allowed to stand for 12 hours to provide solid crystals. Heptane (124L) is loaded into the crystal and stirred for 1-2 hours at 25°C-30°C. The reaction mixture is filtered, washed with heptane (31L) at 25°C-30°C, and dried in an oven at 25°C-30°C for 4-5 hours to obtain the product.

[0202] Final product: 1-isopropyl-3-nitro-1H-pyrazole (2)

[0203] Off-white solid

[0204] Yield: 14.5Kg

[0205] Yield: 68.2%

[0206] Melting point: 45℃-48℃

[0207] 1H NMR (DMSO-d6; 400 MHz): 1.45 (d, 6H), 4.65 (septet, 1H), 7.06 (s, 1H), and 8.12 (s, 1H).

[0208] MS: (M+H + )=156.10

[0209] Water content (by Karl Fischer titration): ≤1.0%

[0210] HPLC purity: 98.61%

[0211] HPLC [X-bridge C18 column, 4.6×150 mm, 3.5 μm, mobile phase A=10 mM ammonium bicarbonate in water, mobile phase B=acetonitrile, gradient program (time / %B)=0 / 10, 7 / 90, 15 / 90, 15.01 / 10; flow rate 1 mL / min, temperature=25°C): R t =6.11 minutes]

[0212] Reaction Scheme 1-Step b

[0213]

[0214] A 0.5 kL clean and dry pressure reactor was charged with 1-isopropyl-3-nitro-1H-pyrazole (2) (14.5 Kg) at 25°C-30°C. Methanol (130.5 L) was charged at 25°C-30°C under nitrogen atmosphere. The reaction mixture was stirred at 25°C-30°C for 30 minutes. Then 5% Pd / C (4.35 Kg) (50% wet) suspended in methanol (14.5 L) was charged at 25°C-30°C under nitrogen. The reaction mixture was degassed under vacuum and filled with argon atmosphere (50 Psi) three times. The reaction mixture was degassed under vacuum and filled with hydrogen atmosphere (50 Psi) three times. Then the reaction mixture was stirred at room temperature under hydrogen pressure (100 Psi) for 14 hours. The temperature was gradually raised to 55°C.

[0215] The absence of 1-isopropyl-3-nitro-1H-pyrazole (2) was confirmed by HPLC (limit: NMT 1.0%). If the reaction mixture did not meet the HPLC limit for a given run, it was maintained at room temperature with stirring until the desired HPLC purity was obtained.

[0216] After the reaction is complete, the reaction mixture is cooled to 25°C-30°C. The reaction mixture is degassed under vacuum and filled with nitrogen atmosphere three times. The reaction mixture is filtered through a candy nutch filter, then through a microfilter, and the bed is washed with methanol (29.0 L). 90%-95% of the solvent is distilled off under vacuum at less than 40°C-45°C and the resulting compound is co-distilled with acetonitrile at less than 40°C-45°C to provide the product.

[0217] Final product: 1-isopropyl-3-amino-1H-pyrazole (3)

[0218] Green black liquid

[0219] Yield: 11.5Kg

[0220] Yield: 98.54%

[0221] 1H NMR (DMSO-d6; 400 MHz): 1.35 (d, 6H), 4.18 (septet, 1H), 4.45 (br s, 2H), 5.37 (s, 1H), and 7.28 (s, 1H).

[0222] MS:(M+H + )=126.17

[0223] HPLC purity: 98.61%

[0224] HPLC [X-bridge C18 column, 4.6×150 mm, 3.5 μm, mobile phase A=10 mM ammonium bicarbonate in water, mobile phase B=acetonitrile, gradient program (time / %B)=0 / 10, 7 / 90, 15 / 90, 15.01 / 10; flow rate 1 mL / min, temperature=25°C): R t =3.84 minutes]

[0225] Reaction Scheme 1-Step c

[0226]

[0227] A 1.0 kL clean reactor was charged with 1-isopropyl-3-amino-1H-pyrazole (3) (12.20 Kg) at 25°C-30°C. Water (122 L) and acetonitrile (61 L) were charged at 25°C-30°C and the reaction mixture was stirred for 10 minutes. The reaction mixture was then cooled to -5°C to 0°C. The sulfuric acid solution was added at -5°C to 0°C. *1 Slowly add to the reaction mixture. The resulting reaction mixture is maintained at -5°C to 0°C for 30 minutes. Then, add sodium nitrite solution at -5°C to 0°C. *2 Slowly add to the reaction mixture. Maintain the resulting reaction mixture at -5°C to 0°C for 30 to 35 minutes to form a diazo solution.

[0228] A 1.0 kiloliter clean reactor was charged with potassium iodide (48.61 Kg) and water (122 L) at 25°C-30°C. The reaction mixture was cooled to -5°C to 0°C. The diazo solution obtained earlier was slowly added to the pre-cooled potassium iodide solution at -5°C to 0°C. The resulting reaction mixture was maintained at -5°C to 0°C for 30 minutes.

[0229] The absence of 1-isopropyl-3-amino-1H-pyrazole (3) was confirmed by HPLC (limit: NMT 1.0%). If the reaction mixture did not meet the HPLC limit for a given run, it was maintained at room temperature with stirring until the desired HPLC purity was obtained.

[0230] After the reaction was completed, solid sodium thiosulfate (6.0 Kg) was charged into the reaction mixture at -5°C to 0°C. Then, 1.25 N sodium hydroxide solution was used at 10°C to 15°C. *3 The pH of the reaction mixture was adjusted to 6-7. MTBE (122 L) was charged to the reaction mixture at 25-30°C and the reaction mixture was stirred at 25-30°C for 30 minutes. The layers were separated and the organic layer was set aside. MTBE (61 L) was charged to the aqueous layer at 25-30°C. The reaction mixture was stirred at 25-30°C for 30 minutes and allowed to settle at 25-30°C for 30 minutes. The layers were separated. Sodium thiosulfate solution*4 The first portion of 20% ethanol was added to the combined organic layers at 25°C-30°C and the reaction mixture was stirred at 25°C-30°C for 30 minutes. The layers were separated. Then the sodium thiosulfate solution was added at 25°C-30°C. *4 The second portion of 20% HCl was charged to the organic layer and the reaction mixture was stirred at 25°C-30°C for 30 minutes. The layers were separated. The saline solution was charged to the organic layer at 25°C-30°C and the reaction mixture was stirred at 25°C-30°C for 30 minutes. The layers were separated. The organic layer was dried over anhydrous Na2SO4 and the solvent was completely distilled under vacuum at less than 40°C-45°C. The obtained crude product was purified by high vacuum distillation in a clean and dry 20L 4-neck round bottom flask at 25°C-30°C, the flask being equipped with a Vigreux column, a T-bend, a condenser, a cow joint and three receiver single-neck round bottom flasks. A vacuum was applied at 720 to 740 mmHg and the bath temperature was raised to 85°C-90°C. The first portion was collected at a vapor temperature of 24°C-90°C. The bath temperature was then raised to 90°C-122°C. The second portion (1-isopropyl-3-iodo-1H-pyrazole (4); 12.03 Kg; HPLC purity 99.28%) was collected at a vapor temperature of 95°C-102°C. The third portion (1-isopropyl-3-iodo-1H-pyrazole (4); 6.0 Kg; HPLC purity 95%) was collected at a vapor temperature of 95°C-104°C. The third portion (6.0 Kg) was redistilled and the pure portion (1-isopropyl-3-iodo-1H-pyrazole (4); 5.3 Kg; HPLC purity 99.28%) was collected at a vapor temperature of 95°C-102°C.

[0231] *1: To prepare sulfuric acid solution, sulfuric acid (10.45 Kg) was slowly added to water (61 L) at 10°C-15°C.

[0232] *2: To prepare sodium nitrite solution, solid sodium nitrite (7.27 Kg) was slowly added to water (61 L) at 25°C-30°C (endothermic reaction).

[0233] *3: To prepare sodium hydroxide solution, sodium hydroxide (6.1 Kg) was slowly added to water (122 L) at 25°C-30°C.

[0234] *4: To prepare a sodium thiosulfate solution, sodium thiosulfate (6 Kg) was slowly added to water (122 L) at 25°C-30°C and the prepared solution was divided into two parts.

[0235] Final product: 1-isopropyl-3-iodo-1H-pyrazole (4)

[0236] Light yellow liquid

[0237] Output: 12.03Kg (batch 1) + 5.3Kg (batch 2) = 17.33Kg

[0238] Total yield (combination of batch 1 and batch 2): 75.34%

[0239] 1H NMR (CDCl 3 ; 500 MHz): 1.50 (d, 6H), 4.51 (septet, 1H), 6.39 (s, 1H), and 7.25 (s, 1H).

[0240] MS: (M+H + )=236.06

[0241] HPLC purity: 99.28%

[0242] HPLC [X-bridge C18 column, 4.6×150 mm, 3.5 μm, mobile phase A=10 mM ammonium bicarbonate in water, mobile phase B=acetonitrile, gradient program (time / %B)=0 / 10, 7 / 90, 15 / 90, 15.01 / 10; flow rate 1 mL / min, temperature=25°C): R t =6.98 minutes]

[0243] Reaction Scheme 1-Step d

[0244]

[0245] 1-Isopropyl-3-iodo-1H-pyrazole (4) (250.0 g, 1 eq) was placed in 2-MeTHF (6.75 vol, 1688 mL) and n-heptane (3 vol, 750 mL) and cooled to 10° C. A solution of iPrMgCl (1.1 eq, 2M in THF, 598 g) was added slowly over 35 minutes. After 60 minutes at 10° C., an IPC (in-process control) was drawn and the conversion was monitored by HPLC (100% conversion).

[0246] The reactor was evacuated slightly (700-800 mbar) and SO2 gas was added above the surface (exothermic). After 79 minutes of adding SO2 (77 g, 1.14 eq), the reaction turned yellow and the addition of SO2 gas was stopped. The reaction was rendered inert and IPC showed 99.32% conversion (measured by HPLC).

[0247] Water (5 vol, 1250 mL) was slowly added at 10 ° C and the reaction mixture was warmed to 20 ° C. The layers were separated and the colorless organic layer was stripped with water (2 vol, 500 mL). The aqueous layers were combined and trisodium citrate (1.75 eq, 545 g) was added. The reaction mixture was cooled to 10 ° C. Hydroxylamine-O-sulfonic acid (1.5 eq, 180 g) was dissolved in water (1 vol, 250 mL) and the solution was slowly added to the reaction mixture over 31 minutes (exothermic). The reaction mixture was warmed to 20 ° C and stirred for 40 minutes. IPC showed 98.87% conversion (measured by HPLC).

[0248] 2-MeTHF (7.5 vol, 1880 mL) was added and the layers were separated. The aqueous layer was stripped with 2-MeTHF (4 vol, 1000 mL). The combined organic layer was filtered through Na2SO4 (3 weight equivalents, 750 g) and the filter cake was washed with 2-MeTHF (4 vol, 1000 mL). The combined filtrate was concentrated in vacuo to 3.5 residual volumes (875 mL) and cooled to room temperature. When no crystallization occurred, a sample (1 mL) of the concentrate was diluted with n-heptane (1 mL). After the sample crystallized, the sample was added back to the reaction mixture. Stirring was continued at 20 ° C for 30 minutes, and then the suspension was warmed to 30 ° C. At 30 ° C, n-heptane (6 vol, 1500 mL) was slowly added over 80 minutes, and the reaction mixture was stirred at 30 ° C for another 60 minutes. The suspension was cooled to 20 ° C over 60 minutes and kept at 20 ° C overnight. The suspension was then filtered and rinsed with the mother liquor, followed by 2-MeTHF / n-heptane (1:2, 3 vol, 750 mL) and n-heptane (2 vol, 500 mL). The filter cake was dried under vacuum to obtain the product.

[0249] Final product: 1-isopropyl-1H-pyrazole-3-sulfonamide (5)

[0250] Brown yellow solid

[0251] Yield: 186.6g

[0252] Yield: 93.1%

[0253] 1H NMR (DMSO-d6; 400 MHz): 7.92 (d, J = 2.28 Hz, 1H), 7.39 (s, 2H), 6.57 (d, J = 2.28 Hz, 1H), 4.57 (septet, J = 6.67 Hz, 1H), and 1.43 (d, J = 6.59 Hz, 6H).

[0254] Dry matter content: 99.24% w / w

[0255] HPLC purity: 99.71%

[0256] Reaction Scheme 1-Step e

[0257]

[0258] 1-Isopropyl-1H-pyrazole-3-sulfonamide (5) (1 eq, 10.0 g) was suspended in dimethyl carbonate (6 vol, 60 mL) and a solution of NaOMe in methanol (30%, 1.75 eq, 16.66 g) was added. The reaction mixture was heated to 65°C overnight and then reduced by 2 volumes (20 mL) of solvent under vacuum at 45°C. The reaction mixture was cooled to room temperature and water (3.25 vol, 32.5 mL) was slowly added. The reaction mixture was further concentrated by 2 volumes (20 mL) of solvent under vacuum at 45°C. n-Heptane (5 vol, 50 mL) was added at 20°C and then 32% aqueous hydrochloric acid (1.9 eq, 11.7 g) was slowly added over 37 minutes. The suspension was stirred at 20°C for 20 minutes and then further diluted with n-heptane (2 vol, 20 mL) and stirred for another 20 minutes. The resulting suspension was filtered, rinsed with the mother liquor, and then washed with water (5 vol, 50 mL), n-heptane (5 vol, 50 mL), a mixture of 2-MeTHF / n-heptane (1:2, 4.5 vol, 45 mL) and n-heptane (2 vol, 20 mL). The filter cake was dried under vacuum to obtain the product.

[0259] Final product: 1-isopropyl-3-(methoxycarbonylaminosulfonyl)-1H-pyrazole (6)

[0260] White solid

[0261] Yield: 12.0g

[0262] Yield: 91.9%

[0263] 1H NMR (DMSO-d6; 400 MHz): 12.09 (br s, 1H), 8.01 (d, J=2.28 Hz, 1H), 6.76 (d, J=2.28 Hz, 1H), 4.61 (septet, J=6.67 Hz, 1H), 3.59 (s, 3H), and 1.43 (d, J=6.59 Hz, 6H).

[0264] Dry matter content: 99.12% w / w

[0265] HPLC purity: 99.69%

[0266] 1,2,3,5,6,7-Hexahydro-s-dicyclopentadienylbenzo-4-amine (16)

[0267] 1,2,3,5,6,7-Hexahydro-s-dicyclopentaphen-4-amine (16) was prepared according to the reaction sequence illustrated in Reaction Scheme 2.

[0268]

[0269] Reaction Scheme 2

[0270] Reaction Scheme 2-Step i (Method A)

[0271]

[0272] DCM (440 L) and AlCl3 (57.08 Kg) were charged into a 500 L clean and dry glass lined reactor at 25°C-30°C under nitrogen atmosphere. A solution of 3-chloropropionyl chloride (51.99 Kg) in DCM (44 L) was slowly added at -10°C to -5°C under nitrogen atmosphere. The reaction mixture was maintained at -10°C under nitrogen atmosphere for 30 minutes. Then a solution of indane (11) (44.00 Kg) in DCM (44 L) was slowly added to the reaction mixture at -10°C to -5°C and the reaction mixture was maintained at 10°C-15°C for 16 hours. The absence of indane (11) was confirmed by HPLC (limit: ≤5.0%).

[0273] After the reaction was complete, the reaction mixture was slowly added to a 3N hydrochloric acid solution (prepared from water (330 L) and concentrated hydrochloric acid (110 L)) at 0°C-10°C. The reaction mixture was stirred at 25°C-30°C for 30 minutes and allowed to settle at 25°C-30°C for 30 minutes. The layers were separated and the organic layer (OL-1) was set aside. DCM (220 L) was charged into the aqueous layer at 25°C-30°C. The reaction mixture was stirred at 25°C-30°C for 30 minutes and allowed to settle at 25°C-30°C for 30 minutes. The layers (aqueous layer and organic layer (OL-2) were separated. 10% saturated sodium bicarbonate solution (prepared from water (880 L) and sodium bicarbonate (88.00 Kg)) was charged to the combined organic layers (OL-1 and OL-2) at 25-30°C. The reaction mixture was stirred at 25-30°C for 30 minutes and allowed to settle at 25-30°C for 30 minutes. The layers were separated. Brine solution (prepared from water (220 L) and sodium chloride (84.48 Kg)) was charged to the organic layer at 25-30°C. The reaction mixture was stirred at 25-30°C for 30 minutes. The reaction mixture was stirred for 30 minutes at 25°C-30°C. The layers were separated. The organic layer was dried over anhydrous Na2SO4. The solvent was distilled under vacuum at 35°C-40°C until 5% was maintained. N-hexane (88 L) was added to the reaction mixture and the solvent was completely distilled at 35°C-40°C until no condensate droplets were formed. N-hexane (88 L) was added to the reaction mixture and the reaction mixture was cooled to 5°C-10°C and maintained at 5°C-10°C for 30 minutes. The solid product was filtered, washed with cooled hexane (44 L), and dried in a 40°C-45°C hot oven for 6 hours to obtain the product.

[0274] Final product: 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (12)

[0275] Off-white solid

[0276] Yield: 50.8Kg

[0277] Yield: 65.59%

[0278] 1H NMR (CDCl3; 500MHz): 7.81 (s, 1H), 7.75 (d, J = 8.0Hz, 1H), 7.31 (d, J = 8.0Hz, 1H), 3.93 (t,J=7.0Hz,2H), 3.45 (t,J=7.0Hz,2H), 2.97, (t,J=7.50Hz,4H), and 2.15-2.09 (m,2H).

[0279] Water content (by Karl Fischer titration): ≤0.5%

[0280] HPLC purity: 99.57%

[0281] Reaction Scheme 2 - Steps ii and iii (Method A)

[0282]

[0283] Sulfuric acid (255.0 L) was charged into a 500 L clean and dry glass lined reactor at 25°C-30°C. 3-Chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (12) (51.00 Kg) was then charged in batches at 25°C-30°C. The reaction mixture was maintained at 25°C-30°C for 30 minutes. The reaction mixture was then slowly heated to 55°C-60°C and maintained at 55°C-60°C for 48 hours. The absence of 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (12) was confirmed by HPLC (limit: ≤1.0%).

[0284] The reaction mixture was then cooled to 0°C-5°C. The nitration reaction mixture was slowly added at 0°C-5°C. *5 And the reaction mixture was maintained at 0° C.-5° C. for 1 hour. The absence of 1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-1-one (13) was confirmed by HPLC (limit: ≤1.0%).

[0285] After the reaction is complete, the reaction mixture is slowly added to water (1275 L) at 0 ° C -10 ° C. The solid crude product is filtered, dissolved in water (510 L) and stirred at 25 ° C -30 ° C for 30 minutes. The solid crude product is filtered, washed with water (255 L), dissolved in methanol (102 L), cooled to 0 ° C -5 ° C, and maintained at 0 ° C -5 ° C for 30 minutes. The solid crude product is filtered, washed with cold methanol (51 L), and dried in a 40 ° C -45 ° C hot oven for 6 hours. The water content of the solid crude product is confirmed to be ≤0.5% by Karl Fischer titration.

[0286] The solid crude product (42.5 Kg) and DCM (510 L) were charged into a 1.0 kiloliter clean and dry reactor at 25°C-30°C. Water (408 L) was slowly added at 25°C-30°C and stirred for 30 minutes. The crude product was filtered through Bed (by (12.75 Kg) and DCM (51 L) were prepared) and the bed was washed with DCM (51 L). The layers were separated. A brine solution (prepared from water (255 L) and sodium chloride (51.0 Kg)) was charged into the organic layer at 25°C-30°C. The reaction mixture was stirred at 25°C-30°C for 30 minutes and allowed to settle at 25°C-30°C for 30 minutes. The layers were separated. The organic layer was dried over anhydrous Na2SO4 (51.0 Kg). The solvent was distilled under vacuum at less than 35°C-40°C until 5% was retained. Methanol (51 L) was charged into the reaction mixture at 35°C-40°C and distilled at 40°C-45°C. Methanol (102 L) was charged into the reaction mixture at 35°C-40°C, cooled to 0°C-5°C and maintained for 30 minutes. The solid product was filtered, washed with cooled methanol (25.5 L), and dried in a hot oven at 40-45 °C for 6 hours to give the product.

[0287] *5: To prepare the nitration reaction mixture, sulfuric acid (16.83 L) was charged into a 160 L clean and dry glass-lined reactor at 25°C-30°C. The reaction mixture was cooled to 0°C-5°C. Nitric acid (16.83 L) was slowly added at 0°C-5°C and the reaction mixture was maintained at 0°C-5°C for 30 minutes to obtain the nitration reaction mixture.

[0288] Final products: 8-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone (14) and 4-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone (15)

[0289] Light brown solid

[0290] The weight ratio of 14:15 is 9.6:1.

[0291] Combined output (14+15): 31.40Kg

[0292] Combined yield (14+15): 59.2%

[0293] 1H NMR (CDCl3; 400MHz): 7.45 (s, 1H), 3.13-3.06 (m, 2H), 3.08-2.97 (m, 4H), 2.82-2.76 (m, 2H), and 2.25-2.16 (m, 2H).

[0294] Water content (by Karl Fischer titration): ≤0.5%

[0295] HPLC purity: 91.61%

[0296] Reaction Scheme 2-Step iv (Method A)

[0297]

[0298] A mixture of 8-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone (14) and 4-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone (15) (17.00 Kg) was charged into a 600 L clean and dry pressure reactor at 25°C-30°C. Methanol (170 L) was charged at 25°C-30°C. THF (85 L) was charged at 25°C-30°C. Methanesulfonic acid (8.272 Kg) was slowly charged at 25°C-30°C. 20% Pd(OH)2 solution was charged. *6 The reaction mixture was maintained for 30 minutes. The reaction mixture was degassed under vacuum and filled with an argon atmosphere (50 Psi) three times. The reaction mixture was degassed under vacuum and filled with a hydrogen atmosphere (50 Psi) three times. The reaction mixture was then stirred at room temperature for 24 hours under a hydrogen pressure (100 Psi). The temperature gradually rose to 55° C. The absence of 8-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone (14) and 4-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone (15) was confirmed by HPLC (limit: ≤1.0%).

[0299] After the reaction was completed, the reaction mixture was cooled to 25°C-30°C. The reaction mixture was filtered through a candy nutch filter, followed by a microfilter, and the bed was washed with methanol (34 L). 95% of the solvent was distilled off under vacuum at less than 45°C-50°C. Water (85 L) was charged to the reaction mixture at 25°C-30°C and maintained for 30 minutes. The reaction mixture was cooled to 5°C-10°C. The pH was adjusted to about 9-10 with a 2N NaOH aqueous solution (prepared from NaOH (4.08 Kg) and water (51 L)) and the reaction mixture was stirred for 30 minutes. DCM (85 L) was then charged to the reaction mixture and the reaction mixture was stirred for 30 minutes. The reaction mixture was stirred for another 30 minutes while the temperature reached 25°C-30°C. The reaction mixture was allowed to settle for 30 minutes while the temperature was maintained at 25°C-30°C. The layers were separated and the organic layer (OL-1) was set aside. DCM (34 L) was charged to the aqueous layer at 25°C-30°C. The reaction mixture was stirred at 25°C-30°C for 30 minutes and allowed to settle at 25°C-30°C for 30 minutes. The layers were separated into an aqueous layer and an organic layer (OL-2). A saline solution (prepared with water (85 L) and sodium chloride (34.0 Kg)) was charged to the combined organic layers (OL-1 and OL-2) at 25°C-30°C. The reaction mixture was stirred at 25°C-30°C for 30 minutes and allowed to settle at 25°C-30°C for 30 minutes. The layers were separated. The organic layer was dried over anhydrous Na2SO4. The solvent was distilled under vacuum at less than 35°C-40°C until 5% was maintained. Methanol (25.5 L) was charged to the reaction mixture at 35°C-40°C and distilled until 5% was maintained. Methanol (61.2 L) and water (6.8 L) were charged to the reaction mixture at 35°C-40°C. The reaction mixture was heated to 50-55° C., stirred at 50-55° C. for 1 hour, slowly cooled to 0-5° C. and maintained at 0-5° C. for 30 minutes. The solid product was filtered and washed with cold methanol (17 L).

[0300] *6: To prepare 20% Pd(OH)2 solution, 20% Pd(OH)2 (3.4 Kg) was added to methanol (17 L).

[0301] Product: 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-amine (16)

[0302] Off-white solid

[0303] Output: 13.90Kg (two batches)

[0304] Yield: 51.2%

[0305] 1H NMR (DMSO-d6; 300MHz): 6.33 (s, 1H), 4.50 (br s, 2H, NH2), 2.70 (t, 4H), 2.57 (t, 4H), and 2.00-1.90 (m, 4H).

[0306] Water content (by Karl Fischer titration): 0.173%

[0307] HPLC purity: 95.43%

[0308] Purification of 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone-4-amine (16) (Method A)

[0309] 1,2,3,5,6,7-Hexahydro-s-dicyclopentadienylbenzophen-4-amine (16) (34 Kg) was charged into a 250 L clean and dry reactor at 25-30°C. Toluene (13.9 L) was charged at 25-30°C and the reaction mixture was stirred at 25-30°C for 30 minutes. Methanol (41.7 L) was charged into the reaction mixture at 25-30°C. The reaction mixture was stirred at 25-30°C for 30 minutes, cooled to -5 to 0°C, and stirred at -5 to 0°C for 30 minutes. The solid product was filtered, washed with cold methanol (13.9 L) and dried at 40-45°C for 6 hours.

[0310] Final product: 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-amine (16)

[0311] Light brown solid

[0312] Yield: 11.40Kg

[0313] Yield: 42.2%

[0314] 1H NMR (DMSO-d6; 300MHz): 6.33 (s, 1H), 4.50 (br s, 2H, NH2), 2.70 (t, 4H), 2.57 (t, 4H), and 2.00-1.90 (m, 4H).

[0315] Water content (by Karl Fischer titration): ≤0.5%

[0316] HPLC purity: 98.43%

[0317] Reaction Scheme 2-Step i (Method B)

[0318]

[0319] At 25 ℃-30 ℃, AlCl3 (1.3eq, 366.7g) and DCM (2.5vol, 625mL) were loaded into a round-bottom flask. The reaction mixture was cooled to -10 ℃ to -8 ℃. 3-Chloropropionyl chloride (1.1eq, 222mL, 140.5g) in DCM (2.5vol, 625mL) was slowly added at -10 ℃ to -8 ℃. The reaction mixture was maintained at -10 ℃ to -8 ℃ for 30 minutes. Indane (11) (1eq, 250g) in DCM (2.5vol, 625mL) was slowly added dropwise at -10 ℃ to -8 ℃. The reaction mixture was then heated to 25 ℃-30 ℃ and maintained at 25 ℃-30 ℃ for 12 hours. The absence of indane (11) was confirmed by HPLC (limit: ≤2.0%).

[0320] After the reaction is completed, the reaction is quenched with 2N hydrochloric acid solution (10vol, 2500mL) at 0℃-5℃. The reaction mixture is heated to 25℃-30℃ and stirred for 15 minutes at 25℃-30℃. The organic layer is separated and the aqueous layer is extracted with DCM (2×5vol, 2×1250mL). The combined organic layer is washed with water (5vol, 1250mL) and dried over Na2SO4 (125g). The solvent is distilled under vacuum at less than 45℃ and co-distilled twice with n-heptane (2×5vol, 2×1250mL). n-heptane (2vol, 500mL) is loaded and the mixture is stirred for 1 hour. The solid product is filtered, washed with cold n-heptane (0.5vol, 125mL), blotted, and vacuum dried at 40℃-45℃.

[0321] Final product: 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (12)

[0322] Light yellow to brown solid

[0323] Yield: 360.0g

[0324] Yield: 82%

[0325] 1H NMR (DMSO-d6; 400MHz): 7.84(s,1H), 7.78(d,1H), 7.37(d,1H), 3.92(t,2H), 3.52(t,2H), 2.92(t,4H), and 2.05(m,2H).

[0326] Water content (by Karl Fischer titration): 0.16%

[0327] HPLC purity: 98%

[0328] Reaction Scheme 2 - Steps ii and iii (Method B)

[0329]

[0330] 3-Chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (12) (350 g) and concentrated sulfuric acid (5 vol, 3185 g) were charged into a round bottom flask at 25°C ± 5°C. The reaction mixture was heated to 70°C ± 2°C and stirred for 8-10 hours. The absence of 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (12) was confirmed by HPLC (limit: ≤ 2.0%).

[0331] The reaction mixture was cooled to 0-5°C. A nitration reaction mixture was prepared starting from concentrated sulfuric acid (0.33 vol, 210.2 g) and concentrated HNO3 (0.5 vol, 248.5 g) at 10-15°C. The nitration reaction mixture was added to the above reaction mixture over a period of 45-60 minutes at 0-5°C. The reaction mixture was maintained at 0-5°C for 2 hours. The absence of 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone (13) was confirmed by HPLC (limit: ≤ 2.0%).

[0332] After the reaction is complete, the reaction mixture is added to ice-cold water (25 vol, 8.75 L) and maintained at 15 ° C ± 10 ° C for 1 hour. The product is extracted into ethyl acetate (1 × 10 vol: 3.5 L, 2 × 5 vol: 1.75 L). The combined organic layer is washed with 10% NaHCO solution (10 vol, 3.5 L) at 25 ° C ± 5 ° C and dried over Na2SO4 (175 g). The solvent is distilled out under vacuum at less than 45 ° C (to 1 vol, 350 mL), followed by complete co-distillation with n-heptane (2 vol, 700 mL). N-heptane (2 vol, 700 mL) is added and the reaction mixture is stirred for 1 hour at 25 ° C ± 5 ° C. The solid product is filtered, washed with n-heptane (0.5 vol, 175 mL) and vacuum dried for 2 hours at 45 ° C-50 ° C. The crude product is dissolved in methanol (2.0 vol, 700 mL) at 55 ° C-60 ° C. Charcoal 5% was added and the reaction mixture was refluxed for 1 hour, then cooled to 45°C. The reaction mixture was filtered through a hyflow bed and washed twice with methanol (2 x (0.5 vol, 175 mL)). The filtrate was cooled to 0°C-5°C and maintained at 0°C-5°C for 2-3 hours. The solid product was filtered, washed with cold methanol (0.25 vol, 87.5 mL) and dried under vacuum at 45°C-50°C for 3 hours.

[0333] Final products: 8-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone (14) and 4-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone (15)

[0334] Brown solid

[0335] The weight ratio of 14:15 is 7:1.

[0336] Combined yield (14+15): 217g

[0337] Combined yield (14+15): 60%

[0338] 1H NMR (DMSO-d6; 400MHz): 7.66 (s, 1H), 3.08 (t, 2H), 2.98 (t, 2H), 2.88 (t, 2H), 2.72 (t, 2H) and 2.12 (m, 2H).

[0339] Water content (by Karl Fischer titration): 0.72%

[0340] HPLC purity: 96.44%

[0341] Reaction Scheme 2-Step iv (Method B)

[0342]

[0343] Methanol (10 vol, 250 mL) and concentrated sulfuric acid (1.25 eq, 14.1 g) were charged into an autoclave at 25°C-30°C. 8-Nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone (14) and 4-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone (15) (25 g) and 10% Pd / C (5 g) (50% wet) were charged into the reaction mixture at 25°C-30°C. The autoclave was purged with nitrogen, degassed, and then hydrogen was applied at an initial gas pressure of 2-3 Kg. After 1 hour, the hydrogen pressure was increased to 7-8 Kg and the pressure was maintained at 25°C-30°C for 12-14 hours. The absence of 8-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-1-one (14) and 4-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-1-one (15) was confirmed by HPLC (limit: ≤ 2.0%).

[0344] After the reaction was completed, the reaction mixture was filtered through a hyflow bed and washed twice with methanol (2×(0.5 vol, 12.5 mL)). The solvent was distilled under vacuum at less than 45° C. to give an oily mass. The reaction mixture was cooled to room temperature, water (10 vol, 250 mL) was added, and the reaction mixture was stirred for 30 minutes. The product was precipitated as a sulfate, which was filtered and washed thoroughly with water (5 vol, 125 mL). The wet cake and water (10 vol, 250 mL) were charged into a round bottom flask. The pH of the reaction mixture was adjusted to 10-12 with 2N NaOH solution (1.5 vol, 37.5 mL) and the reaction mixture was stirred at 25° C.-30° C. for 30-60 minutes. The precipitated solid was filtered, washed with water, blotted dry, and then dried under vacuum at 50° C.-55° C. The crude product was dissolved in methanol-water (90:10, 5 vol, 125 mL) at 55° C.-60° C. Charcoal (1.25 g) was added and the reaction mixture was stirred at 55-60° C. for 30-45 minutes. The reaction mixture was filtered through a hyflow bed at 45-50° C. and washed twice with methanol (2×(0.5 vol, 12.5 mL)). The filtrate was charged into another round bottom flask, cooled to 0-5° C. and maintained at 0-5° C. for 2-3 hours. The solid product was filtered, washed with cold methanol-water (90:10, 0.5 vol, 12.5 mL), sucked dry and dried under vacuum at 45-50° C. for 3-4 hours.

[0345] Final product: 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-amine (16)

[0346] Light brown solid

[0347] Yield: 8g

[0348] Yield: 45%

[0349] 1H NMR (DMSO-d6; 400MHz): 6.33 (s, 1H), 4.52 (s, 2H, NH2), 2.72 (m, 4H), 2.62 (m, 4H), and 1.96 (m, 4H).

[0350] Water content (by Karl Fischer titration): 0.55%

[0351] HPLC purity: 99.32%

[0352] Reaction Scheme 2-Step iv (Method C)

[0353]

[0354] 8-Nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone (14) and 4-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone (15) (25 g) and ethanol (10 vol, 250 mL) were charged into a round bottom flask at 25°C ± 5°C. Zn powder (10 eq, 75.25 g) was slowly added in batches over a period of 15 minutes at 25°C ± 5°C. The reaction mixture was cooled to 15-20°C. Aqueous sulfuric acid (25%, 10 vol, 250 mL) was slowly added over a period of 30-45 minutes while maintaining the reaction mixture temperature at 30°C-40°C. The reaction mixture was then stirred at 25°C-30°C for 3 hours. The absence of 8-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-1-one (14) and 4-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-1-one (15) was confirmed by HPLC (limit: ≤ 2.0%).

[0355] After the reaction is complete, the reaction mixture is filtered and washed with ethanol (2×5vol; 2×125mL). The solvent is concentrated in vacuo to 1-2 volumes (25-50mL) at 45°C-50°C. The reaction mixture is cooled to 20°C-30°C, water (10vol, 250mL) is added and the reaction mixture is stirred for 30-60 minutes. The product is precipitated in the form of sulfate, which is filtered and thoroughly washed with water (5vol, 125mL). The wet cake and water (10vol, 250mL) are loaded into a round-bottom flask. The pH of the reaction mixture is adjusted to 10-12 with 10% aqueous sodium carbonate solution (4vol, 100mL) and the reaction mixture is stirred at 25°C-30°C for 30-60 minutes. The precipitated solid is filtered, washed with water, sucked dry, and then vacuum dried at 50°C-55°C. The crude product is dissolved in methanol-water (90:10, 5vol, 125mL) at 60°C-65°C. Charcoal (1.25 g) was added and the reaction mixture was maintained at reflux for 30-45 minutes. The reaction mixture was then filtered through a hyflow bed at 45°C-50°C and washed with methanol-water (90:10, 0.5 vol, 12.5 mL). The filtrate was charged into another round bottom flask, cooled to 0°C-5°C and maintained at 0°C-5°C for 2-3 hours. The solid product was filtered, washed with cold methanol-water (90:10, 0.5 vol, 12.5 mL), sucked dry and dried under vacuum at 45°C-50°C for 3-4 hours.

[0356] Final product: 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-amine (16)

[0357] Light brown solid

[0358] Yield: 6.5g

[0359] Yield: 37%

[0360] 1H NMR (DMSO-d6; 400MHz): 6.33 (s, 1H), 4.52 (s, 2H, NH2), 2.72 (m, 4H), 2.62 (m, 4H), and 1.96 (m, 4H).

[0361] Water content (by Karl Fischer titration): 0.49%

[0362] HPLC purity: 98.29%

[0363] N-((1,2,3,5,6,7-Hexahydro-s-dicyclopentadienylbenzophenone-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (17)

[0364] N-((1,2,3,5,6,7-Hexahydro-s-dicyclopentaphen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (17) was prepared according to the reaction illustrated in Reaction Scheme 3.

[0365]

[0366] Reaction Scheme 3

[0367] 1-Isopropyl-3-(methoxycarbonylaminosulfonyl)-1H-pyrazole (6) (20.0 g, 1 eq) and 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzene-4-amine (16) (1.05 eq, 14.7 g) were suspended in dimethyl carbonate (5 vol, 100 mL) and heated to 50° C. One volume (20 mL) of solvent was distilled off in vacuo and the reaction mixture was further heated to 85° C. and stirred at 85° C. for 7 hours and 10 minutes. Another volume (20 mL) of solvent was distilled off at 85° C. and the reaction mixture was stirred at 85° C. for 19 hours. The temperature was further increased to 95° C. and stirring was continued for 5 hours, then the reaction was cooled to 30° C. IPC showed 99.3% conversion. 2-MeTHF (5 vol, 100 mL) was slowly added at 30° C. over 35 minutes. The suspension was cooled to 20°C over 30 minutes and maintained at 20°C for another 3.5 hours. The suspension was filtered, rinsed with the mother liquor, then with a mixture of 2-MeTHF / n-heptane (1:1, 4 vol, 80 mL) and with n-heptane (4 vol, 80 mL). The filter cake was dried under vacuum to obtain the product.

[0368] Final product: N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (17)

[0369] Off-white to brown solid

[0370] Yield: 26.80g

[0371] Yield: 85.3%

[0372] 1H NMR (DMSO-d6; 400 MHz): 10.83 (br s, 1H), 8.06 (s, 1H), 7.99 (d, J = 2.28 Hz, 1H), 6.94 (s, 1H), 6.75 (d, J = 2.28 Hz, 1H), 4.62 (septet, J = 6.67 Hz, 1H), 2.78 (t, J = 7.22 Hz, 4H), 2.57 (t, J = 7.22 Hz, 4H), 1.93 (quintet, J = 7.35 Hz, 4H), and 1.43 (d, J = 6.84 Hz, 6H).

[0373] HPLC purity: 99.02%

[0374] N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone-4-yl)carbamoyl)-1-isopropyl-1H-pyrrolidone Azole-3-sulfonamide salt

[0375] N-((1,2,3,5,6,7-Hexahydro-s-dicyclopentaphen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (17) was converted to the monosodium monohydrate salt.

[0376] N-((1,2,3,5,6,7-Hexahydro-s-dicyclopentadienacen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (17) (4.0 g, 1 eq) was suspended in acetone (5.5 vol, 22 mL). NaOMe (30%, 1 eq, 1.83 g) in methanol was added using a syringe (the syringe was rinsed with acetone (2 vol, 8 mL)). The turbid solution was filtered through a layer of charcoal, in-line filtered (0.45 μm) and the in-line filter was rinsed with acetone (3 vol, 16 mL). The clear brown solution was concentrated in vacuo to 5.1 residual volumes (20.4 mL) at 45°C. Water (0.4 vol, 1.62 g) was added and the suspension was heated to 45°C. MTBE (4 vol, 16 mL) was added slowly and the reaction mixture was seeded (0.5% w / w). After stirring for 30 minutes, more MTBE (6 vol, 24 mL) was slowly added over 1 hour. The suspension was stirred for a while, and then more MTBE (13 vol, 52 mL) was added. The suspension was cooled to room temperature and filtered, rinsed with mother liquor, then with a mixture of H2O / acetone / MTBE (1 / 9 / 50, 2 vol, 8 mL) and with MTBE (4 vol, 16 mL). The filter cake was dried in vacuo to obtain the product.

[0377] Final product: N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzo-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide monosodium monohydrate salt

[0378] Off-white solid

[0379] Yield: 4.01 g

[0380] Yield: 91%

[0381] 1H NMR (D2O; 400 MHz): 7.74 (d, J = 2.53 Hz, 1H), 7.07 (s, 1H), 6.68 (d, J = 2.53 Hz, 1H), 4.58 (septet, J = 6.76 Hz, 1H), 2.85 (t, J = 7.35 Hz, 4H), 2.67 (t, J = 7.35 Hz, 4H), 2.01 (quintet, J = 7.35 Hz, 4H), and 1.49 (d, J = 6.84 Hz, 6H).

[0382] Water content (by Karl Fischer titration): 5.2%

[0383] HPLC purity: 99.26%

[0384] It should be understood that the present invention has been described above only by way of example. The examples are not intended to limit the scope of the present invention. Various modifications and embodiments may be made without departing from the scope and spirit of the present invention, which is limited only by the following claims.

Claims

1. A method for preparing N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienolbenzo-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide or a salt thereof, the method comprising the steps of contacting 1-isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole with 1,2,3,5,6,7-hexahydro-s-dicyclopentadienolbenzo-4-amine in the presence of a solvent to obtain N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienolbenzo-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide: Where R is C 1-6 alkyl.

2. The method according to claim 1, wherein R is methyl.

3. The method of claim 1 or 2, wherein the solvent comprises dimethyl carbonate.

4. A method for preparing 1-isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole: Where R is C 1-6 Alkyl, the method comprising one or more steps selected from the following: (a) contacting 3-nitro-1H-pyrazole with iPr-X to obtain 1-isopropyl-3-nitro-1H-pyrazole, wherein X is a leaving group: (b) Reducing 1-isopropyl-3-nitro-1H-pyrazole to obtain 1-isopropyl-3-amino-1H-pyrazole: (c) Converting 1-isopropyl-3-amino-1H-pyrazole into 1-isopropyl-3-iodo-1H-pyrazole: (d) Converting 1-isopropyl-3-iodo-1H-pyrazole to 1-isopropyl-1H-pyrazole-3-sulfonamide: as well as (e) Converting 1-isopropyl-1H-pyrazole-3-sulfonamide into 1-isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole:

5. The method according to claim 1 or 2, wherein the 1-isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole is prepared by the method according to claim 4.

6. The method according to claim 1 or 2, wherein the 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone-4-amine is prepared by a method comprising one or more steps selected from the following: (i) contacting 2,3-dihydro-1H-indene with YCH2CH2COZ to obtain substituted 1-(2,3-dihydro-1H-inden-5-yl)propan-1-one, wherein Y and Z are leaving groups: (ii) contacting the substituted 1-(2,3-dihydro-1H-inden-5-yl)propan-1-one with an acid to obtain 1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-1-one: (iii) converting 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone to 4-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone and / or 8-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzophenone: as well as (iv) reducing 4-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienacene-1-one and / or 8-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienacene-1-one to obtain 1,2,3,5,6,7-hexahydro-s-dicyclopentadienacene-4-amine:

7. The method according to claim 1 or 2, wherein the N-((1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide or a salt thereof has an HPLC purity of 98% or more.

8. The method according to claim 1 or 2, wherein the N-((1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide or a salt thereof has an HPLC purity of 98.5% or more.

9. The method according to claim 1 or 2, wherein the N-((1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide or a salt thereof has an HPLC purity of 98.6% or more.

10. The method according to claim 1 or 2, wherein the N-((1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide or a salt thereof has an HPLC purity of 98.7% or more.

11. The method according to claim 1 or 2, wherein the N-((1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide or a salt thereof has an HPLC purity of 98.8% or more.

12. The method according to claim 1 or 2, wherein the N-((1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide or a salt thereof has an HPLC purity of 98.9% or more.

13. The method according to claim 1 or 2, wherein the N-((1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide or a salt thereof has an HPLC purity of 99% or more.

14. The method according to claim 1 or 2, wherein the N-((1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide or a salt thereof has an HPLC purity of 99.1% or more.

15. The method according to claim 1 or 2, wherein the N-((1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide or a salt thereof has an HPLC purity of 99.2% or more.

16. The method according to claim 1 or 2, wherein the N-((1,2,3,5,6,7-hexahydro-s-dicyclopentaphen-4-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonamide or a salt thereof has an HPLC purity of 99.3% or more.

17. A 1-isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole: Where R is C 1-6 alkyl.

18. 1-Isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole according to claim 17, wherein R is methyl.

19. 1-Isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole according to claim 17 or 18, which has an HPLC purity of 98% or more.

20. 1-Isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole according to claim 17 or 18, which has an HPLC purity of 98.5% or more.

21. 1-Isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole according to claim 17 or 18, which has an HPLC purity of 99% or more.

22. 1-Isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole according to claim 17 or 18, which has an HPLC purity of 99.5% or more.

23. 1-Isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole according to claim 17 or 18, which has an HPLC purity of 99.6% or more.

24. 1-Isopropyl-3-(alkoxycarbonylaminosulfonyl)-1H-pyrazole according to claim 17 or 18, which has an HPLC purity of 99.7% or more.

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