Methods for preparing NLRP3 inhibitors

Abstract

The present invention relates to intermediates and processes useful for preparing 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide and its salts.The present invention further relates to 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide and its salts when prepared by such processes, and related pharmaceutical compositions and uses for the treatment and prevention of medical disorders and diseases, particularly by NLRP3 inhibition.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to intermediates and processes useful for preparing 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide and its salts.The present invention further relates to 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide and its salts when prepared by such processes, and related pharmaceutical compositions and uses for the treatment and prevention of medical disorders and diseases, particularly by NLRP3 inhibition. [Background technology]

[0002] background 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide has been disclosed in WO 2019 / 008025 as an NLRP3 inhibitor (see Example 6). However, there is a need to provide improved methods for preparing 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide and its salts. In particular, there is a need to provide efficient methods that are suitable for large-scale synthesis, for example, avoid expensive chromatography or high-temperature techniques, avoid or minimize the use of expensive reagents, and / or avoid the production of harmful by-products. There is also a need to provide 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide and its salts in higher yields and / or higher purity, especially on a large scale, as compared to the prior art processes. The present invention solves the above problems. Summary of the Invention [Problem to be solved by the invention]

[0003] Summary of the Invention A first aspect of the present invention provides a method for preparing 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide or a salt thereof, comprising the step of contacting 1-ethyl-4-piperidinesulfonamide (A) with a 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) in the presence of a solvent to obtain 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-carbamoyl)piperidine-4-sulfonamide (C) or a salt thereof. [ka] (In the formula, X is a leaving group.)

[0004] In one embodiment of the first aspect of the invention, X is Cl, Br, I, OR 1 , S.R. 1 , N(R 1 )2, OP(=O)(R 1 )2 or OP(R 1 )3 + And each R 1 are independently C1-C 20 Each C-C 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, each C1-C 20 The hydrocarbyl groups may be substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20 The hydrocarbyl group may contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or any two R 1 may be taken together with the nitrogen or phosphorus atom to which they are attached to form a 3- to 16-membered heterocyclic group, which may be monocyclic, bicyclic or tricyclic, and which may further include one or more halo groups, and / or one or more groups R X and each R Xare independently selected from -CN, -OH, -NH2, oxo (=O), =NH or a C1-C6 hydrocarbyl group, each C1-C6 hydrocarbyl group may be linear or branched or may be or contain one or more cyclic groups, each C1-C6 hydrocarbyl group may be substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0005] In the context of this specification, a "hydrocarbyl" substituent or hydrocarbyl moiety in a substituent contains only carbon and hydrogen atoms, but does not contain heteroatoms such as N, O or S in its carbon skeleton, unless otherwise specified. A hydrocarbyl group / moiety may be saturated or unsaturated (including aromatic), straight chain or branched, or may be or contain cyclic groups, and unless otherwise specified, cyclic groups do not contain heteroatoms such as N, O or S in its carbon skeleton. Examples of hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and aryl groups / moieties, and all combinations of these groups / moieties. Typically, a hydrocarbyl group is a C1-C 20 More typically, the hydrocarbyl group is a C-C 15 More typically, the hydrocarbyl group is a C-C 10 A "hydrocarbylene" group is similarly defined as a divalent hydrocarbyl group.

[0006] An "alkyl" substituent or alkyl moiety in a substituent can be straight-chained (i.e., linear) or branched. Examples of alkyl groups / moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and n-pentyl groups / moieties. Unless otherwise specified, the term "alkyl" does not include "cycloalkyl". Typically, alkyl groups are C1-C 12 It is an alkyl group. More typically, the alkyl group is a C1-C6 alkyl group. An "alkylene" group is similarly defined as a divalent alkyl group.

[0007] An "alkenyl" substituent or moiety in a substituent refers to an unsaturated alkyl group or moiety having one or more carbon-carbon double bonds. Examples of alkenyl groups / moieties include ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and 1,4-hexadienyl groups / moieties. Unless otherwise specified, the term "alkenyl" does not include "cycloalkenyl". Typically, alkenyl groups are C2-C 12 An alkenyl group is more typically a C2-C6 alkenyl group. An "alkenylene" group is similarly defined as a divalent alkenyl group.

[0008] An "alkynyl" substituent or moiety in a substituent refers to an unsaturated alkyl group or moiety having one or more carbon-carbon triple bonds. Examples of alkynyl groups / moieties include ethynyl, propargyl, but-1-ynyl and but-2-ynyl groups / moieties. Typically, an alkynyl group is a C2-C 12 An alkynyl group. More typically, the alkynyl group is a C2-C6 alkynyl group. An "alkynylene" group is similarly defined as a divalent alkynyl group.

[0009] A "cyclic" substituent or cyclic moiety in a substituent refers to any hydrocarbyl ring, which may be saturated or unsaturated (including aromatic) and may contain one or more heteroatoms, such as N, O, or S, in its carbon backbone. Examples of cyclic groups include cycloalkyl, cycloalkenyl, heterocyclic, aryl, and heteroaryl groups, as discussed below. Cyclic groups may be monocyclic, bicyclic (e.g., bridged, fused, or spiro), or polycyclic. Typically, cyclic groups are 3-12 membered cyclic groups, meaning that they contain 3-12 ring atoms. More typically, cyclic groups are 3-7 membered monocyclic groups, meaning that they contain 3-7 ring atoms.

[0010] A "heterocyclic" substituent or heterocyclic moiety in a substituent refers to a cyclic group or moiety that contains in the ring structure one or more carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms, such as N, O, or S. Examples of heterocyclic groups include the heteroaryl groups described below, as well as non-aromatic heterocyclic groups, such as azetinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, dioxanyl, morpholinyl, and thiomorpholinyl groups.

[0011] A "cycloalkyl" substituent or cycloalkyl moiety in a substituent refers to a saturated hydrocarbyl ring containing, for example, 3 to 7 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specified, a cycloalkyl substituent or moiety can include monocyclic, bicyclic, or polycyclic hydrocarbyl rings.

[0012] A "cycloalkenyl" substituent or moiety in a substituent refers to a non-aromatic unsaturated hydrocarbyl ring having one or more carbon-carbon double bonds and containing, for example, 3 to 7 carbon atoms, examples of which include cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, and cyclohexa-1,3-dien-1-yl. Unless otherwise specified, a cycloalkenyl substituent or moiety can include monocyclic, bicyclic, or polycyclic hydrocarbyl rings.

[0013] An "aryl" substituent or aryl moiety in a substituent refers to an aromatic hydrocarbyl ring. The term "aryl" includes monocyclic aromatic hydrocarbons and polycyclic fused ring aromatic hydrocarbons in which all of the fused ring systems (excluding any ring systems that are part of or formed by any substituent) are aromatic. Examples of aryl groups / moieties include phenyl, naphthyl, anthracenyl, and phenanthrenyl. Unless otherwise specified, the term "aryl" does not include "heteroaryl".

[0014] A "heteroaryl" substituent or heteroaryl moiety in a substituent refers to an aromatic heterocyclic group or moiety. The term "heteroaryl" includes monocyclic aromatic heterocycles and polycyclic fused-ring aromatic heterocycles in which all of the fused ring systems (except for any ring systems that are part of or formed by any substituent) are aromatic. Examples of heteroaryl groups / moieties include: [ka] (Wherein, G=O, S or NH).

[0015] For purposes of this specification, when a combination of moieties is referred to as a group, e.g., arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl, or alkynylaryl, the last mentioned moiety includes the atom at which the group is attached to the remainder of the molecule. An example of an arylalkyl group is benzyl.

[0016] The term "halo" includes fluoro, chloro, bromo and iodo.

[0017] Unless otherwise stated, when a group is prefixed with the term "halo", such as a haloalkyl or halomethyl group, the group in question should be understood to be substituted with one or more halo groups independently selected from fluoro, chloro, bromo, and iodo. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution in the corresponding group without the halo prefix. For example, a halomethyl group may contain one, two, or three halo substituents. A haloethyl or halophenyl group may contain one, two, three, four, or five halo substituents. Similarly, unless otherwise stated, when a group is prefixed with a particular halo group, the group in question should be understood to be substituted with one or more of the particular halo group. For example, the term "fluoromethyl" refers to a methyl group substituted with one, two, or three fluoro groups.

[0018] Similarly, unless otherwise stated, when a group is said to be "halo-substituted", it should be understood that the group in question is substituted with one or more halo groups independently selected from fluoro, chloro, bromo and iodo. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution on the group said to be halo-substituted. For example, a halo-substituted methyl group may contain one, two or three halo substituents. A halo-substituted ethyl or halo-substituted phenyl group may contain one, two, three, four or five halo substituents.

[0019] Unless otherwise specified, any reference to an element should be considered a reference to all isotopes of that element. Thus, for example, unless otherwise specified, a reference to hydrogen is considered to encompass all isotopes of hydrogen, including deuterium and tritium.

[0020] Unless otherwise stated, any reference to a compound or group should be considered as a reference to all tautomers of that compound or group.

[0021] When referring to a hydrocarbyl or other group that contains one or more heteroatoms N, O or S in its carbon skeleton, or to other groups that are substituted at carbon atoms or N, O or S atoms of a hydrocarbyl, what is intended is as follows. [ka] teeth [ka] is replaced by; -CH2- is replaced by -NH-, -O- or -S-; -CH3 is replaced with -NH2, -OH or -SH; -CH= is replaced by -N=; CH2= is replaced by NH=, O= or S=; or CH≡ is replaced by N≡; provided that the resulting group contains at least one carbon atom. For example, methoxy, dimethylamino and aminoethyl groups are considered to be hydrocarbyl groups containing one or more heteroatoms N, O or S in their carbon skeleton.

[0022] As used herein, when a group, such as a hydrocarbyl group, is described as being substituted with an oxo (=O) group, any two hydrogen atoms bonded to the same atom may be replaced with a π-bonded =O substituent, or, if the group contains a nitrogen or sulfur atom, the oxidation state of the nitrogen or sulfur atom may be changed to allow for the attachment of a π-bonded =O substituent, and one or more hydrogen atoms may be lost from the nitrogen atom, sulfur atom or adjacent atoms to allow for charge neutralization. Thus, for example, -CHCHO, -CHNO and -CHSOH may be replaced with one (-CHCHO, -CHNO) or two ( - -CH2SO3H) are examples of -CH2CH3, -CH2NHOH and -CH2-S-OH groups substituted with oxo groups.

[0023] In the context of this specification, unless otherwise stated, x -C y A group is defined as a group containing x to y carbon atoms. For example, a C1-C4 alkyl group is defined as an alkyl group containing 1 to 4 carbon atoms. Optional substituents and moieties are not taken into account when calculating the total number of carbon atoms in the parent group, including any substituents and / or moieties substituted with it. For the avoidance of doubt, substituted heteroatoms, e.g. N, O or S, are not considered when calculating the total number of carbon atoms in the parent group, including any moiety substituted with it. x -C y It should not be counted as a carbon atom when calculating the number of carbon atoms in a group. For example, a morpholinyl group should be considered a C4 heterocyclic group, not a C6 heterocyclic group.

[0024] In one embodiment of the first aspect of the invention, X is Cl, Br or I. Typically, in such embodiments, X is Cl.

[0025] In another embodiment of the first aspect of the invention, X is OR 1 or S.R. 1 and R 1 is C1-C 20 is a hydrocarbyl group, C1-C 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and may be any of C1-C 20 The hydrocarbyl group may be substituted with one or more oxo (=O) and / or one or more halo groups, and may be C-C 20 The hydrocarbyl group may contain one or more heteroatoms independently selected from N, O and S in its carbon skeleton.

[0026] Typically, in such embodiments, X is OR 1 It is.

[0027] For example, X is OR 1 R 1is selected from alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl groups; R 1 are independently halo, -CN, -OH, -NO2, -NH2, oxo (=O), =NH, -R 10 , -OR 10 , -NHR 10 , -N(R 10 )2, -N(O)(R 10 )2 or =NR 10 and each R 10 are independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl, or C3-C4 halocycloalkyl groups, or any two R directly attached to the same nitrogen atom; 10 may together form a C2-C5 alkylene or C2-C5 haloalkylene group, R including any optional substituents. 1 contains 1 to 20 carbon atoms.

[0028] More typically, X is OR 1 and R 1 is selected from alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl groups; R 1 is optionally substituted with one or more substituents independently selected from halo, -CN, -OH, -NO2, -NH2, oxo (=O), -Me, -Et, -OMe, -OEt, -NHMe, -NHEt, -N(Me)2, -N(Me)Et, or -N(Et)2, any methyl (Me) or ethyl (Et) group may be substituted with one or more halo groups, R 1 contains 1 to 12 carbon atoms.

[0029] In one embodiment, X is OR 1 and R 1 is selected from an aryl or heteroaryl group, the aryl or heteroaryl group being monocyclic, bicyclic or tricyclic; R 1 are independently halo, -CN, -OH, -NO2, -NH2, -R 10 , -OR10 , -NHR 10 , -N(R 10 )2, or -N(O)(R 10 ) 2, each R 10 are independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl, or C3-C4 halocycloalkyl groups, or any two R 10 may together form a C2-C5 alkylene or C2-C5 haloalkylene group, R 1 contains 1 to 20 carbon atoms.

[0030] More typically, X is OR 1 and R 1 is selected from phenyl or a monocyclic heteroaryl group; R 1 is optionally substituted with one or more substituents independently selected from halo, -CN, -OH, -NO2, -NH2, -Me, -Et, -OMe, -OEt, -NHMe, -NHEt, -N(Me)2, -N(Me)Et, or -N(Et)2, any methyl (Me) or ethyl (Et) group may be substituted with one or more halo groups, R including any substituent 1 contains 1 to 12 carbon atoms.

[0031] Even more typically, X is an OR 1 and R 1 is a phenyl group, which may be substituted with one or more fluoro, chloro or -NO2 groups. Most typically, R 1 is an unsubstituted phenyl group, ie, X is OPh.

[0032] R 1is an unsubstituted phenyl group, there is provided a method for preparing 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide, or a salt thereof, by contacting 1-ethyl-4-piperidinesulfonamide (A) with 4-(phenoxycarbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (B') in the presence of a solvent to obtain 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-4-sulfonamide (C), or a salt thereof. [ka]

[0033] In another embodiment of the first aspect of the invention, X is N(R 1 )2, and each R 1 is independent of C1-C 20 Each C-C 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, each C1-C 20 The hydrocarbyl groups may be substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20 The hydrocarbyl group may contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or any two R 1 may be taken together with the nitrogen atom to which they are attached to form a 3- to 16-membered heterocyclic group, which may be monocyclic, bicyclic or tricyclic, and which may further include one or more halo groups and / or one or more groups R X and each R Xare independently selected from -CN, -OH, -NH2, oxo (=O), =NH or a C1-C6 hydrocarbyl group, each C1-C6 hydrocarbyl group may be linear or branched or may be or contain one or more cyclic groups, each C1-C6 hydrocarbyl group may be substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S.

[0034] Typically, in such embodiments, X is N(R 1 )2, and two R 1 together with the nitrogen atom to which they are attached form a 5- to 14-membered heteroaryl group, which may be monocyclic, bicyclic, or tricyclic; R 1 are independently halo, -CN, -OH, -NO2, -NH2, -R 10 , -OR 10 , -NHR 10 , -N(R 10 )2 or -N(O)(R 10 ) 2, each R 10 are independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl or C3-C4 halocycloalkyl groups, or any two R 10 may be taken together to form a C2-C5 alkylene or C2-C5 haloalkylene group, R including any optional substituents 1 contains 1 to 20 carbon atoms.

[0035] More typically, X is N(R 1 )2, then two R 1 together with the nitrogen atom to which they are attached form a 5- to 10-membered heteroaryl group, which may be monocyclic or bicyclic; R 1is optionally substituted with one or more substituents independently selected from halo, -CN, -OH, -NO2, -NH2, -Me, -Et, -OMe, -OEt, -NHMe, -NHEt, -N(Me)2, -N(Me)Et, or -N(Et)2, any methyl (Me) or ethyl (Et) group may be substituted with one or more halo groups, and any substituent R 1 contains 1 to 12 carbon atoms.

[0036] Typically, X is N(R 1 )2, and two R 1 When they are taken together with the nitrogen atom to which they are attached to form a 5-14 or 5-10 membered heteroaryl group, N(R 1 The ring containing the nitrogen atom of 2 is a 5-membered ring.

[0037] In another embodiment of the first aspect of the invention, X is OP(=O)(R 1 )2 or OP(R 1 )3 + And each R 1 is independent of C1-C 20 Each C-C 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, each C1-C 20 The hydrocarbyl group may be substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20 The hydrocarbyl group may contain in its carbon skeleton one or more heteroatoms independently selected from N, O and S, or any two R 1 may be joined together with the phosphorus atom to which they are attached to form a 3- to 16-membered heterocyclic group, which may be monocyclic, bicyclic or tricyclic, and which may further include one or more halo groups, and / or one or more groups R X and each R Xare independently selected from -CN, -OH, -NH2, oxo (=O), =NH or a C1-C6 hydrocarbyl group, each C1-C6 hydrocarbyl group may be linear or branched or may be or contain one or more cyclic groups, each C1-C6 hydrocarbyl group may be substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S.

[0038] Typically, in such embodiments, X is OP(=O)(R 1 )2 or OP(R 1 )3 + And each R 1 is independently selected from alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl groups; each R 1 are independently halo, -CN, -OH, -NO2, -NH2, oxo (=O), =NH, -R 10 , -OR 10 , -NHR 10 , -N(R 10 )2, -N(O)(R 10 )2, or =NR 10 and each R 10 are independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl, or C3-C4 halocycloalkyl groups, or any two R 10 may together form a C2-C5 alkylene or C2-C5 haloalkylene group, R 1 contains 1 to 20 carbon atoms.

[0039] More typically, X is OP(=O)(R 1 )2 or OP(R 1 )3 + And each R 1is independently selected from alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl groups; R 1 is optionally substituted with one or more substituents independently selected from halo, -CN, -OH, -NO2, -NH2, oxo (=O), -Me, -Et, -OMe, -OEt, -NHMe, -NHEt, -N(Me)2, -N(Me)Et, or -N(Et)2, any methyl (Me) or ethyl (Et) group may be substituted with one or more halo groups, R 1 contains 1 to 12 carbon atoms.

[0040] Even more typically, X is OP(=O)(R 1 )2 or OP(R 1 )3 + If, then, for each R 1 is independently selected from a C1-C4 alkyl or phenyl group.

[0041] In one embodiment of the first aspect of the invention, the solvent is a polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide, N,N'-dimethylpropyleneurea, tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetone, acetonitrile, dichloromethane, hexamethylphosphoramide, nitromethane, propylene carbonate, N-methylpyrrolidone, or a mixture thereof. Typically, the solvent does not contain an ester. More typically, the solvent does not contain a carbonyl group. Typically, the solvent is not halogenated. For example, the solvent may be selected from dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, acetonitrile, hexamethylphosphoramide, nitromethane, or a mixture thereof. Even more typically, the solvent does not contain a carbonyl, C=N or C≡N group. Typically, if the solvent does not contain a carbonyl, C=N or C≡N group, the solvent is not halogenated. For example, the solvent may be selected from dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, hexamethylphosphoramide, nitromethane, or mixtures thereof. Most typically, the solvent is dimethylsulfoxide.

[0042] In one embodiment of the first aspect of the present invention, the step of contacting 1-ethyl-4-piperidinesulfonamide (A) with 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B') is carried out in the presence of a base. Typically, the base is an alkoxide base, such as an alkali metal or alkaline earth metal alkoxide. More typically, the base is a tert-butoxide base, such as an alkali metal or alkaline earth metal tert-butoxide. Examples of suitable bases include potassium tert-butoxide and sodium tert-butoxide. Typically, the base is potassium tert-butoxide.

[0043] In one embodiment, the first aspect of the invention provides a method for preparing a salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide, such as a cationic salt. Typically, the salt is pharma- ceutically acceptable.

[0044] For purposes of the present invention, a "cationic salt" of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide is a salt formed between a protonic acid functional group of the compound (such as a urea proton) and a suitable cation by loss of a proton. 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. More preferably, the salt is a mono- or di-potassium salt, and even more preferably, the salt is a mono-potassium salt.

[0045] Advantageously, when a cationic salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (C) is desired, the cation of the salt is provided by the conjugate acid of the base. For example, one embodiment of the first aspect of the present invention provides a method for preparing an alkali metal or alkaline earth metal salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-carbamoyl)piperidine-4-sulfonamide (C), comprising contacting 1-ethyl-4-piperidinesulfonamide (A) with a 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B') in the presence of a solvent and an alkali metal or alkaline earth metal alkoxide to obtain the alkali metal or alkaline earth metal salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-4-sulfonamide, wherein the alkali metal or alkaline earth metal of the salt is the same as the alkali metal or alkaline earth metal of the alkoxide. Typically, in such embodiments, the alkali metal or alkaline earth metal alkoxide is an alkali metal or alkaline earth metal tert-butoxide.

[0046] A further embodiment of the first aspect of the invention provides a method for preparing the potassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (C), comprising contacting 1-ethyl-4-piperidinesulfonamide (A) with 4-(phenoxycarbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (B') in the presence of a solvent and potassium tert-butoxide to obtain the potassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-4-sulfonamide. Typically, in such embodiments, the potassium salt is the monopotassium salt.

[0047] In one embodiment of the first aspect of the invention, the step of contacting 1-ethyl-4-piperidinesulfonamide (A) with 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B') to obtain 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (C) or a salt thereof is carried out at a temperature in the range of -10 to 60°C. Typically, the step is carried out at a temperature in the range of 0 to 50°C, more typically in the range of 10 to 40°C, and most typically in the range of 20 to 30°C.

[0048] Typically, according to the first aspect of the present invention, 1-ethyl-4-piperidine-sulfonamide (A) is present in the solvent or added to the solvent at an initial concentration of 0.1 to 15 mol / L relative to the total volume of the solvent used in the reaction mixture. More typically, 1-ethyl-4-piperidine-sulfonamide (A) is present in the solvent or added to the solvent at an initial concentration of 0.5 to 5.0 mol / L. Most typically, 1-ethyl-4-piperidine-sulfonamide (A) is present in the solvent or added to the solvent at an initial concentration of 1.0 to 1.5 mol / L.

[0049] Typically, according to the first aspect of the present invention, the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B') is present in the solvent or added to the solvent at an initial concentration of 0.1 to 15 mol / L relative to the total volume of the solvent used in the reaction mixture. More typically, the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B') is present in the solvent or added to the solvent at an initial concentration of 0.5 to 5.0 mol / L. Most typically, the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B') is present in the solvent or added to the solvent at an initial concentration of 1.0 to 1.5 mol / L.

[0050] Typically, the process of the first aspect of the invention uses 0.8 to 1.4 molar equivalents of the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B') relative to the initial amount of 1-ethyl-4-piperidinesulfonamide (A). More typically, the process uses 1.0 to 1.2 molar equivalents of the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B'). Most typically, the process uses 1.05 to 1.15 molar equivalents of the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B).

[0051] Typically, when a base is used, the process of the first aspect of the invention uses 1.0 to 2.0 molar equivalents of base relative to the initial amount of 1-ethyl-4-piperidinesulfonamide (A). More typically, the process uses 1.05 to 1.5 molar equivalents of base. More typically, the process uses 1.1 to 1.2 molar equivalents of base.

[0052] In one embodiment of the first aspect of the invention, the method comprises the steps of: (i) dissolving 1-ethyl-4-piperidinesulfonamide (A) in a solvent; (ii) adding a base to the solution formed in step (i); and (iii) adding 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B') to the mixture formed in step (ii).

[0053] In one embodiment of the first aspect of the present invention, 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (C) or a salt thereof is isolated from the reaction mixture by crystallization or precipitation. For example, if the solvent used in the reaction is dimethylsulfoxide (DMSO), additional solvent such as water, acetonitrile (MeCN) and optionally additional DMSO may be added to the reaction mixture to produce a precipitation mixture from which 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (C) or a salt thereof precipitates upon cooling. Typically, the salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (C) is isolated from the reaction mixture by crystallization or precipitation. Typically, the salt is an alkali metal or alkaline earth metal salt, such as a potassium salt.

[0054] In one embodiment of the first aspect of the invention, the precipitation mixture comprises DMSO, MeCN and water, and the solvent of the precipitation mixture is (i) 30-50% by weight DMSO (based on the total weight of the solvent); (ii) 50-70% by weight MeCN (based on the total weight of the solvent); and (iii) consists of 1-10% by weight HO (based on the total weight of the solvent).

[0055] Typically, crystallization or precipitation occurs at a temperature in the range of −10 to 20° C. More typically, crystallization or precipitation occurs at a temperature in the range of −5 to 10° C., most typically in the range of 0 to 5° C.

[0056] In one embodiment of the first aspect of the present invention, the salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (C) is purified by recrystallization or reprecipitation. For example, the crude salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (C) may be dissolved in a first solvent to obtain a first mixture, the mixture may be optionally filtered, and the salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-carbamoyl)piperidine-4-sulfonamide (C) may be precipitated by adding a second solvent, optionally with cooling. Typically, the first solvent is a polar protic solvent, such as methanol. Typically, the second solvent is a polar aprotic solvent, such as acetonitrile.

[0057] A second aspect of the invention provides 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide or a salt thereof prepared or preparable by the process of the first aspect of the invention.

[0058] In one embodiment, the second aspect of the invention provides an alkali metal or alkaline earth metal salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-4-sulfonamide. Typically, the second aspect of the invention provides a potassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-4-sulfonamide. Most typically, the second aspect of the invention provides a monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-4-sulfonamide.

[0059] In one embodiment of the second aspect of the present invention, the 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide or a salt thereof is 1 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide or a salt thereof has a purity of 97.0% or more as determined by HNMR. 1 It has a purity of 98.0% or more, or 99.0% or more, or 99.5% or more, as measured by HNMR.

[0060] In another embodiment of the second aspect of the present invention, the 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide or a salt thereof has an HPLC purity of 95.0% or more. More typically, the 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide or a salt thereof has an HPLC purity of 98.0% or more, or 99.0% or more, or 99.5% or more, or 99.8% or more, or 99.9% or more.

[0061] In one embodiment of the first aspect of the invention, the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B') is prepared by a method according to the third aspect of the invention.

[0062] In one embodiment of the first aspect of the invention, 1-ethyl-4-piperidine-sulfonamide (A) is prepared by a process according to the fifth aspect of the invention.

[0063] A third aspect of the present invention is a method for preparing a 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or a salt thereof, comprising the step of converting 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (D) to the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or a salt thereof. [ka] (wherein X is a leaving group).

[0064] In the third aspect of the invention, X may be defined according to any embodiment of the first aspect of the invention.

[0065] In one embodiment of the third aspect of the present invention, the method comprises reacting 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) with a reagent (E): [ka] wherein X is as defined above and X' is a leaving group, optionally in the presence of a base and / or a solvent.

[0066] In one embodiment of the third aspect of the invention, X' is Cl, Br, I, OR 1 , S.R. 1 , N(R 1 )2, OP(=O)(R 1 )2 or OP(R 1 )3 + And each R 1 is as defined according to the first aspect of the invention. Typically, X' is Cl, Br or I. More typically, X' is Cl or Br. Most typically, X' is Cl.

[0067] X and X' can be the same or different. Typically, X and X' are different. Typically, X and X' are selected such that X' is more easily substituted than X.

[0068] In one embodiment of the third aspect of the invention, X' is Cl, Br or I and X is OR 1 , S.R. 1 , N(R 1 )2, OP(=O)(R 1 )2 or OP(R 1 )3 +More typically, X' is Cl or Br and X is OR 1 , S.R. 1 or N(R 1 )2.

[0069] In a third embodiment of the present invention, X' is Cl, Br or I, and X is OR 1 and R 1 is selected from alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl groups; R 1 are independently halo, -CN, -OH, -NO2, -NH2, oxo (=O), =NH, -R 10 , -OR 10 , -NHR 10 , -N(R 10 )2, -N(O)(R 10 )2 or =NR 10 and each R 10 are independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl, or C3-C4 halocycloalkyl groups, or any two R directly attached to the same nitrogen atom; 10 may together form a C2-C5 alkylene or C2-C5 haloalkylene group, R including any optional substituents. 1 contains 1 to 20 carbon atoms.

[0070] Typically, X' is Cl or Br and X is OR 1 and R 1 is selected from an aryl or heteroaryl group, the aryl or heteroaryl group being monocyclic, bicyclic or tricyclic; R 1 are halo, -CN, -OH, -NO2, -NH2, -R 10 , -OR 10 , -NHR 10 , -N(R 10 )2, or -N(O)(R 10 )2, each R 10are independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl, or C3-C4 halocycloalkyl groups, or any two R 10 may together form a C2-C5 alkylene or C2-C5 haloalkylene group, R 1 contains 1 to 20 carbon atoms.

[0071] Even more typically, X' is Cl and X is OR 1 and R 1 is a phenyl group, which may be substituted with one or more fluoro, chloro or -NO2 groups. Most typically, X' is Cl and X is OPh.

[0072] Thus, in one embodiment of the third aspect of the present invention there is provided a method for preparing 4-(phenoxycarbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (B'), comprising contacting 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (D) with phenyl chloroformate (E'), optionally in the presence of a solvent and / or a base. [ka]

[0073] Typically, 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) is contacted with reagent (E) or (E') in the presence of a solvent. In one embodiment, the solvent is a polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide, N,N'-dimethylpropyleneurea, tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetone, acetonitrile, dichloromethane, hexamethylphosphoramide, nitromethane, propylene carbonate, N-methylpyrrolidone, or a mixture thereof. Typically, the solvent does not contain an ester. More typically, the solvent does not contain a carbonyl group. Typically, the solvent is not halogenated. For example, the solvent may be selected from dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, acetonitrile, hexamethylphosphoramide, nitromethane, or a mixture thereof. Even more typically, the solvent does not contain a carbonyl, C=N or C≡N group. Typically, a solvent is non-halogenated if it does not contain a carbonyl, C=N or C≡N group. For example, the solvent may be selected from dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, hexamethylphosphoramide, nitromethane, or mixtures thereof. Most typically, the solvent is tetrahydrofuran.

[0074] Typically, 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) is contacted with reagent (E) or (E') in the presence of a base. Typically, the base is a sterically hindered base. For example, the base can be a tertiary amine such as N,N-diisopropylethylamine (DIPEA), trimethylamine, triethylamine (TEA), tripropylamine or tributylamine. Most typically, the base is N,N-diisopropylethylamine.

[0075] Typically, according to the third aspect of the present invention, the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B') is prepared in a non-salt form.

[0076] In one embodiment of the third aspect of the present invention, 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) is mixed with reagent (E) or (E') at a temperature in the range of -10 to 40° C. Typically, 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) is mixed with reagent (E) or (E') at a temperature in the range of 0 to 25° C., more typically in the range of 0 to 10° C.

[0077] In one embodiment of the third aspect of the invention, after mixing 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) with reagent (E) or (E'), the reaction mixture is warmed to a temperature in the range of 5 to 50° C. Typically, the reaction mixture is warmed to a temperature in the range of 10 to 30° C., more typically in the range of 15 to 25° C.

[0078] Typically, according to the third aspect of the invention, the 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (D) is present in the solvent or added to the solvent at an initial concentration of 0.01 to 10 mol / L relative to the total volume of solvent used in the reaction mixture. More typically, the 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (D) is present in the solvent or added to the solvent at an initial concentration of 0.1 to 1.0 mol / L. Most typically, the 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (D) is present in the solvent or added to the solvent at an initial concentration of 0.4 to 0.5 mol / L.

[0079] Typically, the process of the third aspect of the invention uses 0.9 to 1.5 molar equivalents of reagent (E) or (E') relative to the initial amount of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D). More typically, the process uses 1.0 to 1.2 molar equivalents of reagent (E) or (E'). Most typically, the process uses 1.05 to 1.15 molar equivalents of reagent (E) or (E').

[0080] Typically, the process of the third aspect of the invention uses 0.8 to 2.0 molar equivalents of base relative to the initial amount of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D). More typically, the process uses 1.0 to 1.5 molar equivalents of base. Most typically, the process uses 1.1 to 1.3 molar equivalents of base.

[0081] In one embodiment of the third aspect of the invention, the method comprises the steps of: (i) dissolving 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) in a first portion of a solvent; (ii) dissolving a base in a second portion of the solvent and adding the resulting solution to the solution formed in step (i); and (iii) dissolving reagent (E) or (E') in a third portion of the solvent and adding the resulting solution to the mixture formed in step (ii).

[0082] In one embodiment of the third aspect of the invention, the method comprises at the end of the reaction: (i) concentrating the reaction mixture under reduced pressure; then (ii) optionally further comprising the step of adding a co-solvent and concentrating the resulting mixture under reduced pressure.

[0083] Step (ii) may be repeated one or more times. Typically, the co-solvent is an alcohol, such as methanol or ethanol. Most typically, the co-solvent is ethanol.

[0084] In one embodiment of the third aspect of the present invention, the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or a salt thereof is purified and / or isolated by crystallization or precipitation. For example, a precipitating solvent may be added to the concentrated reaction mixture to produce a precipitation mixture from which the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or a salt thereof, optionally upon cooling, precipitates. Typically, the precipitating solvent is an alcohol, such as methanol or ethanol. Most typically, the precipitating solvent is ethanol.

[0085] Typically, the non-salt form of the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) is isolated by crystallization or precipitation. Most typically, the non-salt form of the 4-(phenoxycarbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (B') is isolated by crystallization or precipitation.

[0086] Typically, crystallization or precipitation occurs at a temperature in the range of −10 to 20° C. More typically, crystallization or precipitation occurs at a temperature in the range of −5 to 10° C., most typically in the range of 0 to 5° C.

[0087] The fourth aspect of the present invention is a 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) [ka] wherein X is a leaving group, or a salt thereof.

[0088] In the fourth aspect of the invention, X may be defined according to any embodiment of the first aspect of the invention.

[0089] A particular embodiment of the fourth aspect of the invention is 4-(phenoxycarbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (B'). [ka] or a salt thereof.

[0090] The 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or a salt thereof, or 4-(phenoxycarbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (B') or a salt thereof may be prepared or preparable by the method of the third aspect of the present invention.

[0091] Typically, the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or 4-(phenoxy-carbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (B') of the fourth aspect of the invention is in a non-salt form.

[0092] In one embodiment of the fourth aspect of the present invention, the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or a salt thereof has an HPLC purity of 96.0% or more. More typically, the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or a salt thereof has an HPLC purity of 98.0% or more, or 99.0% or more, or 99.5% or more, or 99.6% or more.

[0093] In another embodiment of the fourth aspect of the present invention, 4-(phenoxycarbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (B') or a salt thereof has an HPLC purity of 96.0% or more. More typically, 4-(phenoxycarbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (B') or a salt thereof has an HPLC purity of 98.0% or more, 99.0% or more, or 99.5% or more, or 99.6% or more.

[0094] In one embodiment of the third aspect of the present invention, 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) is prepared by a process comprising one or more steps selected from the following: (i) contacting 2,3-dihydro-1H-indene (L) with YCHCHC(O)Z (M) to obtain substituted 1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (N), wherein Y and Z are leaving groups; [ka]

[0095] (ii) contacting the substituted 1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (N) with an acid to obtain 1,2,3,5,6,7-hexahydro-s-indacen-1-one (P); [ka]

[0096] (iii) converting 1,2,3,5,6,7-hexahydro-s-indacen-1-one (P) into 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (Qa) and / or 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (Qb): [ka] And

[0097] (iv) reducing 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (Qa) and / or 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (Qb) to obtain 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D): [ka]

[0098] In one embodiment, the method comprises one, two, three or all four of steps (i)-(v).

[0099] The preparation method of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine may be as described in WO 2020 / 079207, the contents of which are incorporated herein by reference in their entirety.

[0100] In one embodiment, in step (i), the leaving group Y is independently selected from Cl, Br, I, or a sulfonic acid leaving group, such as a toluenesulfonic acid, methanesulfonic acid, or trifluoromethanesulfonic acid leaving group.

[0101] In one embodiment, in step (i), the leaving group Z is independently Cl, Br, I, OR 1 , S.R. 1 , N(R 1 )2, OP(=O)(R 1 )2 or OP(R 1 )3 + wherein R 1 is as defined in relation to the first embodiment of the invention.

[0102] Y and Z may be the same or different. Typically, Y and Z are independently selected from Cl, Br and I. Typically, at least one of Y and Z is Cl. More typically, Y and Z are both Cl. When Y and Z are both Cl, in step (i), 2,3-dihydro-1H-indene (L) is contacted with 3-chloropropionyl chloride to obtain 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one.

[0103] In one embodiment, the reaction of step (i) is carried out in the presence of a catalyst, for example a Lewis acid such as aluminium chloride.

[0104] Step (i) may be carried out in the presence of a solvent. In one embodiment, the solvent is an aprotic solvent. In one embodiment, the solvent is dichloromethane, dichloroethane, chloroform, diethyl ether, n-pentane, n-hexane, n-heptane, toluene or a mixture thereof. Typically, the solvent is dichloromethane.

[0105] In one embodiment, the reaction in step (i) is carried out at a temperature in the range of −20 to 50° C. Typically, the reaction in step (i) is carried out at a temperature in the range of −15 to 25° C., more typically at a temperature in the range of −10 to 15° C.

[0106] In one embodiment, in step (ii), the acid is sulfuric acid, hydrochloric acid, Eaton's reagent, polyphosphoric acid or a mixture thereof. Typically, the acid is sulfuric acid or hydrochloric acid. More typically, the acid is sulfuric acid. Typically, no additional solvent is used.

[0107] In one embodiment, the reaction in step (ii) is carried out at a temperature in the range of from 10 to 90° C. Typically, the reaction in step (ii) is carried out at a temperature in the range of from 40 to 80° C., more typically at a temperature in the range of from 65 to 70° C.

[0108] In one embodiment, in step (iii), 1,2,3,5,6,7-hexahydro-s-indacen-1-one (P) is converted to 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (Qa) or 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (Qb) or a mixture thereof by treatment with sulfuric acid and nitric acid. Typically, no additional solvent is used.

[0109] In one embodiment, the reaction of step (iii) is carried out at a temperature in the range of 0 to 20° C. Typically, the reaction of step (iii) is carried out at a temperature in the range of 0 to 10° C., more typically at a temperature in the range of 0 to 5° C.

[0110] In one embodiment, the reactions of steps (ii) and (iii) are carried out without isolating 1,2,3,5,6,7-hexahydro-s-indacen-1-one (P).

[0111] In one embodiment, the reduction of step (iv) is carried out using a catalyst and hydrogen gas. Typically, the catalyst is a metal catalyst including platinum, palladium, rhodium, ruthenium or nickel. Typically, the catalyst is Pd / C, Pd(OH)2 / C, Pt / C, PtO2, platinum black or Raney nickel. More typically, the catalyst is Pd / C or Pd(OH)2 / C. Most typically, the catalyst is Pd(OH)2 / C. Typically, the hydrogen gas is provided at a pressure of 80-120 Psi, typically about 100 Psi. The catalyst and hydrogen gas may be used in the presence of an acid such as sulfuric acid, or a sulfonic acid such as methanesulfonic acid or p-toluenesulfonic acid (PTSA). Most typically, Pd(OH)2 / C and hydrogen gas are used in the presence of methanesulfonic acid.

[0112] In one embodiment, the reduction of step (iv) is carried out in the presence of a solvent. Typically, the solvent is a polar solvent such as methanol, ethanol, ethyl acetate, isopropanol, n-butanol, THF, water, acetic acid or a mixture thereof. Typically, the solvent is a polar protic solvent. More typically, the solvent is an alcohol such as methanol, ethanol, isopropanol or n-butanol. Most typically, the solvent is methanol.

[0113] In one embodiment, the reduction in step (iv) is carried out at a temperature in the range of 10 to 80° C. Typically, the reduction in step (iv) is carried out at a temperature in the range of 20 to 60° C.

[0114] In one particular embodiment of the third aspect of the invention, 4-(phenoxycarbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (B') [ka] or a salt thereof, comprising: (i) contacting 2,3-dihydro-1H-indene (L) with 3-chloropropionyl chloride (M') in the presence of a Lewis acid to obtain 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (N'); [ka]

[0115] (ii) contacting 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (N') with an acid to obtain 1,2,3,5,6,7-hexahydro-s-indacen-1-one (P); [ka]

[0116] (iii) converting 1,2,3,5,6,7-hexahydro-s-indacen-1-one (P) to 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (Qa) and / or 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (Qb) by treatment with sulfuric acid and nitric acid: [ka]

[0117] (iv) reducing 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (Qa) and / or 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (Qb) to obtain 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D); [ka] And

[0118] v) converting the 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (D) to 4-(phenoxycarbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (B') by contacting the 1,2,3,5,6,7-hexahydro-s-indacene-4-amine with PhOC(O)L. [ka]

[0119] wherein L is selected from Cl and Br. A method is provided, comprising:

[0120] A fifth aspect of the invention provides a method comprising one or more steps selected from: (a) Converting 4-hydroxypiperidine (F) to N-protected-4-hydroxypiperidine (G): [ka] (In the formula, R 2 is a nitrogen protecting group);

[0121] (b) converting N-protected-4-hydroxypiperidine (G) to N-protected-4-derivatized piperidine (H): [ka] (In the formula, R 2 is a nitrogen protecting group, R 3 is a leaving group):

[0122] (c) converting the N-protected-4-derivatized piperidine (H) into the N-protected-4-(acylthio)-piperidine (I): [ka] (In the formula, R 2 is a nitrogen protecting group, R 3 is a leaving group, and R4 is C1-C 20 is a hydrocarbyl group, C1-C 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and may be any of C1-C 20 The hydrocarbyl group may be substituted with one or more oxo (=O) and / or one or more halo groups, and may be C-C 20 The hydrocarbyl group may contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S.

[0123] (d) converting N-protected-4-(acylthio)-piperidine (I) into N-protected-4-(halosulfonyl)-piperidine (J): [ka] (In the formula, R 2 is a nitrogen protecting group, R 4 is C1-C 20 is a hydrocarbyl group, C1-C 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and may be any of C1-C 20 The hydrocarbyl group may be substituted with one or more oxo (=O) and / or one or more halo groups, and may be C-C 20 The hydrocarbyl group may contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, and Hal is Cl or Br.

[0124] (e) converting N-protected-4-(halosulfonyl)-piperidine (J) into N-protected-4-piperidinesulfonamide (K): [ka] (In the formula, R 2 is a nitrogen protecting group and Hal is Cl or Br); and

[0125] (f) converting N-protected-4-piperidinesulfonamide (K) into 1-ethyl-4-piperidinesulfonamide (A): [ka] (In the formula, R 2 is a nitrogen protecting group)

[0126] In one embodiment of the fifth aspect of the invention, the method comprises one, two, three, four, five or all six of steps (a)-(f).

[0127] In one embodiment, the process of the fifth aspect of the invention comprises reacting 1-ethyl-4-piperidinesulfonamide (A) [ka] or a salt thereof.

[0128] Typically, when the method of the fifth aspect of the present invention is a method for preparing 1-ethyl-4-piperidinesulfonamide (A) or a salt thereof, the method comprises at least step (f). In one embodiment, the method comprises steps (e) and (f). In another embodiment, the method comprises steps (d), (e) and (f). In another embodiment, the method comprises steps (c), (d), (e) and (f). In another embodiment, the method comprises steps (b), (c), (d), (e) and (f). In another embodiment, the method comprises all six of steps (a), (b), (c), (d), (e) and (f).

[0129] As will be appreciated, when the method of the fifth aspect of the present invention comprises two or more successive steps selected from steps (a) to (f), in each successive step, R 2 Similarly, when the method of the fifth aspect of the present invention includes steps (b) and (c), in each step, R 3Similarly, when the method of the fifth aspect of the present invention includes steps (c) and (d), in each step, R 4 is the same.

[0130] As described, R 2 is a nitrogen protecting group. Suitable nitrogen protecting groups are described, for example, in Wuts, "Greene's Protective Groups in Organic Synthesis", Vol. 5 版 , 2014, the contents of which are incorporated herein by reference in their entirety.

[0131] In one embodiment of the fifth aspect of the invention, R 2 is a nitrogen protecting group that is stable under basic conditions. Typically, R 2 is stable under weakly nucleophilic conditions, e.g., upon exposure to MeCOS- 。 For example, R 2 may be selected from the group consisting of benzyloxycarbonyl (CBz), 4-methoxy-benzyloxycarbonyl, benzyl, t-butoxycarbonyl (Boc), 2-(4-biphenylyl)-isopropoxycarbonyl (Bpoc), triphenylmethyl (Trt) and 2,2,2-trichloroethoxycarbonyl (Troc) protecting groups.

[0132] In one embodiment of the fifth aspect of the invention, R 2 is a nitrogen protecting group that can be removed by catalytic hydrogenolysis. Typically, R 2 is a nitrogen protecting group that is stable under basic conditions and can be removed by catalytic hydrogenolysis. More typically, R 2 is a nitrogen protecting group that is stable under basic and weakly nucleophilic conditions and can be removed by catalytic hydrogenolysis. For example, R 2 may be selected from the group consisting of benzyloxycarbonyl (CBz), 4-methoxy-benzyloxycarbonyl, benzyl, 2-(4-biphenylyl)-isopropoxycarbonyl (Bpoc) or triphenylmethyl (Trt) groups.

[0133] In a further embodiment of the fifth aspect of the invention, R 2 Ha-CH2R 20 or -COOCH2R 20 and R 20 is an aryl or heteroaryl group, the aryl or heteroaryl group being monocyclic, bicyclic or tricyclic, the aryl or heteroaryl group being halo, -CN, -OH, NO2, -NH2, -R 21 , -OR 21 , -NHR 21 , -N(R 21 )2, or -N(O)(R 21 )2, each R 21 are independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 cycloalkyl, or C3-C4 halocycloalkyl groups, or any two R directly attached to the same nitrogen atom; 21 may be taken together to form a C2-C5 alkylene or C2-C5 haloalkylene group, R including any optional substituents. 20 contains 1 to 20 carbon atoms.

[0134] In one embodiment of the fifth aspect of the invention, R 2 -COOCH2R 20 It is.

[0135] In one embodiment of the fifth aspect of the invention, R 20 is selected from phenyl or a monocyclic heteroaryl group; R 20 is optionally substituted with one or more substituents independently selected from halo, -CN, -OH, -NO2, -NH2, -Me, -Et, -OMe, -OEt, -NHMe, -NHEt, -N(Me)2, -N(Me)Et, or -N(Et)2, any methyl (Me) or ethyl (Et) group may be substituted with one or more halo groups, R including any substituent 20 contains 1 to 12 carbon atoms.

[0136] Typically, R 20is a phenyl group, which may be substituted with one or more fluoro, chloro, -OMe, -OEt or -NO2 groups.

[0137] More typically, R 20 is a phenyl group. For example, R 2 can be -CH2Ph ​​or -COOCH2Ph.

[0138] Most typically, R 2 is -COOCH2Ph ​​(i.e., a benzyloxycarbonyl (CBz) group).

[0139] As described, R 3 is a leaving group. In one embodiment of the fifth aspect of the invention, R 3 is selected from Cl, Br, I, or a sulfonate leaving group, such as a toluenesulfonate (tosylate or -OTs), methanesulfonate (mesylate or -OMs), or trifluoromethanesulfonate (triflate or -OTf) leaving group. Typically, R 3 is a sulfonate leaving group. Most typically, R 3 is -OMs.

[0140] In one embodiment of the fifth aspect of the invention, R 4 is selected from alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl groups; R 4 is optionally substituted with one or more substituents independently selected from halo, -CN, -OH, -NO2, -NH2, oxo (=O), -Me, -Et, -OMe, -OEt, -NHMe, -NHEt, -N(Me)2, -N(Me)Et, or -N(Et)2, any methyl (Me) or ethyl (Et) group may be substituted with one or more halo groups, R 4 contains 1 to 12 carbon atoms. More typically, R 4 is a C1-C6 alkyl or C1-C6 haloalkyl group, such as a methyl, trifluoromethyl, ethyl or isopropyl group. Most typically, R4 is methyl.

[0141] As noted, Hal is Cl or Br. Typically, Hal is Cl.

[0142] In one embodiment of the fifth aspect of the invention, reacting step (a) comprises contacting 4-hydroxypiperidine (F) with a nitrogen protecting group precursor. In one embodiment, the nitrogen protecting group precursor is X 2 -R 2 and X 2 is a leaving group. For example, X 2 -R 2 X 2 -CH2R 20 where R 20 is as defined above, and X 2 is selected from Cl, Br, I, or a sulfonate leaving group, such as a toluenesulfonate, methanesulfonate or trifluoromethanesulfonate leaving group. Typically, in such embodiments, X 2 is selected from Cl or Br. In one aspect of such an embodiment, X 2 -R 2 is Br-CH2R such as Br-CH2Ph 20 Or, X 2 -R 2 X 2 -COOCH2R 20 wherein R 20 is as defined above, and X 2 are Cl, Br, I, and OR 1 , S.R. 1 , N(R 1 )2, OP(=O)(R 1 )2 or OP(R 1 )3 + wherein R 1 is as defined for the first embodiment of the invention. Typically, X 2 -R 2 X 2- COOCH2R 20 If X 2is selected from Cl, Br or I. More typically, in such embodiments, X 2 -R 2 is Cl-COOCH2R 20 and most typically Cl-COOCH2Ph.

[0143] Typically, the reaction step (a) is carried out in the presence of a solvent. Typically, the solvent is a polar solvent or a mixture of a polar solvent and a non-polar solvent. For example, the solvent may include one or more polar protic solvents and / or one or more polar aprotic solvents and / or one or more non-polar solvents. Suitable polar protic solvents include water and alcohols such as methanol, ethanol, isopropanol or n-butanol. Suitable polar aprotic solvents include dimethylsulfoxide, N,N-dimethylformamide, N,N'-dimethylpropyleneurea, tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetone, acetonitrile, dichloromethane, hexamethylphosphoramide, nitromethane, propylene carbonate and N-methylpyrrolidone. Suitable non-polar solvents include pentane, cyclopentane, hexane, cyclohexane, diethyl ether and toluene.

[0144] In one embodiment, reacting step (a) is carried out in the presence of a polar protic solvent such as water, a polar aprotic solvent such as 1,4-dioxane, and a non-polar solvent such as toluene. Typically, in such an embodiment, the solvent mixture comprises 30-50% by volume of the polar protic solvent, 30-50% by volume of the polar aprotic solvent, and 10-30% by volume of the non-polar solvent.

[0145] Typically, reaction step (a) comprises reacting 4-hydroxypiperidine (F) with a nitrogen protecting group precursor (e.g., X 2 -R 2or Cl-COOCH2Ph) in the presence of a base. In one embodiment, the base is selected from a carbonate, bicarbonate, hydroxide or alkoxide base. Typically, the base is a hydroxide or alkoxide base, such as an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal alkoxide or an alkaline earth metal alkoxide. More typically, the base is a hydroxide, such as an alkali metal hydroxide or an alkaline earth metal hydroxide. Even more typically, the base is an alkali metal hydroxide, such as lithium hydroxide, potassium hydroxide or sodium hydroxide. Most typically, the base is sodium hydroxide.

[0146] In an exemplary embodiment of the fifth aspect of the invention, reacting step (a) comprises contacting 4-hydroxypiperidine (F) with benzyl chloroformate to obtain N-carboxybenzyl-4-hydroxypiperidine (G'): [ka]

[0147] Typically, in such embodiments, 4-hydroxypiperidine (F) is contacted with benzyl chloroformate in the presence of sodium hydroxide and a solvent.

[0148] In one embodiment of the fifth aspect of the present invention, the reaction step (a) is carried out at a temperature in the range of from 0 to 60° C. Typically, the reaction of step (a) is carried out at a temperature in the range of from 10 to 50° C. More typically, the reaction of step (a) is carried out at a temperature in the range of from 20 to 40° C.

[0149] Typically, according to the fifth aspect of the present invention, in step (a), 4-hydroxypiperidine (F) is present in the solvent or added to the solvent at an initial concentration of 0.01-10 mol / L relative to the total volume of solvent used in the reaction mixture. More typically, 4-hydroxypiperidine (F) is present in the solvent or added to the solvent at an initial concentration of 0.5-1.0 mol / L. Most typically, 4-hydroxypiperidine (F) is present in the solvent or added to the solvent at an initial concentration of 0.7-0.8 mol / L.

[0150] Typically, the process of step (a) of the fifth aspect of the present invention comprises the addition of 0.5 to 2.0 molar equivalents of a nitrogen protecting group precursor (e.g., X 2 -R 2 Or Cl-COOCH2Ph). More typically, this method uses 0.8 to 1.1 molar equivalents of the nitrogen protecting group precursor. Most typically, this method uses 0.9 to 1.0 molar equivalents of the nitrogen protecting group precursor.

[0151] Typically, the process of step (a) of the fifth aspect of the invention uses 0.8 to 1.5 molar equivalents of base relative to the initial amount of 4-hydroxypiperidine (F). More typically, the process uses 0.9 to 1.2 molar equivalents of base. Most typically, the process uses 1.0 to 1.1 molar equivalents of base.

[0152] In one embodiment of the fifth aspect of the invention, the process of step (a) comprises: (i) combining 4-hydroxypiperidine (F) with a first portion of a solvent to form a first mixture; (ii) dissolving a base in a second portion of the solvent and adding the resulting solution to the mixture formed in step (i) to form a second mixture; and (iii) dissolving the nitrogen protecting group precursor in a third portion of the solvent and adding the resulting solution to the mixture formed in step (ii) to form a third mixture.

[0153] Typically, the first portion of the solvent is or comprises a polar aprotic solvent, such as 1,4-dioxane. Typically, the second portion of the solvent is or comprises a polar protic solvent, such as water. Typically, the third portion of the solvent is or comprises a non-polar solvent, such as toluene.

[0154] In one embodiment of the fifth aspect of the invention, at the end of the reaction, the process of step (a) further comprises partitioning the reaction mixture between one or more aqueous phases and one or more organic phases, and N-protected-4-hydroxypiperidine (G) or (G') is extracted into one or more organic phases. Typically, the one or more organic phases comprise an ether, such as MTBE.

[0155] One or more organic phases containing N-protected 4-hydroxypiperidine (G) or (G') are (i) Washing with a salt solution, such as a NaCl solution, and / or (ii) dried over a sulfate such as magnesium sulfate or sodium sulfate;

[0156] Typically, after extraction and any washing or drying steps, some or all of the solvent of the organic phase containing the N-protected-4-hydroxypiperidine (G) or (G') is removed under reduced pressure.

[0157] A sixth aspect of the present invention provides an N-protected 4-hydroxypiperidine (G) or a salt thereof. [ka] (In the formula, R 2 is a nitrogen protecting group)

[0158] In a sixth aspect of the present invention, R 2 may be defined according to any embodiment of the fifth aspect of the present invention.

[0159] A particular embodiment of the sixth aspect of the invention provides N-carboxybenzyl-4-hydroxypiperidine (G') or a salt thereof. [ka]

[0160] N-protected 4-hydroxypiperidine (G) or a salt thereof, or N-carboxybenzyl-4-hydroxypiperidine (G') or a salt thereof may be prepared or preparable by the method of step (a) of the fifth aspect of the present invention.

[0161] Typically, the N-protected-4-hydroxypiperidine (G) or N-carboxybenzyl-4-hydroxypiperidine (G') of the sixth aspect of the invention is in a non-salt form.

[0162] In one embodiment of the fifth aspect of the invention, reacting step (b) comprises contacting an N-protected 4-hydroxypiperidine (G), such as N-carboxybenzyl-4-hydroxypiperidine (G′), with a sulfonyl halide or anhydride to produce an N-protected 4-derivatized piperidine (H), where R 3 is a sulfonate leaving group.

[0163] As will be appreciated, the sulfonyl halide or anhydride used is R 3 For example, R 3 When R is a tosylate leaving group, a tosyl halide or tosyl anhydride is used. 3 When is a mesylate leaving group, a mesyl halide or mesyl anhydride is used, and R 3 When is a triflate leaving group, a triflate halide or triflate anhydride is used.

[0164] Typically, a sulfonyl halide is used. In one embodiment, the sulfonyl halide is selected from sulfonyl chloride, sulfonyl bromide, or sulfonyl iodide. Typically, the sulfonyl halide is a sulfonyl chloride or a sulfonyl bromide. More typically, the sulfonyl halide is a sulfonyl chloride.

[0165] In an exemplary embodiment of the fifth aspect of the invention, reacting step (b) comprises contacting an N-protected-4-hydroxypiperidine (G) with a mesyl halide or mesyl anhydride to produce an N-protected-4-derivatized piperidine (H), 3 is a mesylate leaving group. Most typically, in such embodiments, reacting step (b) comprises contacting N-protected-4-hydroxypiperidine (G) with mesyl chloride.

[0166] Typically, the reaction step (b) is carried out in the presence of a solvent. In one embodiment, the solvent is a polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide, N,N'-dimethylpropyleneurea, tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetone, acetonitrile, dichloromethane, hexamethylphosphoramide, nitromethane, propylene carbonate, N-methylpyrrolidone, or a mixture thereof. Typically, the solvent does not contain an ester. More typically, the solvent does not contain a carbonyl group. For example, the solvent may be selected from dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, hexamethylphosphoramide, nitromethane, or a mixture thereof. Even more typically, the solvent does not contain a carbonyl, C=N or C≡N group. For example, the solvent may be selected from dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, dichloromethane, hexamethylphosphoramide, nitromethane, or mixtures thereof. Most typically, the solvent is dichloromethane.

[0167] In one embodiment of the fifth aspect of the present invention, the reaction step (b) is carried out in the presence of a base. Typically, the base is a sterically hindered base. For example, the base can be a tertiary amine such as N,N-diisopropylethylamine (DIPEA), trimethylamine, triethylamine (TEA), tripropylamine or tributylamine. Most typically, the base is triethylamine (TEA).

[0168] In an exemplary embodiment of the fifth aspect of the present invention, reacting step (b) comprises contacting N-carboxybenzyl-4-hydroxypiperidine (G') with mesyl chloride to obtain benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H'). [ka]

[0169] Typically in such embodiments, N-carboxybenzyl-4-hydroxypiperidine (G') is contacted with mesyl chloride in the presence of a tertiary amine base, such as triethylamine, and a polar aprotic solvent, such as dichloromethane.

[0170] In one embodiment of the fifth aspect of the present invention, in step (b), the N-protected 4-hydroxypiperidine (G) or (G') is mixed with the sulfonyl halide or anhydride at a temperature in the range of -20 to 20° C. Typically, the N-protected 4-hydroxypiperidine (G) or (G') is mixed with the sulfonyl halide or anhydride at a temperature in the range of -10 to 10° C., more typically in the range of -5 to 5° C.

[0171] In one embodiment of the fifth aspect of the invention, in step (b), after N-protected-4-hydroxypiperidine (G) or (G') is combined with the sulfonyl halide or anhydride, the reaction mixture is warmed to a temperature in the range of 10 to 50° C. Typically, the reaction mixture is warmed to a temperature in the range of 20 to 40° C., more typically to a temperature in the range of 25 to 30° C.

[0172] Typically, according to the fifth aspect of the present invention, in step (b), the N-protected 4-hydroxypiperidine (G) or (G') is present in the solvent or added to the solvent at an initial concentration of 0.01 to 10 mol / L relative to the total volume of solvent used in the reaction mixture. More typically, the N-protected 4-hydroxypiperidine (G) or (G') is present in the solvent or added to the solvent at an initial concentration of 0.5 to 1.5 mol / L. Most typically, the N-protected 4-hydroxypiperidine (G) or (G') is present in the solvent or added to the solvent at an initial concentration of 0.7 to 0.9 mol / L.

[0173] Typically, the process of step (b) of the fifth aspect of the invention uses 0.9 to 2.0 molar equivalents of sulfonyl halide or sulfonyl anhydride relative to the initial amount of N-protected-4-hydroxypiperidine (G) or (G'). More typically, the process uses 1.0 to 1.5 molar equivalents of sulfonyl halide or sulfonyl anhydride. Most typically, the process uses 1.2 to 1.4 molar equivalents of sulfonyl halide or sulfonyl anhydride.

[0174] Typically, the process of step (b) of the fifth aspect of the invention uses 1.0 to 3.0 molar equivalents of base relative to the initial amount of N-protected-4-hydroxypiperidine (G) or (G'). More typically, the process uses 1.5 to 2.5 molar equivalents of base. Most typically, the process uses 1.8 to 2.2 molar equivalents of base.

[0175] In one embodiment of the fifth aspect of the invention, the process of step (b) comprises: (i) combining N-protected-4-hydroxypiperidine (G) or (G') with a solvent to form a first mixture; (ii) adding a base to the mixture formed in step (i) to form a second mixture; and (iii) adding a sulfonyl halide or sulfonyl anhydride to the mixture formed in step (ii) to form a third mixture.

[0176] In one embodiment of the fifth aspect of the invention, at the end of the reaction, the process of step (b) comprises the following work-up step:

[0177] (i) optionally filtering the solids from the reaction mixture to obtain a filtrate; (ii) washing the reaction mixture or filtrate, in which the N-protected-4-derivatized piperidine (H) or (H') is retained in the organic phase, one or more times with an aqueous wash solution; (iii) optionally drying the organic phase with a sulfate, such as magnesium sulfate or sodium sulfate; and (iv) optionally removing the solvent from the organic phase under reduced pressure.

[0178] Typically the process of step (b) includes all four of the work-up steps (i)-(iv).

[0179] In one embodiment, the one or more aqueous washes include washes with (i) aqueous sodium bicarbonate, (ii) water, and (iii) aqueous sodium chloride.

[0180] Optionally, the N-protected-4-derivatized piperidine (H) or (H') is isolated by precipitation or crystallization from a crystallization solvent, which typically comprises a mixture of a polar aprotic solvent and a non-polar solvent, such as ethyl acetate and hexane.

[0181] A seventh aspect of the present invention relates to N-protected-4-derivatized piperidines (H) [ka] (In the formula, R 2 is a nitrogen protecting group, R 3 is a leaving group) or a salt thereof.

[0182] In a seventh aspect of the present invention, R 2 and R 3may be defined according to any embodiment of the fifth aspect of the present invention.

[0183] A particular embodiment of the seventh aspect of the invention provides benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H') or a salt thereof. [ka]

[0184] The N-protected-4-derivatized piperidine (H) or a salt thereof, or benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H') or a salt thereof may be prepared or preparable by the method of step (b) of the fifth aspect of the present invention.

[0185] Typically, the N-protected-4-derivatized piperidine (H) or benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H') of the seventh aspect of the invention is in a non-salt form.

[0186] In one embodiment of the seventh aspect of the invention, the N-protected-4-derivatized piperidine (H) or a salt thereof has an HPLC purity of 90% or greater. More typically, the N-protected-4-derivatized piperidine (H) or a salt thereof has an HPLC purity of 94% or greater.

[0187] In another embodiment of the seventh aspect of the present invention, benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H') or a salt thereof has an HPLC purity of 90% or more. More typically, benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H') or a salt thereof has an HPLC purity of 94% or more.

[0188] In one embodiment of the fifth aspect of the invention, the reaction in step (c) comprises reacting an N-protected 4-derivatized piperidine (H) with R 4 COS-, contacting R 4is as defined above. Most typically, reaction step (c) comprises reacting the N-protected 4-derivatized piperidine (H) with MeCOS - The method includes contacting the

[0189] R 4 COS - or MeCOS - may be provided in the form of a salt or as the corresponding acid R 4 It may be generated in situ by reaction of COSH or MeCOSH with a base. Typically, R 4 COS - or MeCOS - is generated in situ. R 4 COS - or MeCOS - When generated in situ, typically R 4 COSH or MeCOSH is added to the reaction mixture after the addition of the base.

[0190] R 4 COS - or MeCOS - When provided in the form of a salt, typically the salt is an alkali metal salt, such as a sodium, potassium, rubidium or cesium salt, or an alkaline earth metal salt, such as a magnesium or calcium salt. More typically, the salt is an alkali metal salt. Most typically, the salt is a cesium salt.

[0191] R 4 COS - or MeCOS - When is generated in situ, typically the base is a carbonate, bicarbonate or hydroxide base, such as an alkali metal or alkaline earth metal carbonate, alkali metal bicarbonate or alkali metal or alkaline earth metal hydroxide. Typically the base is a carbonate. In one embodiment the base is selected from cesium carbonate, cesium bicarbonate or cesium hydroxide. Conveniently the base is cesium carbonate.

[0192] Typically, the reaction step (c) is carried out in the presence of a solvent. In one embodiment, the solvent is a polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide, N,N'-dimethylpropyleneurea, tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetone, acetonitrile, dichloromethane, hexamethylphosphoramide, nitromethane, propylene carbonate, N-methylpyrrolidone, or a mixture thereof. Typically, the solvent does not contain an ester. Typically, the solvent is not halogenated. For example, the solvent may be selected from dimethylsulfoxide, N,N-dimethylformamide, N,N'-dimethylpropyleneurea, tetrahydrofuran, 1,4-dioxane, acetone, acetonitrile, hexamethylphosphoramide, nitromethane, propylene carbonate, N-methylpyrrolidone, or a mixture thereof. Most typically, the solvent is N,N-dimethylformamide.

[0193] In an exemplary embodiment of the fifth aspect of the present invention, reacting step (c) comprises reacting benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H') with MeCOS - in a solvent to obtain benzyl 4-(acetylthio)piperidine-1-carboxylate (I'). [ka]

[0194] Typically, in such embodiments, MeCOS - is generated in situ by reaction of MeCOSH with a base such as cesium carbonate. Typically, in such embodiments, the solvent is N,N-dimethylformamide.

[0195] In one embodiment of the fifth aspect of the present invention, the reaction step (c) is carried out at a temperature in the range of from 0 to 70° C. Typically, the reaction of step (c) is carried out at a temperature in the range of from 10 to 60° C. More typically, the reaction of step (c) is carried out at a temperature in the range of from 15 to 50° C.

[0196] Typically, according to the fifth aspect of the invention, in step (c), the N-protected-4-derivatized piperidine (H) or (H') is present in the solvent or added to the solvent at an initial concentration of 0.01 to 10 mol / L relative to the total volume of solvent used in the reaction mixture. More typically, the N-protected-4-derivatized piperidine (H) or (H') is present in the solvent or added to the solvent at an initial concentration of 0.1 to 2.0 mol / L. Most typically, the N-protected-4-derivatized piperidine (H) or (H') is present in the solvent or added to the solvent at an initial concentration of 0.5 to 0.8 mol / L.

[0197] Typically, the process of step (c) of the fifth aspect of the present invention comprises the addition of 0.9 to 3.0 molar equivalents of R relative to the initial amount of N-protected-4-derivatized piperidine (H) or (H′). 4 COS - or MeCOS - More typically, this method uses 1.0 to 2.0 molar equivalents of 4 COS - or MeCOS - Most typically, this method uses 1.4 to 1.6 molar equivalents of R 4 COS - or MeCOS - Use.

[0198] Typically, when the process of step (c) of the fifth aspect of the invention uses a base, the process uses 0.9 to 3.0 molar equivalents of base relative to the initial amount of N-protected-4-derivatized piperidine (H) or (H'). More typically, the process uses 1.0 to 2.0 molar equivalents of base. Most typically, the process uses 1.4 to 1.6 molar equivalents of base.

[0199] In one embodiment of the fifth aspect of the invention, the process of step (c) comprises: (i) combining an N-protected-4-derivatized piperidine (H) or (H') with a solvent to form a first mixture; (ii) adding a base to the mixture formed in step (i) to form a second mixture; and (iii)R 4 adding COSH or MeCOSH to the mixture formed in step (ii) to form a third mixture.

[0200] In one embodiment of the fifth aspect of the invention, at the end of the reaction, the process of step (c) comprises the following work-up step:

[0201] (i) optionally filtering the solids from the reaction mixture to obtain a filtrate; (ii) washing the reaction mixture or filtrate with one or more aqueous washes, optionally with the addition of additional water-immiscible solvent such as ethyl acetate, wherein the N-protected-4-(acylthio)-piperidine (I) or (I') is retained in the organic phase; (iii) optionally drying the organic phase with a sulfate, such as magnesium sulfate or sodium sulfate; and (iv) optionally removing the solvent from the organic phase under reduced pressure.

[0202] Typically the process of step (c) includes all four of the work-up steps (i)-(iv).

[0203] In one embodiment, the one or more aqueous washes include washes with (i) water, (ii) aqueous sodium bicarbonate, and (iii) aqueous sodium chloride.

[0204] An eighth aspect of the present invention relates to N-protected-4-(acylthio)-piperidines (I) [ka] (In the formula, R 2 is a nitrogen protecting group, R 4 is C1-C 20 is a hydrocarbyl group, C1-C 20The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and may be any of C1-C 20 The hydrocarbyl group may be substituted with one or more oxo (=O) and / or one or more halo groups, and may be C-C 20 The hydrocarbyl group may contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S) or salts thereof.

[0205] In an eighth aspect of the present invention, R 2 and R 4 may be defined according to any embodiment of the fifth aspect of the present invention.

[0206] A particular embodiment of the eighth aspect of the invention is benzyl 4-(acetylthio)piperidine-1-carboxylate (I') [ka] or a salt thereof.

[0207] The N-protected-4-(acylthio)-piperidine (I) or a salt thereof, or benzyl 4-(acetylthio)piperidine-1-carboxylate (I') or a salt thereof may be prepared or preparable by the method of step (c) of the fifth aspect of the present invention.

[0208] Typically, the N-protected-4-(acylthio)-piperidine (I) or benzyl 4-(acetylthio)-piperidine-1-carboxylate (I') of the eighth aspect of the invention is in a non-salt form.

[0209] In one embodiment of the fifth aspect of the present invention, reacting step (d) comprises contacting the N-protected-4-(acylthio)-piperidine (I) with a halogenating agent to form the N-protected-4-(halosulfonyl)-piperidine (J).

[0210] In one embodiment, the halogenating agent is selected from n-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, trichloroisocyanuric acid, Cl2, n-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, tribromoisocyanuric acid and Br2. Typically, the halogenating agent is selected from N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, trichloroisocyanuric acid, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin and tribromoisocyanuric acid. More typically, the halogenating agent is selected from N-chlorosuccinimide and N-bromosuccinimide. Most typically, the halogenating agent is N-chlorosuccinimide.

[0211] In one embodiment of the fifth aspect of the invention, N-protected-4-(acylthio)-piperidine (I) is contacted with a halogenating agent in the presence of an acid and an aqueous solvent. In one embodiment, the acid is selected from HCl, HBr, or a carboxylic acid such as formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, malonic acid, succinic acid, tartaric acid, maleic acid or fumaric acid. Typically, the acid is a carboxylic acid, more typically a monocarboxylic acid such as formic acid, acetic acid, propionic acid or butyric acid. In some embodiments, the acid is acetic acid.

[0212] In one embodiment of the fifth aspect of the invention, the aqueous solvent for reaction step (d) is water or a mixture of water and one or more water-miscible solvents such as acetonitrile, methanol, ethanol, propanol, acetone, N,N-dimethylformamide, dioxane or tetrahydrofuran. Typically the aqueous solvent is water.

[0213] In an exemplary embodiment of the fifth aspect of the present invention, reacting step (d) comprises contacting benzyl 4-(acetylthio)piperidine-1-carboxylate (I') with a chlorinating agent to obtain benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J'): [ka]

[0214] Typically, in such embodiments, the chlorinating agent is N-chlorosuccinimide. Typically, in such embodiments, benzyl 4-(acetylthio)piperidine-1-carboxylate (I') is contacted with the chlorinating agent in the presence of acetic acid and water.

[0215] In one embodiment of the fifth aspect of the present invention, the reaction step (d) is carried out at a temperature in the range of 0 to 50° C. Typically, the reaction of step (d) is carried out at a temperature in the range of 10 to 40° C. Typically, the reaction of step (d) is carried out at a temperature in the range of 15 to 30° C.

[0216] Typically, according to the fifth aspect of the present invention, in step (d), the N-protected-4-(acylthio)-piperidine (I) or (I') is present in the solvent or added to the solvent at an initial concentration of 0.01 to 2 mol / L relative to the total volume of acid and solvent used in the reaction mixture. More typically, the N-protected-4-(acylthio)-piperidine (I) or (I') is present in the solvent or added to the solvent at an initial concentration of 0.05 to 0.5 mol / L. Most typically, the N-protected-4-(acylthio)-piperidine (I) or (I') is present in the solvent or added to the solvent at an initial concentration of 0.1 to 0.3 mol / L.

[0217] Typically, the process of step (d) of the fifth aspect of the invention uses 1.0 to 5.0 molar equivalents of halogenating agent relative to the initial amount of N-protected-4-(acylthio)-piperidine (I) or (I'). More typically, the process uses 2.0 to 4.0 molar equivalents of halogenating agent. Most typically, the process uses 2.5 to 3.0 molar equivalents of halogenating agent.

[0218] Typically, when the process of step (d) of the fifth aspect of the invention uses an acid and an aqueous solvent, the acid comprises 50-99% of the total volume of the acid and the solvent. More typically, the acid comprises 75-98% of the total volume of the acid and the solvent. Even more typically, the acid comprises 85-95% of the total volume of the acid and the solvent.

[0219] Typically, when the process of step (d) of the fifth aspect of the present invention uses an acid and an aqueous solvent, water comprises 1-50% of the total volume of the acid and the solvent. More typically, water comprises 2-25% of the total volume of the acid and the solvent combined. Even more typically, water comprises 5-15% of the total volume of the acid and the solvent combined.

[0220] In one embodiment of the fifth aspect of the invention, the process of step (d) comprises: (i) combining an N-protected-4-(acylthio)-piperidine (I) or (I') with an acid to form a first mixture; (ii) adding an aqueous solvent, such as water, to the mixture formed in step (i) to form a second mixture; and (iii) adding a halogenating agent to the mixture formed in step (ii) to form a third mixture.

[0221] In one embodiment of the fifth aspect of the invention, at the end of the reaction, the process of step (d) comprises the following work-up step:

[0222] (i) extracting the N-protected-4-(halosulfonyl)-piperidine (J) or (J') into a water-immiscible organic solvent, such as dichloromethane, to form an organic extract; (ii) optionally washing the organic extract with one or more aqueous washes, wherein the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is retained in the organic phase; and (iii) optionally drying the organic extract over a sulfate, such as magnesium sulfate or sodium sulfate;

[0223] Typically, the method of step (d) includes all three of the work-up steps (i)-(iii).

[0224] In one embodiment, the one or more aqueous washes include a wash with (i) water and (ii) an aqueous sodium bicarbonate solution.

[0225] A ninth aspect of the present invention provides an N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof. [ka] (In the formula, R 2 is a nitrogen protecting group, and Hal is Cl or Br.

[0226] In a ninth aspect of the present invention, R 2 and Hal may be defined according to any embodiment of the fifth aspect of the invention.

[0227] A particular embodiment of the ninth aspect of the invention provides benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J'). [ka]

[0228] N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof, or benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') or a salt thereof may be prepared or preparable by the method of step (d) of the fifth aspect of the present invention.

[0229] Typically, the N-protected-4-(halosulfonyl)-piperidine (J) or benzyl 4-(chloro-sulfonyl)-1-piperidinecarboxylate (J') of the ninth aspect of the invention is in a non-salt form.

[0230] In one embodiment of the fifth aspect of the invention, reacting step (e) comprises contacting N-protected-4-(halosulfonyl)-piperidine (J) with ammonia to form N-protected-4-piperidinesulfonamide (K).

[0231] Typically, N-protected-4-(halosulfonyl)-piperidine (J) is contacted with ammonia in the presence of a solvent. Typically, the reaction step (e) comprises purging the solution of N-protected-4-(halosulfonyl)-piperidine (J) with ammonia gas. Typically, the solvent is a polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide, N,N'-dimethylpropyleneurea, tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetone, acetonitrile, dichloromethane, hexamethylphosphoramide, nitromethane, propylene carbonate, N-methylpyrrolidone, or a mixture thereof. Typically, the solvent does not contain an ester. More typically, the solvent does not contain a carbonyl group. For example, the solvent may be selected from dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, hexamethylphosphoramide, nitromethane, or a mixture thereof. Even more typically, the solvent does not contain a carbonyl, C=N or C≡N group. For example, the solvent may be selected from dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, dichloromethane, hexamethylphosphoramide, nitromethane, or a mixture thereof. Most typically, the solvent is dichloromethane.

[0232] In an exemplary embodiment of the fifth aspect of the invention, reacting step (e) comprises contacting benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') with ammonia to obtain 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K'): [ka]

[0233] Typically in such embodiments, benzyl 4-(chlorosulfonyl)-1-piperidine-carboxylate (J') is contacted with ammonia in the presence of a polar aprotic solvent such as dichloromethane.

[0234] In one embodiment of the fifth aspect of the present invention, in step (e), the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is combined with ammonia at a temperature in the range of -70 to 0° C. Typically, the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is combined with ammonia at a temperature in the range of -50 to -20° C., more typically in the range of -40 to -30° C.

[0235] In one embodiment of the fifth aspect of the invention, in step (e) after N-protected-4-(halosulfonyl)-piperidine (J) or (J') is combined with ammonia, the reaction mixture is warmed to a temperature in the range of 10 to 50° C. Typically, the reaction mixture is warmed to a temperature in the range of 20 to 40° C., more typically to a temperature in the range of 25 to 30° C.

[0236] Typically, according to the fifth aspect of the present invention, in step (e), the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is present in the solvent or added to the solvent at an initial concentration of 0.01 to 10 mol / L relative to the total volume of solvent used in the reaction mixture. More typically, the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is present in the solvent or added to the solvent at an initial concentration of 0.1 to 1.0 mol / L. Most typically, the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is present in the solvent or added to the solvent at an initial concentration of 0.2 to 0.4 mol / L.

[0237] In one embodiment of the fifth aspect of the invention, at the end of the reaction, the process of step (e) comprises the following work-up step: (i) filtering the solids from the reaction mixture to obtain a filtrate; (ii) optionally drying the filtrate over a sulfate, such as magnesium sulfate or sodium sulfate; and (iii) optionally removing the solvent from the filtrate under reduced pressure.

[0238] Typically, the method of step (e) includes all four of the work-up steps (i)-(iii).

[0239] Optionally, the N-protected-4-piperidinesulfonamide (K) or (K') is isolated by precipitation or crystallization from a crystallization solvent. Typically, the crystallization solvent comprises a mixture of a polar aprotic solvent and a non-polar solvent, such as ethyl acetate and hexane.

[0240] Optionally, the N-protected-4-piperidinesulfonamide (K) or (K') undergoes one or more purification steps selected from the following:

[0241] (i) treating a solution of N-protected-4-piperidinesulfonamide (K) or (K') with neutral alumina; and (ii) precipitating or crystallizing the N-protected-4-piperidinesulfonamide (K) or (K') from a recrystallization solvent.

[0242] Typically, the purification of the N-protected-4-piperidinesulfonamide (K) or (K') comprises both purification steps (i) and (ii).

[0243] In one embodiment of the fifth aspect of the invention, in purification step (i), the solvent is a mixture of a polar aprotic solvent and a polar protic solvent, such as a mixture of dichloromethane and methanol.

[0244] Typically, after treatment, the neutral alumina is removed by filtration.

[0245] In one embodiment of the fifth aspect of the invention, in the purification step (ii), the recrystallization solvent is a mixture of a polar aprotic solvent, a polar protic solvent and a non-polar solvent, such as a mixture of dichloromethane, methanol and hexane. Typically, when the purification comprises both steps (i) and (ii), the recrystallization solvent is formed by adding a non-polar solvent to the filtrate from step (i).

[0246] A tenth aspect of the present invention provides an N-protected-4-piperidinesulfonamide (K) or a salt thereof. [ka] (In the formula, R 2 is a nitrogen protecting group)

[0247] In a tenth aspect of the present invention, R 2 may be defined according to any embodiment of the fifth aspect of the present invention.

[0248] A particular embodiment of the tenth aspect of the invention provides 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') or a salt thereof. [ka]

[0249] N-protected-4-piperidinesulfonamide (K) or a salt thereof, or 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') or a salt thereof may be prepared or preparable by the method of step (e) of the fifth aspect of the present invention.

[0250] Typically, the N-protected-4-piperidinesulfonamide (K) or 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') of the tenth aspect of the invention is in a non-salt form.

[0251] In one embodiment of the tenth aspect of the present invention, the N-protected-4-piperidinesulfonamide (K) or a salt thereof has an HPLC purity of 90% or more. More typically, the N-protected-4-piperidinesulfonamide (K) or a salt thereof has an HPLC purity of 95% or more. Even more typically, the N-protected-4-piperidinesulfonamide (K) or a salt thereof has an HPLC purity of 96% or more.

[0252] In another embodiment of the tenth aspect of the present invention, 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') or a salt thereof has an HPLC purity of 90% or more. More typically, 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') or a salt thereof has an HPLC purity of 95% or more. More typically, 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') or a salt thereof has an HPLC purity of 96% or more.

[0253] In one embodiment of the fifth aspect of the present invention, reacting step (f) comprises (i) deprotecting N-protected-4-piperidinesulfonamide (K) to form piperidine-4-sulfonamide; and (ii) alkylating piperidine-4-sulfonamide to form 1-ethyl-4-piperidine-sulfonamide (A).

[0254] As will be appreciated, the reaction conditions for the deprotection step (i) correspond to the nitrogen protecting group being removed. For example, R 2 benzyloxycarbonyl (CBz), 4-methoxy-benzyloxycarbonyl, benzyl, -CHR 20 or -COOCH2R 20 If R is a cyclic group, it may be removed by catalytic hydrogenolysis or by treatment with HBr in a carboxylic acid such as acetic acid or trifluoroacetic acid. 2 When R is a t-butoxycarbonyl (Boc) group, R can be removed under acidic conditions, for example by treatment with trifluoroacetic acid. 2When R is a 2-(4-biphenylyl)-isopropoxycarbonyl (Bpoc) or triphenylmethyl (Trt) group, R can be removed under acidic conditions, for example by treatment with trifluoroacetic acid, or by catalytic hydrogenolysis. 2 When R is a 2,2,2-trichloroethoxycarbonyl (Troc) group, R can be removed by treatment with zinc in acetic acid. Suitable conditions for deprotection are described, for example, in Wuts, 'Greene's Protective Groups in Organic Synthesis', Vol. 5. 版 Ed., 2014, the contents of which are incorporated herein by reference in their entirety.

[0255] Typically, according to the fifth aspect of the invention, R 2 is a nitrogen protecting group that can be removed by catalytic hydrogenolysis. When the nitrogen protecting group is removed by catalytic hydrogenolysis, typically the process of step (i) comprises contacting the N-protected-4-piperidinesulfonamide (K) with a catalyst in the presence of hydrogen gas. Suitable catalysts include Raney nickel and palladium catalysts. In one embodiment, the catalyst is a palladium catalyst, such as palladium on carbon or palladium oxide on carbon. Typically, the catalyst is palladium hydroxide on carbon. Typically, hydrogen gas is used at a pressure in the range of 0.1 to 5 bar. In one embodiment, hydrogen gas is used at a typical pressure in the range of 0.5 to 2 bar, more typically in the range of 0.8 to 1.2 bar. In another embodiment, hydrogen gas is used at a typical pressure in the range of 2 to 4 bar, more typically in the range of 2.5 to 3.5 bar.

[0256] Typically, N-protected-4-piperidinesulfonamide (K) is contacted with the catalyst in the presence of hydrogen gas and a solvent. Typically, the solvent is a polar protic solvent, or a polar aprotic solvent, or a mixture thereof. For example, the solvent can be selected from tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, water, methanol, ethanol, isopropanol, butanol, or a mixture thereof.

[0257] Typically, the catalytic hydrocracking of step (i) is carried out at a temperature in the range of 0 to 70°C. In one embodiment of the fifth aspect of the present invention, the catalytic hydrocracking of step (i) of reaction step (f) is carried out at a temperature in the range of 0 to 50°C. Typically, in such an embodiment, the catalytic hydrocracking of step (i) is carried out at a temperature in the range of 10 to 35°C. More typically, the catalytic hydrocracking of step (i) is carried out at a temperature in the range of 15 to 25°C. In another embodiment of the fifth aspect of the present invention, the catalytic hydrocracking of step (i) of reaction step (f) is carried out at a temperature in the range of 10 to 50°C. Typically, in such an embodiment, the catalytic hydrocracking of step (i) is carried out at a temperature in the range of 15 to 30°C.

[0258] The alkylation step (ii) of reaction step (f) may be carried out under a variety of conditions.

[0259] In one embodiment, the alkylation step (ii) comprises reacting piperidine-4-sulfonamide with Et-X f (X f is a leaving group. Typically in such embodiments, X f is selected from Cl, Br, I, or a sulfonic acid leaving group, such as a toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid leaving group. More typically, X f is selected from Cl, Br or I.

[0260] In one embodiment, piperidine-4-sulfonamide is reacted with Et-X in the presence of a solvent and, optionally, a base. fTypically, the solvent is a polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide, N,N'-dimethylpropyleneurea, tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetone, acetonitrile, dichloromethane, hexamethylphosphoramide, nitromethane, propylene carbonate, N-methylpyrrolidone, or mixtures thereof. Typically, the base is a carbonate base, such as an alkali metal carbonate or an alkaline earth metal carbonate.

[0261] In another embodiment, piperidine-4-sulfonamide is alkylated by reductive alkylation. For example, piperidine-4-sulfonamide can be contacted with acetonitrile or acetaldehyde in the presence of a hydride source such as NaCNBH3.

[0262] Alternatively, piperidine-4-sulfonamide may be contacted with acetonitrile or acetaldehyde in the presence of a catalyst and hydrogen gas. Typically, piperidine-4-sulfonamide is contacted with acetonitrile in the presence of a catalyst and hydrogen gas. Suitable catalysts include Raney nickel and palladium catalysts. In one embodiment, the catalyst is a palladium catalyst, such as palladium on carbon or palladium oxide on carbon. Typically, the catalyst is palladium hydroxide on carbon. In another embodiment, the catalyst is Raney nickel. Typically, hydrogen gas is used at a pressure in the range of 0.1 to 5 bar. In one embodiment, hydrogen gas is used at a typical pressure in the range of 0.5 to 2 bar, most typically in the range of 0.8 to 1.2 bar. In another embodiment, hydrogen gas is used at a typical pressure in the range of 2 to 4 bar, more typically in the range of 2.5 to 3.5 bar.

[0263] When piperidine-4-sulfonamide is contacted with acetonitrile or acetaldehyde, in one embodiment, acetonitrile or acetaldehyde, or a mixture of acetonitrile or acetaldehyde and water, is used as the solvent.

[0264] In another embodiment, when piperidine-4-sulfonamide is contacted with acetonitrile or acetaldehyde, the contacting is carried out in the presence of a solvent. Typically, the solvent is a polar protic solvent, or a polar aprotic solvent (other than acetonitrile or acetaldehyde), or a mixture thereof. For example, the solvent may be selected from tetrahydrofuran, 1,4-dioxane, dichloromethane, water, methanol, ethanol, isopropanol, butanol, or a mixture thereof. More typically, the solvent is a polar protic solvent, such as water, methanol, ethanol, isopropanol, butanol, or a mixture thereof. Most typically, the solvent is a mixture of ethanol and water. Typically, in such an embodiment, 1 to 10 molar equivalents of acetonitrile or acetaldehyde are used relative to the amount of piperidine-4-sulfonamide. More typically, 1.2 to 5 molar equivalents of acetonitrile or acetaldehyde are used. Most typically, 1.5 to 3.5 molar equivalents of acetonitrile or acetaldehyde are used.

[0265] In one embodiment of the fifth aspect of the present invention, the alkylation in step (ii) is carried out at a temperature in the range of 0 to 50° C. Typically, the alkylation in step (ii) is carried out at a temperature in the range of 10 to 35° C. More typically, the alkylation in step (ii) is carried out at a temperature in the range of 15 to 25° C.

[0266] In another embodiment of the fifth aspect of the invention, the alkylation in step (ii) is carried out at a temperature in the range of 0 to 60° C. Typically, in such embodiments, the alkylation in step (ii) is carried out at a temperature in the range of 10 to 50° C. In one aspect of such embodiments, the alkylation in step (ii) is carried out at a temperature in the range of 35 to 45° C. In another aspect of such embodiments, the alkylation in step (ii) is carried out at a temperature in the range of 15 to 30° C.

[0267] As will be appreciated, advantageously, R 2 is a nitrogen protecting group that can be removed by catalytic hydrogenolysis; (i) deprotecting N-protected-4-piperidinesulfonamide (K) to form piperidine-4-sulfonamide; and (ii) alkylating piperidine-4-sulfonamide to form 1-ethyl-4-piperidine-sulfonamide (A), They may be carried out simultaneously or sequentially in a one-pot reaction.

[0268] Therefore, R 2 In one embodiment of the fifth aspect of the invention, where is a nitrogen protecting group that can be removed by catalytic hydrogenolysis, reacting step (f) comprises contacting N-protected-4-piperidinesulfonamide (K) with acetonitrile or acetaldehyde in the presence of a catalyst and hydrogen gas to obtain 1-ethyl-4-piperazinesulfonamide (A). Typically, in such an embodiment, reacting step (f) comprises contacting N-protected-4-piperidinesulfonamide (K) with acetonitrile in the presence of a catalyst and hydrogen gas. Suitable catalysts include Raney nickel and palladium catalysts. In one embodiment, the catalyst is a palladium catalyst, such as palladium on carbon or palladium oxide on carbon. Typically, the catalyst is palladium hydroxide on carbon.

[0269] In an exemplary embodiment of the fifth aspect of the present invention, reacting step (f) comprises contacting 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') with acetonitrile or acetaldehyde in the presence of a catalyst and hydrogen gas to obtain 1-ethyl-4-piperazinesulfonamide (A): [ka]

[0270] Typically, in such embodiments, 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') is contacted with acetonitrile in the presence of a catalyst and hydrogen gas. Typically, the catalyst is a palladium catalyst, such as palladium hydroxide on carbon.

[0271] In either of the above two embodiments, the catalyst is palladium on carbon or palladium hydroxide on carbon, and typically 5-35 wt% palladium on carbon or palladium hydroxide on carbon is used. More typically, 10-30 wt% palladium on carbon or palladium hydroxide on carbon is used. Most typically, 15-25 wt% palladium on carbon or palladium hydroxide on carbon is used.

[0272] When reaction step (f) involves contacting the N-protected-4-piperidinesulfonamide (K) or (K') with acetonitrile or acetaldehyde in the presence of a catalyst and hydrogen gas, typically hydrogen gas is used at a pressure in the range of 0.1 to 5 bar, more typically in the range of 0.5 to 2 bar, and most typically in the range of 0.8 to 1.2 bar.

[0273] When reaction step (f) involves contacting the N-protected-4-piperidinesulfonamide (K) or (K') with acetonitrile or acetaldehyde in the presence of a catalyst and hydrogen gas, reaction step (f) can be carried out at a temperature in the range of 0 to 50° C. Typically, reaction step (f) is carried out at a temperature in the range of 10 to 35° C. More typically, reaction step (f) is carried out at a temperature in the range of 15 to 25° C.

[0274] When N-protected-4-piperidinesulfonamide (K) or (K') is contacted with acetonitrile or acetaldehyde, typically acetonitrile or acetaldehyde or a mixture of acetonitrile or acetaldehyde and water is used as a solvent. In one embodiment, acetonitrile or a mixture of acetonitrile and water is used as a solvent. Typically, a mixture of acetonitrile and water is used as a solvent.

[0275] When a mixture of acetonitrile and water is used as the solvent in step (f), typically the solvent mixture contains 25-50 wt.% water based on the total weight of the solvent. More typically, the solvent mixture contains 30-45 wt.% water. Most typically, the solvent mixture contains 35-40 wt.% water.

[0276] Typically, according to the fifth aspect of the present invention, in step (f), the N-protected-4-piperidinesulfonamide (K) or (K') is present in the solvent or added to the solvent at an initial concentration of 0.01 to 10 mol / L relative to the total volume of the solvent used in the reaction mixture. More typically, the N-protected-4-piperidinesulfonamide (K) or (K') is present in the solvent or added to the solvent at an initial concentration of 0.1 to 1.0 mol / L. Most typically, the N-protected-4-piperidinesulfonamide (K) or (K') is present in the solvent or added to the solvent at an initial concentration of 0.3 to 0.5 mol / L.

[0277] In one embodiment of the fifth aspect of the present invention, the reaction step (f) comprises contacting N-protected-4-piperidinesulfonamide (K) or (K'), or piperidine-4-sulfonamide, with acetonitrile or acetaldehyde in the presence of a catalyst and hydrogen gas, and at the end of the reaction, the process of step (f) comprises the following work-up step: (i) removing hydrogen; (ii) removing the catalyst, for example by filtration; (iii) optionally decolorizing the reaction mixture using activated carbon; (iv) optionally contacting the reaction mixture with a metal scavenger, e.g., SiliaMetS thiol; and (v) Optionally, removing the reaction solvent, for example by co-evaporation with an alcohol such as n-butanol, at reduced pressure to obtain 1-ethyl-4-piperazine-sulfonamide (A).

[0278] Typically, the method of step (f) includes all five of the work-up steps (i)-(v).

[0279] In another embodiment of the fifth aspect of the invention, R 2 When is a nitrogen protecting group that can be removed by catalytic hydrogenolysis, reaction step (f) is (i) contacting an N-protected-4-piperidinesulfonamide (K) with a first catalyst in the presence of hydrogen gas and a solvent to form an intermediate mixture comprising piperidine-4-sulfonamide and a solvent; and (ii) contacting the intermediate mixture comprising piperidine-4-sulfonamide and a solvent with acetonitrile or acetaldehyde in the presence of a second catalyst and hydrogen gas to obtain 1-ethyl-4-piperidine-sulfonamide (A).

[0280] In an exemplary embodiment of the fifth aspect of the present invention, reacting step f) comprises: (i) contacting 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') with a first catalyst in the presence of hydrogen gas and a solvent to form an intermediate mixture comprising piperidine-4-sulfonamide and a solvent; and (ii) contacting the intermediate mixture comprising piperidine-4-sulfonamide and a solvent with acetonitrile or acetaldehyde in the presence of a second catalyst and hydrogen gas to obtain 1-ethyl-4-piperidine-sulfonamide (A).

[0281] In either of the above two embodiments, the first catalyst and the second catalyst may be the same or different. Suitable catalysts include Raney nickel and palladium catalysts.

[0282] In one embodiment, the first catalyst and the second catalyst are different.In one aspect of such an embodiment, the first catalyst is a palladium catalyst, such as palladium on carbon or palladium hydroxide on carbon.Typically, in such an embodiment, the first catalyst is palladium on carbon.Typically, in such an embodiment, the second catalyst is Raney nickel.

[0283] The inventors of the present application have found that it can be advantageous to use a palladium catalyst, such as palladium on carbon, as the first catalyst and Raney nickel as the second catalyst. This is because it surprisingly allows for a lower amount of the more expensive palladium catalyst to be used and / or a lower carbon loading level. Typically, palladium catalyst is used in both steps, whereas when Raney nickel is used as the second catalyst, only about half the amount of palladium catalyst, or half the loading, is required. Furthermore, the use of a lower amount of palladium catalyst makes it easier to remove the catalyst from the reaction mixture.

[0284] When palladium on carbon or palladium hydroxide on carbon is used as the first catalyst and Raney nickel is used as the second catalyst, typically 2-30 wt% palladium on carbon or palladium hydroxide on carbon is used as the first catalyst. More typically, 3-20 wt% palladium on carbon or palladium hydroxide on carbon is used as the first catalyst. Most typically, 5-10 wt% palladium on carbon or palladium hydroxide on carbon is used as the first catalyst.

[0285] When the first catalyst and the second catalyst are different, in one embodiment, the first catalyst is removed, for example, by filtration and / or centrifugation, before contacting the intermediate mixture with acetonitrile or acetaldehyde and the second catalyst.As can be understood, piperidine-4-sulfonamide can be retained in the intermediate mixture, typically in solution, thus avoiding isolation of piperidine-4-sulfonamide.

[0286] Alternatively, the first catalyst may be retained in the reaction mixture prior to contacting the intermediate mixture with acetonitrile or acetaldehyde and the second catalyst. Thus, in such an embodiment, the second catalyst and acetonitrile or acetaldehyde may be added to the intermediate mixture comprising piperidine-4-sulfonamide, a solvent and the first catalyst.

[0287] In another embodiment, the first catalyst and the second catalyst are the same. In one aspect of such an embodiment, the first catalyst and the second catalyst are palladium catalysts, such as palladium on carbon or palladium hydroxide on carbon. Typically, in such an embodiment, the first catalyst and the second catalyst are palladium hydroxide on carbon. When the first catalyst and the second catalyst are the same, a first portion of the catalyst may be added to the reaction mixture before step (i), and a second portion of the catalyst may be added to the intermediate mixture after step (i) and before step (ii). Alternatively, a single portion of the catalyst may be added to the reaction mixture before step (i) and used for both steps (i) and (ii).

[0288] Palladium on carbon or palladium hydroxide on carbon is used as the first and second catalysts, typically 5-35 wt% palladium on carbon or palladium hydroxide on carbon. More typically 10-30 wt% palladium on carbon or palladium hydroxide on carbon is used. Most typically 15-25 wt% palladium on carbon or palladium hydroxide on carbon is used.

[0289] Typically, when reaction step (f) comprises steps (i) and (ii) above, step (ii) of reaction step (f) comprises contacting an intermediate mixture comprising piperidine-4-sulfonamide and a solvent with acetonitrile in the presence of a second catalyst and hydrogen gas.

[0290] When step (i) of reaction step (f) comprises contacting the N-protected-4-piperidinesulfonamide (K) or (K') with the first catalyst in the presence of hydrogen gas and a solvent, typically hydrogen gas is used at a pressure in the range of 0.1 to 5 bar, more typically in the range of 2 to 4 bar, and most typically in the range of 2.5 to 3.5 bar.

[0291] When step (ii) of reaction step (f) involves contacting an intermediate mixture comprising piperidine-4-sulfonamide and a solvent with acetonitrile or acetaldehyde in the presence of a second catalyst and hydrogen gas, typically hydrogen gas is used at a pressure in the range of 0.1 to 5 bar, more typically in the range of 2 to 4 bar, most typically in the range of 2.5 to 3.5 bar.

[0292] The hydrogen pressures used in steps (i) and (ii) of reaction step (f) may be the same or different. Typically, the hydrogen pressures used in steps (i) and (ii) of reaction step (f) are the same.

[0293] When reaction step (f) comprises contacting the N-protected 4-piperidinesulfonamide (K) or (K') with the first catalyst in the presence of hydrogen gas and a solvent, step (i) of reaction step (f) may be carried out at a temperature in the range of 0 to 70° C. Typically, step (i) of reaction step (f) is carried out at a temperature in the range of 10 to 50° C. More typically, step (i) of reaction step (f) is carried out at a temperature in the range of 15 to 30° C.

[0294] When reaction step (f) comprises contacting an intermediate mixture comprising piperidine-4-sulfonamide and a solvent with acetonitrile or acetaldehyde in the presence of a second catalyst and hydrogen gas, step (ii) of reaction step (f) may be carried out at a temperature in the range of 0 to 60°C. Typically, step (ii) of reaction step (f) may be carried out at a temperature in the range of 10 to 50°C. In one embodiment, for example, when Raney nickel is used as the second catalyst, step (ii) of reaction step (f) is carried out at a temperature in the range of 35 to 45°C. In another embodiment, for example, when a palladium catalyst is used as the second catalyst, step (ii) of reaction step (f) is carried out at a temperature in the range of 15 to 30°C.

[0295] The temperature ranges used for steps (i) and (ii) of reaction step (f) may be the same or different. Typically, when the first and second catalysts are the same, the temperature ranges used for steps (i) and (ii) of reaction step (f) are the same.

[0296] Typically, the solvent used in steps (i) and (ii) of reaction step (f) is a polar protic solvent, or a polar aprotic solvent (other than acetonitrile or acetaldehyde), or a mixture thereof. For example, the solvent may be selected from tetrahydrofuran, 1,4-dioxane, dichloromethane, water, methanol, ethanol, isopropanol, butanol, or a mixture thereof. More typically, the solvent is a polar protic solvent such as water, methanol, ethanol, isopropanol, butanol, or a mixture thereof. Even more typically, the solvent is a mixture of alcohol (solvents such as methanol, ethanol, isopropanol or butanol) and water. Most typically, the solvent is a mixture of ethanol and water.

[0297] When the solvent is a mixture of alcohol and water, for example a mixture of ethanol and water, typically the ratio of alcohol:water is 90:10 to 10:90 (v / v). More typically the ratio of alcohol:water is 80:20 to 30:70 (v / v). More typically the ratio of alcohol:water is 80:20 to 40:60 (v / v).

[0298] In one embodiment, when the solvent is a mixture of alcohol and water, such as a mixture of ethanol and water, additional water is added to the solvent after step (i) and before step (ii). For example, additional water may be added in step (i) such that the ratio of alcohol:water is 80:20 to 60:40 (v / v) and in step (ii) such that the ratio of alcohol:water is 65:35 to 45:55 (v / v).

[0299] When the reaction step (f) includes a step (ii) of contacting an intermediate mixture containing piperidine-4-sulfonamide and a solvent with acetonitrile or acetaldehyde in the presence of a second catalyst and hydrogen gas, typically 1 to 10 molar equivalents of acetonitrile or acetaldehyde are used relative to the amount of piperidine-4-sulfonamide. More typically, 1.2 to 5 molar equivalents of acetonitrile or acetaldehyde are used. Most typically, 1.5 to 3.5 molar equivalents of acetonitrile or acetaldehyde are used.

[0300] The inventors of the present application have surprisingly found that the reductive alkylation reaction proceeds successfully using such small amounts of acetaldehyde or, more specifically, acetonitrile. This is in contrast to the simultaneous one-pot procedure outlined above, in which acetonitrile or acetaldehyde is used as the reaction solvent and is therefore present in large excess. For example, the use of small amounts of acetonitrile avoids the production of significant amounts of amines and / or ammonia. Furthermore, the use of low specific amounts of acetonitrile or acetaldehyde allows the reaction to be monitored by analysis of hydrogen consumption.

[0301] Typically, when the reaction step (f) includes steps (i) and (ii), in step (i), the N-protected 4-piperidinesulfonamide (K) or (K') is present in the solvent or added to the solvent at an initial concentration of 0.01 to 10 mol / L relative to the total volume of the solvent used in the reaction mixture of step (i). More typically, the N-protected 4-piperidinesulfonamide (K) or (K') is present in the solvent or added to the solvent at an initial concentration of 0.1 to 1.0 mol / L. Most typically, the N-protected 4-piperidinesulfonamide (K) or (K') is present in the solvent or added to the solvent at an initial concentration of 0.4 to 0.6 mol / L.

[0302] Typically, when the reaction step (f) comprises steps (i) and (ii), in step (ii), piperidine-4-sulfonamide is present in the solvent at an initial concentration of 0.01-10 mol / L relative to the total volume of the solvent used in the reaction mixture of step (ii). More typically, piperidine-4-sulfonamide is present in the solvent at an initial concentration of 0.1-1.0 mol / L. Most typically, piperidine-4-sulfonamide is present in the solvent at an initial concentration of 0.3-0.5 mol / L.

[0303] In one embodiment of the fifth aspect of the present invention, when reacting step (f) comprises steps (i) and (ii), reacting step (f) comprises (iii) removing hydrogen; (iv) removing the catalyst, for example by filtration; (v) optionally decolorizing the reaction mixture using activated carbon; (vi) optionally contacting the reaction mixture with a metal scavenger, e.g., SiliaMetS thiol; and (vii) Optionally, further comprising removing the reaction solvent by co-evaporation with an alcohol such as n-butanol at reduced pressure to obtain 1-ethyl-4-piperazine-sulfonamide (A).

[0304] Typically, when reaction step (f) comprises steps (i) and (ii), reaction step (f) comprises the following work-up steps: (iii) removing hydrogen; (iv) removing the catalyst, for example by filtration; (v) optionally decolorizing the reaction mixture using activated carbon; and (vi) Removal of the reaction solvent under reduced pressure, for example by co-evaporation with an alcohol such as n-butanol, to give 1-ethyl-4-piperazine-sulfonamide (A).

[0305] Optionally, the 1-ethyl-4-piperazinesulfonamide (A) produced by any method of step (f) is purified by precipitation or crystallization from a crystallization solvent. Typically, the crystallization solvent comprises a polar aprotic solvent, such as ethyl acetate, or a mixture of a polar protic solvent and a polar aprotic solvent, such as a mixture of n-butanol and ethyl acetate.

[0306] An eleventh aspect of the present invention provides 1-ethyl-4-piperazinesulfonamide (A) or a salt thereof. [ka]

[0307] 1-Ethyl-4-piperazinesulfonamide (A) or a salt thereof may be prepared or preparable by the process of step (f) of the fifth aspect of the present invention.

[0308] Typically, the 1-ethyl-4-piperazinesulfonamide (A) of the eleventh aspect of the invention is in a non-salt form.

[0309] In one embodiment of the eleventh aspect of the present invention, the 1-ethyl-4-piperazine-sulfonamide (A) or a salt thereof has a purity of 95% or more. 1 More typically, the 1-ethyl-4-piperazinesulfonamide (A) or a salt thereof has a HNMR purity of 98.5% or more. 1 HNMR purity.

[0310] In one embodiment of the eleventh aspect of the present invention, 1-ethyl-4-piperazine-sulfonamide (A) or a salt thereof has a GC purity of 95% or more. More typically, 1-ethyl-4-piperazine-sulfonamide (A) or a salt thereof has a GC purity of 99% or more.

[0311] Even more typically, the 1-ethyl-4-piperazinesulfonamide (A) or a salt thereof has a GC purity of 99.5% or greater, or 99.7% or greater.

[0312] In one particular embodiment of the fifth aspect of the present invention, there is provided a method for preparing 1-ethyl-4-piperidinesulfonamide (A) or a salt thereof, comprising the steps of: [ka]

[0313] (a) A process for converting 4-hydroxypiperidine (F) into N-carboxybenzyl-4-hydroxypiperidine (G'): [ka]

[0314] (b) converting N-carboxybenzyl-4-hydroxypiperidine (G') into benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H'): [ka]

[0315] (c) benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H'), Steps for converting to benzyl 4-(acetylthio)piperidine-1-carboxylate (I'): [ka]

[0316] (d) converting benzyl 4-(acetylthio)piperidine-1-carboxylate (I') into benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J'): [ka]

[0317] (e) converting benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') into 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K'): [ka]

[0318] (f) and converting 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') into 1-ethyl-4-piperazinesulfonamide (A). [ka] A method is provided that includes:

[0319] The compounds used in and provided by the present invention may be used in both their free base form and their acid addition salt form. For the purposes of the present invention, the "salt" of the compound of the present invention includes acid addition salts. Acid addition salts are preferably formed from an inorganic acid, such as a hydrohalic acid (e.g., hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid) or other inorganic acid (e.g., nitric acid, perchloric acid, sulfuric acid or phosphoric acid); or an organic acid, such as an organic carboxylic acid (e.g., propionic acid, butyric acid, glycolic acid, lactic acid, mandelic acid, citric acid, acetic acid, benzoic acid, salicylic acid, succinic acid, malic acid or hydroxysuccinic acid, tartaric acid, fumaric acid, maleic acid, hydroxymaleic acid, mucic acid or galacic acid). The acid addition salts are pharma- ceutically acceptable non-toxic addition salts with suitable acids, including, but not limited to, organic sulfonic acids (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluene-p-sulfonic acid, naphthalene-2-sulfonic acid or camphorsulfonic acid) or amino acids (e.g., ornithine acid, glutamic acid or aspartic acid). The acid addition salts may be mono-, di-, tri- or multi-acid addition salts. Preferred salts are hydrogen halide, sulfuric acid, phosphoric acid or organic acid addition salts. Preferred salts are hydrochloric acid addition salts.

[0320] When the compound of the present invention comprises quaternary ammonium group, the compound is typically used in its salt form.The counterion for quaternary ammonium group can be any pharma-ceutically acceptable non-toxic counterion.The example of suitable counterion includes the conjugate base of protonic acid mentioned above for acid addition salt.

[0321] The compounds used in the present invention and provided by the present invention can be used in both their free acid form and their salt form. For the purposes of the present invention, the "salt" of the compound of the present invention includes those formed between the protonic acid functional group of the compound of the present invention (such as a carboxylic acid group or a urea group) 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-salt, di-salt, tri-salt 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.

[0322] Preferably, any salts are pharma- ceutically acceptable, non-toxic salts, but in addition to pharma- ceutically acceptable salts, other salts are included in the invention because, for example, they may serve as intermediates in the purification or preparation of pharma- ceutically acceptable salts, or because they are useful in identifying, characterizing, or purifying free acids or free bases.

[0323] The compounds and / or salts used in and provided by the present invention may be anhydrous or in the form of a hydrate (e.g., 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 such as methanol, ethanol or isopropanol.

[0324] The compounds, salts and solvates used in and provided by the present invention are 12 C. 13 C. 1 H, 2 H(D), 14 N, 15 N, 16 O. 17 O. 18 O. 19 F and 127 I, is any stable isotope, including but not limited to, and 11 C. 14 C. 3 H(T), 13 N, 15 O. 18 F, 123 I, 124 I, 125 I and 131 The antibody may contain any radioisotope, including, but not limited to, I.

[0325] Unless otherwise specified, the compounds, salts and solvates used in and provided by the present invention may be in any polymorphic or amorphous form.

[0326] A twelfth aspect of the present invention provides a pharmaceutical composition comprising 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-4-sulfonamide or a salt thereof according to the second aspect of the present invention and a pharma- ceutically acceptable excipient.

[0327] Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Aulton's Pharmaceutics-The Design and Manufacture of Medicines", MEAulton and KMG Taylor, Churchill Livingstone Elsevier, 4th Edition, 2013. Pharmaceutically acceptable additives, including adjuvants, diluents or carriers, that may be used in the pharmaceutical composition of the present invention are those conventionally used in the field of pharmaceutical formulations.

[0328] A thirteenth aspect of the invention provides 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide or a salt thereof according to the second aspect of the invention, or a pharmaceutical composition according to the twelfth aspect of the invention, for use in medicine and / or in the treatment or prevention of a disease, disorder or condition.

[0329] Most particularly, when 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-carbamoyl)piperidine-4-sulfonamide is used to treat or prevent diseases, disorders and conditions, 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-carbamoyl)piperidine-4-sulfonamide acts as an NLRP3 inhibitor.

[0330] In one embodiment, the disease, disorder or condition to be treated or prevented is selected from the following: (i) Inflammation; (ii) autoimmune diseases; (iii) cancer; (iv) infectious diseases; (v) central nervous system disorders; (vi) metabolic diseases; (vii) cardiovascular disease; (viii) respiratory diseases; (ix) liver disease; (x) Kidney disease; (xi) eye diseases; (xii) skin diseases; (xiii) Lymphatic symptoms; (xiv) psychological disorders; (xv) pain; and (xvi) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0331] Typically, the treatment or prevention of the disease, disorder or condition involves the administration of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-4-sulfonamide or a salt thereof according to the second aspect of the invention, or a pharmaceutical composition according to the twelfth aspect of the invention to a subject.

[0332] Any of the medicaments used in the present invention may be administered by oral, parenteral (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural), respiratory (aerosol), rectal, vaginal or topical (including transdermal, buccal, mucosal and sublingual) administration.

[0333] Typically, the mode of administration selected will be that which is most suitable for the disorder, disease or condition being treated or prevented.

[0334] A fourteenth aspect of the present invention provides a method of inhibiting NLRP3, the method comprising inhibiting NLRP3 using 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-carbamoyl)piperidine-4-sulfonamide or a salt thereof according to the second aspect of the invention, or a pharmaceutical composition according to the twelfth aspect of the invention.

[0335] For the avoidance of doubt, wherever practicable, any embodiment of a given aspect of the invention may be practiced in combination with any other embodiment of the same aspect of the invention. Further, it is to be understood that, wherever practicable, any preferred, exemplary or optional embodiment of any aspect of the invention is also to be considered as a preferred, exemplary or optional embodiment of any other aspect of the invention. EXAMPLES

[0336] Unless otherwise noted, all solvents, reagents and compounds were purchased and used without further purification.

[0337] Abbreviation Cbz: carboxybenzyl / benzyloxycarbonyl SAc: Acetylthio [ka] GC: Gas chromatography HPLC: High-performance liquid chromatography THF: tetrahydrofuran RBF: Round-bottom flask MTBE: Methyl tertiary butyl ether DCM: dichloromethane DMFL Dimethylformamide TEA: Triethylamine HDPE: High density polyethylene NMT: Below Vol: Volume AKX Reagent: AQUAMICRON® AKX % a / a: (area under the peak of compound (a) / total area under the peaks of compound (a) and all other components) x 100 As used herein, unless otherwise stated, all references to pressure in bars refer to absolute pressure.

[0338] Experimental Method NMR method: NMR spectra were obtained on a Bruker AV 400 MHz spectrometer (model: Advance IIID) operated at room temperature (25° C.).

[0339] GC method: GC analyses were performed on one of the following instruments: Agilent 7890, 6890 or Agilent 6890N equipped with an ALS injector.

[0340] HPLC method: HPLC in Reaction Scheme 3 was performed on an Agilent 1100, 1200 or 1260 using ammonium acetate in water:MeCN (for both mobile phases).

[0341] HPLC of Reaction Scheme 1, step (i) and step (ii), as well as Reaction Scheme 2, steps (i) to (iv), was carried out on a Waters Alliance e2695 HPLC equipped with a PDA detector using 10 Mm aqueous ammonium bicarbonate as mobile phase A and acetonitrile as mobile phase B.

[0342] KF method: Coulometric KF (Karl Fischer) titrations were performed on a Mitsubishi CA-20 or Predicta OM1000 using AKX reagent.

[0343] Synthesis of Examples 1-Ethyl-4-piperidinesulfonamide (7) 1-Ethyl-4-piperidinesulfonamide (7) was prepared according to the reaction sequence shown in Reaction Scheme 1. [ka]

[0344] Reaction Scheme 1-Step (i) [ka]

[0345] Methanol (138.0 L) was charged to a clean, dry, four-neck RBF (equipped with a mechanical stirrer, nitrogen inlet, thermopocket, and reflux condenser) under nitrogen atmosphere and heated to reflux at 60-65°C for 20-30 min. The temperature was reduced to 25-30°C, the refluxed methanol was removed, and the RBF was rinsed with methanol (23.0 L) and dried under nitrogen and reduced pressure.

[0346] 4-Hydroxypiperidine (1) (46.0 Kg) was charged to the RBF at 25-30°C. 1,4-Dioxane (226.0 L) was charged to the RBF at 25-30°C. The reaction mixture was stirred for 5-10 minutes and then cooled to 15-20°C. 2N NaOH solution (prepared by mixing NaOH (18.4 Kg) with cold purified water (230.0 L) at 25-30°C in a separate RBF) was slowly charged to the reaction mixture at 15-25°C. The reaction mixture was stirred for 5-10 minutes. 50% benzyl chloroformate in toluene solution (147.2 L) was slowly added to the reaction mixture over 1-2 hours. The temperature was raised to 25-30°C and stirred for 1-2 hours.

[0347] A sample of the reaction mixture was analyzed for the presence of 4-hydroxypiperidine (1) by GC. GC, %a / a: Limit: NMT 10% Sampling Procedure: Take 2 mL of reaction product, add 4 mL of water, 2 mL of ethyl acetate, stir for 2 minutes, separate and present the upper organic layer (ethyl acetate) for GC %a / a.

[0348] Purified water (230.0 L) was added to the reaction mixture and the reaction mixture was stirred at 25-30 °C for 10-15 min. MTBE (230.0 L) was charged to the RBF at 30-35 °C. The reaction mixture was stirred at 25-30 °C for 15-20 min and then allowed to stand for 20-30 min. The organic layer (OL-1) and aqueous layer (AL-1) were separated into separate vessels and AL-1 was recharged to the RBF. MTBE (230.0 L) was charged to the RBF at 25-30 °C. The reaction mixture was stirred at 25-30 °C for 15-20 min and then allowed to stand for 20-30 min. The organic layer (OL-2) and aqueous layer (AL-2) were separated into separate vessels. OL-1 and OL-2 were combined and charged to the RBF at 25-30 °C. Purified water (138.0 L) was charged into the RBF at 25-30° C. The reaction mixture was stirred at 25-30° C. for 15-20 minutes and then allowed to stand for 20-30 minutes. The aqueous layer (AL-3) was separated from the organic layer (OL-3).

[0349] 10% NaCl solution (prepared by adding NaCl (13.80 Kg) to purified water (138.0 L) in RBF at 25-30 °C with stirring) was charged to OL-3 at 25-30 °C. The reaction mixture was stirred at 25-30 °C for 15-20 min and then allowed to settle for 20-30 min. The organic layer (OL-4) and aqueous layer (AL-4) were separated into separate vessels. OL-4 was dried over sodium sulfate (23.0 Kg). OL-4 was filtered through a Buchner funnel and washed with MTBE (46.0 L). OL-4 was distilled under reduced pressure (650 mmHg) at 40-45 °C to 46-92 L. The vacuum was released and DCM (138.0 L) was charged to the mixture and the mixture was co-distilled under reduced pressure at 35-40 °C to 46-92 L. The mixture was cooled to 25-30°C and the vacuum was released. DCM (552.0 L) was charged to the mixture at 25-30°C and the mixture was stirred for 5-10 min. The reaction mixture was cooled to 20-25°C. TEA (127.8 L) was added at 20-25°C. The reaction mixture was cooled to -5-5°C.

[0350] Methanesulfonyl chloride (67.62 kg) was slowly added over 1 to 2 hours at -5 to 5° C. The reaction mixture was warmed to 25 to 30° C. and stirred at 25 to 30° C. for 1 to 2 hours.

[0351] A sample of the reaction mixture was analyzed by HPLC to confirm the presence of benzyl 4-hydroxy-1-piperidinecarboxylate (2). HPLC, %a / a: (Limit: NMT 3.0%). Sampling procedure: Take 5 mL of reaction product, add 5 ml of water, separate and give the bottom organic layer (DCM) for HPLC %a / a.

[0352] The undesired salts were filtered, washed with DCM (92.0 L) at 25-30°C, and sucked dry completely under reduced pressure at 25-30°C. The filtrate was charged into a RBF at 25-30°C. 10% sodium bicarbonate solution (prepared by adding sodium bicarbonate (23.0 Kg) to purified water (230.0 L) at 25-30°C) was charged into the filtrate at 25-30°C. The reaction mixture was stirred at 25-30°C for 15-20 minutes and then allowed to stand for 20-30 minutes. The organic layer (OL-5) and aqueous layer (AL-5) were separated into separate vessels and OL-5 was charged into a RBF at 25-30°C.

[0353] Purified water (230.0 L) was charged into the RBF at 25-30°C. The reaction mixture was stirred at 25-30°C for 15-20 minutes and then allowed to stand for 20-30 minutes. The organic layer (OL-6) and layer (AL-6) were separated into separate containers, and OL-6 was charged back into the RBF at 25-30°C. A 10% sodium chloride solution (sodium chloride (11.50 Kg) added to purified water (230.0 L) at 25-30°C) was added to the RBF at 25-30°C. The reaction mixture was stirred at 25-30°C for 15-20 minutes and then allowed to stand for 20-30 minutes.

[0354] The organic layer (OL-7) and aqueous layer (AL-7) were separated into separate vessels. OL-7 was dried over sodium sulfate (23.0 Kg). OL-7 was filtered through a Buchner filter and washed with DCM (46.0 L). OL-7 was distilled under reduced pressure (650 mmHg) at 40-45°C to 46-92 L. The vacuum was released and ethyl acetate (92.0 L) was charged to the mixture and the mixture was co-distilled under reduced pressure at 40-45°C to 46-92 L. The mixture was cooled to 30-40°C and the vacuum was released. Ethyl acetate (115.0 L) was charged to the mixture at 30-40°C and the mixture was stirred at 30-35°C for 10-15 minutes. Hexane (1150.0 L) was slowly charged to the mixture at 30-35°C and the mixture was stirred at 25-30°C for 2-3 hours. The solid was filtered through a Nutsche filter under reduced pressure, washed with hexane (92.0 L) at 25-30° C., and sucked dry thoroughly under reduced pressure at 25-30° C. The solid material was dried in a vacuum oven at 30-35° C. for 6-8 h, scraping the material every 3-4 h.

[0355] A dried sample of benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (3) was analyzed for cumulative solvent content by GC (limit: NMT 10% (hexane, ethyl acetate). The dried material was removed into a clean HDPE container for weighing. The product was stored at 2-8 °C under nitrogen atmosphere. A sample was sent for analysis.

[0356] Final product: benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate Grayish white (solid) Yield: 121.87Kg Yield: 85.5% HPLC purity: 94.7% 1 H NMR:(CDCl3400MHz):δ 1.82-1.86(m,2H),δ 1.96-1.97(m,2H),δ 3.03(s,3H),δ 3.41-3.45(m,2H)δ 3.72-3.78(m,2H),δ 4.88-4.92(m,1H)δ 5.13(s,2H),δ 7.26-7.37(m,5H)

[0357] Reaction Scheme 1-Step (ii) [ka]

[0358] DMF (water content analyzed by KF (limit: NMT 0.2% w / v)) was charged to a clean, dry, four-neck RBF (equipped with a mechanical stirrer, nitrogen inlet, thermopocket, and reflux condenser) under nitrogen atmosphere and heated to reflux at 60-65°C for 20-30 min. The temperature was reduced to 25-30°C, the refluxed DMF was unloaded (water content analyzed by KF (limit: NMT 0.5% w / v)) and the RBF was dried under nitrogen and reduced pressure.

[0359] Benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (3) (29.0 Kg) was charged to the RBF at 25-30° C. DMF (145.0 L) was charged to the RBF at 25-30° C. The reaction mixture was stirred for 5-10 minutes, cooled to 15-20° C., and then allowed to stand for 20-30 minutes.

[0360] 44.95 Kg of Cesium Carbonate was charged into the RBF at 15-25°C. The reaction mixture was stirred for 5-10 minutes. 10.56 Kg of Thioacetic Acid was charged at 15-25°C (vent was connected to alkaline scrubber / KMnO4 aqueous solution). The reaction mixture was brought to 45-50°C and stirred for 24 hours.

[0361] A sample of the reaction mixture was analyzed for benzyl 4-((methylsulfonyl)oxy)-piperidine-1-carboxylate (3) content by HPLC (% a / a): (limit: NMT 3%). Sampling procedure: take 2 mL of reaction product, add 4 ml water, 2 ml ethyl acetate, stir for 2 minutes, separate and provide the upper organic layer (ethyl acetate) for HPLC % a / a.

[0362] The reaction mixture was cooled to 25-30°C. The undesired salts were filtered through a Büchner funnel under reduced pressure at 25-30°C, washed with ethyl acetate (145.0 L) and sucked dry completely under reduced pressure at 25-30°C. The filtrate was recharged to the RBF at 25-30°C and cooled to 15-20°C. Purified water (145.0 L) was charged to the RBF at 15-25°C and the reaction mixture was stirred for 5-10 min. Ethyl acetate (145.0 L) was charged to the RBF at 25-30°C. The reaction mixture was stirred at 25-30°C for 15-20 min and allowed to stand for 20-30 min.

[0363] The organic layer (OL-1) and aqueous layer (AL-1) were separated into separate vessels. AL-1 was charged into a RBF at 25-30°C. Ethyl acetate (145.0 L) was charged at 25-30°C. The reaction mixture was stirred at 25-30°C for 15-20 minutes and allowed to stand for 20-30 minutes.

[0364] The organic layer (OL-2) and the aqueous layer (AL-2) were separated into separate vessels. OL-1 and OL-2 were combined and charged into a RBF at 25-30°C.

[0365] A 10% NaHCO3 solution (prepared by adding sodium bicarbonate (14.50 Kg) to purified water (145.0 L) at 25-30°C and stirring well to mix) was charged into the RBF at 25-30°C. The reaction mixture was stirred at 25-30°C for 15-20 minutes and allowed to stand for 20-30 minutes.

[0366] The organic layer (OL-3) and aqueous layer (AL-3) were separated into separate containers. OL-3 was charged into the RBF at 25-30°C. 10% NaCl solution (prepared by adding NaCl (14.50 Kg) to purified water (145 L) at 25-30°C and mixing well) was charged into the RBF at 25-30°C. The reaction mixture was stirred at 25-30°C for 15-20 minutes and allowed to stand for 20-30 minutes.

[0367] The organic layer (OL-4) and aqueous layer (AL-4) were separated into separate vessels. OL-4 was dried over sodium sulfate (14.50 Kg), filtered through a Buchner funnel and washed with ethyl acetate (29.0 L). The filtrate was distilled completely in a RBF under reduced pressure (650 mmHg) at 45-50°C until no droplets remained. The vacuum was released and the mixture was cooled to 25-30°C. The sample was analyzed for ethyl acetate content by GC (limit: NMT 20% by weight (%w / w)). Sampling procedure: Take 2 mL of crude sample and send out for HPLC %a / a.

[0368] Acetic acid (377.0 L) was charged into the RBF at 25-30°C. The reaction mixture was stirred at 25-30°C for 5-10 minutes. Purified water (37.7 L) was charged at 25-30°C. The reaction mixture was stirred at 25-30°C for 5-10 minutes and then cooled to 17-25°C. N-chlorosuccinimide (33.64 Kg) was added slowly in portions at 18-25°C for 1-2 hours. The reaction mixture was stirred at 25-30°C for 1 hour.

[0369] The samples were analyzed for benzyl 4-(acetylthio)-piperidine-1-carboxylate (4) content by HPLC (% a / a): (limit: NMT 3%). Sampling procedure: take 2 mL of reaction product, add 4 ml water, 2 ml DCM, stir for 2 min, separate and provide the lower organic layer (DCM) as HPLC % a / a.

[0370] The reaction mixture was cooled to 15-20°C. Purified water (377.0 L) was added to the reaction mixture at 15-20°C and the reaction mixture was stirred at 25-30°C for 5-10 min. DCM (145.0 L) was charged into the RBF at 25-30°C. The reaction mixture was stirred at 25-30°C for 10-15 min and allowed to stand for 20-30 min. The organic layer (OL-5) and aqueous layer (AL-5) were separated into separate vessels. AL-5 was charged into the RBF. DCM (145.0 L) was charged into the RBF at 25-30°C. The reaction mixture was stirred at 25-30°C for 10-15 min and allowed to stand for 20-30 min.

[0371] The organic layer (OL-6) and aqueous layer (AL-6) were separated into separate vessels. OL-5 and OL-6 were combined and charged into the RBF at 25-30°C. Purified water (145.0 L) was charged into the RBF at 25-30°C. The reaction mixture was stirred at 25-30°C for 5-10 minutes and allowed to stand for 25-30 minutes.

[0372] The organic layer (OL-7) and the aqueous layer (AL-7) were separated into separate containers. OL-7 was charged into the RBF. A portion of 2% sodium bicarbonate solution (prepared by adding purified water (435.0 L) to sodium bicarbonate (8.70 Kg) and dividing the solution into three equal parts) was charged into the RBF at 25-30°C. The reaction mixture was stirred at 25-30°C for 5-10 minutes and allowed to stand for 25-30 minutes.

[0373] The organic layer (OL-8) and aqueous layer (AL-8) were separated into separate vessels. OL-8 was charged into the RBF. The second portion of the above 2% sodium bicarbonate solution was charged into the RBF at 25-30°C. The reaction mixture was stirred at 25-30°C for 5-10 minutes and allowed to stand for 25-30 minutes.

[0374] The organic layer (OL-9) and aqueous layer (AL-9) were separated into separate vessels. OL-9 was charged into the RBF. The third portion of the above 2% sodium bicarbonate solution was charged into the RBF at 25-30°C. The reaction mixture was stirred at 25-30°C for 5-10 minutes and allowed to stand for 25-30 minutes.

[0375] The organic layer (OL-10) and aqueous layer (AL-10) were separated into separate vessels. OL-10 was dried over sodium sulfate (14.50 Kg), filtered at 25-30°C, and washed with DCM (29.0 L). The filtrate was charged into a RBF at 25-30°C.

[0376] The reaction mixture was cooled to -40 to -30°C and purged with ammonia gas for 2 to 3 hours. The temperature was raised to 25 to 30°C and stirred at 25 to 30°C for 10 to 12 hours. A sample of the reaction mixture was analyzed for 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (5) content by HPLC (%a / a): (limit: NMT 3%). Sampling procedure: take 2 mL of reaction product, add 4 ml of water, separate and provide bottom organic layer (DCM) for HPLC %a / a.

[0377] The undesired salts were filtered under reduced pressure at 25-30°C, washed with DCM (14.50 L) and sucked dry thoroughly. The filtrate was dumped into a clean, dry RBF at 25-30°C and dried over sodium sulfate (14.50 Kg). The mixture was filtered at 25-30°C and the sodium sulfate was washed with DCM (14.50 L). The mixture was dumped through a 0.2 micron filter cartridge into a clean, dry RBF and distilled under reduced pressure at 35-40°C to 29-58 L.

[0378] The vacuum was released and the reaction mixture was cooled to 25-30°C. Ethyl acetate (58.0 L) was charged to the RBF at 25-30°C and the mixture was vacuum distilled at 35-40°C to 29-58 L. The vacuum was released and the reaction mixture was cooled to 25-30°C. Ethyl acetate (72.5 L) was charged to the RBF at 25-30°C and the mixture was stirred at 25-30°C for 30 min. Hexane (36.25 L) was charged to the RBF at 25-30°C and stirred at 25-30°C for 1-2 h. The solid was filtered under vacuum at 25-30°C, washed with hexane (58.0 L) and sucked dry thoroughly. The wet sample was analyzed for HPLC purity %a / a.

[0379] Yield: 11.0Kg Yield: 39.85% HPLC purity: 90.5% purification Wet material (53.95 Kg) from four batches of Reaction Scheme 1, step (ii) was charged into a clean, dry RBF at 25-30°C. DCM (580 L) was charged at 25-30°C and the mixture was stirred at 25-30°C for 5-10 minutes. Methanol (25.0 L) was charged at 25-30°C and the mixture was stirred at 25-30°C for 5-10 minutes. Neutral alumina (174.0 Kg) was charged at 25-30°C and the mixture was stirred at 25-30°C for 1 hour. Neutral alumina was filtered at 25-30°C. The salts were washed with DCM (150.0 L). The filtrate was charged into a clean, dry RBF at 25-30°C. Hexane (1050 L) was charged at 25-30°C and the mixture was stirred at 25-30°C for 1-2 hours. The precipitate was filtered under vacuum at 25-30°C, washed with hexane (116.0 L) and sucked dry thoroughly (until no liquid remained). The wet material was dried under vacuum at 30-35°C for 6-8 hours, stripping every 3 hours. The dried material was removed into a clean HDPE container and weighed. The product was stored at 2-8°C under nitrogen. A sample was sent for analysis.

[0380] Final product: 1-(benzyloxycarbonyl)-4-piperidinesulfonamide White (solid powder) Yield: 41.60Kg Yield: 41.80% HPLC purity: 96.1% 1 H NMR: (DMSO 400MHz):δ 1.41-1.51(m,2H),δ 1.99-2.01(m,2H),δ 2.50-286(m,2H),δ 3.022-3.05(m,1H)δ 4.08-4.11(m,2H),δ 5.75(s,2H)δ 6.78(s,2H),δ 7.40-7.30(m,5H)

[0381] Reaction Scheme 1-Step (iii) [ka]

[0382] 1-(Benzyloxycarbonyl)-4-piperidinesulfonamide (6) (21.85 Kg) was charged to the vessel which was then purged with nitrogen. Acetonitrile (propionitrile free) (109.8 Kg) and purified water (65.0 L) were charged to the vessel and the temperature was adjusted to 15-25°C. The vessel was vacuum / nitrogen purged 3 times at 15-25°C and then charged with palladium hydroxide on carbon (20% by weight; 50% water) (0.455 Kg). The vessel was vacuum / nitrogen purged 3 times at 15-25°C. The vessel was vacuum / hydrogen purged 3 times at 15-25°C and maintained under a hydrogen atmosphere (approximately 1 bar absolute pressure). The reaction mixture was stirred until completion. After approximately 1.5 hours reaction time, the vessel was vacuum / hydrogen purged to remove CO2. Completion was determined by 1 HNMR analysis determined the content of 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (6) with an acceptance criterion of 10.0 mol % or less.

[0383] The vessel was vacuum / nitrogen purged three times at 15-25° C. and then charged with palladium hydroxide on carbon (20% by weight; 50% water) (2.265 Kg) at 15-25° C. The vessel was vacuum / nitrogen purged three times at 15-25° C. The vessel was vacuum / hydrogen purged three times at 15-25° C. and maintained under a hydrogen atmosphere (approximately 1 bar absolute pressure).

[0384] The reaction mixture was stirred at 15-25°C until completion. After approximately 1.5 hours reaction time, the vessel was purged with vacuum / hydrogen to remove ammonia. Completion was confirmed by 1 HNMR analysis determined the pass criterion for 4-piperidinesulfonamide to be 5.0 mol or less.

[0385] 1 Once the acceptance criteria by HNMR analysis was met, the reaction mixture was stirred at 15-25 °C until completion by GC analysis. Acceptance criteria: the combined area of ​​4-piperidinesulfonamide and intermediates at the intermediate with relative retention time of 0.939 was 0.05% or less.

[0386] Once the reaction was deemed complete by GC, the vessel was purged with nitrogen and the reaction mixture was filtered through a 1 μm filter at 15-25° C. to remove the catalyst. The filter cake was washed twice with premixed purified water and acetonitrile (17.5 Kg: 22.0 Kg, 17.2 Kg: 21.9 Kg) at 15-25° C.

[0387] The filtrate was charged with decolorizing charcoal (activated carbon) (4.40 Kg) and stirred at 15-25 °C for at least 60 minutes (target 60-120 minutes). The mixture was filtered through a 1 μm filter at 15-25 °C to remove the charcoal. The filter cake was washed twice at 15-25 °C with premixed purified water and acetonitrile (17.4 Kg: 22.0 Kg, 17.0 Kg: 22.0 Kg). The filtrate was charged with SiliaMetS Thiol 40-63 μm 60 Å (4.515 Kg) and stirred at 15-25 °C for at least 60 minutes (target 60-120 minutes). The mixture was filtered through a 0.6 μm filter at 15-25 °C to remove the SiliaMetS Thiol. The filter cake was washed twice with premixed purified water and acetonitrile (18.2 Kg:22.0 Kg and 18.1 Kg:22.0 Kg) at 15-25°C.

[0388] The filtrate was placed in a vessel, adjusted to 50-60°C, and concentrated under reduced pressure at 50-60°C to approximately 110 L. n-Butanol (89.8 Kg) was charged at 50-60°C, and the mixture was concentrated under reduced pressure at 50-60°C to approximately 110 L. n-Butanol (86.9 Kg) was charged at 50-60°C, and the mixture was concentrated under reduced pressure at 50-60°C to approximately 110 L. n-Butanol (88.4 Kg) was charged at 50-60°C, and the mixture was concentrated under reduced pressure at 50-60°C to approximately 90 L. The supernatant of the concentrated mixture was analyzed for water content by KF analysis with a pass criterion of 0.5% water by weight or less.

[0389] The temperature was adjusted to 15-25°C and ethyl acetate (98.6 Kg) was charged at 15-25°C. The reaction mixture was cooled to -2 to +2°C over at least 60 minutes (target 60-120 minutes). The mixture was stirred at -2 to 2°C for at least 4 hours (target 4-6 hours). The solids were filtered through a 20 μm filter cloth at -2 to 2°C and washed twice with ethyl acetate (38.1 Kg and 39.9 Kg) at -2 to 2°C.

[0390] Until the n-butanol content is 0.5% by weight or less and the ethyl acetate content is 0.5% by weight or less ( 1 The solid was dried under a nitrogen stream at up to 60° C. The dry weight of the solid 1-ethyl-4-piperidinesulfonamide (7) was determined, 1 Assayed using 1 H NMR spectroscopy.

[0391] Final product: 1-ethyl-4-piperidinesulfonamide Yield: 12.00Kg Yield: 85% GC purity: 99.7% NMR purity: 98.7% 1 H NMR:(DMSO)0.95(t),1.55(dq),1.80(app t),1.95(app d),2.30(q),2.75(m),2.90(app d)

[0392] Reaction Scheme 1 - Step (iii) - Alternative Procedure A [ka]

[0393] 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (6) (20 g) was charged to a vessel and suspended in a mixture of ethanol (78.9 g) and purified water (40.0 g) at room temperature. The vessel was purged with a light stream of argon, charged with 10% Pd / C Evonik type Noblyst® P1070 (1.00 g, water content 53.9%), purged three times with argon (8 bar) at room temperature, and then purged five times with hydrogen (6 bar) at room temperature. The vessel was heated to 25±2° C. and maintained under a hydrogen atmosphere (approximately 3 bar). The reaction mixture was stirred until completion (typically 1-2 hours) as judged by the amount of hydrogen consumption detected. Reaction completion was then determined by GC analysis with an acceptance criterion of 1.0% relative area of ​​1-(benzyloxycarbonyl)-4-piperidinesulfonamide (6) or less.

[0394] The vessel was purged three times with argon (8 bar) at 25±2° C. and then charged with Raney Nickel (Johnson Matthey Type A-5000) (2.0 g) as a slurry in water (60.0 mL). Acetonitrile (8.26 g) was added and the vessel was purged three times with argon (8 bar) at 25±2° C. The vessel was purged five times with hydrogen (6 bar) at 25±2° C. and then heated to 40±2° C. and maintained under an atmosphere of hydrogen (approximately 3 bar).

[0395] The reaction mixture was stirred at 40±2° C. until completion (typically 12-18 h) as judged by the detected consumption of hydrogen, which was determined by GC analysis with an acceptance criterion of ≦0.05% relative area of ​​4-piperidinesulfonamide (6a).

[0396] Once the reaction was deemed complete by GC analysis, the vessel was purged with argon and the reaction mixture was filtered through a glass fiber filter (Macherey-Nagel MN GF-5, porosity 0.4 μm) by applying a light vacuum. The filter cake was washed 2-3 times with premixed purified water and ethanol (100 g:78.9 g) at 25 ± 2 °C.

[0397] The filtrate was charged to a vessel and concentrated under reduced pressure. n-Butanol (81.0 g) was charged and the mixture was concentrated under reduced pressure to a residue. n-Butanol (64.8 g) was charged at room temperature followed by ethyl acetate (90.2 g) and the mixture was cooled from room temperature to 0±5° C. over at least 4 hours.

[0398] The resulting solid was filtered through a Buchner funnel equipped with a sintered glass disc (porosity 3) and washed with ethyl acetate (90.2 g) at 0°C.

[0399] The solid product was dried under a stream of nitrogen at a maximum of 50° C. for up to 24 hours.

[0400] Final product: 1-ethyl-4-piperidinesulfonamide (7) Yield: 9.36g Yield: 71.3% GC purity: 98.3%

[0401] Reaction Scheme 1 - Step (iii) - Alternative Procedure B [ka]

[0402] 1-(Benzyloxycarbonyl)-4-piperidinesulfonamide (6) (21.85 Kg) was charged to the vessel which was then purged with nitrogen. Ethanol (85.2 Kg) and purified water (43.7 L) were charged to the vessel and the temperature was adjusted to 15-25°C. The vessel was vacuum / nitrogen purged three times at 15-25°C and then charged with palladium hydroxide on carbon (20% by weight; 50% water) (0.66 Kg). The vessel was vacuum / nitrogen purged three times at 15-25°C. The vessel was vacuum / hydrogen purged three times at 15-25°C and maintained under a hydrogen atmosphere (approximately 3 bar). The reaction mixture was stirred until completion, which was determined by 1 HNMR analysis determined the content of 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (6) with an acceptance criterion of 5.0 mol % or less.

[0403] The vessel was vacuum / nitrogen purged three times at 15-25° C. and then charged with palladium hydroxide on carbon (20% by weight; 50% water) (1.09 Kg) as a slurry in water (21.85 Kg) and acetonitrile (9.2 Kg) at 15-25° C. The vessel was heated to 35-45° C. and vacuum / nitrogen purged three times at 15-25° C. The vessel was vacuum / hydrogen purged three times at 15-25° C. and maintained under a hydrogen atmosphere (approximately 3 bar).

[0404] The reaction mixture was stirred at 15-25°C until completion. At approximately 6 hour intervals, the reactor was purged with vacuum / hydrogen to remove ammonia. Completion was determined by: 1 HNMR analysis determined the pass criterion for 4-piperidinesulfonamide to be 5.0 mol or less.

[0405] 1 Once the acceptance criteria by HNMR analysis was met, the reaction mixture was stirred at 15-25 °C until completion by GC analysis. Acceptance criteria: 4-piperidinesulfonamide at intermediate with relative retention time of 0.939 and total area of ​​intermediate of 0.05%.

[0406] Once the reaction was deemed complete by GC, the vessel was purged with nitrogen, the reaction mixture was cooled to 15-25°C, and filtered through a 1 μm filter at 15-25°C to remove the catalyst. The filter cake was washed twice with premixed purified water and ethanol (13.1 Kg:10.9 Kg, and 13.1 Kg:10.9 Kg) at 15-25°C.

[0407] The filtrate was charged with decolorizing carbon (activated charcoal) (4.37 Kg) and stirred for at least 60 minutes (target 60-120 minutes) at 15-25°C. The mixture was filtered through a 1 μm filter at 15-25°C to remove the charcoal. The filter cake was washed twice with premixed purified water and ethanol (13.1 Kg:10.9 Kg and 13.1 Kg:10.9 Kg) at 15-25°C.

[0408] The filtrate was placed in a vessel, adjusted to 50-60°C, and concentrated under reduced pressure at 50-60°C to approximately 110 L. n-Butanol (89.8 Kg) was charged at 50-60°C, and the mixture was concentrated under reduced pressure at 50-60°C to approximately 110 L. n-Butanol (86.9 Kg) was charged at 50-60°C, and the mixture was concentrated under reduced pressure at 50-60°C to approximately 110 L. n-Butanol (88.4 Kg) was charged at 50-60°C, and the mixture was concentrated under reduced pressure at 50-60°C to approximately 90 L. The supernatant of the concentrated mixture was analyzed for water content by KF analysis with a pass criterion of 0.5% water by weight or less.

[0409] The temperature was adjusted to 15-25°C and ethyl acetate (98.6 Kg) was charged at 15-25°C. The reaction mixture was cooled to -2 to +2°C over at least 60 minutes (target 60-120 minutes). The mixture was stirred at -2 to 2°C for at least 4 hours (target 4-6 hours). The solids were filtered through a 20 μm filter cloth at -2 to 2°C and washed twice with ethyl acetate (38.1 Kg and 39.9 Kg) at -2 to 2°C.

[0410] n-butanol content is 0.5% by weight or less, ethanol content is 0.5% by weight or less, and ethyl acetate content is 0.5% by weight or less ( 1The solid was dried under a nitrogen flow at up to 60° C. until the solid was 0.05% (as determined by H NMR spectroscopy). The dry weight of the solid 1-ethyl-4-piperidinesulfonamide (7) was determined. 1 Assayed using 1 H NMR spectroscopy.

[0411] Final product: 1-ethyl-4-piperidinesulfonamide Yield: 10.98Kg Yield: 78% 4-(Phenoxycarbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (13) 4-(Phenoxycarbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (13) was prepared according to the reaction sequence illustrated in Reaction Scheme 2. [ka]

[0412] Reaction Scheme 2-Step (i) [ka]

[0413] The reagent contained less than 0.5% methanol by GC.

[0414] DCM (385 L) and AlCl3 (99.86 Kg) were charged into a 2.0 KL clean, dry glass-lined reactor under nitrogen atmosphere at 25-30° C. The reaction mixture was cooled to −10° C.

[0415] 3-Chloropropanoyl chloride (90.99 Kg) was added slowly under nitrogen atmosphere at -10 to -5° C. The reaction mixture was maintained at -10° C. for 30 minutes under nitrogen atmosphere. Then, 2,3-dihydro-1H-indene (8) (77.00 Kg) was added slowly to the reaction mixture under nitrogen atmosphere at -10 to -5° C.

[0416] The reaction mixture was kept for 2 h at 10-15° C. The absence of 2,3-dihydro-1H-indene (8) was confirmed by HPLC (limit: ≦5.0%).

[0417] After completion of the reaction, the reaction mixture was slowly added to 6N hydrochloric acid solution (prepared from water (308 L) and concentrated hydrochloric acid (308 L)) at 0-10 °C. DCM (231 L) was added and the temperature of the reaction mixture was increased to 30-35 °C. The reaction mixture was stirred at 30-35 °C for 30 min and allowed to stand at 30-35 °C for 30 min. The layers were separated and the organic layer (OL-1) was set aside. DCM (231 L) was charged to the aqueous layer at 25-30 °C. The reaction mixture was stirred at 25-30 °C for 30 min and allowed to stand at 25-30 °C for 30 min. The layers were separated (aqueous layer (AL-1) and organic layer (OL-2)) and AL-1 was set aside. OL-1 and OL-2 were combined at 25-30 °C. Demineralized water (385 L) was added to the combined organic layer. The reaction mixture was stirred for 30 min at 25-30° C. and allowed to stand for 30 min at 25-30° C. The layers were separated (aqueous layer (AL-2) and organic layer (OL-3)) and AL-2 was set aside.

[0418] 10% saturated sodium bicarbonate solution (prepared from demineralized water (385 L) and sodium bicarbonate (38.5 Kg)) was charged to OL-3 at 25-30°C. The reaction mixture was stirred for 30 min at 25-30°C and allowed to stand for 30 min at 25-30°C. The layers were separated (aqueous layer (AL-3) and organic layer (OL-4)) and AL-3 was set aside. OL-4 was dried over anhydrous Na2SO4 (38.5 Kg) and the anhydrous Na2SO4 was washed with DCM (150 L) at 25-30°C.

[0419] The solvent was distilled under reduced pressure at 35°C to <40°C until 5% remained.

[0420] Charge n-hexane (308 L) to the reaction mixture at 35-40 °C and distill the solvent completely at 35-40 °C until no condensation droplets were formed. Charge n-hexane (150 L) to the reaction mixture at 35-40 °C and cool the reaction mixture to 5-10 °C and maintain it at 5-10 °C for 30 min.

[0421] The solid product was filtered, washed with chilled hexane (77 L) and dried in a hot air oven at 40-45°C for 6 h to obtain the product.

[0422] Final product: 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (9) Yield: 120.5Kg Yield: 88.63% HPLC purity: 99.3% Moisture content: 0.09% 1 H NMR:(500MHz,CDCl3):δ 7.81(S,1H),7.76(d,1H),7.31(d,1H),3.93(t,2H),3.45(t,2H),2.97(t,4H),2.15(q,2H)

[0423] Reaction Scheme 2 - Step (ii) and Step (iii) [ka]

[0424] Sulfuric acid (300.0 L) was charged into a 2.0 KL clean, dry glass-lined reactor at 25-30° C. 3-Chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (9) (60.0 Kg) was charged in lots at 25-30° C. and the reaction mixture was maintained at 25-30° C. for 30 minutes. The reaction mixture was slowly heated to 65-70° C. and maintained at 65-70° C. for 24 hours. Absence of 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (9) was confirmed by HPLC (limit: ≦1.0%).

[0425] The reaction mixture was then cooled to 0-5° C. Nitration mixture *1 was added slowly at 0-5° C. and the reaction mixture was maintained at 0-5° C. for 1 h. Absence of 1,2,3,5,6,7-hexahydro-s-indacen-1-one (10) was confirmed by HPLC (limit: ≦1.0%). The reaction mixture was maintained at 0-5° C.

[0426] Demineralized water (900.0 L) was charged to a 2.0 KL clean dry glass lined reactor at 25-30°C. The reaction mixture was cooled to 0-5°C. The reaction mixture was slowly added to the reactor at 0-5°C. Toluene (480.0 L) was added and the temperature was raised to 30-35°C. The reaction mixture was maintained at 30-35°C for 30 minutes and allowed to settle at 30-35°C for 30 minutes. The reaction mixture was filtered through a Celite® bed (prepared using Celite® (6.0 Kg) and toluene (30.0 L)). The Celite® bed was washed with toluene (60.0 L). The solids were filtered and suction dried for 30 minutes.

[0427] The reaction mixture was charged into a 2.0 KL clean, dry glass-lined reactor. The reaction mixture was allowed to stand at 30-35°C for 30 minutes. The layers were separated (aqueous layer (AL-1) and organic layer (OL-1)) and OL-1 was set aside. Toluene (60.0 L) was charged into AL-1. The reaction mixture was stirred at 35-40°C for 30 minutes and allowed to stand at 35-40°C for 30 minutes. The layers were separated (aqueous layer (AL-2) and organic layer (OL-2)) and OL-2 was set aside. OL-1 and OL-2 were combined to form OL-3.

[0428] 5% saturated sodium bicarbonate solution (prepared from demineralized water (300.0 L) and sodium bicarbonate (15.0 Kg)) was charged slowly into OL-3 at 30-35°C. The reaction mixture was stirred for 30 minutes at 35-40°C and allowed to stand for 30 minutes at 35-40°C. The reaction mixture was filtered through a Celite® bed (prepared using Celite® (6.0 Kg) and demineralized water (60.0 L)). The Celite® bed was washed with toluene (60.0 L).

[0429] The reaction mixture was charged into a 3.0 KL clean, dry glass-lined reactor. The reaction mixture was allowed to settle for 30 minutes at 30-35° C. The layers were separated (aqueous layer (AL-3) and organic layer (OL-4)) and OL-4 was set aside.

[0430] 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 set aside. OL-4 and OL-5 were combined to form OL-6. Brine solution (prepared from demineralized water (300.0 L) and sodium chloride (12.0 Kg)) was added at 25-30°C. The reaction mixture was stirred at 30-35°C for 30 minutes and allowed to stand at 30-35°C for 30 minutes. The layers were separated (aqueous layer (AL-5) and organic layer (OL-7)) and OL-7 was set aside. OL-7 was dried with anhydrous Na2SO4 (9.0 Kg) and the anhydrous Na2SO4 was washed with toluene (30.0 L) at 25-30°C. The solvent was distilled under reduced pressure at less than 40°C-45°C until 5% remained. Methanol (60.0 L) was charged to the reaction mixture at 40-45 °C up to a reaction mass of 60 L.

[0431] Methanol (120.0 L) was charged to the reaction mixture at 40-45° C., the reaction mixture was cooled to 5-10° C. and held at 5-10° C. for 30 min. The solid product was filtered, washed with chilled methanol (30.0 L) and dried in a hot air oven at 40-45° C. for 6 h to obtain the product.

[0432] *1: To prepare the nitration mixture, sulfuric acid (27.0 L) was charged into a 160 L clean, dry glass-lined reactor at 25-30°C. The reaction mixture was cooled to 0-5°C. Nitric acid (27.0 L) was slowly added at 0-5°C, and the reaction mixture was maintained at 0-5°C for 30 minutes to obtain the nitration mixture.

[0433] Final products: 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (11a) and 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (11b) Combined output (11a+11b): 38.87Kg Composite yield (11a+11b): 62.24% Weight ratio (11a:11b):9:1 HPLC purity: 95.9% Moisture content: 0.19% 1H NMR:(500MHz,CDCl3):δ7.44(S,1H),2.21(m,2H),2.78(t,2H),3.02(m,4H),3.13(t,2H)

[0434] Reaction Scheme 2-Step (iv) [ka]

[0435] A mixture of 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (11a) and 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (11b) (9:1 ratio; 27.0 Kg) was charged into a 600 L clean, dry pressure reactor at 25-30 °C.

[0436] Methanol (270 L) was charged at 25-30°C. Methanesulfonic acid (14.3 Kg) was charged slowly at 25-30°C and the reaction mixture was maintained for 30 minutes. 15% Pd(OH)2 slurry (60% wet) *2 was added.

[0437] The reaction mixture was degassed under reduced pressure and filled with argon atmosphere (0.5 Kg) three times. The reaction mixture was degassed under reduced pressure and filled with hydrogen atmosphere (0.5 Kg) three times. The reaction mixture was then stirred under hydrogen pressure (100 Psi) at room temperature for 32 hours. The temperature was gradually raised to 55° C. The absence of 8-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (11a) and 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (11b) was confirmed by HPLC (limit:≦1.0%).

[0438] After completion of the reaction, the reaction mixture was cooled to 25-30° C. The reaction mixture was degassed under reduced pressure and filled with nitrogen atmosphere (0.5 Kg) three times.

[0439] The reaction mixture was filtered through a candy filter to remove Pd(OH)2, followed by microfiltration and washing the bed with methanol (54 L). 95% of the solvent was distilled off under reduced pressure below 45-50°C. Demineralized water (135 L) was charged into the reaction mixture at 25-30°C and maintained for 30 minutes. The reaction mixture was cooled to 5-10°C. The pH was adjusted to about 9-10 with 2N aqueous NaOH solution (prepared from NaOH (6.48 Kg) and demineralized water (81 L)) and the reaction mixture was stirred for 30 minutes. Toluene (135 L) was then charged into the reaction mixture and the reaction mixture was stirred for 30 minutes. The reaction mixture was stirred for another 30 minutes while the temperature was increased to 25-30°C. The reaction mixture was allowed to stand for 30 minutes while maintaining the temperature at 25-30°C.

[0440] 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).

[0441] The layers were separated (aqueous layer (AL-1) and organic layer (OL-1)) and OL-1 was set aside. Toluene (54 L) was added to AL-1 at 25-30°C. The reaction mixture was stirred at 25-30°C for 30 minutes and allowed to stand at 25-30°C for 30 minutes. The layers were separated (aqueous layer (AL-2) and organic layer (OL-2)) and AL-2 was set aside. Toluene (54 L) was added to AL-1 at 25-30°C. A salt solution (prepared with demineralized water (135 L) and sodium chloride (54 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 stand at 25-30°C for 30 minutes.

[0442] 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 35-40°C for 30 minutes. The reaction mixture was filtered through a Celite® bed (prepared using Celite® (5.4 Kg) and toluene (54 L)) at 35-40°C. The Celite® bed was washed with toluene (54 L). The organic layer was dried over anhydrous Na2SO4 (13.5 Kg). The Na2SO4 was washed with toluene (27 L).

[0443] The solvent was distilled under reduced pressure below 35-40°C until 5% remained. Methanol (40.5 L) was charged to the reaction mixture at 35-40°C and distilled until 5% remained. Methanol (97.2 L) and water (10.8 L) were charged to the reaction mixture at 35-40°C. The reaction mixture was heated to 50-55°C, stirred at 50-55°C for 1 h, cooled slowly to 0-5°C and maintained at 0-5°C for 30 min.

[0444] The solid product was filtered, washed with cold methanol (13.5 L) and dried in a hot air oven at 40-45°C for 6 h to obtain the product.

[0445] *2: To prepare 15% Pd(OH)2 slurry, 20% Pd(OH)2 on carbon (60% wet; 4.05 Kg) was added to methanol (27 L).

[0446] Final product: 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) Yield: 11.3Kg Yield: 41.85% HPLC purity: 98.1% Moisture content: 0.10 1 H NMR:(400MHz,DMSO-d6):δ 6.38(S,1H),4.45(S,2H),2.75(t,4H),2.58(t,4H),1.98(t,4H). Purification of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) (A) 1,2,3,5,6,7-Hexahydro-s-indacen-4-amine (12) (54.5 Kg) was charged into a 250 L clean dry reactor at 25-30 °C. Toluene (27.2 L) was charged at 25-30 °C and the reaction mixture was stirred at 25-30 °C for 30 minutes. Methanol (163 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 -5-0 °C and stirred at -5-0 °C for 30 minutes. The solid product was filtered, washed with cold methanol (54.5 L) and dried at 40-45 °C for 6 hours.

[0447] Final product: 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) Yield: 40.5Kg Yield: 74.31% HPLC purity: 99.5% Moisture content: 0.3% 1 H NMR:(400MHz,DMSO-d6):δ 6.33(s,1H),4.53(s,2H),2.72(t,4H),2.57(t,4H),1.98(t,4H). Purification of the product 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) (B)

[0448] The filtered mother liquors from five batches of Reaction Scheme 2, step (iv) were combined and concentrated to give crude 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) (25 Kg), which was purified through a 100-200 mesh silica gel column. The column was eluted with 5-10% ethyl acetate (42 L) in hexane (658 L).

[0449] The pure fractions were concentrated under reduced pressure (600 mmHg) at 40-45°C to give crude 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) (15 Kg).

[0450] Toluene (7.5 L) was added at 25-30 °C and the reaction mixture was stirred at 25-30 °C for 30 min. Methanol (45 L) was added at 25-30 °C and the reaction mixture was stirred at 25-30 °C for 30 min. The reaction mixture was cooled to -5-10 °C and stirred for 30 min. Purity was confirmed using HPLC (limit 98%, single maximum purity: NMT: 1%).

[0451] The solid was filtered, washed with cold methanol (15 L) and dried in a vacuum tray dryer at 40-45° C. for 6 hours.

[0452] Final product: 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) Yield: 10.2Kg Yield: 9.36% HPLC purity: 99.3% Moisture content: 0.12% 1 H NMR:(400MHz,DMSO-d6):δ 6.33(S,1H),4.51(S,2H),2.72(t,4H),2.59(t,4H),1.99(t,4H). Total yield of five batches of Reaction Scheme 2, step iv, including purification (A) and product purification (B): 46.56%

[0453] Reaction Scheme 2-Step (v) [ka]

[0454] 1,2,3,5,6,7-Hexahydro-s-indacene-4-amine (12) (7.50 Kg) was charged to a clean, dry reactor. THF (60.05 Kg) was added to the reactor and the temperature was adjusted to 0-10 °C to form a clear brown solution. N,N'-Diisopropylethylamine (6.66 Kg) dissolved in THF (6.78 Kg) was charged to the reactor while maintaining the temperature at 0-10 °C (lines were rinsed with THF (6.78 Kg) at 0-10 °C). The temperature was maintained at 0-5 °C.

[0455] Phenyl chloroformate (7.44 Kg) dissolved in THF (6.74 Kg) was charged to the reactor over a minimum of 1 hour to form a slurry (lines rinsed with THF (6.66 Kg) at 0-10° C.) while maintaining the temperature at 0-10° C. The temperature of the reaction mixture was increased to 15-25° C. and stirred until completion. 1 HNMR analysis determined. The pass criterion for 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) was less than 1.0 mol%.

[0456] The temperature of the reaction mixture was increased to 30-40°C. The reaction mixture was concentrated under reduced pressure to approximately 37.5 L. Absolute ethanol (31.50 Kg) was charged to the reaction mixture at 30-40°C. The reaction mixture was concentrated under reduced pressure to approximately 37.5 L. Absolute ethanol (29.60 Kg) was charged to the reaction mixture at 30-40°C. The reaction mixture was concentrated under reduced pressure to approximately 37.5 L. Absolute ethanol (29.74 Kg) was charged to the reaction mixture at 30-40°C. The reaction mixture was concentrated under reduced pressure to approximately 37.5 L. A sample of the reaction mixture was 1 Absolute ethanol was added and concentrated repeatedly until analysis by HNMR was passed. Pass criteria: 0.5 wt% THF (based on product).

[0457] Absolute ethanol (30.12 Kg) was charged to the reaction mixture at 15-40° C. The reaction mixture was cooled to 0-5° C. and stirred for 45-90 minutes. The solid was filtered on a 20 μm filter cloth at 0-5° C. The solid was washed with absolute ethanol (11.72 Kg and 12.00 Kg) at 0-5° C. and pumped onto the filter under nitrogen purge for 30-90 minutes.

[0458] The solid was identified and analyzed by HPLC. Acceptance criterion for product was ≦0.5% DIPEA.HCl. The solid was dried under reduced pressure at ≦50° C. under nitrogen flow until the ethanol content was ≦0.5 wt%.

[0459] Final product: 4-(phenoxycarbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (13) Yield: 11.78Kg Yield: 93% HPLC purity: 99.6% 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (potassium salt) (14)

[0460] Reaction Scheme 3 [ka]

[0461] 1-Ethyl-4-piperidinesulfonamide (7) (7.85 Kg) was charged to the vessel. Dimethylsulfoxide (33.5 Kg) was charged to the vessel and the mixture was adjusted to 20-25°C. The mixture was stirred at 20-25°C for at least 60 minutes (target 60-90 minutes) until complete solution was obtained. Potassium tert-butoxide (5.1 Kg) was charged to the vessel in at least six portions over a period of at least 60 minutes (target 60-90 minutes) while maintaining a temperature of 20-30°C (target 20-25°C). The mixture was adjusted to 20-25°C and stirred at 20-25°C for at least 30 minutes (target 30-60 minutes).

[0462] 4-(Phenoxycarbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (13) (12.55 Kg) was charged to the vessel in at least six portions over a period of at least 30 minutes (target 30-90 minutes) while maintaining the temperature at 20-30°C. The reaction mixture was stirred at 20-30°C for at least 60 minutes or until the reaction was complete. The samples were 1 Analysis by HNMR showed that successive pass samples were obtained with the pass criterion of 1-ethyl-4-piperidinesulfonamide (7) being less than 5.0 mol %.

[0463] The reaction mixture was weighed into a separate vessel, then dimethyl sulfoxide (17.2 Kg) was rinsed through the lines and returned to the vessel. The mixture was stirred and adjusted to 20-25°C. The water content was analyzed by KF.

[0464] Acetonitrile (62.0 Kg) was charged to the vessel over a period of at least 30 minutes while maintaining the temperature at 20-25°C. Water (3.00 Kg) was charged to the vessel over a period of 2 to 3 hours while maintaining the temperature at 20-25°C. Acetonitrile (19.4 Kg) was charged to the vessel while maintaining the temperature at 20-25°C. The mixture was stirred at 20-25°C for at least 1 hour (target 1-3 hours). The mixture was cooled to 0-5°C over a period of at least 1 hour (target 1-2 hours), stirred at 0-5°C for at least 1 hour (target 1-4 hours), filtered through a 1-2 μm cloth at 0-5°C, and the filter cake was washed with premix (6:13:0.4, dimethylsulfoxide / acetonitrile / water, 5.34 Kg:8.32 Kg:0.31 Kg) at 0-5°C.

[0465] The solid was dried under vacuum for approximately 2 hours until suitable for processing, and the moisture content of the filter cake was analyzed by KF. Pass criteria, 5.5 wt.% or less.

[0466] The filter cake was slurry washed with acetonitrile (62.3 Kg) at 15-25°C for 30-60 minutes and then filtered at 15-25°C. The filter cake was washed with acetonitrile (19.6 Kg) at 15-25°C. The filter cake was slurry washed with acetonitrile (61.9 Kg) at 15-25°C for at least 30 minutes (target 30-60 minutes) and then filtered at 15-25°C. The filter cake was washed with acetonitrile (19.2 Kg) at 15-25°C. The filter cake was slurry washed with acetonitrile (62.0 Kg) at 15-25°C for at least 30 minutes (target 30-60 minutes) and then filtered at 15-25°C. The filter cake was washed with acetonitrile (18.5 Kg) at 15-25°C.

[0467] The solids were dried under nitrogen flow at 50°C or less and analyzed by KF for residual moisture content. Pass criteria: 2.8 wt% water or less. 1 The solids were analyzed for residual DMSO levels by HNMR. Pass criteria: 12.2 wt% DMSO or less. 1The residual acetonitrile concentration was analyzed by HNMR. Pass criteria: 2.0 wt% MeCN or less. The dry weight of the crude solid was measured and identified. 1 HNMR spectroscopy and HPLC were used for analysis.

[0468] Final product: 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (potassium salt) (14) Yield: 13.95Kg Yield: 80% NMR purity: 97.3% Purification of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-carbamoyl)piperidine-4-sulfonamide (potassium salt) (14) Crude 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (potassium salt) (14) (14.71 Kg) was charged to a reactor. Methanol (116.4 Kg) was charged to the vessel and stirred for 10-20 minutes (until a homogeneous hazy solution was formed with no solid chunks present), adjusting the temperature to 15-25 °C as needed. The solution was filtered through a 1 μm filter at 15-25 °C. The filter was washed with methanol (11.3 Kg) at 15-25 °C. The solution was concentrated to approximately 44 L at 25-35 °C. Acetonitrile (116.6 Kg) was charged to the mixture and the solution was concentrated to 74 L at 25-35 °C. Acetonitrile (58.7 Kg) was charged to the mixture, and the mixture was concentrated to about 74 L at 35° C. or less. 1 Analyzed for residual methanol content by HNMR. Pass criteria, ≤3.0 wt% methanol.

[0469] Acetonitrile (58.8 Kg) was charged to the vessel and the temperature was adjusted to 15-25° C. The slurry was aged at 15-25° C. for at least 1 hour (target 1-2 hours) and then filtered through a 20 μm cloth at 15-25° C. The filter cake was washed twice with acetonitrile (23.9 Kg, 23.6 Kg) at 15-25° C.

[0470] The wet filter cake was analyzed for residual phenol by HPLC. Pass criteria: 0.20 area % phenol or less. The solids were dried under nitrogen flow at 50° C. or less for at least 2 hours and analyzed for residual moisture content using KF. Pass criteria, 2.0 wt % or less. Drying continued while the sample was analyzed.

[0471] Solid 1 The solid was analyzed for residual acetonitrile by HNMR. Pass criteria: 0.2 wt% MeCN or less. 1 Analyzed for residual DMSO by HNMR. Pass criteria: 0.4 wt% DMSO or less. Solids were analyzed for residual solvent levels by GC. Pass criteria: 3750 ppm DMSO or less, 2250 ppm MeOH or less, and 308 ppm MeCN or less.

[0472] Final product: 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (potassium salt) (14) Yield: 14.42Kg Yield: 98% HPLC purity: 99.5%

Claims

1. A method for preparing 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide or a salt thereof, comprising the step of contacting 1-ethyl-4-piperidinesulfonamide (A) with a 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) in the presence of a solvent to obtain 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (C) or a salt thereof. 【Chemical 1】 (In the formula, X is a leaving group).

2. X is Cl, Br, I, OR １ , SR １ , N(R １ ), ２ , OP(=O)(R １ ), ２ or OP(R １ ), ３ ＋ and each R １ is independently selected from C １ -C ２０ hydrocarbyl groups, each C １ -C ２０ hydrocarbyl group may be linear or branched, or may be one or more cyclic groups or may contain one or more cyclic groups, each C １ -C ２０ hydrocarbyl group may be optionally substituted with one or more oxo(=O) and / or one or more halo groups, each C １ -C ２０ hydrocarbyl group may optionally contain one or more heteroatoms independently selected from N, O and S in its carbon skeleton, or any two R １ may together with the nitrogen or phosphorus atom to which they are attached form a 3- to 16-membered heterocyclic group, said heterocyclic group may be monocyclic, bicyclic or tricyclic, said heterocyclic group may be optionally substituted with one or more halo groups and / or one or more groups R Ｘ , each R Ｘ is independently -CN, -OH, -NH ２ , oxo(=O), =NH or C １ -C ６ hydrocarbyl groups, each C １ -C ６ hydrocarbyl group may be linear or branched, or may be one or more cyclic groups or may contain one or more cyclic groups, each C １ -C ６ hydrocarbyl group may be optionally substituted with one or more halo groups, each C １ -C ６ The method according to claim 1, wherein the hydrocarbyl group may optionally contain one or more heteroatoms independently selected from N, O, and S in its carbon skeleton.

3. X is OR １ and R １ is selected from an aryl or heteroaryl group, said aryl or heteroaryl group being monocyclic, bicyclic or tricyclic, and R １ is halo, -CN, -OH, -NO ２ , -NH ２ , -R １０ , -OR １０ , -NHR １０ , -N(R １０ ), ２ or -N(O)(R １０ ), ２ and is optionally substituted with one or more substituents independently selected from, and each R １０ is independently C １ -C ４ alkyl, C １ -C ４ haloalkyl, C ３ -C ４ cycloalkyl, or C ３ -C ４ halocycloalkyl group, or any two Rs １０ directly bonded to the same nitrogen atom may together form a C ２ -C ５ alkylene or C ２ -C ５ haloalkylene group, and R １ containing any substituents contains 1 to 20 carbon atoms, the method according to claim 1.

4. The method according to claim 1, wherein X is OPh.

5. The method according to claim 1, wherein the solvent is dimethyl sulfoxide.

6. The method according to claim 1, wherein the step of contacting 1-ethyl-4-piperidinesulfonamide (A) with a 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) is carried out in the presence of a base such as a tertiary butoxide base.

7. 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide or a salt thereof, prepared or preparable by the method according to claim 1.

8. A method for preparing a 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or a salt thereof, comprising the step of converting 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) into a 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or a salt thereof. 【Chemical 2】 (In the formula, X is a leaving group).

9. Contacting 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) with a reagent (E) [Chemical 3] (In the formula, X and X' are leaving groups.) in the presence of an optional base and / or solvent, according to the method of claim 8.

10. The method according to claim 9, wherein (i) the solvent is tetrahydrofuran and / or (ii) the base is a tertiary amine such as N,N-diisopropylethylamine.

11. X is Cl, Br, I, OR １ , SR １ , N(R １ ), ２ , OP(=O)(R １ ), ２ or OP(R １ ), ３ ＋ and each R １ is independently selected from C １ -C ２０ hydrocarbyl groups, each C １ -C ２０ hydrocarbyl group may be linear or branched, or may be one or more cyclic groups or may contain one or more cyclic groups, each C １ -C ２０ hydrocarbyl group may be optionally substituted with one or more oxo(=O) and / or one or more halo groups, each C １ -C ２０ hydrocarbyl group may optionally contain one or more heteroatoms independently selected from N, O and S in its carbon skeleton, or any two R １ may together with the nitrogen or phosphorus atom to which they are attached form a 3- to 16-membered heterocyclic group, said heterocyclic group may be monocyclic, bicyclic or tricyclic, said heterocyclic group may be optionally substituted with one or more halo groups and / or one or more groups R Ｘ , and each R Ｘ is independently -CN, -OH, -NH ２ , oxo(=O), =NH or C １ -C ６ hydrocarbyl groups, each C １ -C ６ hydrocarbyl group may be linear or branched, or may be one or more cyclic groups or may contain one or more cyclic groups, each C １ -C ６ hydrocarbyl group may be optionally substituted with one or more halo groups, each C １ -C ６ The method according to claim 8, wherein the hydrocarbyl group may optionally contain one or more heteroatoms independently selected from N, O, and S in its carbon skeleton.

12. X is OR １ and R １ is selected from an aryl or heteroaryl group, said aryl or heteroaryl group being monocyclic, bicyclic or tricyclic, and R １ is halo, -CN, -OH, -NO ２ , -NH ２ , -R １０ , -OR １０ , -NHR １０ , -N(R １０ ), ２ , or -N(O)(R １０ ), ２ and may be optionally substituted with one or more substituents independently selected from, and each R １０ is independently C １ -C ４ alkyl, C １ -C ４ haloalkyl, C ３ -C ４ cycloalkyl, or C ３ -C ４ halocycloalkyl group, or any two Rs １０ directly bonded to the same nitrogen atom may together form a C ２ -C ５ alkylene or C ２ -C ５ haloalkylene group, and R １ containing any substituents contains 1 to 20 carbon atoms, the method according to claim 8.

13. The method according to claim 8, wherein X is OPh.

14. The method according to claim 8, wherein X' is Cl or Br.

15. A method comprising one or more steps selected from the following: (a) Converting 4-hydroxypiperidine (F) to N-protected-4-hydroxypiperidine (G); 【Chemical 4】 (wherein R ２ is a nitrogen protecting group); (b) Converting N-protected-4-hydroxypiperidine (G) to N-protected-4-derivatized piperidine (H); 【Chemical Formula 5】 (wherein, R ２ is a nitrogen protecting group, and R ３ is a leaving group); (c) Converting N-protected-4-derivatized piperidine (H) to N-protected-4-(acylthio)-piperidine (I); 【Chemical Formula 6】 (wherein R ２ is a nitrogen protecting group, R ３ is a leaving group, R ４ is a C １ -C ２０ hydrocarbyl group, and the C １ -C ２０ hydrocarbyl group may be linear or branched, or may be one or more cyclic groups or may contain one or more cyclic groups, and the C １ -C ２０ hydrocarbyl group may be optionally substituted with one or more oxo(=O) and / or one or more halo groups, and the C １ -C ２０ hydrocarbyl group may optionally contain one or more heteroatoms independently selected from N, O and S in its carbon skeleton); (d) Converting N-protected-4-(acylthio)-piperidine (I) to N-protected-4-(halosulfonyl)-piperidine (J); 【Chemical Formula 7】 (wherein R ２ is a nitrogen protecting group, and R ４ is a C １ -C ２０ hydrocarbyl group, and the C １ -C ２０ hydrocarbyl group may be linear or branched, or may be one or more cyclic groups or may contain one or more cyclic groups, and the C １ -C ２０ hydrocarbyl group may be optionally substituted with one or more oxo(=O) and / or one or more halo groups, and the C １ -C ２０ hydrocarbyl group may optionally contain one or more heteroatoms independently selected from N, O, and S in its carbon skeleton, and Hal is Cl or Br); (e) Converting N-protected-4-(halosulfonyl)-piperidine (J) to N-protected-4-piperidinesulfonamide (K); 【Chemical Formula 8】 (wherein R ２ is a nitrogen protecting group, and Hal is Cl or Br); and (f) Converting N-protected-4-piperidinesulfonamide (K) to 1-ethyl-4-piperidinesulfonamide (A); 【Chemical Formula 9】 (wherein R ２ is a nitrogen protecting group).

16. R ２ The method according to claim 15, wherein R is a nitrogen protecting group that can be removed by catalytic hydrogenolysis.

17. The method according to claim 16, wherein the reaction step (f) comprises contacting N-protected-4-piperidinesulfonamide (K) with acetonitrile or acetaldehyde in the presence of a catalyst and hydrogen gas to obtain 1-ethyl-4-piperazinesulfonamide (A).

18. The reaction step (f) is (i) contacting N-protected-4-piperidinesulfonamide (K) with a first catalyst in the presence of hydrogen gas and a solvent to form an intermediate mixture comprising piperidine-4-sulfonamide and the solvent; and (ii) contacting the intermediate mixture comprising piperidine-4-sulfonamide and the solvent with acetonitrile or acetaldehyde in the presence of a second catalyst and hydrogen gas to obtain 1-ethyl-4-piperidine-sulfonamide (A) The method according to claim 16, comprising.

19. R ２ is -CH ２ R ２０ or -COOCH ２ R ２０ wherein R ２０ is an aryl or heteroaryl group, said aryl or heteroaryl group being monocyclic, bicyclic or tricyclic, said aryl or heteroaryl group being halo, -CN, -OH, NO ２ , -NH ２ , -R ２１ , -OR ２１ , -NHR ２１ , -N(R ２１ ), ２ or -N(O)(R ２１ ), ２ and may be optionally substituted with one or more substituents independently selected from, each R ２１ being independently C １ -C ４ alkyl, C １ -C ４ haloalkyl, C ３ -C ４ cycloalkyl or C ３ -C ４ halocycloalkyl group, or any two R ２１ directly bonded to the same nitrogen atom may together form C ２ -C ５ alkylene or C ２ -C ５ haloalkylene group, and R ２０ containing any substituents is a method according to claim 15, containing 1 to 20 carbon atoms.

20. R ２ is - COOCH ２ Ph, the method according to claim 15.

21. R ３ The method according to claim 15, wherein R is a sulfonate leaving group such as -OMs.

22. The method according to claim 21, wherein the reaction step (b) comprises contacting N-protected-4-hydroxypiperidine (G) with a sulfonyl halide or sulfonyl anhydride in the presence of a base to form N-protected-4-derivatized piperidine (H).

23. R ４ The method according to claim 15, wherein R is methyl.

24. The method according to claim 15, wherein Hal is Cl.

25. The method according to claim 15, wherein the reaction step (a) comprises contacting 4-hydroxypiperidine (F) with a nitrogen protecting group precursor in the presence of a base.

26. The reaction step (c) comprises contacting the N-protected-4-derivatized piperidine (H) with R ４ COS － The method according to claim 15, wherein the method comprises contacting the N-protected-4-derivatized piperidine (H) with R

27. The method according to claim 15, wherein reaction step (d) comprises contacting N-protected-4-(acylthio)-piperidine (I) with a halogenating agent in the presence of an acid and an aqueous solvent.

28. The method according to claim 15, wherein reaction step (e) comprises contacting N-protected-4-(halosulfonyl)-piperidine (J) with ammonia to form N-protected-4-piperidinesulfonamide (K).

29. 1-Ethyl-4-piperidinesulfonamide (A) or a salt thereof: 【Chemical Formula 10】 The method according to claim 15, which is a method for preparing the same.

30. A compound selected from the group consisting of: (i) A 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or a salt thereof: 【Chemical 11】 (wherein X is a leaving group); or (ii) N-protected-4-hydroxypiperidine (G) or a salt thereof: 【Chemical 12】 (wherein, R ２ is a nitrogen protecting group); or (iii) N-protected-4-derivatized piperidine (H) or a salt thereof: 【Chemical 13】 (wherein R ２ is a nitrogen protecting group, and R ３ is a leaving group); or (iv) N-protected-4-(acylthio)-piperidine (I) or a salt thereof: 【Chemical Formula 14】 (wherein R ２ is a nitrogen protecting group, and R ４ is a C １ -C ２０ hydrocarbyl group, and the C １ -C ２０ hydrocarbyl group may be linear or branched, or may be one or more cyclic groups or may contain one or more cyclic groups, and the C １ -C ２０ hydrocarbyl group may be optionally substituted with one or more oxo(=O) and / or one or more halo groups, and the C １ -C ２０ hydrocarbyl group may optionally contain one or more heteroatoms independently selected from N, O, and S in its carbon skeleton); or (v) N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof: 【Chemical Formula 15】 (wherein R ２ is a nitrogen protecting group, and Hal is Cl or Br); or (vi) N-protected-4-piperidinesulfonamide (K) or a salt thereof: 【Chemical 16】 (wherein, R ２ is a nitrogen protecting group); or (vii) 1-Ethyl-4-piperazinesulfonamide (A) or a salt thereof: 【Chemical 17】

31. A pharmaceutical composition comprising the 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide or a salt thereof according to claim 7 and a pharmaceutically acceptable additive.

32. The method according to any one of claims 1 to 6, wherein (i) the 1-ethyl-4-piperidinesulfonamide (A) is prepared by the method according to claim 29, and / or (ii) the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) is prepared by the method according to claim 8.

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