Process for the preparation of NLRP3 inhibitors

Abstract

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

Description

[Technical Field]

[0001] FIELD OF THE INVENTION 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, as well as related pharmaceutical compositions and uses for the treatment and prevention of medical disorders and diseases, particularly through 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 as an NLRP3 inhibitor in WO 2019 / 008025 (see Example 6). However, there is a need to provide an improved process 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 an efficient process that is suitable for large-scale synthesis, avoids, for example, expensive chromatography or high-temperature techniques, avoids or minimizes the use of expensive or environmentally unfriendly reagents, and / or avoids 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, and intermediates on the route to such compounds, in higher yields and / or higher purity, especially on large scale, compared to prior art processes. The present invention solves the above problems. Summary of the Invention

[0003] Summary of the Invention A first aspect of the present invention is a process for preparing a thiourea adduct (I) or a salt thereof, comprising the steps of converting an N-protected-4-derivatized piperidine (H) into the thiourea adduct (I) or a salt thereof: [ka] providing a process including During the ceremony: R 2 is a nitrogen protecting group; R 3 is a leaving group; and Each R 4 are independently hydrogen or C1-C 20 hydrocarbyl groups, wherein each C-C 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C-C 20 The hydrocarbyl group may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20 The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or any two or more R 4 may, together with the atom(s) to which they are attached, form a 3- to 16-membered heterocyclic group, which may be monocyclic, bicyclic, or tricyclic, and which may contain one or more halo groups and / or one or more groups R 40 and each R 40 are independently selected from -CN, -OH, -NH, oxo (=O), =NH or a C1-C6 hydrocarbyl group, each C1-C6 hydrocarbyl group may be straight chained or branched or may be or contain one or more cyclic groups, each C1-C6 hydrocarbyl group may be optionally substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may optionally include one or more heteroatoms independently selected from N, O and S in its carbon skeleton. DETAILED DESCRIPTION OF THE INVENTION

[0004] 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.

[0005] An "alkyl" substituent or alkyl moiety in a substituent can be linear (i.e., straight-chain) 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-C6 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.

[0006] 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-C6 12 An alkenyl group is more typically a C2-C6 alkenyl group. An "alkenylene" group is similarly defined as a divalent alkenyl group.

[0007] 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 is a C2-C6 alkynyl group. More typically, the alkynyl group is a C2-C6 alkynyl group. An "alkynylene" group is similarly defined as a divalent alkynyl group.

[0008] 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 skeleton. Examples of cyclic groups include cycloalkyl, cycloalkenyl, heterocyclic, aryl, and heteroaryl groups, as discussed below. Cyclic groups can be monocyclic, bicyclic (e.g., bridged, fused, or spiro), or polycyclic. Typically, cyclic groups are 3- to 12-membered cyclic groups, meaning they contain 3 to 12 ring atoms. More typically, cyclic groups are 3- to 7-membered monocyclic groups, meaning they contain 3 to 7 ring atoms.

[0009] A "heterocyclic" substituent or heterocyclic moiety in a substituent refers to a cyclic group or moiety that includes 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.

[0010] 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 stated, a cycloalkyl substituent or moiety can include monocyclic, bicyclic, or polycyclic hydrocarbyl rings.

[0011] 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 stated, a cycloalkenyl substituent or moiety can include monocyclic, bicyclic, or polycyclic hydrocarbyl rings.

[0012] 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 optional substituents) are aromatic. Examples of aryl groups / moieties include phenyl, naphthyl, anthracenyl, and phenanthrenyl. Unless otherwise specified, the term "aryl" does not include "heteroaryl."

[0013] 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 (excluding any ring systems that are part of or formed by any optional substituents) are aromatic. Examples of heteroaryl groups / moieties include: [ka] wherein G=O, S or NH.

[0014] 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 contains the atom through which the group is attached to the rest of the molecule. An example of an arylalkyl group is benzyl.

[0015] The term "halo" includes fluoro, chloro, bromo and iodo.

[0016] Unless otherwise specified, when a group is prefixed with the term "halo," such as a haloalkyl or halomethyl group, it is 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 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 specified, when a group is prefixed with a specific halo group, it is understood that the group in question is substituted with one or more of the specified halo groups. For example, the term "fluoromethyl" refers to a methyl group substituted with one, two, or three fluoro groups.

[0017] Similarly, unless otherwise specified, when a group is referred to as "halo-substituted," it is 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 referred to as 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.

[0018] 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, any reference to hydrogen is considered to encompass all isotopes of hydrogen, including deuterium and tritium.

[0019] Unless otherwise stated, any reference to a compound or group should be considered to refer to all tautomeric forms of that compound or group.

[0020] When referring to a hydrocarbyl or other group that contains one or more heteroatoms N, O or S in its carbon skeleton, or when referring to other groups that are substituted with carbon atoms or N, O or S atoms of a hydrocarbyl, the following is intended: [ka] -CH2- is replaced by -NH-, -O- or -S-; -CH3 is replaced by -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.

[0021] As used herein, when a group, such as a hydrocarbyl group, is said to be substituted with an oxo (=O) group, any two hydrogen atoms bonded to the same atom may be replaced with π-bonded =O substituents, or It should be understood that when a 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 optionally, 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 by one (-CHCHO, -CHNO) or two (-CHSOH). - are examples of -CH2CH3, -CH2NHOH and -CH2-S-OH groups substituted with oxo groups, respectively (CH2SO3H).

[0022] In the context of this specification, unless otherwise stated, C x -C yA 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 substituted with optional substituents and / or containing optional moieties. For the avoidance of doubt, a replacing heteroatom, e.g., N, O, or S, is not included in the C x -C y It should not be counted as a carbon atom when calculating the number of carbon atoms in the group. For example, a morpholinyl group should be considered a C4 heterocyclic group, not a C6 heterocyclic group.

[0023] In one embodiment of the first aspect of the present invention, the process comprises reacting an N-protected-4-derivatized piperidine (H) with a reagent (IX): [ka] and optionally in the presence of a base and / or a solvent, wherein each R 4 is as defined above.

[0024] 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", 5 th Ed., 2014, the contents of which are incorporated herein by reference in their entirety.

[0025] In one embodiment of the first aspect of the present invention, R 2 is a nitrogen protecting group that is stable under basic conditions. Typically, R 2 is stable under weakly nucleophilic conditions, such as when exposed to thiourea. For example, R 2may 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.

[0026] In one embodiment of the first aspect of the present 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) and triphenylmethyl (Trt) groups.

[0027] In a further embodiment of the first aspect of the invention, R 2 is -CH2R 20 or -COOCH2R 20 where 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 21may together form a C2-C5 alkylene or C2-C5 haloalkylene group, R 20 contains 1 to 20 carbon atoms, including any optional substituents.

[0028] In one embodiment of the first aspect of the present invention, R 2 HA-COOCH2R 20 is.

[0029] In one embodiment of the first aspect of the present 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, -NO, -NH, -Me, -Et, -OMe, -OEt, -NHMe, -NHEt, -N(Me), -N(Me)Et, or -N(Et), any methyl (Me) or ethyl (Et) group is optionally substituted with one or more halo groups; R 20 contains 1 to 12 carbon atoms, including any optional substituents.

[0030] Typically, R 20 is a phenyl group, which is optionally substituted with one or more fluoro, chloro, -OMe, -OEt, or -NO2 groups.

[0031] More typically, R 20 is a phenyl group. For example, R 2 can be -CH2Ph ​​or -COOCH2Ph.

[0032] Most typically, R 2 is —COOCH2Ph ​​(i.e., a benzyloxycarbonyl (CBz) group).

[0033] As described, R 3 is a leaving group. In one embodiment of the first aspect of the present invention, R 3is selected from Cl, Br, I, or a sulfonate leaving group such as a toluenesulfonate (tosylate or -OT), methanesulfonate (mesylate or -OM), or trifluoromethanesulfonate (triflate or -OTf) leaving group. Typically, R 3 is a sulfonate leaving group. Most typically, R 3 is -OMs.

[0034] In one embodiment of the first aspect of the present invention, each R 4 is hydrogen or C1-C 12 Alkyl or -L 41 -R 41 or any two R 4 Together -L 42 - group, wherein: Each C1-C 12 An alkyl group may optionally be halo-substituted and may optionally contain 1, 2 or 3 oxygen atoms in its carbon skeleton; Each L 41 are independently selected from a bond or a C1-C4 alkylene group, each C1-C4 alkylene group may optionally be halo-substituted and may optionally include 1, 2 or 3 oxygen atoms in its carbon skeleton; Each R 41 are independently selected from C3-C7 cycloalkyl, phenyl, naphthyl, or monocyclic or bicyclic heteroaryl groups, where any C3-C7 cycloalkyl group optionally includes one or two oxygen atoms in its carbon skeleton, and any C3-C7 cycloalkyl, phenyl, naphthyl, or monocyclic or bicyclic heteroaryl group is selected from each -L 41 -R 41 one or more halo groups and / or one or more R 43 optionally substituted with a group; Each L 42are independently selected from C2-C6 alkylene groups, any C2-C6 alkylene group may optionally contain one or two oxygen atoms in its carbon skeleton, and any C2-C6 alkylene group may be selected from each -L 42 -one or more halo groups and / or R, provided that the group contains no more than 12 carbon atoms including any optional substituents 43 optionally substituted with a group; and Each R 43 The groups are independently selected from C1-C4 alkyl-O—(C1-C4 alkyl), C1-C4 haloalkyl, —O—(C1-C4 haloalkyl), C3-C4 cycloalkyl-O—(C3-C4 cycloalkyl), C3-C4 halocycloalkyl or —O—(C3-C4 halocycloalkyl) groups.

[0035] In a further embodiment of the first aspect of the invention, each R 4 are independently selected from hydrogen or a C1-C6 alkyl or C3-C6 cycloalkyl group, or any two R 4 may be taken together to form a C2-C6 alkylene group, wherein any C1-C6 alkyl, C3-C6 cycloalkyl, or C2-C6 alkylene group may be optionally fluoro-substituted.

[0036] Typically, according to the first aspect of the present invention, at least one R 4 is hydrogen. For example, the thiourea adduct (I) according to the first aspect of the present invention has the formula (Ia): [ka] and In the formula, R 2 and R 4 is as defined above. Typically, in such embodiments, the thiourea adduct (Ia) or a salt thereof is prepared by reacting an N-protected-4-derivatized piperidine (H) with a reagent (I-Xa): [ka] and optionally in the presence of a base and / or a solvent, 4 is as defined above.

[0037] Most typically, according to the first aspect of the invention, each R 4 is hydrogen. As will be appreciated, in such embodiments, the thiourea adduct (I) according to the first or second aspect of the present invention has the formula (Ib): [ka] and In the formula, R 2 is as defined above. Typically, in such embodiments, the thiourea adduct (Ib) or a salt thereof is prepared by reacting an N-protected-4-derivatized piperidine (H) with a reagent (I-Xb): [ka] and Optionally, in the presence of a base and / or a solvent.

[0038] Typically, the process of the first aspect of the invention is carried out in the presence of a solvent.

[0039] In one embodiment, the solvent is a polar solvent or a mixture of a polar solvent and a nonpolar 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 nonpolar solvents. Typically, the solvent does not contain esters. Typically, the solvent is not halogenated. Suitable polar protic solvents include water and alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, and tert-amyl alcohol. Suitable polar aprotic solvents include dimethyl sulfoxide, N,N-dimethylformamide, N,N'-dimethylpropylene urea, tetrahydrofuran, 1,4-dioxane, acetone, acetonitrile, dichloromethane, hexamethylphosphoramide, nitromethane, propylene carbonate, and N-methylpyrrolidone. Suitable nonpolar solvents include pentane, cyclopentane, hexane, cyclohexane, diethyl ether, and toluene.

[0040] Typically, the solvent is a polar protic solvent or a mixture of a polar protic solvent and a non-polar solvent. Typically, in such embodiments, the polar protic solvent is selected from water or an alcohol, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, iso-butanol, tert-butanol, tert-amyl alcohol, or any mixture thereof. More typically, the polar protic solvent is selected from an alcohol, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, iso-butanol, tert-butanol, tert-amyl alcohol, or a mixture thereof. Most typically, the polar protic solvent is n-butanol. Typically, when a non-polar solvent is present, the non-polar solvent is selected from pentane, cyclopentane, hexane, cyclohexane, diethyl ether, toluene, or a mixture thereof. Most typically, the non-polar solvent is toluene.

[0041] In an exemplary embodiment of the first aspect of the present invention, the solvent is a mixture of n-butanol and toluene.

[0042] When the solvent is a mixture of a polar protic solvent and a non-polar solvent, such as a mixture of n-butanol and toluene, typically the ratio of polar protic solvent to non-polar solvent is >3:1 by volume. More typically, the ratio of polar protic solvent to non-polar solvent is >10:1 by volume. Even more typically, the ratio of polar protic solvent to non-polar solvent is >20:1 by volume.

[0043] Optionally, the process of the first aspect of the present invention 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 alkoxide base such as a tertiary butoxide base, or a tertiary amine such as N,N-diisopropylethylamine (DIPEA), trimethylamine, triethylamine (TEA), tripropylamine or tributylamine. Most typically, the base, when present, is triethylamine.

[0044] Optionally, the process of the first aspect of the present invention is carried out in the presence of a nucleophilic catalyst. For example, an iodide source such as NaI may be used. However, it should be noted that the process of the first aspect of the present invention can proceed in the absence of a nucleophilic catalyst, which may be advantageous because it allows for easier post-treatment procedures. Thus, in one embodiment of the first aspect of the present invention, no nucleophilic catalyst is added to the reaction mixture.

[0045] In an exemplary embodiment of the first aspect of the present invention, the process comprises the steps of contacting benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H′) with reagent (I-Xb) in a solvent to obtain benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I′) or a salt thereof: [ka] Includes.

[0046] Typically, in such embodiments, the solvent is n-butanol or a mixture of n-butanol and toluene.

[0047] Typically, according to the first aspect of the present invention, the N-protected-4-derivatized piperidine (H) or (H') is combined with the reaction mixture in a non-salt form.

[0048] Typically, according to the first aspect of the present invention, reagent (IX), (I-Xa) or (I-Xb) is combined with the reaction mixture in a non-salt form.

[0049] Typically, according to the first aspect of the present invention, the thiourea adduct (I) or (I') is obtained in the form of a salt. More typically, the thiourea adduct (I) or (I') is obtained as a sulfonic acid addition salt. Most typically, the thiourea adduct (I) or (I') is obtained as a methanesulfonate salt.

[0050] In one embodiment of the first aspect of the present invention, the step of converting the N-protected-4-derivatized piperidine (H) or (H') to the thiourea adduct (I) or (I') or a salt thereof is carried out at a temperature in the range of 20 to 150° C. Typically, the step is carried out at a temperature in the range of 75 to 125° C., more typically in the range of 90 to 110° C.

[0051] Typically, according to the first aspect of the present invention, the N-protected 4-derivatized piperidine (H) or (H') is present in 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 or added to the solvent at an initial concentration of 0.5 to 2.0 mol / L. Most typically, the N-protected 4-derivatized piperidine (H) or (H') is present in or added to the solvent at an initial concentration of 0.8 to 1.2 mol / L.

[0052] Typically, the process of the first aspect of the present invention uses 0.9 to 3.0 molar equivalents of reagent (IX), (I-Xa), or (I-Xb) relative to the initial amount of N-protected-4-derivatized piperidine (H) or (H'). More typically, the process uses 0.95 to 1.5 molar equivalents of reagent (IX), (I-Xa), or (I-Xb). Most typically, the process uses 1.0 to 1.2 molar equivalents of reagent (IX), (I-Xa), or (I-Xb).

[0053] Typically, when the process of the first aspect of the present 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 0.95 to 1.5 molar equivalents of base. Most typically, the process uses 1.0 to 1.2 molar equivalents of base.

[0054] Typically, when the process of the first aspect of the present invention uses a nucleophilic catalyst, the process uses 0.01 to 0.5 molar equivalents of nucleophilic catalyst relative to the initial amount of N-protected-4-derivatized piperidine (H) or (H'). More typically, the process uses 0.02 to 0.3 molar equivalents of nucleophilic catalyst. Most typically, the process uses 0.05 to 0.15 molar equivalents of nucleophilic catalyst.

[0055] In one embodiment of the first aspect of the present invention, the process comprises the steps of: (1) providing a solution of N-protected-4-derivatized piperidine (H) or (H') in a non-polar solvent such as toluene; (2) adding a polar protic solvent, such as n-butanol, and reagent (IX), (I-Xa), or (I-Xb) to the solution of step (1) to form a mixture; (3) optionally removing a portion of the solvent from step (2), for example by distillation under reduced pressure; (4) optionally adding an additional portion of a polar protic solvent; and (5) heating the mixture to a temperature typically in the range of 75 to 125°C, more typically in the range of 90 to 110°C.

[0056] Typically, according to the first aspect of the present invention, steps (3) and (4) are not optional steps.

[0057] In one embodiment of the first aspect of the present invention, the thiourea adduct (I) or (I') or a salt thereof is isolated from the reaction mixture by crystallization or precipitation. For example, the reaction mixture may be cooled, optionally with seeding, to form a slurry of solid product, which may then be collected by filtration. The collected solid may then be washed with an alcohol, such as isopropanol, and optionally dried under vacuum. For example, the process of the first aspect of the present invention, which comprises steps (1) to (5) above, may comprise the following steps: (6) seeding the mixture with crystals of thiourea adduct (I) or (I') or a salt thereof; (7) maintaining the seeded mixture at an elevated temperature, typically within the range of 75-125°C, more typically within the range of 90-110°C, for at least 1 hour; (8) cooling the seeded mixture to a temperature typically in the range of 0 to 50°C, more typically in the range of 15 to 30°C, to form a slurry comprising the thiourea adduct (I) or (I'), or a salt thereof, as a solid; (9) collecting the solids by filtration; (10) optionally washing the collected solid with a solvent, e.g., an alcohol such as isopropanol; and (11) Optionally, the method may further comprise the step of drying the collected solid under vacuum.

[0058] Typically, according to the first aspect of the present invention, steps (10) and (11) are not optional steps.

[0059] In one embodiment of the first aspect of the present invention, the N-protected-4-derivatized piperidine (H) is prepared by the following process: (ii) converting N-protected-4-hydroxypiperidine (G) to N-protected-4-derivatized piperidine (H): [ka] In the formula, R 2 is a nitrogen protecting group, and R 3 is a leaving group, The compound is obtained by a process including:

[0060] In other words, in one embodiment of the first aspect of the present invention, there is provided a process for preparing a thiourea adduct (I) or a salt thereof, the process comprising at least the following steps: (ii) converting N-protected-4-hydroxypiperidine (G) to N-protected-4-derivatized piperidine (H): [ka] (iii) converting the N-protected-4-derivatized piperidine (H) into the thiourea adduct (I) or a salt thereof: [ka] A process comprising: During the ceremony: R 2 is a nitrogen protecting group; R 3 is a leaving group; Each R 4 are independently hydrogen or C1-C 20 hydrocarbyl groups, wherein each C-C 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C-C 20 The hydrocarbyl group may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or any two or more R 4 may, together with the atom(s) to which they are attached, form a 3- to 16-membered heterocyclic group, which may be monocyclic, bicyclic, or tricyclic, and which may contain one or more halo groups and / or one or more groups R 40 and each R 40 are independently selected from -CN, -OH, -NH, oxo (=O), =NH or a C1-C6 hydrocarbyl group, each C1-C6 hydrocarbyl group may be straight chained or branched or may be or contain one or more cyclic groups, each C1-C6 hydrocarbyl group may be optionally substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may optionally include one or more heteroatoms independently selected from N, O and S in its carbon skeleton.

[0061] As will be appreciated, when the first aspect of the present invention comprises steps (ii) and (iii), R 2 and R 3 is the same for each step. All optional exemplary and illustrative embodiments described above in relation to the first aspect of the present invention apply equally to step (iii).

[0062] In one embodiment of the first aspect of the present invention, reacting step (ii) comprises contacting N-protected-4-hydroxypiperidine (G) with SOCl, SOBr, or a mixture of PhP and Cl or Br to form N-protected-4-derivatized piperidine (H), wherein R 3 is a Cl or Br leaving group as appropriate.

[0063] In another embodiment of the first aspect of the present invention, reacting step (ii) comprises contacting N-protected-4-hydroxypiperidine (G) with a sulfonyl halide or sulfonyl anhydride to produce N-protected-4-derivatized piperidine (H), where R 3is a sulfonate leaving group).

[0064] As will be appreciated, the sulfonyl halide or sulfonyl anhydride used is R 3 corresponds to a sulfonate leaving group of, for example, R 3 When R is a tosylate leaving group, tosyl halide or tosyl anhydride is used. 3 When R 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.

[0065] 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 sulfonyl chloride or sulfonyl bromide. More typically, the sulfonyl halide is sulfonyl chloride.

[0066] In an exemplary embodiment of the first aspect of the present invention, reacting step (ii) comprises contacting N-protected-4-hydroxypiperidine (G) with mesyl halide or mesyl anhydride to produce N-protected-4-derivatized piperidine (H), where R 3 is a mesylate leaving group). Most typically, in such embodiments, reacting step (ii) comprises contacting N-protected-4-hydroxypiperidine (G) with mesyl chloride.

[0067] Typically, reaction step (ii) is carried out in the presence of a solvent. Typically, the solvent is aprotic. Typically, reaction step (ii) comprises contacting N-protected-4-hydroxypiperidine (G) with a sulfonyl halide or sulfonyl anhydride in an aprotic solvent.

[0068] In one embodiment, the solvent is a polar aprotic solvent such as dimethyl sulfoxide, N,N-dimethylformamide, N,N'-dimethylpropylene urea, 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 can be selected from dimethyl sulfoxide, 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 can be selected from dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, dichloromethane, hexamethylphosphoramide, nitromethane, or a mixture thereof. In one embodiment, the solvent is dichloromethane.

[0069] In another embodiment, the solvent is a non-polar solvent such as pentane, cyclopentane, hexane, cyclohexane, diethyl ether, toluene, or a mixture thereof. Typically, the non-polar solvent is non-halogenated. Most typically, the non-polar solvent is toluene.

[0070] In one embodiment of the first aspect of the present invention, reacting step (ii) is carried out in the presence of a base. Typically, reacting step (ii) comprises contacting N-protected-4-hydroxypiperidine (G) with a sulfonyl halide or sulfonyl anhydride 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).

[0071] In an exemplary embodiment of the first aspect of the present invention, there is provided a process for preparing benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I′) or a salt thereof, the process comprising the steps of: (ii) contacting N-carboxybenzyl-4-hydroxypiperidine (G') with mesyl chloride to obtain benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H'); [ka] (iii) contacting benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H') with reagent (I-Xb) in a solvent to obtain benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I') or a salt thereof: [ka] Includes.

[0072] Typically, in such embodiments, in step (ii), N-carboxybenzyl-4-hydroxypiperidine (G') is contacted with mesyl chloride in the presence of a tertiary amine base, such as triethylamine, and an aprotic solvent, which is typically a non-polar solvent, such as toluene.

[0073] Typically, when the process of the first aspect of the present invention includes step (ii), the N-protected-4-hydroxypiperidine (G) or (G') is combined with the reaction mixture of step (ii) in non-salt form.

[0074] Typically, when the process of the first aspect of the invention comprises step (ii), the N-protected-4-derivatized piperidine (H) or (H') is obtained in step (ii) in non-salt form.

[0075] In one embodiment of the first aspect of the present invention, the N-protected-4-derivatized piperidine (H) or (H') is not isolated between steps (ii) and (iii).

[0076] In another embodiment of the first aspect of the present invention, at the end of the reaction, the process in step (ii) further comprises a work-up step in which the reaction mixture is subjected to aqueous washes so that the N-protected-4-derivatized piperidine (H) or (H') is retained in the organic phase. Typically, in such embodiments, the reaction solvent is a nonpolar solvent such as toluene. In one embodiment, the solvent is removed from the organic phase to obtain the N-protected-4-derivatized piperidine (H) or (H'). Alternatively, the N-protected-4-derivatized piperidine (H) or (H') in the organic phase may be used directly in step (iii). Optionally, in such embodiments, a portion of the solvent, e.g., about 50-75% by volume, is removed from the organic phase by, for example, distillation under reduced pressure. The remaining organic solvent containing the N-protected-4-derivatized piperidine (H) or (H'), may then be used directly in step (iii). As will be appreciated, in such embodiments, the solvent in the organic phase provides all or a portion of the solvent used in the reaction in step (iii). In one embodiment of the first aspect of the present invention, N-protected-4-hydroxypiperidine (G) can be prepared by the following process: (i) converting 4-hydroxypiperidine (F) to N-protected-4-hydroxypiperidine (G): [ka] In the formula, R 2 is a nitrogen protecting group, The compound is obtained by a process including: In other words, in one embodiment of the first aspect of the present invention, there is provided a process for preparing a thiourea adduct (I) or a salt thereof, the process comprising the steps of: (i) converting 4-hydroxypiperidine (F) to N-protected-4-hydroxypiperidine (G): [ka] (ii) converting N-protected-4-hydroxypiperidine (G) to N-protected-4-derivatized piperidine (H): [ka] (iii) converting the N-protected-4-derivatized piperidine (H) into the thiourea adduct (I) or a salt thereof: [ka] Including, During the ceremony: R 2 is a nitrogen protecting group; R 3 is a leaving group; Each R 4 are independently hydrogen or C1-C 20 hydrocarbyl groups, wherein each C-C 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C-C 20 The hydrocarbyl group may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20 The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or any two or more R 4 may, together with the atom(s) to which they are attached, form a 3- to 16-membered heterocyclic group, which may be monocyclic, bicyclic, or tricyclic, and which may contain one or more halo groups and / or one or more groups R 40 and each R 40are independently selected from -CN, -OH, -NH, oxo (=O), =NH or a C1-C6 hydrocarbyl group, each C1-C6 hydrocarbyl group may be straight chained or branched or may be or contain one or more cyclic groups, each C1-C6 hydrocarbyl group may be optionally substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may optionally include one or more heteroatoms independently selected from N, O and S in its carbon skeleton.

[0077] As will be appreciated, when the first aspect of the present invention comprises steps (i), (ii) and (iii), R 2 is the same for each process, and R 3 are the same for steps (ii) and (iii). All optional exemplary and illustrative embodiments described above in relation to the first aspect of the present invention apply equally to steps (ii) and (iii) of this embodiment.

[0078] In one embodiment of the first aspect of the present invention, reacting step (i) 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 and R 2 is as defined above. For example, X 2 -R 2 is X 2 -CH2R 20 wherein 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 -R2 is X 2 -COOCH2R 20 wherein R 20 is as defined above, and X 2 are Cl, Br, I, OR 1 , S.R. 1 , N(R 1 )2, OP(=O)(R 1 )2 or OP(R 1 )3 + wherein each R 1 are independently C1-C 20 Each C-C hydrocarbyl group is selected from 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C-C 20 The hydrocarbyl group may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20 The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or in which any two R 1 may be taken together with the phosphorus or 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 contain one or more halo groups and / or one or more groups R X and each R X are independently selected from -CN, -OH, -NH, oxo (=O), =NH or a C1-C6 hydrocarbyl group, each C1-C6 hydrocarbyl group may be straight chained or branched or may be or contain one or more cyclic groups, each C1-C6 hydrocarbyl group may be optionally substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may optionally include one or more heteroatoms independently selected from N, O and S in its carbon skeleton.

[0079] Typically, X 2 -R 2 is X2 -COOCH2R 20 If X 2 is selected from Cl, Br or I. More typically, in such embodiments, X 2 -R 2 is Cl-COOCH2R 20 and most typically Cl-COOCH2Ph.

[0080] Typically, reaction step (i) 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 nonpolar 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 nonpolar solvents. Suitable polar protic solvents include water and alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, and tert-amyl alcohol. Suitable polar aprotic solvents include dimethyl sulfoxide, N,N-dimethylformamide, N,N'-dimethylpropyleneurea, tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetone, acetonitrile, dichloromethane, hexamethylphosphoramide, nitromethane, propylene carbonate, and N-methylpyrrolidone. Suitable nonpolar solvents include pentane, cyclopentane, hexane, cyclohexane, diethyl ether, and toluene.

[0081] In one embodiment, reacting step (i) 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.

[0082] In one embodiment, reacting step (i) is carried out in the presence of a polar protic solvent, such as water, and a non-polar solvent, such as toluene. Typically, in such embodiments, the solvent system is biphasic. Typically, in such embodiments, reacting step (i) is carried out in the absence or substantial absence of a polar aprotic solvent. Typically, in such embodiments, the solvent mixture comprises 15-70% by volume of the polar protic solvent and 30-85% by volume of the non-polar solvent. More typically, in such embodiments, the solvent mixture comprises 25-45% by volume of the polar protic solvent and 55-75% by volume of the non-polar solvent.

[0083] As used herein, when a reaction or process step is performed "in the substantial absence" of a particular substance or a particular solvent, or a reaction mixture or solvent system is said to be "substantially free" of a particular substance or a particular solvent, it should be understood that typically the reaction mixture or solvent system contains less than 1% by weight of the particular substance or particular solvent. More typically, the reaction mixture or solvent system contains less than 0.1% by weight of the particular substance or particular solvent. Even more typically, the reaction mixture or solvent system contains less than 0.01% by weight of the particular substance or particular solvent. Most typically, the reaction mixture or solvent system does not contain a detectable amount of the particular substance or particular solvent.

[0084] Typically, reaction step (i) involves reacting 4-hydroxypiperidine (F) with a nitrogen protecting group precursor (e.g., X 2 -R 2or Cl-COOCHPh) 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, alkaline earth metal hydroxide, alkali metal alkoxide, or alkaline earth metal alkoxide. More typically, the base is a hydroxide, such as an alkali metal hydroxide or 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.

[0085] In an exemplary embodiment of the first aspect of the present invention, there is provided a process for preparing benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I′) or a salt thereof, the process comprising the steps of: (i) contacting 4-hydroxypiperidine (F) with benzyl chloroformate to obtain N-carboxybenzyl-4-hydroxypiperidine (G'); [ka] (ii) contacting N-carboxybenzyl-4-hydroxypiperidine (G') with mesyl chloride to obtain benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H'); [ka] (iii) contacting benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H') with reagent (I-Xb) in a solvent to obtain benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I') or a salt thereof: [ka] Includes.

[0086] Typically, in such embodiments, in step (i), 4-hydroxypiperidine (F) is contacted with benzyl chloroformate in the presence of sodium hydroxide and a solvent.

[0087] Typically, when the process of the first aspect of the present invention includes step (i), 4-hydroxypiperidine (F) is combined with the reaction mixture of step (i) in non-salt form.

[0088] Typically, when the process of the first aspect of the present invention comprises step (i), the N-protected-4-hydroxypiperidine (G) or (G') is obtained in step (i) in non-salt form.

[0089] In one embodiment of the first aspect of the present invention, the N-protected-4-hydroxypiperidine (G) or (G') is not isolated between steps (i) and (ii).

[0090] In another embodiment of the first aspect of the present invention, at the end of the reaction, the process of step (i) further comprises a work-up step of separating the biphasic mixture comprising the reaction mixture into an aqueous phase and an organic phase, the organic phase comprising the N-protected-4-hydroxypiperidine (G) or (G'). In one embodiment, the organic phase is washed, for example with water. Optionally, the organic phase is dried, for example by azeotropic distillation. In one embodiment, the N-protected-4-hydroxypiperidine (G) or (G') in the organic phase is used directly in step (ii). As will be appreciated, in such embodiments, the solvent of the organic phase provides all or part of the solvent used in the reaction of step (ii).

[0091] A second aspect of the present invention provides a process for preparing an N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof, the process comprising the steps of converting a thiourea adduct (I) into an N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof: [ka] Including, During the ceremony: R 2 is a nitrogen protecting group; Each R 4 are independently hydrogen or C1-C 20 hydrocarbyl groups, wherein each C-C 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C-C 20 The hydrocarbyl group may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20 The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or any two or more R 4 may, together with the atom(s) to which they are attached, form a 3- to 16-membered heterocyclic group, which may be monocyclic, bicyclic, or tricyclic, and which may contain one or more halo groups and / or one or more groups R 40 and each R 40 are independently selected from -CN, -OH, -NH, 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 optionally substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may optionally include one or more heteroatoms in its carbon skeleton independently selected from N, O and S; and Hal is Cl or Br.

[0092] As will be appreciated, in relation to the first aspect of the invention, R 2 and R 4 The embodiment further defining is equally applicable to the second aspect of the invention.

[0093] As stated, Hal is Cl or Br. Typically, Hal is Cl.

[0094] In one embodiment of the second aspect of the present invention, the process comprises contacting the thiourea adduct (I) with a halogenating agent to form an N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof.

[0095] 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. Typically, the halogenating agent is a chlorinating agent. Most typically, the halogenating agent is N-chlorosuccinimide.

[0096] In one embodiment of the second aspect of the present invention, the thiourea adduct (I) is contacted with a halogenating agent in the presence of one or more acids and an aqueous solvent.

[0097] In one embodiment, the one or more acids are selected from HCl, HBr, and carboxylic acids, such as formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, malonic acid, succinic acid, tartaric acid, maleic acid, and fumaric acid. Typically, at least one acid is a carboxylic acid, more typically a monocarboxylic acid such as formic acid, acetic acid, propionic acid, or butyric acid. Most typically, at least one acid is acetic acid. Typically, at least one acid is HCl or HBr. Most typically, at least one acid is HCl.

[0098] In one embodiment of the second aspect of the present invention, the aqueous solvent 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.

[0099] In one embodiment, the thiourea adduct (I) is contacted with a halogenating agent in the presence of a carboxylic acid, such as formic acid, acetic acid, propionic acid, or butyric acid, water, and optionally a second acid selected from HCl or HBr. Typically, in such an embodiment, 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, in such an embodiment, the halogenating agent is selected from N-chlorosuccinimide and N-bromosuccinimide. Most typically, the thiourea adduct (I) is contacted with N-chlorosuccinimide in the presence of acetic acid, water, and optionally HCl.

[0100] In an exemplary embodiment of the second aspect of the present invention, the process comprises the steps of contacting benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I') with a chlorinating agent to obtain benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') or a salt thereof: [ka] Includes.

[0101] Typically, in such embodiments, the chlorinating agent is N-chlorosuccinimide. Typically, in such embodiments, benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I') is contacted with the chlorinating agent in the presence of acetic acid, water, and optionally HCl.

[0102] Typically, according to the second aspect of the present invention, the thiourea adduct (I) or (I') is combined with the reaction mixture in the form of a salt. More typically, a sulfonic acid addition salt of the thiourea adduct (I) or (I') is combined with the reaction mixture. Most typically, a methanesulfonate salt of the thiourea adduct (I) or (I') is combined with the reaction mixture.

[0103] Typically, according to the second aspect of the present invention, the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is obtained in non-salt form.

[0104] In one embodiment of the second aspect of the present invention, the step of converting the thiourea adduct (I) or (I') to the N-protected-4-(halosulfonyl)-piperidine (J) or (J') or a salt thereof is carried out at a temperature in the range of 0 to 50°C. Typically, the reaction is carried out at a temperature in the range of 10 to 40°C. More typically, the reaction is carried out at a temperature in the range of 20 to 35°C.

[0105] Typically, according to the second aspect of the present invention, the thiourea adduct (I) or (I') is present in or added to the solvent at an initial concentration of 0.1 to 2 mol / L based on the total combined volume of the acid and solvent used in the reaction mixture. More typically, the thiourea adduct (I) or (I') is present in or added to the solvent at an initial concentration of 0.3 to 1.5 mol / L. Most typically, the thiourea adduct (I) or (I') is present in or added to the solvent at an initial concentration of 0.7 to 1.0 mol / L.

[0106] Typically, according to the second aspect of the present invention, the process employs 1.0 to 5.0 molar equivalents of halogenating agent relative to the initial amount of thiourea adduct (I) or (I'). More typically, the process employs 2.0 to 4.0 molar equivalents of halogenating agent. Most typically, the process employs 2.5 to 3.0 molar equivalents of halogenating agent.

[0107] Typically, when the process of the second aspect of the present invention uses one or more acids and an aqueous solvent, the one or more acids comprise 50-99% of the total combined volume of the acids and solvent. More typically, the one or more acids comprise 60-90% of the total combined volume of the acids and solvent. Even more typically, the one or more acids comprise 65-75% of the total combined volume of the acids and solvent.

[0108] Typically, when the process of the second aspect of the invention uses one or more acids and aqueous solvents, water comprises 1 to 50% of the total combined volume of the acid and solvent. More typically, water comprises 10 to 40% of the total combined volume of the acid and solvent. Even more typically, water comprises 25 to 35% of the total combined volume of the acid and solvent.

[0109] When the process of the second aspect of the present invention uses a carboxylic acid and a second acid selected from HCl or HBr, typically the molar ratio of carboxylic acid to second acid is 2:1 to 50:1. More typically, the molar ratio is 5:1 to 20:1. Even more typically, the molar ratio is 10:1 to 15:1.

[0110] In one embodiment of the second aspect of the present invention, the process comprises the steps of: (1) combining thiourea adduct (I) or (I') with one or more acids and an aqueous solvent to form a first mixture; and (2) adding a halogenating agent to the mixture formed in step (1) to form a second mixture.

[0111] Typically, the halogenating agent is added in portions or continuously to the mixture formed in step (1) over a period of at least 30 minutes. More typically, the halogenating agent is added in portions or continuously to the mixture formed in step (1) over a period of at least 60 minutes.

[0112] In one embodiment of the second aspect of the invention, the process comprises the following post-treatment steps: (3) quenching any remaining halogenating agent with a sulfite salt such as NaSO; (4) optionally adding additional water; (5) allowing a precipitate to form; (6) isolating the precipitate, for example by filtration, to obtain N-protected-4-(halosulfonyl)-piperidine (J) or (J') or a salt thereof; (7) optionally washing the precipitate with, for example, water and / or a mixture of water and acetic acid; and (8) Optionally, further comprising the step of drying the precipitate, for example under vacuum.

[0113] Typically, according to the second aspect of the present invention, steps (4), (7) and (8) are not optional steps.

[0114] Optionally, the reaction mixture is seeded with crystals of N-protected-4-(halosulfonyl)-piperidine (J) or (J') or a salt thereof. Seeding may occur during and / or after the addition of the halogenating agent in step (2).

[0115] In one embodiment of the second aspect of the present invention, the thiourea adduct (I) or a salt thereof is prepared by the process of the first aspect of the present invention. In other words, in such an embodiment, the present invention provides a process for preparing N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof, the process comprising the steps of: (iii) Converting the N-protected-4-derivatized piperidine (H) to the thiourea adduct (I): [ka] (iv) converting the thiourea adduct (I) into N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof: [ka] Including, During the ceremony: R2 is a nitrogen protecting group; R 3 is a leaving group; Each R 4 are independently hydrogen or C1-C 20 hydrocarbyl groups, wherein each C-C 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C-C 20 The hydrocarbyl group may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20 The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or any two or more R 4 may, together with the atom(s) to which they are attached, form a 3- to 16-membered heterocyclic group, which may be monocyclic, bicyclic, or tricyclic, and which may contain one or more halo groups and / or one or more groups R 40 and each R 40 are independently selected from -CN, -OH, -NH, 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 optionally substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may optionally include one or more heteroatoms in its carbon skeleton independently selected from N, O and S; and Hal is Cl or Br.

[0116] Typically, in such embodiments, the N-protected-4-derivatized piperidine (H) is prepared by the process of step (ii) or by the process of steps (i) and (ii), as defined above in relation to the first aspect of the invention.

[0117] As will be appreciated, when the second aspect of the invention comprises steps (iii) and (iv), R 2 is the same for each process, and each R 4 is the same for each step.

[0118] All optional typical and exemplary embodiments described herein in connection with the first aspect of the present invention apply equally to step (iii), and all optional typical and exemplary embodiments described herein in connection with the second aspect of the present invention apply equally to step (iv). Accordingly, in an exemplary embodiment of the second aspect of the present invention, there is provided a process for preparing benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J'), or a salt thereof, comprising the steps of: (iii) contacting benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H') with reagent (I-Xb) in a solvent to obtain benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I'): [ka] (iv) contacting benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I') with a chlorinating agent to obtain benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') or a salt thereof: [ka] Includes.

[0119] Typically, when the process of the second aspect of the present invention includes step (iii), the N-protected-4-derivatized piperidine (H) or (H') is combined with the reaction mixture of step (iii) in non-salt form.

[0120] Typically, when the process of the second aspect of the present invention includes step (iii), reagent (IX), (I-Xa) or (I-Xb) is combined with the reaction mixture of step (iii) in a non-salt form.

[0121] Typically, when the process of the second aspect of the present invention includes step (iii), the thiourea adduct (I) or (I') is obtained in step (iii) in salt form. More typically, the thiourea adduct (I) or (I') is obtained as a sulfonic acid addition salt. Most typically, the thiourea adduct (I) or (I') is obtained as a methanesulfonate salt.

[0122] In one embodiment of the second aspect of the present invention, the process comprises the steps of: (v) converting the N-protected-4-(halosulfonyl)-piperidine (J) into N-protected-4-piperidinesulfonamide (K) or a salt thereof: [ka] In the formula, R 2 is a nitrogen protecting group and Hal is Cl or Br; Further includes:

[0123] In other words, in one embodiment of the second aspect of the present invention, there is provided a process for preparing an N-protected-4-piperidinesulfonamide (K) or a salt thereof, the process comprising at least the following steps: (iv) converting the thiourea adduct (I) into N-protected-4-(halosulfonyl)-piperidine (J): [ka] (v) converting the N-protected-4-(halosulfonyl)-piperidine (J) into N-protected-4-piperidinesulfonamide (K) or a salt thereof: [ka] Including, During the ceremony: R 2 is a nitrogen protecting group, Each R 4are independently hydrogen or C1-C 20 hydrocarbyl groups, wherein each C-C 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C-C 20 The hydrocarbyl group may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20 The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or any two or more R 4 may, together with the atom(s) to which they are attached, form a 3- to 16-membered heterocyclic group, which may be monocyclic, bicyclic, or tricyclic, and which may contain one or more halo groups and / or one or more groups R 40 and each R 40 are independently selected from -CN, -OH, -NH, 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 optionally substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may optionally include one or more heteroatoms in its carbon skeleton independently selected from N, O and S; and Hal is Cl or Br.

[0124] As will be appreciated, when the second aspect of the present invention comprises steps (iv) and (v), R 2 is the same for each step, and Hal is the same for each step.

[0125] In one embodiment of the second aspect of the present invention, reacting step (v) comprises contacting N-protected-4-(halosulfonyl)-piperidine (J) with ammonia to form N-protected-4-piperidinesulfonamide (K) or a salt thereof. Typically, N-protected-4-(halosulfonyl)-piperidine (J) is contacted with ammonia in the presence of a solvent.

[0126] Typically, the solvent is a polar aprotic solvent such as dimethyl sulfoxide, N,N-dimethylformamide, N,N'-dimethylpropylene urea, 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 can be selected from dimethyl sulfoxide, 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 can be selected from dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, dichloromethane, hexamethylphosphoramide, nitromethane, or a mixture thereof. Even more typically, the solvent is non-halogenated. For example, the solvent can be selected from dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, hexamethylphosphoramide, nitromethane, or a mixture thereof. Most typically, the solvent is tetrahydrofuran.

[0127] In one embodiment, reacting step (v) comprises purging a solution of N-protected-4-(halosulfonyl)-piperidine (J) in a solvent with ammonia gas.

[0128] In another embodiment, reacting step (v) comprises the steps of: (1) forming a solution of ammonia in a solvent; and (2) adding N-protected-4-(halosulfonyl)-piperidine (J) to the solution formed in step (1).

[0129] Typically, in step (1) of step (v), a 10% or greater saturated solution of ammonia in the solvent is formed. More typically, a 25% or greater or 50% or greater saturated solution of ammonia in the solvent is formed. Even more typically, a 75% or greater saturated solution of ammonia in the solvent is formed. Most typically, a saturated solution of ammonia in the solvent is formed.

[0130] Typically, in step (2), the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is added in portions or continuously to the solution formed in step (1) over a period of at least 30 minutes. More typically, the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is added in portions or continuously to the solution formed in step (1) over a period of at least 60 minutes.

[0131] Optionally, in step (2), a solution of N-protected-4-(halosulfonyl)-piperidine (J) in a second solvent is added to the solution formed in step (1). Typically, the second solvent is the same as the (first) solvent used in step (1).

[0132] Typically, in any embodiment of step (v) of the second aspect of the present invention, N-protected-4-(halosulfonyl)-piperidine (J) is contacted with ammonia or an ammonia solution in the absence or substantial absence of water and alcohol. More typically, N-protected-4-(halosulfonyl)-piperidine (J) is contacted with ammonia or an ammonia solution in the absence or substantial absence of a polar protic solvent.

[0133] In an exemplary embodiment of the second aspect of the present invention, reacting step (v) comprises contacting benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') with ammonia to obtain 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') or a salt thereof: [ka] Includes.

[0134] Typically, in such embodiments, reacting step (v) comprises forming a solution of ammonia in a solvent and adding benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') to the formed solution to obtain 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') or a salt thereof. Typically, the solvent is a polar aprotic solvent such as tetrahydrofuran. Typically, the solution of ammonia is a saturated solution of ammonia in the solvent.

[0135] Typically, when the process of the second aspect of the present invention includes step (v), the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is combined in non-salt form with the reaction mixture of step (v).

[0136] Typically, when the process of the second aspect of the present invention comprises step (v), the N-protected-4-piperidinesulfonamide (K) or (K') is obtained in step (v) in non-salt form.

[0137] In one embodiment of the second aspect of the present invention, the N-protected-4-piperidinesulfonamide (K) or (K') is isolated by crystallization.

[0138] In one embodiment of the second aspect of the present invention, the process comprises the steps of: (vi) converting N-protected-4-piperidinesulfonamide (K) into 1-ethyl-4-piperidinesulfonamide (A) or a salt thereof: [ka] In the formula, R 2 is a nitrogen protecting group, Further includes:

[0139] In other words, in one embodiment of the second aspect of the present invention, there is provided a process for preparing 1-ethyl-4-piperidinesulfonamide (A) or a salt thereof, the process comprising at least the following steps: (iv) converting the thiourea adduct (I) into N-protected-4-(halosulfonyl)-piperidine (J): [ka] (v) converting N-protected-4-(halosulfonyl)-piperidine (J) into N-protected-4-piperidinesulfonamide (K): [ka] (vi) converting N-protected-4-piperidinesulfonamide (K) into 1-ethyl-4-piperidinesulfonamide (A) or a salt thereof: [ka] Including, During the ceremony: R 2 is a nitrogen protecting group, Each R 4 are independently hydrogen or C1-C 20 hydrocarbyl groups, wherein each C-C 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C-C 20 The hydrocarbyl group may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or any two or more R 4 may, together with the atom(s) to which they are attached, form a 3- to 16-membered heterocyclic group, which may be monocyclic, bicyclic, or tricyclic, and which may contain one or more halo groups and / or one or more groups R 40 and each R 40 are independently selected from -CN, -OH, -NH, 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 optionally substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may optionally include one or more heteroatoms in its carbon skeleton independently selected from N, O and S; and Hal is Cl or Br.

[0140] As will be appreciated, when the second aspect of the present invention comprises steps (iv), (v) and (vi), R 2 is the same for each step.

[0141] In one embodiment of the second aspect of the present invention, reacting step (vi) comprises the steps of: (vi-a) deprotecting N-protected-4-piperidinesulfonamide (K) to form piperidine-4-sulfonamide; and (vi-b) alkylating piperidine-4-sulfonamide to form 1-ethyl-4-piperidine-sulfonamide (A) or a salt thereof.

[0142] As will be appreciated, the reaction conditions for the deprotection step (vi-a) correspond to the nitrogen protecting group being removed. For example, R 2 benzyloxycarbonyl (CBz), 4-methoxy-benzyloxycarbonyl, benzyl, -CHR 20or -COOCH2R 20 If R is a hydroxyl group, it can be removed by catalytic hydrogenolysis or by treatment with HBr in a carboxylic acid such as acetic acid or trifluoroacetic acid. 2 is a t-butoxycarbonyl (Boc) group, R 2 can be removed under acidic conditions, for example by treatment with trifluoroacetic acid. 2 is a 2-(4-biphenylyl)-isopropoxycarbonyl (Bpoc) or triphenylmethyl (Trt) group, R 2 R can be removed under acidic conditions, for example by treatment with trifluoroacetic acid, or by catalytic hydrogenolysis. 2 is a 2,2,2-trichloroethoxycarbonyl (Troc) group, R 2 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.

[0143] Typically, according to the first and second aspects of the present 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, the process of step (vi-a) typically comprises contacting 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 hydroxide on carbon. Typically, the catalyst is palladium on carbon. Typically, hydrogen gas is used at a pressure in the range of 0.1 to 100 bar. In one embodiment, hydrogen gas is used at a pressure in the range of 0.5 to 50 bar, more typically in the range of 5 to 25 bar.

[0144] Typically, N-protected-4-piperidinesulfonamide (K) is contacted with a catalyst in the presence of hydrogen gas and a solvent. Typically, the solvent is a polar protic solvent, a polar aprotic solvent, or a mixture thereof. For example, the solvent can be selected from tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, water, alcohols such as methanol, ethanol, isopropanol, and butanol, or a mixture thereof.

[0145] Typically, the catalytic hydrogenolysis of step (vi-a) is carried out at a temperature in the range of 0 to 100°C. In one embodiment of the second aspect of the present invention, the catalytic hydrogenolysis of step (vi-a) is carried out at a temperature in the range of 15 to 80°C. Typically, in such embodiments, the catalytic hydrogenolysis of step (vi-a) is carried out at a temperature in the range of 20 to 70°C. More typically, the catalytic hydrogenolysis of step (vi-a) is carried out at a temperature in the range of 55 to 65°C.

[0146] The alkylation step (vi-b) can be carried out under a variety of conditions.

[0147] In one embodiment, the alkylation step (vi-b) comprises alkylating 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 sulfonate leaving group such as a toluenesulfonate, methanesulfonate or trifluoromethanesulfonate leaving group. More typically, X f is selected from Cl, Br or I.

[0148] 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 dimethyl sulfoxide, 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 base is a carbonate base, such as an alkali metal carbonate or an alkaline earth metal carbonate.

[0149] In another embodiment, piperidine-4-sulfonamide is alkylated by reductive alkylation. For example, piperidine-4-sulfonamide may be contacted with acetonitrile or acetaldehyde in the presence of a hydride source such as NaCNBH.

[0150] 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 hydroxide on carbon. Typically, the catalyst is palladium on carbon. Typically, hydrogen gas is used at a pressure within the range of 0.1 to 100 bar. In one embodiment, hydrogen gas is used at a pressure within the range of 0.5 to 50 bar, more typically within the range of 5 to 25 bar.

[0151] 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.

[0152] In another embodiment, when piperidine-4-sulfonamide is contacted with acetonitrile or acetaldehyde, contact 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 can be selected from tetrahydrofuran, 1,4-dioxane, dichloromethane, water, alcohol such as methanol, ethanol, isopropanol or butanol, or a mixture thereof.More typically, the solvent is a polar protic solvent such as water or alcohol, or a mixture thereof.

[0153] In one embodiment, when piperidine-4-sulfonamide is contacted with acetonitrile, the contact is carried out in the presence of water and alcohol.Typically, the alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, tert-amyl alcohol, and mixtures thereof.More typically, the contact is carried out in the presence of water and butanol, most typically water and n-butanol.

[0154] Typically, the alkylation in step (vi-b) is carried out at a temperature in the range of 0 to 100°C. In one embodiment of the second aspect of the present invention, the alkylation in step (vi-b) is carried out at a temperature in the range of 15 to 80°C. Typically, in such an embodiment, the alkylation in step (vi-b) is carried out at a temperature in the range of 20 to 70°C. More typically, the alkylation in step (vi-b) is carried out at a temperature in the range of 55 to 65°C. As will be appreciated, advantageously, R 2 is a nitrogen protecting group that can be removed by catalytic hydrogenolysis, the following steps: (vi-a) deprotecting N-protected-4-piperidinesulfonamide (K) to form piperidine-4-sulfonamide; and (vi-b) alkylating piperidine-4-sulfonamide to form 1-ethyl-4-piperidine-sulfonamide (A) or a salt thereof, They may be carried out simultaneously or sequentially in a one-pot reaction.

[0155] Therefore, R 2 In one embodiment of the second aspect of the present invention, where K is a nitrogen-protecting group that can be removed by catalytic hydrogenolysis, reacting step (vi) 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) or a salt thereof. 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 hydroxide on carbon. Typically, the catalyst is palladium on carbon.

[0156] In an exemplary embodiment of the second aspect of the present invention, reacting step (vi) 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) or a salt thereof: [ka] Includes.

[0157] 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 on carbon.

[0158] Typically, when the process of the second aspect of the present invention includes step (vi), the N-protected-4-piperidinesulfonamide (K) or (K') is combined with the reaction mixture of step (vi) in non-salt form.

[0159] Typically, when the process of the second aspect of the present invention comprises step (vi), 1-ethyl-4-piperazinesulfonamide (A) is obtained in step (vi) in non-salt form.

[0160] When reacting step (vi) involves contacting N-protected-4-piperidinesulfonamide (K) or (K') with acetonitrile or acetaldehyde in the presence of a catalyst and hydrogen gas, typically the hydrogen gas is used at a pressure in the range of 0.1 to 100 bar. In one embodiment, the hydrogen gas is used at a pressure in the range of 0.5 to 50 bar, more typically in the range of 5 to 25 bar.

[0161] When the N-protected-4-piperidinesulfonamide (K) or (K') 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.

[0162] In another embodiment, when the N-protected-4-piperidinesulfonamide (K) or (K') is contacted with acetonitrile or acetaldehyde, the contact 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 can be selected from tetrahydrofuran, 1,4-dioxane, dichloromethane, water, alcohols such as methanol, ethanol, isopropanol or butanol, or a mixture thereof. More typically, the solvent is a polar protic solvent such as water or alcohol, or a mixture thereof.

[0163] In one embodiment, when N-protected-4-piperidinesulfonamide (K) or (K') is contacted with acetonitrile, the contact is carried out in the presence of water and an alcohol. Typically, when the contact is carried out in the presence of water and an alcohol, the ratio of water to alcohol present is 1:1 to 1:10 by volume. More typically, the ratio of water to alcohol is 1:2 to 1:5 by volume. Typically, the alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, iso-butanol, tert-butanol, tert-amyl alcohol, and mixtures thereof. More typically, the contact is carried out in the presence of water and ethanol or water and a butanol (such as n-butanol).

[0164] When reacting step (vi) comprises contacting N-protected-4-piperidine-sulfonamide (K) or (K') with acetonitrile or acetaldehyde in the presence of a catalyst and hydrogen gas, reacting step (vi) is typically carried out at a temperature in the range of 0 to 100°C. In one embodiment, reacting step (vi) is carried out at a temperature in the range of 15 to 80°C. Typically, in such embodiments, reacting step (vi) is carried out at a temperature in the range of 20 to 70°C. More typically, in such embodiments, reacting step (vi) is carried out at a temperature in the range of 55 to 65°C.

[0165] When the catalyst in any of steps (vi), (vi-a), or (vi-b) is palladium on carbon or palladium hydroxide on carbon, typically 2 to 35 wt% palladium on carbon or palladium hydroxide on carbon is used. More typically, 5 to 30 wt% palladium on carbon or palladium hydroxide on carbon is used. Most typically, 5 to 15 wt% palladium on carbon or palladium hydroxide on carbon is used.

[0166] As will be appreciated, where the second aspect of the invention comprises steps (iii) and (iv) as outlined above, the N-protected-4-derivatized piperidine (H) or (H') may be prepared by the process of step (ii) or the process of steps (i) and (ii) of the first aspect of the invention.

[0167] Thus, in one embodiment of the second aspect of the present invention, there is provided a process for preparing an N-protected-4-piperidinesulfonamide (K) or a salt thereof, the process comprising at least the following steps: (i) converting 4-hydroxypiperidine (F) to N-protected-4-hydroxypiperidine (G): [ka] (ii) converting N-protected-4-hydroxypiperidine (G) to N-protected-4-derivatized piperidine (H): [ka] (iii) Converting the N-protected-4-derivatized piperidine (H) to the thiourea adduct (I): [ka] (iv) converting the thiourea adduct (I) into N-protected-4-(halosulfonyl)-piperidine (J): [ka] (v) converting the N-protected-4-(halosulfonyl)-piperidine (J) into N-protected-4-piperidinesulfonamide (K) or a salt thereof: [ka] Including, During the ceremony: R 2 is a nitrogen protecting group; R3 is a leaving group; Each R 4 are independently hydrogen or C1-C 20 hydrocarbyl groups, wherein each C-C 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C-C 20 The hydrocarbyl group may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20 The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or any two or more R 4 may, together with the atom(s) to which they are attached, form a 3- to 16-membered heterocyclic group, which may be monocyclic, bicyclic, or tricyclic, and which may contain one or more halo groups and / or one or more groups R 40 and each R 40 are independently selected from -CN, -OH, -NH, 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 optionally substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may optionally include one or more heteroatoms in its carbon skeleton independently selected from N, O and S; and Hal is Cl or Br.

[0168] In an illustrative example of such an embodiment, a process for preparing 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K′) or a salt thereof is provided, the process comprising at least the following steps: (i) contacting 4-hydroxypiperidine (F) with benzyl chloroformate to obtain N-carboxybenzyl-4-hydroxypiperidine (G'); [ka] (ii) contacting N-carboxybenzyl-4-hydroxypiperidine (G') with mesyl chloride to obtain benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H'); [ka] (iii) contacting benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H') with reagent (I-Xb) in a solvent to obtain benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I'): [ka] (iv) contacting benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I') with a chlorinating agent to obtain benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J'): [ka] (v) contacting benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') with ammonia to obtain 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') or a salt thereof; [ka] Includes.

[0169] In a further embodiment of the second aspect of the present invention, there is provided a process for preparing 1-ethyl-4-piperazinesulfonamide (A) or a salt thereof, the process comprising at least the following steps: (i) converting 4-hydroxypiperidine (F) to N-protected-4-hydroxypiperidine (G): [ka] (ii) converting N-protected-4-hydroxypiperidine (G) to N-protected-4-derivatized piperidine (H): [ka] (iii) Converting the N-protected-4-derivatized piperidine (H) to the thiourea adduct (I): [ka] (iv) converting the thiourea adduct (I) into N-protected-4-(halosulfonyl)-piperidine (J): [ka] (v) converting N-protected-4-(halosulfonyl)-piperidine (J) into N-protected-4-piperidinesulfonamide (K): [ka] (vi) converting N-protected-4-piperidinesulfonamide (K) into 1-ethyl-4-piperidinesulfonamide (A) or a salt thereof: [ka] Including, During the ceremony: R 2 is a nitrogen protecting group; R 3 is a leaving group; Each R 4 are independently hydrogen or C1-C 20 hydrocarbyl groups, wherein each C-C 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C-C 20The hydrocarbyl group may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20 The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or any two or more R 4 may, together with the atom(s) to which they are attached, form a 3- to 16-membered heterocyclic group, which may be monocyclic, bicyclic, or tricyclic, and which may contain one or more halo groups and / or one or more groups R 40 and each R 40 are independently selected from -CN, -OH, -NH, 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 optionally substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may optionally include one or more heteroatoms in its carbon skeleton independently selected from N, O and S; and Hal is Cl or Br.

[0170] In an illustrative example of such an embodiment, a process for preparing 1-ethyl-4-piperazinesulfonamide (A) or a salt thereof is provided, the process comprising at least the following steps: (i) contacting 4-hydroxypiperidine (F) with benzyl chloroformate to obtain N-carboxybenzyl-4-hydroxypiperidine (G'); [ka] (ii) contacting N-carboxybenzyl-4-hydroxypiperidine (G') with mesyl chloride to obtain benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H'); [ka] (iii) contacting benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H') with reagent (I-Xb) in a solvent to obtain benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I'): [ka] (iv) contacting benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I') with a chlorinating agent to obtain benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J'): [ka] (v) contacting benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') with ammonia to obtain 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K'); [ka] (vi) 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) or a salt thereof; [ka] Includes.

[0171] Typically, when the process of the second aspect of the present invention includes step (i), 4-hydroxypiperidine (F) is combined with the reaction mixture in step (i) in a non-salt form.

[0172] Typically, when the process of the second aspect of the present invention comprises step (i), the N-protected-4-hydroxypiperidine (G) or (G') is obtained in step (i) in non-salt form.

[0173] Typically, when the process of the second aspect of the present invention includes step (ii), the N-protected-4-hydroxypiperidine (G) or (G') is combined with the reaction mixture in step (ii) in non-salt form.

[0174] Typically, when the process of the second aspect of the invention includes step (ii), the N-protected-4-derivatized piperidine (H) or (H') is obtained in step (ii) in non-salt form. A third aspect of the present invention provides a method for producing a pharmaceutical composition comprising one or more steps selected from the following: (i) converting 4-hydroxypiperidine (F) to N-protected-4-hydroxypiperidine (G): [ka] The transformation is carried out in a two-phase solvent system; (ii) converting N-protected-4-hydroxypiperidine (G) to N-protected-4-derivatized piperidine (H): [ka] The conversion is carried out in the presence of a non-polar solvent; (iii) Converting the N-protected-4-derivatized piperidine (H) to the thiourea adduct (I): [ka] (iv) converting the thiourea adduct (I) into N-protected-4-(halosulfonyl)-piperidine (J): [ka] (v) converting N-protected-4-(halosulfonyl)-piperidine (J) into N-protected-4-piperidinesulfonamide (K): [ka] The conversion comprises the steps of: (1) forming a solution of ammonia in a solvent; and (2) adding N-protected-4-(halosulfonyl)-piperidine (J) to the solution formed in step (1); and (vi) converting N-protected-4-piperidinesulfonamide (K) into 1-ethyl-4-piperidinesulfonamide (A): [ka] The conversion is carried out in the presence of a C3-C5 alcohol; A process is provided, comprising: and wherein: R 2 is a nitrogen protecting group; R 3 is a leaving group; Each R 4 are independently hydrogen or C1-C 20 hydrocarbyl groups, wherein each C-C 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C-C 20 The hydrocarbyl group may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20 The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or any two or more R 4 may, together with the atom(s) to which they are attached, form a 3- to 16-membered heterocyclic group, which may be monocyclic, bicyclic, or tricyclic, and which may contain one or more halo groups and / or one or more groups R 40 and each R 40are independently selected from -CN, -OH, -NH, 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 optionally substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may optionally include one or more heteroatoms in its carbon skeleton independently selected from N, O and S; and Hal is Cl or Br.

[0175] As will be appreciated, in relation to the first and second aspects of the invention, R 2 , R 3 , R 4 and Hal are equally applicable to the third aspect of the invention.

[0176] This typically occurs according to any of steps (i) to (vi) of the third aspect of the present invention, where R 2 is -CH2R 20 or -COOCH2R 20 where 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 together form a C2-C5 alkylene or C2-C5 haloalkylene group, R 20contains 1 to 20 carbon atoms, including any optional substituents. More typically, R 2 HA-COOCH2R 20 Most typically, R 2 is -COOCH2Ph.

[0177] Typically, according to step (ii) and / or (iii) of the third aspect of the present invention, R 3 is a sulfonate leaving group, such as a toluenesulfonate (tosylate or -OT), methanesulfonate (mesylate or -OM), or trifluoromethanesulfonate (triflate or -OTf) leaving group. Most typically, R 3 is -OMs.

[0178] Typically, according to step (iii) and / or (iv) of the third aspect of the present invention, each R 4 are independently selected from hydrogen or a C1-C6 alkyl or C3-C6 cycloalkyl group, or any two R 4 may together form a C2-C6 alkylene group, where any C1-C6 alkyl, C3-C6 cycloalkyl, or C2-C6 alkylene group may be optionally fluoro-substituted. Most typically, each R 4 is hydrogen.

[0179] Typically, according to step (iv) and / or (v) of the third aspect of the present invention, Hal is Cl.

[0180] It will also be understood that steps (i)-(vi) of the third aspect of the invention correspond to the equivalent steps (i)-(vi) of the first and second aspects of the invention. Thus, to the extent practicable, any typical or exemplary embodiment described herein with respect to either steps (i)-(vi) of the first or second aspects of the invention applies equally to the corresponding steps (i)-(vi) of the third aspect of the invention. Thus, exemplary embodiments of the third aspect of the invention include one or more steps selected from: (i) contacting 4-hydroxypiperidine (F) with benzyl chloroformate in a two-phase solvent system to obtain N-carboxybenzyl-4-hydroxypiperidine (G'); [ka] (ii) contacting N-carboxybenzyl-4-hydroxypiperidine (G') with mesyl chloride in a non-polar solvent to obtain benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H'); [ka] (iii) contacting benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H') with reagent (I-Xb) in a solvent to obtain benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I'): [ka] (iv) contacting benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I') with a chlorinating agent to obtain benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J'): [ka] (v) forming a solution of ammonia in a solvent and adding benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') to the formed solution to obtain 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K'); [ka] (vi) contacting 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') with acetonitrile or acetaldehyde in the presence of a catalyst, hydrogen gas, and a C3-C5 alcohol to obtain 1-ethyl-4-piperazinesulfonamide (A); [ka] A process is provided that includes:

[0181] In one embodiment of the third aspect of the present invention, the process comprises at least step (i).

[0182] Typically, when the process of the third aspect of the invention includes step (i), 4-hydroxypiperidine (F) is combined with the reaction mixture in step (i) in a non-salt form.

[0183] Typically, when the process of the third aspect of the present invention comprises step (i), the N-protected-4-hydroxypiperidine (G) or (G') is obtained in step (i) in non-salt form.

[0184] When the process of the third aspect of the present invention includes step (i), typically, the biphasic solvent system in step (i) comprises a polar protic solvent, such as water, and a non-polar solvent, such as pentane, cyclopentane, hexane, cyclohexane, diethyl ether, or toluene. More typically, the biphasic solvent system comprises water and toluene. Typically, in such embodiments, the solvent mixture comprises 15-70% by volume of the polar protic solvent and 30-85% by volume of the non-polar solvent. More typically, in such embodiments, the solvent mixture comprises 25-45% by volume of the polar protic solvent and 55-75% by volume of the non-polar solvent.

[0185] Typically, the two-phase solvent system is free or substantially free of 1,4-dioxane. More typically, the two-phase solvent system is free or substantially free of polar aprotic solvents.

[0186] In one embodiment of the third aspect of the present invention, reacting step (i) 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 and R 2 is as defined above. For example, X 2 -R 2 is X 2 -CH2R 20 wherein 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 is X 2 -COOCH2R 20 wherein R 20 is as defined above, and X 2 are Cl, Br, I, OR 1 , S.R. 1 , N(R 1 )2, OP(=O)(R 1 )2 or OP(R 1 )3 + wherein each R 1 are independently C1-C 20 Each C-C hydrocarbyl group is selected from 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C-C 20 The hydrocarbyl group may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or in which any two R 1 may be taken together with the phosphorus or 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 contain one or more halo groups and / or one or more groups R X and each R X are independently selected from -CN, -OH, -NH, oxo (=O), =NH or a C1-C6 hydrocarbyl group, each C1-C6 hydrocarbyl group may be straight chained or branched or may be or contain one or more cyclic groups, each C1-C6 hydrocarbyl group may be optionally substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may optionally include one or more heteroatoms independently selected from N, O and S in its carbon skeleton.

[0187] Typically, X 2 -R 2 is X 2 -COOCH2R 20 If X 2 is selected from Cl, Br or I. More typically, in such embodiments, X 2 -R 2 is Cl-COOCH2R 20 and most typically Cl-COOCH2Ph.

[0188] Typically, reaction step (i) involves reacting 4-hydroxypiperidine (F) with a nitrogen protecting group precursor (e.g., X 2 -R 2or Cl-COOCHPh) 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, alkaline earth metal hydroxide, alkali metal alkoxide, or alkaline earth metal alkoxide. More typically, the base is a hydroxide, such as an alkali metal hydroxide or 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.

[0189] In an exemplary embodiment of the third aspect of the present invention, reacting step (i) comprises contacting 4-hydroxypiperidine (F) with benzyl chloroformate in a biphasic solvent system to obtain N-carboxybenzyl-4-hydroxypiperidine (G') or a salt thereof: [ka] Includes. Typically, in such embodiments, 4-hydroxypiperidine (F) is contacted with benzyl chloroformate in the presence of sodium hydroxide, and the two-phase solvent system comprises water, a non-polar solvent such as toluene, and is substantially free of polar aprotic solvents.

[0190] In one embodiment of any of the first to third aspects of the present invention, the reaction step (i) is carried out at a temperature in the range of -20 to 80°C. Typically, the reaction in step (i) is carried out at a temperature in the range of -10 to 50°C. More typically, the reaction in step (i) is carried out at a temperature in the range of 0 to 30°C.

[0191] Typically, in step (i) according to any of the first to third aspects of the present invention, 4-hydroxypiperidine (F) is present in 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, 4-hydroxypiperidine (F) is present in or added to the solvent at an initial concentration of 0.5 to 2.0 mol / L. Most typically, 4-hydroxypiperidine (F) is present in or added to the solvent at an initial concentration of 0.8 to 1.5 mol / L.

[0192] Typically, the process of step (i) of any of the first to third aspects of the present invention uses X as a nitrogen protecting group precursor. 2 -COOCH2R 20 (e.g., Cl-COOCH2Ph), the nitrogen protecting group precursor contains less than 20 mol% X 2 -CH2R 20 (e.g., Cl-CHPh). More typically, the nitrogen protecting group precursor contains less than 10 mol % or less than 5 mol % X 2 -CH2R 20 Most typically, the nitrogen protecting group precursor contains less than 1 mol % X 2 -CH2R 20 Advantageously, it has been discovered that using nitrogen protecting group precursors that are low in such contaminants improves yield and facilitates purification in step (iii).

[0193] Typically, the process of step (i) of any of the first to third aspects of the present invention comprises adding 0.5 to 2.0 molar equivalents of a nitrogen protecting group precursor (e.g., X) to the initial amount of 4-hydroxypiperidine (F). 2 -R 2 or Cl-COOCHPh). More typically, the process uses 0.8 to 1.1 molar equivalents of the nitrogen protecting group precursor. Most typically, the process uses 0.9 to 1.0 molar equivalents of the nitrogen protecting group precursor.

[0194] Typically, the process of step (i) of any of the first to third aspects of the present invention uses 0.8 to 3.0 molar equivalents of base relative to the initial amount of 4-hydroxypiperidine (F). 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. In one embodiment of any of the first to third aspects of the present invention, the process of step (i) comprises the following steps: (1) combining 4-hydroxypiperidine (F) and a base with a first portion of a solvent to form a first mixture; and (2) dissolving the nitrogen protecting group precursor in a second portion of the solvent and adding the resulting solution to the mixture formed in step (1) to form a second mixture.

[0195] Typically, the first portion of the solvent comprises or consists of a polar protic solvent, such as water, and a non-polar solvent, such as toluene. Typically, the second portion of the solvent comprises or consists of a non-polar solvent, such as toluene.

[0196] In one embodiment, step (2) is carried out at a temperature in the range of 0 to 10° C. Typically, after step (2) is completed, the second mixture is warmed to a temperature in the range of 15 to 30° C.

[0197] In one embodiment of the third aspect of the present invention, at the end of the reaction, the process of step (i) further comprises a work-up step of separating the biphasic reaction mixture into an aqueous phase and an organic phase, the organic phase comprising N-protected-4-hydroxypiperidine (G) or (G'). In one embodiment, the organic phase is washed, for example with water. Optionally, the organic phase is dried, for example by azeotropic distillation. In one embodiment, the solvent is removed from the organic phase to provide N-protected-4-hydroxypiperidine (G) or (G'). Alternatively, the N-protected-4-hydroxypiperidine (G) or (G') in the organic phase may be used directly in step (ii). As will be appreciated, in such embodiments, the solvent of the organic phase provides all or a portion of the solvent used in the reaction of step (ii).

[0198] In one embodiment of the third aspect of the present invention, the process comprises at least step (ii).

[0199] Typically, when the process of the third aspect of the present invention includes step (ii), the N-protected-4-hydroxypiperidine (G) or (G') is combined with the reaction mixture in step (ii) in non-salt form.

[0200] Typically, when the process of the third aspect of the invention includes step (ii), the N-protected-4-derivatized piperidine (H) or (H') is obtained in step (ii) in non-salt form.

[0201] When the process of the third aspect of the present invention includes step (ii), typically the non-polar solvent in step (ii) is non-halogenated. In one embodiment, the non-polar solvent is selected from pentane, cyclopentane, hexane, cyclohexane, diethyl ether, toluene, or a mixture thereof. Most typically, the non-polar solvent is toluene.

[0202] In one embodiment of the third aspect of the present invention, reacting step (ii) comprises contacting N-protected-4-hydroxypiperidine (G) or (G′) with SOCl, SOBr, or a mixture of PhP and Cl or Br to form N-protected-4-derivatized piperidine (H), wherein R 3 is a Cl or Br leaving group as appropriate.

[0203] In another embodiment of the third aspect of the present invention, reacting step (ii) comprises contacting N-protected-4-hydroxypiperidine (G) or (G′) with a sulfonyl halide or sulfonyl anhydride to produce N-protected-4-derivatized piperidine (H) or (H′), where R 3 is a sulfonate leaving group).

[0204] As will be appreciated, the sulfonyl halide or sulfonyl anhydride used is R 3 corresponds to a sulfonate leaving group of, for example, R3 When R is a tosylate leaving group, tosyl halide or tosyl anhydride is used. 3 When R 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.

[0205] 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 sulfonyl chloride or sulfonyl bromide. More typically, the sulfonyl halide is sulfonyl chloride.

[0206] In an exemplary embodiment of the third aspect of the present invention, reacting step (ii) comprises contacting N-protected-4-hydroxypiperidine (G) or (G′) with mesyl halide or mesyl anhydride to form N-protected-4-derivatized piperidine (H) or (H′), where R 3 is a mesylate leaving group). Most typically, in such embodiments, reacting step (ii) comprises contacting the N-protected-4-hydroxypiperidine (G) or (G') with mesyl chloride.

[0207] In one embodiment of the third aspect of the present invention, reacting step (ii) is carried out in the presence of a base. Typically, reacting step (ii) involves contacting N-protected-4-hydroxypiperidine (G) or (G') with a sulfonyl halide or sulfonyl anhydride 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). In an exemplary embodiment of the third aspect of the present invention, reacting step (ii) comprises contacting N-carboxybenzyl-4-hydroxypiperidine (G') with mesyl chloride in a non-polar solvent to obtain benzyl 4-((methylsulfonyl)oxy)-piperidine-1-carboxylate (H'): [ka] Includes.

[0208] 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. Typically, the non-polar solvent is a non-halogenated non-polar solvent such as toluene.

[0209] In one embodiment of any of the first to third aspects of the present invention, the reaction step (ii) is carried out at a temperature within a range of -20 to 40°C. Typically, the reaction in step (ii) is carried out at a temperature within a range of -10 to 20°C. More typically, the reaction in step (ii) is carried out at a temperature within a range of -5 to 10°C.

[0210] Typically, in step (ii) according to any of the first to third aspects of the present invention, the N-protected 4-hydroxypiperidine (G) or (G') is present in 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 or added to the solvent at an initial concentration of 0.5 to 2.0 mol / L. Most typically, the N-protected 4-hydroxypiperidine (G) or (G') is present in or added to the solvent at an initial concentration of 1.2 to 1.6 mol / L.

[0211] Typically, the process of step (ii) of any of the first through third aspects of the present invention uses 0.8 to 2.0 molar equivalents of sulfonyl halide or sulfonyl anihydride relative to the initial amount of N-protected-4-hydroxypiperidine (G) or (G'). More typically, the process uses 0.9 to 1.5 molar equivalents of sulfonyl halide or sulfonyl anihydride. Most typically, the process uses 1.0 to 1.1 molar equivalents of sulfonyl halide or sulfonyl anihydride.

[0212] Typically, the process of step (ii) of any of the first to third aspects of the present invention uses 0.9 to 2.0 molar equivalents of base 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 base. Most typically, the process uses 1.05 to 1.15 molar equivalents of base.

[0213] In one embodiment of any of the first to third aspects of the present invention, the process of step (ii) comprises the following steps: (1) combining N-protected-4-hydroxypiperidine (G) or (G') with a base and a solvent to form a first mixture; and (2) adding a sulfonyl halide or sulfonyl anhydride to the mixture formed in step (1) to form a second mixture.

[0214] Typically, in step (2), the sulfonyl halide or sulfonyl anhydride is added dropwise.

[0215] In one embodiment of the third aspect of the present invention, at the end of the reaction, the process in step (ii) further comprises a work-up step in which the reaction mixture is subjected to aqueous washes so that the N-protected-4-derivatized piperidine (H) or (H') is retained in the organic phase. Typically, in such an embodiment, the reaction solvent is toluene. In one embodiment, the solvent is removed from the organic phase to obtain the N-protected-4-derivatized piperidine (H) or (H'). Alternatively, the N-protected-4-derivatized piperidine (H) or (H') in the organic phase may be used directly in step (iii). Optionally, in such an embodiment, a portion of the solvent, e.g., about 50-75% by volume, is removed from the organic phase by, for example, distillation under reduced pressure. The remaining organic solvent containing the N-protected-4-derivatized piperidine (H) or (H') may then be used directly in step (iii). As will be appreciated, in such an embodiment, the solvent in the organic phase provides all or a portion of the solvent used in the reaction in step (iii).

[0216] In one embodiment of the third aspect of the present invention, the process comprises at least step (iii). As will be appreciated, step (iii) of the third aspect of the present invention corresponds to the first aspect of the present invention. All optional exemplary and illustrative embodiments described above in relation to the first aspect of the present invention apply equally to step (iii) of the third aspect of the present invention.

[0217] Typically, when the process of the third aspect of the invention includes step (iii), the N-protected-4-derivatized piperidine (H) or (H') is combined with the reaction mixture of step (iii) in non-salt form.

[0218] Typically, when the process of the third aspect of the present invention includes step (iii), reagent (IX), (I-Xa) or (I-Xb) is combined with the reaction mixture of step (iii) in a non-salt form.

[0219] Typically, when the process of the third aspect of the present invention includes step (iii), the thiourea adduct (I) or (I') is obtained in step (iii) in salt form. More typically, the thiourea adduct (I) or (I') is obtained as a sulfonic acid addition salt. Most typically, the thiourea adduct (I) or (I') is obtained as a methanesulfonate salt.

[0220] In one embodiment of the third aspect of the present invention, the process comprises at least step (iv). As will be appreciated, step (iv) of the third aspect of the present invention corresponds to the second aspect of the present invention. All optional exemplary and illustrative embodiments described above in relation to the second aspect of the present invention apply equally to step (iv) of the third aspect of the present invention.

[0221] Typically, when the process of the third aspect of the present invention includes step (iv), the thiourea adduct (I) or (I') is combined with the reaction mixture of step (iv) in salt form. More typically, a sulfonic acid addition salt of the thiourea adduct (I) or (I') is combined with the reaction mixture. Most typically, a methanesulfonate salt of the thiourea adduct (I) or (I') is combined with the reaction mixture.

[0222] Typically, when the process of the third aspect of the present invention comprises step (iv), the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is obtained in step (iv) in non-salt form.

[0223] In one embodiment of the third aspect of the present invention, the process comprises at least step (v).

[0224] As mentioned above, the conversion of step (v) of the third aspect of the present invention comprises the steps of: (1) forming a solution of ammonia in a solvent; and (2) adding N-protected-4-(halosulfonyl)-piperidine (J) to the solution formed in step (1).

[0225] Advantageously, it has been discovered that by adding N-protected-4-(halosulfonyl)-piperidine (J) or (J') to a preformed solution of ammonia in a solvent, N-protected-4-piperidinesulfonamide (K) or (K') can be obtained in higher purity than by passing ammonia through a preformed solution of N-protected-4-(halosulfonyl)-piperidine (J) or (J') in a solvent.

[0226] Typically, when the process of the third aspect of the present invention comprises step (v), the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is added in non-salt form to the solution of step (2) in step (v).

[0227] Typically, when the process of the third aspect of the present invention comprises step (v), the N-protected-4-piperidinesulfonamide (K) or (K') is obtained in step (v) in non-salt form.

[0228] Typically, in step (1) of step (v), a 10% or greater saturated solution of ammonia in the solvent is formed. More typically, a 25% or greater or 50% or greater saturated solution of ammonia in the solvent is formed. Even more typically, a 75% or greater saturated solution of ammonia in the solvent is formed. Most typically, a saturated solution of ammonia in the solvent is formed.

[0229] Typically, in step (2), the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is added in portions or continuously to the solution formed in step (1) over a period of at least 30 minutes. More typically, the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is added in portions or continuously to the solution formed in step (1) over a period of at least 60 minutes.

[0230] Typically, the solvent in step (1) of step (v) is a polar aprotic solvent such as dimethyl sulfoxide, 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 can be selected from dimethyl sulfoxide, 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 can be selected from dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, dichloromethane, hexamethylphosphoramide, nitromethane, or a mixture thereof. Even more typically, the solvent is non-halogenated. For example, the solvent can be selected from dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, hexamethylphosphoramide, nitromethane, or a mixture thereof. Most typically, the solvent is tetrahydrofuran.

[0231] Optionally, in step (2), a solution of N-protected-4-(halosulfonyl)-piperidine (J) in a second solvent is added to the solution formed in step (1). Typically, the second solvent is the same as the (first) solvent used in step (1).

[0232] In one embodiment of step (v) of the third aspect of the present invention, step (2), in which N-protected-4-(halosulfonyl)-piperidine (J) is added to the solution formed in step (1), is carried out in the absence or substantially absence of water and alcohol. That is, the solution of step (1), the N-protected-4-(halosulfonyl)-piperidine (J) used in step (2), and any solution containing N-protected-4-(halosulfonyl)-piperidine (J) used in step (2) all contain no or substantially no water or alcohol. More typically, step (2), in which N-protected-4-(halosulfonyl)-piperidine (J) is added to the solution formed in step (1), is carried out in the absence or substantially absence of a polar protic solvent.

[0233] In an exemplary embodiment of the third aspect of the present invention, reacting step (v) comprises forming a solution of ammonia in a solvent and adding benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') to the formed solution to obtain 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K'): [ka] Includes:

[0234] Typically, in such embodiments, the solvent is a non-halogenated polar aprotic solvent such as tetrahydrofuran. Typically, the solution of ammonia is a saturated solution of ammonia in the solvent.

[0235] In one embodiment of the second or third aspect of the present invention, in step (v), the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is combined with ammonia or a solution of ammonia at a temperature in the range of -70 to 30° C. Typically, the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is combined with ammonia or a solution of ammonia at a temperature in the range of -20 to 20° C., more typically in the range of -10 to 10° C.

[0236] Typically, according to the second or third aspect of the present invention, in step (v), the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is initially present in the solvent or added to the solvent in a total amount of 0.01 to 10 mol / L, based on the total volume of the solvent used in the reaction mixture. More typically, the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is initially present in the solvent or added to the solvent in a total amount of 0.1 to 1.0 mol / L. Most typically, the N-protected-4-(halosulfonyl)-piperidine (J) or (J') is initially present in the solvent or added to the solvent in a total amount of 0.4 to 0.6 mol / L.

[0237] In one embodiment of the third aspect of the present invention, the N-protected-4-piperidinesulfonamide (K) or (K') is isolated by crystallization.

[0238] In one embodiment of the second or third aspect of the present invention, at the end of the reaction, the process of step (v) comprises the following work-up step: (3) optionally removing a portion of the solvent from the reaction mixture, for example by distillation; (4) optionally diluting the remaining reaction mixture after step (3) with a second solvent; (5) washing the resulting mixture with aqueous washes and separating the organic and aqueous phases; (6) optionally removing a portion of the solvent from the organic phase, for example by distillation; (7) crystallizing the N-protected-4-piperidinesulfonamide (K) or (K') from the organic phase; and (8) Optionally, further comprising isolating the crystalline N-protected-4-piperidinesulfonamide (K) or (K'), for example, by filtration.

[0239] Typically, steps (3), (4), (6) and (8) are not optional steps.

[0240] When a portion of the solvent is removed in step (3), typically about 50 to 75% by volume of the solvent is removed.

[0241] The second solvent in step (4) is typically a polar aprotic solvent such as dimethyl sulfoxide, N,N-dimethylformamide, N,N'-dimethylpropylene urea, tetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate, acetone, acetonitrile, dichloromethane, hexamethylphosphoramide, nitromethane, propylene carbonate, N-methylpyrrolidone, or a mixture thereof. Typically, the second solvent is a C1-C6 alkyl acetate such as ethyl acetate, n-propyl acetate, or isopropyl acetate. Most typically, the second solvent is isopropyl acetate.

[0242] Typically, water is used as the aqueous wash in step (5).

[0243] Optionally, in step (6), when a portion of the solvent is removed by distillation, an additional portion of the second solvent is introduced. Typically, in such embodiments, an approximately constant volume of the organic phase is maintained.

[0244] The crystallization in step (7) can be induced, for example, by cooling from a temperature of 40-80° C. to a temperature of 0-30° C. and / or by the use of an anti-solvent such as water. Optionally, the crystallization in step (7) can be induced by seeding the organic phase with crystals of N-protected-4-piperidinesulfonamide (K) or (K').

[0245] Typically, after the crystalline N-protected-4-piperidinesulfonamide (K) or (K') is isolated by filtration in step (8), the crystalline N-protected-4-piperidinesulfonamide (K) or (K') is washed with, for example, water and / or isopropyl acetate and dried under vacuum.

[0246] In one embodiment of the third aspect of the present invention, the process comprises at least step (vi).

[0247] Typically, when the process of the third aspect of the present invention includes step (vi), the N-protected-4-piperidinesulfonamide (K) or (K') is combined with the reaction mixture of step (vi) in non-salt form.

[0248] Typically, when the process of the third aspect of the present invention comprises step (vi), 1-ethyl-4-piperazinesulfonamide (A) is obtained in step (vi) in non-salt form.

[0249] When the process of the third aspect of the present invention includes step (vi), typically the C3-C5 alcohol is selected from n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, tert-amyl alcohol, or any mixture thereof. More typically, the C3-C5 alcohol is selected from n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, or tert-butanol. Most typically, the C3-C5 alcohol is a butanol, such as n-butanol.

[0250] Typically, according to the third aspect of the invention, R 2 is a nitrogen protecting group that can be removed by catalytic hydrogenolysis.

[0251] R 2In one embodiment of the third aspect of the present invention, where K is a nitrogen-protecting group that can be removed by catalytic hydrogenolysis, reacting step (vi) comprises contacting N-protected 4-piperidinesulfonamide (K) with acetonitrile or acetaldehyde in the presence of a catalyst, hydrogen gas, and a C3-C5 alcohol 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, hydrogen gas, and a C3-C5 alcohol. Suitable catalysts include Raney nickel and palladium catalysts. In one embodiment, the catalyst is a palladium catalyst, such as palladium on carbon or palladium hydroxide on carbon. Typically, the catalyst is palladium on carbon.

[0252] When the catalyst in step (vi) is palladium on carbon or palladium hydroxide on carbon, typically 2 to 35 wt% palladium on carbon or palladium hydroxide on carbon is used, more typically 5 to 30 wt% palladium on carbon or palladium hydroxide on carbon is used, and most typically 5 to 15 wt% palladium on carbon or palladium hydroxide on carbon is used.

[0253] In an exemplary embodiment of the third aspect of the present invention, reacting step (vi) comprises contacting 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') with acetonitrile or acetaldehyde in the presence of a catalyst, hydrogen gas, and a C3-C5 alcohol to obtain 1-ethyl-4-piperazinesulfonamide (A): [ka] Includes.

[0254] Typically, in such embodiments, 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') is contacted with acetonitrile in the presence of a catalyst, hydrogen gas, and a butanol, such as n-butanol. Typically, the catalyst is a palladium catalyst, such as palladium on carbon.

[0255] When reaction step (vi) of the third aspect of the present invention comprises contacting N-protected-4-piperidinesulfonamide (K) or (K') with acetonitrile or acetaldehyde in the presence of a catalyst and hydrogen gas, the hydrogen gas is typically used at a pressure in the range of 0.1 to 100 bar. In one embodiment, the hydrogen gas is used at a pressure in the range of 0.5 to 50 bar, more typically in the range of 5 to 25 bar.

[0256] In one embodiment of the third aspect of the present invention, N-protected 4-piperidinesulfonamide (K) or (K') is contacted with acetonitrile or acetaldehyde in the presence of a catalyst, hydrogen gas, a C3-C5 alcohol, and water. Typically, when contacting is carried out in the presence of water and a C3-C5 alcohol, the ratio of water to C3-C5 alcohol present is 1:1 to 1:10 by volume. More typically, the ratio of water to C3-C5 alcohol is 1:2 to 1:5 by volume. Typically, in such an embodiment, N-protected 4-piperidinesulfonamide (K) or (K') is contacted with acetonitrile in the presence of a catalyst, hydrogen gas, a C3-C5 alcohol, and water.

[0257] When reacting step (vi) of the third aspect of the present invention comprises contacting N-protected-4-piperidinesulfonamide (K) or (K') with acetonitrile or acetaldehyde in the presence of a catalyst and hydrogen gas, reacting step (vi) is typically carried out at a temperature in the range of 0 to 100°C. In one embodiment, reacting step (vi) is carried out at a temperature in the range of 15 to 80°C. Typically, in such embodiments, reacting step (vi) is carried out at a temperature in the range of 20 to 70°C. More typically, in such embodiments, reacting step (vi) is carried out at a temperature in the range of 55 to 65°C.

[0258] The process of the third aspect of the present invention may comprise at least two of steps (i) to (vi).

[0259] Thus, in one embodiment of the third aspect of the invention, the process comprises at least steps (i) and (ii). Typically, in any embodiment of the third aspect of the invention comprising steps (i) and (ii), the N-protected-4-hydroxypiperidine (G) or (G') is not isolated between steps (i) and (ii).

[0260] In another embodiment of the third aspect of the invention, the process comprises at least steps (ii) and (iii). Typically, in any embodiment of the third aspect of the invention comprising steps (ii) and (iii), the N-protected-4-derivatized piperidine (H) or (H') is not isolated between steps (ii) and (iii).

[0261] In further embodiments of the third aspect of the invention, the process comprises at least steps (iii) and (iv). Typically, in any embodiment of the third aspect of the invention comprising steps (iii) and (iv), the thiourea adduct (I) or (I') is isolated between steps (iii) and (iv). Typically, when the thiourea adduct (I) or (I') is isolated, it is isolated in salt form, for example as a sulfonic acid addition salt such as the methanesulfonate salt.

[0262] In yet another embodiment of the third aspect of the present invention, the process comprises at least steps (iv) and (v). Typically, in any embodiment of the third aspect of the present invention comprising steps (iv) and (v), N-protected-4-(halosulfonyl)-piperidine (J) or (J') is isolated between steps (iv) and (v). Typically, when N-protected-4-(halosulfonyl)-piperidine (J) or (J') is isolated, it is isolated in a non-salt form.

[0263] In further embodiments of the third aspect of the present invention, the process comprises at least steps (v) and (vi). Typically, in any embodiment of the third aspect of the present invention comprising steps (v) and (vi), N-protected-4-piperidinesulfonamide (K) or (K') is isolated between steps (v) and (vi). Typically, when N-protected-4-piperidinesulfonamide (K) or (K') is isolated, it is isolated in a non-salt form.

[0264] The process of the third aspect of the present invention may comprise at least three of steps (i) to (vi).

[0265] Thus, in one embodiment of the third aspect of the present invention, the process comprises at least steps (i), (ii) and (iii).

[0266] In another embodiment of the third aspect of the present invention, the process comprises at least steps (ii), (iii) and (iv).

[0267] In a further embodiment of the third aspect of the invention, the process comprises at least steps (iii), (iv) and (v).

[0268] In yet another embodiment of the third aspect of the present invention, the process comprises at least steps (iv), (v) and (vi).

[0269] The process of the third aspect of the invention may comprise at least four of steps (i) to (vi).

[0270] Thus, in one embodiment of the third aspect of the invention, the process comprises at least steps (i), (ii), (iii) and (iv).

[0271] In another embodiment of the third aspect of the present invention, the process comprises at least steps (ii), (iii), (iv) and (v).

[0272] In a further embodiment of the third aspect of the invention, the process comprises at least steps (iii), (iv), (v) and (vi).

[0273] The process of the third aspect of the invention may comprise at least five of steps (i) to (vi).

[0274] Thus, in one embodiment of the third aspect of the invention, the process comprises at least steps (i), (ii), (iii), (iv) and (v).

[0275] In another embodiment of the third aspect of the present invention, the process comprises at least steps (ii), (iii), (iv), (v) and (vi).

[0276] Typically, the process of the third aspect of the invention comprises all six of steps (i) to (vi).

[0277] Typically, the process of any of the first, second, or third aspects of the present invention is a process for preparing 1-ethyl-4-piperazinesulfonamide (A) or a salt thereof. Such a process may involve conversion of any of N-protected-4-hydroxypiperidine (G) or (G'), N-protected-4-derivatized piperidine (H) or (H'), thiourea adduct (I) or (I'), N-protected-4-(halosulfonyl)-piperidine (J) or (J'), N-protected-4-piperidinesulfonamide (K) or (K'), or a salt thereof, to 1-ethyl-4-piperazinesulfonamide (A) or a salt thereof.

[0278] In one embodiment of any of the first, second or third aspects of the invention, the process is for the preparation of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide or a salt thereof. Such a process may involve the conversion of N-protected-4-hydroxypiperidine (G) or (G'), N-protected-4-derivatized piperidine (H) or (H'), thiourea adduct (I) or (I'), N-protected-4-(halosulfonyl)-piperidine (J) or (J'), N-protected-4-piperidinesulfonamide (K) or (K'), 1-ethyl-4-piperazinesulfonamide (A), or any of their salts, to 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide or a salt thereof. Typically, such a process comprises the steps of contacting 1-ethyl-4-piperidinesulfonamide (A) (prepared according to any of the first to third aspects of the present invention) 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] Including, In the formula, X is a leaving group.

[0279] In one embodiment, 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 hydrocarbyl group is selected from 20The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C-C 20 The hydrocarbyl group may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20 The hydrocarbyl group may optionally 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 contain one or more halo groups and / or one or more groups R X and each R X are independently selected from -CN, -OH, -NH, oxo (=O), =NH or a C1-C6 hydrocarbyl group, each C1-C6 hydrocarbyl group may be straight chained or branched or may be or contain one or more cyclic groups, each C1-C6 hydrocarbyl group may optionally be substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may optionally include one or more heteroatoms in its carbon skeleton independently selected from N, O and S.

[0280] In one embodiment, X is Cl, Br or I. Typically, in such embodiments, X is Cl.

[0281] In another embodiment, X is OR 1 or SR 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 C-C 20 The hydrocarbyl group may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and may be C-C20 The hydrocarbyl group may optionally contain one or more heteroatoms independently selected from N, O and S in its carbon skeleton.

[0282] Typically, in such embodiments, X is OR 1 is.

[0283] For example, X is OR 1 wherein R 1 is selected from alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl groups; R 1 are 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 be taken together to form a C2-C5 alkylene or C2-C5 haloalkylene group, R 1 contains 1 to 20 carbon atoms, including any optional substituents.

[0284] More typically, X is OR 1 where R 1 is selected from alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl groups; R 1is optionally substituted with one or more substituents independently selected from halo, -CN, -OH, -NO, -NH, oxo (=O), -Me, -Et, -OMe, -OEt, -NHMe, -NHEt, -N(Me), -N(Me)Et, or -N(Et), any methyl (Me) or ethyl (Et) group is optionally substituted with one or more halo groups; R 1 contains 1 to 12 carbon atoms, including any optional substituents.

[0285] 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 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 directly attached to the same nitrogen atom 10 may together form a C2-C5 alkylene or C2-C5 haloalkylene group, R 1 contains 1 to 20 carbon atoms, including any optional substituents.

[0286] More typically, X is OR 1 where R 1 is selected from phenyl or a monocyclic heteroaryl group, and R 1is optionally substituted with one or more substituents independently selected from halo, -CN, -OH, -NO, -NH, -Me, -Et, -OMe, -OEt, -NHMe, -NHEt, -N(Me), -N(Me)Et, or -N(Et), any methyl (Me) or ethyl (Et) group is optionally substituted with one or more halo groups; R 1 contains 1 to 12 carbon atoms, including any optional substituents.

[0287] Even more typically, X is OR 1 where R 1 is a phenyl group, which may be optionally substituted with one or more fluoro, chloro, or —NO groups. Most typically, R 1 is an unsubstituted phenyl group, i.e., X is OPh.

[0288] R 1 is an unsubstituted phenyl group, a process 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 contacting 1-ethyl-4-piperidinesulfonamide (A) (prepared according to any of the first to third aspects of the present invention) 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] A process is provided that includes:

[0289] In another embodiment, X is N(R 1 )2, and each R 1 are independently C1-C 20 Each C-C hydrocarbyl group is selected from 20The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C-C 20 The hydrocarbyl group may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20 The hydrocarbyl group may optionally 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 contain one or more halo groups and / or one or more groups R X and each R X are independently selected from -CN, -OH, -NH, oxo (=O), =NH or a C1-C6 hydrocarbyl group, each C1-C6 hydrocarbyl group may be straight chained or branched or may be or contain one or more cyclic groups, each C1-C6 hydrocarbyl group may optionally be substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may optionally include one or more heteroatoms in its carbon skeleton independently selected from N, O and S.

[0290] 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, wherein 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 directly attached to the same nitrogen atom 10 may be joined together to form a C2-C5 alkylene or C2-C5 haloalkylene group, R 1 contains 1 to 20 carbon atoms, including any optional substituents.

[0291] 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 1 is optionally substituted with one or more substituents independently selected from halo, -CN, -OH, -NO, -NH, -Me, -Et, -OMe, -OEt, -NHMe, -NHEt, -N(Me), -N(Me)Et, or -N(Et), any methyl (Me) or ethyl (Et) group is optionally substituted with one or more halo groups; R 1 contains 1 to 12 carbon atoms, including any optional substituents.

[0292] Typically, X is N(R 1 )2 and two R 1 together with the nitrogen atom to which they are attached to form a 5- to 14- or 5- to 10-membered heteroaryl group, N(R 1 The ring containing the nitrogen atom of 2 is a five-membered ring.

[0293] In another embodiment, X is OP(=O)(R 1 )2 or OP(R 1 )3 + and each R 1 are independently C1-C 20 Each C-C hydrocarbyl group is selected from 20The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C-C 20 The hydrocarbyl group may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20 The hydrocarbyl group may optionally 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 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 contain one or more halo groups and / or one or more groups R X and each R X are independently selected from -CN, -OH, -NH, oxo (=O), =NH or a C1-C6 hydrocarbyl group, each C1-C6 hydrocarbyl group may be straight chained or branched or may be or contain one or more cyclic groups, each C1-C6 hydrocarbyl group may optionally be substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may optionally include one or more heteroatoms in its carbon skeleton independently selected from N, O and S.

[0294] Typically, in such embodiments, X is OP(=O)(R 1 )2 or OP(R 1 )3 + where each R 1 is independently selected from alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl groups, wherein each R 1 are 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 10wherein 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 be joined together to form a C2-C5 alkylene group or a C2-C5 haloalkylene group, and each R 1 contains 1 to 20 carbon atoms, including any optional substituents.

[0295] More typically, X is OP(=O)(R 1 )2 or OP(R 1 )3 + If R 1 is independently selected from alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl groups; and each R 1 is optionally substituted with one or more substituents independently selected from halo, -CN, -OH, -NO, -NH, oxo (=O), -Me, -Et, -OMe, -OEt, -NHMe, -NHEt, -N(Me), -N(Me)Et, or -N(Et), any methyl (Me) or ethyl (Et) group is optionally substituted with one or more halo groups; and each R 1 contains 1 to 12 carbon atoms, including any optional substituents.

[0296] Even more typically, X is OP(=O)(R 1 )2 or OP(R 1 )3 + If R 1 are independently selected from C1-C4 alkyl or phenyl groups.

[0297] Typically, when the process includes the step of contacting 1-ethyl-4-piperidinesulfonamide (A) with the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B'), the 1-ethyl-4-piperidinesulfonamide (A) is combined with the reaction mixture in a non-salt form.

[0298] Typically, when the process includes the step of contacting 1-ethyl-4-piperidinesulfonamide (A) with a 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B'), the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B') is combined with the reaction mixture in a non-salt form.

[0299] In one embodiment, 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 polar aprotic solvent such as dimethyl sulfoxide, 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 dimethyl sulfoxide, 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 can be selected from dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, hexamethylphosphoramide, nitromethane, or a mixture thereof. Most typically, the solvent is dimethyl sulfoxide.

[0300] In one embodiment, the step of contacting 1-ethyl-4-piperidinesulfonamide (A) with the 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 tertiary butoxide base, such as an alkali metal or alkaline earth metal tertiary butoxide. Examples of suitable bases include potassium tertiary butoxide and sodium tertiary butoxide. Typically, the base is potassium tertiary butoxide.

[0301] Typically, 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-piperidine-4-sulfonamide (C) is obtained in the form of a salt.

[0302] Thus, one embodiment of any of the first, second or third aspects of the invention provides a process 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 pharmaceutically acceptable.

[0303] For purposes of this 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 poly-salt. Preferably, the salt is a mono- or di-lithium, sodium, potassium, magnesium, calcium, or ammonium salt. More preferably, the salt is a mono- or di-sodium salt or a mono- or di-potassium salt. More preferably, the salt is a mono- or di-potassium salt, and even more preferably, the salt is a mono-potassium salt.

[0304] 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, in one embodiment, there is provided a process 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 the step of 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 tertiary butoxide.

[0305] A further embodiment provides a process 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 provide 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.

[0306] In one embodiment, 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.

[0307] Typically, when the process includes contacting 1-ethyl-4-piperidinesulfonamide (A) with a 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B'), the 1-ethyl-4-piperidinesulfonamide (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 solvent used in the reaction mixture. More typically, the 1-ethyl-4-piperidinesulfonamide (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, the 1-ethyl-4-piperidinesulfonamide (A) is present in the solvent or added to the solvent at an initial concentration of 1.0 to 1.5 mol / L. 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 0.1 to 15 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 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.

[0308] Typically, when the process includes contacting 1-ethyl-4-piperidinesulfonamide (A) with a 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B'), the process 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').

[0309] Typically, when the process includes contacting 1-ethyl-4-piperidinesulfonamide (A) with the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B') in the presence of a base, the process 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. Even more typically, the process uses 1.1 to 1.2 molar equivalents of base.

[0310] In one embodiment, the process comprises the steps of: (1) dissolving 1-ethyl-4-piperidinesulfonamide (A) in a solvent; (2) adding a base to the solution formed in step (1); and (3) adding the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B') to the mixture formed in step (2).

[0311] In one embodiment, 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 dimethyl sulfoxide (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, optionally upon cooling. In one embodiment, the precipitation mixture comprises DMSO, MeCN, and water, and the solvent of the precipitation mixture consists of 30-50 wt% DMSO (based on the total weight of the solvent), 50-70 wt% MeCN (based on the total weight of the solvent), and 1-10 wt% HO (based on the total weight of the solvent). 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. 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.

[0312] In one embodiment, the isolated salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (C) is further purified by recrystallization or reprecipitation. For example, the isolated 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.

[0313] When the process of the present invention involves the use of a 1,2,3,5,6,7-hexahydro-s-indacene derivative (B), the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) can be prepared by the following steps: (e) converting 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (D) into 1,2,3,5,6,7-hexahydro-s-indacene derivative (B): [ka] wherein X is as defined above. It can be prepared by a process comprising:

[0314] In one embodiment, such a process comprises reacting 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) with reagent (E): [ka] with, optionally in the presence of a base and / or a solvent, X is as defined above and X' is a leaving group.

[0315] In one embodiment, 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 above. Typically, X' is Cl, Br, or I. More typically, X' is Cl or Br. Most typically, X' is Cl.

[0316] 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 displaced than X.

[0317] In one embodiment, 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.

[0318] In a further embodiment, X' is Cl, Br or I and X is OR 1 where R 1 is selected from alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl groups; R 1 are 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 10and 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 be taken together to form a C2-C5 alkylene or C2-C5 haloalkylene group, R 1 contains 1 to 20 carbon atoms, including any optional substituents.

[0319] More 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 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 1 contains 1 to 20 carbon atoms, including any optional substituents.

[0320] Even more typically, X' is Cl and X is OR 1 where R 1 is a phenyl group, which may be optionally substituted with one or more fluoro, chloro, or —NO2 groups. Most typically, X' is Cl and X is OPh.

[0321] Thus, in an exemplary embodiment, the process in step (e) comprises contacting 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) with phenyl chloroformate (E′), optionally in the presence of a solvent and / or a base: [ka] Includes.

[0322] 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 dimethyl sulfoxide, 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 can be selected from dimethyl sulfoxide, 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 dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, hexamethylphosphoramide, nitromethane, or a mixture thereof. Most typically, the solvent is tetrahydrofuran.

[0323] 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.

[0324] Typically, when the process of the present invention includes step (e), the 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) is combined with the reaction mixture of step (e) in a non-salt form.

[0325] Typically, when the process of the invention includes step (e), reagent (E) or (E') is combined with the reaction mixture of step (e) in a non-salt form.

[0326] Typically, when the process of the present invention comprises step (e), the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) or (B') is obtained in step (e) in a non-salt form.

[0327] In one embodiment, 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) is combined 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 combined 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. In one embodiment, after combining 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.

[0328] Typically, when the process includes contacting 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (D) with reagent (E) or (E') in the presence of a solvent, 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.

[0329] Typically, the process 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').

[0330] Typically, when the process includes contacting 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) with reagent (E) or (E') in the presence of a base, the process 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.

[0331] In one embodiment, the process of step (e) comprises the steps of: (1) dissolving 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (D) in a first portion of a solvent; (2) dissolving a base in a second portion of the solvent and adding the resulting solution to the solution formed in step (1); and (3) dissolving reagent (E) or (E') in a third portion of the solvent and adding the resulting solution to the mixture formed in step (2).

[0332] In one embodiment, at the end of the reaction between 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) and reagent (E) or (E′), the process comprises the steps of: (4) concentrating the reaction mixture under vacuum; and then (5) optionally adding a co-solvent and concentrating the resulting mixture under vacuum.

[0333] Step (5) 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.

[0334] In one embodiment, the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) is purified and / or isolated by crystallization or precipitation. For example, a precipitating solvent may be added to the concentrated reaction mixture after step (4) or (5) above to produce a precipitation mixture, from which the 1,2,3,5,6,7-hexahydro-s-indacene derivative (B) may be precipitated, optionally under cooling. Typically, the crystallization or precipitation occurs at a temperature in the range of -10 to 20°C. More typically, the 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. Typically, the precipitating solvent is an alcohol, such as methanol or ethanol. Most typically, the precipitating solvent is ethanol.

[0335] 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.

[0336] In one embodiment, when the process of the present invention comprises the use of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D), 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) is prepared by one or more steps selected from the following: (a) 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), where Y and Z are leaving groups; [ka] (b) contacting 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] (c) 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] (d) 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] It is prepared by a process comprising:

[0337] In one embodiment, the process comprises one, two, three or all four of steps (a) through (d).

[0338] The process for preparing 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) may be as described in WO 2020 / 079207, the contents of which are incorporated herein by reference in their entirety.

[0339] In one embodiment, in step (a), the leaving group Y is independently selected from Cl, Br, I, or a sulfonate leaving group, such as a toluenesulfonate, methanesulfonate, or trifluoromethanesulfonate leaving group.

[0340] In one embodiment, in step (a), the leaving group Z is Cl, Br, I, OR 1 , S.R. 1 , N(R 1 )2, OP(=O)(R 1 )2 or OP(R 1 )3 + wherein R is independently selected from 1 is as defined above.

[0341] Y and Z may be the same or different. Typically, Y and Z are each independently selected from Cl, Br, and I. Typically, at least one of Y and Z is Cl. More typically, both Y and Z are Cl. When both Y and Z are Cl, in step (a), 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.

[0342] In one embodiment, the reaction of step (a) is carried out in the presence of a catalyst, such as a Lewis acid, such as aluminum chloride.

[0343] Step (a) 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.

[0344] In one embodiment, the reaction in step (a) is carried out at a temperature in the range of −20 to 50° C. Typically, the reaction in step (a) 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.

[0345] In one embodiment, in step (b), 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.

[0346] In one embodiment, the reaction in step (b) is carried out at a temperature in the range of 10 to 90° C. Typically, the reaction in step (b) is carried out at a temperature in the range of 40 to 80° C., more typically at a temperature in the range of 65 to 70° C.

[0347] In one embodiment, in step (c), 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.

[0348] In one embodiment, the reaction in step (c) is carried out at a temperature in the range of 0 to 20° C. Typically, the reaction in step (c) 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.

[0349] In one embodiment, the reactions of steps (b) and (c) are carried out without isolating 1,2,3,5,6,7-hexahydro-s-indacen-1-one (P).

[0350] In one embodiment, the reduction in step (d) is carried out using a catalyst and hydrogen gas. Typically, the catalyst is a metal catalyst containing 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 supplied at a pressure of 80 to 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.

[0351] In one embodiment, the reduction in step (d) 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.

[0352] In one embodiment, the reduction in step (d) is carried out at a temperature in the range of 10 to 80° C. Typically, the reduction in step (d) is carried out at a temperature in the range of 20 to 60° C.

[0353] Typically, when the process of the present invention comprises step (d), the 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) is obtained in a non-salt form.

[0354] In an exemplary embodiment, when the process of the present invention involves the use of 4-(phenoxycarbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (B'), 4-(phenoxycarbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (B') can be prepared by the following steps: (a) 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] (b) 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] (c) 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] (d) 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] (e) converting 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (D) to 4-(phenoxycarbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (B') by contacting 1,2,3,5,6,7-hexahydro-s-indacen-4-amine with PhOC(O)L; [ka] wherein L is selected from Cl and Br; It is prepared by a process comprising:

[0355] A fourth 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, to provide.

[0356] In a fourth aspect of the present invention, R 2 may be as defined according to any embodiment of any of the first to third aspects of the present invention.

[0357] A particular embodiment of the fourth aspect of the present invention is N-carboxybenzyl-4-hydroxypiperidine (G') or a salt thereof: [ka] to provide.

[0358] N-protected-4-hydroxypiperidine (G) or a salt thereof, or N-carboxybenzyl-4-hydroxypiperidine (G') or a salt thereof, may be prepared by or preparable by the process of step (i) of any of the first, second, or third aspects of the present invention. Typically, N-protected-4-hydroxypiperidine (G) or a salt thereof, or N-carboxybenzyl-4-hydroxypiperidine (G') or a salt thereof, is prepared by or preparable by the process of step (i) of the third aspect of the present invention.

[0359] Typically, the N-protected-4-hydroxypiperidine (G) or N-carboxybenzyl-4-hydroxypiperidine (G') of the fourth aspect of the present invention is in a non-salt form.

[0360] A fifth aspect of the present invention provides an N-protected-4-derivatized piperidine (H) or a salt thereof: [ka] provide In the formula, R 2 is a nitrogen protecting group, and R 3 is a leaving group.

[0361] In a fifth aspect of the present invention, R 2 and R 3 may be as defined according to any embodiment of any of the first to third aspects of the present invention.

[0362] A particular embodiment of the fifth aspect of the present invention is benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H') or a salt thereof: [ka] to provide.

[0363] 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 by or preparable by the process of step (ii) of any of the first, second or third aspects of the present invention. Typically, the N-protected-4-derivatized piperidine (H) or a salt thereof, or benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H') or a salt thereof, is prepared by or preparable by the process of step (ii) of the third aspect of the present invention.

[0364] Typically, the N-protected-4-derivatized piperidine (H) or benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H') of the fifth aspect of the invention is in a non-salt form.

[0365] A sixth aspect of the present invention is a thiourea adduct (I) or a salt thereof: [ka] provide During the ceremony: R 2 is a nitrogen protecting group; and Each R 4 are independently hydrogen or C1-C 20 hydrocarbyl groups, wherein each C-C 20 The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C-C 20 The hydrocarbyl group may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C-C 20 The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or any two or more R 4may, together with the atom(s) to which they are attached, form a 3- to 16-membered heterocyclic group, which may be monocyclic, bicyclic, or tricyclic, and which may contain one or more halo groups and / or one or more groups R 40 and each R 40 are independently selected from -CN, -OH, -NH, oxo (=O), =NH or a C1-C6 hydrocarbyl group, each C1-C6 hydrocarbyl group may be straight chained or branched or may be or contain one or more cyclic groups, each C1-C6 hydrocarbyl group may be optionally substituted with one or more halo groups, and each C1-C6 hydrocarbyl group may optionally include one or more heteroatoms independently selected from N, O and S in its carbon skeleton.

[0366] In a sixth aspect of the present invention, R 2 and each R 4 may be as defined according to any embodiment of any of the first to third aspects of the present invention.

[0367] A particular embodiment of the sixth aspect of the present invention is benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I′) or a salt thereof: [ka] to provide.

[0368] The thiourea adduct (I) or a salt thereof, or benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I') or a salt thereof, may be prepared by or preparable by the process of step (iii) of any of the first, second or third aspects of the present invention. Typically, the thiourea adduct (I) or a salt thereof, or benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I') or a salt thereof, is prepared by or preparable by the process of the first aspect of the present invention.

[0369] Typically, the thiourea adduct (I) or benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I') is in the form of a salt. More typically, a sulfonic acid addition salt of the thiourea adduct (I) or benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I') is provided. Most typically, the sixth aspect of the present invention provides a methanesulfonate salt of the thiourea adduct (I) or benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I').

[0370] Typically, the thiourea adduct (I) or a salt thereof, or benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I') or a salt thereof is in a solid form, most typically a crystalline solid form.

[0371] In one embodiment of the sixth aspect of the present invention, the thiourea adduct (I) or a salt thereof has an HPLC purity of 90% or greater. More typically, the thiourea adduct (I) or a salt thereof has an HPLC purity of 95% or greater. Even more typically, the thiourea adduct (I) or a salt thereof has an HPLC purity of 99% or greater.

[0372] In another embodiment of the sixth aspect of the present invention, benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I') or a salt thereof has an HPLC purity of 90% or greater. More typically, benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I') or a salt thereof has an HPLC purity of 95% or greater. Even more typically, benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I') or a salt thereof has an HPLC purity of 99% or greater. A seventh aspect of the present invention provides an N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof: [ka] In the formula, R2 is a nitrogen protecting group and Hal is Cl or Br; to provide.

[0373] In a seventh aspect of the present invention, R 2 and Hal may be as defined according to any embodiment of any of the first to third aspects of the present invention.

[0374] A particular embodiment of the seventh aspect of the present invention is benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') or a salt thereof: [ka] to provide.

[0375] The N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof, or benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') or a salt thereof may be prepared by or preparable by the process of step (iv) of the second or third aspect of the present invention. Typically, the N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof, or benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') or a salt thereof is prepared by or preparable by the process of the second aspect of the present invention.

[0376] Typically, the N-protected-4-(halosulfonyl)-piperidine (J) or benzyl 4-(chloro-sulfonyl)-1-piperidinecarboxylate (J') of the seventh aspect of the invention is in a non-salt form.

[0377] Typically, the N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof, or benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') or a salt thereof is in a solid form, most typically a crystalline solid form.

[0378] In one embodiment of the seventh aspect of the present invention, the N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof has an HPLC purity of 90% or greater. More typically, the N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof has an HPLC purity of 95% or greater. Even more typically, the N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof has an HPLC purity of 99% or greater.

[0379] In one embodiment of the seventh aspect of the present invention, benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') or a salt thereof has an HPLC purity of 90% or greater. More typically, benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') or a salt thereof has an HPLC purity of 95% or greater. Even more typically, benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') or a salt thereof has an HPLC purity of 99% or greater. An eighth 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, to provide.

[0380] In an eighth aspect of the present invention, R 2 may be as defined according to any embodiment of any of the first to third aspects of the present invention.

[0381] A particular embodiment of the eighth aspect of the present invention is 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') or a salt thereof: [ka] to provide.

[0382] 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 process of step (v) of the second or third aspect of the present invention. Typically, N-protected-4-piperidinesulfonamide (K) or a salt thereof, or 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') or a salt thereof is prepared or preparable by the process of step (v) of the third aspect of the present invention.

[0383] Typically, the N-protected-4-piperidinesulfonamide (K) or 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') of the eighth aspect of the invention is in a non-salt form.

[0384] Typically, the N-protected-4-piperidinesulfonamide (K) or a salt thereof, or the 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') or a salt thereof is in a solid form, most typically a crystalline solid form.

[0385] In one embodiment of the eighth aspect of the present invention, the N-protected-4-piperidinesulfonamide (K) or a salt thereof has an HPLC purity of 96.2% or greater. More typically, the N-protected-4-piperidinesulfonamide (K) or a salt thereof has an HPLC purity of 98% or greater. Even more typically, the N-protected-4-piperidinesulfonamide (K) or a salt thereof has an HPLC purity of 99.5% or greater.

[0386] In another embodiment of the eighth aspect of the present invention, 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') or a salt thereof has an HPLC purity of 96.2% or greater. More typically, 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') or a salt thereof has an HPLC purity of 98% or greater. Even more typically, 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (K') or a salt thereof has an HPLC purity of 99.5% or greater. A ninth aspect of the present invention is 1-ethyl-4-piperazinesulfonamide (A) or a salt thereof: [ka] to provide.

[0387] 1-ethyl-4-piperazinesulfonamide (A) or a salt thereof may be prepared or preparable by the process of step (vi) of the second or third aspect of the present invention. Typically, 1-ethyl-4-piperazinesulfonamide (A) or a salt thereof is prepared or preparable by the process of step (vi) of the third aspect of the present invention.

[0388] Typically, the 1-ethyl-4-piperazinesulfonamide (A) of the eleventh aspect of the present invention is in a non-salt form.

[0389] A tenth aspect of the present invention provides 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide or a salt thereof, which is prepared by or preparable by the process of any of the first to third aspects of the present invention.

[0390] In one embodiment, the tenth 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 tenth 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 tenth 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.

[0391] In one embodiment of the tenth aspect of the present invention, 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide or a salt thereof is 1 More typically, 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 greater as determined by H NMR. 1 It has a purity of 98.0% or greater, or 99.0% or greater, or 99.5% or greater, as measured by H NMR.

[0392] In another embodiment of the tenth aspect of the present invention, 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 greater. More typically, 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 greater, or 99.0% or greater, or 99.5% or greater, or 99.8% or greater, or 99.9% or greater.

[0393] The compounds used in and provided by the processes of the present invention may be used and provided in their free base form or in their acid addition salt form, as appropriate. For purposes of this invention, a "salt" of a compound of the present invention includes an acid addition salt. 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 pharmaceutically acceptable non-toxic addition salts with suitable acids, including, but not limited to, organic sulfonic acids (e.g., octadecanoic acid, guconic acid, pantothenic acid, or pamoic acid), 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 poly-acid addition salts. Preferred salts are hydrohalic acid, sulfuric acid, phosphoric acid, or organic acid addition salts. Preferred salts are hydrochloric acid addition salts.

[0394] When the compound used in or provided by the process of the present invention contains a quaternary ammonium group, the compound is typically used or provided in its salt form.The counterion of the quaternary ammonium group can be any pharmaceutically acceptable non-toxic counterion.Examples of suitable counterions include the conjugate base of the protic acid mentioned above for acid addition salts.

[0395] The compounds used in and provided by the processes of the present invention may also be used and provided in their free acid form and their salt form, as appropriate. For purposes of the present invention, a "salt" of a compound of the present invention includes one formed between a protonic acid functional group of a 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-, di-, tri-, or poly-salt. Preferably, the salt is a mono- or di-lithium, sodium, potassium, magnesium, calcium, or ammonium salt. More preferably, the salt is a mono- or di-sodium salt or a mono- or di-potassium salt.

[0396] Preferably, any salts are pharmaceutically acceptable non-toxic salts. However, in addition to pharmaceutically acceptable salts, other salts are included in the context of the present invention because they may serve as intermediates in the purification or preparation of other pharmaceutically acceptable salts, or because they are useful in identifying, characterizing, or purifying free acids or free bases.

[0397] 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 using common organic solvents, including, but not limited to, alcoholic solvents such as methanol, ethanol, or isopropanol.

[0398] 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 and127 any stable isotope, including but not limited to I, and 11 C. 14 C. 3 H(T), 13 N, 15 O. 18 F, 123 I, 124 I, 125 I and 131 It may contain any radioactive isotope, including but not limited to I.

[0399] Unless otherwise specified, the compounds, salts and solvates used in and provided by the present invention may be in any polymorphic or amorphous form.

[0400] An eleventh aspect of the present invention provides 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 the tenth aspect of the present invention, and a pharmaceutically acceptable excipient.

[0401] 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", M.E. Aulton and K.M.G. Taylor, Churchill Livingstone Elsevier, 4 th Ed., 2013. The pharmaceutically acceptable excipients, including adjuvants, diluents or carriers, that can be used in the pharmaceutical composition of the present invention are those conventionally used in the field of pharmaceutical formulations.

[0402] A twelfth aspect of the present 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 tenth aspect of the invention, or a pharmaceutical composition according to the eleventh aspect of the invention, for use in medicine and / or in the treatment or prophylaxis of a disease, disorder or condition.

[0403] 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.

[0404] 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.

[0405] Typically, the treatment or prevention of the disease, disorder or condition involves administering to a subject 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 tenth aspect of the invention, or the pharmaceutical composition according to the eleventh aspect of the invention.

[0406] Any of the medicaments used in the present invention can 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.

[0407] Typically, the mode of administration selected will be that which is most suitable for the disorder, disease or condition being treated or prevented.

[0408] A thirteenth aspect of the present invention provides a method for 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 tenth aspect of the present invention, or the pharmaceutical composition according to the eleventh aspect of the present invention.

[0409] For the avoidance of doubt, where practicable, any embodiment of a given aspect of the invention may be made in combination with any other embodiment of the same aspect of the invention. Further, where practicable, it is to be understood that any preferred, exemplary, optional or exemplary embodiment of any aspect of the invention shall also be deemed to be a preferred, exemplary, optional or exemplary embodiment of any other aspect of the invention. [Example]

[0410] Unless otherwise stated, all solvents, reagents and compounds were purchased and used without further purification.

[0411] Abbreviation Aq:Aqueous solution Cbz: carboxybenzyl / benzyloxycarbonyl GC: Gas chromatography HPLC: High-performance liquid chromatography THF: tetrahydrofuran RBF: Round-bottom flask Eq: equivalent min:minutes h: time MTBE: Methyl tertiary butyl ether Ms: Meshir DCM: dichloromethane DMFL Dimethylformamide TEA: Trimethylamine IPA: Isopropyl alcohol HDPE: High density polyethylene NMT: Below NCS: N-chlorosuccinimide V, vol: volume AKX reagent: AQUAMICRON (registered trademark) AKX %a / a: (area under the peak of compound (a) / total area under the peaks of compound (a) and all other components) × 100

[0412] As used herein, unless otherwise stated, all references to pressure in bar refer to absolute pressure.

[0413] Experimental Method NMR method: NMR spectra were obtained on a Bruker AV 400 MHz spectrometer (model: Advance IIID) operated at room temperature (25°C).

[0414] GC method: GC analyses were performed on one of the following instruments: Agilent 7890, 6890, or Agilent 6890N equipped with an ALS injector.

[0415] HPLC method: HPLC in Reaction Scheme 1, steps (i) to (vi) was performed on an Agilent 1260 Infinity II HPLC equipped with a UV detector using 0.05% TFA in water as mobile phase A and 0.05% TFA in acetonitrile as mobile phase B.

[0416] HPLC in Reaction Scheme 2, steps (a)-(d) was performed on a Waters Alliance e2695 HPLC equipped with a PDA detector using 10 Mm ammonium bicarbonate in water as mobile phase A and acetonitrile as mobile phase B.

[0417] HPLC in Reaction Scheme 3 was performed on an Agilent 1100, 1200 or 1260 using ammonium acetate in water:MeCN (for both mobile phases).

[0418] As used herein, unless otherwise specified, all references to HPLC purity are measured as % a / a.

[0419] KF method: Coulometric KF (Karl Fischer) titrations were performed on a Mitsubishi CA-20 or Predicta OM1000 using AKX reagent.

[0420] Synthesis Example 1-Ethyl-4-piperidinesulfonamide (7) 1-Ethyl-4-piperidinesulfonamide (7) can be reacted with 1-ethyl-4-piperidinesulfonamide (7) according to Reaction Scheme 1: [ka] It was prepared according to the reaction sequence shown in

[0421] Reaction Scheme 1 - Step (i) [ka] 4-Hydroxypiperidine (1) (20.0 g, 198 mmol, 1.0 equiv.) was charged to a 250 mL glass reactor along with toluene (80 mL, 4 V), water (30 mL, 1.5 V), and 30% aqueous NaOH (40.2 g, 297 mmol, 1.5 equiv.), and the mixture was cooled to 0-5 °C. A solution of CbzCl (33.7 g, 198 mmol, 1.0 equiv.) in toluene (30 mL, 1.5 V) was added to the vigorously stirred biphasic mixture at 0-10 °C. The reaction mixture was warmed to 20-25 °C, and the aqueous layer was drained. The organic layer was washed twice with water (20 mL, 1 V) and subsequently dried by azeotropic distillation to give a solution of benzyl 4-hydroxy-1-piperidinecarboxylate (2) in toluene. The resulting solution was used directly in the next step without further purification. Alternatively, the solvent may be removed and the residue redissolved in toluene to provide the reaction mixture for the next step.

[0422] Reaction Scheme 1 - Step (ii) [ka] Benzyl 4-hydroxy-1-piperidinecarboxylate (2) (200.0 g, 850 mmol, 1.0 equiv.), MsCl (102.2 g, 893 mol, 1.05 equiv.), and toluene (600 ml, 3 V) were charged to a 1.0 L glass reactor. The thin slurry was cooled to 0-5 °C. Triethylamine (94.6 g, 130 ml, 935 mmol, 1.1 equiv.) was then added dropwise while maintaining the temperature at 0-5 °C. The reaction is strongly exothermic and proceeds completely with controlled addition to limit the reaction rate. The jelly-like slurry was aged for at least 10 min and then analyzed by HPLC (starting material <0.5% a / a). Water (200 ml, 2 V) was added to the reaction mixture, and the temperature was adjusted to 10-25 °C. The aqueous layer was drained, and the organic layer was washed with water (200 ml, 2 V). 400 ml (2V) of the remaining organic layer was evaporated under reduced pressure to give a solution of benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (3) in toluene, which was used directly in the next step without further purification.

[0423] Reaction Scheme 1 - Step (iii) [ka] To a solution of crude benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (3) in toluene from step (ii) was added n-butanol (600 ml, 3 V) and thiourea (71.2 g, 935 mmol, 1.1 equiv.). 200 ml (1 V) was distilled off under reduced pressure and replaced with n-butanol (200 ml, 1 V). The temperature was then adjusted to 95–100°C. After stirring at this temperature for 1 h, the reaction mixture was seeded with thiourea adduct (4) (prepared from a previous batch without seeding) and stirred for an additional 4–5 h. The slurry was then cooled to 20–25°C over at least 2 h and aged for at least 1 h. The solid was filtered off, and the wet cake was washed with IPA (200 ml, 1 V). The solid was dried in a vacuum cabinet at 50° C. to give benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate methanesulfonate (4) (175.2 g) as a colorless solid. Yield: 53% over 3 steps HPLC purity: 99.4% 1 H NMR(400MHz,DMSO-d6):δ 9.17(s,4H),7.67-7.19(m,5H),5.08(s,2H),4.12-3.75(m,3H),2.41(s ,3H),1.99(dd,J=13.2,3.8Hz,2H),1.52(dtd,J=13.0,10.9,4.1Hz,2H). 13 C NMR(101MHz,DMSO):δ 168.68,154.72,137.30,128.89,128.34,128.06,66.79,43.35,41.39,40.24,31.76.

[0424] Reaction Scheme 1 - Step (iv) [ka] The methanesulfonate salt of benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (4) (100.0 g, 256.7 mmol, 1.0 equiv.) was charged to a mixture of acetic acid (200 mL, 2 V) and 10% w / w hydrochloric acid (100 mL, 1.0 V), and the temperature was adjusted to 25–30 °C. Most of the starting material dissolved endothermically, resulting in a thin suspension. NCS (101.1 g, 757.4 mmol, 2.95 equiv.) was then added in at least 10 portions over at least 1 h at 25–30 °C. After approximately 25% NCS addition, a clear solution was obtained. After 50% addition, the mixture was seeded with sulfonyl chloride (5) (prepared from a previous batch without seeding). The addition of NCS was continued after crystallization began. The oxidation with NCS is exothermic and proceeds well with controlled addition to limit the reaction rate. After addition, the reaction mixture was aged at 20-25°C for at least 30 min before confirming conversion by HPLC. Based on the HPLC results, additional NCS was added (area % of starting material = mol % of additional NCS added), and conversion was checked again after 30 min (target: starting material <1% a / a). Residual NCS was quenched with 20% w / w Na2SO3 until a KI / starch test was negative. Water (100 ml, 1 V) was then added over at least 15 min, and the temperature was adjusted to 18-22°C. After stirring for at least 1 h, the product was isolated by filtration, and the filter cake was washed with AcOH / water 1:1 (100 ml, 1 V) and water (100 ml, 1 V). The wet product was dried at 50° C. in a vacuum cabinet to give 76.0 g of benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (5) as a colorless solid. Yield: 93.2% HPLC purity: 99.1% 1 H NMR(400MHz,CDCl3):δ 7.49-7.32(m,5H),5.17(s,2H),4.43(s,2H),3.69(tt,J=11.8,3.8Hz,1H) ,2.92(s,2H),2.38(d,J=12.9Hz,2H),1.97(qd,J=12.1,11.5,4.0Hz,2H). 13C NMR (101MHz, CDCl3): δ 154.81,136.22,128.61,128.30,128.10,72.16,67.68,42.54,26.59.

[0425] Reaction Scheme 1 - Step (v) [ka] THF (300 ml, 6V) was charged to a dry 500 ml glass reactor and the temperature was adjusted to -5 to 0 °C. The atmosphere was changed to ammonia, and the solution was stirred at 1000 rpm until no further ammonia uptake was observed. At -5 to 5 °C, under an NH3 atmosphere, benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (5) (50.0 g, 157.3 mmol, 1.0 equiv.) was added in at least five portions over at least 1 h with continued stirring at 1000 rpm. The addition of the starting material proceeded with slight outgassing of ammonia caused by the temperature increase. The light slurry was aged for at least 15 min, and conversion was confirmed by HPLC (sulfonyl chloride (5) <0.5% a / a). After distillation of 150 to 200 ml at atmospheric pressure, the residue was diluted with AcOiPr (100 ml) and water (50 ml). The aqueous layer was drained at 50 to 70 °C. After that, 200 ml was distilled off at atmospheric pressure while maintaining the volume constant by feeding AcOiPr (200 ml). Water (50 ml) was then added and the temperature was adjusted to 60°C. The two-phase mixture was seeded with sulfonamide 6 (prepared from a previous batch without seeding), and the slurry was cooled to 20°C over at least 1 hour. The product was isolated by filtration, and the filter cake was washed with water (25 ml) and AcOiPr (25 ml). The wet product (51 g) was dried in a vacuum cabinet at 50°C to give 1-(benzyloxycarbonyl)-4-piperidinesulfonamide 6 (42.7 g) as a colorless solid. Yield: 91.0% HPLC purity: 99.6% 1H 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)

[0426] Reaction Scheme 1 - Step (vi) [ka] Combined Cbz deprotection / ethylation was carried out using 10% Pd / C as the catalyst and water-saturated 1-butanol as the solvent. Specifically, 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (6) (2.0 g), water (4.0 ml), 1-butanol (16.0 ml), acetonitrile (0.6 ml), and 10% Pd / C (0.20 g) were placed in a Hastelloy autoclave and hydrogenated at 10-20 bar for 24 hours. The catalyst was filtered off, and the filtrate was concentrated to dryness, leaving 1-ethyl-4-piperidinesulfonamide (7) as a colorless solid. After hydrogenation at 60 °C overnight with 10-20 bar H2, clean and quantitative conversion without by-products was detected ( 1 H-NMR). 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)

[0427] Reaction Scheme 1 - Step (vi) - Alternative Procedure 1-(Benzyloxycarbonyl)-4-piperidinesulfonamide (6) (21.85 Kg) was charged to a 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 palladium hydroxide on carbon (20% by weight; 50% water) (0.66 Kg) was charged. 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 Determined by H NMR analysis, acceptance criteria ≦5.0 mol % 1-(benzyloxycarbonyl)-4-piperidinesulfonamide (6).

[0428] 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).

[0429] The reaction mixture was stirred at 15-25°C until completion. At approximately 6 hour intervals, the reaction vessel was purged with vacuum / hydrogen to remove ammonia. Completion was indicated by 1 Determined by H NMR analysis, acceptance criteria ≦5.0 mol % 4-piperidinesulfonamide.

[0430] 1 Once the acceptance criteria by H NMR analysis were met, the reaction mixture was stirred at 15-25 °C until complete by GC analysis. Acceptance criteria: ≤ 0.05% 4-piperidinesulfonamide + total area of ​​intermediates (relative retention time: 0.939 intermediate).

[0431] 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.

[0432] The filtrate was charged with activated decolorizing 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.

[0433] The filtrate was charged to a vessel, adjusted to 50-60°C, and concentrated under reduced pressure to approximately 110 L at 50-60°C. n-Butanol (89.8 kg) was charged at 50-60°C, and the mixture was concentrated under reduced pressure to approximately 110 L at 50-60°C. n-Butanol (86.9 kg) was charged at 50-60°C, and the mixture was concentrated under reduced pressure to approximately 110 L at 50-60°C. n-Butanol (88.4 kg) was charged at 50-60°C, and the mixture was concentrated under reduced pressure to approximately 90 L at 50-60°C. The supernatant of the concentrated mixture was analyzed for water content by KF analysis, with an acceptance criterion of ≤0.5% w / w water.

[0434] 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.

[0435] n-butanol content ≤ 0.5% w / w, ethanol content ≤ 0.5% w / w, and ethyl acetate content ≤ 0.5% w / w ( 1The solid was dried under a stream of nitrogen at a maximum of 60°C until the solid was 1-ethyl-4-piperidinesulfonamide (7) (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. Yield: 10.98Kg Yield: 78% 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)

[0436] 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]

[0437] Reaction Scheme 2 - Step (a) [ka] The reagent had a methanol content of less than 0.5% by GC.

[0438] DCM (385 L) and AlCl (99.86 kg) were charged to a clean, dry, 2.0 KL, glass-lined reactor at 25-30°C under a nitrogen atmosphere. The reaction mixture was cooled to -10°C. 3-Chloropropanoyl chloride (90.99 kg) was added slowly at -10 to -5°C under a nitrogen atmosphere. The reaction mixture was maintained at -10°C for 30 minutes under a nitrogen atmosphere. 2,3-Dihydro-1H-indene (8) (77.00 kg) was then added slowly to the reaction mixture at -10 to -5°C under a nitrogen atmosphere. The reaction mixture was maintained at 10-15°C for 2 hours. The absence of 2,3-dihydro-1H-indene (8) was confirmed by HPLC (limit: ≦5.0%).

[0439] After completion of the reaction, the reaction mixture was slowly added to a 6N hydrochloric acid solution (prepared from water (308 L) and concentrated hydrochloric acid (308 L)) at 0-10°C. DCM (231 L) was added, and the temperature of the reaction mixture was raised to 30-35°C. The reaction mixture was stirred at 30-35°C for 30 minutes and then allowed to stand at 30-35°C for 30 minutes. The layers were separated, and the organic layer (OL-1) was set aside. DCM (231 L) was added to the aqueous layer at 25-30°C. The reaction mixture was stirred at 25-30°C for 30 minutes and then allowed to stand at 25-30°C for 30 minutes. The layers were separated (aqueous layer (AL-1) and organic layer (OL-2)), and AL-1 was set aside. OL-1 and OL-2 were combined at 25-30°C. Demineralized water (385 L) was added to the combined organic layer. The reaction mixture was stirred for 30 minutes at 25-30° C. and allowed to stand for 30 minutes at 25-30° C. The layers were separated (aqueous layer (AL-2) and organic layer (OL-3)), and AL-2 was set aside.

[0440] A 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 at 25-30°C for 30 minutes and then allowed to stand at 25-30°C for 30 minutes. The layers were separated (aqueous layer (AL-3) and organic layer (OL-4)), and AL-3 was set aside. OL-4 was dried over anhydrous Na2SO4 (38.5 Kg), and the anhydrous Na2SO4 was washed with DCM (150 L) at 25-30°C.

[0441] The solvent was distilled under vacuum below 35-40°C until 5% remained.

[0442] n-Hexane (308 L) was charged to the reaction mixture at 35-40°C, and the solvent was completely distilled at 35-40°C until no condensed droplets formed. n-Hexane (150 L) was charged to the reaction mixture at 35-40°C, and the reaction mixture was cooled to 5-10°C and maintained at 5-10°C for 30 minutes.

[0443] The solid product was filtered, washed with chilled hexane (77 L), and dried in a hot air oven at 40-45°C for 6 hours to give 120.5 kg of 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (9). 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)

[0444] Reaction Scheme 2 - Steps (b) and (c) [ka] Sulfuric acid (300.0 L) was charged to a clean, dry, 2.0 KL, 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. The absence of 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one (9) was confirmed by HPLC (limit: ≦1.0%).

[0445] The reaction mixture was then cooled to 0-5°C. *1 was added slowly at 0-5°C, and the reaction mixture was maintained at 0-5°C for 1 hour. The 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.

[0446] Demineralized water (900.0 L) was charged to a clean, dry, 2.0 KL, glass-lined reactor at 25-30°C. The water was cooled to 0-5°C. The reaction mixture was slowly added to the reactor at 0-5°C. Toluene (480.0 L) was added, and the temperature was raised to 30-35°C. The reaction mixture was maintained at 30-35°C for 30 minutes and then allowed to 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 solid was filtered and sucked dry for 30 minutes.

[0447] The reaction mixture was charged to a clean, dry, glass-lined 2.0 KL 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 to 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.

[0448] A 5% saturated sodium bicarbonate solution (prepared from demineralized water (300.0 L) and sodium bicarbonate (15.0 kg)) was slowly charged into OL-3 at 30-35°C. The reaction mixture was stirred at 35-40°C for 30 minutes and then allowed to stand at 35-40°C for 30 minutes. The reaction mixture was 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).

[0449] The reaction mixture was charged into a 3.0 KL clean, dry, glass-lined reactor. The reaction mixture was allowed to stand at 30-35°C for 30 minutes. The layers were separated (aqueous layer (AL-3) and organic layer (OL-4)), and OL-4 was set aside.

[0450] 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. A 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 then allowed to stand at 30-35 °C for 30 minutes. The layers were separated (aqueous layer (AL-5) and organic layer (OL-7)), and OL-7 was set aside. OL-7 was dried with anhydrous Na2SO4 (9.0 Kg), and the anhydrous Na2SO4 was washed with toluene (30.0 L) at 25-30 °C. The solvent was distilled under vacuum at below 40-45 °C until 5% remained. Methanol (60.0 L) was charged to the reaction mixture at 40-45° C. and brought down to a reaction mass of 60 L.

[0451] Methanol (120.0 L) was charged to the reaction mixture at 40-45°C, and the reaction mixture was cooled to 5-10°C and held at 5-10°C for 30 minutes. 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 hours to give 38.87 kg of 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). Combined yield (11a+11b): 62.24% Weight ratio (11a:11b):9:1 HPLC purity: 95.9% Moisture content: 0.19% 1 H NMR:(500MHz,CDCl3):δ 7.44(S,1H),2.21(m,2H),2.78(t,2H),3.02(m,4H),3.13(t,2H)

[0452] *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) at 0-5°C was slowly added, and the reaction mixture was maintained at 0-5°C for 30 minutes to obtain the nitration mixture.

[0453] Reaction Scheme 2 - Step (d) [ka] 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) at 25-30 °C was charged into a 600 L clean, dry pressure reactor.

[0454] 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.

[0455] The reaction mixture was degassed under vacuum and filled with argon atmosphere (0.5 kg) three times. The reaction mixture was degassed under vacuum 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 increased 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%).

[0456] After the reaction was completed, the reaction mixture was cooled to 25-30° C. The reaction mixture was degassed under vacuum and filled with nitrogen atmosphere (0.5 Kg) three times.

[0457] The reaction mixture was filtered through a candy filter to remove Pd(OH)2, followed by a microfilter, and the bed was washed with methanol (54 L). 95% of the solvent was removed under vacuum at less than 45-50°C. Demineralized water (135 L) was charged to the reaction mixture at 25-30°C and maintained for 30 minutes. The reaction mixture was cooled to 5-10°C. The pH was adjusted to approximately 9-10 with 2N aqueous NaOH (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 to the reaction mixture, and the reaction mixture was stirred for 30 minutes. The reaction mixture was stirred for an additional 30 minutes while the temperature was raised to 25-30°C. The reaction mixture was allowed to settle for 30 minutes, maintaining the temperature at 25-30°C.

[0458] The reaction mixture was filtered through a Celite® bed (prepared using Celite® (5.4 Kg) and toluene (13.5 L). The Celite® bed was washed with toluene (54 L).

[0459] The layers were separated (aqueous layer (AL-1) and organic layer (OL-1)), and OL-1 was set aside. Toluene (54 L) was added to AL-1 at 25-30°C. The reaction mixture was stirred at 25-30°C for 30 minutes and then allowed to stand at 25-30°C for 30 minutes. The layers were separated (aqueous layer (AL-2) and organic layer (OL-2)), and AL-2 was set aside. Toluene (54 L) was added to AL-1 at 25-30°C. Brine solution (prepared 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 then allowed to stand at 25-30°C for 30 minutes.

[0460] The layers were separated (aqueous layer (AL-3) and organic layer (OL-3)), and AL-3 was set aside. Charcoal (1.3 Kg) was added to OL-3, the temperature was raised to 35-40°C, and maintained at 35-40°C for 30 minutes. The reaction mixture was filtered through a Celite® bed (prepared with 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).

[0461] The solvent was distilled under vacuum 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 hour, slowly cooled to 0-5°C, and maintained at 0-5°C for 30 minutes.

[0462] The solid product was filtered, washed with cold methanol (13.5 L), and dried in a hot air oven at 40-45°C for 6 hours to give 11.3 kg of crude 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12). 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).

[0463] *2: To prepare a 15% Pd(OH)2 slurry, 20% Pd(OH)2 on carbon (60% wet; 4.05 Kg) was added to methanol (27 L).

[0464] Purification of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) (A) Crude 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (12) (54.5 kg) was charged to a clean, dry 250 L 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 to the reaction mixture at 25-30°C. The reaction mixture was stirred at 25-30°C for 30 minutes, cooled to -5-0°C, and stirred at -5-0°C for 30 minutes. The solid product was filtered, washed with cold methanol (54.5 L), and dried at 40-45°C for 6 hours to yield 40.5 kg of purified 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (12). 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).

[0465] Crop purification of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) (B) The filtered mother liquors from the five batches of Reaction Scheme 2, step (d) 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).

[0466] The pure fractions were concentrated under reduced pressure (600 mm Hg) at 40-45°C to give crude 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12) (15 Kg).

[0467] Toluene (7.5 L) was added at 25-30°C, and the reaction mixture was stirred at 25-30°C for 30 minutes. Methanol (45 L) was added at 25-30°C, and the reaction mixture was stirred at 25-30°C for 30 minutes. The reaction mixture was cooled to -5-10°C and stirred for 30 minutes. Purity was confirmed using HPLC (limit 98%, single maximum purity: NMT: 1%).

[0468] The solid was filtered, washed with cold methanol (15 L), and dried in a vacuum tray dryer at 40-45° C. for 6 hours to give 10.2 kg of purified 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12). 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 (d), including purification (A) and crop purification (B): 46.56%

[0469] Reaction Scheme 2 - Step (e) [ka] 1,2,3,5,6,7-Hexahydro-s-indacen-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 between 0-10°C (line rinse with THF (6.78 kg) at 0-10°C). The temperature was maintained between 0-5°C.

[0470] Phenyl chloroformate (7.44 Kg) dissolved in THF (6.74 Kg) was charged to the reactor over a minimum of 1 hour while maintaining the temperature between 0-10°C to form a slurry (line rinse with THF (6.66 Kg) at 0-10°C). The temperature of the reaction mixture was raised to 15-25°C and stirred until completion. 1 The pass criteria was ≦1.0 mol% 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (12), as determined by H NMR analysis.

[0471] The temperature of the reaction mixture was raised 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 between 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 between 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 between 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 charging and concentration was repeated until analysis by H NMR was passed, with a pass criterion of ≦0.5% w / w THF (relative to product).

[0472] Absolute ethanol (30.12 kg) was charged to the reaction mixture between 15 and 40°C. The reaction mixture was cooled to 0 to 5°C and stirred for 45 to 90 minutes. The solid was filtered at 0 to 5°C onto a 20 μm filter cloth. The solid was washed with absolute ethanol (11.72 kg and 12.00 kg) at 0 to 5°C and pumped onto the filter under a nitrogen purge for 30 to 90 minutes.

[0473] The solid was identified and analyzed by HPLC. Acceptance criteria: ≦0.5% DIPEA.HCl (based on the product). The solid was dried under vacuum at up to 50° C. under a nitrogen stream until the ethanol content was ≦0.5% w / w, yielding 11.78 kg of 4-(phenoxycarbonylamino)-1,2,3,5,6,7-hexahydro-s-indacene (13). Yield: 93% HPLC purity: 99.6%

[0474] 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (potassium salt) (14) 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (potassium salt) (14) can be reacted with 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)piperidine-4-sulfonamide (potassium salt) according to Reaction Scheme 3: [ka] It was prepared according to the reaction sequence shown in

[0475] 1-Ethyl-4-piperidinesulfonamide (7) (7.85 kg) was charged to a vessel. Dimethyl sulfoxide (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 a 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), maintaining the temperature at 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).

[0476] 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 Analyze for completion by H NMR. Acceptance criteria: ≦5.0 mol % 1-ethyl-4-piperidinesulfonamide (7), consecutively obtain acceptable samples.

[0477] The reaction mixture was weighed into a separate vessel and then returned to the vessel using a line rinse of dimethyl sulfoxide (17.2 Kg). The mixture was stirred and adjusted to 20-25°C. The water content was analyzed by KF.

[0478] Acetonitrile (62.0 Kg) was charged to the vessel over at least 30 minutes while maintaining the temperature at 20-25°C. Water (3.00 Kg) was charged to the vessel over 2-3 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 at least 1 hour (target 1-2 hours), stirred at 0-5°C for at least 1 hour (target 1-4 hours), filtered at 0-5°C through 1-2 μm cloth, and the filter cake was washed at 0-5°C with a premix (6:13:0.4) dimethyl sulfoxide / acetonitrile / water (5.34 Kg:8.32 Kg:0.31 Kg).

[0479] The solids were dried under vacuum for approximately 2 hours until suitable for handling and the filter cake was analyzed for moisture content by KF, acceptance criteria ≦5.5% w / w.

[0480] 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.

[0481] The solid was dried under a nitrogen stream at a maximum of 50°C and analyzed by KF for residual water content. Acceptance criteria: ≦2.8% w / w water. 1 The solid was analyzed for residual DMSO levels by H NMR. The pass criterion was ≦12.2% w / w DMSO. 1 The residual acetonitrile level was analyzed by H NMR. Acceptance criteria was ≦2.0% w / w MeCN. The dry weight of the crude solid was determined and identified. 1 Analysis was performed using H NMR spectroscopy and HPLC. 13.95 kg of crude 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-carbamoyl)piperidine-4-sulfonamide (potassium salt) (14) was obtained. Yield: 80% NMR purity: 97.3%

[0482] Preparation 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 reaction vessel. Methanol (116.4 kg) was charged to the vessel and stirred for 10-20 minutes (until a homogeneous, cloudy solution was formed with no solid lumps 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 approximately 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 about 35° C. or less. 1 Analyzed for residual methanol content by H NMR. Acceptance criteria: ≦3.0% w / w methanol.

[0483] 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 over 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.

[0484] The wet filter cake was analyzed for residual phenol by HPLC. Pass criteria: ≦0.20% area phenol. The solid was dried under a nitrogen stream at a maximum of 50° C. for at least 2 hours and analyzed for residual moisture content using KF. Pass criteria: ≦2.0% w / w. Drying continued as the sample was analyzed.

[0485] Solid 1 The solid was analyzed for residual acetonitrile by H NMR. Acceptance criteria: ≤ 0.2% w / w MeCN. 1 Residual DMSO was analyzed by H NMR. Acceptance criteria: ≦0.4% w / w DMSO. The solid was analyzed for residual solvent levels by GC. Acceptance criteria: ≦3750 ppm DMSO, ≦2250 ppm MeOH, and ≦308 ppm MeCN. 14.42 kg of purified 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-carbamoyl)piperidine-4-sulfonamide (potassium salt) (14) was obtained. Yield: 98% HPLC purity: 99.5%

Claims

1. A process for preparing a thiourea adduct (I) or a salt thereof, comprising the steps of converting an N-protected-4-derivatized piperidine (H) into said thiourea adduct (I) or a salt thereof: 【Chemistry 1】 Including, During the ceremony: R ２ is a nitrogen protecting group; R ３ is a leaving group; and Each R ４ are independently hydrogen or C １ -C ２０ hydrocarbyl groups, wherein each C １ -C ２０ The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C １ -C ２０ The hydrocarbyl groups may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C １ -C ２０ The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or any two or more R ４ may be taken together with the atom(s) to which they are attached to form a 3- to 16-membered heterocyclic group, which may be monocyclic, bicyclic or tricyclic, and which may contain one or more halo groups and / or one or more groups R ４０ and each R ４０ is -CN, -OH, -NH ２ , oxo (=O), =NH or C １ -C ６ hydrocarbyl groups, each C １ -C ６ The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C １ -C ６ The hydrocarbyl group may be optionally substituted with one or more halo groups, and each C １ -C ６ The hydrocarbyl group may optionally contain one or more heteroatoms independently selected from N, O and S in its carbon skeleton.

2. R ２ 10. The process of claim 1, wherein is a nitrogen protecting group that can be removed by catalytic hydrogenolysis.

3. R ２ But -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 each R ２１ But C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C ３ -C ４ Cycloalkyl or C ３ -C ４ halocycloalkyl groups or any two R directly attached to the same nitrogen atom ２１ Together they form C ２ -C ５ Alkylene or C ２ -C ５ may form a haloalkylene group, R ２０ The process of claim 1 or claim 2, wherein contains 1 to 20 carbon atoms including any optional substituents.

4. R ２ Ga-COOCH ２ The process according to any one of claims 1 to 3, wherein the hydroxybenzoate is Ph.

5. R ３ The process of any one of claims 1 to 4, wherein is a sulfonate leaving group such as -OMs.

6. Each R ４ are independently hydrogen or C １ -C ６ Alkyl or C ３ -C ６ cycloalkyl groups, or any two R ４ Together they form C ２ -C ６ may form an alkylene group, １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl or C ２ -C ６ The process of any one of claims 1 to 5, wherein the alkylene group is optionally fluoro-substituted.

7. Each R ４ The process of any one of claims 1 to 6, wherein is hydrogen.

8. The N-protected-4-derivatized piperidine (H) can be reacted with reagents (IX): 【Chemistry 2】 8. The process of any one of claims 1 to 7, comprising contacting with, optionally in the presence of a base and / or a solvent,

9. contacting benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (H') with reagent (I-Xb) in a solvent to obtain benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I') or a salt thereof; 【Transformation 3】 The process according to any one of claims 1 to 8, comprising:

10. The process of any one of claims 1 to 9, wherein the thiourea adduct (I) or (I') is obtained as a methanesulfonate salt.

11. The N-protected-4-derivatized piperidine (H) or (H′) can be prepared by the following steps: (i) converting 4-hydroxypiperidine (F) into N-protected-4-hydroxypiperidine (G): 【Chemistry 4】 (ii) converting the N-protected-4-hydroxypiperidine (G) to the N-protected-4-derivatized piperidine (H): 【Transformation 5】 The process according to any one of claims 1 to 10, wherein the process is obtained by

12. A process for preparing an N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof, comprising the steps of converting a thiourea adduct (I) into said N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof: 【Transformation 6】 Including, During the ceremony: R ２ is a nitrogen protecting group; Each R ４ are independently hydrogen or C １ -C ２０ hydrocarbyl groups, wherein each C １ -C ２０ The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C １ -C ２０ The hydrocarbyl groups may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C １ -C ２０ The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or any two or more R ４ may be taken together with the atom(s) to which they are attached to form a 3- to 16-membered heterocyclic group, which may be monocyclic, bicyclic or tricyclic, and which may contain one or more halo groups and / or one or more groups R ４０ and each R ４０ is -CN, -OH, -NH ２ , oxo (=O), =NH or C １ -C ６ hydrocarbyl groups, each C １ -C ６ The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C １ -C ６ The hydrocarbyl group may be optionally substituted with one or more halo groups, and each C １ -C ６ The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S; and The process wherein Hal is Cl or Br.

13. R ２ 13. The process of claim 12, wherein is a nitrogen protecting group that can be removed by catalytic hydrogenolysis.

14. R ２ But -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 each R ２１ But C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C ３ -C ４ Cycloalkyl or C ３ -C ４ halocycloalkyl groups or any two R directly attached to the same nitrogen atom ２１ Together they form C ２ -C ５ Alkylene or C ２ -C ５ may form a haloalkylene group, R ２０ The process of claim 12 or claim 13, wherein contains 1 to 20 carbon atoms inclusive of any optional substituents.

15. R ２ Ga-COOCH ２ The process according to any one of claims 12 to 14, wherein the hydroxybenzoate is Ph.

16. Each R ４ are independently hydrogen or C １ -C ６ Alkyl or C ３ -C ６ cycloalkyl groups, or any two R ４ Together they form C ２ -C ６ may form an alkylene group, １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl or C ２ -C ６ The process of any one of claims 12 to 15, wherein the alkylene group is optionally fluoro-substituted.

17. Each R ４ The process of any one of claims 12 to 16, wherein is hydrogen.

18. The process of any one of claims 12 to 17, wherein Hal is Cl.

19. 19. The process of any one of claims 12 to 18, comprising contacting the thiourea adduct (I) with a halogenating agent, such as N-chlorosuccinimide, to form the N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof.

20. 20. The process of claim 19, wherein the thiourea adduct (I) is contacted with the halogenating agent in the presence of a carboxylic acid, such as acetic acid, water, and optionally a second acid selected from HCl or HBr.

21. contacting benzyl 4-(carbamimidoylthio)-piperidine-1-carboxylate (I') with a chlorinating agent to obtain benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (J') or a salt thereof; 【Transformation 7】 21. The process of claim 19 or claim 20, comprising:

22. The process of any one of claims 12 to 21, wherein the thiourea adduct (I) or (I') is obtained by the process of any one of claims 1 to 11.

23. The following steps: (v) converting the N-protected-4-(halosulfonyl)-piperidine (J) or (J') into N-protected-4-piperidinesulfonamide (K): 【Transformation 8】 (vi) optionally, converting the N-protected-4-piperidinesulfonamide (K) to 1-ethyl-4-piperidinesulfonamide (A): 【Chemistry 9】 The process of any one of claims 12 to 22, further comprising:

24. One or more steps selected from the following: (i) converting 4-hydroxypiperidine (F) into N-protected-4-hydroxypiperidine (G): 【Chemistry 10】 The conversion is carried out in a two-phase solvent system; (ii) converting N-protected-4-hydroxypiperidine (G) to N-protected-4-derivatized piperidine (H): 【Chemistry 11】 The conversion is carried out in the presence of a non-polar solvent; (iii) converting the N-protected-4-derivatized piperidine (H) into the thiourea adduct (I): 【Chemistry 12】 (iv) converting the thiourea adduct (I) into N-protected-4-(halosulfonyl)-piperidine (J): 【Chemistry 13】 (v) converting N-protected-4-(halosulfonyl)-piperidine (J) into N-protected-4-piperidinesulfonamide (K): 【Chemistry 14】 The conversion comprises the steps of: (1) forming a solution of ammonia in a solvent; and (2) adding the N-protected-4-(halosulfonyl)-piperidine (J) to the solution formed in step (1); and (vi) Converting N-protected-4-piperidinesulfonamide (K) into 1-ethyl-4-piperidinesulfonamide (A): 【Chemistry 15】 The transformation is ３ -C ５ carried out in the presence of alcohol; Including, and wherein: R ２ is a nitrogen protecting group; R ３ is a leaving group; Each R ４ are independently hydrogen or C １ -C ２０ hydrocarbyl groups, wherein each C １ -C ２０ The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C １ -C ２０ The hydrocarbyl groups may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C １ -C ２０ The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or any two or more R ４ may be taken together with the atom(s) to which they are attached to form a 3- to 16-membered heterocyclic group, which may be monocyclic, bicyclic or tricyclic, and which may contain one or more halo groups and / or one or more groups R ４０ and each R ４０ is -CN, -OH, -NH ２ , oxo (=O), =NH or C １ -C ６ hydrocarbyl groups, each C １ -C ６ The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C １ -C ６ The hydrocarbyl group may be optionally substituted with one or more halo groups, and each C １ -C ６ The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S; and The process wherein Hal is Cl or Br.

25. a step of contacting the 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; 【Chemistry 16】 wherein X is a leaving group.

25. The process of claim 23 or claim 24, further comprising:

26. 26. 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 claim 25.

27. Thiourea adduct (I) or a salt thereof, 【Chemistry 17】 During the ceremony: R ２ is a nitrogen protecting group; and Each R ４ are independently hydrogen or C １ -C ２０ hydrocarbyl groups, wherein each C １ -C ２０ The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C １ -C ２０ The hydrocarbyl groups may be optionally substituted with one or more oxo (=O) and / or one or more halo groups, and each C １ -C ２０ The hydrocarbyl group may optionally contain one or more heteroatoms in its carbon skeleton independently selected from N, O and S, or any two or more R ４ may be taken together with the atom(s) to which they are attached to form a 3- to 16-membered heterocyclic group, which may be monocyclic, bicyclic or tricyclic, and which may contain one or more halo groups and / or one or more groups R ４０ and each R ４０ is -CN, -OH, -NH ２ , oxo (=O), =NH or C １ -C ６ hydrocarbyl groups, each C １ -C ６ The hydrocarbyl group may be linear or branched, or may be or contain one or more cyclic groups, and each C １ -C ６ The hydrocarbyl group may be optionally substituted with one or more halo groups, and each C １ -C ６ The thiourea adduct (I) or a salt thereof, wherein the hydrocarbyl group may optionally contain one or more heteroatoms independently selected from N, O and S in its carbon skeleton.

28. R ２ Ga-COOCH ２ Ph, and each R ４ 28. The thiourea adduct (I) or a salt thereof according to claim 27, wherein is hydrogen.

29. A compound selected from the group consisting of: (i) N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof: [Chemistry 18] In the formula, R ２ is a nitrogen protecting group and Hal is Cl or Br; or (ii) N-protected-4-piperidinesulfonamide (K) or a salt thereof: 【Chemistry 19】 In the formula, R ２ is a nitrogen protecting group, A compound selected from the group consisting of:

30. R ２ Ga-COOCH ２ 30. The compound of claim 29, wherein Ph is Hal and Hal, if present, is Cl.

31. (i) the N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof is in solid form; and / or (ii) the N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof has an HPLC purity of 90% or more; and / or (iii) The compound according to claim 29 or 30, wherein the N-protected-4-piperidinesulfonamide (K) or a salt thereof has an HPLC purity of 96.2% or more.

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