Process for the synthesis of (r)-n-hydroxy-2-((4-(4-(methylcarbamoyl)phenoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decane-2-carboxamide and intermediates thereof

Abstract

The present invention relates to a process for the synthesis of the anti-haemorrhagic agent (R)-N-hydroxy-2-((4-(4-(methylcarbamoyl)phenoxy)phenyl)-sulfonyl)-8- azaspiro[4.5]decane-2-carboxamide and intermediates thereof. The invention also relates to a process for the preparation of a synthetic intermediate of said anti- haemorrhagic agent, (R)-8-(tert-butoxycarbonyl)-2-((4-fluorophenyl)sulfonyl)-8- azaspiro[4.5]decane-2-carboxylic acid and intermediates thereof.

Description

[0001] PROCESS FOR THE SYNTHESIS OF (R)-N-HYDROXY-2-((4-(4- (METHYLCARBAMOYL)PHENOXY)PHENYL)SULFONYL)-8- AZASPIRQ[4.51DECANE-2-CARBOXAMIDE AND INTERMEDIATES THEREOF

[0002] FIELD OF THE INVENTION

[0003]

[0001] The present invention relates to a process for the synthesis of the anti- haemorrhagic agent (R)-N-hydroxy-2-((4-(4-(methylcarbamoyl)phenoxy)phenyl)- sulfonyl)-8-azaspiro[4.5]decane-2-carboxamide and intermediates thereof. The invention also relates to a process for the preparation of a synthetic intermediate of said anti-haemorrhagic agent, (R)-8-(terf-butoxycarbonyl)-2-((4-fluorophenyl)sulfonyl)-8- azaspiro[4.5]decane-2-carboxylic acid and intermediates thereof.

[0004] BACKGROUND

[0005]

[0002] (R)- / V-hydroxy-2-((4-(4-(methylcarbamoyl)phenoxy)phenyl)sulfonyl)-8-azaspiro- [4.5]decane-2-carboxamide, also called CM-352 and herein referred to as compound of formula (V), is an inhibitor of matrix metalloprotease useful as anti-haemorrhagic agent thanks to its ability to inhibit fibrinolysis. This compound has the following molecular formula

[0006] This compound and its anti-haemorrhagic activity are disclosed in Orbe, J. et al, J. Med. Chem. 2015, 58, 7, 2941-2957 and in WO 2014 / 012964 A1.

[0007]

[0003] Various synthetic routes have been disclosed in the art for the preparation of this compound. In this regard, WO 2014 / 012964 A1 discloses the synthesis of the same compound (referred to therein as 1-08), obtained as a racemic mixture of enantiomers according to the following synthetic scheme, starting from a key carboxylic acid intermediate of formula (I a):

[0008] The carboxylic acid synthetic intermediate employed for this synthesis was prepared according to the following synthetic scheme:

[0009] Said patent application also discloses that the (R) enantiomer of the compound of formula (V) can be obtained by separation of enantiomers of said compound from a racemic mixture of the compounds by supercritical fluid chiral chromatography.

[0010]

[0004] An identical route of synthesis of the carboxylic acid intermediate (IVa) is disclosed in WO 2015 / 104343 A1 , in De Miguel, I. et al. ACS Med. Chem. Lett. 2018, 9, 5, 428-433 and in Orbe, J. et al. J. Med. Chem. 2015, 58, 5, 2465-2488.

[0011]

[0005] Orbe, J. et al, J. Med. Chem. 2015, 58, 7, 2941-2957 discloses the same synthetic route as WO 2014 / 012964 A1 and further discloses that the synthesis of the (R)-enantiomer of the compound of formula (V) may be carried out from the enantiomerically enriched carboxylic acid synthetic intermediate (IVa) with no substantial racemization of the quaternary chiral carbon atom. In this aspect, said enantiomerically enriched carboxylic acid synthetic intermediate is obtained by supercritical fluid chiral chromatography separation of enantiomers of the carboxylic acid intermediate.

[0012]

[0006] The disclosed procedures for the preparation of the compound of formula (V), and in particular of the carboxylic acid synthetic intermediate (IVa) present several drawbacks. For instance, the starting material for this synthesis, that is 8-(tert- butoxycarbonyl)-8-azaspiro[4.5]decane-2-carboxylic acid (IVa), represents an expensive reagent that is available in limited amounts from commercial suppliers.

[0013]

[0007] From what is disclosed in the art, it derives that there is still a need for alternative procedures for the preparation of a product of formula (V) and intermediates thereof, in particular for procedures employing starting materials which are inexpensive and available in large amounts from commercial suppliers.

[0014] SUMMARY OF THE INVENTION

[0015]

[0008] After exhaustive research, the inventors have developed a novel process for the synthesis of the compound of formula (V).

[0016]

[0009] Said synthesis goes through the preparation of the carboxylic acid intermediate (IV) which advantageously allows building the spirocyclic scaffold of this compound and thus eliminates the need to use commercial reagents comprising said spirocyclic scaffold, which in turn presents advantages in terms of price and availability at scale of these reagents. The process developed by the inventors comprises as a key step the formation of the spirocyclic structure by a double cyclization step involving the reaction of a compound of formula (I) with a compound of formula (II)

[0017] (I) (H)

[0010] Thus, a first aspect of the invention relates to a process for the preparation of a compound of formula (IV) wherein R is F or 4-(methylcarbamoyl)phenyloxy; said process comprising the steps of:

[0018] (i) causing a compound of formula (I) to react with a compound of formula (II)

[0019] (I) (H) to form a compound of formula (III); wherein PG is an amine protecting group; each LG is a leaving group and Ri is a linear or branched (Ci-C6)alkyl chain; wherein, when in the compound of formula (IV) R is 4- (methylcarbamoyl)phenyloxy, a further step (ii) is carried out whereby a compound of formula (III) is caused to react with 4-hydroxy-N-methylbenzamide to form a compound of formula (III’)

[0020] (iii) causing the compound of formula (III) or the compound of formula (III’) to react in hydrolysis conditions to form a compound of formula (IV).

[0021]

[0011] The compound of formula (IV) is particularly useful in the synthesis of a compound of formula (V) as defined above. Thus, a second aspect of the invention relates to a process for the preparation of a compound of formula (V) said process comprising the steps of:

[0022] (i) preparing a compound of formula (IV) or a compound of formula (IV’) according to the process of the first aspect of the invention;

[0023] (ii) converting the compound of formula (IV) or the compound of formula (IV’) in the compound of formula (V).

[0024]

[0012] Specific synthetic intermediates also form part of the invention. A third aspect of the invention thus relates a compound of formula (I’) or a salt thereof, wherein PG is an amine protecting group selected from the group consisting of benzyl, p-methoxybenzyl, a group of formula -SO2R3’ and a group of formula -C(=O)OR3, wherein R3 is selected from the group consisting of tert-butyl, benzyl, allyl and fluorenyl; and wherein R3’ is selected from the group consisting of p-tolyl, phenyl optionally substituted with one or two nitro groups and trifluoromethyl; and provided that when PG is te / Y-butoxycarbonyl or benzyloxycarbonyl and each LG represents the same group, LG is other than methylsulfonate.

[0025] DETAILED DESCRIPTION

[0026]

[0013] All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition.

[0027]

[0014] For the purposes of the invention, any ranges given include both the lower and the upper end-points of the range. Ranges given, such as temperatures, times, molar ratio, volume ratio and the like, should be considered approximate (i.e. with a 5% margin of variation around indicated point), unless specifically stated.

[0028]

[0015] In the context of the present invention, the term “alkyl” refers to a saturated hydrocarbon chain that is linear or branched and comprises the number of carbon atoms specified in the description and in the claims. Examples of alkyl groups include, for instance, methyl, ethyl, propyl, / so-propyl, butyl, terf-butyl, pentyl and hexyl.

[0029]

[0016] In the context of the present invention, the term “alkoxy” refers to an alkyl group as defined above that is attached to the remainder part of the molecule to which it belongs through an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, and tert-butyloxy.

[0030]

[0017] In the context of the present invention, the term “haloalkyl” refers to an alkyl group as defined above wherein at least one hydrogen atom is replaced by a halo group, said halo group being selected from fluoro, chloro, bromo and iodo. In particular embodiments, the term “haloalkyl” represents an alkyl group wherein all the hydrogen atoms are replaced by a halo group, said halo group being preferably a fluoro group.

[0031]

[0018] In the context of the present invention, the term “catalytically effective amount” refers to the amount of a given substance used as catalyst that is sufficiently high to accelerate a chemical reaction between two components, taking as reference the same reaction carried out in the absence of said catalyst, and said substance being kept intact during the chemical transformation, such that it can be used in sub-stoichiometric amount. This amount is typically determined by the needs of the particular reaction and may vary depending on factors such as the nature of the reactants, the type of catalyst, the desired rate of reaction, and the specific conditions of the reaction.

[0032]

[0019] In the context of the present invention, the term “enantiomerically enriched compound” refers to a compound that exists in two enantiomeric forms and characterized in that one of the enantiomers is present in a larger amount than the other. A common parameter to measure said enantiomeric enrichment is provided by the enantiomeric excess, which is expressed as a percentage and is calculated as the ratio of the difference of the amounts of each enantiomer to the sum of the amounts of each enantiomer in a mixture of said enantiomers. In preferred embodiments of the invention, the term “enantiomerically enriched compound” refers to a compound having an enantiomeric excess of at least 50%; preferably of at least 80%; more preferably of at least 95% and even more preferably of at least 98% or of at least 99%.

[0033]

[0020] In the context of the present invention, the term “resolution of a compound”, when applied to a compound that possesses a chiral center, refers to a process through which an enantiomerically enriched compound is provided from a mixture of enantiomers of said compound, in particular from a racemic mixture of said compound. Methods for resolving mixtures of enantiomers are well-known in the art and include, for instance, separation (e.g. by chiral chromatography), fractional crystallization (e.g. through the formation of diastereomeric salts), kinetic or enzymatic resolution, covalent linkage of a chiral auxiliary and separation of formed diastereomers, among others.

[0034]

[0021] A first aspect of the invention relates to a process as defined above.

[0022] In an embodiment of the first aspect, the invention relates to a process for the preparation a compound of formula (IV) said process comprising the steps of

[0035] (i) causing a compound of formula (I) to react with a compound of formula (II)

[0036] (I) (II) to form a compound of formula (III); wherein PG is an amine protecting group; each LG is a leaving group and Ri is a linear or branched (Ci-C6)alkyl chain; and

[0037] (ii) causing the compound of formula (III) to react in hydrolysis conditions to form a compound of formula (IV).

[0038]

[0023] The compound of formula (I) of the invention is one wherein LG is a leaving group. Suitable leaving groups are those employed in nucleophilic substitution reactions; such groups will become apparent to the skilled person on the basis of common general knowledge and include, for instance, halo groups and sulfonate groups. Thus, in preferred embodiments, each LG is independently selected from the group consisting of chloro, bromo, iodo and a group of formula -OSO2R2; wherein R2 is selected from the group consisting of linear or branched (Ci-C6)alkyl chain, a linear or branched (C1- Ce)haloalkyl chain and a phenyl group optionally substituted at any available position with a linear or branched (Ci-Ce)alkyl chain.

[0039]

[0024] In more preferred embodiments, each LG in the compound of formula (I) is selected from the groups consisting of chloro, bromo, iodo, methylsulfonato and trifluoromethylsulfonato.

[0040]

[0025] Even more preferably, each LG in the compound of formula (I) is bromo or methylsulfonato.

[0041]

[0026] In particular embodiments, each LG in the compound of formula (I) is a bromo group.

[0042]

[0027] In particular embodiments, each LG in the compound of formula (I) is a methylsulfonato group.

[0043]

[0028] The compound of formula (I) of the process of the invention is also one wherein PG is an amine protecting group. Such amine protecting groups are well known in the art and will become apparent to the skilled person upon reduction to practice of the invention. Such groups are disclosed for instance in Greene's Protective Groups in Organic Synthesis, Chapter 7, 2007, Wiley & Sons, ISBN:9780471697541 , the content of which is incorporated herein by reference.

[0044]

[0029] In preferred embodiments, PG is selected from the group consisting of benzyl, p- methoxybenzyl, carbamate protecting groups and sulfonamide protecting groups.

[0045]

[0030] In preferred embodiments, PG is selected from the group consisting of benzyl, p- methoxybenzyl, a group of formula -SO2R3’ and a group of formula -C(=O)OR3, wherein R3 is selected from the group consisting of tert-butyl, benzyl, allyl and fluorenyl; and wherein R3’ is selected from the group consisting of p-tolyl, phenyl optionally substituted with one or two nitro groups (e.g. 2-nitrophenyl, 2,4-dinitrophenyl) and trifluoromethyl.

[0046]

[0031] In preferred embodiments, PG represents an amine protecting group selected from the group consisting of benzyl and a group of formula -C(=O)OR3, wherein R3 is selected from the group consisting of tert-butyl, benzyl, allyl and fluorenyl.

[0047]

[0032] In more preferred embodiments, PG represents a carbamate protecting group, such as a tert-butyloxycarbonyl group (Boc). This protecting group is particularly suitable as it is removed in a straight forward manner by treatment of the protected amine in acidic medium. Other protecting groups which may be removed in similar conditions are also suitable.

[0048]

[0033] Noteworthy, and as will be obvious to the skilled person, the choice of PG in the compound of formula (I) determines the nature of PG in compounds prepared from the compound of formula (I), as is the case of the compounds of formulae (II), (IV), (VI), (VII), (VIII) and (IX) defined herein.

[0049]

[0034] In further preferred embodiments, the compound of formula (I) is one wherein each LG is independently selected from the group consisting of chloro, bromo, iodo and a group of formula -OSO2R2; wherein R2 is selected from the group consisting of linear or branched (Ci-C6)alkyl chain, a linear or branched (Ci-C6)haloalkyl chain and a phenyl group optionally substituted at any available position with a linear or branched (Ci- Ce)alkyl chain and

[0050] PG represents an amine protecting group selected from the group consisting of benzyl and a group of formula -C(=O)OR3, wherein R3 is selected from the group consisting of tert-butyl, benzyl, allyl and fluorenyl.

[0051]

[0035] More preferably, the compound of formula (I) is one wherein each LG is bromo and PG is tert-butoxycarbonyl.

[0052]

[0036] More preferably, the compound of formula (I) is one wherein each LG is methylsulfonato and PG is tert-butoxycarbonyl.

[0053]

[0037] The compound of formula (II) is preferably one wherein R1 is selected from the group consisting of methyl, ethyl and tert-butyl. Preferably, the compound of formula (II) is one wherein R1 is a methyl group. In another preferred embodiment, the compound of formula (II) is one wherein R1 is a ethyl group.

[0054]

[0038] Step (i) of the process of the first aspect of the invention is preferably carried out in the presence of a base. Said base should be suitable for neutralizing the conjugated acid of each LG group in the compound of formula (I).

[0055]

[0039] In preferred embodiments, step (i) of the process of the first aspect of the invention is carried out in the presence of a base selected from the group consisting of alkali salts of carbonate and alkali salts of (Ci-Cejalkoxide; preferably the base is an alkali salt of carbonate.

[0056]

[0040] In more preferred embodiments, step (i) of the process of the first aspect of the invention is carried out in the presence of a base that is potassium carbonate.

[0057]

[0041] In more preferred embodiments, step (i) of the process of the first aspect of the invention is carried out in the presence of a base that is cesium carbonate.

[0058]

[0042] The base used in step (i) is preferably present in an amount suitable for neutralizing the conjugated acid of each LG group in the compound of formula (I). Such amount may be for instance of at least two moles of base per each mole of the compound of formula (I). More preferably, the base is present in an amount of from 2 to 8 moles of base per each mole of the compound of formula (I); even more preferably of 5 moles of base per each mole of the compound of formula (I).

[0059]

[0043] Step (i) is preferably one wherein the molar ratio of compound of formula (II) to compound of formula (I) is between 1 :1 and 1.5; preferably of 1 :1 or 1 :1.3.

[0060]

[0044]

[0061]

[0045] In preferred embodiments, step (i) of the process of the invention is carried out in an aprotic solvent. Such solvents are particularly suitable for nucleophilic substitution reactions. Suitable solvents thus include, / V, / V-dimethylformamide, acetonitrile, dimethylsulfoxide, / V-methylpyrrolidone, tetrahydrofurane, toluene, methyltetrahydrofurane, 1 ,4-dioxane and hexamethylphosphoramide. More particularly, step (i) of the process of the invention may be carried out in a solvent selected from the group consisting of / V, / V-dimethylformamide, dimethylsulfoxide, tetrahydrofurane, toluene, methyltetrahydrofurane, / V-methylpyrrolidone and hexamethylphosphoramide; preferably, the solvent is / V, / V-dimethylformamide or methyltetrahydrofurane.

[0062]

[0046] In further preferred embodiments, step (i) of the process of the invention is carried out in the presence of a catalytically effective amount of a nucleophilic catalyst. Suitable nucleophilic catalysts include among others, inorganic salts (e.g. alkaline iodide salts such as potassium iodide), tetraalkylammonium iodide salts, / V, / V-dimethylaminopyridine (DMAP), 1 ,4-diazabicyclo[2.2.2]octane (DABCO), 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine, 1 ,5-diazabicyclo[4.3.0]non-5-ene (DBN), triazabicycodecene (TBD) and pyridine. Preferably, said nucleophilic catalyst is N,N- dimethylaminopyridine (DMAP).

[0063]

[0047] The nucleophilic catalyst of step (i) is preferably present in an amount of from 1 to 10 moles per each mole of compound of formula (I); more preferably of 5 moles per each 100 moles of compound of formula (I).

[0064]

[0048] It has been however found that the reaction may be carried out in the absence of said nucleophilic catalyst. This is particularly the case when step (i) is carried out in methyltetrahydrofurane and / or in the presence of a base that is cesium carbonate.

[0065]

[0049] In further preferred embodiments, step (i) of the process of the invention is carried out in the presence of a catalytically effective amount of a phase transfer agent, that may be selected from the group constisting of a tetraalkylammonium salt of a halide, a phosphonium organic salt and a crown ether. Phase transfer agents for chemical synthesis are well known in the art and will become apparent to the skilled person upon reduction to proactice of the invention. Suitable tetraalkylammonium salts include bromide salts of a cation of formula+NRaRbRcRd, wherein each one of Ra, Rb, Rcand Rd is independently a (Ci-Ce)alkyl group. More preferably, step (i) of the process of the invention is carried out in the presence of a catalytically effective amount of tetrabutylammonium bromide. It is believed that said phase transfer agent promotes the solubilisation of the base and of the formed intermediate enolate species, thus providing for a faster reaction.

[0066]

[0050] The phase transfer agent of step (i) is preferably present in an amount of from 1 to 10 moles per each mole of compound of formula (I); more preferably of 5 moles per each 100 moles of compound of formula (I).

[0067]

[0051] It has been however found that the reaction may be carried out in the absence of said phase transfer agent. This is particularly the case when step (i) is carried out in methyltetrahydrofurane and / or in the presence of a base that is cesium carbonate.

[0068]

[0052] In a preferred embodiment, step (i) of the process of the invention is one wherein the compound of formula (I) is a compound of formula (Ia1)

[0069] Boc i

[0053] In another preferred embodiment, step (i) of the process of the invention is one wherein the compound of formula (I) is a compound of formula (Ib1)

[0070]

[0054] In a preferred embodiment, preferably when the compound of formula (I) is a compound of formula (Ia1), step (i) of the process of the invention is carried out in the presence of:

[0071] - potassium carbonate;

[0072] - a catalytically effective amount of (i) N,N-dimethylaminopyridine and (ii) tetrabutylammonium bromide; and

[0073] - a polar aprotic solvent that is preferably N,N-dimethylformamide.

[0074]

[0055] In a more preferred embodiment, preferably when the compound of formula (I) is a compound of formula (I a1 ) , step (i) of the process of the invention is one wherein the compound of formula (I) is a compound of formula (Ia1) as defined above and is carried out in the presence of:

[0075] - potassium carbonate;

[0076] - a catalytically effective amount of (i) N,N-dimethylaminopyridine and (ii) tetrabutylammonium bromide; and

[0077] - a polar aprotic solvent that is preferably N,N-dimethylformamide.

[0078]

[0056] In a preferred embodiment, preferably when the compound of formula (I) is a compound of formula (Ib1), step (i) of the process of the invention is carried out in the presence of:

[0079] - cesium carbonate; and

[0080] - an aprotic solvent that is preferably methyltetrahydrofuran.

[0081]

[0057] Step (i) of the process of the first aspect of the invention is preferably carried out at a temperature comprised between 50 °C and 100 °C.

[0082]

[0058] When in the compound of formula (I), R is 4-(methylcarbamoyl)phenyloxy, a further step (ii) is carried out whereby a compound of formula (III) is caused to react with 4-hydroxy-N-methylbenzamide to form a compound of formula (III’)

[0083]

[0059] Step (ii) is preferably carried out in the presence of a base, such an alkali carbonate salt and / or by heating a solution of the compound of formula (III) and 4- hydroxy-N-methylbenzamide at a temperature of between 100 °C and 150 °C. Accordingly, this step is preferably carried out in a polar aprotic solvent selected from / V, / V-dimethylformamide, acetonitrile, dimethylsulfoxide, / V-methyl pyrrolidone, tetrahydrofurane, toluene, methyltertrahydrofurane, 1 ,4-dioxane and hexamethylphosphoramide; preferably, / V, / V-dimethylformamide.

[0084]

[0060] In a preferred embodiment, the process of the invention comprises, before step (i), a previous step (a) consisting in the preparation of the compound of formula (I) by treating a compound of formula (VII) in conditions sufficient for forming a compound of formula (I) wherein PG is as defined above in any of the embodiments defining PG. Preferably, PG is tert-butoxycarbonyl.

[0085]

[0061] Step (a) of the process of the invention may, in a first alternative, comprise causing a compound of formula (VII) to react with a compound of formula PX3, wherein X is a halo group to form a compound of formula (I) wherein each LG is a halo group.

[0086]

[0062] Alternatively, step (a) of the process of the invention may, in a second alternative, comprise causing a compound of formula (VII) to react with a compound of formula R2SO2CI or (R2SO2)2O, wherein R2 is as defined above to form a compound of formula (I) wherein each LG is a group of formula -OSO2R2. Further sulfonate leaving groups may be obtained by careful selection of R2. This alternative is particularly suitable for preparing compound (Ib1) defined above.

[0087] In a further alternative, step (a) of the process may comprise a step (a-1) of causing a compound of formula (VII) to react with a compound of formula R2SO2CI or (R2SO2)2O, wherein R2 is as defined above to form a compound of formula (I) wherein each LG is a group of formula -OSO2R2; and a further step (a-2) of causing a compound of formula (I) wherein each LG is a group of formula -OSO2R2 to react with a halide salt to form a compound of formula (I) wherein each LG is a halo group. Said alternative is preferred when the compound of formula (I) is (Ia1) as defined above.

[0088]

[0063] Step (a-1) of the process of the invention is preferably one wherein, in the compound of formula R2SO2CI or (R2SO2)2O, R2 is a methyl group. Step (a-1) of the process of the invention is preferably carried out in the presence of a base, such as a tertiary amine of formula NRaRbRc, being each of Ra, Rb and Rcas defined above. The base is preferably in an amount of at least two moles of base per each mole of compound of formula (VII). The compound of formula R2SO2CI or (R2SO2)2O is preferably in an amount of between 2 and 5 moles base per each mole of compound of formula (VII).

[0089]

[0064] Step (a-2) of the process of the invention is preferably one wherein the halide salt is a bromide salt. Even more preferably, the halide salt is an inorganic bromide salt, such as an alkali metal bromide salt, for instance, lithium bromide. Step (a-2) of the process of the invention is preferably carried out in a polar aprotic solvent, such as acetone or methyl ethyl ketone.

[0090]

[0065] In a preferred embodiment, the process of the invention comprises, before step (a), a previous step (b) consisting in the preparation of the compound of formula (VII) defined above by causing a compound of formula (VI) to react in reducing conditions to form a compound of formula (VII)

[0091] PG CO2R4

[0092] CO2R5

[0093] (VI) wherein PG is as defined above and R4and Rs, which may be identical or different to each other, are independently selected from a (Ci-Cs)alkyl chain.

[0094]

[0066] In preferred embodiments, R4and Rs are the same group. R4and Rs are also preferably selected from the group consisting of methyl and ethyl; more preferably, R4and Rs are ethyl groups.

[0095]

[0067] In another embodiment, the process of the invention comprises, before step (a), a previous step (b’) consisting in the preparation of the compound of formula (VII) by causing a compound of formula (XVI) to react in reducing conditions to form a compound of formula (VII) wherein PG is as defined above.

[0096]

[0068] Suitable reducing conditions for carrying out step (b) or (b’) of the process of the invention will become apparent to the skilled person upon reduction to practice of the invention. In particular, step (b) comprises causing the compound of formula (VI) to react with a hydride source for reducing esters to alcohols. Suitable hydride sources for carrying out step (b) are well known in the art and include, for instance, lithium aluminium hydride, diisobutylaluminium hydride and sodium borohydride. When sodium borohydride is employed as hydride source, it is preferably employed jointly with methanol. Also, step (b’) preferably comprises causing the compound of formula (XVI) to react with a hydride source for reducing esters to alcohols. Suitable hydride sources for carrying out step (b) are well known in the art and include, for instance, lithium aluminium hydride, diisobutylaluminium hydride and sodium borohydride. Step (b’) may in particular be carried out in the presence of sodium borohydride; preferably in the further presence of a lithium salt such as lithium chloride.

[0097]

[0069] The amount of hydride source employed in step (b) or step (b’) must be at least sufficient to reduce both ester groups of the compound of formula (VI) to alcohols, i.e. at least it must provide at least 4 moles of hydride per each mole of the compound of formula (VI); or to reduce the lactone group of the compoudn of formula (XVI) to alcohols, i.e. at least it must provide at least 4 moles of hydride per each mole of the compound of formula (XVI).

[0098]

[0070] In a preferred embodiment, the process of the invention comprises, before step (b), a previous step (c) consisting in the preparation of a compound of formula (VI) by causing a compound of formula (X) to react with a compound of formula (XI) to form a compound of formula (VI)

[0099] (X) (XI) wherein LG’ is a leaving group, and PG, R4 and R5 are as defined above.

[0100]

[0071] The compound of formula (XI) of the process of the invention is preferably one wherein LG’ is selected from the group consisting of chloro, bromo, iodo and a group of formula -OSO2R2; wherein R2 is selected from the group consisting of linear or branched (Ci-Ce)alkyl chain, a linear or branched (Ci-Ce)haloalkyl chain and a phenyl group optionally substituted at any available position with a linear or branched (Ci-Ce)alkyl chain. Preferably, in the compound of formula (XI), LG’ is a bromo group.

[0101]

[0072] Step (c) of the process of the invention is preferably carried out in the presence of a base suitable for abstracting the hydrogen atom by the carbon atom adjacent to the group of formula CO2R4 in the compound of formula (X). Such base is preferably an organolithium reagent, such as n- butyllithium, s-butyllithium, t-butyllithium and lithium diisopropylamide. In such cases, the reaction must be carried out in a polar aprotic solvent, such as / V, / V-dimethylformamide, acetonitrile, dimethylsulfoxide, N- methylpyrrolidone, tetrahydrofurane, 1 ,4-dioxane and hexamethylphosphoramide; preferably, the solvent is tetra hydrofuran.

[0102]

[0073] In a preferred embodiment, the process of the invention comprises, before step (b’) a previous step (o’) consisting in the preparation of a compound of formula (XVI) by causing a compound of formula (XVII) to react in oxidating conditions to form a compound of formula (XVI)

[0103] Suitable oxidating agents for carrying out this step will become apparent to the skilled person upon reduction to practice of the invention on the basis of common general knowledge. In particular, oxone is particularly suitable. Other oxidants, such as peracids, may be used, a well known example of such peracids being m-chloroperbenzoic acid.

[0104]

[0074] In a preferred embodiment, the process of the invention comprises, before step (i), a previous step (d) consisting in the preparation of a compound of formula (II) by causing a compound of formula (XII) to react with a compound of formula (XIII) to form a compound of formula (II) wherein M is an alkali metal, LG” is a leaving group and R1 is as defined above for the compound of formula (II).

[0105]

[0075] In the compound of formula (XII), M is preferably Na.

[0106]

[0076] The compound of formula (XIII) of the process of the invention is preferably one wherein LG” is a leaving group identical to LG as defined above. Preferably, LG” is selected from the group consisting of chloro, bromo, iodo and a group of formula - OSO2R2; wherein R2 is selected from the group consisting of linear or branched (C1- Ce)alkyl chain, a linear or branched (Ci-Ce)haloalkyl chain and a phenyl group optionally substituted at any available position with a linear or branched (Ci-Ce)alkyl chain. More preferably, in the compound of formula (XIII), LG” is a chloro group.

[0107]

[0077] Step (d) of the process of the invention is preferably carried out in a polar aprotic solvent, such as / V, / V-dimethylformamide, acetonitrile, dimethylsulfoxide, / V- methylpyrrolidone, tetrahydrofurane, acetone, 1 ,4-dioxane and hexamethylphosphoramide; preferably, the solvent is / V, / V-dimethylformamide.

[0108]

[0078] In a preferred embodiment, the process of the invention comprises, before step (i), a previous step (d’-1) consisting in the preparation of a compound of formula (XX) by causing a compound of formula (XXI) to react in oxidating conditions, and the step (d’-2) consisting in causing the compound of formula (XX) to react with an alcohol of formula RiOH in acidic conditions

[0109]

[0079] Suitable oxidating agents for carrying out step (d’-1) will become apparent to the skilled person upon reduction to practice of the invention on the basis of common general knowledge. In particular, oxone is particularly suitable.

[0110]

[0080] The compound of formula RiOH of step d’-2 is preferably methanol or ethanol. Suitable acidic conditions comprise employing a mixture of sulfuric acid and the compound of formula RiOH as solvent of reaction.

[0111]

[0081] Step (iii) of the process of the invention refers to the hydrolysis of the ester group of formula CO2R1 in the compound of formula (III) to a group of formula CO2H. Suitable conditions for carrying such transformation are known in the art and will become apparent to the skilled person.

[0112]

[0082] In preferred embodiments, step (iii) of the process of the invention comprises contacting a compound of formula (III) with an alkali metal salt of hydroxide, preferably lithium hydroxide or potassium hydroxide, in the presence of water.

[0113]

[0083] The compound of formula (IV) is obtained as a racemic mixture of enantiomers.

[0114]

[0084] In preferred embodiments, the process of the invention further comprises the step (iv) wherein the compound of formula (IV) is subsequently resolved to produce an enantiomerically enriched compound of formula (IV’)

[0085] Methods for resolving mixtures of enantiomers are well-known in the art and include, for instance, separation (e.g. by chiral chromatography), fractional crystallization (e.g. through the formation of diastereomeric salts), kinetic or enzymatic resolution, covalent linkage of a chiral auxiliary and separation of formed diastereomers, among others.

[0115]

[0086] In preferred embodiments, step (iv) of the process of the invention is carried out by supercritical fluid chromatography. Preferably, said method comprises separating the mixture of enantiomers by supercritical fluid chromatography using Thar SFC Pre-80 with a ChiralPak AD-H column (250 x 30 mm), and employing Solvent A: CO2; Solvent B: methanol. Mobile phase 25% of B and 75% of A at 65 mL / min at a back pressure of 100 bar and UV detector at 220 nm. Retention times for both enantiomers are respectively 1.61 min and 1.87 min, with enantiomeric excess (ee) of >99%.

[0116]

[0087] The general synthetic scheme of the process of the first aspect of the invention is preferably as follows: wherein each one of steps (i), (ii), (iii), (a), (b), (c) and (d) is preferably carried out as described above and wherein, even more preferably M is Na; PG is terf-butoxycarbonyl, R1 is methyl, R is F or 4-(methylcarbamoyl)phenyloxy; R4 and R5 are ethyl, and LG” is bromo.

[0088] In a further alternative, the general synthetic scheme of the process of the first aspect of the invention is preferably as follows: wherein each one of steps (i), (ii), (iii), (iv), (a), (b’) and (o’) is preferably carried out as described above and wherein, even more preferably PG is te / Y-butoxycarbonyl, Ri is ethyl and R is F or 4-(methylcarbamoyl)phenyloxy.

[0117]

[0089] As mentioned above, the second aspect of the invention refers to a process for the preparation of a compound of formula (V) as defined above.

[0118]

[0090] In preferred embodiments, step (i) of the process of the second aspect of the invention is as defined in any of the embodiments defining the process of the first aspect of the invention as described above.

[0119]

[0091] The conversion of a compound of formula (IV’), obtained from step (iii), or of a compound of formula (IV), obtained from step (ii), to a compound of formula (V) is known in the art and has been disclosed in Orbe, J. et al, J. Med. Chem. 2015, 58, 7, 2941- 2957 and in WO 2014 / 012964 A1. Briefly, said synthetic route may be summarized according to the following scheme:

[0120]

[0121]

[0092] In preferred embodiments, step (ii) of the process of the second aspect of the invention comprises converting the compound of formula (IV) or (IV’) to a compound of formula (V) following the procedure disclosed in Orbe, J. et al, J. Med. Chem. 2015, 58, 7, 2941-2957 and in WO 2014 / 012964 A1 , the content of which is incorporated herein by reference.

[0122]

[0093] Thus, step (ii) of the process of the second aspect of the invention may comprise the step (e) of causing a compound of formula (IV) or (IV’) to react with O- (Tetra hydro- 2H-pyran-2-yl)hydroxylamine to form a compound of formula (VIII) as defined above, or a compound of formula (VIII’), respectively, the compound (VIII’) being an enantiomerically enriched (R)-enantiomer of the compound of formula (VIII). This is particularly the case when, in the compound of formula (IV) or the compound of formula (IV’), R is F.

[0123]

[0094] In addition, step (ii) of the process of the second aspect of the invention may comprise the step (f), subsequent to step (e), of causing the compound of formula (VIII) or (VIII’) to react with 4-hydroxy-N-methylbenzamide to form a compound of formula (IX) as defined above, or a compound of formula (IX’) respectively, the compound (IX’) being an enantiomerically enriched (R)-enantiomer of the compound of formula (IX). Such step (f) is not carried out when R is 4-methylcarbamoylphenyloxy in the compound of formula (IV). Suitable conditions of reaction to carry out this step are as decribed above for step (ii) of the process of the first aspect of the invention.

[0095] Alternatively to step (f), step (II) of the process of the second aspect of the invention may comprise the step (g), which consists of steps (g-1), (g-2) and (g-3), said steps being subsequent to step (e), step (g-1) comprising causing the compound of formula (VIII) or (VIII’) to react with methyl 4-hydroxy-benzoate to form a compound of formula (XIV) or a compound of formula (XIV’), respectively, the compound (XIV’) being an enantiomerically enriched (R)-enantiomer of the compound of formula (XIV). In such embodiment, step (iv) further comprises step (g-2) of causing a compound of formula (XIV) or (XIV’) to react in hydrolysis conditions to form a compound of formula (XV) or (XV’), respectively, the compound (XV’) being an enantiomerically enriched ( / ?)- enantiomer of the compound of formula (XV)

[0124]

[0096] In this embodiment, step (iv) further comprises step (g-3) of causing a compound of formula (XV) or (XV’) to react with methylamine to form a compound of formula (IX) or (IX’) as defined above.

[0125]

[0097] Step (g-1) is preferably carried out in the presence of a base, that is preferably selected from the group consisting of alkali salts of carbonate and alkali salts of (Ci- Ce)alkyloxy; more preferably, said base is caesium carbonate. Step (g-1) is further preferably carried out in the presence of a fluoride salt, such as an alkali metal salt of fluoride, e.g. potassium fluoride. Said fluoride salt is preferably present in a catalytically effective amount. Step (g-1) is carried out in the presence of a polar aprotic solvent as defined above, preferably, / V, / V-dimethylformamide. Suitable conditions for carrying out step (g-2) and (g-3) are as defined above for steps (ii) and (e), respectively, in any embodiment disclosing these steps. As the skilled person will appreciate, small variations of the above procedures may be accepted.

[0126]

[0098] In addition, step (ii) of the process of the second aspect of the invention may comprise the step (h), subsequent to step (e), (f) or (g), of forming a compound of formula (V) from a compound of formula (IX) or (IX’) by causing said compound of formula (IX) o (IX’) to react in conditions for removing the THP and PG groups.

[0127]

[0099] As is known in the art, suitable reaction conditions for removing THP group comprise treating the compound of formula (IX) or (IX’) in an acidic medium. Suitable reaction conditions for the deprotection step of PG depend on the nature of PG and will become apparent to the skilled person on the basis of common general knowledge. It is preferred that -PG is chosen such that -THP and -PG may be removed in one sole synthetic step. This is for instance the case when -PG is tert-butoxycarbonyl, in which case step (h) comprises contacting the compound of formula (IX) or (IX’) with hydrochloric acid, which allows removing both -THP and -PG groups in one sole step. When a compound of formula (IX) is used as starting material, step (h) preferably further comprises resolving the racemic product to form an enantiomerically enriched compound of formula (V). Said resolution step may be carried out as disclosed in the art in Orbe, J. et al, J. Med. Chem. 2015, 58, 7, 2941-2957 and in WO 2014 / 012964 A1.

[0128]

[0100] Steps (e), (f) or (g) and (h) are particularly preferred when R is F in the compound of formula (IV) or the compound of formula (IV’).

[0129]

[0101] Step (ii) of the process of the second aspect of the invention may in a further alternative comprise the step (j) of causing a compound of formula (IV) or a compound of formula (IV’), wherein R is preferably 4-methylcarbamoyl)phenyloxy, to react with a compound of formula (Ci-C6)alkylCOCI, such as isobutyl chloroformate, to form a compound of formula (XVIII)

[0130]

[0102] When in the compound of formula (IV) or in the compound of formula (IV’) R is F, a step (j’) prior to step (j) may be carried out comprising causing to react a compound of formula (IV) or a compound of formula (IV’) wherein R is F with 4-hydroxy-N- methylbenzamine to form a compound of formula (IV) or a compound of formula (IV’) wherein R is 4-methylcarbamoyl)phenyloxy. Suitable conditions to carry out this reaction are as disclosed for step (ii) of the first aspect of the inventions.

[0131]

[0103] Step (ii) of the process of the second aspect of the invention may comprise the step (k), subsequent to step (j) of causing a compound of formula (XVIII) to react with hydroxylamine to form a compound of formula (XIX)

[0132] The compound of formula (V) can be prepared from this compound of formula (XIX) following step (h) described below.

[0133]

[0104] The third aspect of the invention relates to a compound of formula (I’) or a salt thereof,

[0134] PG i

[0135] N.

[0136] JX^LG

[0137] LGZ

[0138] (I’) wherein PG is an amine protecting group as defined in the first aspect of the invention and wherein each LG represents the same or different groups and is a leaving group as defined the first aspect of the invention and provided that when PG is tert-butoxycarbonyl or benzyloxycarbonyl and each LG represents the same group, LG is other than methylsulfonate.

[0139]

[0105] In preferred embodiments, the compound of formula (I’) is one wherein each LG is selected from the group consisting of chloro, bromo, iodo and a group of formula - OSO2R2; wherein R2 is selected from the group consisting of a linear or branched (C1- Ce)haloalkyl chain and a phenyl group optionally substituted at any available position with a linear or branched (Ci-C6)alkyl chain.

[0140]

[0106] In preferred embodiments, the compound of formula (I’) is one wherein each LG is selected from the group consisting of chloro, bromo and iodo.

[0107] In preferred embodiments, the compound of formula (I’) is one wherein each LG is bromo.

[0141]

[0108] In preferred embodiments, the compound of formula (la) is one wherein PG is as defined in any of the embodiments defining PG; preferably, PG is tert- butyloxycarbonyl.

[0142]

[0109] In preferred embodiments, the compound of formula (I’) is tert-butyl 4-(2- bromoethyl)-4-(bromomethyl)piperidine-1 -carboxylate.

[0143]

[0110] Throughout the description and claims the word “comprises" and variations of the word, are not intended to exclude other technical features, additives, components or steps. Furthermore, the word “comprise” encompasses the cases of “consist of’ and “consists essentially of”. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration, and they are not intended to be limiting of the present invention.

[0144]

[0111] The invention may also be defined according to the following clauses:

[0145] 1 . A process for the preparation of a compound of formula (IV) said process comprising the steps of:

[0146] (i) causing a compound of formula (I) to react with a compound of formula (II) to form a compound of formula (III); wherein PG is an amine protecting group; each LG is a leaving group and R1 is a linear or branched (Ci-C6)alkyl chain; and

[0147] (ii) causing the compound of formula (III) to react in hydrolysis conditions to form a compound of formula (IV).

[0148] 2. Process according to clause 1 wherein, in the compound of formula (I), each LG is independently selected from the group consisting of chloro, bromo, iodo and a group of formula -OSO2R2; wherein R2 is selected from the group consisting of linear or branched (Ci-Ce)alkyl chain, a linear or branched (Ci-Ce)haloalkyl chain and a phenyl group optionally substituted at any available position with a linear or branched (Ci-Ce)alkyl chain and

[0149] PG represents an amine protecting group selected from the group consisting of benzyl and a group of formula -C(=O)OR3, wherein R3 is selected from the group consisting of tert-butyl, benzyl, allyl and fluorenyl.

[0150] 3. Process according to any one of clauses 1 to 2 wherein, in the compound of formula

[0151] (I), each LG is bromo and PG is tert-butoxycarbonyl.

[0152] 4. Process according to any one of clauses 1 to 3 wherein, in the compound of formula

[0153] (II), R1 is methyl.

[0154] 5. Process according to any one of clauses 1 to 4 wherein step (i) is carried out in the presence of a base, said base being preferably selected from the group consisting of alkali salts of carbonate and alkali salts of (Ci-C6)alkoxide; more preferably, the base is potassium carbonate.

[0155] 6. Process according to clause 5 wherein step (i) is carried out in the presence of a catalytically effective amount of (i) a nucleophilic catalyst and (ii) a phase transfer agent, said nucleophilic catalyst being preferably / V, / V-dimethylaminopyridine and said phase transfer agent being preferably a bromide salt of a cation of formula+NRaRbRcRd, wherein each one of Ra, Rb, Rcand Rd is independently a (Ci-Ce)alkyl group.

[0156] 7. Process according to any one of clauses 5 to 6 wherein step (i) is carried out in a polar aprotic solvent, said solvent being preferably / V, / V-dimethylformamide.

[0157] 8. Process according to any one of clauses 1 to 7 wherein:

[0158] Ri is a methyl group and the compound of formula (I) is a compound of formula (la) wherein PG is a tert-butoxycarbonyl group and step (i) is carried out in the presence of:

[0159] - potassium carbonate;

[0160] - a catalytically effective amount of (i) N,N-dimethylaminopyridine and (ii) tetrabutylammonium bromide; and

[0161] -a polar aprotic solvent that is preferably N,N-dimethylformamide.

[0162] 9. Process according to any one of clauses 1 to 8 wherein before step (i) a previous step (a) is carried out consisting in the preparation of the compound of formula (I) by treating a compound of formula (VII) in conditions sufficient for forming a compound of formula (I) wherein PG is as defined in any one of clauses 1 to 3.

[0163] 10. Process according to clause 9 wherein before step (a) a previous step (b) is carried out consisting in the preparation of the compound of formula (VII) by causing a compound of formula (VI) to react in reducing conditions to form a compound of formula (VII) wherein PG is as defined in any one of clauses 1 to 3 and R4 and R5, which may be identical or different to each other, are independently selected from a (Ci-Ce)alkyl chain; preferably R4 and R5 are each a ethyl group.

[0164] 11 . Process according to clause 10 wherein before step (b) a previous step (c) is carried out consisting in the preparation of a compound of formula (VI) by causing a compound of formula (X) to react with a compound of formula (XI) to form a compound of formula (VI)

[0165] RsC^C^LG'

[0166] (X) (XI) wherein LG’ is a leaving group, PG is as defined in any one of clauses 1 to 3 and each of R4 and R5 is independently a (Ci-C6)alkyl chain; preferably LG’ is bromo and R4 and Rs are each a ethyl group.

[0167] 12. Process according to any one of clauses 1 to 11 wherein the compound of formula

[0168] (IV) is subsequently resolved in step (iii) to produce an enantiomerically enriched compound of formula (IV’)

[0169] 13. A process for the preparation of a compound of formula (V) said process comprising the steps of:

[0170] (i) causing a compound of formula (I) to react with a compound of formula (II) to form a compound of formula (III); wherein PG is an amine protecting group; each LG is a leaving group and Ri is a linear or branched (Ci-C6)alkyl chain; and

[0171] (iv) converting the compound of formula (III) in the compound of formula (V).

[0172] 14. Process according to clause 13 wherein step (i) is as defined in any one of clauses 1 to 12 and step (iv) comprises step (ii) as defined in any one of clauses 1 to 12 and step (iii) as defined in clause 12. 15. A compound of formula (I’) or a salt thereof, wherein PG is an amine protecting group as defined in any one of clauses 1 to 3 and wherein each LG represents the same or different groups and is a leaving group as defined in any one of clauses 1 to 3 and provided that when PG is te / Y-butoxycarbonyl or benzyloxycarbonyl and each LG represents the same group, LG is other than methylsulfonate; preferably, each LG represents bromo.

[0173] EXAMPLES

[0174] General information'.

[0175] All air sensitive manipulations were carried out under a dry nitrogen atmosphere, and all reagents and reactants were used as delivered from the purchasers without any further purification. Drying of organic extracts during work-up of reactions was performed with Na2SO4. Evaporation of solvent was accomplished with a rotatory evaporator. Thin-layer chromatography was performed on SiO2 (silica gel 60 F254), and the spots were revealed by UV light (254 nm), and either 1% KMnO4 solution or bromocresol green solution. Chromatography refers to flash chromatography and was carried out on SiO2 (silica gel 60, 230-400 mesh). NMR spectra were recorded at a 300, 400 MHz (1H) and chemical shifts are reported in 5 values, in parts per million (ppm) relative to Me4Si (0 ppm) or relative to residual chloroform (7.26 ppm), methanol (3.31 ppm) as internal standards, at 25 °C. Data are reported in the following manner: chemical shift, multiplicity, coupling constant (J), in hertz (Hz), integrated intensity, and assignment (when possible).

[0176] Abbreviations

[0177] Na2SO4: soldium sulphate

[0178] KMnO4: potassium permanganate

[0179] DMF: / V, / V-dimethylformamide

[0180] MeOH: methanol

[0181] H2O: water

[0182] MTBE: methyl terf-buthyl ether

[0183] CUSO4: copper sulphate LDA: lithium diisopropylamide

[0184] THF: tetrahydrofuran

[0185] RT: room temperature

[0186] DCM or CH2CI2: dichloromethane

[0187] NaBH4: sodium borohydride fBuOH: tert-butyl alcohol

[0188] MsCI: methanesulfonyl chloride

[0189] TBAB: tetrabutylammonium bromide

[0190] DMAP: / V, / V-dimethylaminopyridine

[0191] NEt3: triethylamine

[0192] EDC' HCI: (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride

[0193] HOBt: 1 -hydroxybenzotriazole

[0194] NMM: / V-methylmorpholine

[0195] EXAMPLE 1

[0196]

[0112] Alternative 1: Methyl chloroacetate (3.4 mL, 38.4 mmol, 1 eq.) was added to a stirred solution of sodium 4-fluorophenylsulfinate (7 g, 38.4 mmol, 1 eq.) in N,N- dimethylformamide (21 mL) at RT. The resulting mixture was stirred at 80 °C for two hours. Once the reaction mixture was cooled down to RT, ethyl acetate (50 mL) was added and the resulting organic phase was washed 5 times with a saturated aqueous solution of CuSO4 (5 x 40 mL). After drying of the organic phase with anhydrous sodium sulfate and filtration, the solvent was eliminated under vacuum using heptane as coevaporation solvent (3 x 21 mL). Compound (Ila) was isolated with a yield of 67%.1H- NMR (400 MHz, CDCI3) 5 (ppm): 8.00-7.96 (m, 2H, H-Ar), 7.29-7.24 (m, 2H, H-Ar), 4.13 (s, 2H, CH2), 3.73 (s, 3H, CH3). Preparation of l-(tert-butyl) 4-ethyl 4-(2-ethoxy-2-oxoethyl)piperidine-1 ,4-dicarboxylate lYla)

[0197] Boc

[0198] CO2Et

[0199] (Via)

[0200]

[0113] A 2M LDA in THF (15.2 mL, 30.3 mmol, 1.5 eq.) was added dropwise to a stirring solution of l-(tert-butyl) 4-ethyl piperidine-1 ,4-dicarboxylate (5.2 g, 20.2 mmol, 1 eq.) in THF (31 .2 mL) at - 78 °C. The resulting mixture was stirred for 2h at - 78 °C. After this time ethyl bromoacetate (4.2 mL, 32.3 mmol, 1 .6 eq.) was added dropwise with a syringe pump during a period of two hours at - 78 °C. The resulting mixture was warmed up to RT and stirred overnight. After this period of time, the reaction mixture was diluted with ethyl acetate (20 mL), then was cooled down to 0 °C and neutralized with an aqueous saturated solution of ammonium chloride (35 mL). The resulting mixture was extracted twice with ethyl acetate (2 x 50 mL). The gathered organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was eliminated under vacuum, yielding compound (Via) which was used in the subsequent step without further purification.

[0201] Preparation of tert-butyl 4-(2-hydroxyethyl)-4-(hydroxymethyl)piperidine-1 -carboxylate (Vila)

[0202] Boc ?oc (Via) (Vila)

[0203]

[0114] Methanol (4.9 mL) was added over a period of 3.5 hours to a refluxing stirring solution of sodium borohydride (2.29 g, 60.6 mmol, 3 eq.) and compound (Via) (20.2 mmol, 1 eq.) in tert-butanol (69.6 mL). The resulting mixture was stirred at 83 °C for a period of two hours. After this time a second portion of sodium borohydride (2.29 g, 3 eq.) was added, followed by methanol dropwise addition (4 x 1 mL, one addition of 1 mL per hour) and the mixture was stirred for 4 hours. After this time a third portion of sodium borohydride (2.29 g, 3 eq.) was added, followed by methanol dropwise addition (4 x 1 mL, one addition of 1 mL per hour) and the mixture was stirred for 4 hours. Finally, a fourth portion of sodium borohydride (2.29 g, 3 eq.) was added and the resulting mixture was stirred 18 hours at refluxing temperature. The reaction mixture was then cooled down to RT and diluted with dichloromethane (50 mL) and water (10 mL) and pH was brought back to neutrality by addition of HCI 2M at 0 °C. The resulting aqueous phase was decanted and extracted with dichloromethane three times (3 x 50 mL) and the gathered organic phases were dried over anhydrous sodium sulfate, filtered, and solvent was eliminated under vacuum. Crude product was purified by column chromatography using DCM:MeOH = 9:1 as elution system, affording 2.77 g of compound (Vila) with a 53% overall yield from l-(tert-butyl) 4-ethyl 4-(2-ethoxy-2-oxoethyl)piperidine-1 ,4- dicarboxylate.1H-NMR (300 MHz, CDCI3) 6 (ppm): 3.76 (t, J = 5.1 Hz, 2H), 3.41 (t, J = 5.6 Hz, 4H), 1.69-1.67 (m, 2H), 1.58-1.37 (m, 15H).

[0204] Preparation of tert-butyl 4-(2-((methylsulfonyl)oxy)ethyl)-4-(((methylsulfonyl)oxy)- methyl)piperidine-1 -carboxylate (lb)

[0205] Boc

[0206]

[0115] Mesyl chloride (14 mL, 182.18 mmol, 3.5 eq.) was added dropwise to a stirred solution of compound (Vila) (13.5 g, 52.05 mmol, 1 eq.) and triethylamine (50.6 mL, 364.4 mmol, 7 eq.) in dichloromethane (142 mL) at 0 °C. The resulting mixture was stirred two hours at 0 °C and then was stirred at RT for 18 hours. After this time, the salts precipitated in the reaction mixture were eliminated by filtration and the solvent was eliminated under vacuum. The obtained resulting crude product was used in the next step without any further purification.

[0207] Preparation of tert-butyl 4-(2-bromoethyl)-4-(bromomethyl)piperidine-1-carboxylate (Ia1)

[0208] Boc

[0209] (Ia1)

[0210]

[0116] Lithium bromide (45.2 g, 520.5, 10 eq.) was added to a solution of the crude (lb) (52.05 mmol) in acetone (150 mL). The resulting suspension was stirred at reflux temperature for 4.5 hours. The resulting mixture was warmed up to room temperature and diluted with 150 mL of MTBE and 100 mL of H2O. The resulting organic phase was separated and washed twice with 150 mL of brine, and then was dried over anhydrous sodium sulfate, filtered and the solvent was eliminated under vacuum to yield 16.6 g of compound (Ia1). The obtained crude product was used in the next step without any further purification. Preparation of 8-(tert-butyl) 2-methyl 2-((4-fluorophenyl)sulfonyl)-8-azaspirof4.51decane-

[0211] 2,8-dicarboxylate (Illa)

[0212] Boc

[0213] (Illa), 62% from (Vila)

[0214]

[0117] Potassium carbonate (29.8 g, 215.5 mmol, 5 eq.), / V, / V-dimethylaminopyridine (264 mg, 2.16 mmol, 0.05 eq.), tetrabutylammonium bromide (695 mg, 2.16 mmol, 0.05 eq.) and compound (Ila) (10, 43.1 mmol, 1 eq.) were successively added to a solution of a compound (Ia1) (16.6 g, 43.1 mmol, 1 eq.) in DMF (166 mL). The resulting suspension was stirred at 60 °C for 20 hours. After this period of time, the reaction mixture was filtered and the obtained filtrate was diluted with ethyl acetate (150 mL). The resulting organic phase was washed four times with water (4 x 200 mL). After drying with anhydrous sodium sulfate and filtration, the solvent of the organic phase was eliminated under vacuum. The obtained crude product was purified by silica gel column chromatography using mixtures of 100:0 to 75:25 of n-heptane / ethyl acetate as elution system, affording compound (Illa) with an overall yield of 62% from compound (Vila).1H- NMR (300 MHz, CDCI3) 6 (ppm): 7.85-7.80 (m, 2H), 7.25-7.20 (m, 2H), 3.68 (s, 3H), 3.47-3.24 (m, 4H), 2.58-2.40 (m, 3H), 2.33-2.28 (m, 1), 1.80-1.71 (m, 1 H), 1.61-1.51 (m, 3H), 1.44 (s, 9H), 1.33-1.30 (m, 2H).

[0215] Preparation of 8-(tert-butoxycarbonyl)-2-((4-fluorophenyl)sulfonyl)-8-azaspirof4.51- decane-2-carboxylic acid (IV’a)

[0216]

[0217]

[0118] Lithium hydroxide hydrate (3.78 g, 158 mmol, 10 eq.) was added to a stirred solution of compound (Illa) (7.2 g, 15.8 mmol, 1 eq.) in THF / MeOH / H2O (3:2:3 volume ratio respectively, 29 mL) at RT. The resulting mixture was stirred at room temperature for 6 hours. The resulting reaction mixture was then diluted with water (10 mL) and cooled down to 0 °C. HC1 1 M was added till reaching a pH of 5-6. The resulting aqueous phase was extracted 3 times with ethyl acetate (3 x 30 mL). The gathered organic phases were dried with anhydrous sodium sulfate, filtered and the solvent was eliminated under vacuum. The resulting crude product was purified by silica gel chromatography using a mixture of 100:0 to 80:20 of C^Ch / MeOH as elution system, affording 3.07 g of compound (IV’a) (44% yield).1H-NMR (400 MHz, CDCI3) 6 (ppm): 7.92-7.88 (m, 2H), 7.24-7.19 (m, 2H), 3.45- (s, 3H), 3.47-3.24 (m, 4H), 2.58-2.40 (m, 3H), 2.33-2.28 (m, 1 H), 1.80-1.71 (m, 1 H), 1.61-1.51 (m, 3H), 1.44 (s, 9H), 1.33-1.30 (m, 2H).

[0218]

[0119] Compound (IV’a) was obtained as a racemic mixture of enantiomers. Compound (IVa), which is the (R)-enantiomer of compound (IV’a), or a mixture of enantiomers of compound (IV’a) enriched in said (R)-enantiomer may be obtained according to methods well-known in the art for enantiomeric resolution or according to the procedure described in Orbe, J. et al. J. Med. Chem. 2015, 58 (7), 2941-2957, the content of which is incorporated herein by reference. Briefly, said method comprises separating the mixture of enantiomers by supercritical fluid chromatography using Thar SFC Pre-80 with a ChiralPak AD-H column (250 x 30 mm), and employing Solvent A: CO2; Solvent B: methanol. Mobile phase 25% of B and 75% of A at 65 mL / min at a back pressure of 100 bar and UV detector at 220 nm. Retention times for both enantiomers are respectively 1 .61 min and 1.87 min, with enantiomeric excess (ee) of >99%. As will be obvious to the skilled person, synthetic steps described herein starting from compound (IV’a) may be equally performed using compound (IVa) as starting material.

[0219] Preparation of tert-butyl-2-((4-fluorophenyl)sulfonyl)-2-(((tetrahvdro-2H-pyran-2- yl)oxy)carbamoyl)-8-azaspirof4.51decane-8-carboxylate (Villa)

[0220]

[0120] To a solution of compound (IV’a) (198 mg, 0.448 mmol, 1 eq.) in DMF (3 mL) were successively added EDO HCI (172 mg, 0.897 mmol, 2 eq.), HOBt (121 mg, 0.897 mmol, 2 eq.), O-(tetrahydro-2 / 7-pyran-2-yl)hydroxylamine (THP-ONH2, 105 mg, 0.897 mmol, 2 eq.) and / V-methylmoprholine (136 mg, 1.35 mmol, 3 eq.) at RT. The resulting mixture was stirred overnight at room temperature. The reaction mixture was then diluted with water (7 mL) and the resulting mixture was extracted twice with ethyl acetate (2 x 15 mL). The gathered organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and the solvent was eliminated under vacuum to afford compound (Villa) as a white solid that was used in subsequent steps without any further purification (240 mg, 99% yield).

[0221] Preparation of tert-butyl-2-((4-(4-(methylcarbamoyl)phenoxy)phenyl)sulfonyl)-2-

[0222] (((tetrahydro-2H-pyran-2-yl)oxy)carbamoyl)-8-azaspirof4.51decane-8-carboxylate (IXa)

[0223]

[0121] Alternative 1: Cesium carbonate (95 mg, 0.3 mmol, 2.2 eq.) was added to a stirring mixture of compound (Villa) (75 mg, 0.139 mmol, 1 eq.), 4-hydroxy- / V- methylbenzamide (135 mg, 0.3 mmol, 2.2 eq.) in DMF (2 mL) at room temperature, and the resulting mixture was stirred overnight at 80 °C. After this time the reaction mixture was cooled down to room temperature and neutralized with HC1 1 M till reaching a pH of 5-6. The resulting mixture was extracted with ethyl acetate twice (2 x 7 mL) and the gathered organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography using a mixture of 100:0 to 90: 10 of C^Ch / MeOH as elution system affording compound (IXa) in 74% yield.1H-NMR (400 MHz, CDCI3) 6 (ppm): 7.89-7.84 (m, 2H), 7.77-7.75 (m, 2H), 7.21-7.17 (m, 2H), 7.06-7.04 (m, 2H), 6.17 (br, 1 H, NH), 6.02-5.97 (m, 2H), 4.93 (s, 1 H), 3.83-3.79 (m, 1 H), 3.63-3.57 (m, 1 H), 3.49- 3.14 (m, 5H), 3.14 (s, 3H, CH3), 2.52-2.28 (m, 4H), 1.80-1.71 (m, 2H), 1.69-1.66 (m, 5H), 1.46 (s, 9H), 1.39-1.35 (m, 3H).

[0224] Alternative 2

[0225] (Villa) (IXa)

[0226]

[0122] Step (i): A mixture of compound (Villa) (240 mg, 0.448 mmol, 1 eq.), methyl 4- hydroxybenzoate (143 mg, 0.94 mmol, 2.1 eq) in DMF (4.4 mL) , cesium carbonate (292 mg, 0.896 mmol, 2 eq) and potassium fluoride (0.022 mmol, 0.05 eq) was stirred at 90°C for 18 hours. After this time, cesium carbonate (292 mg, 0.896 mmol, 2.0 eq) and potassium fluoride (0.022 mmol, 0.05 eq) were added and the resulting mixture was further stirred at 110 °C for 24 hours. Water (10 mL) was then added to the reaction mixture and the resulting mixture was extracted with ethyl acetate twice (2 x 15 mL). The gathered organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under vacuum. The resulting crude product was used in the next step without any further purification.

[0227]

[0123] Step (ii): A mixture of the product resulting from step (i) (0.448 mmol, 1.0 eq.), lithium hydroxide (188 mg, 4.48 mmol, 10 eq.) in a mixture of THF (15 mL), water (6 mL) and methanol (5 mL) was stirred for four hours at RT. The reaction mixture was then neutralized with HCI 1 M until reaching a pH of 3-4 and then extracted with ethyl acetate (2 x 20 mL). The gathered organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness under vacuum. The resulting crude product was used in the next step without any further purification.

[0228]

[0124] Step (iii): To a stirring solution of the product of step (ii) described above (265 mg, 0.4 mmol, 1 eq.) in DMF (2 mL) were successively added EDC HCI (155 mg, 0.8 mmol, 2 eq.), HOBt (109 mg, 0.8 mmol, 2 eq.), methylamine hydrochloride (55 mg, 0.8 mmol, 2 eq.), and / V-methylmorpholine (132 pL, 1.2 mmol, 3 eq). The resulting mixture was left stirring overnight at room temperature. The reaction mixture was then diluted with water (10 mL) and the resulting mixture was extracted twice with ethyl acetate (2 x 15 mL). The gathered organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under vacuum to afford a crude compound that was purified by silica gel column chromatography using 1 :1 to 0:100 heptane / ethyl acetate mixtures as elution system. Compound (IXa) was isolated with a yield of 28% from compound (Villa).1H-NMR (400 MHz, CDCI3) 5 (ppm): 7.89- 7.84 (m, 2H), 7.77-7.75 (m, 2H), 7.21-7.17 (m, 2H), 7.06-7.04 (m, 2H), 6.17 (br, 1 H, NH), 6.02-5.97 (m, 2H), 4.93 (s, 1 H), 3.83-3.79 (m, 1 H), 3.63-3.57 (m, 1 H), 3.49-3.14 (m, 5H), 3.14 (s, 3H, CH3), 2.52-2.28 (m, 4H), 1.80-1.71 (m, 2H), 1.69-1.66 (m, 5H), 1.46 (s, 9H), 1.39-1.35 (m, 3H).

[0229] Preparation of / V-hvdroxy-2-((4-(4-(methylcarbamoyl)phenoxy)phenyl)sulfonyl)-8- azaspirof4.51decane-2-carboxamide (V)

[0230]

[0125] A solution of compound (IXa) (85 mg, 0.13 mmol, 1 eq.), HCI 4 M in dioxane (0.96 mL, 3.8 mmol, 5.5 eq.) was stirred at room temperature for 1 hour. The reaction mixture was neutralized with a saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted twice with ethyl acetate (2 x 3 mL). The gathered organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and solvent was eliminated under vacuum to afford a crude compound that was purified by silica gel column chromatography using 9:1 DCM / methanol as elution system. Compound (V) was obtained in 19.4% yield.1H-NMR (300 MHz, MeOD) 5 (ppm): 7.94-7.85 (m, 4H), 7.21- 7.18 (m, 4H), 3.36-3.34 (m, 3H), 3.24-3.12 (m, 4H), 2.94 (s, 3H, CH3), 2.59-2.54 (m, 2H), 2.46-2.39 (m, 1 H), 2.31-2.25 (m, 1 H), 1.90-1.79 (m, 3H), 1.74-1.62 (m, 3H).

[0231] EXAMPLE 2

[0232]

[0126] The present Example 2 describes the following synthetic route:

[0233] In this synthetic route, all compounds are racemic.

[0234] Preparation of tert-butyl 3-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate

[0127] A mixture of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (50.0 g, 208.9 mmol, 1.0 equiv) in MeOH (104 mL, 2.1 vol) was stirred at room temperature until the starting material was dissolved. Water (104 mL, 2.1 vol) was added and the flask containing the mixture was placed in a water bath at room temperature. Oxone (89.92 g, 292.5 mmol, 1.4 equiv) and NaHCOs (35.10 g, 418.0 mmol, 2.0 equiv) were added portionwise (4 additions every 1 h) into the mixture to maintain the internal temperature below 40 °C and the reaction was stirred for 1 h more after the last addition. The reaction mixture was quenched adding an aqueous saturated solution of Na2S20s (150 mL, 3.0 vol) and water (150 mL, 3.0 vol). The crude residue was extracted with EtOAc (550 mL, 11.0 vol) and washed with an aqueous saturated solution of NH4CI (200 mL, 4.0 vol), twice with water (200 mL, 4.0 vol) and brine (200 mL, 4.0 vol). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the compound tert-butyl 3-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate 2 as a beige compact solid (56.92 g, 90% yield, 95% pure). The solid was dissolved in CH2CI2 (100 mL, 2.0 vol) and cyclohexane (50 mL, 1.0 vol) was added. CH2CI2 was removed under reduced pressure, additional cyclohexane (400 mL, 8.0 vol) was added and the suspension was stirred at room temperature overnight before filtration through a filter plate (pore 3). The resulting filtration cake was washed with cyclohexane and dried to afford the compound tert-butyl 3-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate as a white powder (46.54 g, 87% yield, >99% pure) that was used in the next step without further purification.

[0235] 1H NMR (400 MHz, CDCI3) 64.07 (s, 2H), 3.62 - 3.50 (m, 2H), 3.30 - 3.19 (m, 2H), 2.42 (s, 2H), 1.63 - 1.56 (m, 4H), 1.44 (s, 9H).

[0236] Preparation of tert-butyl 4-(2-hydroxyethyl)-4-(hydroxymethyl) piperidine- 1 -carboxylate

[0237] Boc

[0238]

[0128] Under argon atmosphere, a mixture of tert-butyl 3-oxo-2-oxa-8- azaspiro[4.5]decane-8-carboxylate (42.17 g, 163.5 mmol, 1.0 equiv, 99% pure), NaBH4 (12.37 g, 327.0 mmol, 2.0 equiv) and LiCI (13.86 g, 327.04 mmol, 2.0 equiv) in degassed THF (130.8 mL, 3.1 vol) was stirred at 0 °C for 15 min. Degassed water (32.70 mL, 0.8 vol) was slowly added dropwise into the mixture in order to maintain the temperature of the reaction below 10 °C. The mixture was stirred at 0 °C for 1 h. NaBH4 (6.186 g, 163.5 mmol, 1.0 equiv) and LiCI (6.932 g, 163.5 mmol, 1.0 equiv) were added again, and the mixture was stirred for 1 h at 0 °C and 1 h at room temperature. The reaction was quenched with a saturated aqueous solution of NH4CI (150 mL, 3.6 vol) and stirred until no more gas release was observed before water was added (150 mL, 3.6 vol). The mixture was extracted with EtOAc (600 mL, 14.0 vol), washed twice with water (300 mL, 7.0 vol) and brine (200 mL, 4.7 vol). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the compound tert-butyl 4-(2- hydroxyethyl)-4-(hydroxymethyl)piperidine-1 -carboxylate as a colorless oil (41.77 g, 97% yield, 98% pure) that was used in the next step without further purification.1H NMR (400 MHz, CDCI3) 6 3.81 - 3.73 (m, 2H), 3.52 (s, 2H), 3.44 - 3.32 (m, 4H), 1.71 - 1.63 (m, 2H), 1.56 - 1 .47 (m, 2H), 1.45 (s, 9H), 1 .44 - 1.33 (m, 2H).

[0239] Preparation of tert-butyl 4-(2-((methylsulfonyl)oxy)ethyl)-4-

[0240] ( ((methylsulfonyl) oxy) methyl) piperidine- 1 -carboxylate

[0241] Boc Boc

[0242]

[0129] Under argon atmosphere, triethylamine (55.0 mL, 395 mmol, 2.5 equiv) was added into a solution of tert-butyl 4-(2-hydroxyethyl)-4-(hydroxymethyl)piperidine-1- carboxylate (41.77 g, 157.8 mmol, 1 equiv, 98% pure) in anhydrous THF (225.5 mL, 5.3 vol) at 0 °C and the mixture was stirred at 0 °C for 10 min. Methanesulfonyl chloride (36.6 mL, 474 mmol, 3.0 equiv) was added dropwise (5 mL every 5 min) to maintain the reaction temperature below 40 °C. The mixture was allowed to warm to room temperature and stirred for 18 h. The reaction was cooled down to 0 °C, quenched with a saturated aqueous solution of K2CO3 (200 mL, 4.8 vol) and diluted with water (100 mL, 2.4 vol). The mixture was extracted with EtOAc (500 mL, 12.0 vol), washed twice with water (200 mL, 4.8 vol) and brine (200 mL, 2.4 vol). The organic layer was dried over Na2SC>4, filtered and concentrated under reduced pressure to afford the compound tertbutyl 4-(2-((methylsulfonyl)oxy)ethyl)-4-(((methylsulfonyl)oxy)methyl)piperidine-1- carboxylate a brown oil (63.55 g, 92% yield, 95% pure) that was used in the next step without further purification.

[0243] 1H NMR (400 MHz, CDCI3) 6 4.34 (t, J = 6.7 Hz, 2H), 4.13 (s, 2H), 3.50 - 3.32 (m, 4H), 3.05 (s, 3H), 3.03 (s, 3H), 1.95 (t, J = 6.7 Hz, 2H), 1.58 - 1.49 (m, 4H), 1.45 (s, 9H).

[0244] Preparation of Ethyl 2-((4-fluorophenyl)sulfonyl)acetate

[0245] First step: Oxidation

[0246]

[0130] 2-((4-fluorophenyl)thio)acetonitrile (20.0 g, 120 mmol, 1 equiv) was dissolved in MeOH (200 mL, 10.0 vol) at room temperature with vigorous stirring. Oxone (18.0 g, 60 mmol, 0.5 equiv) was added portionwise (6 additions every 40 minutes) and the resulting heterogenic mixture was stirred for 20 h. The mixture was filtered, the solid residue washed with acetone and the filtrate concentrated under reduced pressure. The crude material was dissolved in EtOAc (200 mL, 10.0 vol) and the organic phase was washed five times with water (100 mL, 5.0 vol), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the compound 2-((4-fluorophenyl)sulfonyl)acetonitrile as white solid (21.31 g, 89% yield).

[0247] 1H NMR (400 MHz, CDCI3) 5 8.10 - 8.05 (m, 2H), 7.38 - 7.32 (m, 2H), 4.06 (s, 2H).

[0248] Second step: Nitrile activation

[0249]

[0131] A round bottom flask was charged with EtOH (119 mL, 5.6 vol) and cooled down to 0 °C. Sulfuric acid (59 mL, 2.8 vol) was added carefully with vigorous stirring, and the mixture was stirred at 0 °C for 5 min. 2-((4-fluorophenyl)sulfonyl)acetonitrile (21.31 g, 107 mol, 1.0 equiv) was added, and the mixture was stirred at 80 °C for 48 h. The reaction was cooled down to room temperature and then to 0 °C, diluted with EtOAc (200 mL, 9.4 vol) and water (150 mL, 7.0 vol) was added slowly. Layers were separated, and the organic phase was washed four times with water (150 mL, 7.0 vol) and five times with an aqueous solution of NaOH 1 M (150 mL, 7.0 vol), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (gradient cyclohexane / acetone 100 / 0 to 80 / 20) to afford the compound ethyl 2-((4-fluorophenyl)sulfonyl)acetate as a yellowish oil (15.8 g, 60% yield).

[0250] 1H NMR (400 MHz, CDCI3) 6 8.00 - 7.95 (m, 2H), 7.29 - 7.23 (m, 2H), 4.17 (q, J = 7.1 Hz, 2H), 4.11 (s, 2H), 1.22 (q, J = 7.1 Hz, 3H).

[0251] Boc

[0252]

[0132] Under argon atmosphere, a mixture of ethyl 2-((4-fluorophenyl)sulfonyl)acetate (500.0 mg, 2.03 mmol, 1.0 equiv), tert-butyl 4-(2-((methylsulfonyl)oxy)ethyl)-4- (((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (1.146 g, 2.54 mmol, 1.25 equiv, 92% pure) and cesium carbonate (1.985 g, 6.09 mmol, 3.0 equiv) in anhydrous Me-THF (4.0 mL, 3.5 vol) was stirred at 50 °C for 48 h. The reaction was quenched with water (15 mL, 13.0 vol) and extracted with EtOAc (40 mL, 35.0 vol). The organic layer was washed twice with water (15 mL, 13.0 vol) and brine (15 mL, 13.0 vol), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (gradient cyclohexane / EtOAc 100 / 0 to 80 / 20) to afford the compound 8-(tert-butyl) 2-ethyl 2-((4-fluorophenyl)sulfonyl)-8- azaspiro[4.5]decane-2, 8-dicarboxylate as a yellow oil (738.3 mg, 78% yield).

[0253] 1H NMR (400 MHz, CDCI3) 6 7.89 - 7.79 (m, 2H), 7.25 - 7.18 (m, 2H), 4.13 (q, J = 7.2 Hz, 2H), 3.49 - 3.23 (m, 4H), 2.58 - 2.39 (m, 3H), 2.30 (d, J = 14.2 Hz, 1 H), 1.76 (ddd, J = 12.9, 8.0, 6.4 Hz, 1 H), 1.66 - 1.47 (m, 3H), 1.44 (s, 9H), 1.35 - 1.29 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H). Preparation of 8-(tert-butyl) 2-ethyl 2-((4-(4-

[0254] (methylcarbamoyl)phenoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decane-2,8-dicarboxylate

[0255]

[0133] Under argon atmosphere, 4-hydroxy-N-methylbenzamide (1.3 g, 8.3 mmol, 1.0 equiv) and 8-(tert-butyl) 2-ethyl 2-((4-fluorophenyl)sulfonyl)-8-azaspiro[4.5]decane-2,8- dicarboxylate (4.1 g, 8.7 mmol, 1.05 equiv) were dissolved in DMF (17 mL, 13.1 vol), with vigorous stirring. Potassium carbonate (2.33 g, 17 mmol, 2.0 equiv) was added and the reaction was stirred at 120 °C for 2 h. The mixture was allowed to cool down to room temperature, the solid was filtered over Celite and washed three times with EtOAc. The filtrate was concentrated under reduced pressure, and the residue diluted with EtOAc (100 mL, 24.4 vol) and washed five times with water (50 mL, 12.2 vol) and five times with aqueous solution of NH4CI (50 mL, 12.2 vol). Combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (gradient cyclohexane / acetone 100 / 0 to 60 / 40) to afford the compound 8-(tert-butyl) 2-ethyl 2-((4-(4-

[0256] (methylcarbamoyl)phenoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decane-2,8-dicarboxylate as a white solid (3.46 g, 69% yield).

[0257] 1H NMR (400 MHz, CDCI3) 5 7.83 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.9 Hz, 2H), 7.11 - 7.06 (m, 4H), 6.18 (bs, N-H, 1 H), 4.12 (q, J = 7.1 Hz, 2H), 3.47 - 3.24 (m, 4H), 3.02 (d, J = 4.8 Hz, 3H), 2.55 - 2.41 (m, 3H), 2.3 (d, J = 14.3 Hz, 1 H), 1.78 - 1.71 (m, 1 H), 1.61 - 1.48 (m, 3H), 1.44 (s, 9H), 1.33 - 1.31 (m, 2H), 4.12 (t, J = 7.1 Hz, 3H).

[0258] Preparation of 8-(tert-butoxycarbonyl)-2-((4-(4-

[0259] (methylcarbamoyl)phenoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decane-2-carboxylic acid

[0134] S-(tert-butyl) 2-ethyl 2-((4-(4-(methylcarbamoyl)phenoxy)phenyl)sulfonyl)-8- azaspiro[4.5]decane-2,8-dicarboxylate (3.46 g, 5.76 mmol, 1.0 equiv) was dissolved in toluene (11.5 mL, 3.3 vol) and cooled down to 0 °C. At this temperature, 18-crown-6 ether (304 mg, 1.15 mmol, 0.2 equiv) was added followed after 5 minutes by the addition of KOH (970 mg, 17.3 mmol, 3.0 equiv) with vigorous stirring. The temperature of the reaction was allowed to warm to room temperature and was stirred for 16 h. Additional KOH (970 mg, 17.3 mmol, 3.0 equiv) was added and the mixture was stirred for 4 h. The mixture was diluted with EtOAc (100 mL, 29.0 vol) and quenched by a saturated aqueous solution of NH4CI (60 mL, 17.3 vol). Layers were separated, and the organic phase was washed five times with water (60 mL, 17.3 vol), dried over Na2SO4, filtered and concentrated. The crude residue was dissolved in the minimum volume of CH2CI2, Et20 was added until appearance of a precipitate and the mixture was aged for 16 h. The solid was filtered and washed three times with cold Et20 to afford the compound 8-(tert- butoxycarbonyl)-2-((4-(4-(methylcarbamoyl)phenoxy)phenyl)sulfonyl)-8- azaspiro[4.5]decane-2-carboxylic acid as a white solid (2.83 g, 86% yield).

[0260] 1H NMR (500 MHz, CDCI3) 5 7.79 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 8.9 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H), 6.61 (bs, N-H, 1 H), 5.36 (bs, O-H, 1 H), 3.46 -

[0261] 3.41 (m, 1 H), 3.36 - 3.27 (m, 2H), 3.26 - 3.21 (m, 1 H), 3.0 (d, J = 4.85 Hz, 3H), 2.53 -

[0262] 2.41 (m, 3H), 2.26 (d, J = 14.1 Hz, 1 H) 1.76 - 1.71 (m, 1 H), 1.64 - 1.56 (m, 2H), 1.52 - 1 .47 (m, 1 H), 1.43 (s, 9H), 1.35 - 1.32 (m, 2H).

[0263] Preparation of tert-butyl 2-(hydroxycarbamoyl)-2-((4-(4-

[0264] (methylcarbamoyl)phenoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decane-8-carboxylate Boc

[0265]

[0135] Under argon atmosphere, 8-(tert-butoxycarbonyl)-2-((4-(4- (methylcarbamoyl)phenoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decane-2-carboxylic acid (100 mg, 0.175 mmol, 1.0 equiv) was dissolved in THF (0.22 mL, 2.2 vol) with vigorous stirring and the mixture was cooled down to 0 °C. N-methylmorpholine (38 pL, 0.349 mmol, 2.0 equiv) was added dropwise, and the resulting solution was stirred for 5 min. Isobutyl chloroformate (48 pL, 0.367 mmol, 2.1 equiv) was added dropwise and the mixture was stirred for 30 min. The reaction was cooled down to -15 °C, diluted with precooled THF at -15 °C (10 mL, 100.0 vol) and the resulting solution was stirred for 10 min. A cooled solution of hydroxylamine (50% wt in water, 0.161 mL, 2.62 mmol, 15 equiv) in THF (10 mL, 100.0 vol) at -15 °C was added dropwise over the previous solution and the mixture was stirred at -15 °C for 40 min. The precipitate formed was removed by filtration, washed with cold THF and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (gradient cyclohexane / acetone 100 / 0 to 60 / 40) to afford the compound tert-butyl 2- (hydroxycarbamoyl)-2-((4-(4-(methylcarbamoyl)phenoxy)phenyl)sulfonyl)-8- azaspiro[4.5]decane-8-carboxylate as a white powder (61.2 mg, 59% yield).

[0266] 1H NMR (400 MHz, CDCI3) 5 9.67 (s, 1 H), 7.81 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.9 Hz, 2H), 6.39 (d, J = 4.4 Hz, 1 H), 3.45 - 3.22 (m, 4H), 3.0 (d, J = 4.8 Hz, 3H), 2.55 - 2.50 (m, 1 H), 2.42 - 2.36 (m, 2H), 2.22 (d, J = 14.1 Hz, 1 H), 1.77 - 1.46 (m, 4H), 1.42 (s, 9H), 1.37 - 1.34 (m, 2H).

[0267] Preparation of 2-(hydroxycarbamoyl)-2-((4-(4-

[0268] ( methylcarbamoyl) phen oxy) phenyl) sulfonyl) - 8-azaspiro[4.5]decan- 8-ium chloride

[0269]

[0136] Under argon atmosphere, tert-butyl 2-(hydroxycarbamoyl)-2-((4-(4- (methylcarbamoyl)phenoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decane-8-carboxylate (58.5 mg, 0.1 mmol, 1.0 equiv) was dissolved in THF (1.0 mL, 17.1 vol). HCI 4 M in dioxane (0.3 mL, 1 mmol, 10 equiv) was added and the reaction was stirred for 1 h. HCI 4 M in dioxane (1.0 mL, 1 mmol, 40 equiv) was added again and the reaction was stirred for 1 h more. The precipitate was filtered and washed three times with THF (3 mL, 51.3 vol) to afford 2-(hydroxycarbamoyl)-2-((4-(4-

[0270] (methylcarbamoyl)phenoxy)phenyl)sulfonyl)-8-azaspiro[4.5]decan-8-ium chloride as a white solid (46.9 mg, 90% yield).

[0271] 1H NMR (500 MHz, CD3OD) 5 7.93 (d, J = 8.9 Hz, 2H), 7.87 (d, J = 8.9 Hz, 2H), 7.21 - 7.18 (m, 4H), 3.26 - 3.23 (m, 2H), 3.17 - 3.13 (m, 2H) 3.02 (s, 3H), 2.61 - 2.55 (m, 2H), 2.46 - 2.41 (m, 1 H), 2.3 (d, J = 14.3 Hz, 1 H), 1.92 - 1.80 (m, 3H), 1.73 - 1.69 (m, 1 H), 1.68 - 1.65 (m, 2H).

Claims

CLAIMS1. A process for the preparation of a compound of formula (IV)wherein R is F or 4-(methylcarbamoyl)phenyloxy; said process comprising the steps of:(i) causing a compound of formula (I) to react with a compound of formula (II)to form a compound of formula (III);wherein PG is an amine protecting group; each LG is a leaving group and Ri is a linear or branched (Ci-C6)alkyl chain; wherein, when in the compound of formula (IV) R is 4- (methylcarbamoyl)phenyloxy, a further step (ii) is carried out whereby a compound of formula (III) is caused to react with 4-hydroxy-N-methylbenzamide to form a compound of formula (III )(iii) causing the compound of formula (III) or the compound of formula (III’) to react in hydrolysis conditions to form a compound of formula (IV).

2. Process according to claim 1 wherein, in the compound of formula (I), each LG is independently selected from the group consisting of chloro, bromo, iodo and a group of formula -OSO2R2; wherein R2 is selected from the group consisting of linear or branched (Ci-C6)alkyl chain, a linear or branched (Ci-C6)haloalkyl chain and a phenyl group optionally substituted at any available position with a linear or branched (Ci-C6)alkyl chain andPG represents an amine protecting group selected from the group consisting of benzyl and a group of formula -C(=O)OR3, wherein R3 is selected from the group consisting of tert-butyl, benzyl, allyl and fluorenyl.

3. Process according to any one of claims 1 to 2 wherein, in the compound of formula(I), each LG is bromo and PG is tert-butoxycarbonyl.

4. Process according to any one of claims 1 to 3 wherein, in the compound of formula(II), Ri is methyl or ethyl.

5. Process according to any one of claims 1 to 4 wherein step (i) is carried out in the presence of a base, said base being preferably selected from the group consisting of alkali salts of carbonate and alkali salts of (Ci-C6)alkoxide; more preferably, the base is potassium carbonate or cesium carbonate.

6. Process according to claim 5 wherein step (i) is carried out in the presence of a catalytically effective amount of (i) a nucleophilic catalyst and (ii) a phase transfer agent, said nucleophilic catalyst being preferably / V, / V-dimethylaminopyridine and said phase transfer agent being preferably a bromide salt of a cation of formula+NRaRbRcRd, wherein each one of Ra, Rb, Rcand Rd is independently a (Ci-Ce)alkyl group.

7. Process according to any one of claims 5 to 6 wherein step (i) is carried out in an aprotic solvent, said solvent being preferably / V, / V-dimethylformamide or methyltetrahydrofurane.

8. Process according to any one of claims 1 to 7 wherein: the compound of formula (I) is a compound of formula (la)wherein PG is a tert-butoxycarbonyl group and step (i) is carried out in the presence of:- potassium carbonate;- a catalytically effective amount of (i) N,N-dimethylaminopyridine and (ii) tetrabutylammonium bromide; and-a polar aprotic solvent that is preferably N,N-dimethylformamide; or, alternatively, the compound of formula (I) is a compound of formula (lb)wherein PG is a tert-butoxycarbonyl group and step (i) is carried out in the presence of:- cesium carbonate;-an aprotic solvent that is preferably methyltetrahydrofurane.

9. Process according to any one of claims 1 to 8 wherein before step (i) a previous step (a) is carried out consisting in the preparation of the compound of formula (I) by treating a compound of formula (VII) for forming a compound of formula (I)wherein PG is as defined in any one of claims 1 to 3 and wherein: in a first alternative, step (a) comprises causing a compound of formula (VII) to react with a compound of formula PX3, wherein X is a halo group to form a compound of formula (I) wherein each LG is a halo group; in a second alternative step (a) comprises causing a compound of formula (VII) to react with a compound of formula R2SO2CI or (R2SO2)2O, wherein R2 is selected from the group consisting of linear or branched (Ci-C6)alkyl chain, a linear or branched (C1- Ce)haloalkyl chain and a phenyl group optionally substituted at any available position with a linear or branched (Ci-C6)alkyl chain to form a compound of formula (I) wherein each LG is a group of formula -OSO2R2; or, in a third alternative step (a) comprises step (a-1) of causing a compound of formula (VII) to react with a compound of formula R2SO2CI or (R2SO2)2O, wherein R2 is selected from the group consisting of linear or branched (Ci-C6)alkyl chain, a linear or branched (C1- Ce)haloalkyl chain and a phenyl group optionally substituted at any available position with a linear or branched (Ci-C6)alkyl chain to form a compound of formula (I) wherein each LG is a group of formula -OSO2R2; and a further step (a-2) of causing a compound of formula (I) wherein each LG is a group of formula -OSO2R2 to react with a halide salt to form a compound of formula (I) wherein each LG is a halo group.

10. Process according to claim 9 wherein before step (a) a previous step (b) is carried out consisting in the preparation of the compound of formula (VII) by causing a compound of formula (VI) to react in reducing conditions to form a compound of formula (VII)9 CO2R4CO2R5(VI) wherein PG is as defined in any one of claims 1 to 3 and R4 and R5, which may be identical or different to each other, are independently selected from a (Ci-Ce)alkyl chain; preferably R4 and R5 are each a ethyl group.11 . Process according to claim 10 wherein before step (b) a previous step (c) is carried out consisting in the preparation of a compound of formula (VI) by causing a compound of formula (X) to react with a compound of formula (XI) to form a compound of formula (VI)R5O2C^LG'(X) (XI) wherein LG’ is a leaving group, PG is as defined in any one of claims 1 to 3 and each of R4 and R5 is independently a (Ci-C6)alkyl chain; preferably LG’ is bromo and R4 and R5 are each a ethyl group12. Process according to claim 9 wherein before step (a), a previous step (b’) is carried consisting in the preparation of the compound of formula (VII) by causing a compound of formula (XVI) to react in reducing conditions to form a compound of formula (VII)Boc(XVI) wherein PG is as defined in any one of claims 1 to 3.13 Process according to claim 12 wherein before step (b’) a previous step (o’) is carried out consisting in the preparation of a compound of formula (XVI) by causing a compound of formula (XVII) to react in oxidating conditions to form a compound of formula (XVI)14. Process according to any one of claims 1 to 13 wherein the compound of formula (IV) is subsequently resolved in step (iv) to produce an enantiomerically enriched compound of formula (IV’)15. A process for the preparation of a compound of formula (V)said process comprising the steps of:(i) preparing a compound of formula (IV) or a compound of formula (IV’) according to the process of anyone of claims 1 to 14;(ii) converting the compound of formula (IV) or the compound of formula (IV’) in the compound of formula (V).

16. Process according to claim 15 wherein step (ii) is carried out by: in a first alternative, carrying out a step (e) of causing a compound of formula (IV) or (IV’) to react with O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine to form a compound of formula (VIII) or a compound of formula (VIII’), respectively, the compound (VIII’) being an enantiomerically enriched ( ?)-enantiomer of the compound of formula (VIII)when in the compound of formula (VIII) or in the compound of formula (VIII’), R is F, carrying out a step (f), subsequent to step (e), which comprises causing the compound of formula (VIII) or (VIII’) to react with 4-hydroxy-N-methylbenzamide to form a compound of formula (IX) or a compound of formula (IX’) respectively, the compound (IX’) being an enantiomerically enriched (R)-enantiomer of the compound of formula (IX)and carrying out a step (h), subsequent to step (e), or (f) of forming a compound of formula (V) or a compound of formula (V’) from a compound of formula (IX) or (IX’) by causing said compound of formula (IX) o (IX’) to react in conditions for removing the THP and PG groups; or in a second alternative, carrying out a step (e) of causing a compound of formula (IV) or (IV’) to react with O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine to form a compound of formula (VIII) or a compound of formula (VIII’), respectively, the compound (VIII’) being an enantiomerically enriched ( ?)-enantiomer of the compound of formula (VIII)when in the compound of formula (VIII) or in the compound of formula (VIII’), R is F, carrying out a step (g) which consists of steps (g-1), (g-2) and (g-3), said steps being subsequent to step (e), step (g-1) comprising causing the compound of formula (VIII) or the compound of formula (VIII’) to react with methyl 4-hydroxy-benzoate to form a compound of formula (XIV)or a compound of formula (XIV’), respectively, the compound (XIV’) being an enantiomerically enriched ( ?)-enantiomer of the compound of formula (XIV); carrying out step (g-2), subsequent to step (g-1), of causing a compound of formula (XIV) or a compound of formula (XIV’) to react in hydrolysis conditions to form a compound of formula (XV) or a compound of formula (XV’), respectively, the compound (XV’) being an enantiomerically enriched (R)-enantiomer of the compound of formula (XV)carrying out step (g-3) of causing a compound of formula (XV) or a compound of formula (XV’) to react with methylamine to form a compound of formula (IX) or (IX’); and carrying out a step (h), subsequent to step (e), or (g), of forming a compound of formula (V) or a compound of formula (V’) from a compound of formula (IX) or (IX’) by causing said compound of formula (IX) o (IX’) to react in conditions for removing the THP and PG groups; or in a third alternative, carrying out step (j) of causing a compound of formula (IV) or a compound of formula (IV’), wherein R is preferably 4-methylcarbamoyl)phenyloxy, to react with a compound of formula (Ci-C6)alkylCOCI, such as isobutyl chloroformate, to form a compound of formula (XVIII) or a compound of formula (XVIII’), the compound (XVI 11’) being an enantiomerically enriched (R)-enantiomer of the compound of formula(XVIII) when in the compound of formula (IV) or in the compound of formula (IV’) R is F, carrying out step (j’) prior to step (j) comprising causing to react a compound of formula (IV) or a compound of formula (IV’) wherein R is F with 4-hydroxy-N-methylbenzamine to form a compound of formula (IV) or a compound of formula (IV’) wherein R is 4- methylcarbamoyl)phenyloxy; carrying out step (k) subsequent to step (j) of causing a compound of formula (XVIII) or a compound of formula (XVIII’) to react with hydroxylamine to form a compound of formula (XIX) or a compound of formula (XIX’), the compound (XIX’) being an enantiomerically enriched (R)-enantiomer of the compound of formula (XIX);and carrying out a step (h), subsequent to step (k), of forming a compound of formula (V) or a compound of formula (V’) from a compound of formula (XIX) or a compound of formula (XIX’) by causing said compound of formula (XIX) or the compound of formula (XIX’) to react in conditions for removing the PG group.

17. A compound of formula (I) or a salt thereof,wherein PG is an amine protecting group selected from the group consisting of benzyl, p-methoxybenzyl, a group of formula -SO2R3’ and a group of formula -C(=O)OR3, wherein R3 is selected from the group consisting of tert-butyl, benzyl, allyl and fluorenyl; and wherein R3’ is selected from the group consisting of p-tolyl, phenyl optionally substituted with one or two nitro groups and trifluoromethyl; and provided that when PG is te / Y-butoxycarbonyl or benzyloxycarbonyl and each LG represents the same group, LG is other than methylsulfonate.

18. The compound according to claim 17 wherein each LG is bromo and PG is terf- butoxycarbonyl.

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