Preparation of Compounds and Compositions for Inhibiting the Activity of SHP2

Abstract

The present invention relates to a process for the preparation of a compound of Formula I or a pharmaceutically acceptable salt, acid co-crystal, hydrate or other solvate thereof, said process comprising reacting a compound of Formula II with a compound of Formula III according to the following reaction scheme: wherein LG, A, n, m and p are as defined in the Summary of the Invention, and said preparation comprises making and using a compound of Formula VI: wherein R1 is a secondary amino protecting group and R5 is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl or unsubstituted or substituted aryl. [Formula 1] TIFF2023532748000113.tif70170

Description

[Technical Field]

[0001] The present invention relates to a method for preparing compounds capable of inhibiting the activity of SHP2 and to intermediates useful therein. [Background technology]

[0002] Src homology-2 phosphatase (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to multiple cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 is involved in signal transduction through the Ras mitogen-activated protein kinase, JAK-STAT, or phosphoinositol 3-kinase-AKT pathways.

[0003] Formula I: [ka] A compound designated (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, represented by the formula: and pharmaceutically acceptable salts thereof, is described in WO 2015 / 107495 A1 as an inhibitor of SHP2. Various methods of treatment and therapy are also described.

[0004] Src homology-2 phosphatase (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to multiple cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 is involved in signal transduction through the Ras mitogen-activated protein kinase, JAK-STAT, or phosphoinositol 3-kinase-AKT pathways.

[0005] SHP2 contains two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains regulate the subcellular localization and function of SHP2. The molecule exists in an inactive, autoinhibited conformation stabilized by a network of bonds involving residues from both the N-SH2 and PTP domains. Stimulation by, for example, cytokines or growth factors, leads to exposure of the catalytic site, resulting in the enzymatic activation of SHP2.

[0006] Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several human diseases, such as Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and colon cancer. Therefore, SHP2 is a very attractive target for the development of novel therapeutics for the treatment of various diseases. Compounds that can be produced according to the present invention fulfill the need for small molecules that inhibit the activity of SHP2.

[0007] WO 2020 / 065452A1 describes three methods for producing compounds of formula I, which can be characterized by the following reaction scheme (see WO 2020 / 065452A1 for further details). While these synthesis methods are inherently feasible, they can be improved (e.g., improve reaction safety, use fewer materials, and generate less waste). These methods can be essentially summarized as follows:

[0008] Scheme 1: This shows the three routes B to D disclosed in WO 2020 / 065452. Route B: [ka] Route C: [ka] Route D: [ka]

[0009] The HCl salt compound A17 (equivalent to B7, C10 and D10) is then converted to a compound of formula I as follows. [ka]

[0010] The preparation of Y10a (equivalent to Z17a and Y7a) (detailed in WO 2020 / 065452 A1) was carried out as follows: Variation (i): [ka] Or alternatively, the following route, variant (ii): [ka] This is achieved by:

[0011] Further alternatively, compound Z17a is made by the following route (variant (iii)): [ka]

[0012] Each of the above routes is suitable for the commercial synthesis of compounds of Formula I. However, synthetic route B (above) requires the use of an equal (equimolar) amount of lactone B2 (equivalent to C2 and D2) to obtain B3. This represents a relatively large amount of B2 for commercial production, especially since it is used in the first step of the overall synthesis.

[0013] Furthermore, to achieve good conversion of compound B3 to B4, at least a 5-fold molar excess (5 equivalents) of hydroxylamine hydrochloride is required, which is far from ideal for large-scale synthesis due to thermal safety risks.

[0014] Surprisingly, the present invention overcomes both the large amount of material required and the thermal safety risk by producing B4 using a novel intermediate B3', which has a chemical structure that is uniquely different from B3 and C3.

[0015] Fewer materials are required in this improved synthesis to synthesize B4. First, much less hydroxylamine hydrochloride is required (much less than 5 equivalents) to achieve the reaction from B3' to B4. Furthermore, less L-lactide B2 (roughly half the relative (equivalent) amount of B2) is required for the reaction with B1 (equivalent to A5).

[0016] This novel method for the preparation of intermediate B4 can be illustrated in a particular form, which is not meant to be limiting to the scope of the present invention, by the following reaction scheme, Scheme A. [ka]

[0017] Thus, the reaction via the novel intermediate B3' (1-(tert-butyl) 4-ethyl (S)-4-(2-hydroxypropanoyl)piperidine-1,4-dicarboxylate) allows for a significant improvement in the reaction for preparation, resulting in the synthesis of compounds of formula I.

[0018] Further improvement of the synthesis of the compound of formula I disclosed in WO 2020 / 065452 A1 relates to variant (i) for the preparation of compound Y7c (above). The anhydrous Na2S used in this reaction is pyrophoric and not commercially available on a large scale. Furthermore, the use of tetrabutylammonium salt required for post-treatment is poorly biodegradable.

[0019] Compound Z17c can also be prepared by variants (ii) or (iii) above, but these also have the disadvantage of using thiol compounds and requiring very strong reaction conditions and strong reagents, e.g., sodium ethoxylate.

[0020] However, this problem can be solved in a surprisingly advantageous way, which can be illustrated in a particular form, which is not meant to be limiting to the scope of the present invention, by the following reaction scheme, Scheme B. [ka] (Note that Y7c' corresponds to Z17c in variants (ii) and (iii) above.) Instead, sodium sulfide is replaced with sodium thiosulfate, which is not pyrophoric and is available on a large scale. Furthermore, the materials used are cheaper and use more environmentally friendly solvents. Workup is simplified and the reaction mixture is tetrabutylammonium salt-free and odorless. Summary of the Invention

[0021] In one aspect, the present invention provides a process for preparing a compound of formula I, as described above, or a pharmaceutically acceptable salt, acid co-crystal, hydrate, or other solvate thereof.

[0022] In a further aspect, the present invention provides a process for the preparation of a compound of formula I as described above, or a pharmaceutically acceptable salt, acid co-crystal, hydrate or other solvate thereof (where subsequently only reference is made to the compound of formula I, these variations are also included), said process comprising the steps of: [ka] wherein LG is a leaving group, in particular chloro, A is an anion of a protic acid, in particular Cl anion, and n, m and p are integers, preferably 1, 2 or 3, preferably m is 1, n is 1 and p is 2, so that the salt of formula II is electrically neutral; wherein the compound of formula II is preferably a compound of formula IV [ka] (wherein in the case of formula (i) R1 is a secondary amino protecting group (meaning a protecting group that protects a secondary amino), in particular tert-butoxycarbonyl, R2 is a protected amino group, in particular acetylamino or tert-butoxycarbonylamino, and R3 is hydrogen, or in the case of formula (ii) R1 is a secondary amino protecting group, preferably tert-butoxycarbonyl, R2 is amino, and R3 is hydroxyl), by (i) deprotection or (ii) reduction, and if necessary (i.e., if the acid is not already present, for example by deprotection), a compound of formula II * The compound thus obtained [ka] and formula H n Reaction of A with an acid (as described herein) provides a compound of formula II.

[0023] In both cases (i) and (ii) just described, in a preferred independent second aspect of the present invention (meaning that the reaction from a compound of formula V to a compound of formula VI is an embodiment according to the invention in itself), or as part of the preparation of a compound of formula I, the preparation of a compound of formula II in a first step, preferably followed by a further step as defined by a further embodiment according to the invention as defined below, comprises the reaction of a compound of formula V in the presence of a strong base [ka] wherein R1 is a secondary amino protecting group, particularly tert-butoxycarbonyl, and R4 is a carboxyl (—COOH) protecting group, particularly alkyl, e.g., ethyl, with L-lactide of the formula [ka] and reacting the compound of formula VI with [ka] wherein R1 is as defined for compounds of formula IV and R5 is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl or unsubstituted or substituted aryl, in particular ethyl.

[0024] This reaction of the second embodiment of the invention is itself also one embodiment of the present invention.

[0025] As a further independent embodiment of the present invention, or preferably in a further step, a compound of formula VI as just described may be cyclized with hydroxylamine, or a salt thereof, to give a hydroxylamine compound of formula VII, respectively. [ka] where R1 is as defined for compounds of formula IV.

[0026] The two steps of reaction of a compound of formula V with L-lactide to give a compound of formula VI, and subsequent cyclization with hydroxylamine to give a compound of formula VII also form an independent important embodiment of the present invention.

[0027] In a further independent embodiment, in a further step, the compound of formula VII is (ai) hydrogenated to form an amino compound of formula VIII [ka] wherein R1 is as defined for compounds of formula IV, or (a-ii) acylation under reducing conditions (with an amino protecting group inserting agent, such as acetic anhydride or di-tertbutyl dicarbonate) to give compounds of formula VIII * Compounds of [ka] wherein R1 is as defined for compounds of formula IV; * R2 is an acylated amino (=acyl-protected amino; preferably acetylamino) is obtained.

[0028] In another preferred embodiment, in a further step after the immediately preceding reaction (ai), the compound of formula VIII is (bi) reduced to give a compound of formula IX [ka] wherein R1 is as defined for the compound of formula IV, preferably tert-butoxycarbonyl, which is a compound of formula IV, wherein R1 is a secondary amino protecting group, in particular tert-butoxycarbonyl, R2 is amino and R3 is hydroxyl; where reduction step (ii) as described above for the corresponding compound of formula IV falling within the definition of the compound of formula IX is preferably carried out in a further step using a trialkylsilane to give a compound of formula H as defined above. n After subsequent addition of an acid of A, in particular HCl, the compound of formula II as shown above is obtained; Alternatively (ci), the compound of formula VIII may, in a further embodiment according to the invention, be reacted in a further step with an amino protecting group inserting compound, in particular (Boc)2O, to give a compound of formula X [ka] wherein R1 is as defined for the compound of formula IV and R2 is a protected amino group, in particular tert-butoxycarbonylamino, is obtained, which compound of formula X can preferably be converted in a further step to a compound of formula XI [ka] wherein R1 is as defined for the compound of formula IV and R2 is a protected amino group, in particular tert-butoxycarbonylamino; this compound of formula XI is preferably reduced in a further step at the hydroxy of the hydroxymethyl group (directly attached to the ring) to a compound of formula LG * -X (wherein LG * is reacted with an electrophilic group capable of forming, together with the hydroxy to which it is attached, a leaving group LG2, in particular tosyloxy or preferably 2,4,6-triisopropylbenzenesulfonyl)oxy, and X is a halogen, in particular chloro, to give a compound of formula XII [ka] wherein R1 is as defined for the compound of formula IV, R2 is a protected amino group, in particular tert-butoxycarbonylamino, and LG2 is a leaving group, in particular tosyloxy or, preferably, 2,4,6-triisopropylbenzenesulfonyloxy; This compound of formula XII can then, in a further embodiment of the present invention, be cyclized under basic conditions in a further step to give the compound of formula XIII [ka] wherein R1 is a secondary amino protecting group, in particular tert-butoxycarbonyl, and R2 is a protected amino group, in particular tert-butoxycarbonylamino, which gives a compound of formula IV wherein R1 is a secondary amino protecting group, in particular tert-butoxycarbonyl, R2 is a protected amino group, in particular tert-butoxycarbonylamino, and R3 is hydrogen, in which the deprotection step (i) of the compound of formula XIII as described above for the corresponding compound of formula IV can preferably be carried out in a further embodiment according to the invention by deprotection with an acid H as defined for the compound of formula II. n A to give compounds of formula II as shown above.

[0029] In another preferred embodiment, in a further step after the above reaction (a-ii), * is hydrogenated in the presence of a chiral hydrogenation catalyst to give a compound of formula X * Compounds of [ka] wherein R1 is as defined for compounds of formula IV; * R2 is an acylated amino group, in particular acetylamino), to give a compound of formula X * In a further embodiment of the invention, the compound of formula XI * Compounds of [ka] wherein R1 is as defined for compounds of formula IV; * R2 is reduced to an acylated amino group, in particular acetylamino; Formula XI * In a further embodiment of the invention, the compound of formula XI * In the case of a hydroxy group of the formula LG* -X (wherein LG * is reacted with an electrophilic group capable of forming a leaving group LG2 with the hydroxy to which it is attached, particularly tosyloxy, and X is a halogen, particularly chloro, to give a compound of formula XII * Compounds of [ka] wherein R1 is as defined for compounds of formula IV, R2 is a protected amino group, in particular acetylamino, and LG2 is a leaving group, in particular tosyloxy; Formula XII * is then, in a further embodiment of the present invention, cyclized under basic conditions in a further step to give the compound of formula XIII * Compounds of [ka] wherein R1 is a secondary amino protecting group, in particular tert-butoxycarbonyl; * R2 is an acylated amino group, in particular acetylamino), which corresponds to a compound of formula IV, in which R1 is a secondary amino-protecting group, in particular tert-butoxycarbonyl, R2 is an acylated (=acyl-protected) amino group, in particular acetylamino, and R3 is hydrogen; * The deprotection step (i) (deprotection here means deacylation) of the compound of formula II described above for the corresponding compound of formula IV can preferably be carried out in a further embodiment according to the present invention by the addition of an acid H n A to give compounds of formula II as shown above.

[0030] The following novel key intermediates also represent embodiments in accordance with the present invention in their own right.

[0031] Compound of Formula VI [ka] wherein R1 is as defined for compounds of formula IV, in particular tert-butoxycarbonyl, and R5 is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl or unsubstituted or substituted aryl, in particular ethyl; or a salt thereof.

[0032] A further embodiment of the present invention is the preparation of intermediates of formula (III), both as separate embodiments of the present invention or as part of the overall synthesis of compounds of formula (III) and / or as a synthesis of compounds of formula (I). [ka] wherein LG is a leaving group, [ka] wherein LG is a leaving group and Mt is an alkaline earth metal atom (especially half an atom of metal relative to each sulfur atom in terms of charge) or (preferably) an alkali metal atom (especially in a ratio of 1 Mt to 1 S) with a compound of formula (XVI) [ka] to obtain a compound of formula (III), wherein the reaction occurs under transition metal-free reaction conditions. DETAILED DESCRIPTION OF THE INVENTION

[0033] The following definitions define more general features in a preferred, more specific manner, and one, more than one, or all of the more general features in alternative embodiments of the invention may be replaced with more specific definitions that define more specific embodiments of the invention.

[0034] The conditions for the above-mentioned reaction are particularly selected as follows:

[0035] The reaction of compound II with a compound of formula III (wherein LG is a leaving group, preferably halo, particularly bromo or more particularly chloro) is preferably carried out in the presence of a weak base, such as an alkali metal carbonate or metal bicarbonate, in a mixed solvent composed of an aprotic solvent, such as an N,N-dialkylamide of an alkanoic acid, for example, dimethylacetamide or dimethylformamide, and water, or in a mixed solvent composed of an aprotic solvent, such as sulfolane, and an alcoholic solvent, for example, isopropanol, and water, preferably at an elevated temperature, for example, in the range of from 30°C to the boiling point of the reaction mixture, for example, 50-100°C.

[0036] The deprotection (i) of a compound of formula IV (wherein R1 is a secondary amino protecting group, R2 is a protected amino group, and R3 is hydrogen) to give a compound of formula II is preferably carried out with a strong acid H n The reaction is carried out in the presence of an acid such as trifluoroacetic acid, trifluoromethanesulfonic acid or preferably an inorganic acid such as sulfuric acid, phosphoric acid or especially a hydrogen halide, most especially hydrogen chloride, in a solvent such as an alcohol, for example ethanol or especially methanol, or a mixture of alcohols (especially when R2 is benzyloxycarbonyl or especially alkoxycarbonyl, for example tert-butoxycarbonyl), or in an ester solvent such as isopropyl acetate (IPAc), or in the presence of water (especially when R2 is acyl, especially lower alkanoyl, for example acetyl), at a preferred temperature in the range of from 10°C to the boiling temperature of the solvent, for example 20°C to 115°C (especially when R2 is acyl).

[0037] The alternative reduction (ii) of compounds of formula IV (wherein R1 is a secondary amino protecting group, R2 is amino and R3 is hydroxyl) is preferably carried out with a trialkylsilane, in particular triethylsilane, in the presence of a strong inorganic acid or preferably a (strong) organic acid, in particular trifluoromethanesulfonic acid, in a suitable aprotic solvent, such as ether or in particular acetonitrile, to form a compound with the acid H n Subsequent addition of A gives the compound of formula II (as a salt or co-crystal).

[0038] The reaction of the compound of formula V with L-lactide to give the compound of formula VI is preferably carried out in the presence of a strong base, particularly an alkyl-alkali metal, such as n-butyllithium, and a nitrogen base, particularly diisopropylamine or diethylamine, in a solvent, such as an acyclic or, particularly, a cyclic ether, particularly tetrahydrofuran or, preferably, 2-methyltetrahydrofuran, preferably at a low temperature, for example, in the range of −80 to −5° C. When the reaction is carried out near −80 to −40° C., particularly in the range of −60 to −50° C., the result is preferably a compound of formula VI when the amount of the compound L-lactide (L-form of lactide) is 30 to 70 mol percent, preferably 45 to 65 mol%, more preferably 50 to 60 mol%, relative to the molar amount of the compound of formula V, i.e., roughly about half the molar amount of the compound of formula V. Mol% refers to molar percent.

[0039] The cyclization of a compound of formula VI with hydroxylamine, or a salt thereof, to a compound of formula VII preferably occurs with an acid addition salt of hydroxylamine, for example its hydrohalide salt, for example its hydrochloride salt, in the presence of a weak base, for example an alkali metal alkanoate, for example sodium acetate, in a solvent, for example an acyclic or, especially, a cyclic ether, in particular tetrahydrofuran or preferably 2-methyltetrahydrofuran, at a preferred temperature in the range of 0 to 80°C, for example 10 to 50°C.

[0040] The hydrogenation (ai) of the hydroxylamine compound of formula VII to the corresponding amine of formula VIII is preferably carried out as a heterogeneous hydrogenation in the presence of a hydrogenation catalyst such as platinum, palladium, rhodium, or ruthenium, or other highly active catalysts operating at lower temperatures (e.g., 0-40°C) and lower pressures (e.g., 1 bar) of H2, or at higher temperatures and higher H2 pressures, e.g., in the range of 5-50 bar, e.g., 10-20 bar, in the presence of a non-noble metal catalyst, in particular a catalyst based on nickel (such as Raney nickel and Urushihara nickel). The reaction is carried out in a polar solvent, in particular an alcohol, e.g., an alkanol, e.g., ethanol, or especially methanol.

[0041] Formula VIII * The acylation of the hydroxyl compound of formula VII (a-ii) under reducing conditions to give a compound of formula VII is preferably carried out at elevated temperatures, preferably in the range of from 25° C. to the boiling point of the reaction mixture, for example in the range of from 40 to 80° C., in an inert organic solvent, such as a hydrocarbon or aromatic compound, for example toluene or xylylene, in the presence of a base metal, for example zinc (such as zinc amalgam) or especially iron, as reducing agent, and an acid, either an inorganic acid, for example a hydrogen halide, for example hydrogen chloride, sulfuric acid, or an organic acid, for example a carboxylic acid anhydride corresponding to the anhydride, in particular an alkanoic acid, in particular acetic acid, as an acylating agent, in particular an anhydride of a carboxylic acid, for example an alkanoic anhydride, in particular acetic anhydride.

[0042] Acyl, in the context of the present invention, refers to a moiety of an organic acid in which the carboxyl (-COOH) group is attached to a carbon (e.g., as in acetyl = H3CCOO-) rather than to an oxygen (e.g., as in tert-butoxycarbonyl) in the acyl rest itself.

[0043] The reduction (bi) of a compound of formula VIII to a compound of formula IX is preferably carried out using a complex hydride, such as diisobutylaluminium hydride, which reduces the oxo in formula VIII to the hydroxy in formula IX, preferably at low temperature in the range of from −100 to −20° C., for example from −80 to −70° C., in an aprotic solvent, such as an ether or especially a cyclic ether, such as tetrahydrofuran.

[0044] Next, when the compound of formula IX, corresponding to the respective compound of formula IV, is reduced to the compound of formula II, the reduction is preferably carried out using a trialkylsilane, especially triethylsilane, in an aprotic solvent, such as a hydrocarbon, ester or especially a nitrile, such as acetonitrile, at an elevated temperature, preferably in the range of from 30° C. to the boiling point of the reaction mixture, for example 50-95° C., in an acid, especially a strong organic sulfonic acid, such as trifluoromethanesulfonic acid. n The subsequent reaction with A is preferably carried out in a protic, potentially aqueous solvent, such as isopropyl alcohol.

[0045] The reaction (ci) of a compound of formula VIII with an amino group inserting agent, in particular a dialkanoyl dicarbonate, in particular di-tert-butyl dicarbonate (=Boc anhydride), is preferably carried out in the presence of a tertiary amine, such as a tri-alkyl-amine, in particular diisopropylethylamine, or in the presence of a weak inorganic base, such as an alkali metal carbonate or metal hydrogen carbonate, in an aprotic solvent, in particular a halogenated hydrocarbon, for example dichloromethane, or in an ether or in particular a cyclic ether, for example tetrahydrofuran, at a preferred temperature in the range of 0 to 50°C, for example 20 to 30°C, to give a compound of formula X.

[0046] The reduction of a compound of formula X to a compound of formula XI is preferably carried out in the presence of a complex hydride, such as lithium borohydride and / or sodium borohydride, capable of reducing the lactone group in formula X to the open ring in formula XI bearing two hydroxy groups, in an aprotic solvent, such as a linear or preferably cyclic ether, such as tetrahydrofuran or 2-methyltetrahydrofuran, preferably at a temperature in the range of 0-50°C, for example 20-40°C.

[0047] a leaving group forming agent LG2, which results in the introduction of a leaving group of formula LG2, giving rise to a compound of formula XII * -X (wherein X is halogen, in particular chloro) and LG * is an electrophilic group capable of forming a leaving group LG2 together with the hydroxy to which it is attached, in particular a sulfonyl halide, preferably toluenesulfonyl chloride or more preferably 2,4,6-triisopropylbenzenesulfonyl chloride), preferably occurs in the presence of a base, for example an alkali metal hydroxide, for example sodium hydroxide, in an aqueous organic solvent, for example an aqueous halogenated hydrocarbon, for example dichloromethane, or in an ether or especially a cyclic ether, for example tetrahydrofuran, at a preferred temperature in the range of -10 to 50°C, for example -5 to 30°C.

[0048] Cyclization of a compound of formula XII to a compound of formula XIII under basic conditions in the presence of a base, especially an alkali metal hydroxide, for example sodium hydroxide, in the presence or absence of a phase transfer catalyst, for example a tetraalkylammonium halide, for example tetra-n-butylammonium bromide, in an aqueous organic solvent, for example an aqueous halogenated hydrocarbon, for example dichloromethane, or in an ether or especially a cyclic ether, for example tetrahydrofuran, at a preferred temperature in the range of 0 to 50°C, for example 20 to 30°C.

[0049] The deprotection of the compound of formula XIII is preferably carried out in a polar solvent, such as an alcohol, for example an alkanol, for example ethanol or, in particular, methanol, or in an ester solvent, for example isopropyl acetate (IPAc), at a preferred temperature in the range of 0-50°C, for example, at 20-30°C, with the acid H, which is part of the salt of formula II thus obtained. n It occurs due to A.

[0050] For example, in the presence of a chiral hydrogenation catalyst (typically formed from, for example, a ruthenium(I)-based precatalyst such as bis(norbornadiene)rhodium(I) tetrafluoroborate and a chiral ligand), as defined below, * to a compound of formula VIII * The hydrogenation of the compound (I) is preferably carried out using hydrogen at a temperature in the range of 30 to 80°C, e.g., 40 to 60°C, in a polar solvent, particularly 2,2,2-trifluoroethanol, under high pressure, e.g., 3 to 50 bar, e.g., 20 to 40 bar. This hydrogenation is more commonly carried out using hydrogen in the presence of a transition metal catalyst, preferably a transition metal catalyst comprising an organometallic complex and a chiral ligand. This reduction can be carried out under heterogeneous or homogeneous hydrogenation conditions, preferably homogeneous hydrogenation conditions. The transition metal is selected from Group 9 or 10 of the periodic table. Thus, transition metal catalysts include, for example, cobalt (Co), rhodium (Rh), iridium (Ir), nickel (Ni), palladium (Pd), and / or platinum (Pt).

[0051] Among the chiral catalysts, those of formula X * To create a stereochemistry at the previous double bond shown in formula VIII * Suitable are all those which allow hydrogenation of the double bond in the compound of formula (I). It is further preferred that the chiral ligand comprises a chiral ferrocene.

[0052] Preferred chiral ferrocenes are of the formula [ka] but others are also possible, for example selected from the group comprising any one of the following formulae: [ka]

[0053] Mixtures of two or more such ligands, in particular those defined by the above formula, are also possible.

[0054] Typically, an active catalyst is formed by mixing 0.9-1.2, preferably 1.0-1.1, more preferably 1.0-1.05 moles of chiral ligand with 1.0 mole of transition metal atom contained in the transition metal catalyst. For example, when a dimeric transition metal catalyst is used, preferably 2 moles of chiral ligand are reacted with 1 mole of transition metal catalyst to form the "active catalyst."

[0055] The chiral ligand is typically added to the reaction mixture in a solution prepared in the same solvent used in the reaction.

[0056] Formula XI under ring opening * to a compound of formula X * is preferably carried out in the presence of a complex hydride, such as lithium borohydride, capable of reducing the lactone group in formula X to the ring-opened compound in formula XI with the two hydroxy groups, in an aprotic solvent, such as a linear ether or preferably a cyclic ether, such as tetrahydrofuran, at a temperature in the range of 0-50°C, for example 20-30°C.

[0057] The amino protecting group is preferably a hydrogen halide such as, for example, HCl, or a compound of formula H as defined for compounds of formula II when the compound of formula II is the direct reaction product. nA is a group that can be cleaved under moderately acidic conditions in the presence of an acid A (particularly where n is 1 and A is a halide anion, especially a chloride anion). Examples include 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, and especially tert-butoxycarbonyl. However, acyl groups, especially alkanoyl groups having, for example, 2 to 10 carbon atoms, such as acetyl, are also suitable amino-protecting groups.

[0058] Formula XII * a leaving group forming agent LG to give a compound of formula * -X (wherein X is halogen, particularly chloro), LG * which leads to the introduction of a leaving group of formula LG2 with an electrophilic group, in particular a sulfonyl halide, preferably toluenesulfonyl chloride, capable of forming a leaving group LG2 together with the hydroxy to which it is (to be) attached, * The reaction of the compounds of formula (I) is preferably carried out in the presence of a base, for example an alkali metal hydroxide, for example sodium hydroxide, in an aqueous organic solvent, for example an aqueous halogenated hydrocarbon, for example dichloromethane, at a preferred temperature in the range of 0 to 50°C, for example 20 to 30°C.

[0059] Formula XIII * to compound p of formula XII * The cyclization of the compound of formula (I) is preferably carried out under basic conditions in the presence of a phase transfer catalyst, for example a tetraalkylammonium halide, for example tetra-n-butylammonium bromide, in an aqueous organic solvent, for example an aqueous halogenated hydrocarbon, for example dichloromethane, in the presence of a base, in particular an alkali metal hydroxide, for example sodium hydroxide, at a preferred temperature in the range of 0 to 50°C, for example 20 to 30°C.

[0060] Formula XIII * is preferably deprotected at elevated temperatures in the range of 50-120°C, for example 100-115°C, in a polar solvent, for example an alcohol, for example an alkanol, for example ethanol or especially methanol, with an acid Hn A is preferably used.

[0061] The compound of formula III can be obtained as described in WO 2020 / 065452 A1. Preferably, however, it can be prepared as follows:

[0062] The compound of formula III can be prepared in a further single embodiment according to the invention or as part of the total synthesis of the compound of formula I according to the invention, which involves the steps described above and below, by the addition of a compound of formula XIV in a suitable solvent, preferably in the presence of an acid, according to one embodiment. [ka] (This can be obtained from the corresponding trichloro compound 2,3-5-trichloropyrazine (chloro instead of NH and LG, respectively, present in the precursor of compound XIV) and ammonia, as described in WO 2020 / 065452 A1, where LG is a leaving group as defined for compounds of formula III, in particular halo, more preferably iodo, bromo or especially chloro, with a metal thiosulfate (which may or may not be a hydrate), in particular an alkali metal thiosulfate or alkaline earth metal thiosulfate, more preferably an alkali metal thiosulfate, most preferably sodium thiosulfate, followed by treatment with aqueous base to give compounds of formula XV. [ka] where Mt is an alkaline earth metal atom (relatively half an atom of metal per sulfur atom in terms of charge) or preferably an alkali metal atom (in a ratio of 1 Mt to 1 S), in particular a sodium atom, and LG is a leaving group as defined immediately above.

[0063] The reaction is preferably carried out in a suitable solvent, for example an aqueous alcohol, for example methanol or ethanol in a mixture with water, in the presence of an acid, for example an inorganic acid, for example phosphoric acid and / or sodium dihydrogen phosphate, or preferably an organic acid, for example a sulfonic acid or more preferably a strong carboxylic acid, for example a trihaloacetic acid, for example trifluoroacetic acid, or especially a carboxylic acid having multiple carboxyl (—COOH) groups, for example 2-3 such groups, most especially citric acid (which generates less waste than phosphate buffer 85% H3PO4 / NaH2PO4), at a temperature in the range of 20° C. to boiling temperature, preferably in the range of 20-100° C., most preferably in the range of 50-90° C., for example at about 85° C.

[0064] The compound of formula XV may then be prepared in a further preferred embodiment of the present invention after preparation of the compound of formula XV as just described, as part of the total synthesis of the compound of formula I, in a still further preferred embodiment of the present invention, by the addition of a compound of formula XVI [ka] to react with a compound of formula III [ka] wherein LG is in particular a leaving group as defined above for compounds of formula III, most in particular chloro.

[0065] The reaction is preferably carried out in the presence of a noble metal complex, especially formed from Pd2(dbba)2, in the presence of a ligand, for example, Xantphos, and a tertiary nitrogen base, for example, diisopropylamine, in an aprotic solvent, for example, an ether, for example, a cyclic ether, especially dioxane, preferably at elevated temperatures, for example, in the range from 30° C. to the boiling point of the reaction mixture. Alternatively, the reaction can be carried out in a suitable solvent or solvent mixture, for example, an aqueous alcohol, for example, aqueous methanol, ethanol, propanol, or especially isopropanol, at a preferred temperature in the range from 25 to 100° C., for example, 50 to 75° C., under Ullmann-type reaction conditions with, for example, a copper salt, for example, copper(I) iodide, as a complexing agent, and a diamine ligand, for example, a phenanthroline ligand.

[0066] In the case of the novel embodiment according to the invention of the preparation of compounds of formula (III) from compounds of formula XV under transition metal-free reaction conditions, i.e. in the absence of a catalyst which comprises or is in particular an organometallic catalyst, in particular in the absence of catalytic copper salts or catalytic noble metal complexes, the reaction is preferably carried out in a suitable solvent or solvent mixture, for example in aqueous alcohol, for example aqueous methanol, ethanol, propanol or in particular isopropanol, in the presence of an acid, for example an inorganic acid, for example phosphoric acid and / or sodium dihydrogen phosphate, or preferably Alternatively, the reaction may be carried out in the presence of an organic acid such as acetic acid or, more preferably, a strong carboxylic acid such as a trihaloacetic acid, e.g., trifluoroacetic acid, or especially a carboxylic acid having multiple carboxyl (—COOH) groups, e.g., 2-3 such groups, most especially citric acid (which has the added advantage of producing less waste than phosphate buffer 85% H3PO4 / NaH2PO4), at a temperature ranging from 20°C to the boiling temperature of the reaction mixture, preferably in the range of 20-100°C, most preferably in the range of 60-80°C.

[0067] Among the advantages of this synthesis variant, which corresponds to a further variant for the preparation of compound (III) according to variants (i), (ii) or (iii) as described above and is therefore also referred to herein as variant (iv) for the preparation of compound (III), in particular in the form of intermediates Y7a=Y10a=Z17a, in contrast to variant (i) above, it does not require the removal of the copper catalyst by oxidation of the copper by bubbling oxygen (for example with charcoal), which may lead to safety issues, and it does not require the use of potentially mutagenic phenanthroline ligands; on the other hand, compared to variants (ii) and (iii) above, it does not require expensive Pd catalysts, and therefore this variant is highly advantageous, in particular in larger scale syntheses, for example on a scale of more than 1 kg.

[0068] Preferably, this variant (iv) is represented by the following reaction scheme: [ka] where Y7c' = Z17c corresponds to a compound of formula (XV) and Y7b = Z17b corresponds to a compound of formula (XVI). Particular variations of this embodiment are described in the Examples.

[0069] In a preferred embodiment of the invention, the novel reaction is part of the overall preparation of a compound of formula (III) with the preceding reaction steps as described herein, in particular part of the overall preparation of a compound of formula (I), including this particular variant of the preparation of a compound of formula (III) as described herein.

[0070] The compound of formula XVI is preferably reacted with a compound of formula XVII in the presence of a strong base. [ka] It can be obtained by reacting with iodine.

[0071] The reaction is preferably carried out at low temperatures, for example in the range of -80 to -5°C, in a solvent such as an acyclic or, especially, a cyclic ether, preferably tetrahydrofuran, in the presence of a strong base, especially an alkyl-alkali metal, for example n-butyllithium, and a nitrogen base, especially diisopropylamine or diethylamine.

[0072] This provides a compound of formula XVIII: [ka] is obtained, which is then treated with ammonia to give the compound of formula XVI.

[0073] This reaction is then preferably carried out at an elevated temperature, preferably in the range of from 30°C to the boiling point of the reaction mixture, for example 85-95°C, in the presence of free ammonia and an inert polar solvent, for example DMSO.

[0074] Another embodiment of the present invention includes a process for preparing compounds of formula II and III as described above, i.e., compounds of formula I, or pharmaceutically acceptable salts, acid co-crystals, hydrates or other solvates thereof, which process comprises the following reaction scheme: [ka] wherein LG is a leaving group, A is an anion of a protonic acid, and n, m, and p are independently 1, 2, or 3, such that the salt of formula II is electrically neutral.

[0075] Where a compound is referred to above during the process description or by itself, the description of the compound also includes salts, hydrates or solvates thereof, where such forms are not excluded, for example, by the absence of groups capable of forming salts.

[0076] Unsubstituted (preferred) or substituted alkyl, where stated, is in particular C1-C20 -Alkyl, preferably C1-C8-alkyl, which may be linear or branched; preferred are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

[0077] Unsubstituted (preferred) or substituted cycloalkyl refers in particular to saturated rings having 3 to 20 ring carbon atoms, in particular C3-C8-cycloalkyl, such as cyclopentyl, cyclohexyl or cycloheptyl.

[0078] Unsubstituted or substituted aryl is in particular C-C 22 -aryl, in particular phenyl, naphthyl or fluorenyl.

[0079] Where substitution is mentioned, this preferably refers to substitution with one or more substituents known to those skilled in the art as not interfering with any of the reactions described, in particular with a moiety selected from C1-C8-alkoxy, C1-C8-alkanoyloxy, hydroxyl, carboxy, C1-C8-alkoxycarbonyl, or (especially in the case of substituted alkyl) phenyl, naphthyl or fluorenyloxymethyl. [Example]

[0080] The following examples serve to illustrate the present invention without limiting the scope otherwise defined herein. However, they are also preferred embodiments according to the present invention. Abbreviations used: Ac (acetate); AcOH (acetic acid); Ac2O (acetic anhydride); aq (aqueous); Boc (tert-butoxycarbonyl); Boc2O (di-tert-butyl dicarbonate); brine (saturated sodium chloride solution at RT); n-Bu4NBr (tetra-(n-butyl)ammonium bromide); n-BuLi (n-butyllithium); calcd (calculated); DCM (dichloromethane); DIBAL-H (diisobutylaluminum hydride); DIPEA (di(isopropyl)ethylamine); DMAc (dimethylacetamide); DMSO (dimethylsulfoxide); DMSO-d6 ( Perdeuterated dimethyl sulfoxide; eq or equiv. (equivalent); Et (ethyl); EtOAc (ethyl acetate); EtOH (ethanol); HRMS (high-resolution mass spectrometry); hrs. (hours); IPA (isopropyl alcohol); IPAc (isopropyl acetate); IT (internal temperature (of the reaction mixture)); L (liters); LDA (lithium diisopropylamide); LOQ (lower limit of quantitation); MCC (microcrystalline cellulose); Me (methyl); MeOH (methanol); 2-MeTHF (2-methyltetrahydrofuran); MTBE (methyl tert-butyl ether); NMR (nuclear magnetic resonance); PA (polyamide); i PrOH (isopropanol); i PrNH (diisopropylamine); qNMR (quantitative NMR); rt, Rt or RT (room temperature (approximately 20-25°C)); TBAB (tetra-(n-butyl)ammonium bromide); Tf-OH (triflic acid); THF (tetrahydrofuran); TsCl (tosyl chloride); TPSCl (2,4,6-triisopropylbenzenesulfonyl chloride); triflic acid (trifluoromethanesulfonic acid); wt% (weight percent) and Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene).

[0081] Example 1 Route Alpha [ka]

[0082] In detail, the synthesis steps are as follows: Step a (also a preferred embodiment according to the invention in itself): [ka] A 630 L reactor equipped with an impeller agitator was charged with diisopropylamine (17.0 kg, 168 mol, 1.2 equiv.) and 2-methyltetrahydrofuran (185 kg) under a nitrogen atmosphere. The mixture was stirred (medium to high speed) and cooled to IT = 0 ± 5 °C. A solution of n-BuLi (2.5 M in hexanes, 41.6 kg, 154 mol, 1.1 equiv.) was added at IT = 0 ± 5 °C. Freshly prepared LDA in 2-methyltetrahydrofuran was then cooled to IT = -60 ± 10 °C. A solution of B1 (36.0 kg, 140 mol, 1.0 equiv.) in 2-methyltetrahydrofuran (31 kg) was added at IT = -60 ± 10 °C. The resulting yellow solution was stirred at IT = -60 ± 10 °C for 0.5 h. A solution of B2 (11.1 kg, 77 mol, 0.55 equiv.) in 2-methyltetrahydrofuran (91.8 kg) was then added dropwise at IT = -60 ± 10 °C. The mixture was stirred for an additional 1.0 h at IT = -60 ± 10 °C. A solution of acetic acid (21.9 kg, 365 mol, 2.6 equiv.) in 2-methyltetrahydrofuran (10 kg) was added at IT = -60 ± 10 °C (Note: Highly exothermic). The resulting suspension was warmed to IT = 0 ± 5 °C, and then a solution of 0.5% hydrochloric acid (145 kg) was added to the reactor. The biphasic mixture was warmed to IT = 25 ± 5 °C. The reaction mixture was transferred to an extraction vessel, and the lower aqueous layer was discarded. 10 wt % aqueous NaCl solution (72 kg) was added, and the biphasic mixture was stirred for 0.5 h. The lower aqueous layer was discarded. The upper organic phase was collected and stored as a solution of B3' in 2-methyltetrahydrofuran (416 kg) under nitrogen at 25±5°C. HRMS m / z, C 16 H 28 NO6[M+H] +The calculated value is 330.1911, and the measured value is 330.2708.

[0083] Step b (also a preferred embodiment according to the invention in itself): [ka] A 1000 L reactor equipped with an impeller agitator was charged with B3' (407 kg) in 2-methyltetrahydrofuran. 246 kg of 2-methyltetrahydrofuran was added, and the resulting mixture was distilled under vacuum at an IT ≦ 50 °C until 324 kg of distillate was collected. Additional 2-methyltetrahydrofuran (154 kg) was added, and the resulting mixture was distilled under vacuum at an IT ≦ 50 °C until 154 kg of distillate was collected. The water content in the residue was tested and found to be < 3000 ppm. Hydroxylamine hydrochloride (11.7 kg, 168 mol, 1.2 eq) and sodium acetate (13.8 kg, 168 mol, 1.2 eq) were then added. The resulting suspension was stirred (high speed) at an IT = 35 ± 5 °C for 18 hours. The suspension was cooled to an IT = 25 ± 5 °C. Water (144 kg) was then added, and the mixture was stirred for 0.5 hours. The lower aqueous phase was discarded. 7 wt. % aqueous NaCl solution (108 kg) was added, and the biphasic mixture was stirred for 0.5 hours. The lower aqueous phase was discarded. The upper organic phase was collected and distilled under vacuum at an IT ≦ 60 °C until 216 kg of distillate was collected. Toluene (316 kg) was added, and the suspension was distilled under vacuum at an IT ≦ 60 °C until 307 kg of distillate was collected. The resulting suspension was heated to an IT ≦ 80 ± 5 °C with stirring (stirring speed = 56 rpm). n-Heptane (297 kg) was slowly added over 2 hours (stirring speed = 90 rpm). The resulting suspension was cooled to 25 ± 5 °C over 4 hours and filtered through a Nutsche filter (20 μM, PA). The filter cake was rinsed with n-heptane (62 kg), collected, and dried under vacuum. B4 was obtained as a white solid, 22.68 kg (ee=93.74%, assay by qNMR=101.74%, yield over two steps=52.6%). 1H NMR(400MHz,DMSO-d6)δ=11.45(s,1H),5.33(q,J=6.6Hz,1H),3.73-3.58(m,2H),3.56- 3.43(m,1H),3.43-3.35(m,1H),1.87-1.65(m,4H),1.52(d,J=6.7Hz,3H),1.41(s,9H).

[0084] Steps a and b together in their sequential processing also represent a preferred embodiment according to the present invention. Step c: [ka] To a 1 L reactor equipped with an impeller stirrer under a nitrogen atmosphere were added Raney Ni (5 g) and MeOH (250 mL), followed by tert-butyl (S)-4-(hydroxyimino)-3-methyl-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate B4 (25.0 g, 83.80 mmol). The reactor was purged with nitrogen three times and then with hydrogen three times. The mixture was stirred at IT = 80 °C under 20 bar hydrogen pressure for 16 h. The reaction mixture was filtered through microcrystalline cellulose, and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated to dryness to give a white solid (23.0 g). EtOAc (220 mL) was added to the solid, and the resulting suspension was heated to reflux (JT = 100 °C), and n-heptane (550 mL) was added portionwise. The resulting clear solution was cooled to room temperature over 2 hours and allowed to stand overnight to give B5 as a colorless crystalline product (16.7 g, cis / trans >99 / 1, 70%). 1 H NMR (400MHz, CDCl3)δ=4.75-4.64(m,1H), 3.89-3.80(m,1H), 3.68-3.58(m,1 H), 3.48-3.33(m,3H), 1.92-1.61(m,4H), 1.46(s,9H), 1.40(d,J=6.5Hz, 3H).

[0085] Process d: [ka] Under a nitrogen atmosphere, a 500 mL three-necked round-bottom flask was charged with tert-butyl (3S,4S)-4-amino-3-methyl-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate B5 (6.0 g, 21.1 mmol) and THF (200 mL). The solution was cooled to an IT of -78 °C, and 1.0 M DIBAL (42.2 mL, 42.2 mmol, 2.0 equiv.) was added dropwise over a 30 min period. The reaction was stirred at -78 °C for 30 min. The reaction was quenched by careful addition of saturated aqueous Na,K tartrate (150 mL), maintaining an IT of -78 °C to -60 °C. The mixture was vigorously stirred at 20-25 °C until two clear phases were obtained (approximately 1.5 h), and then extracted with EtOAc (200 mL x 2). The combined organic extracts were washed with 20 wt% brine (200 mL), dried over Na2SO4, filtered, and concentrated to give B6 as a viscous oil (6.1 g, 64 wt%, 65% assay yield), which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3)δ=5.06(s,1H), 4.39-4.29(m,1H), 3.68-3.57(m,2H), 3.35-3.24(m,2H), 3 .18(d,J=4.4Hz, 1H), 1.98-1.85(m,1H), 1.75-1.54(m,3H), 1.46(s,9H), 1.35(d,J=6.6Hz, 3H).

[0086] Process e: [ka] To a 100 mL round-bottom flask were added 6.0 g of the above viscous oil and acetonitrile (150 mL). The flask was cooled in an ice-water bath, and triethylsilane (7.4 g, 63.3 mmol) and triflic acid (9.5 g, 63.3 mmol) were added sequentially. The reaction was then stirred in a 90 °C oil bath for 1 h. The reaction was then cooled to 20-25 °C, poured into a separatory funnel, and washed with n-heptane (100 mL x 2). The acetonitrile layer was separated and concentrated to dryness to give a colorless oil, which was diluted with EtOAc (150 mL). 6 N HCl in isopropanol (30 mL) was added dropwise with stirring, precipitating a white solid. MTBE (150 mL) was added, and the white suspension was stirred for 2 h and filtered. The filter cake was washed with EtOAc (50 mL × 2) to give a white solid, which was dissolved in MeOH (6.0 mL) and EtOAc (18 mL) was added dropwise with stirring. The resulting white suspension was filtered and washed with EtOAc (10 mL × 2) to give B7 as a white solid (2.5 g, 81 wt%, 39% over two steps). 1 H NMR (400MHz, DMSO-d6) δ=9.37(br s,1H), 9.25(br s,1H), 8.42(br s,3H), 4.26-4.17(m,1H), 3.72(ABq,J=9.1Hz, 2H), 3.50-3.41(m,1H), 3.28-3.18(m, 1H), 3.18-3.09(m,1H), 2.99-2.74(m,2H), 2.07-1.63(m,4H), 1.22(d,J=6.5Hz, 3H).

[0087] Process f: [ka] A 10 mL Schlenk tube was charged with 3-((2-amino-3-chloropyridin-4-yl)thio)-6-chloropyrazin-2-amine Y7a (0.1 g, 0.347 mmol), (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine dihydrochloride B7 (0.1 g, 0.416 mmol, 1.2 equiv.), DMAc (0.6 mL), and 36 wt% aqueous KCO (0.66 g, 1.735 mmol, 5.0 equiv.). The mixture was stirred in a 100 °C oil bath for 16 h and cooled to 20–25 °C. 20 wt% brine (10 mL) was added, and the mixture was extracted with EtOAc (20 mL × 2). The combined extracts were washed with 20 wt% brine (10 mL × 4), dried over anhydrous NaSO, and filtered. The filtrate was concentrated to dryness to give B8 as a yellow solid (121 mg, 83%). 1 H NMR (400MHz, DMSO-d6)δ=7.64(d,J=6.2Hz, 1H), 7.62(s,1H), 6.26(s,2H), 6. 13(s,2H), 5.74(d,J=5.3Hz, 1H), 4.12-4.02(m,1H), 3.90-3.78(m,2H), 3.67( d,J=8.4Hz, 1H), 3.49(d,J=8.4Hz, 1H), 3.33(s,2H), 2.91(d,J=5.1Hz, 1H), 1. 78-1.68(m,1H), 1.67-1.57(m,1H), 1.56-1.41(m,2H), 1.08(d,J=6.5Hz, 3H).

[0088] Example 2 Route Beta [ka] Step a and Step b: These two steps correspond to steps a and b in route alpha (see Example 1) and give compounds C4=B4.

[0089] Step c: [ka] Under a nitrogen atmosphere, tert-butyl-4-(hydroxyimino)-3-methyl-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate C4 (27.9 g, 93.5 mol), toluene (150 mL), acetic anhydride (29.1 g, 280.6 mmol), acetic acid (16.8 g, 280.6 mmol), and iron (10.4 g, 187.0 mmol) were sequentially added to a 500 mL round-bottom flask. The mixture was vigorously stirred in a 70 °C oil bath for 4 hours and cooled to room temperature. The suspension was filtered through microcrystalline cellulose to remove solid residue, which was then washed with EtOAc (150 mL × 2). The combined filtrate was cooled in an ice-water bath and washed with 5 wt% NaHCO3 (300 mL) and 20 wt% brine (300 mL). The organic layer was separated, dried over NaSO, and filtered. The filtrate was evaporated to dryness. The residue was purified by column chromatography (silica gel, EtOAc / n-heptane = 1 / 1 to 3 / 1, v / v) and further purified by recrystallization from EtOAc / n-heptane to give C5 as white needles (16.7 g, 55%). 1 H NMR (400MHz, CDCl3)δ=7.43(s,1H), 4.10-3.78(m,2H), 3.55-3.38(m,2H), 2.10(s,3H), 1.94(s,3H), 1.76-1.58(m,4H), 1.45(s,9H).

[0090] Process d: [ka] Under a nitrogen atmosphere, a vial was charged with [Rh(NBD)2]BF4 (2.0 mg, 0.005 mmol), ligand L *(Johnson Matthey & Brandenberger AG, Zuerich, Schweiz) (3.3 mg, 0.005 mmol) and DCM (1 mL) were added. The resulting solution was stirred for 30 minutes, and then the solvent was removed to give a yellow solid. To a vial under a nitrogen atmosphere, tert-butyl 4-acetamido-3-methyl-1-oxo-2-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylate C5 (86 mg, 0.27 mmol) and 2,2,2-trifluoroethanol (TFE) (2.7 mL) were added. The vial was placed in a hydrogenation reactor. The reactor was purged three times with nitrogen and then three times with hydrogen. The mixture was stirred at IT = 50 °C under 30 bar hydrogen pressure for 16 hours. The reaction was cooled to 20-25° C., filtered through a short silica pad, and concentrated to dryness to give C6 as a white solid (86 mg, 100%). 1 H NMR (400MHz, DMSO-d6)δ=8.33(br d,J=10.3Hz, 1H), 4.94-4.84(m,1H), 4.71-4.56(m,1H), 3.78-3.65(m,2H), 3.22-3.02(m,1 H), 2.87-2.69(m,1H), 1.89(s,3H), 1.64-1.50(m,4H), 1.40(s,9H), 1.19(d,J=6.7Hz, 3H).

[0091] Process e: [ka] Under a nitrogen atmosphere, a 10 mL Schlenk flask was charged with tert-butyl (3S,4S)-4-acetamido-3-methyl-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate C6 (300 mg, 0.919 mmol) and THF (3.0 mL). The flask was cooled in an ice-water bath. 2.0 M LiBH4 in THF (0.7 mL) was added dropwise, and the reaction was stirred at 20–25 °C for 4 h. The reaction was cooled in an ice-water bath and quenched by the dropwise addition of 5 wt% NaHCO3 (1.0 mL). The mixture was separated, and the aqueous layer was extracted with EtOAc (10 mL × 3). The combined extracts were washed with 20 wt% brine (20 mL). The organic layer was separated, dried over Na2SO4, and filtered. The filtrate was evaporated to dryness. The residue was purified by column chromatography (silica gel, EtOAc / n-heptane=1 / 1 to 1 / 3, v / v) to give C7 as a colorless viscous oil (258 mg, 85%). 1 H NMR (400MHz, DMSO-d6) δ=7.48(br d,J=10.1Hz, 1H), 5.23(br s,1H), 5.15(br s,1H), 4.09-4.04(m,1H), 3.92-3.82(m,1H), 3.75(d,J=10.1Hz, 1H), 3.56(d,J=5.1Hz, 1H), 3.54-3 .44(m,4H), 1.98(s,3H), 1.68-1.57(m,2H), 1.52-1.46(m,2H), 1.44(s,9H), 1.00(d,J=6.2Hz, 3H).

[0092] Process f: [ka] To a 25 mL Schlenk tube under a nitrogen atmosphere were added NaOH (94 mg, 2.35 mmol) and water (5.0 mL). The tube was cooled in an ice-water bath, and a solution of tert-butyl 4-((1S,2S)-1-acetamido-2-hydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylate C7 (650 mg, 1.97 mmol) and TsCl (450 mg, 2.36 mmol) in DCM (5.0 mL) was added dropwise. The mixture was then stirred at 20-25 °C for 16 h. n-BuNBr (65 mg, 0.202 mmol) was added, followed by NaOH (94 mg, 2.35 mmol) in water (2.0 mL). The mixture was then stirred at 20-25 °C for 16 h. The organic layer was separated, washed with 20 wt% brine (5 mL), dried over NaSO, and filtered. The filtrate was evaporated to dryness to give C9 as a white solid (500 mg, 81%). 1 H NMR (400MHz, DMSO-d6)δ=7.82(br d,J=10.0Hz, 1H), 4.18-4.06(m,2H), 3.65-3.56(m,1H), 3.55(ABq,J=8.7Hz, 2H), 3. 32-3.11(m,3H), 1.89(s,3H), 1.57-1.40(m,4H), 1.38(s,9H), 1.01(d,J=6.1Hz, 3H).

[0093] Process g: [ka] To a 10 mL sealed tube was added tert-butyl (3S,4S)-4-acetamido-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate C9 (25 mg, 0.077 mmol) and 6 N aqueous HCl (1.0 mL). The reaction was stirred in a 110 °C oil bath for 16 h. The reaction was then cooled to 20-25 °C and concentrated to dryness to afford C10 as a white solid (17.0 mg, 90%). 1H NMR (400MHz, DMSO-d6) δ=9.37(br s,1H), 9.25(br s,1H), 8.42(br s,3H), 4.26-4.17(m,1H), 3.72(ABq,J=9.1Hz, 2H), 3.50-3.41(m,1H), 3.28-3.18(m, 1H), 3.18-3.09(m,1H), 2.99-2.74(m,2H), 2.07-1.63(m,4H), 1.22(d,J=6.5Hz, 3H).

[0094] Process h: [ka] A 10 mL Schlenk tube was charged with 3-((2-amino-3-chloropyridin-4-yl)thio)-6-chloropyrazin-2-amine Y10a (0.1 g, 0.347 mmol), (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine dihydrochloride C10 (0.1 g, 0.416 mmol, 1.2 equiv.), DMAc (0.6 mL), and 36 wt% aqueous K2CO3 (0.66 g, 1.735 mmol, 5.0 equiv.). The mixture was stirred in a 100 °C oil bath for 16 h and cooled to 20–25 °C. 20 wt% brine (10 mL) was added, and the mixture was extracted with EtOAc (20 mL × 2). The combined extracts were washed with 20 wt% brine (10 mL × 4), dried over anhydrous NaSO, and filtered. The filtrate was concentrated to dryness to give C11 as a yellow solid (121 mg, 83%). 1 H NMR (400MHz, DMSO-d6)δ=7.64(d,J=6.2Hz, 1H), 7.62(s,1H), 6.26(s,2H), 6. 13(s,2H), 5.74(d,J=5.3Hz, 1H), 4.12-4.02(m,1H), 3.90-3.78(m,2H), 3.67( d,J=8.4Hz, 1H), 3.49(d,J=8.4Hz, 1H), 3.33(s,2H), 2.91(d,J=5.1Hz, 1H), 1. 78-1.68(m,1H), 1.67-1.57(m,1H), 1.56-1.41(m,2H), 1.08(d,J=6.5Hz, 3H).

[0095] Example 3 Route Gamma [ka] Step a and Step b: These two steps correspond to steps a and b in route alpha (see Example 1) and give compounds D4=B4.

[0096] Step c: [ka] To a 1 L reactor equipped with an impeller stirrer under a nitrogen atmosphere were added Raney Ni (5 g) and MeOH (250 mL), followed by tert-butyl (S)-4-(hydroxyimino)-3-methyl-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate D4 (25.0 g, 83.80 mmol). The reactor was purged with nitrogen three times and then with hydrogen three times. The mixture was stirred at IT = 80 °C under 20 bar hydrogen pressure for 16 h. The reaction mixture was filtered through microcrystalline cellulose, and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated to dryness to give a white solid (23.0 g). EtOAc (220 mL) was added to the solid, and the resulting suspension was heated to reflux (IT = 100 °C), and n-heptane (550 mL) was added portionwise. The resulting clear solution was cooled to room temperature over 2 hours and allowed to stand overnight to give D5 as colorless crystals (16.7 g, cis / trans >99 / 1, 70%). 1 H NMR (400MHz, CDCl3)δ=4.75-4.64(m,1H), 3.89-3.80(m,1H), 3.68-3.58(m,1 H), 3.48-3.33(m,3H), 1.92-1.61(m,4H), 1.46(s,9H), 1.40(d,J=6.5Hz, 3H).

[0097] Process d [ka] To a 10 mL Schlenk tube was added tert-butyl (3S,4S)-4-amino-3-methyl-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate D5 (100 mg, 0.352 mmol) and DCM (5.0 mL). The tube was cooled in an ice-water bath. Diisopropylamine (182 mg, 1.41 mmol) was added dropwise, followed by BocO (230 mg, 1.05 mmol). The reaction was then stirred at 20-25 °C for 44 h. The organic layer was separated, washed with 20 wt% brine (5 mL), dried over NaSO, and filtered. The filtrate was evaporated to dryness to give D6 as a colorless oil (95 mg, 70%), which gradually solidified upon standing. HRMS m / z C 19 H 33 N2O6[M+H] + The calculated value is 385.2333, and the measured value is 385.2334.

[0098] Process e [ka] Under a nitrogen atmosphere, a 10 mL Schlenk flask was charged with tert-butyl (3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate D6 (126 mg, 0.335 mmol) and THF (3.0 mL). The flask was cooled in an ice-water bath. 2.0 M LiBH4 in THF (0.25 mL) was added dropwise, and the reaction was stirred at 20–25 °C for 16 h. The reaction was cooled in an ice-water bath and quenched by the dropwise addition of 5 wt% NaHCO3 (1.0 mL). The mixture was separated, and the aqueous layer was extracted with EtOAc (10 mL × 3). The combined extracts were washed with 20 wt% brine (20 mL). The organic layer was separated, dried over Na2SO4, and filtered. The filtrate was evaporated to dryness to give D7 as a colorless viscous oil (91 mg, 70%). HRMS m / z C 19 H 37 N2O6[M+H] +The calculated value is 389.2646 and the measured value is 389.2628.

[0099] process f [ka] To a 25 mL Schlenk tube under a nitrogen atmosphere were added NaOH (14 mg, 0.34 mmol) and water (2.0 mL). The tube was cooled in an ice-water bath, and a solution of tert-butyl 4-((1S,2S)-1-((tert-butoxycarbonyl)amino)-2-hydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylate D7 (110 mg, 0.283 mmol) and TsCl (65 mg, 0.34 mmol) in DCM (2.0 mL) was added dropwise. The mixture was then stirred at 20-25 °C for 16 h. n-Bu4NBr (9.1 mg, 0.028 mmol) was added, followed by NaOH (14 mg, 0.34 mmol) in water (1.0 mL). The mixture was then stirred at 20-25 °C for 16 h. The organic layer was separated, washed with 20 wt% brine (2 mL), dried over Na2SO4, and filtered. The filtrate was evaporated to dryness to give D9 as a colorless oil (45 mg, 43%). HRMS m / z C 19 H 35 N2O5[M+H] + The calculated value is 371.2540 and the measured value is 371.2533.

[0100] Process g [ka] To a 10 mL Schlenk tube was added tert-butyl (3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate D9 (100 mg, 0.27 mmol), 6 N HCl in isopropanol (1.0 mL), and methanol (3.0 mL). The reaction was stirred at 20-25 °C for 16 h and concentrated to dryness to give D10 as a white solid (59 mg, 90%). 1H NMR (400MHz, DMSO-d6) δ=9.37(br s,1H), 9.25(br s,1H), 8.42(br s,3H), 4.26-4.17(m,1H), 3.72(ABq,J=9.1Hz, 2H), 3.50-3.41(m,1H), 3.28-3.18(m, 1H), 3.18-3.09(m,1H), 2.99-2.74(m,2H), 2.07-1.63(m,4H), 1.22(d,J=6.5Hz, 3H).

[0101] Process h [ka] A 10 mL Schlenk tube was charged with 3-((2-amino-3-chloropyridin-4-yl)thio)-6-chloropyrazin-2-amine Y10a (0.1 g, 0.347 mmol), (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine dihydrochloride D10 (0.1 g, 0.416 mmol, 1.2 equiv.), DMAc (0.6 mL), and 36 wt% aqueous KCO solution (0.66 g, 1.735 mmol, 5.0 equiv.). The mixture was stirred in an oil bath at 100 °C for 16 h and cooled to 20–25 °C. 20 wt% brine (10 mL) was added, and the mixture was extracted with EtOAc (20 mL × 2). The combined extracts were washed with 20 wt% brine (10 mL × 4), dried over anhydrous NaSO, and filtered. The filtrate was concentrated to dryness to give D11 as a yellow solid (121 mg, 83%). 1 H NMR (400MHz, DMSO-d6)δ=7.64(d,J=6.2Hz, 1H), 7.62(s,1H), 6.26(s,2H), 6. 13(s,2H), 5.74(d,J=5.3Hz, 1H), 4.12-4.02(m,1H), 3.90-3.78(m,2H), 3.67( d,J=8.4Hz, 1H), 3.49(d,J=8.4Hz, 1H), 3.33(s,2H), 2.91(d,J=5.1Hz, 1H), 1. 78-1.68(m,1H), 1.67-1.57(m,1H), 1.56-1.41(m,2H), 1.08(d,J=6.5Hz, 3H).

[0102] Example 4 Alternative Route Delta for the Production of D11=C11=B8: D11=C11=B8 were prepared by the following procedure. [ka] Steps a and b are carried out as described in Example 1, Route alpha.

[0103] Step c: [ka] MeOH (1643 kg, 11 V) and D4 (187.8 kg, 1.0 equiv.) were added to a hydrogenation reactor at room temperature. The reactor was flushed with nitrogen five times. Raney Ni (37.6 kg) was then added to the reactor, and the reactor was flushed with hydrogen five times. The reactor was heated to 45-55°C and stirred for 1 hour. The hydrogen pressure was then adjusted to 11-13 bar, and the temperature was slowly adjusted to 75-85°C. The reaction mixture was stirred at 75-85°C under 11-13 bar for 20 hours. The mixture was filtered through celite, and the filter cake was washed with MeOH. The filtrate was concentrated to a residue of 2.5 wt., and then IPA (3 V) was added. The mixture was heated to 65-75°C, resulting in a clear solution. The solution was cooled to 50-60°C and stirred for 1.5 hours. n-Heptane (3 V) was added dropwise to the solution. The mixture was stirred for 1 h, cooled to 25-35 °C, and stirred for an additional 1 h. Then, n-heptane (3.5 V) was added dropwise to the mixture. The mixture was cooled to 15-25 °C, stirred for 6 h, and filtered. The filter cake was washed with a mixture of IPA (0.13 w) and n-heptane (0.57 w), then with n-heptane (2 V), and dried at 60 °C to give D5 (107 kg, 60% yield, ee=100%, de=99.2%, purity=99.5%).

[0104] Process d: [ka] A 1 L Radley reactor was charged with D5 (100 g, 352 mmol), (Boc)O (100 g, 457 mmol), IPAc (600 mL), and KHCO (105.6 g, 1055 mmol) in water (400 mL). The mixture was stirred at 25 °C for 16 h. The organic layer was separated, washed with water (194 g), and concentrated to give a residue (400 g). The residue was heated to 45 °C, and n-heptane (473 g) was added over 1 h. The mixture was cooled to 5 °C, stirred for 1 h, and filtered. The filter cake was washed with n-heptane (50 mL) and dried under vacuum to give D6 as a white solid (122 g, 90% yield).

[0105] Process e: [ka] To a 250 mL flexible cube reactor under a N atmosphere were added D6 (20 g, 52 mmol), NaBH4 (3.0 g, 78 mmol, 1.5 equiv.), and 2-MeTHF (200 mL). The mixture was stirred at 50 °C for 18 h and then cooled to 5 °C. MeOH (8.8 g, 0.5 V) was added and stirred for 10 min. 20 wt% aqueous citric acid solution (81.8 g) was added, and the mixture was separated. The organic layer was washed with 0.5 wt% aqueous NaOH solution (81 g × 2) and then with 20 wt% aqueous NaCl solution (83 g). The organic layer was filtered through MCC, concentrated, and exchanged with THF to give D7 (61.8 g, 31.7 wt%, 96% yield) in THF, which was used directly in the next step.

[0106] Process f: [ka] A 250 mL Radley reactor was charged with 5 wt% aqueous NaOH (61.1 g). The solution was cooled to -2 ± 5 °C. D7 (61.1 g, 32.7 wt%) in THF was added. Then, a solution of TPSCl (16.37 g) in THF (50 mL) was added over 1 h. The reaction was stirred at -2 ± 5 °C for 30 min to obtain complete conversion to D8. Then, 32 wt% aqueous NaOH (19.3 g) was slowly added, and the reaction mixture was heated to 25 ± 5 °C and stirred for 4 h. The organic phase was separated and concentrated to give a residue (74 g). The residue was stirred at 50 °C for 30 min. Water (160 mL) was then added over 2 h at 50 °C. The mixture was cooled to 20 °C over 2 h, stirred at 20 °C for 1 h, and filtered. The filter cake was washed with water (40 mL x 2) and transferred to a 250 mL Radley reactor. MTBE (140 mL) and 5 wt% NaCl (40 mL) were added. The mixture was stirred for 0.5 hours and separated. The organic phase was distilled to give a residue (37 g). The residue was stirred at 50 °C for 0.5 hours. n-Heptane (160 mL) was added dropwise over 2 hours. The mixture was cooled to 0 °C over 2 hours, stirred at 0 °C for 1 hour, and filtered. The filter cake was washed with n-heptane (40 mL) and dried to give D9 as a white solid (15 g, 79% yield).

[0107] Process g: [ka] To a 250 mL flexible cube reactor was added D9 (20 g, 54 mmol) and IPAc (120 mL). HCl in IPA (28 wt%, 54 g) was added over 1 h. The reaction mixture was then stirred for 3 h and filtered. The filter cake was washed with IPAc and dried to give D10 as a white solid (14 g, 98% yield).

[0108] Process h: [ka] A 250 mL flexy cube reactor was charged with Y10a (10 g, 34.7 mmol), IPA (40 mL), water (30 mL), sulfolane (10 mL), D10 (10.5 g, 41.6 mmol), and K2CO3 (24 g, 173.5 mmol). The mixture was heated to 90 °C and stirred for 15 h. Water (30 g) was charged, and the mixture was stirred at 90 °C for 30 min, then cooled to 50 °C. THF (20 mL) was added, and the mixture was stirred at 50 °C for 30 min. The organic phase was separated at 50 °C and then concentrated under vacuum at 75 °C to give a residue (40 g). Water (10 g) was charged at 75 °C, and the solution was stirred for 30 min. Seeds (100 mg) were added, and the mixture was stirred at 75 °C for 2 h. Water (70 g) was charged over 2 h at 75 °C. The mixture was cooled to 20° C. over 3 hours, stirred at 20° C. for 3 hours, and then filtered. The filter cake was washed with water (20 mL×3) and dried to give D11 as a beige solid (13.7 g, 92% yield, 99.9% purity).

[0109] Example 4 Synthesis of compound Y7a=Z17a [ka] The reaction steps are carried out as follows: Step a (for Variants A and B): 2,3,5-trichloropyrazine (70.50 g, 384.36 mmol, 1 equiv.) and ammonia solution (25 wt.%, 364.00 g, 400 mL, 2.68 mol, 6.14 equiv.) were added to a sealed 1 L reactor. The mixture was heated to 80° C. and stirred for 24 hours, at which time the reaction was complete. The reaction mixture was cooled to 30° C. and filtered to obtain a brown filter cake. The brown filter cake was dissolved in acetone (50 mL) and filtered. Petroleum ether (300 mL) was added to the filtrate. The suspension was stirred for 4 hours and filtered to obtain the crude product. The crude product was slurried in a combined solvent of petroleum ether and acetone (10 / 1, 200 mL) and filtered to obtain product Y7d (51.00 g, 307.91 mmol, 80% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 7.63 (s, 1H). The advantage of this (and general) method is that no column chromatography is required to obtain Y7d.

[0110] Step b (for variants A and B) (also a preferred embodiment according to the invention in itself): [ka] The conversion was demonstrated in a kilolab and detailed experimental procedures are described below. A 100 L reactor equipped with an impeller stirrer was charged with Y7d (3.2 kg, 19.5 mol), EtOH (20 L), water (13 L), and citric acid monohydrate (4.1 kg, 19.5 mol) under a nitrogen atmosphere. The brown suspension was heated to IT = 75 ± 5 °C, resulting in a clear, dark solution. 35 wt% aqueous NaSO·5H0 (20.8 kg, 29.3 mol) was added at IT = 75 ± 5 °C over 1 h, and the resulting yellow suspension was stirred at this temperature for 2 h. A solution of citric acid monohydrate (4.1 kg, 19.5 mol) in water (7.4 L) was slowly added, followed by 35 wt% aqueous NaSO·5H0 (20.8 kg, 29.3 mol) over 1 h at IT = 75 ± 5 °C. The yellow suspension was stirred at IT = 75 ± 5 °C for 15 hours, cooled to IT = 25 ± 5 °C, and filtered. The filter cake was washed with water (16 L) and transferred to another reactor under a nitrogen atmosphere. 10.5 wt% aqueous NaOH solution (8.3 kg, 21.8 mol) was then slowly added, and the resulting yellow suspension was stirred at IT = 25 ± 5 °C for 1 hour and filtered. The filter cake was washed with water (6.4 kg). The filtrate was obtained as a brown aqueous solution of Y7c' (25.4 kg, 11.6 wt%, 99.5% HPLC purity, 82% yield), which was used directly in the next step. 1 H NMR(400MHz,D2O)δ=7.37(s,1H).

[0111] Step c (for variants A and B): [ka] Under a nitrogen atmosphere, n-BuLi (2.5 M, 7.6 L) was added dropwise to a solution of 3-chloro-2-fluoropyridine (2 kg) in THF (15 L) at −78 °C. The resulting mixture was then stirred for 1 h. A solution of I2 (4.82 kg) in THF (6 L) was then added dropwise. After the addition, the reaction mixture was stirred for 30 min, then quenched with saturated Na2SO3 (10 L) and warmed to 20–25 °C. The phases were separated. The aqueous phase was extracted with EA (2 × 10 L). The combined organic phases were washed with saturated Na2SO3 (2 × 8 L), brine (8 L), and dried over Na2SO4. The organic phase was concentrated under reduced pressure. The residue was slurried in MeOH (4 L), filtered, and dried to give 3-chloro-2-fluoro-4-iodopyridine 1c (2.2 kg, 68% yield).

[0112] Step d (for variants A and B): [ka] NH3 (gas) was passed through a solution of compound 1c (8 kg) in DMSO (48 L) overnight at 80 °C. TLC showed the reaction was complete. The reaction mixture was cooled to room temperature. The reaction mixture was added to water (140 L). The solid was collected, washed with water (25 L), and dried to give Z17b (= Y7b) (6.91 kg, 87% yield). 1 H NMR (400MHz, CDCl3) δ=7.61(d,J=6.8Hz, 1H), 7.14(s,J=6.8Hz, 1H), 5.09(bs,2H).

[0113] Step e (for Variant A only): [ka] A 500 mL Radley reactor was charged with an aqueous solution of Y7c' (82.3 g, 12.2 wt%, 54.5 mmol), water (80 mL), and IPA (150 mL) under a nitrogen atmosphere. The brown solution was degassed with nitrogen for 5 minutes. Citric acid monohydrate (2.29 g, 10.9 mmol) was added with stirring, resulting in a yellow suspension. Y7b (16.6 g, 65.4 mmol), CuI (207 mg, 1.1 mmol), and 1,10-phenanthroline (393 mg, 2.2 mmol) were subsequently added. The mixture was heated to 50°C and stirred for 5 hours, and then the temperature was increased to 75°C over 3 hours. The mixture was stirred at 75°C for 18 hours. The reaction was then cooled to room temperature and filtered. The filter cake was washed with a THF / water (25 mL / 25 mL) mixture and transferred to another reactor. THF (200 mL) and water (10 mL) were added, activated carbon (1 g) was then added, and the mixture was stirred at 50°C for 1 hour. The mixture was then filtered at 40°C and filtered through MCC. The MCC was rinsed with a THF / water (50 mL / 5 mL) mixture, and the filtrate was concentrated to give 140 g of residue. The residue was stirred at 50°C for 0.5 hours, water (150 g) was added dropwise over 1 hour, and the resulting suspension was cooled to 25°C over 2 hours and stirred at this temperature for 1 hour. The mixture was filtered, and the filter cake was washed with a THF / water (25 mL / 25 mL) mixture to give a yellow solid (13.6 g, 85% yield).

[0114] Step f (for Variant B only): [ka] To a mixture of Z17c (6.95 kg, assay 72%, 27.23 mol) in 1,4-dioxane (72 L) was added Xantphos (233 g, 411 mmol, 0.015 equiv.), Pd2(dba)3 (186 g, 206 mmol, 0.0075 equiv.), Z17b (7.13 kg, 28.02 mol), and DIPEA (7.02 kg, 54.46 mol). The system was evacuated and purged with nitrogen gas three times. The mixture was stirred at 65 °C under N2 for 16 h. The mixture was cooled to room temperature, water (50 L) was added, and filtered. The cake was washed with EA (25 L). The filtrate was extracted with EA (4 × 20 L). The organic phase was concentrated under reduced pressure to give the crude product, which was combined with the cake. DCM (60 L) was then added to the crude product, stirred at 25-30° C. for 18 hours, and then filtered. The filter cake was slurried with CHCl (30 L) for 4 hours and filtered. The filter cake was slurried in CHCl (30 L) for 16 hours and filtered. The filter cake was then dried under reduced pressure to provide Z17a (9.1 kg, 84%) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ=7.89(s,1H), 7.7(d,J=7.6Hz, 1H), 7.18(bs,2H), 6.40(bs,2H), 5.97(d,J=7.6Hz, 1H).

[0115] Alternative route for the preparation of compounds Z17a=Y7a=Y10a: This route (also inventive in its own right) is carried out as follows: [ka] This reaction was successfully scaled up to a 50 kg scale in a pilot plant, and the detailed experimental procedures are as follows.

[0116] A 1-L Radley reactor was charged with Y7c' (258.6 g, 11.6 wt%, 163.4 mmol) in aqueous solution, water (240 mL), and isopropanol (450 mL) under a nitrogen atmosphere. The brown solution was degassed with nitrogen for 10 minutes. Y7b (49.8 g, 196.1 mmol) and citric acid monohydrate (10.3 g, 49.0 mmol) were added with stirring, resulting in a yellow suspension. The mixture was heated to 60°C and stirred for 5 hours, then the temperature was increased to 80°C over 3 hours. The mixture was stirred at 80°C for 18 hours. The reaction was then cooled to room temperature and filtered. The filter cake was washed with a THF / water (75 mL / 75 mL) mixture and transferred to another reactor. THF (750 mL) and water (75 mL) were added, and the mixture was stirred at 65°C for 1 hour. The mixture was then cooled to 25°C and filtered through MCC. The MCC was rinsed with a THF / water (60 mL / 6 mL) mixture, and the filtrate was concentrated to give 420 g of residue. The residue was stirred at 65°C for 0.5 hours, and water (450 g) was added dropwise over 2 hours. The resulting suspension was cooled to 10°C over 2 hours and stirred at this temperature for 1 hour. The mixture was filtered, and the filter cake was washed with a THF / water (75 mL / 75 mL) mixture to give compounds Y7a, Y10a, and Z17a as yellow solids (42.2 g, 89% yield). The inventions described in the original claims of this application are set forth below. [1] A process for preparing a compound of formula I, or a pharmaceutically acceptable salt, acid co-crystal, hydrate, or other solvate thereof, comprising the steps of: [ka] wherein LG is a leaving group, A is an anion of a protic acid, and n, m, and p are independently 1, 2, or 3, such that the salt of formula II is electrically neutral, wherein the compound of formula II is reacted with a compound of formula V in the presence of a strong base. [ka] (In the formula, R 1 is a secondary amino protecting group, and R 4 is a carboxyl protecting group) and L-lactide of formula [ka] and reacting the compound of formula VI with [ka] (In the formula, R 1 is a secondary amino protecting group, and R 5 is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted aryl), The compound of formula VI is cyclized with hydroxylamine, or a salt thereof, to give the hydroxylamine compound of formula VII.

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[10] The method according to [8], wherein Mt in formula XV is sodium, LG is chloro, and thiosulfate is sodium thiosulfate.

[11] The method of either [8] or [9], wherein the compound of formula XIV is made by reacting 2,3-5-trichloropyrazine with ammonia.

[12] Compound of Formula III

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[10] ; and a compound of formula XVI

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[13] Compound of formula (III)

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[14] A method for producing a compound of formula I according to [1], comprising the steps of:

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[10] , and the compound of formula XVI, which is described in

[11] , by the method described in

[11] .

Claims

1. A process for the preparation of a compound of Formula I, or a pharmaceutically acceptable salt, acid co-crystal, hydrate or other solvate thereof, comprising the steps of: 【Chemical 1】 wherein LG is halo, A is an anion of a protic acid, and n, m, and p are independently 1, 2, or 3, such that the salt of formula II is electrically neutral, wherein the compound of formula II is reacted with a compound of formula V in the presence of a strong base. 【Chemistry 2】 (In the formula, R １ is tert-butoxycarbonyl, and R ４ is alkyl) and L-lactide of the following formula 【Chemistry 3】 to form a compound of formula VI 【Chemistry 4】 (In the formula, R １ is tert-butoxycarbonyl, and R ５ is alkyl, and R 5 is the same as R 4 in formula V), The compound of formula VI is cyclized with hydroxylamine, or a salt thereof, to give the hydroxylamine compound of formula VII. 【Chemistry 5】 (In the formula, R １ is tert-butoxycarbonyl).

2. The compound of formula VII is hydrogenated to give an amino compound of formula VIII 【Chemistry 6】 (In the formula, R １ is tert-butoxycarbonyl), which compound of formula VIII is then reacted with (bi) reduced to a compound of formula IX 【Chemistry 7】 (In the formula, R １ is tert-butoxycarbonyl), which compound is a compound of formula IV 【Chemistry 8】 (In the formula, R １ is tert-butoxycarbonyl, and R ２ is amino, and R ３ is a hydroxyl), which is then reduced in a further step using a trialkylsilane to give the compound of formula H ｎ After addition of an acid A, where A is an acid anion and n is 1, 2 or 3, a compound of formula II according to claim 1 is obtained; or (ci) The compound of formula VIII is reacted with an amino-protecting group inserting compound to give a compound of formula X 【Chemistry 9】 (In the formula, R １ is tert-butoxycarbonyl, and R ２ is a protected amino group), which can then be converted to a compound of formula XI 【Chemistry 10】 (In the formula, R １ is tert-butoxycarbonyl, and R ２ is a protected amino group), which compound of formula XI can be further reduced at the hydroxy of the hydroxymethyl group to a compound of formula LG ＊ A leaving group forming agent of -X (wherein LG ＊ is an electrophilic group capable of forming a leaving group LG2 with the hydroxy to which it is attached, and X is a halogen, to give a compound of formula XII 【Chemistry 11】 (In the formula, R １ is tert-butoxycarbonyl, and R ２ is a protected amino group, and LG2 is tosyloxy or 2,4,6-triisopropylbenzenesulfonyloxy), which is then cyclized under basic conditions to give a compound of formula XIII. 【Chemistry 12】 (In the formula, R １ is tert-butoxycarbonyl, and R ２ is a protected amino group), which can be reacted with a compound of formula IV shown above, １ is tert-butoxycarbonyl, and R ２ is a protected amino group, and R ３ is hydrogen), followed by the acid H ｎ a deprotection step of the compound of formula XIII using A, where A is an anion of a protonic acid and n is 1, 2 or 3, to obtain a compound of formula II as defined in claim 1; wherein in both cases (bi) and (ci), a compound of formula II reacts with a compound of formula III as shown in the reaction scheme below to give a compound of formula I 【Chemistry 13】 wherein LG is halo, A is an anion of a protic acid, and n, m, and p are independently 1, 2, or 3, such that the salt of Formula II is electrically neutral, to obtain a compound of Formula I, or a pharmaceutically acceptable salt, acid co-crystal, hydrate, or other solvate thereof.

3. Acylation of a compound of formula VII under reducing conditions to give a compound of formula VIII ＊ Compounds of 【Chemistry 14】 (In the formula, R １ is tert-butoxycarbonyl, ＊ R ２ is an acylated amino), which is subsequently reacted with a compound of formula VIII in the presence of a chiral hydrogenation catalyst. ＊ to hydrogenate a compound of formula X ＊ Compounds of 【Chemistry 15】 (In the formula, R １ is represented by formula VIII ＊ is as defined for the compound ＊ R ２ is an acylated amino group), which is subsequently reacted with a compound of formula XI ＊ Compounds of 【Chemistry 16】 (In the formula, R １ is represented by formula VIII ＊ is as defined for the compound ＊ R ２ is an acylated amino group) to a compound of formula X ＊ and in a further step, reducing the hydroxy of the hydroxymethyl group to a compound of formula XI ＊ and a compound of formula LG ＊ A leaving group forming agent of -X (wherein LG ＊ is an electrophilic group capable of forming a leaving group LG2 with the hydroxy to which it is attached to form a compound of formula XII ＊ Compounds of 【Chemistry 17】 (In the formula, R １ is represented by formula VIII ＊ and R ２ is a protected amino group, and LG2 is tosyloxy or 2,4,6-triisopropylbenzenesulfonyloxy), which is then reacted under basic conditions to give a compound of formula XII ＊ to form a compound of formula XIII ＊ Compounds of 【Chemistry 18】 (In the formula, R １ is tert-butoxycarbonyl, ＊ R ２ is an acylated amino group), which can be converted into a compound of formula IV 【Chemistry 19】 (In the formula, R １ is tert-butoxycarbonyl, and R ２ is an acylated amino group, and R ３ is hydrogen), followed by an acid H as defined for compounds of formula II. ｎ A, where A is the anion of a protonic acid and n is 1, 2, or 3, to prepare a compound of formula XIII ＊ to obtain a compound of formula II according to claim 1; wherein the compound of formula II is then reacted with a compound of formula III as shown in the reaction scheme below to give a compound of formula I: 【Chemistry 20】 wherein LG is halo, A is an anion of a protic acid, and n, m, and p are independently 1, 2, or 3, such that the salt of Formula II is electrically neutral, to obtain a compound of Formula I, or a pharmaceutically acceptable salt, acid co-crystal, hydrate, or other solvate thereof.

4. Compound of Formula VI 【Chemical 21】 (In the formula, R １ is tert-butoxycarbonyl, and R ５ is alkyl and R 5 is the same as R 4 in formula V, in the presence of a strong base 【Chemical 22】 (In the formula, R １ is tert-butoxycarbonyl, and R ４ is alkyl) and L-lactide of the following formula 【Chemical 23】 to obtain a compound of formula VI.

5. Hydroxylamine Compounds of Formula VII 【Chemistry 24】 (In the formula, R １ is tert-butoxycarbonyl), comprising the step of: 【Chemistry 25】 (In the formula, R １ is tert-butoxycarbonyl, and R ５ is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted aryl) with hydroxylamine, or a salt thereof, to provide a compound of formula VII.

6. Compound of Formula VI 【Chemical 26】 (In the formula, R １ is tert-butoxycarbonyl, benzyloxycarbonyl or fluoren-9-yloxacarbonyl, R ５ is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted aryl).

7. R ５ But C １ ~C ８ 7. The compound of formula VI according to claim 6, wherein: - alkyl.

8. R １ is tert-butoxycarbonyl, and R ５ 7. The compound of formula VI according to claim 6, wherein is ethyl.

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