Manufacture of compounds and compositions for inhibiting shp2 activity

Abstract

The present invention relates to a process for manufacturing 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, said manufacturing comprising manufacturing 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.

Description

BACKGROUND TECHNICAL FIELD

[0002] The present invention relates to processes for making compounds capable of inhibiting SHP2 activity and intermediates useful therein. BACKGROUND

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

[0005] The compound having the name (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4- yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine of Formula I:

[0006]

[0007] and pharmaceutically acceptable salts thereof are described in WO 2015 / 107495 Al as SHP2 inhibitors. Various methods of treatment and management are also described.

[0008] Src Homology-2 phosphatase (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to a variety of cellular functions including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 is involved in signaling through the Ras-mitogen-activated protein kinase, JAK-STAT, or phosphoinositol 3-kinase-AKT pathways.

[0009] SHP2 has 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 control subcellular localization and functional regulation of SHP2. The molecule exists in an inactive, autoinhibited conformation stabilized by a binding network 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 enzymatic activation of SHP2.

[0010] Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in a variety of human diseases such as Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, as well as breast, lung, and colon cancer. Thus, SHP2 represents an extremely attractive target for the development of new therapies to treat a variety of diseases. The compounds that can be manufactured according to the present application meet the need for small molecules that inhibit SHP2 activity.

[0011] WO 2020 / 065452 A1 describes three methods for manufacturing compounds of Formula I, which can be characterized by the following reaction schemes (for further details, see WO 2020 / 065452 A1). These synthetic methods, while fundamentally viable, can be improved (e.g., using less material and producing less waste, while improving reaction safety). These methods can be summarized as follows, fundamentally:

[0012] Scheme 1: This shows three routes B to D disclosed in WO 2020 / 065452

[0013] Route B:

[0014]

[0015] Route C:

[0016]

[0017] Route D:

[0018]

[0019] HCl salt Compound A17 (equivalent to B7, C10 and D10) is then converted to compounds of Formula I as follows:

[0020]

[0021] The manufacture of Y10a (equivalent to Z17a and Y7a, and detailed in WO 2020 / 065452 A1) is achieved as follows:

[0022] Variant (i):

[0023]

[0024] or alternatively by the following route, variant (ii):

[0025]

[0026] Yet alternatively, compound Z17a is made according to the following route, variant (iii):

[0027]

[0028] Each of the above routes is suitable for the commercial synthesis of compounds of Formula I. However, synthesis route B (above) requires the use of an equimolar (equal molar) amount of lactone B2 (corresponding to C2 and D2) to obtain B3. This represents a relatively large amount of B2 for commercial manufacturing, especially since it is used in the first step of the entire synthesis.

[0029] Furthermore, to achieve a good conversion of the compound from B3 to B4, at least a five-fold molar excess (5 equivalents) of hydroxylamine hydrochloride is required. This is less than ideal for large scale synthesis due to thermal safety risks.

[0030] Surprisingly, the present invention overcomes both the large material requirement and the thermal safety risk by manufacturing B4 using a new intermediate B3’ having a chemically distinct structure from B3 and C3.

[0031] The synthesis of B4 in this improved synthesis requires less material. First, the reaction to complete from B3’ to B4 requires much less hydroxylamine hydrochloride (far less than 5 equivalents). Furthermore, the reaction with B1 (corresponding to A5) requires less L-lactide B2, approximately half the relative (equivalent) amount of B2.

[0032] This new method of manufacturing intermediate B4 in a specific form (not meant to limit the scope of the invention) can be described by the following reaction scheme, Scheme A:

[0033]

[0034] The reaction through the novel intermediate B3’ ((S)-4-(2-hydroxypropanoyl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester) thus allows for a significant improvement of the reaction for manufacturing (ending up in the synthesis of compounds of Formula I).

[0035] A further improvement of the synthesis of compounds of Formula I disclosed in WO 2020 / 065452 Al relates to variant (i) for manufacturing compound Y7c (above). The anhydrous Na2S used in this reaction is pyrophoric and cannot be obtained in large scale commercialization. Furthermore, the use of tetrabutylammonium salts required for the work-up is poorly biodegradable.

[0036] While compound Z17c can also be manufactured by the above variants (ii) or (iii), these also have the disadvantage of requiring a thiol compound and very strong reaction conditions and strong reagents (e.g. the use of ethoxylated sodium).

[0037] However, this problem can be solved in a surprising and convenient way, which in a particular form (not meant to limit the scope of the invention) can be described by the following reaction scheme, Scheme B:

[0038]

[0039] (Note that Y7c’ corresponds to Z17c in variants (ii) and (iii) above). Alternatively, sodium thiosulfate is used instead of sodium sulfide. Sodium thiosulfate is not pyrophoric and is available on a large scale. Furthermore, the materials used are cheaper and a more environmentally friendly solvent is used. The work-up is simplified and the reaction mixture is free of tetrabutylammonium salts and odorless. SUMMARY

[0040] In one aspect, the present invention provides a process for manufacturing a compound of formula I or a pharmaceutically acceptable salt, acid co-crystal, hydrate or other solvate thereof as mentioned above.

[0041] In another aspect, the present invention provides a process for manufacturing a compound of formula I or a pharmaceutically acceptable salt, acid co-crystal, hydrate or other solvate thereof as mentioned above, which process comprises reacting a compound of formula II with a compound of formula III according to the following reaction scheme:

[0042]

[0043] wherein LG is a leaving group, especially chlorine, A is an anion of a protic acid, especially a Cl anion, and n, m and p are integers, preferably 1, 2 or 3, such that the salt of formula II is electrically neutral, preferably m is 1, n is 1 and p is 2; wherein preferably (i) the compound of formula II is obtained by deprotection of a compound of formula IV or (ii) the compound of formula II is obtained by reduction of a compound of formula IV:

[0044]

[0045] wherein in case (i) R1is a secondary amino protecting group (meaning that the protecting group protects a secondary amino group), especially tert-butoxycarbonyl, and R2is a protected amino group, especially acetylamino or tert-butoxycarbonylamino, and R3is hydrogen, or in case (ii) R1is a secondary amino protecting group, preferably tert-butoxycarbonyl, R2is amino and R3is hydroxyl, and if necessary (i.e. if the acid is not already absent, for example due to deprotection) the resulting compound of formula II*:

[0046]

[0047] with a compound of formula Hn an acid of A (as described herein) is reacted to give said compound of formula II.

[0048] In both of the just mentioned cases (i) and (ii), in a preferred independent second aspect of the present application (meaning that the reaction from the compound of formula V up to and including the compound of formula VI is an own embodiment of the application), or as part of the manufacture of the compound of formula I, in a first step, preferably followed by a further step defined by the further embodiments defined below, the manufacture of the compound of formula II comprises reacting the compound of formula V:

[0049]

[0050] wherein R1is a secondary amino protecting group, especially tert-butoxycarbonyl, and R4is a carboxyl (-COOH) protecting group, especially an alkyl group such as ethyl, with L-lactide of the following formula:

[0051]

[0052] to give the compound of formula VI:

[0053]

[0054] wherein R1is as defined for the compound of formula IV and R5is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl or unsubstituted or substituted aryl, especially ethyl.

[0055] This reaction of the second embodiment of the present application is likewise an embodiment of the present application.

[0056] As a further independent embodiment of the present application or preferably in a further step, the compound of formula VI as just described is cyclized with hydroxylamine or a salt thereof to give the hydroxylamine compound of formula VII, respectively:

[0057]

[0058] wherein R1is as defined for the compound of formula IV.

[0059] The two reaction steps of the compound of formula V with L-lactide to give the compound of formula VI and subsequent cyclization with hydroxylamine to give the compound of formula VII also form an independent and important embodiment of the present application.

[0060] As a further independent embodiment, in a further step, the compound of formula VII (a-i) is hydrogenated to give the amino compound of formula VIII:

[0061]

[0062] wherein R1is as defined for compounds of formula IV, or (a-ii) acylation under reducing conditions (with an amino protecting group intercalator, such as acetic anhydride or di-tert-butyl dicarbonate) to give a compound of formula VIII*:

[0063]

[0064] wherein R1is as defined for compounds of formula IV, and *R2is an acylated amino group (= acyl-protected amino group; preferably an acetylamino group).

[0065] In another preferred embodiment, in a further step after the reaction (a-i) just described, the compound of formula VIII (b-i) is reduced to give a compound of formula IX:

[0066]

[0067] wherein R1is as defined for compounds of formula IV, preferably tert-butoxycarbonyl, said compound of formula IV being a compound of formula IV wherein R1is a secondary amino protecting group, in particular tert-butoxycarbonyl, R2is an amino group and R3is a hydroxyl group; wherein preferably in a further step the reduction step (ii) mentioned above for the compound of formula IX falling under the definition of a compound of formula IV of the corresponding formula IV is performed using a trialkylsilane to give subsequently after addition of an acid (in particular HCI) of formula H n A as defined above to give a compound of formula II as described above;

[0068] or (c-i) As another inventive embodiment, in a further step the compound of formula VIII is reacted with an amino protecting group intercalator compound (in particular (Boc)20) to give a compound of formula X:

[0069]

[0070] wherein R1is as defined for compounds of formula IV and R2is a protected amino group, in particular a tert-butoxycarbonyl amino group, the compound of formula X is reduced, preferably in a further step, to a compound of formula XI:

[0071]

[0072] wherein R1is as defined for compounds of formula IV and R2is a protected amino group, especially tert-butoxycarbonylamino; preferably in a further step the compound of formula XI is reacted with a leaving group forming agent of formula LG*-X, wherein LG*is an electrophilic group capable of forming a leaving group LG2from a hydroxyl group to which it is bonded (especially tosylate oxy or preferably 2,4,6-triisopropylbenzenesulfonyl oxy) and X is halogen (especially chlorine), to give a compound of formula XII:

[0073]

[0074] wherein R1is as defined for compounds of formula IV, R2is a protected amino group, especially tert-butoxycarbonylamino, and LG2is a leaving group, especially tosylate oxy or preferably 2,4,6-triisopropylbenzenesulfonyl oxy;

[0075] Then, in a further inventive embodiment, in a further step the compound of formula XII is cyclized under basic conditions to give a compound of formula XIII:

[0076]

[0077] wherein R1is a secondary amino protecting group, especially tert-butoxycarbonyl, and R2is a protected amino group, especially tert-butoxycarbonylamino, which is a compound of formula IV wherein R1is a secondary amino protecting group, especially tert-butoxycarbonyl, and R2is a protected amino group, especially tert-butoxycarbonylamino, and R3is hydrogen, wherein preferably in a further inventive embodiment in a further step an acid H n A (as defined for compounds of formula II) is performed on the compound of formula XIII (for which see above for compounds of formula IV) to give a compound of formula II as described above.

[0078] In another preferred embodiment, after reaction (a-ii) above, in a further step the compound of formula VIII* is hydrogenated in a further reaction (b-ii) in the presence of a chiral hydrogenation catalyst to give a compound of formula X*:

[0079]

[0080] wherein R1is as defined for compounds of formula IV and *R2is an acylated amino group, especially acetylamino, the compound of formula X* is reduced in a further inventive embodiment in a further step to a compound of formula XI*:

[0081]

[0082] wherein R1is as defined for compounds of formula IV, and *R2is an acylated amino group, especially an acetylamino group;

[0083] In another inventive embodiment, the compound of formula XI*is reacted in a further step with a leaving group forming agent of formula LG*-X, wherein LG*is an electrophilic group capable of forming a leaving group LG2from a hydroxyl group to which it is bonded, especially a tosylate group, and X is a halogen, especially chlorine, on the hydroxyl group of the hydroxymethyl group directly bonded to the ring in formula XI*to give a compound of formula XII*:

[0084]

[0085] wherein R1is as defined for compounds of formula IV, R2is a protected amino group, especially an acetylamino group, and LG2is a leaving group, especially a tosylate group;

[0086] Then, in another inventive embodiment, the compound of formula XII*is cyclized under basic conditions in a further step to give a compound of formula XIII*:

[0087]

[0088] wherein R1is a secondary amino protecting group, especially a tert-butoxycarbonyl group, and *R2is an acylated amino group, especially an acetylamino group, corresponding to a compound of formula IV, wherein R1is a secondary amino protecting group, especially a tert-butoxycarbonyl group, R2is an acylated (= acyl-protected) amino group, especially an acetylamino group, and R3is hydrogen; wherein, preferably in another inventive embodiment, the deprotection step (i) mentioned above for the compound of formula XIII*corresponding to a compound of formula IV, wherein here deprotection means deacylation, uses an acid H n A is carried out to give a compound of formula II as described above.

[0089] The following novel key intermediates also represent their own inventive embodiments:

[0090] A compound of formula VI:

[0091]

[0092] wherein R1is as defined for compounds of formula IV, especially a tert-butoxycarbonyl group, and R5is an unsubstituted or substituted alkyl group, an unsubstituted or substituted cycloalkyl group, or an unsubstituted or substituted aryl group, especially an ethyl group; or a salt thereof.

[0093] Another embodiment of the present application, as a separate inventive embodiment or as part of the overall synthesis of compounds of formula (III) and / or of the synthesis of compounds of formula (I), relates to a novel process of manufacturing (synthesizing) intermediates of formula (III)

[0094]

[0095] wherein LG is a leaving group, said process comprising reacting a compound of formula (XV),

[0096]

[0097] wherein LG is a leaving group and Mt is (in particular with respect to each half metal atom relative to the charge of sulfur) an alkaline earth metal or (preferably) (in particular in a ratio of one Mt to one S) an alkali metal atom, with a compound of formula (XVI),

[0098]

[0099] to give said compound of formula (III), wherein said reaction is carried out under transition metal-free reaction conditions.

[0100] Description of preferred embodiments

[0101] The following definitions define the more general features in a preferred more specific way and it is possible to replace one, more than one or all of the more general features in a variant = embodiment of the application by the more specific definitions defining a more specific inventive embodiment.

[0102] The conditions of the above reaction are chosen in particular as follows:

[0103] The reaction of compound II with a compound of formula III, wherein LG is a leaving group, preferably a halogen, in particular bromine or more particularly chlorine, is preferably carried out in the presence of a weak base, such as an alkali metal carbonate or metal-bicarbonate, in a mixed solvent consisting 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 consisting of an aprotic solvent (such as sulfolane) and an alcoholic solvent (such as isopropanol) and water, at preferably elevated temperature, for example in the range from 30 °C to the boiling point of the reaction mixture, for example from 50 °C to 100 °C.

[0104] Deprotection (i) of a compound of formula IV, wherein R1is a secondary amino protecting group and R2is a protected amino group and R3is hydrogen, to give a compound of formula II is preferably carried out in a strong acid H nA is carried out in the presence of 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 such as ethanol or especially methanol or a mixture of alcohols (especially if R2 is benzyloxycarbonyl or especially alkoxycarbonyl, such as tert-butoxycarbonyl) or in an ester solvent such as isopropyl acetate (IPAc) or in the presence of water (especially if R2 is acyl, especially lower alkanoyl, such as acetyl), at a preferred temperature in the range of from 10°C to the boiling temperature of the solvent, for example from 20°C to 115°C (especially when R2 is acyl).

[0105] The alternative reduction (ii) of the compound of formula IV, wherein R1 is a secondary amino protecting group, R2 is an amino group and R3 is a hydroxyl group, is preferably carried out with a trialkylsilane, especially triethylsilane, in the presence of a strong mineral acid or preferably a (strong) organic acid, especially trifluoromethanesulfonic acid, in a suitable aprotic solvent such as an ether or especially acetonitrile, followed by addition of the acid H n A, to obtain a compound (salt or co-crystal) having formula II.

[0106] 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, especially an alkali metal alkyl such as n-butyllithium, and a nitrogen base, especially diisopropylamine or diethylamine, in a solvent such as an acyclic or especially cyclic ether, especially tetrahydrofuran or preferably 2-methyltetrahydrofuran, at preferably low temperatures, for example, in the range of -80°C to -5°C. If the reaction is carried out at approximately -80°C to -40°C, especially in the range of -60°C to -50°C, and preferably if the amount of L-lactide (L-form of lactide) corresponds to 30 to 70 mol %, preferably 45 to 65 mol %, more preferably 50 to 60 mol % (relative to the molar amount of the compound of formula V, i.e., approximately half the molar amount of the compound of formula V), the result is a compound of formula VI. Mol % refers to molar percentage.

[0107] The cyclization of the compound of formula VI to the compound of formula VII with hydroxylamine or a salt thereof is preferably carried out with an acid addition salt of hydroxylamine, for example a hydrohalide salt thereof, such as its hydrochloride, in the presence of a weak base, for example an alkali metal alkanoate, such as sodium acetate, in a solvent, for example an acyclic or especially cyclic ether, especially tetrahydrofuran or preferably 2-methyltetrahydrofuran, at a preferred temperature, in the range of from 0° C. to 80° C., for example from 10° C. to 50° C.

[0108] Hydrogenation of a hydroxylamine compound of formula VII (a-i) to give the corresponding amine of formula VIII is preferably carried out 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. from 0 to 40 °C) and lower H2 pressures (e.g. 1 bar), or in the presence of non-noble metal catalysts, especially those based on nickel (such as Raney nickel and Urushibara nickel), at elevated temperatures and higher H2 pressures, e.g. at pressures ranging from 5 to 50 bar, such as 10 to 20 bar. The reaction is carried out in a polar solvent, especially an alcohol, e.g. an alkanol, such as ethanol or especially methanol.

[0109] Acylation of a hydroxyl compound of formula VII under reductive conditions (a-ii) to give a compound of formula VIII* is preferably carried out in the presence of an acylating agent, especially an acid anhydride of a carboxylic acid, such as an alkanoic acid anhydride, especially acetic anhydride, in the presence of a base metal, such as zinc (e.g. zinc amalgam) or especially iron, as reducing agent, and an acid (an inorganic acid, such as a hydrogen halide, e.g. hydrogen chloride, sulfuric acid, or an organic acid, such as a carboxylic acid corresponding to the acid anhydride, especially an alkanoic acid, especially acetic acid), in an inert organic solvent, such as a hydrocarbon or an aromatic compound, e.g. toluene or xylene, at a preferably elevated temperature ranging from 25 °C to the boiling point of the reaction mixture, e.g. at a temperature ranging from 40 °C to 80 °C.

[0110] In the context of the present application, acyl refers to a moiety of an organic acid, wherein in the case of an acyl residue as such, the carboxyl (-COOH) group is bound to carbon (e.g. in acetyl = H3CCOO-), and not to oxygen (e.g. in tert-butyloxycarbonyl = C(CH3)3CO-). Oxygen Group

[0111] Reduction of a compound of formula VIII (b-i) to a compound of formula IX is preferably carried out with a complex hydride reducing the oxo group in formula VIII to the hydroxyl group in formula IX, such as diisobutylaluminum hydride, in an aprotic solvent, such as an ether or especially a cyclic ether, such as tetrahydrofuran, preferably at low temperatures ranging from -100 °C to -20 °C, e.g. from -80 °C to -70 °C.

[0112] Subsequent reduction of a compound of formula IX to a compound of formula II as corresponding compound of formula IV is preferably carried out with a trialkylsilane, especially triethylsilane, in an acid, especially a strong organic sulfonic acid, such as trifluoromethanesulfonic acid, in an aprotic solvent, such as a hydrocarbon, an ester or especially a nitrile, such as acetonitrile, at a preferably elevated temperature ranging from 30 °C to the boiling point of the reaction mixture, e.g. from 50 °C to 95 °C. Subsequent reaction with an acid H n A is preferably carried out in a protic, potentially aqueous solvent, such as isopropanol. ​

[0113] The reaction (c-i) of a compound of formula VIII with an amino group inserting agent, especially a dialkyl dicarbonic acid ester, especially di-tert-butyl dicarbonic acid ester (= Boc anhydride), is preferably carried out in the presence of a tertiary amine, such as a trialkylamine, especially diisopropylethylamine, or in the presence of a weak inorganic base, such as an alkali metal carbonate or metal-bicarbonate, in an aprotic solvent, especially a halogenated hydrocarbon, such as dichloromethane, or in an ether or especially cyclic ether, such as tetrahydrofuran, at a preferred temperature ranging from 0 °C to 50 °C, for example, from 20 °C to 30 °C, to give a compound of formula X.

[0114] 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 capable of reducing the lactone group in formula X to an open ring in formula XI with two hydroxyl groups, such as lithium borohydride and / or sodium borohydride, in an aprotic solvent, such as a linear or preferably cyclic ether, for example tetrahydrofuran or 2-methyltetrahydrofuran, preferably at a temperature ranging from 0 °C to 50 °C, for example, from 20 °C to 40 °C.

[0115] The reaction of a compound of formula XI with a leaving group forming agent LG*-X, wherein X is halogen, especially chlorine, and LG* is an electrophilic group capable of forming a leaving group LG2 with a hydroxyl group bound thereto, especially a sulfonyl halogenide, preferably tosyl chloride or more preferably 2,4,6-triisopropylbenzenesulfonyl chloride, leads to the introduction of a leaving group of formula LG2 to give a compound of formula XII, preferably in the presence of a base, such as an alkali metal hydroxide, for example sodium hydroxide, in an aqueous organic solvent, such as an aqueous halogenated hydrocarbon, for example dichloromethane, or in an ether or especially cyclic ether, such as tetrahydrofuran, at a preferred temperature ranging from -10 °C to 50 °C, for example, from -5 °C to 30 °C.

[0116] The cyclization of a compound of formula XII to a compound of formula XIII is carried out under basic conditions, in the presence or absence of a phase transfer catalyst, for example a tetraalkylammonium halogenide, such as tetra-n-butylammonium bromide, in the presence of a base, especially an alkali metal hydroxide, such as sodium hydroxide, in an aqueous organic solvent, such as an aqueous halogenated hydrocarbon, for example dichloromethane, or in an ether or especially cyclic ether, such as tetrahydrofuran, at a preferred temperature ranging from 0 °C to 50 °C, for example, from 20 °C to 30 °C.

[0117] The deprotection of a compound of formula XIII is preferably carried out with an acid H n A, which is part of the resulting salt of formula II, in a polar solvent, such as an alcohol, for example an alkanol, such as ethanol or especially methanol, or in an ester solvent, such as isopropyl acetate (IPAc), at a preferred temperature ranging from 0 °C to 50 °C, for example, from 20 °C to 30 °C.

[0118] The hydrogenation of a compound of formula VIII* to a compound of formula X* is carried out in the presence of a chiral hydrogenation catalyst, typically formed from a precatalyst, e.g. a ruthenium(I)-based precatalyst such as bis(norbornadiene)rhodium(I) tetrafluoroborate, and a chiral ligand, preferably with hydrogen gas at elevated pressure, e.g. a pressure ranging from 3 to 50 bar, such as 20 bar to 40 bar, in a polar solvent, especially in 2,2,2-trifluoroethanol, at a temperature ranging from 30 °C to 80 °C, e.g. from 40 °C to 60 °C, as defined below. The hydrogenation is more generally carried out with hydrogen gas in the presence of a transition metal catalyst, preferably in the presence of a transition metal catalyst comprising an organometallic complex and a chiral ligand. The reduction can occur under heterogeneous or homogeneous hydrogenation conditions, preferably under homogeneous hydrogenation conditions. The transition metal is selected from group 9 or group 10 of the periodic table of elements. Thus, the transition metal catalyst comprises, for example, cobalt (Co), rhodium (Rh), iridium (Ir), nickel (Ni), palladium (Pd) and / or platinum (Pt).

[0119] In the chiral catalyst, all catalysts are suitable which allow hydrogenation of the double bond in the compound of formula VIII* to the configuration of the preceding double bond shown in formula X*. Further preferred chiral ligands comprise chiral ferrocenes.

[0120] Preferred chiral ferrocenes have the following formula:

[0121]

[0122] but also other formulae are possible, for example selected from the group comprising any one of the following formulae:

[0123]

[0124] Mixtures of two or more such ligands, especially those defined by the above formulae, are also possible.

[0125] Typically, the active catalyst is formed by mixing 0.9 to 1.2, preferably 1.0 to 1.1, more preferably 1.0 to 1.05 moles of the chiral ligand with 1.0 mole of transition metal atoms comprised in the transition metal catalyst. For example, if a dimeric transition metal catalyst is used, it is preferred to react two moles of the chiral ligand with one mole of the transition metal catalyst to form the “active catalyst”.

[0126] Typically, the chiral ligand is added to the reaction mixture in a solution prepared in the same solvent as used for the reaction.

[0127] The reduction of the compound of formula X* to the compound of formula XI* under ring opening is preferably carried out in the presence of a complex hydride capable of reducing the lactone group in formula X to the ring opened compound of formula XI with two hydroxyl groups, such as lithium borohydride, in an aprotic solvent, such as a linear or preferably cyclic ether, for example tetrahydrofuran, preferably at a temperature in the range of from 0 °C to 50 °C, for example from 20 °C to 30 °C.

[0128] The amino protecting group is preferably a group which can be cleaved by less harsh acidic conditions, for example in the presence of a hydrogen halide, such as HC1, or, in the case where the compound of formula II is a direct reaction product, a group of formula H n A (which is part of the resulting salt of formula II) in a polar solvent, such as an alcohol, for example an alkanol, such as ethanol or, especially, methanol, at a preferred elevated temperature in the range of from 50 °C to 120 °C, for example from 100 °C to 115 °C. The amino protecting group is preferably a group which can be cleaved by less harsh acidic conditions, for example in the presence of a hydrogen halide, such as HC1, or, in the case where the compound of formula II is a direct reaction product, a group of formula H

[0129] The compound of formula XI* is reacted with a leaving group forming agent LG*-X (wherein X is halogen, especially chlorine, and LG* is an electrophilic group capable of forming a leaving group LG2 with the hydroxyl group to which it is (to be) bound, especially a sulfonyl halide, preferably tosyl chloride), leading to the introduction of a leaving group of formula LG2, to give a compound of formula XII*, preferably in the presence of a base, such as an alkali metal hydroxide, for example sodium hydroxide, in an aqueous organic solvent, such as an aqueous halogenated hydrocarbon, for example dichloromethane, at a preferred temperature in the range of from 0 °C to 50 °C, for example from 20 °C to 30 °C.

[0130] The compound of formula XII* is cyclized to the compound of formula XIII* preferably under basic conditions, in the presence of a phase transfer catalyst, for example a tetraalkylammonium halide, such as tetra-n-butylammonium bromide, in the presence of a base, especially an alkali metal hydroxide, such as sodium hydroxide, in an aqueous organic solvent, such as an aqueous halogenated hydrocarbon, for example dichloromethane, at a preferred temperature in the range of from 0 °C to 50 °C, for example from 20 °C to 30 °C.

[0131] The deprotection of the compound of formula XIII* is preferably carried out with an acid H n A (which is part of the resulting salt of formula II) in a polar solvent, such as an alcohol, for example an alkanol, such as ethanol or, especially, methanol, at a preferred elevated temperature in the range of from 50 °C to 120 °C, for example from 100 °C to 115 °C. The amino protecting group is preferably a group which can be cleaved by less harsh acidic conditions, for example in the presence of a hydrogen halide, such as HC1, or, in the case where the compound of formula II is a direct reaction product, a group of formula H

[0132] The compound of formula III can be obtained as described in WO 2020 / 065452 A1. Preferably, however, it can be prepared as follows:

[0133] In another single inventive embodiment or as part of the total synthesis of a compound of Formula I according to the application with the above and below mentioned steps, the compound of Formula III is obtained according to one embodiment by reacting a compound of Formula XIV:

[0134]

[0135] which is obtainable from the corresponding trichloro compound, 2,3,5-trichloropyrazine (instead of NH2and LG, the chloro is accordingly present in the precursor of compound XIV) and ammonia (as described in WO 2020 / 065452 Al), wherein LG is a leaving group as defined for the compound of Formula III, especially halogen, more preferably iodine, bromine or in particular chlorine, with a metal thiosulfate (which can or can not be a hydrate), especially an alkali metal or alkaline earth metal thiosulfate, more preferably an alkali metal thiosulfate, most preferably with sodium thiosulfate, in the presence of an acid, in a suitable solvent, and then treated with an aqueous base to give a compound of Formula XV:

[0136]

[0137] wherein Mt is an alkaline earth metal or preferably (in a ratio of one Mt to one S) an alkali metal atom, especially a sodium atom, and LG is a leaving group as just defined.

[0138] This reaction is preferably carried out in a suitable solvent, such as an aqueous alcohol, e.g. methanol or ethanol mixed with water, in the presence of an acid, such as a mineral acid, e.g. phosphoric acid and / or sodium dihydrogen phosphate, or preferably an organic acid, such as a sulfonic acid or more preferably a strong carboxylic acid, e.g. a trihaloacetic acid, such as trifluoroacetic acid, or especially a carboxylic acid carrying more than one carboxyl group (-COOH), e.g. two to three such groups, most especially citric acid (which generates less waste than phosphate buffer 85% H3PO4 / NaH2PO4), at a temperature ranging from 20 °C to the boiling temperature of the reaction mixture, preferably at a temperature ranging from 20 to 100 °C, most preferably ranging from 50 °C to 90 °C, e.g. at about 85 °C.

[0139] Then, in another preferred inventive embodiment after the manufacture of a compound of Formula XV as just described, in yet another preferred embodiment of the application as part of the total synthesis of a compound of Formula I, the compound of Formula XV is reacted with a compound of Formula XVI:

[0140]

[0141] to give a compound of Formula III:

[0142]

[0143] wherein LG is a leaving group, especially as defined above for compounds of formula III, most especially chlorine.

[0144] The reaction is preferably carried out in the presence of a noble metal complex, especially a noble metal complex formed from Pd2(dbba)2, in the presence of a ligand such as Xantphos and a tertiary nitrogen base such as diisopropylamine, in an aprotic solvent such as an ether, for example a cyclic ether, especially dioxane, at preferably elevated temperatures, for example at temperatures ranging from 30 °C to the boiling point of the reaction mixture. Alternatively, the reaction can be carried out under Ullmann-type reaction conditions, for example with a copper salt such as copper (I) iodide and a diamine ligand such as a phenanthroline ligand as complex forming agents, in a suitable solvent or solvent mixture, for example, in an aqueous alcohol such as aqueous methanol, ethanol, propanol or especially isopropanol, at a preferred temperature ranging from 25 °C to 100 °C, for example at 50 °C to 75 °C.

[0145] In the case of the novel embodiments of the invention where compounds of formula (III) are manufactured from compounds of formula XV under transition metal-free reaction conditions, i.e. especially in the absence of a catalyst comprising or being an organometallic catalyst, in particular in the absence of a catalytic copper salt or catalytic noble metal complex, the reaction is preferably carried out in a suitable solvent or solvent mixture (for example, in an aqueous alcohol such as aqueous methanol, ethanol, propanol or especially isopropanol), in the presence of an acid (such as a mineral acid, for example phosphoric acid and / or sodium dihydrogen phosphate, or preferably an organic acid, such as acetic acid or more preferably a strong carboxylic acid, for example a trihaloacetic acid such as trifluoroacetic acid, or especially a carboxylic acid bearing more than one carboxyl group (-COOH) (for example two to three such groups), most especially citric acid (which has the additional 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 at a temperature ranging from 20 to 100 °C, most preferably at a temperature ranging from 60 °C to 80 °C.

[0146] Among the advantages of this synthesis variant, which corresponds to a further variant of the manufacture of compound (III) by variant (i), (ii) or (iii) as described above and which is therefore also referred to herein as variant (iv) for the manufacture of compound (III) herein, especially in the form of intermediate Y7a=Y10a=Z17a, compared to variant (i) mentioned above, there is no need to remove the copper catalyst (for example with charcoal), especially by oxidation of the copper via bubbling of oxygen, which can pose safety problems, and there is no need to use potentially mutagenic phenanthroline ligands; at the same time compared to variants (ii) and (iii) described above, there is no need for an expensive Pd catalyst, so that the variant of the application is very advantageous, especially in large-scale synthesis, for example in more than 1 kg scale.

[0147] Preferably, this variant (iv) is characterized by the following reaction scheme:

[0148]

[0149] wherein Y7c'=Z17c corresponds to a compound of formula (XV) and Y7b=Z17b corresponds to a compound of formula (XVI). Specific variations of this embodiment are mentioned in the examples.

[0150] In a preferred embodiment of the application, the new reaction is part of the total manufacture of a compound of formula (III) with previous reaction steps as described herein, especially part of the total manufacture of a compound of formula (I), including the manufacture of this particular variant of a compound of formula (III) as described herein.

[0151] The compound of formula XVI can preferably be obtained by reacting a compound of formula XVII:

[0152]

[0153] with iodine in the presence of a strong base.

[0154] The reaction is preferably carried out in the presence of a strong base, especially an alkylalkali metal such as n-butyllithium, and a nitrogen base, especially diisopropylamine or diethylamine, in a solvent such as an acyclic or especially cyclic ether, preferably tetrahydrofuran, preferably at low temperature, for example at a temperature ranging from -80°C to -5°C.

[0155] This gives a compound of formula XVIII:

[0156]

[0157] which is then treated with ammonia to give a compound of formula XVI.

[0158] The reaction is then preferably carried out in the presence of free ammonia and an inert polar solvent, such as DMSO, especially at elevated temperature, preferably at a temperature ranging from 30°C to the boiling point of the reaction mixture, for example at 85°C to 95°C.

[0159] Another embodiment of the present application comprises the manufacture of a compound of formula II and a compound of formula III as described above, i.e. a process for the manufacture 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:

[0160]

[0161] 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 charge neutral.

[0162] In the above, where a compound is mentioned during the process description or in this connection, mention of the compound also includes salts, hydrates or solvates thereof, where such forms are not excluded, for example due to the lack of groups which can form salts.

[0163] Unsubstituted (preferred) or substituted alkyl, especially refers to a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms, especially to a C1-C20-alkyl group, preferably to a C1-C8-alkyl group, and can be straight-chain or branched; preferred are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or t-butyl. 20 - alkyl, preferably C1-C8-alkyl, and can be straight-chain or branched; preferred are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or t-butyl.

[0164] Unsubstituted (preferred) or substituted cycloalkyl especially refers to a saturated ring having from 3 to 20 ring carbon atoms, especially to a C3-C8-cycloalkyl group, such as cyclopentyl, cyclohexyl or cycloheptyl.

[0165] Unsubstituted or substituted aryl especially refers to a C6-C 22 - aryl, especially phenyl, naphthyl or fluorenyl.

[0166] In the case of substitution, this preferably means substitution with one or more substituents which the skilled person knows not to interfere with any of the reactions, especially selected from the group consisting of C1-C8-alkoxy, C1-C8-alkanoyloxy, hydroxy, carboxy, C1-C8-alkoxycarbonyl, or (especially in the case of substituted alkyl) phenyl, naphthyl or fluorenyloxymethyl moieties.

[0167] Example

[0168] The following examples serve to illustrate the present application without limiting the scope as otherwise defined herein; however, they are also preferred embodiments of the application. Abbreviations used: Ac (acetate); AcOH (acetic acid); Ac20 (acetic anhydride); aq (aqueous); Boc (tert-butyloxycarbonyl); Boc20 (di-tert-butyl dicarbonate); brine (saturated sodium chloride solution at room temperature); 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 (dimethyl sulfoxide); DMSO-d6 (perdeuterated dimethyl sulfoxide); eq or equiv. (equivalents); Et (ethyl); EtOAc (ethyl acetate); EtOH (ethanol); HRMS (high resolution mass spectrometry); hrs. (hours); IPA (isopropanol); IPAc (isopropyl acetate); IT (internal temperature (of the reaction mixture)); L (liter(s)); LDA (lithium diisopropylamide); LOQ (limit of quantification); 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 Pr2NH (diisopropylamine); qNMR (quantitative NMR); rt, Rt or RT (room temperature (about 20 to 25 °C)); TBAB (tetra-(n-butyl)ammonium bromide); Tf-OH (triflic acid); THF (tetrahydrofuran); TsCl (p-toluenesulfonyl chloride); TPSCl (2,4,6-triisopropylbenzenesulfonyl chloride); triflic acid (trifluoromethanesulfonic acid); wt% (weight percent) and Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene).

[0169] Example 1

[0170] Route a

[0171]

[0172] In detail, the synthesis steps are as follows:

[0173] Step a (which is also a preferred inventive embodiment in itself):

[0174]

[0175] Under nitrogen atmosphere, diisopropylamine (17.0 kg, 168 mol, 1.2 eq) and 2-methyltetrahydrofuran (185 kg) were charged into a 630 L reactor with a propeller stirrer. The mixture was stirred (medium to high speed) and cooled to IT = 0 ± 5°C. At IT = 0 ± 5°C, a solution of n-BuLi (2.5 M solution in hexanes, 41.6 kg, 154 mol, 1.1 eq) was added. The freshly prepared LDA in 2-methyltetrahydrofuran was then cooled to IT = -60 ± 10°C. At IT = -60 ± 10°C, a solution of B1 (36.0 kg, 140 mol, 1.0 eq) in 2-methyltetrahydrofuran (31 kg) was added. The resulting yellow solution was stirred at IT = -60 ± 10°C for 0.5 h. Then a solution of B2 (11.1 kg, 77 mol, 0.55 eq) in 2-methyltetrahydrofuran (91.8 kg) was added dropwise at IT = -60 ± 10°C. The mixture was stirred at IT = -60 ± 10°C for an additional 1.0 h. At IT = -60 ± 10°C, a solution of acetic acid (21.9 kg, 365 mol, 2.6 eq) in 2-methyltetrahydrofuran (10 kg) was added (caution: highly exothermic). The resulting suspension was allowed to warm up to IT = 0 ± 5°C, then a 0.5% solution of hydrochloric acid (145 kg) was added to the reactor. The biphasic mixture was allowed to warm up to IT = 25 ± 5°C. The reaction mixture was transferred to an extraction vessel, the bottom aqueous layer was worked up. A 10 wt% aq. NaCl (72 kg) was added, and the biphasic mixture was stirred for 0.5 h. The bottom aqueous layer was worked up. The top organic phase was collected and stored under nitrogen at 25 ± 5°C as a solution of B3' in 2-methyltetrahydrofuran (416 kg). 16 H 28 NO6[M+H] + The calculated HRMS m / z is 330.1911, found 330.2708.

[0176] Step b (which is also a preferred embodiment of the invention in itself):

[0177]

[0178] B3' (407 kg) in 2-methyltetrahydrofuran was charged into a 1000 L reactor with an impeller stirrer. 2-methyltetrahydrofuran (246 kg) was added and the resulting mixture was vacuum distilled at IT < 50 °C until 324 kg of distillate was collected. Additional 2-methyltetrahydrofuran (154 kg) was added and the resulting mixture was vacuum distilled at IT < 50 °C until 154 kg of distillate was collected. The water content in the residue was tested 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) for 18 hours at IT = 35 ± 5 °C. The suspension was cooled to IT = 25 ± 5 °C. Water (144 kg) was then added and the mixture was stirred for 0.5 hours. The bottom aqueous phase was worked up. 7 wt% aq. NaCI (108 kg) was added and the two-phase mixture was stirred for 0.5 hours. The bottom aqueous phase was worked up. The top organic phase was collected and vacuum distilled at IT < 60 °C until 216 kg of distillate was collected. Toluene (316 kg) was added and the suspension was vacuum distilled at IT < 60 °C until 307 kg of distillate was collected. The resulting suspension was heated to IT = 80 ± 5 °C with stirring (stirring speed = 56 rpm). n-Heptane (297 kg) was added slowly over 2 hours (stirring speed = 90 rpm). The resulting suspension was cooled to 25 ± 5 °C over 4 hours and filtered with a Nutsche filter (20 pm, PA). The filter cake was rinsed with n-heptane (62 kg), collected and vacuum dried. B4 was obtained as a white solid, 22.68 kg (ee = 93.74%, = 101.74% by qNMR, two-step yield = 52.6%). 1 H NMR (400 MHz, DMSO-d6) d = 11.45 (s, 1H), 5.33 (q, J = 6.6 Hz, 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 = 6.7 Hz, 3H), 1.41 (s, 9H).

[0179] Step a and step b are also denoted as preferred embodiments of the invention, arranged in their order.

[0180] Step c:

[0181]

[0182] To a 1 L reactor with an impeller stirrer under nitrogen atmosphere was added Raney-Ni (5 g) and MeOH (250 mL) followed by (S)-tert-butyl 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 for 16 hours under a hydrogen pressure of 20 bar. 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, 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 left to stand overnight to give B5 as a colorless crystalline product (16.7 g, cis / trans > 99 / 1, 70%). 1 H NMR (400 MHz, CDC13) δ = 4.75-4.64 (m, 1H), 3.89-3.80 (m, 1H), 3.68-3.58 (m, 1H), 3.48-3.33 (m, 3H), 1.92-1.61 (m, 4H), 1.46 (s, 9H), 1.40 (d, J = 6.5 Hz, 3H).

[0183] Step d:

[0184]

[0185] A 500 mL three-necked round-bottom flask under nitrogen atmosphere was charged with (3S,4S)-tert-butyl 4-amino-3-methyl-l-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 IT = -78 °C, 1.0 M DIBAL (42.2 mL, 42.2 mmol, 2.0 eq) was added dropwise over 30 min. The reaction was stirred at -78 °C for 30 min. A saturated Na,K-tartrate aqueous solution (150 mL) was added carefully to quench the reaction while maintaining IT = -78 °C to -60 °C. The mixture was stirred vigorously at 20-25 °C until two clear phases were obtained (ca. 1.5 hours) and extracted with EtOAc (200 mL x 2). The combined organic extracts were washed with 20 wt% brine (200 mL), dried over Na2S04, 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. 1H NMR (400 MHz, CDC13) 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 = 4.4 Hz, 1H), 1.98-1.85 (m, 1H), 1.75-1.54 (m, 3H), 1.46 (s, 9H), 1.35 (d, J = 6.6 Hz, 3H).

[0186] Step e:

[0187]

[0188] To a 100 mL round bottom flask was added 6.0 g of the above viscous oil and acetonitrile (150 mL). The flask was cooled in an ice water bath followed by the addition of triethylsilane (7.4 g, 63.3 mmol), triflic acid (9.5 g, 63.3 mmol). The reaction was then stirred in a 90 °C oil bath for 1 hr. 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 in EtOAc (150 mL). 6N HC1 / isopropyl alcohol (30 mL) was added dropwise with stirring, precipitating a white solid. MTBE (150 mL) was added and the white suspension was stirred for 2 hours and filtered. The filter cake was washed with EtOAc (50 mL x 2) to give a white solid which was dissolved in MeOH (6.0 mL), EtOAc (18 mL) was added dropwise with stirring. The resulting white suspension was filtered and washed with EtOAc (10 mL x 2) to give B7 as a white solid (2.5 g, 81 wt%, 39% over two steps). 1 H NMR (400 MHz, 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 = 9.1 Hz, 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 = 6.5 Hz, 3H).

[0189] Step f:

[0190]

[0191] To a 10 mL Schlenk tube was added 3-((2-amino-3-chloropyridinyl-4-yl)thio)-6- chloropyrazin-2-amine Y7a (0.1 g, 0.347 mmol), (3S,4S)-3-methyl-2-oxa-8- azaspiro[4.5]decane-4-amine dihydrochloride B7 (0.1 g, 0.416 mmol, 1.2 equiv), DMAc (0.6 mL), and 36 wt% aq. 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 x 2). The combined extracts were washed with 20 wt% brine (10 mL x 4), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to dryness to give B8 (121 mg, 83%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) d = 7.64 (d, J = 6.2 Hz, 1H), 7.62 (s, 1H), 6.26 (s, 2H), 6.13 (s, 2H), 5.74 (d, J = 5.3 Hz, 1H), 4.12-4.02 (m, 1H), 3.90-3.78 (m, 2H), 3.67 (d, J = 8.4 Hz, 1H), 3.49 (d, J = 8.4 Hz, 1H), 3.33 (s, 2H), 2.91 (d, J = 5.1 Hz, 1H), 1.78-1.68 (m, 1H), 1.67-1.57 (m, 1H), 1.56-1.41 (m, 2H), 1.08 (d, J = 6.5 Hz, 3H).

[0192] Example 2

[0193] Route b

[0194]

[0195] Steps a and b:

[0196] These two steps correspond to steps a and b in Route a (cf. Example 1) and give compound C4 = B4.

[0197] Step c:

[0198]

[0199] Subsequently, a 500 mL round bottom flask under nitrogen atmosphere was charged with 4-(hydroxyimino)-3-methyl-l-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester C4 (27.9 g, 93.5 mmol), 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). The mixture was stirred vigorously in a 70 °C oil bath for 4 h and cooled to room temperature. The suspension was filtered through microcrystalline cellulose to remove solid residues which were then washed with EtOAc (150 mL x 2). The combined filtrates were 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 Na2SO4 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 (16.7 g, 55%) as white needle-like crystals. 1 H NMR (400 MHz, CDC13) 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).

[0200] Step d:

[0201]

[0202] To a vial under nitrogen atmosphere was added [Rh(NBD)2]BF4 (2.0 mg, 0.005 mmol), ligand L* (from Johnson Matthey & Brandenberger AG, Zurich, Switzerland) (3.3 mg, 0.005 mmol) and DCM (1 mL). The resulting solution was stirred for 30 min and then the solvent was removed to give a yellow solid. To a vial under nitrogen atmosphere was added 4-acetamido-3-methyl-l-oxo-2-oxa-8-azaspiro[4.5]dec-3-ene-8-carboxylic acid tert-butyl ester C5 (86 mg, 0.27 mmol) and 2,2,2-trifluoroethanol (TFE) (2.7 mL). 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 for 16 h at a hydrogen pressure of 30 bar. The reaction was cooled to 20-25 °C, filtered through a short pad of silica gel and concentrated to dryness to give C6 (86 mg, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6) d = 8.33 (br d, J = 10.3 Hz, 1H), 4.94-4.84 (m, 1H), 4.71-4.56 (m, 1H), 3.78-3.65 (m, 2H), 3.22-3.02 (m, 1H), 2.87-2.69 (m, 1H), 1.89 (s, 3H), 1.64-1.50 (m, 4H), 1.40 (s, 9H), 1.19 (d, J = 6.7 Hz, 3H).

[0203] Step e:

[0204]

[0205] To a 10 mL Schlenk flask under nitrogen atmosphere was added (3S,4S)-4- acetylamino-3-methyl-1-oxo-2-oxa-8-azaspiro[4.5]decan-8-carboxylic acid tert-butyl ester 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 hours. The reaction was cooled in an ice water bath and quenched by dropwise addition of 5 wt% NaHC03 (1.0 mL). The mixture was separated and the aqueous layer was extracted with EtOAc (10 mL x 3). The combined extracts were washed with 20 wt% brine (20 mL). The organic layer was separated, dried over Na2S04 and filtered. The filtrate was evaporated to dryness. The residue was purified by column chromatography (silica gel, EtOAc / n-hexane = 1 / 1 to 1 / 3, v / v) to give C7 (258 mg, 85%) as a colorless viscous oil. 1 H NMR (400 MHz, DMSO-d6) d = 7.48 (br d, J = 10.1 Hz, 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 = 10.1 Hz, 1H), 3.56 (d, J = 5.1 Hz, 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 = 6.2 Hz, 3H).

[0206] Step f:

[0207]

[0208] To a 25 mL Schlenk tube under nitrogen atmosphere was 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-acetylamino-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 hours. n-Bu4NBr (65 mg, 0.202 mmol) was added followed by a solution of NaOH (94 mg, 2.35 mmol) in water (2.0 mL). The mixture was then stirred at 20-25 °C for 16 hours. The organic layer was separated, washed with 20 wt% brine (5 mL), dried over Na2SO4 and filtered. The filtrate was evaporated to dryness to give C9 (500 mg, 81%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 7.82 (br d, J = 10.0 Hz, 1H), 4.18-4.06 (m, 2H), 3.65-3.56 (m, 1H), 3.55 (AB q, J = 8.7 Hz, 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 = 6.1 Hz, 3H).

[0209] Step g:

[0210]

[0211] To a 10 mL sealed tube was added tert-butyl (3S,4S)-4-acetylamino-3-methyl-2-oxa-8- azaspiro[4.5]decane-8-carboxylate C9 (25 mg, 0.077 mmol) and 6N aq. HCl (1.0 mL). The reaction was stirred in a 110 °C oil bath for 16 hours. The reaction was then cooled to 20-25 °C and concentrated to dryness to give C10 (17.0 mg, 90%) as a white solid. 1 H NMR (400 MHz, 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 (AB q, J = 9.1 Hz, 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 = 6.5 Hz, 3H).

[0212] Step h:

[0213]

[0214] To a 10 mL Schlenk tube was added 3-((2-amino-3-chloropyridinyl-4-yl)thio)-6- chloropyrazin-2-amine Y10a (0.1 g, 0.347 mmol), (3S,4S)-3-methyl-2-oxa-8- azaspiro[4.5]decane-4-amine dihydrochloride C10 (0.1 g, 0.416 mmol, 1.2 equiv), DMAc (0.6 mL), and 36 wt% aq. 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 x 2). The combined extracts were washed with 20 wt% brine (10 mL x 4), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to dryness to give C11 as a yellow solid (121 mg, 83%). 1 H NMR (400 MHz, DMSO-d6) d = 7.64 (d, J = 6.2 Hz, 1H), 7.62 (s, 1H), 6.26 (s, 2H), 6.13 (s, 2H), 5.74 (d, J = 5.3 Hz, 1H), 4.12-4.02 (m, 1H), 3.90-3.78 (m, 2H), 3.67 (d, J = 8.4 Hz, 1H), 3.49 (d, J = 8.4 Hz, 1H), 3.33 (s, 2H), 2.91 (d, J = 5.1 Hz, 1H), 1.78-1.68 (m, 1H), 1.67-1.57 (m, 1H), 1.56-1.41 (m, 2H), 1.08 (d, J = 6.5 Hz, 3H).

[0215] Example 3

[0216] Route g

[0217]

[0218] Steps a and b:

[0219] These two steps correspond to steps a and b in Route a (cf. Example 1) and give compound D4 = B4.

[0220] Step c:

[0221]

[0222] To a 1 L reactor with an impeller stirrer under nitrogen atmosphere was added Raney-Ni (5 g) and MeOH (250 mL) followed by (S)-4-(hydroxyimino)-3-methyl-1-oxo-2-oxa-8- azaspiro[4.5]decan-8-carboxylic acid tert-butyl ester D4 (25.0 g, 83.80 mmol). The reactor was purged three times with nitrogen and then three times with hydrogen. The mixture was stirred at IT = 80 °C for 16 hours under a hydrogen pressure of 20 bar. 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, 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, left to stand overnight to give D5 as colorless crystals (16.7 g, cis / trans > 99 / 1, 70%). 1 HNMR (400 MHz, CDC13) δ = 4.75-4.64 (m, 1H), 3.89-3.80 (m, 1H), 3.68-3.58 (m, 1H), 3.48-3.33 (m, 3H), 1.92-1.61 (m, 4H), 1.46 (s, 9H), 1.40 (d, J = 6.5 Hz, 3H).

[0223] Step d:

[0224]

[0225] To a 10 mL Schlenk tube was added (3S,4S)-4-amino-3-methyl-1-oxo-2-oxa-8- azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester 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 Boc20 (230 mg, 1.05 mmol). The reaction was then stirred at 20-25 °C for 44 hours. The organic layer was separated, washed with 20 wt% brine (5 mL), dried over Na2S04and filtered. The filtrate was evaporated to dryness to give D6 as a colorless oil (95 mg, 70%) which solidified upon standing. For C 19 H 33 N2O6[M+H] + The calculated HRMS m / z was 385.2333, found was 385.2334.

[0226] Step e:

[0227]

[0228] To a 10 mL Schlenk flask under nitrogen atmosphere was added (3S,4S)-4-((tert- butoxycarbonyl)amino)-3-methyl-l-oxo-2-oxa-8-azaspiro[4.5]decan-8-carboxylic acid tert-butyl ester 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 hours. The reaction was cooled in an ice water bath and quenched by dropwise addition of 5 wt% NaHC03 (1.0 mL). The mixture was separated and the aqueous layer was extracted with EtOAc (10 mL x 3). The combined extracts were washed with 20 wt% brine (20 mL). The organic layer was separated, dried over Na2S04 and filtered. The filtrate was evaporated to dryness to give D7 (91 mg, 70%) as a colorless viscous oil. For C 19 H 37 N2O6[M+H] + The calculated HRMS m / z was 389.2646, found was 389.2628.

[0229] Step f:

[0230]

[0231] To a 25 mL Schlenk tube under nitrogen atmosphere was 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-((lS,2S)-l-((tert-butoxycarbonyl)amino)-2-hydroxypropyl)-4- (hydroxymethyl)piperidine-l-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 hours. 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 hours. The organic layer was separated, washed with 20 wt% brine (2 mL), dried over Na2S04 and filtered. The filtrate was evaporated to dryness to give D9 (45 mg, 43%) as a colorless oil. For C 19 H 35 N2O5[M+H] + The calculated HRMS m / z was 371.2540, found was 371.2533.

[0232] Step g:

[0233]

[0234] To a 10 mL Schlenk tube was added tert-butyl (3S,4S)-4-((tert-butoxycarbonyl)amino)- 3-methyl-2-oxa-8-azaspiro[4.5]decan-8-carboxylate D9 (100 mg, 0.27 mmol), 6N HC1 in isopropanol (1.0 mL), and methanol (3.0 mL). The reaction was stirred at 20-25 °C for 16 hours, concentrated to dryness to give D10 (59 mg, 90%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) d = 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 = 9.1 Hz, 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 = 6.5 Hz, 3H).

[0235] Step h:

[0236]

[0237] To a 10 mL Schlenk tube was added 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% aq. K2CO3 (0.66 g, 1.735 mmol, 5.0 equiv). The mixture was stirred at 100 °C oil bath for 16 hours and cooled to 20-25 °C. 20 wt% brine (10 mL) was added, and the mixture was extracted with EtOAc (20 mL x 2). The combined extracts were washed with 20 wt% brine (10 mL x 4), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to dryness to give D11 (121 mg, 83%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 7.64 (d, J = 6.2 Hz, 1H), 7.62 (s, 1H), 6.26 (s, 2H), 6.13 (s, 2H), 5.74 (d, J = 5.3 Hz, 1H), 4.12 - 4.02 (m, 1H), 3.90 - 3.78 (m, 2H), 3.67 (d, J = 8.4 Hz, 1H), 3.49 (d, J = 8.4 Hz, 1H), 3.33 (s, 2H), 2.91 (d, J = 5.1 Hz, 1H), 1.78 - 1.68 (m, 1H), 1.67 - 1.57 (m, 1H), 1.56 - 1.41 (m, 2H), 1.08 (d, J = 6.5 Hz, 3H).

[0238] Example 4:

[0239] Alternative route d for manufacturing D11 = C11 = B8:

[0240] D11 = C11 = B8 was made according to the following procedure:

[0241]

[0242] Steps a and b were performed as described in Example 1, Route a.

[0243] Step c:

[0244]

[0245] To a hydrogenation reactor was added MeOH (1643 kg, 11 V) and D4 (187.8 kg, 1.0 eq) at room temperature. The reactor was purged with nitrogen 5 times. Then Raney Ni (37.6 kg) was added to the reactor and the reactor was purged with hydrogen 5 times. The reactor was heated to 45-55 °C and stirred for 1 h. Then the hydrogen pressure was adjusted to 11-13 bar and the temperature was slowly adjusted to 75-85 °C. The reaction was stirred at 75-85 °C for 20 h at 11-13 bar. The mixture was filtered through Celite and the filter cake was washed with MeOH. The filtrate was concentrated until 2.5 w of residue remained and then IPA (3 V) was added. The mixture was heated to 65-75 °C and a clear solution was obtained. The solution was cooled to 50-60 °C and stirred for 1.5 h. 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 another 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%).

[0246] Step d:

[0247]

[0248] To a 1 L Radley reactor was added D5 (100 g, 352 mmol), (Boc)20 (100 g, 457 mmol), IPAc (600 mL), and KHCO3 (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 (122 g, 90% yield) as a white solid.

[0249] Step e:

[0250]

[0251] To a 250 mL flexible cube reactor under N2atmosphere was 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 (81.8 g) was added and the mixture was separated. The organic layer was washed with 0.5 wt% aq. NaOH (81 g x 2) and then with 20 wt% aq. NaCl (83 g). The organic layer was filtered through MCC, concentrated and exchanged with THF to give D7 in THF (61.8 g, 31.7 wt%, 96% yield) which was used directly in the next step.

[0252] Step f:

[0253]

[0254] To a 250 mL Radley reactor was added 5 wt% aq. NaOH (61.1 g). The solution was cooled to -2 ± 5 °C. D7 in THF (61.1 g, 32.7 wt%) was added. Then a solution of TPSCl (16.37 kg) in THF (50 mL) was added over 1 h. The reaction was stirred at -2 ± 5 °C for 30 min to give complete conversion to D8. Then 32 wt% aq. NaOH (19.3 g) was added slowly 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. Then water (160 mL) was added over 2 h. 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 h and separated. The organic phase was distilled to give a residue (37 g). The residue was stirred at 50 °C for 0.5 h. n-Heptane (160 mL) was added dropwise over 2 h. The mixture was cooled to 0 °C over 2 h, stirred at 0 °C for 1 h 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).

[0255] Step g:

[0256]

[0257] To a 250 mL flexible cube reactor was added D9 (20 g, 54 mmol) and IP Ac (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 IP Ac and dried to give D10 (14 g, 98% yield) as a white solid.

[0258] Step h:

[0259]

[0260] To a 250 mL flexible cube reactor was added Y10a (10 g, 34.7 mmol), IPA (40 mL), water (30 mL), sulfolane (10 mL), D10 (10.5 g, 41.6 mmol), and then 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. Seed (100 mg) was added and stirred at 75 °C for 2 h. Water (70 g) was charged at 75 °C over 2 h. The mixture was cooled to 20 °C over 3 h, and stirred at 20 °C for 3 h, then filtered. The filter cake was washed with water (20 mL x 3) and dried to give D11 (13.7 g, 92% yield, 99.9% purity) as a beige solid.

[0261] Example 4

[0262] Synthesis of compound Y7a = Z17a

[0263]

[0264] The reaction steps were carried out as follows:

[0265] Step a (for variants A and B): Add 2,3,5-trichloropyrazine (70.50 g, 384.36 mmol, 1 eq) and ammonia solution (25% wt, 364.00 g, 400 mL, 2.68 mol, 6.14 eq) to a 1 L sealed reactor. Heat the mixture to 80 °C and stir for 24 h, reaction complete. Cool the reaction mixture to 30 °C and filter to give a brown filter cake. Dissolve the brown filter cake in acetone (50 mL) and filter. To the filtrate add petroleum ether (300 mL). Stir the suspension for 4 h and filter to give the crude product. Slurry the crude product in a mixed solvent of petroleum ether and acetone (10 / 1, 200 mL) and filter to give the product Y7d as a light yellow solid (51.00 g, 307.91 mmol, 80% yield).1H NMR (400 MHz, DMSO-d6) d = 7.63 (s, 1H). This (also generic) method has the advantage that no column chromatography is required to obtain Y7d.

[0266] Step b (for variants A and B) (which is also a preferred inventive embodiment) itself:

[0267]

[0268] The conversion was demonstrated in a kilo-lab, the detailed experimental procedure is described below:

[0269] To a 100 L reactor with an impeller stirrer under a nitrogen atmosphere was added Y7d (3.2 kg, 19.5 mol), EtOH (20 L), water (13 L) and citric acid monohydrate (4.1 kg, 19.5 mol). The brown suspension was heated to IT = 75 ± 5 °C to give a clear black solution. A solution of 35 wt% aq. Na2S2O3·5H2O (20.8 kg, 29.3 mol) was added over 1 h at IT = 75 ± 5 °C 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 added slowly and then 35 wt% aq. Na2S2O3·5H2O (20.8 kg, 29.3 mol) was added over 1 h at IT = 75 ± 5 °C. The yellow suspension was stirred at IT = 75 ± 5 °C for 15 h, 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. Then 10.5 wt% aq. NaOH (8.3 kg, 21.8 mol) was added slowly, the resulting yellow suspension was stirred at IT = 25 ± 5 °C for 1 h 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 (400 MHz, D20) δ = 7.37 (s, 1H).

[0270] Step c (for variants A and B):

[0271]

[0272] Under 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 and then quenched with saturated Na2S03(10 L) and warmed to 20-25 °C. The phases were separated. The aqueous phase will be extracted with EA (2 x 10 L). The combined organic phases were washed with saturated Na2S03(2 x 8 L), brine (8 L) and dried over Na2S04. The organic phase was concentrated in vacuo. The residue was slurry in MeOH (4 L), filtered and dried to give 3-chloro-2-fluoro-4-iodopyridine 1c (2.2 kg, yield 68%).

[0273] Step d (for variants A and B):

[0274]

[0275] To a solution of compound 1c (8 kg) in DMSO (48 L) was bubbled NH3(gas) at 80 °C overnight. 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 and washed with water (25 L), dried to provide Z17b (= Y7b) (6.91 kg, yield 87%). 1 H NMR (400 MHz, CDC13) δ = 7.61 (d, J = 6.8 Hz, 1H), 7.14 (s, J = 6.8 Hz, 1H), 5.09 (bs, 2H).

[0276] Step e (only for variant A):

[0277]

[0278] To a 500 mL radley reactor under nitrogen atmosphere was added Y7c' aqueous solution (82.3 g, 12.2 wt%, 54.5 mmol), water (80 mL) and IPA (150 mL). The brown solution was degassed with nitrogen for 5 min. Citric acid monohydrate (2.29 g, 10.9 mmol) was added with stirring to give 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 then added. The mixture was heated to 50 °C and stirred for 5 h, then the temperature was raised to 75 °C over 3 h. The mixture was stirred at 75 °C for 18 h. The reaction was then cooled to room temperature and filtered. The filter cake was washed with a mixture solvent of THF / water (25 mL / 25 mL) and transferred to another reactor. THF (200 mL) and water (10 mL) were added, then activated carbon (1 g) was added and the mixture was stirred at 50 °C for 1 h. The mixture was then cooled to 40 °C and filtered through MCC. The MCC was rinsed with a mixture solvent of THF / water (50 mL / 5 mL) and the filtrate was concentrated to give 140 g of residue. The residue was stirred at 50 °C for 0.5 h, water (150 g) was added dropwise over 1 h, the resulting suspension was cooled to 25 °C over 2 h and stirred at this temperature for 1 h. The mixture was filtered, and the filter cake was washed with a mixture solvent of THF / water (25 mL / 25 mL) to give a yellow solid (13.6 g, 85% yield).

[0279] Step f (only for variant B):

[0280]

[0281] 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 eq), Pd2(dba)3 (186 g, 206 mmol, 0.0075 eq), Z17b (7.13 kg, 28.02 mol) and DIPEA (7.02 kg, 54.46 mol). The system was evacuated and purged with nitrogen three times. The mixture was stirred at 65 °C under N2for 16 h. The mixture was cooled to room temperature and water (50 L) was added, filtered. The filter cake was washed with EA (25 L). The filtrate was extracted with EA (4 x 20 L). The organic phase was concentrated in vacuo to give the crude product which was combined with the filter cake. Then DCM (60 L) was added to the crude product and stirred at 25-30 °C for 18 h, and then filtered. The filter cake was slurried in CH2Cl2(30 L) for 4 hours and filtered. The filter cake was slurried in CH2Cl2(30 L) for 16 hours and filtered. The filter cake was then dried in vacuo to give Z17a (9.1 kg, 84%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 7.89 (s, 1H), 7.7 (d, J = 7.6 Hz, 1H), 7.18 (bs, 2H), 6.40 (bs, 2H), 5.97 (d, J = 7.6 Hz, 1H)

[0282] Alternative route for manufacturing compound Z17a = Y7a = Y10a:

[0283] This (in itself also an invention) route is carried out as follows:

[0284]

[0285] This reaction was successfully scaled up in a 50 kg scale pilot plant and the detailed experimental procedure is as follows:

[0286] To a 1 L radley reactor under nitrogen atmosphere was added Y7c' in aqueous solution (258.6 g, 11.6 wt%, 163.4 mmol), water (240 mL) and isopropanol (450 mL). The brown solution was degassed with nitrogen for 10 min. Y7b (49.8 g, 196.1 mmol) and citric acid monohydrate (10.3 g, 49.0 mmol) were added with stirring to give a yellow suspension. The mixture was heated to 60 °C and stirred for 5 h, then the temperature was increased to 80 °C over 3 h. The mixture was stirred at 80 °C for 18 h. The reaction was then cooled to room temperature and filtered. The filter cake was washed with a mixture solvent of THF / water (75 mL / 75 mL) and transferred to another reactor. THF (750 mL) and water (75 mL) were added and the mixture was stirred at 65 °C for 1 h. The mixture was then cooled to 25 °C and filtered through MCC. The MCC was rinsed with a mixture solvent of THF / water (60 mL / 6 mL) and the filtrate was concentrated to give 420 g of residue. The residue was stirred at 65 °C for 0.5 h, water (450 g) was added dropwise over 2 h, the resulting suspension was cooled to 10 °C over 2 h and stirred at this temperature for 1 h. The mixture was filtered and the filter cake was washed with a mixture solvent of THF / water (75 mL / 75 mL) to give compound Y7a = Y10a = Z17a as a yellow solid (42.2 g, 89% yield).

Claims

1. A method for producing a compound of formula I or a pharmaceutically acceptable salt, acid cocrystal, hydrate or other solvate thereof, the method comprising reacting a compound of formula II with a compound of formula III according to the following reaction scheme: 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 made in a process comprising: reacting a compound of Formula V: wherein R1 is a secondary amino protecting group and R4 is a carboxyl protecting group, reacting with L-lactide having the following formula in the presence of a strong base: To obtain a compound of formula VI: wherein R1 is a secondary amino protecting group and R5 is an unsubstituted or substituted alkyl group, an unsubstituted or substituted cycloalkyl group or an unsubstituted or substituted aryl group, and The compound of formula VI is cyclized with hydroxylamine or a salt thereof to obtain a hydroxylamine compound of formula VII: Wherein R1 is a secondary amino protecting group.

2. The process according to claim 1, further comprising hydrogenating the compound of formula VII to obtain an amino compound of formula VIII: Wherein R1 is a secondary amino protecting group, the compound of formula VIII is then: (bi) Reduction to give a compound of formula IX: wherein R1 is a secondary amino protecting group, and the compound is a compound having formula IV: wherein R1 is a secondary amino protecting group, R2 is an amino group and R3 is a hydroxyl group, which is then reduced in another step using trialkylsilane to subsequently add a protecting group having the formula H n Acid of A, wherein A is an acid anion and n is 1, 2 or 3, then gives a compound of formula II as defined in claim 1; or (ci) The compound of formula VIII is reacted with an amino protecting group insertion compound to obtain a compound of formula X: wherein R1 is a secondary amino protecting group and R2 is a protected amino group, and then the compound of formula X is reduced to a compound of formula XI: wherein R1 is a secondary amino protecting group and R2 is a protected amino group, the compound of formula XI is reacted in a further step at the hydroxyl group of the hydroxymethyl group with a leaving group forming agent of formula LG*-X, wherein LG* is an electrophilic group capable of forming a leaving group LG2 with the hydroxyl group to which it is bound and X is a halogen, to obtain a compound of formula XII: wherein R1 is a secondary amino protecting group, R2 is a protected amino group, and LG2 is a leaving group, and then the compound having formula XII is cyclized under basic conditions to obtain a compound having formula XIII: wherein R1 is a secondary amino protecting group and R2 is a protected amino group, which is a compound having formula IV shown above - wherein R1 is a secondary amino protecting group, R2 is a protected amino group and R3 is hydrogen, followed by the use of an acid H n A - wherein A is an anion of a protic acid, and n is 1, 2 or 3 - a deprotection step of the compound of formula XIII to obtain the compound of formula II as defined in claim 1; wherein in both cases (bi) and (ci), the compound of formula II is reacted with a compound of formula III as indicated in the following reaction scheme to obtain a compound of formula I, 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, to obtain a compound of Formula I or a pharmaceutically acceptable salt, acid cocrystal, hydrate, or other solvate thereof.

3. The method of claim 1, further comprising acylating the compound of formula VII under reducing conditions to obtain a compound of formula VIII*: wherein R1 is a secondary amino protecting group and *R2 is an acylated amino group; and then hydrogenating the compound of formula VIII* in the presence of a chiral hydrogenation catalyst to obtain a compound of formula X*: wherein R1 is as defined for the compound of formula VIII* and *R2 is an acylated amino group, said compound of formula X* is then reduced to a compound of formula XI*: wherein R1 is as defined for the compound of formula VIII* and *R2 is an acylated amino group; in a further step, the compound of formula XI* is reacted at the hydroxyl group of the hydroxymethyl group with a leaving group former of the formula LG*-X, wherein LG* is an electrophilic group capable of forming a leaving group LG2 with the hydroxyl group to which it is bound, to obtain a compound of formula XII*: wherein R1 is as defined for the compound of formula VIII*, R2 is a protected amino group, and LG2 is a leaving group, and the compound of formula XII* is then cyclized under basic conditions to give the compound of formula XIII*: wherein R1 is a secondary amino protecting group and *R2 is an acylated amino group, which corresponds to a compound having formula IV: Where R1 is a secondary amino protecting group, R2 is an acylated amino group and R3 is hydrogen, followed by the use of an acid H n A - wherein A is an anion of a protic acid and n is 1, 2 or 3, as defined for the compound of formula II - deprotecting the compound of formula XIII* to obtain the compound of formula II as defined in claim 1; wherein the compound of formula II is then reacted with a compound of formula III to obtain a compound of formula I as indicated in the following reaction scheme: 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, to obtain a compound of Formula I or a pharmaceutically acceptable salt, acid cocrystal, hydrate, or other solvate thereof.

4. A method for producing 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, the method comprising reacting a compound having formula V: wherein R1 is a secondary amino protecting group and R4 is a carboxyl protecting group, reacting with L-lactide having the following formula in the presence of a strong base: To obtain the compound of formula VI.

5. A method for producing a hydroxylamine compound having formula VII: wherein R1 is a secondary amino protecting group, and the method comprises cyclizing a compound having formula VI with hydroxylamine or a salt thereof, respectively: wherein R1 is a secondary amino protecting group and R5 is an unsubstituted or substituted alkyl, an unsubstituted or substituted cycloalkyl or an unsubstituted or substituted aryl, to obtain the compound having formula VII.

6. A compound of formula VI: wherein R1 is a secondary amino protecting group and R5 is an unsubstituted or substituted alkyl group, an unsubstituted or substituted cycloalkyl group or an unsubstituted or substituted aryl group.

7. The compound of formula VI according to claim 6, wherein R1 is tert-butoxycarbonyl, benzyloxycarbonyl or fluoren-9-yloxacarbonyl and R5 is C1-C8-alkyl.

8. The compound of formula VI according to claim 6, wherein R1 is tert-butoxycarbonyl and R5 is ethyl.

Images